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WITHDRAWN: Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches
Accepted Manuscript Medicinal plants used in the treatment of tuberculosis Ethnobotanical and ethnopharmacological approaches
Javad Sharifi-Rad, Bahare Salehi, Zorica Z. Stojanović-Radić, Patrick Valere Tsouh Fokou, Marzieh Sharifi-Rad, Gail B. Mahady, Majid Sharifi-Rad, Mohammad-Reza Masjedi, Temitope O. Lawal, Seyed Abdulmajid Ayatollahi, Javid Masjedi, Razieh Sharifi-Rad, William N. Setzer, Mehdi Sharifi-Rad, Farzad Kobarfard, Atta-ur Rahman, Muhammad Iqbal Choudhary, Athar Ata, Marcello Iriti PII: DOI: Reference:
S0734-9750(17)30077-0 doi: 10.1016/j.biotechadv.2017.07.001 JBA 7134
To appear in:
Biotechnology Advances
Received date: Revised date: Accepted date:
29 December 2016 22 June 2017 5 July 2017
Please cite this article as: Javad Sharifi-Rad, Bahare Salehi, Zorica Z. Stojanović-Radić, Patrick Valere Tsouh Fokou, Marzieh Sharifi-Rad, Gail B. Mahady, Majid Sharifi-Rad, Mohammad-Reza Masjedi, Temitope O. Lawal, Seyed Abdulmajid Ayatollahi, Javid Masjedi, Razieh Sharifi-Rad, William N. Setzer, Mehdi Sharifi-Rad, Farzad Kobarfard, Atta-ur Rahman, Muhammad Iqbal Choudhary, Athar Ata, Marcello Iriti , Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches, Biotechnology Advances (2017), doi: 10.1016/j.biotechadv.2017.07.001
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ACCEPTED MANUSCRIPT Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches Javad Sharifi-Rada,*, Bahare Salehib*, Zorica Z. Stojanović-Radićc, Patrick Valere Tsouh Fokoud,e, Marzieh Sharifi-Radf, Gail B. Mahadyg, Majid Sharifi-Radh, Mohammad-Reza Masjedii, Temitope O. Lawalg,j, Seyed Abdulmajid Ayatollahia,k, Javid Masjedil, Razieh Sharifi-
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Radm, William N. Setzern, Mehdi Sharifi-Rado,*, Farzad Kobarfarda,p , Atta-ur Rahmanq,
a
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Muhammad Iqbal Choudharyq, Athar Atar, Marcello Iritis,*
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
b
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Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases
(NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran c
Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš,
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Višegradska 33, Niš, Serbia d
Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health
e
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Sciences, University of Ghana, Accra LG 581, Ghana
Antimicrobial Agents Unit, LPMPS, Department of Biochemistry, Faculty of Science, University of
f
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Yaoundé 1, Yaoundé 812, Cameroon
Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran
g
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Department of Pharmacy Practice, Clinical Pharmacognosy Laboratories, University of Illinois at
Chicago, USA h
Zabol, Iran i
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Department of Range and Watershed Management, Faculty of Natural Resources, University of Zabol,
Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung
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Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran j
Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Nigeria
k
Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences
Tehran, Iran l
Tobacco Control Strategic Research Center, Shahid Beheshti University of Medical Sciences Tehran,
Iran m
Department of Biology, Faculty of Science, University of Zabol, Zabol, Iran
n
Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA
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Department of Medical Parasitology, Zabol University of Medical Sciences, 61663335 Zabol, Iran
p
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Iran q
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi 75270, Pakistan r
Department of Chemistry, Richardson College for the Environmental Science Complex The University
Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan
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of Winnipeg, Winnipeg, Canada
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20133, Italy
* Corresponding authors at: Phytochemistry Research Center, Shahid Beheshti University of Medical
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Sciences, Tehran, Iran. E-mail address: [email protected] (J. Javad Sharifi-Rad). Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases
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(NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail address: [email protected] (B. Salehi).
Department of Medical Parasitology, Zabol University of Medical Sciences, 61663335 Zabol, Iran. E-
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mail address: [email protected] (M. Sharifi-Rad). Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan
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ABSTRACT
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20133, Italy. E-mail address: [email protected] (M. Iriti).
Tuberculosis is a highly infectious disease declared a global health emergency by the World Health Organization, with approximately one third of the world’s population being latently infected with Mycobacterium tuberculosis. Tuberculosis treatment consists in an intensive phase and a continuation phase. Unfortunately, the appearance of multi drug-resistant tuberculosis, mainly due to low adherence to prescribed therapies or inefficient healthcare structures, requires at least 20 months of treatment with second-line, more toxic and less efficient drugs, i.e., capreomycin, kanamycin, amikacin and fluoroquinolones. Therefore, there exists an urgent need for discovery and development of new drugs to 2
ACCEPTED MANUSCRIPT reduce the global burden of this disease, including the multi-drug-resistant tuberculosis. To this end, many plant species, as well as marine organisms and fungi have been and continue to be used in various traditional healing systems around the world to treat tuberculosis, thus representing a nearly unlimited source of active ingredients. Besides their antimycobacterial activity, natural products can be useful in
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adjuvant therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their
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adverse effects and to reverse mycobacterial multi-drug resistance due to the genetic plasticity and
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environmental adaptability of Mycobacterium. However, even if some natural products have still been investigated in preclinical and clinical studies, the validation of their efficacy and safety as
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antituberculosis agents is far from being reached, and, therefore, according to an evidence-based
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approach, more high-level randomized clinical trials are urgently needed.
Keywords:
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Mycobacterium
Traditional healing systems
Antimycobacterial agents
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Evidence-based medicine
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Herbal medicine
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Multi drug-resistance
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ACCEPTED MANUSCRIPT 1. Introduction Pulmonary tuberculosis (TB) is a humankind disease. Available evidence shows that some pharaohs in ancient Egypt suffered from TB and recent radiological studies using computerized tomography revealed spinal involvement in some cases. Therefore, TB is a historical disorder that had centuries of history
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accompanied with human life. Since the detection of tubercle bacilli as the causal agent by Robert Koch
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in 1882, and after the introduction of first anti-TB drugs by Schatz and Waksman in 1940, great
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developments have transpired in the fields of biology, microbiology, pathogenesis, immunology, drug therapy and, recently, molecular genetics of this disease and its etiological agent. However, TB is still a
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worldwide problem. It has been estimated, that almost one billion people have died from TB during the last 200 years (Paulson, 2013). According to the latest report, World Health Organization (WHO)
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declared that, in 2014, nearly 1,400,000 people had died from TB, from this number, 890,000 were men, 480,000 women and 140,000 were children. Currently, TB with HIV are the main killers globally. In the
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year 2014, almost 9,600,000 people had TB, 5,400,000 of whom were men, 3,200,000 women and 1
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million children. Around 12% of these people were HIV positive. At the same time, 6,000,000 new cases of TB were reported by WHO, that is 63% of the total estimated figures. This means that almost 37% of
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patients with TB were undiagnosed and/or unreported (WHO, 2015). In 2014, 480,000 cases of multi
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drug-resistant (MDR) TB were estimated, while only one quarter of this number, around 123,000 were diagnosed and treated worldwide. According to the sustainable development goals (SDG), all countries
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are obliged to reduce the number of death from TB, 90% by the year 2030, and to reduce the number of new cases to 80%, simultaneously. In addition, all countries should plan in a manner that no family will be compromised because of this disease. Following the Oslo meeting in 1995, WHO defined two major targets as success criteria of national TB programs. First, at least 70% of patients should be diagnosed (case finding), and at least 80% of smear positive cases should be cured (cure rate). After a vast struggle and hard work at the national, regional and global level, and following the discovery of new rapid and applicable molecular diagnostic techniques and affordable therapeutic regimens, WHO has modified its strategy from ”Stop TB” to ”End TB“ strategy. 4
ACCEPTED MANUSCRIPT MDR TB is defined as cases infected with tubercle bacilli that are resistant to the major essential drugs, rifampin (RIF) and isoniazid (INH), while XDR (Masjedi et al., 2006; Masjedi et al., 2008; Velayati et al., 2012; Masjedi et al., 2013) (extensively drug-resistant) refers to cases which are MDR and resistant to fluoroquinolone and two injectable drugs (amikacin and capreomycin). Recently TDR (totally drug-
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resistant) patterns were reported which include cases resistant to all antibiotics. These resistant cases raise
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difficult issues in the subject of successful control and management of tuberculosis. Although 2-3 billion
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of currently living people are infected with tubercle bacilli, only 5-15% of them will develop active disease during their lifetime, which is mainly pulmonary tuberculosis (Talavera et al., 2001; Tiemersma et
subject of different branches of research (Smith, 2003).
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al., 2011). This fact explains the complicated interaction between the microbe and the host, which is the
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Tuberculosis bacilli are mycobacteria related to the actinomycete group (the mycobacterium TB complex) which include human and bovine types, Mycobacterium africanum, M. microtti and M. canetti. These
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aerobic bacilli in 80 to 90% of cases invade the lungs, and in 5 to 20% colonize other extra-pulmonary
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organs, mainly lymph nodes, bones and joints, and genitourinary system 9 (Tiemersma et al., 2011). The main route of entrance of tubercle bacilli into the body is in form of aerosol droplets via the lung. As
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these microbes reach the alveoli, they face and are engulfed by alveolar macrophages, and may infect type
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II pneumocytes. Later, dendritic cells, T lymphocytes, cytokines and many other mediators and biologic factors interfere and appear in the scene and lead to the development of typical granulomatas and necrosis
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which we are not described in detail in this introduction (Mehta et al., 1996; Tascon et al., 2000). The main strategy of TB treatment was focused on DOT‘s strategy, that is “Directly Observed Treatment short course“, which is 6 months treatment. In the initial two months, the patient receives 4 major drugs (RIF, INH, pyrazinamide, ethambutol) under close observation by health worker or defined volunteer person, and the following 4 months will continue with two drugs (RIF and INH). This six months regimen is recommended to all cases of pulmonary and extra-pulmonary cases including children and older patients. As mentioned earlier, MDR TB which includes cases resistant to both RIF and INH, was reported in 1990 by WHO and is a real obstacle in the general control of this disease worldwide. In the 5
ACCEPTED MANUSCRIPT year 2006, XDR types were reported and it seems that 3.2% of all new cases of TB and 20% of those who received treatment were MDR (Holtz and Cegielski, 2007; Chiang et al., 2010; Millardet al., 2015; Ghanashyam, 2016). In the year 2014, almost 190,000 patients with MDR had died and only 50% of those with MDR were treated successfully. With the introduction of linezolid (Farshidpour et al., 2013;
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Lee et al., 2015) in 2000, and bedaquiline (Diacon et al., 2009; WHO, 2013) in 2009, WHO
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recommended new therapeutic regimens to deal with MDR and XDR cases. A relevant issue in the field
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of tuberculosis is vaccine use. Historically, the extensively used vaccine worldwide is BCG (Bacillus Calmette-Guérin) vaccine. This vaccine, made from a weak strain of Mycobacterium bovis, was
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introduced 80 years ago and is still recommended by WHO to be used in early childhood as one of the 6 essential vaccines, particularly in prevalent areas. BCG vaccine is effective in preventing development of
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severe forms of TB in children, mainly biliary tuberculosis and meningitis. This vaccine is less effective in preventing tuberculous disease among adults (Bedi, 2005).
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Recent advances in the molecular biology and immunopathogenesis of mycobacterial diseases have led to
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extensive research in these fields and different vaccines have been introduced to be used as a preventive or therapeutic (Lalvani et al., 2013; Mangtani et al., 2014; Kaufmann et al., 2015). However, we should
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wait for affordable and effective vaccines in the coming years. The complex scenario is the interaction
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between the immune system and tubercle bacilli after the preliminary infection, which, in most cases, leads to latent tuberculosis infection (LTI). As mentioned earlier, in more than 80% of cases, the human
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body is able to contain the infection and the bacilli remain dormant through the whole life of infected people. This phenomenon is a subject of extensive research (Parrish et al., 1998; Wayne et al., 2001; Cardona, and Ruiz-Manzano, 2004). It is worthwhile to mention that WHO, international organizations, research institutions, charities and supporters altogether are working very hard to tackle different aspects of this problem and to achieve the projected targets in the coming decades.
2. Traditional knowledge on plants used against tuberculosis
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ACCEPTED MANUSCRIPT Medicinal plants have been in use for centuries to cure various ailments including tuberculosis. Infusions, macerations, tinctures and decoctions of medicinal plant parts such as leaves, roots, stem bark, stem, flowers and fruits have been used for centuries as traditional treatments of TB by native people worldwide. Commercial preparations of some of these remedies are available and continue to be used considerable
success
in
affected
communities.
Even
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ethnobotanical
and
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with
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ethnopharmacological studies confirmed their wide use in the treatment of TB, the therapeutic and safe
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doses are still to be established for most of them. Most of the studies also failed to provide scientific evidence to traditional beliefs and therapeutic practices. Therefore, this work is an attempt to document
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medicinal plants traditionally used to control TB. Different traditional healing systems have been applied to cure TB, ranging from the poor documented oral African medicine to the well documented Asian or
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Chinese, Ayurveda and so on.
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2.1. Indigenous knowledge on tuberculosis
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The unique and exclusive indigenous knowledge in Africa is orally transferred to the next generation especially in rural communities (Lawal et al., 2014). Tuberculosis is believed to be a contagious disease
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transmitted mainly through sharing contaminated food and eating-utensils, and droplet infection is known by the African traditional system by signs and symptoms that include cough, wheezing cough, labored
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breathing and weight loss (Tabuti et al., 2010). However, some of these symptoms are not specific and
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can be related to other pulmonary diseases such as asthma, different infections, cancer and ordinary cough. In Ayurveda (Indian traditional medicine system), TB is aptly referred as Rajayakshma, a disease of grave prognosis, along with ascites and marasmus, that spreads from one person to another (Jayana) like the flight of birds. It is attributable to tissue emaciation or loss (Dhatukshaya) involved in pathogenesis accompanied by metabolic dysfunction (Dhatwagninasana): fluid, blood, muscle, adipose tissue and generative tissue are lost leading to immunosuppression (Debnath et al., 2012; Samal, 2016). Conventional anti-TB medications have been prescribed to control symptoms, but they result in side effects and, therefore, the use of herbal medicine has been promoted (Arya, 2011). Finally, traditional 7
ACCEPTED MANUSCRIPT Chinese medicine cure TB by combining antibacterial treatments, strengthening QI (vital energy) and administering herbs to protect the liver (Liu et al., 2008). 2.2. Medicinal plants used in African traditional medicine for the management of tuberculosis A total of 222 plant species used in Africa for TB treatment were recorded, belonging to 71 families
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(Table 1). The families with the most species of plants used to cure TB are Leguminosae (or Fabaceae, 28 species) and Compositae (or Asteraceae, 20 species) (Table 1). Overall, the most frequently used plant
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parts are leaves, whole root and stem bark (Tabuti et al., 2010). The most frequently cited species are
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Erythrina abyssinica Lam. ex DC. and Allium sativum L. (4 occurrences), Ficus platyphylla Delile, Bidens pilosa L., Asparagus africanus Lam., Carissa edulis (Forssk.) Vahl. and Allium cepa L. (3
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occurrences) (Table 1). The anti-TB activity of E. abyssinica and A. sativum have been demonstrated extensively. E. abyssinica crude methanol extract showed antimicrobial activity on the sensitive strain
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H37Rv and the rifampicin resistant strain TMC-331, with MIC values of 0.39 mg/ml and 2.35 mg/ml,
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respectively (Bunalema, 2010). A. sativum extract inhibited both non-MDR and MDR M. tuberculosis isolates, with MIC values ranging from 1000 to 3000 μg/mL (Hannan et al., 2011). The leaf ethanol
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extract of B. pilosa exhibited activity against M. tuberculosis at 100 μg/mL (Gautam et al. 2007). C. edulis showed antibacterial activity against slow (M. tuberculosis, M. kansasii) and fast (M. fortuitum and
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M. smegmatis) growing mycobacteria (Mariita, 2006). A. cepa anti-mycobacterial activities have
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previously been reported (Arya, 2011).
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ACCEPTED MANUSCRIPT Table 1. Common medicinal plants in African traditional medicine for tuberculosis treatment. Plant family Botanical name Mode of preparation/administration Acanthaceae
Acanthus pubescens (Thomson ex Oliv.) Engl. Brillantaisia owariensis P. Beauv.
Roots are used to treat TB and related diseases Leaves are used to treat TB and related diseases Leaves and whole plant are used to treat TB and related diseases
Hygrophila auriculata (Schumach.) Heine Acanthus montanus (Nees) T.Anderson Aizoaceae
Carpobrotus edulis (L.) N.E.Br.
Amaranthaceae
Chenopodium ambrosioides L.
U N
A
Achyranthes aspera L.
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Uganda
(Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010; Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Nguta etl al., 2015; Lall aand Meyer, 1999) (Tabuti et al., 2010) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Lawal et al., 2014; Nguta etl al., 2015) (Faleyimu et al., 2009; Greene et al., 2010; Tabuti et al., 2010; Nguta etl al., 2015) (Madikizela, 2014) (Lawal et al., 2014)
Uganda
Uganda, Ghana Nigeria
South Africa South Africa, Ghana
Flowers are used to treat TB and related diseases Leaves are used to treat TB and related diseases Leaves and bulbs are used in the treatment of TB
Uganda
Allium sativum L.
Bulbs, tubers and leaves are used for the treatment of TB and related symptoms
South Africa, Nigeria, Ghana
Brunsvigia grandiflora Lindl.
Bulbs against coughs and colds
South Africa
Haemanthus albiflos Jacq.
Used for the treatment of TB
South Africa
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Amaranthus spinosus L. Amaryllidace
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References
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I R
Leaf infusion is used in the treatment of TB Leaf decoction is used orally for the treatment of TB Leaves are used in curing TB and related symptoms
Locations
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Allium cepa L.
E C
C A
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Uganda Ghana, Nigeria, South Africa
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Anacardiaceae
Tulbaghia acutiloba Harv.
Used for the treatment of TB
South Africa
Tulbaghia violacea Harv.
Used for the treatment of TB
South Africa
Mangifera indica L.
Stem bark is used to treat TB and related diseases
Uganda
Pistacia aethiopica Kokwaro Rhus rogersii Schönland
Leaves are used to treat TB Used in the treatment of TB-related diseases or their symptoms Bark is used in the treatment of TBrelated diseases or their symptoms Leaf infusion is used in the treatment of TB Leaves or roots are pound, boiled and filtered for drinking Dried pound bark is boiled in water for drinking Used for the treatment of TB
Sclerocarya birrea (A Rich) Hochst. Spondias mombin L. Annonaceae
Annona senegalensis Pers.
Apiaceae
Centella asiatica (L.) Urb.
Daucus carota L.
U N
D E
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South Africa Nigeria Nigeria Nigeria South Africa
Used for the treatment of TB
South Africa
Leaf decoction and bark maceration are used in the treatment of TB
Nigeria
Araujia sericifera Brot.
Used for the treatment of TB
South Africa
Carissa edulis (Forssk.) Vahl.
Leaves, roots and root bark are used in the treatment of TB-related diseases or their symptoms
South Africa, Uganda, Kenya
Cryptolepis sanguinolenta (Lindl.) Schltr.
Root bark is used for the treatment of TB symptoms and lung infections
Uganda
Cocos nucifera L.
Husk decoction is used in the treatment
Nigeria,
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Alstonia boonei De Wild
E C
C A
Arecaceae
C S
A
Centella coriacea Nannf.
Apocynaceae
I R
T P
Kenya South Africa
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(Lawal et al., 2014) [ (Lawal et al., 2014) (Tabuti et al., 2010; Orodho et al., 2014) (Mariita, 2006) (Greene et al., 2010) (Greene et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Lawal et al., 2014) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Mariita, 2006; Tabuti et al., 2010; Greene et al., 2010) (Bunalema, 2010; Orodho et al., 2014) (Ogbole and
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Asclepiadaceae
of TB
Ghana
Elaeis guineensis Jacq.
Oil soup is used in the treatment of TB
Nigeria
Asclepias fruticosa L.
Roots are used in the treatment of TBrelated diseases or their symptoms Leaves are used to treat TB and related symptoms Shoots and stem (wood) are used for the treatment of TB
South Africa
Gomphocarpus physocarpus E. Mey. Asparagaceae
Asparagus africanus Lam.
I R
T P
C S
U N
Uganda
South Africa, Uganda
Asparagus falcatus (L.) Oberm.
Leaves and roots are used to treat TB
Balanophoraceae
Thonningia sanguinea Vahl.
Nigeria
Bignoniaceae
Stereospermum kunthianum Cham.
Burseraceae
Boswellia dalzielii Hutch.
Fruit decoction is used in the treatment of TB Boiled leaves or bark or roots in water to drink for TB or their symptoms Bark is pounded, powdered and mixed with porridge for the treatment of TB or their symptoms Bark boiled in water for the treatment of TB or their symptoms Leaves and stem bark are used for the treatment of TB or symptoms
Warburgia ugandensis Sprague
Used for the treatment of TB or their symptoms
Cannabaceae
Cannabis sativa L.
Used for the treatment of TB
Uganda, Kenya, Tanzania South Africa
Capparaceae
Capparis erythrocarpos Isert.
Roots are used for the treatment of TB
Uganda
A
D E
T P
E C
Commiphora africana (A.Rich.) Endl. Canellaceae
Warburgia salutaris (G. Bertol.) Chiov.
C A
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South Africa
Nigeria Nigeria
Nigeria South Africa, Uganda
Ajaiyeoba, 2010; Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Greene et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010; Lawal et al., 2014; Madikizela, 2014) (Madikizela, 2014) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Tabuti et al., 2010; Greene et al., 2010; Greene et al., 2010) (Orodho et al., 2014) (Lawal et al., 2014) (Tabuti et al.,
ACCEPTED MANUSCRIPT or symptoms Used for the treatment of TB or symptoms Tubers are used for the treatment of TB or symptoms Used for the treatment of TB
Capparis tomentosa Lam.
Uganda
Caprifoliaceae
Maerua edulis (Gilg & Gilg-Ben.) DeWolf. Scabiosa albanensis R.A. Dyer
Caricaceae
Carica papaya L.
Caryophyllaceae
Silene undulata Aiton
Leaves and seeds are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
Celastraceae
Cassine papillosa (Hochst.) Kuntze
Used to cure TB-related symptoms
South Africa
Maytenus senegalensis (Lam.) Excell
Roots and root bark are used to cure TBrelated symptoms Leaf decoction is used in the treatment of TB
South Africa
Clusiaceae
Colchicaceae Combretaceae
Uganda
T P
I R
C S
Garcinia kola Heckel; Garcinia spp.
U N
A
D E
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South Africa South Africa, Uganda South Africa
Nigeria, Uganda, Kenya Nigeria
Anogeissus leiocarpus (DC.) Guill. & Perr.
Leaf decoction is used in the treatment of TB Roots boiled in water for drinking in the treatment of TB
Anogeissus schimperi Hochst. ex Hutch. & Dalziel
Bark socked or boiled in water to drink for the treatment of TB
Nigeria
Combretum apiculatum Sond.
Dried leaves boiled for drinking in the treatment of TB Leaves used in the treatment of TBrelated diseases or their symptoms Used in the treatment of TB-related symptoms Bark boiled in salted water for drinking in the treatment of TB
Nigeria
Gloriosa superba L.
T P
E C
C A
Combretum erythrophyllum (Burch) Sond. Combretum molle R. Br. Ex G. Don. Terminalia brownii Fresen.
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Nigeria
South Africa South Africa Nigeria
2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010; Greene et al., 2010) (Lawal et al., 2014) (Lall aand Meyer, 1999) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Faleyimu et al., 2009; Ofukwu et al., 2008) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Greene et al., 2010) (Lall aand Meyer, 1999) (Ofukwu et al., 2008)
ACCEPTED MANUSCRIPT Terminalia phanerophlebia Engl. & Diels Terminalia sericea Burch ex D.C. Asteraceae
Artemisia afra Jacq. ex Willd. Aspilia africana (Pers.) C. D. Adams
Roots are used for the treatment of TB
South Africa
Bark are used in the treatment of TBrelated diseases or their symptoms Used for the treatment of TB
South Africa
Roots are used for the treatment of TB and related symptoms Flowers or whole plant are used to treat TB
South Africa
I R
T P
Bidens pilosa L.
C S
Conyza ivifolia Burm.f.
Conyza sumatrensis (Retz.) E. Walker (syn. C. floribunda) Gutenbergia cordifolia Benth. ex Oliv. Helichrysum appendiculatum (L.f.) Less.
T P
D E
Helichrysum caespititium (DC.) Sond. ex Harv.
E C
Helichrysum imbricatum (L.) Less.
C A
Helichrysum krausii Sch.Bip.
Helichrysum leiopodium DC.
Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Leaves are used in the treatment of TB or related symptoms Roots and leaves are used for the treatment of TB and related symptoms Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Exudates are used against TB and related disorders, such as bronchopneumonial diseases, and symptoms such as cough, fever, blood in the sputum The tea and infusion are used as a demulcent in coughs and in pulmonary affections The smoke of dried flowers and seeds in a pipe is used for the relief of cough and as a remedy for TB Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum
A
U N
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Uganda
Uganda, Ghana, South Africa South Africa
Uganda Uganda South Africa
(Madikizela, 2014) (Greene et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Tabuti et al., 2010; Lawal et al., 2014) (Meyer et al., 2002) (Tabuti et al., 2010) (Tabuti et al., 2010) (Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
ACCEPTED MANUSCRIPT Helichrysum melanacme DC. Helichrysum nudifolium (L.) Less.
Helichrysum odoratissimum (L.) Sweet Microglossa pyrifolia (Lam.) Kuntze Nidorella anomala Steetz.
Senecio serratuloides DC. var. serratuloides Vernonia amygdalina Delile
D E
T P
Ipomoea batatas (L.) Lam.
U N
A
Vernonia woodii O.Hoffm.
E C
Ipomoea involucrata P.Beauv.
C A
South Africa South Africa
M
Uganda, South Africa Uganda
T P
I R
C S
Nidorella auriculata DC.
Convolvulaceae
Used in the treatment of TB-related symptoms Tea and infusion are used as a demulcent in coughs and in pulmonary affections Leaves are used in the treatment of TBrelated symptoms Roots are used in the treatment of TBrelated symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Pounded fresh leaves fresh and squeezed for drinking are used in the treatment of TB-related symptoms. Root barks used to treat TB and asthma Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Peeling maceration is used in the treatment of TB Leaf infusion is used to cure TB
South Africa South Africa South Africa Nigeria, Uganda, Kenya South Africa
Nigeria Nigeria
Costaceae
Costus afer Ker Gawl.
Stem decoction and leaf infusion are used in the treatment of TB
Nigeria
Crassulaceae
Kalanchoe spp.
Leaves are used in the treatment of TBrelated symptoms Leaf infusion is used in the treatment of TB
Uganda
Bryophyllum pinnatum (Lam.) Oken
14
Nigeria
(Lall aand Meyer, 1999) (Meyer et al., 2002) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lall aand Meyer, 1999) (Lall aand Meyer, 1999) (Lall aand Meyer, 1999) (Mariita, 2006; Ofukwu et al., 2008; Tabuti et al., 2010) (Meyer et al., 2002) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010)
(Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010)
ACCEPTED MANUSCRIPT Cucurbitaceae
Momordica foetida Schum. Lagenaria sphaerica (Sond.) Naudin Momordica charantia L.
Cyperaceae
Cyperus articulatus L.
Roots are used in the treatment of TBrelated symptoms Roots are used in the treatment of TBrelated symptoms Leaves/bark are used in the treatment of TB-related diseases or their symptoms
C S
Cyperus rotundus L. ssp. rotundus Diospyros mespiliformis Hochst
U N
A
Euclea natalensis A. DC.
Uganda Kenya
T P Ghana
Uganda Uganda
South Africa
Used in the treatment of TB-related symptoms Roots are used in the treatment of TBrelated symptoms Bark is used in the treatment of TBrelated diseases or their symptoms Stem bark is used to treat TB, asthma, and coughs Leaves are used to treat TB
South Africa
Croton pseudopulchellus Pax
(Tabuti et al., 2010) (Tabuti et al., 2010) (Mariita, 2006) (Nguta etl al., 2015) (Tabuti et al., 2010) (Tabuti et al., 2010) (Greene et al., 2010)
Kenya
(Lall aand Meyer, 1999) (Tabuti et al., 2010) (Greene et al., 2010) (Mariita, 2006)
Kenya
(Mariita, 2006)
Used to treat TB-related symptoms
South Africa
Euphorbia scarlatica (L) O. Kuntz
Stems are used to treat common cold and TB
Kenya
(Lall aand Meyer, 1999) (Mariita, 2006)
Euphorbia schimperiana Scheele
Leaves are used in the treatment of TBrelated symptoms Stems are used to treat TB and asthma Roots are used in the treatment of TB-
Uganda
Euclea divinorum Hiern. Euphorbiaceae
Uganda
I R
Cyperus latifolius Poir.
Ebanaceae
Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Whole plant is used to treat asthma, TB, and pneumonia Roots are used to treat TB
D E
Bridelia micrantha (Hochst.) Baill.
T P
Croton macrostachyus Hochst. ex Ferret et Galinier Croton megalocarpus Hutch.
E C
C A
Euphorbia tirucalli L. Tragia brevipes Pax
M
15
Uganda South Africa
Kenya Uganda
(Tabuti et al., 2010) (Mariita, 2006) (Tabuti et al.,
ACCEPTED MANUSCRIPT related symptoms Tragia subsessilis Pax Geraniaceae
Pelargonium sidoides DC. Pelargonium reniforme Curtis
Gunneraceae
Gunnera perpensa L.
Hypoxidaceae
Hypoxis argentea Harv. ex Baker
Hypericaceae
Hypericum revolutum Vahl
Iridaceae
Zygotritonia bongensis (Pax) Mildbr
Lamiaceae
Achyrospermum carvalhoi Gürke
T P
E C
C A
Leonotis nepetifolia (L.) R. Br. Mentha longifolia (L.) L. Ocimum gratissimum L.
Uganda
Roots are used in the treatment of coughs and tuberculosis Used in the treatment of TB-related symptoms Used for the treatment of TB
T P
South Africa South Africa
I R
C S
Used for the treatment of TB or symptoms Bulb tincture is used to cure TB
U N
South Africa South Africa Uganda Nigeria
Leaves are used in the treatment of TBrelated symptoms Leaf decoction is used in the treatment of TB Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Leaves and stem (wood) are used in the treatment of TB-related symptoms Leaves and stems are used in the treatment of colds, coughs, bronchitis, asthma and TB Leaves are used in the treatment of TBrelated symptoms Used for the treatment of TB
Uganda
Bulb is boiled in water for drinking and used in the treatment of TB-related symptoms.
Nigeria
D E
Iboza multiflora (Benth.) E. A. Bruce
Leonotis intermedia Lindl.
Roots are used in the treatment of TBrelated symptoms Roots are used to treat coughs and TB
A
Clerodendrum capitatum (Willd.) Schum. & Thonn Hoslundia opposita Vahl
Iboza riparia (Hochst.) N. E. Br.
2010)
M
16
Nigeria Uganda Uganda Uganda South Africa
Uganda South Africa
(Tabuti et al., 2010) (Mativandlela et al., 2006) (Mativandlela et al., 2006) (Lall aand Meyer, 1999) (Lawal et al., 2014) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Madikizela, 2014) (Tabuti et al., 2010) (Lawal et al., 2014) (Ofukwu et al., 2008; Ogbole and Ajaiyeoba,
ACCEPTED MANUSCRIPT
Rosmarinus officinalis L.
Leaf tincture is used in the treatment of TB Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Used for the treatment of TB
Cryptocarya latifolia Sond.
Used to cure TB-related symptoms
Persea americana Mill.
Leaves, stem (wood) and seeds are used in the treatment of TB-related symptoms
Abrus precatorius L.
Leaves and roots are used to treat TB, bronchitis, whooping cough, chest complaints and asthma. Seed decoction is used in TB treatment Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Stem bark, stem (wood) and fruits are used in the treatment of TB-related symptoms Used for the treatment of TB
South Africa, Nigeria
Stem bark is used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Stem bark is used in the treatment of TB-related symptoms
Uganda
Ocimum suave Willd. Plectranthus barbatus Andr. Pycnostachys erici-rosenii R.E.Fr.
Lauraceae
Leguminosae (Fabaceae)
D E
T P
Acacia hebecladoides Harms Acacia hockii De Wild.
U N
A
E C
C A
Acacia karroo Hayne
Acacia mearnsii De Wild. Acacia nilotica (L.) Delile Acacia polyacantha Willd.
M
17
Uganda Uganda
T P
I R
C S
Acacia albida Delile
2010)
Uganda
South Africa South Africa Uganda
Nigeria Nigeria Uganda
South Africa
Nigeria Uganda
(Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Lall aand Meyer, 1999) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Madikizela, 2014) (Faleyimu et al., 2009) (Faleyimu et al., 2009) (Tabuti et al., 2010; Orodho et al., 2014) (Lawal et al., 2014) (Tabuti et al., 2010) (Faleyimu et al., 2009) (Tabuti et al., 2010)
ACCEPTED MANUSCRIPT Acacia xanthophloea Benth.
Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Bark infusion is used to cure TB
Albizia coriaria Oliv. Baphia nitida Lodd. Cassia alata L.
South Africa Uganda Nigeria
Fairly dried leaves boiled for drinking in the treatment of TB-related symptoms Dried leaves boiled for drinking in the treatment of TB-related symptoms Bark is used in the treatment of TBrelated diseases or their symptoms Leaves are used for the treatment of TB symptoms and pulmonary infections
I R
T P
Cassia occidentalis L.
C S
Cassia petersiana Bolle Desmodium repandum (Vahl) DC.
U N
A
Nigeria Nigeria
South Africa Uganda
(Lall aand Meyer, 1999) (Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Greene et al., 2010) (Tabuti et al., 2010)
Entada abbysinica A.Rich.
Used in the treatment of TB-related symptoms
Kenya, Tanzania
(Orodho et al., 2014)
Erythrina abyssinica Lam. ex DC.
Root and stem barks are used for the treatment of TB symptoms and pulmonary infections
Uganda, Kenya, Tanzania
Roots are used in the treatment of TBrelated symptoms Leaf infusion is used in the treatment of TB Leaves are used in the treatment of TBrelated symptoms Roots are used in the treatment of TBrelated symptoms Bark is used in the treatment of TBrelated diseases or their symptoms
South Africa
(Mariita, 2006; Tabuti et al., 2010; Bunalema, 2010; Orodho et al., 2014) (Madikizela, 2014) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Greene et al., 2010)
Used in the treatment of TB-related symptoms
Nigeria
D E
T P
Indigofera arrecta Benth. ex Harv. & Sond. Lonchocarpus cyanescens (Schumach. & Thonn.) Benth. Mucuna pruriens (L.) DC.
E C
C A
Ormocarpum trichocarpum (Taub.)Harms Peltophorum africanum Sond Piliostigma reticulatum (DC.) Hochst.
M
18
Nigeria Uganda Uganda South Africa
(Faleyimu et al., 2009)
ACCEPTED MANUSCRIPT Piliostigma thonningii (Schumach.) Milne-Redh. Schotia brachypetala Sond Senna siamea (Lam.) Irwin & Barneby Tamarindus indica L.
Stem (wood) is used in the treatment of TB-related symptoms Bark used in the treatment of TB-related diseases or their symptoms Stem bark is used in the treatment of TB-related symptoms Leaves are used in the treatment of TBrelated symptoms
Uganda South Africa Uganda
I R
T P Uganda, Nigeria
Loranthaceae
Tapinanthus dodoneifolius (DC.) Danser
Leaves, Bark boiled in water for drinking in the treatment of TB
Malvaceae
Adansonia digitata L.
Dried leaves boiled in water for drinking 2 times for 24 days only in the treatment of TB Fresh leaves is boils in water for drinking and are used in the treatment of TB Roots are used in the treatment of TBrelated diseases or their symptoms Fruit infusion is used in the treatment of TB Leaf decoction is used in TB treatment
Nigeria
Leaf is used in the treatment of TB
Nigeria
Antherotoma senegambiensis (Guill. & Perr.) Jacq.-Fél. Dissotis rotundifolia (Sm.) Triana
Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TB
Uganda
Azadirachta indica A. Juss.
Seeds, leaves, stem (wood) and stem bark are used in the treatment of TB
Ghana, Uganda
Ekebergia capensis Sparm.
Used in the treatment of TB-related symptoms
South Africa
C S
Ceiba pentandra (L.) Gaertn.
A
Grewia villosa Willd.
D E
Cola acuminata (P.Beauv.) Schott & Endl.
T P
Glyphaea brevis (Spreng.) Monach.
E C
Hibiscus sabdariffa L. Melastomataceae
Meliaceae
C A
U N
M
19
Nigeria
Nigeria
South Africa Nigeria Nigeria
Ghana
(Tabuti et al., 2010) (Greene et al., 2010) (Tabuti et al., 2010) (Faleyimu et al., 2009; Tabuti et al., 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008; Faleyimu et al., 2009) (Ofukwu et al., 2008) (Greene et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Nguta etl al., 2015) (Tabuti et al., 2010; Nguta etl al., 2015) (Lall aand Meyer, 1999)
ACCEPTED MANUSCRIPT Menispermaceae Moraceae
Jateorhiza macrantha (Hook.f.) Exell & Mendonça Ficus asperifolia Miq.
Leaf infusion is used in the treatment of TB Leaf maceration is used in TB treatment
Nigeria
Ficus platyphylla Delile
Stem bark, squeezed fresh leaves or boiled for drinking in the treatment of TB-related symptoms
Nigeria, Uganda, South Africa
Nigeria
I R
T P
Ficus sur Forssk
Bark and roots are used to treat TB and lung ulceration
Moringaceae
Moringa oleifera Lam.
Seeds are used in the treatment of TBrelated symptoms
Musaceae
C S
South Africa
Musa nana Lour.
U N
Uganda, Nigeria
Leaf meal is used in the treatment of TB
Myristicaceae
Pycnanthus angolensis (Welw.) Warb.
Bark maceration is used in TB treatment
Nigeria
Myrsinaceae
Maesa lanceolata Forssk.
Myrtaceae
Callistemon citrinus (Curtis) Skeels
D E
T P
E C
Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson Eucalyptus spp.
C A
Psidium guajava L. Syzygium cordatum Hochst. ex Krauss Olacaceae
Ximenia caffra Sond. var. caffra
A
M
Nigeria
Roots are used in the treatment of TBrelated symptoms
Uganda
Leaves are used in the treatment of TBrelated symptoms Used for the treatment of TB
Uganda
Leaves and stem bark are used in the treatment of TB-related symptoms
Uganda, Kenya, Tanzania Nigeria
Bark maceration is used in the treatment of TB Used for the treatment of TB Leaves are used in the treatment of TBrelated diseases or their symptoms 20
South Africa
South Africa South Africa
(Ogbole and Ajaiyeoba, 2010) (Hannan et al., 2011) (Ofukwu et al., 2008; Tabuti et al., 2010; Lawal et al., 2014) (Lawal et al., 2014) (Madikizela, 2014) (Faleyimu et al., 2009; Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010; Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Greene et al., 2010)
ACCEPTED MANUSCRIPT Orobanchaceae
Alectra sessiliflora (Vahl) Kuntz
Leaf infusion is used in TB treatment
Nigeria
Phyllanthaceae
Phyllanthus fraternus G.L. Webster
Leaves are used in the treatment of TB
Ghana
Piperaceae
Piper capense L.f.
South Africa
Poaceae
Coix lacryma-jobi L.
Roots used in the treatment of TBrelated diseases or their symptoms Glumes are used in the treatment of TB
Cymbopogon giganteus Chiov.
Leaves are used in the treatment of TB
Cymbopogon citratus (DC.) Stapf.
Leaf infusion is used in TB treatment
Nigeria
Polygala fruticosa P.J.Bergius
Whole plant is used in TB treatment
Polygala myrtifolia L.
U N
South Africa
Used in the treatment of TB-related symptoms Roots are used in the treatment of TBrelated diseases or their symptoms
South Africa
Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Bark/leaves are used in the treatment of TB-related diseases or their symptoms Leaves and stem (wood) are used in the treatment of TB-related diseases or their symptoms Bark, leaves and roots are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
South Africa
Leaves are used in the treatment of TBrelated diseases or their symptoms
Uganda
Polygalaceae
I R
T P
C S
Securidaca longipedunculata Fresen.
A
D E
Polygonaceae
Rumex crispus L.
Primulaceae
Rapanea melanophloeos (L.) Mez.
Rhamnaceae
Berchemia discolor (Klotzsch) Hemsl.
T P
E C
Rhamnus prinoides L’Herit.
C A
Ziziphus mucronata Willd.
Rosaceae
Prunus africana (Hook.f.) Kalkman
Rubiaceae
Coffea spp.
M
21
Ghana Ghana
South Africa, Uganda
South Africa South Africa Uganda
South Africa
South Africa
(Ogbole and Ajaiyeoba, 2010) (Nguta etl al., 2015) (Greene et al., 2010) (Nguta etl al., 2015) (Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Madikizela, 2014) (Lall aand Meyer, 1999) (Tabuti et al., 2010; Greene et al., 2010) (Lall aand Meyer, 1999) (Lall aand Meyer, 1999) (Greene et al., 2010) (Tabuti et al., 2010) (Greene et al., 2010; Lawal et al., 2014) (Lawal et al., 2014) (Tabuti et al., 2010)
ACCEPTED MANUSCRIPT Gardenia ternifolia Schumach. & Thonn. ssp. jovis-tonantis (Welw.) Hiern. Pentanisia prunelloides Schinz Rubia cordifolia L. Rubia petiolaris DC. Rutaceae
Uganda
(Tabuti et al., 2010)
Roots are used to treat TB and chest disorders Used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
South Africa
(Madikizela, 2014) (Orodho et al., 2014) (Lawal et al., 2014) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Mariita, 2006) (Madikizela, 2014; Orodho et al., 2014) (Mariita, 2006)
Used for the treatment of TB
Citrus medica L.
Fruit infusion is used in TB treatment
Clausena anisata (Willd.) Hook.f. ex Benth. Harrisonia abyssinica Oliv.
Used for the treatment of TB
E C
Toddalia asiatica (L.) Lam. Zanthoxylum chalybeum Engl.
C A
Zanthoxylum gillettii De Wild. Waterm. Dodonaea angustifolia L. f. Haplocoelum foliolosum (Heirn) Bullock Hippobromus pauciflorus Radlk.
U N
A
M
South Africa Nigeria Nigeria South Africa
Root bark is used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
Uganda
Leaves are used in the treatment of TBrelated diseases or their symptoms Roots are used to treat TB Roots are used in the treatment of TBrelated diseases or their symptoms
Uganda
Stem bark is used to treat TB and asthma Leaves are used in the treatment of TBrelated diseases or their symptoms Stem bark is used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
Kenya
D E
T P
Teclea nobilis Del.
C S
Fruit infusion is used in TB treatment
Uganda, Kenya South Africa
T P
I R
Agathosma betulina (P.J.Bergius) Pillans Citrus aurantifolia (Christm.) Swingle
Ptaeroxylon obliquum (Thunb.) Radlk.
Sapindaceae
Roots are used in the treatment of TBrelated diseases or their symptoms
22
South Africa
Kenya Uganda, Kenya
Uganda Uganda South Africa
(Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014)
ACCEPTED MANUSCRIPT Sapotaceae
Vitellaria paradoxa C.F.Gaertn
Oil decoction is used in TB treatment
Nigeria
Solanaceae
Capsicum frutescens L.
Used for the treatment of TB
South Africa
Solanum incanum L.
Fruits are used in the treatment of TB symptoms and chest-related infections
Kenya
Solanum torvum Sw.
Unripe fruits/leaves are used to treat TB
Withania somnifera (L.) Dunal
Used for the treatment of TB
Clerodendrum myricoides (Hochst)Vatke Lantana trifolia L.
Roots are used to treat TB and chest disorders Leaves are used for the treatment of TB and related symptoms Leaves are used to treat TB, pneumonia, and chest pains Leaves are used to treat TB and cough Stem (wood), leaves and tubers are used in the treatment of TB-related diseases or their symptoms Tubers, leaves and stem (wood) are used in the treatment of TB-related diseases or their symptoms Leaves are used in the treatment of TB
Kenya
Verbenaceae
C S
Lantana camara L.
Vitaceae
Lantana trifolia L. Cyphostemma cyphopetalum (Fresen.) Desc. Ex Wild & Drumm.
E C
U N
A
D E
T P
Rhoicissus tridentata (L.f.) Wild & R.B.Drumm.
I R
M
T P Ghana
South Africa
Uganda Kenya
(Mariita, 2006) (Tabuti et al., 2010)
South Africa, Uganda
(Tabuti et al., 2010; Greene et al., 2010) (Nguta etl al., 2015) (Tabuti et al., 2010; Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010)
Aloe vera var. barbadensis
Zingiberaceae
Zingiber officinale Roscoe
Rhizomes are used in TB treatment
Ghana, Uganda
Fruit tincture is used in TB treatment
Nigeria
Zygophyllaceae
Aframomum melegueta (Roscoe) K.Schum. Balanites aegyptiaca (L.) Delile
Stem bark and roots are used in the treatment of TB-related diseases or their symptoms
Uganda
23
(Tabuti et al., 2010) (Mariita, 2006)
Kenya Uganda
Xanthorrhoeaceae
C A
(Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Bunalema, 2010; Orodho et al., 2014) (Nguta etl al., 2015) (Lawal et al., 2014) (Mariita, 2006)
Ghana
ACCEPTED MANUSCRIPT 2.3. Medicinal plants used in Asian traditional medicine for the management of tuberculosis From Asian traditional medicine including Ayurveda, 84 plant species have been recorded, belonging to 44 plant families. The most represented families are Leguminosae (or Fabaceae, 8 species), Lamiaceae (6 species) and Compositae (4 species) (Table 2). The most cited species are
T P
Adhatoda vasica (5 occurences), Tinospora cordifolia (3 occurences), Allium sativum, Acalypha indica, Asparagus racemosus, Cedrus deodara,
I R
Pinus contorta, Piper longum, Rubus occidentalis, Aloe vera, Glycyrrhiza glabra, Vitex negundo and Vitex trifolia (2 occurences) (Table 2).
C S
Adhatoda vasica oil from leaves, roots and flowers significantly inhibited the growth of M. tuberculosis B19-4 at a concentration of 4 µg/mL
U N
(Gautam et al., 2012). As well, the anti-TB activity of Tinospora cordifolia, Allium sativum, Acalypha indica, Aloe vera, Vitex negundo and Vitex trifolia have been documented (Arya, 2011).
A
D E
M
Table 2. Common medicinal plants used in Asia for tuberculosis treatment.
Plant family
Botanical name
Acanthaceae
C A
E C
T P
Adhatoda vasica Nees
Mode of preparation/administration
Leaves, flowers and roots are used for the treatment of asthma, gasping cough, bronchitis, cold and TB. Leaf juice (30 ml) with honey removes mucus from lungs
24
Locations Ayurveda
References (Ayyanar and Ignacimuthu, 2008; Arya, 2011; Debnath et al., 2012; Gautam et al., 2012; Alvin et al., 2014;
ACCEPTED MANUSCRIPT Tewari et al., 2015)
Amaranthaceae Amaryllidaceae
Andrographis paniculata (Burm.f.) Nees Spinacia oleracea L.
Ground leaves with mortar and pestle, served with honey for TB treatment Leaf decoction is taken orally against weight loss and TB Bulbs are used for the treatment of asthma, cough, bronchitis and TB
T P
I R
Allium cepa L.
Bulbs are used for the treatment of asthma, cough, bronchitis and TB Decoction of bulbs is used orally to treat TB
C S
Allium sativum L.
Apiaceae
Centella asiatica (L.) Urb.
U N
Whole plant is used for leprosy, bronchitis, asthma and TB. Boiled water extract of ground plant (all aerial parts) is used for TB treatment
A
D E
Hemidesmus indicus R.Br Apocynaceae
Arecaceae
Root is used in Rasayana as adjuvant therapy for TB
T P
Tabernaemontana coronaria (L.) Willd.
E C
Borassus flabellifer L.
C A
Licuala spinosa Thunb.
Berberidaceae
Berberis aristata DC.
Boraginaceae
Heliotropium indicum L.
M
Leaves are used to treat TB Old cane jaggery is used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Leaves are used to treat TB Hydroalcoholic extract is used as part of 200 mg Liv600 capsule administer thrice a day as adjuvant therapy for TB (hepatoprotective properties) Leaves, flowers or roots decoctions to treat TB 25
Indonesia Iraq Ayurveda Iraq, Ayurveda
Ayurveda, Indonesia
Ayurveda Malaysia Ayurveda
Malaysia Ayurveda
Arabian Peninsula
(Ahmed, 2016) (Arya, 2011) (Arya, 2011; Viswanathan et al., 2014; Ahmed, 2016) (Ayyanar and Ignacimuthu, 2008; Alvin et al., 2014) (Samal, 2016) (Mohamad et al., 2011) (Samal, 2016)
(Mohamad et al., 2011) (Samal, 2016) (Saganuwan, 2010)
ACCEPTED MANUSCRIPT Brassicaceae
Nasturtium indicum (L.) DC.
Burseraceae
Commiphora mukul (Hook. ex Stocks) Engl.
Calophyllaceae
Boiled water extract of all aerial parts is used for TB treatment Used for centuries. Commercial products are promoted for use in TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Roots are used to treat TB
T P
Mesua ferrea L.
I R
Pseudostellaria heterophylla (Miq.) Pax Caryophyllaceae
Whole plant juice rich in vitamin C is used in treatment of weakness after illness, lung congestion and TB
A
Terminalia chebula Retz
Commelinaceae
Rhoeo spathacea (Sw.) Stearn
Eclipta prostrata L.
D E
T P
E C
Pluchea indica (L.) Less.
C A
Saussurea lappa (Decne.) Sch.Bip. Taraxacum officinale F.H. Wigg
Crassulaceae
U N
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months
Combretaceae
Compositae (Asteraceae)
C S
Stellaria rubra Scop.
Kalanchoe integra (Medik.) Kuntze Benincasa hispida (Thunb.) Cogn.
M
Boiled water leaf extract is used for TB treatment Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Boiled water leaf and root extracts are used for TB treatment Roots are used in Rasayana capsules as ½ part in adjuvant therapy for TB Leaf decoction is taken orally against TB Leaves are used in the treatment of TB Remedy against TB 26
Indonesia Ayurveda Ayurveda
Ayurveda
Ayurveda
Ayurveda
Indonesia Ayurveda
Indonesia Ayurveda Iraq Ayurveda Philippine
(Alvin et al., 2014) (Dhanabal et al., 2015) (Samal, 2016)
(Chandra and Rawat, 2015) (Chandra and Rawat, 2015) (Samal, 2016)
(Alvin et al., 2014) (Samal, 2016)
(Alvin et al., 2014) (Samal, 2016) (Ahmed, 2016) (Arya, 2011) (Batugal et al., 2004)
ACCEPTED MANUSCRIPT
Euphorbiaceae
Trichosanthes dioica Roxb.
Roots and fruits are used in the treatment of TB
Acalypha indica L.
Leaves are used as expectorant, diuretic, respiratory disease, pneumonia, asthma and TB
Jatropha curcas L.
Stem bark decoction (30-50 ml) is taken orally thrice a day for TB treatment
T P
I R
Mallotus philippensis (Lam.) Müll.Arg. Ricinus communis L.
Glandular trichomes and hairs of fruit are used in the treatment of TB
C S
Boiled water extract of leaves and roots are used for TB
Flacourtiaceae
Hydnocarpus anthelminthica Pierre ex Laness
Seeds are used against leprosy and TB
Gentianaceae
Canscora decussata (Roxb.) Schult. & Schult.f.
Roots are used in the treatment of TB
U N
A
M
Leaves, fruits and roots are used in the treatment of TB Colebrookea oppositifolia Sm.
Ocimum sanctum L.
T P
Lamiaceae
D E
E C
Vitex negundo L.
C A
Leaves, flowers and seeds are used in the treatment of TB
Cinnamomum cassia (Nees & T.Nees) J.Pres
Ayurveda
Ayurveda Indonesia Chinese Ayurveda
Ayurveda
Ayurveda
Ayurveda Leaves and seeds as well as a decoction of the stem bark is used to treat TB
Vitex trifolia L.
Lauraceae
Ayurveda Ayurveda
Leaves, roots and fruits are used in the treatment of TB. Boiled water extract of leaves is used for TB treatment
Powder of stem bark is used against cough and TB
27
Ayurveda, Indonesia
Iraq
(Arya, 2011) (Arya, 2011; Dhanabal et al., 2015) (Poonam and Singh, 2009) (Arya, 2011) (Alvin et al., 2014) (Wang et al., 2010) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012; Ahuja et al., 2015) (Batugal et al., 2004; Arya, 2011; Alvin et al., 2014) (Ahmed, 2016)
ACCEPTED MANUSCRIPT
Cinnamomum tamala (Buch.Ham.) T.Nees & Eberm.
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Leaves are used to treat cough, respiratory tract infections, bronchitis Leaves and flowers are used in the treatment of TB
T P
Cinnamomum zeylanicum Blume
I R
Acacia senegal (L.) Willd.
C S
Caesalpinia pulcherrima (L.) Sw. Caesalpinia sappan L.
Leguminosae (Fabaceae)
U N
Boiled water extract of chopped pieces is used for TB
Flemingia strobilifera (L.) W.T. Aiton
Leaves are used to treat respiratory diseases including symptoms of TB
Glycyrrhiza glabra L.
Roots to treat TB. Roots are used in Rasayana capsules as 1 parts in adjuvant therapy for TB
A
D E
T P
Mimosa pudica L.
Trigonella foenum-graecum L.
E C
M
(Samal, 2016)
Ayurveda
(Samal, 2016)
Ayurveda
(Gautam et al., 2012) (Arya, 2011)
Ayurveda Indonesia Malaysia Chinese, Ayurveda
Leaves and roots are used in the treatment of TB
Ayurveda
Oil, leaves, roots and seeds are used as cough suppressant, to treat asthma, pneumonias and TB
Arabian Peninsula Ayurveda
Liliaceae
Asparagus racemosus Willd.
Malvaceae
Hibiscus tilliaceus L.
Menispermaceae
Tinospora cordifolia (Willd.) Miers
Stem and leaves benefit the general weakness and TB. Used in Rasayana capsules as 1 parts in adjuvant therapy of TB
Tinospora crispa (L.) Miers ex
Leaves are used to treat TB
C A
Ayurveda
Roots are useful in TB, cough and bronchitis Boiled water extract of leaves is used for TB treatment
28
Indonesia Ayurveda
Malaysia
(Alvin et al., 2014) (Mohamad et al., 2011) (Namita and Mukesh, 2012; Samal, 2016) (Arya, 2011) (Saganuwan, 2010) (Nair, 1998; Warrier, 2002) (Alvin et al., 2014) (Dhanabal et al., 2015; Samal, 2016) (Mohamad
ACCEPTED MANUSCRIPT Hook. f. & Thoms.
et al., 2011) Ayurveda
(Poonam and Singh, 2009) (Samal, 2016)
Azadirachta indica Juss. A.
Leaf paste is used against TB, 1 tea spoon twice a day by oral route.
Ayurveda
Myristica fragrans Houtt.
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months
Myrtus communis L.
Fruits are used in the treatment of TB
Ayurveda
(Arya, 2011)
Myrtaceae
Ayurveda
Syzygium aromaticum (L.) Merr. & L.M.Perry
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months
(Samal, 2016)
Ophioglossaceae
Helmintostachys zeylanica (L.) Hook.
Used to treat TB
Philippines
(Batugal et al., 2004) (Samal, 2016) (Samal, 2016)
Meliaceae
Myristicaceae
T P
C S
Phyllanthus fraternus G.L. Webster
Piperaceae
D E
T P
M
Pericarp is used in Rasayana capsules as 1 parts in adjuvant therapy for TB Freshly prepared decoction of aerial parts is used as part of 10 mg and administered thrice a day as adjuvant therapy of TB
Emblica officinalis Gaertn.
Fruit juice is useful for cough, asthma and TB
Cedrus deodara Roxb.
Leaves are used in the treatment of TB
E C
Pinaceae
U N
A
Emblica officinalis Gaertn. Phyllanthaceae
I R
C A
Ayurveda Ayurveda
Ayurveda Ayurveda
Ayurveda
Pinus contorta Douglas. ex Loudon.
The inner bark to treat TB
Pinus pinea L.
Leaves, roots and stem are used to treat TB
Piper longum L.; Piper spp.
Fruit is used in Rasayana capsules as ½ parts in adjuvant therapy of TB 29
Arabian Pennisula Ayurveda
(Tewari et al., 2015) ( Nair, 1998; Warrier, 2002) (Nair, 1998; Warrier, 2002) (Saganuwan, 2010) (Arya, 2011; Samal,
ACCEPTED MANUSCRIPT
Plantaginaceae Poaceae
Polygonaceae
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Fruits and leaves are used to treat TB, hemorrhage and pneumonia
Plantago major L. Imperata cylindrical (L.) Raeuschel Saccharum spontaneum L.
Rhizome decoction is used to treat TB To treat TB
Rumex hastatus D. Don
Root and bark are used in the treatment of TB
Ranunculus ternatus Thunb.
Roots are used alone or combined with other herbal remedies in the treatment of TB. Radix Ranunculi Ternati is now the only commercially available medicine for the treatment of TB Leaves, oil and flowers are used to treat TB and cough
D E
T P
E C
Ixora chinensis Lam.
C A
U N
A
Prunus amygdalus Batsch
Rubus occidentalis L.
Salicaceae
C S
Seeds, flowers and leaves are used to treat cough and TB
Prunus armeniaca L.
Rubiaceae
I R
Sorghum bicolor (L.) Moench
Ranunculaceae Rosaceae
T P
M
Kernels are used in the treatment of TB
Arabian Peninsula Philippine Philippine Arabian Peninsula Ayurveda
Remedy against incipient TB, hemorrhage and headache
(Zhang et al., 2015)
Arabian Pennisula Ayurveda
(Saganuwan, 2010) (Arya, 2011)
Ayurveda
(Nair, 1998; Warrier, 2002) (Batugal et al., 2004) (Arya, 2011; Tewari et al., 2015) (Alvin et al., 2014) (Arya, 2011)
Philippine Ayurveda
Leaves, roots and fruits are used in the treatment of TB
Morinda citrifolia L.
Boiled water extract of aerial parts are used for TB treatment Leaves, roots, bark and fruits are used in TB treatment
30
(Saganuwan, 2010) (Batugal et al., 2004) (Batugal et al., 2004) (Saganuwan, 2010) (Arya, 2011)
Chinese
A decoction of the roots is used in the treatment of TB
Morinda citrifolia L.
Flacourtia ramontchi L'Hér.
2016)
Indonesia Ayurveda
ACCEPTED MANUSCRIPT Simaroubaceae
Brucea javanica (L.) Merr.
Ground fruits with mortar and pestle for TB treatment
Solanum nigrum L. Solanaceae
T P
Withania somnifera L. Verbenaceae
Hydroalcoholic extract is used as part of 200 mg capsules Liv-600 administered thrice a day as adjuvant therapy of TB Root is used in Rasayana capsules as 1 parts in adjunct treatment of TB Boiled water extract of leaves and flowers are used for TB treatment Rhizome is used in Rasayana capsules as ¼ part in adjuvant therapy of TB Rhizome is used in Rasayana capsules as ½ part in adjuvant therapy of TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Whole plant is used as remedy for common cold, bronchitis and TB
I R
Lantana camara L.
C S
Alpinia galanga (L.) Willd. Curcuma longa L. Zingiberaceae
U N
Indonesia Ayurveda
Ayurveda Indonesia Ayurveda Ayurveda Ayurveda
A
Elettaria cardamomum (L.) Maton Kaempferia galanga L.
D E
M
Philippine
(Alvin et al., 2014) (Samal, 2016) (Samal, 2016) (Alvin et al., 2014) (Samal, 2016) (Samal, 2016) (Samal, 2016)
(Batugal et al., 2004)
T P
E C
2.4. Medicinal plants used in South Pacific and American traditional medicine for the management of tuberculosis From American traditional medicine, which, in some cases, is a mixture of African and Asian knowledges, we recorded 52 plant species,
C A
belonging to 27 families, used to treat TB and related symptoms (Table 3). The most represented families are Compositae (12 species), Leguminosae (or Fabaceae, 5 species) and Lamiaceae (4 species) (Table 3). Most cited species is Chenopodium ambrosiodes L., whose anti-TB activity has been reported previously (Ahmad et al., 2016).
31
ACCEPTED MANUSCRIPT Table 3. Medicinal plants used against tuberculosis in Americas. Plant family
Botanical name
Mode of preparation/administration
Locations
References
Amaranthaceae
Chenopodium ambrosiodes L.
Brazil, Amazonia
Aspidosperma carapanauba Pichon.
1 bunch of fresh leaves in 500 ml water as juice/syrup/condensed milk/tea, daily dosage 200/400 ml, for the treatment of lung problems, cough and TB Used in the treatment of TB-related symptoms
Parahancornia amapa (Huber) Ducke
Used in the treatment of TB-related symptoms
Amazonia
Aspidosperma carapanauba Pichon
Used in the treatment of TB-related symptoms
Amazonia
Aloe arborescens Mill.
Syrup and juice are indicated for the treatment of lung problems, cough and TB
Brazil
(Storey and Salem,1997; Leitão et al., 2013) (Storey and Salem,1997) (Storey and Salem,1997) (Storey and Salem,1997) (Leitão et al., 2013)
Leaves and gel from leaves are used in the treatment of TB. Hydroalcoholic extract as parts of 200 mg capsule Liv-600 administered thrice a day as adjuvant therapy for TB Stem bark is used in treating TB
Ayurveda
(Arya, 2011; Samal, 2016)
South Pacific Amazonia
(WHO,1998)
Apocynaceae
Asphodelaceae
T P
I R
C S
U N
A
D E
Aloe vera (L.) Burm.f.
Barringtoniaceae Bignoniaceae
T P
Barringtonia asiatica (L.) Kurz
E C
Arrabidaea chica (H.B.K.) Verlot.
M
Used in the treatment of TB-related symptoms
Amazonia
(Storey and Salem,1997) (Leitão et al., 2013)
Brassicaceae
Nasturtium officinale R. Br
Syrup and juice are indicated for the treatment of lung problems, cough and TB
Brazil
Combretaceae
Terminalia catappa L.
Leaves are used to treat bronchitis and TB
Tahiti
(WHO,1998)
Compositae
Artemisia spp.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Bidens pilosa L.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
C A
32
ACCEPTED MANUSCRIPT Elephantopus mollis Kunth.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Heterocondylus alatus (Vell.) R.M.King and H.Rob.
Tea and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Hypochaeris brasiliensis (Less.) Hook. and Arn.
Tea and juice are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Mikania laevigata Sch. Bip. ex Baker
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Solidago chilensis Meyen
Juice is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Vernonia phaeoneura Toledo
Juice is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Vernonia polyanthes Less.
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Syrup is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Tea and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
A handful of fresh leaves and flowers in 500 ml water as juice/condensed milk, daily dosage ad libitum Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Amazonia
(Storey and Salem,1997)
Amazonia Brazil
South Pacific South Pacific
(Storey and Salem,1997; Leitão et al., 2013) (WHO,1998)
U N
A
D E
T P
E C
Spilanthes acmella (L.) L. Crassulaceae
I R
C S
Vernonia westiniana Less. Vernonia spp.
T P
C A
Kalanchoe brasiliensis Cambess.
M
Euphorbiaceae
Euphorbia fidjiana Boiss.
Leaf is used in treating TB
Goodeniaceae
Scaevola taccada (Gaertner) Roxb.
Leaves, stem bark and roots are used to treat coughs and TB 33
(WHO,1998)
ACCEPTED MANUSCRIPT Lamiaceae
Leguminosae (Fabaceae)
Mentha pulegium L.
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Mentha x piperita L.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Ocimum campechianum Mill.
Used in the treatment of TB-related symptoms
Brazil
(Leitão et al., 2013)
Ocimum gratissimum L.
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Hymenaea spp.
Tea and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Acacia cochliacantha Humb. & Bonpl. ex Willd.
Shoots are used to treat TB and cold
Mexico
Bowdichia virgilioides Η.Β.Κ.
Used in the treatment of TB-related symptoms
Amazonia
Used in the treatment of TB-related symptoms
Amazonia
2 dry pods in 1 liter water as infusion/tea, daily dosage ad libitum Syrup are indicated for the treatment of lung problems, cough and TB
Amazonia
(CoronadoAceves et al., 2016) (Storey and Salem,1997) (Storey and Salem,1997) (Storey and Salem,1997) (Leitão et al., 2013)
T P
I R
D E
Hymenaea courbaril L. Caesalpinia ferrea Mart. Loranthaceae
T P
Struthanthus concinnus Mart.
E C
C S
U N
A
M
Brazil
Struthanthus marginatus (Desr.) G. Don
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Lythraceae
Punica granatum L.
Amazonia
Malvaceae
Hibiscus tiliaceus L. var. tiliaceus
Treatment of TB, pulmonary diseases or symptoms of these disorders Stem bark is used to prepare a remedy against cough which is also used for TB. Leaves are used in treating cough, sore throat and open wounds In the Solomon Islands, parts of the plant are used in treating cuts, TB and conjunctivitis.
(Storey and Salem,1997) (WHO,1998)
C A
34
South Pacific
ACCEPTED MANUSCRIPT In New Guinea, the bark is used to make a cough remedy which is also used for TB Syrup is indicated for the treatment of lung problems, cough and TB
Malva spp.
Brazil
(Leitão et al., 2013) (Storey and Salem,1997) (CoronadoAceves et al., 2016) (WHO,1998)
Meliaceae
Carapa guianensis Aubl.
Used in the treatment of TB-related symptoms
Amazonia
Myrtaceae
Eucalyptus camaldulensis Dehnh.
Leaves are used to treat TB, bronchitis and cough
Mexico
Syzygium malaccense (L.) Merr. & Perry
Leaves are used to treat bronchitis and TB. Stem bark infusion is used to treat TB and digestive tract problems. Tea is indicated for the treatment of lung problems, cough and TB
South Pacific
Eugenia uniflora L.
T P
I R
C S
U N
A
Orbiaceae
Bischofia javanica Blume
The cambium of the plant is used to treat TB
Piperaceae
Potomorphe peltata ( L ) Miq.
Used in the treatment of TB-related symptoms
Poaceae
Cymbopogon citratus (DC.) Stapf
Rhamnaceae
Ampelozizyphus amazonicus Ducke.
Rubiaceae
Morinda citrifolia L.
Rutaceae
D E
T P
E C
C A
Citrus limon (L.) Osbeck Citrus aurantium L.
M
Brazil
(Leitão et al., 2013)
South Pacific Amazonia
(WHO,1998)
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
Used in the treatment of TB-related symptoms
Amazonia
Liquid pressed from young fruit is used in the treatment of TB. Used for the treatment of TB, pulmonary disease or symptoms of these diseases Indicated for the treatment of lung problems, cough and TB
South Pacific South Pacific Brazil South Pacific South Pacific
Solanaceae
Capsicum frutescens L.
Used as a remedy for TB
Urticaceae
Dendrocnide harveyi (Seemann) Chew
A preparation made from scrapings of the stem bark is used in treating illnesses described as pain in the lungs with vomiting 35
(Storey and Salem,1997) (Leitão et al., 2013) (Storey and Salem,1997) (WHO,1998) (WHO,1998) (Leitão et al., 2013) (WHO,1998) (WHO,1998)
ACCEPTED MANUSCRIPT of blood (TB) Zingiberaceae
Used in the treatment of TB-related symptoms
Zingiber officinale Roscoe.
Amazonia
(Storey and Salem,1997)
T P
To summarize, most of plant species belongs to Leguminosae (Fabaceae) and Compositae families. Amongst all the identified species, only few
I R
are shared across continents. Allium cepa, Allium sativum, Aloe vera, Azadirachta indica, Lantana camara, Centella asiatica and Withania somnifera were recorded in Asia and Africa (Fig. 1). On the other hand, Bidens pilosa, Capsicum frutescens, Chenopodium ambrosiodes, Hibiscus
C S
tiliaceus, Cymbopogon citratus and Zingiber officinale were recorded in South Pacific-Americas and Africa, while only Morinda citrifolia was
U N
identified both in Asia and South Pacific-Americas (Fig. 1). In general, very little uniformity has been observed in the plants mentioned,
A
highlighting the low consensus regarding TB remedies among the different traditional healing systems. This is likely due to the poor
M
experimentation or evidence of efficacy for TB treatment, as well as the limited availability and accessibility of some endangered medicinal
D E
species.
T P
E C
C A
36
ACCEPTED MANUSCRIPT
T P
Africa 6
222
South PacificAmericas
I R
52
0
C S
1
7
U N
Asia
A
84
D E
M
Fig. 1. Distribution of medicinal plants identified in the traditional treatment of tuberculosis across continents.
T P
E C
C A
37
ACCEPTED MANUSCRIPT 3. Targeting multidrug resistance in tuberculosis: management with phytochemicals and medicinal plants
3.1. Impact of MDR- and XDR-TB on public health Despite significant advances in treating the disease, tuberculosis continues to be a serious global
IP
T
health threat, with over 10.4 million cases, and 1.8 million deaths reported in 2015 (Smith et al., 2004; WHO, 2015; Nguyen, 2016; WHO, 2016). Mycobacterium tuberculosis (MTb), the etiologic agent of
CR
tuberculosis, is now considered one of the most successful pathogens among those causing infectious
US
diseases, and the incidence of MTb infections is on the rise globally due, in part, to the advent of HIV/AIDS. The continued prevalence of MTb is due to the fact that this pathogen has an innate ability to
AN
survive host defense mechanisms, as well as the lack of new therapies, the inappropriate use of anti-TB drugs, disease states that complicate treatment such as diabetes mellitus and HIV, as well as the
M
emergence of multi-drug resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains (WHO,
ED
2015).
Over the last two decades, there has been a focus on the research and development of novel
PT
therapies for TB and several drugs have been evaluated in clinical trials (WHO, 2016). However, the number of effective drugs for TB is still very small, and treatment is complicated and very lengthy,
CE
leading to patient non-compliance and an increase in drug resistance. Over the past 40 years, the
AC
resistance of MTb has moved from mono-drug to multidrug resistance (MDR), extensively drug resistant (XDR), and eventually totally drug resistant (TDR), through sequential accumulation of resistance mutations as reported by Nguyen et al., (2016). MDR-TB strains are resistant to both isoniazid and rifampicin, and these strains were responsible for over 480,000 reported cases and approximately 210,000 deaths in 2013(Nguyen, 2016). Extensively drug-resistant (XDR) MTb strains are also resistant to the quinolones and other second-line drugs and have been reported in at least 100 countries (WHO, 2015). The morbidity of XDR is 40-50% and poses a serious public health threat, especially in areas with high HIV prevalence. Antibiotic resistance of MTb strains continues to be a serious global health threat as 38
ACCEPTED MANUSCRIPT some clinical strains have developed the means to evade all available antibiotics (Adhvaryu and Vakharia, 2011; Mishra et al., 2015; WHO, 2016). As a consequence, there is an urgent need to develop novel anti-tuberculosis agents, particularly adjunct treatments that may be used to reverse antibiotic resistance, treat MDR- and XDR-TB, and to
T
enhance the immune system to improve MTb recovery rates. In addition, most of the anti-TB drugs
IP
currently target metabolic reactions and proteins that are critical for the proliferation of M. tuberculosis
CR
(Adhvaryu and Vakharia, 2011). Future studies should focus on research and development of new drugs based on novel molecular targets related to the establishment of mycobacterial dormancy in human
US
macrophages or inhibition of bacterial virulence factors that interfere with the signaling pathways of host
3.2. Natural products for MDR- and XDR-TB
AN
cells and affect immunity, leading to the persistence of the disease (Koul et al., 2011).
M
Medicinal plants have been used since the beginning of time to treat all diseases, including
ED
infectious diseases, and have been excellent leads for the development of new drugs. In fact, over the past 25 years, almost 50% of new drugs reviewed and approved by the US Food and Drug Administration
PT
have been derivatives of natural products (Newman and Cragg, 2007; Kinghorn et al., 2011; Cragg and
CE
Newman, 2013; Atanasov et al., 2015). Reviews of recently published scientific literature show that there are more than 350 species of plants used for the treatment of TB, from countries around the world, and
AC
many naturally occurring compounds have been isolated and identified with activity against MTb, MDRTB and XDR-TB (Camacho‐Corona et al., 2008; Samad et al., 2008). The following is an overview of some of the classes of natural products showing some promising activity against MDR- and XDR-TB.
3.3. Bisbenzylisoquinolone alkaloids In a study by Sureram et al. (2012) bisbenzylisoquinoline alkaloids including tiliacorinine, 20nortiliacorinine and tiliacorine isolated from roots of the edible plant Tiliacora triandra, as well as one synthetic derivative, 130-bromotiliacorinine, were active against MDR-TB strains. The 59 strains of M. 39
ACCEPTED MANUSCRIPT tuberculosis included 12 isolates resistant to isoniazid (INH) and rifampin (RMP); five isolates resistant to INH, RMP, and ethambutol (EMB); 23 isolates resistant to INH, RMP, and streptomycin (SM); nine isolates resistant to INH, RMP, EMB, and SM; one isolate resistant to INH, RMP, EMB, and ofloxacin (OFX); one isolate resistant to INH, RMP, SM, and OFX; and eight isolates resistant to INH, RMP, EMB,
T
SM, and OFX. The results of this study showed that tiliacorinine, 20-nortiliacorinine, tiliacorine, and 130-
IP
bromotiliacorinine were active against MDR-MTB strains with median inhibitory concentration (MIC)s
CR
ranging from 0.7 to 6.2 µg/mL. Cytotoxicity in normal MRC-5 (human fetal lung fibroblast) cell line was also determined. The alkaloids were cytotoxic in this cell line with median inhibitory concentration (IC50)
US
of 3.13-20.0 µg/mL (Sureram et al., 2012).
AN
3.4. Cinnamic acid derivatives
M
In a 2011 study by Lakshmanan et al., (2012) a compound isolated from the rhizomes of Kaempferia galanga and identified as ethyl p-methoxycinnamate (EPMC) was tested against MTb strains.
ED
Antimycobacterial activity of EPMC was evaluated in MTb strains H37Ra (ATCC 25177) and H37Rv
PT
(ATCC 25618). Eight MTb clinical isolates, six of which from patients with MDR-TB, were obtained from the Swedish National Strain Collection at the Swedish Institute for Infectious Disease Control
CE
(SMI), Solna, Sweden. The results of this study showed that EPMC inhibited the growth of all MTb strains tested, with a MIC of 0.485 mM. Four strains, irrespective of their drug resistance profiles (fully
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susceptible or MDR), were inhibited at 0.242 mM. EPMC toxicity was also tested on the human macrophage cell line THP-1 cells. An IC50 value of 3.8 mM was reported, indicating that EPMC was not toxic to macrophage cells at concentrations that could inhibit M. tuberculosis (Lakshmananet al., 2011). Interestingly, the study also showed that the MDR strains did not exhibit higher MIC value than the susceptible ones, suggesting that the mechanism of action may be different from the target of any of the current anti-TB drugs (Lakshmananet al., 2011).
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ACCEPTED MANUSCRIPT 3.5. Fungal metabolites Ganihigama et al. (2015) evaluated the anti-MTb activity of 27 naturally occurring compounds from fungi against MDR-TB isolates. Many of these natural products included anthraquinones, diterpenoids, alkaloids and flavonoids. The fungal metabolites were tested against a non-virulent H37Ra
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strain of M. tuberculosis and showed MIC values ranging from 3.1 µg/mL to > 100µg/mL. Among the
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compounds tested, vermelhotin exhibited activity with MIC of 3.1 mg/mL (Ganihigama et al., 2015).
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Vermelhotin, a tetramic acid isolated from an unidentified marine fungus (CRI247-01) demonstrated antimycobacterial activity towards five reference strains (MIC 3.1 - 6.2 µg/mL) and exhibited activity
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against the MDR-TB strains with MIC ranging between 1.5 µg/mL and 12.5 µg/mL (Ganihigama et al., 2015). Unfortunately, this compound was also cytotoxic in normal cells, MRC-5 cell line (human lung
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fibroblast cells), with IC50 value of 6.97 µg/mL.
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3.6. Iridoids
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Plants used in the Ayurvedic system of medicine containing iridoids, terpenes and other compounds have been shown to exert anti-MTb activities (Kumar et al., 2013). In one study on tree bark
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from Plumeria bicolor, a plant from India commonly known as Champa, several iridoids have been
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isolated and identified (Kumar et al., 2013). A methanol extract of the dried bark of P. bicolor, plumericin and isoplumericin were tested against susceptible MTb and four MDR-TB strains (Kumar et al.,
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2013).The extract showed a MIC between 20-25 µg/mL for all strains tested. Plumericin was very active against all strains with a MIC between 1.3 and 2.1 µg/mL, with higher activity against the MDR strains. Isoplumericin was also active with MICs between 2.0-2.6 µg/mL for all strains tested. No cytotoxicity was reported for other cell lines.
3.7 Marine natural products New interesting marine natural products have also been discovered with relevant activity against MTb and MDR-TB. From marine Streptomyces spp., cyclomarin A, a novel anti-inflammatory cyclic 41
ACCEPTED MANUSCRIPT peptide, was isolated and showed high activity against MTb with MIC of 0.3 µg/mL (Lee and Suh, 2016). The MIC90 of the drug was 2.5 μM after 5 days of treatment, suggesting a high efficacy within short treatment times. The occurrence of anti-mycobacterial metabolites from marine invertebrates, namely sponges, corals and gorgonians has been recently investigated (Daletos et al., 2016; Sansinenea and Ortiz,
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2016). The compound (–)-8,15-diisocyano-11(20)-amphilectene, a diterpene isolated from the Carribean
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sponge Svenzea flava, showed a promising activity with MIC value of 3.2 µg/mL; the calculated
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selectivity index (SI; i.e., IC50/MIC) of compound was equal to 10.2, suggesting that amphilectane-type diterpenes are important anti-tuberculosis pharmacophores (Nieves et al., 2016). Agelasines, purine
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diterpenes isolated from Agelasidae (Agelas spp.) marine sponges, were found to exhibit biological activity against the dormant state of MTb, which plays an important role in latent tuberculosis infection
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(Arai et al., 2014). Very recently, three haliclocyclamines, dimeric 3-alkyl piridinium alkaloids isolated from the Indonesian marine sponge Haliclona spp., showed a dose-dependent anti-mycobacterial activity,
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with the highest inhibition zone (10 mm) at 5 µg/disc (Maarisit et al., 2017).
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3.8. Peptides
Anti-mycobacterial peptides have been recently reviewed (Silva et al., 2016; Dong et al., 2017),
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though they have been investigating since many decades. In the 1960’s, a cyclic peptide named
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griselimycin (GM) was discovered from Streptomyces spp.; it was effective against MTb, though its pharmacokinetic properties were poor (Holzgrabe, 2015). In 2015, Rolf Müller and colleagues retested GM after they increased the metabolic stability of the peptide by alkylating a proline residue in position 8. A novel metabolically stable cyclohexyl derivative was obtained with improved penetration of the mycobacterial cell wall, with a MIC of 0.06 μg/mL. The activity against MDR-TB was similar. Investigation on the mechanism of action showed that there was an amplification of the dnaN gene. This gene encodes for DnaN, a DNA polymerase sliding clamp that anchors the DNA to DNA polymerase, thus enhancing the replicatory strength of the enzyme and accelerating DNA replication and repair in 42
ACCEPTED MANUSCRIPT prokaryotes. DnaN is a molecular target of GM, and GM derivatives appear to bind to a hydrophobic pocket of the DNA polymerase sliding clamp, making it an extremely novel mechanism of action (Lee and Suh, 2016). Lassomycin, a peptide composed of 16 amino acids, was identified from Lentzea kentuckyensis IO0009804, another actinomycete. This peptide had activity against MDR and XDR MTb, with MICs
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ranging from 0.41 to 1.65 μM (Lee and Suh, 2016). Another peptide named ecumicin, produced by Nonomuraea spp. MJM5123 and composed of 13 amino acids, also showed promising anti-TB activity
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against MDR and XDR MTb, with MIC values ranging from 0.16 to 0.62 μM. The minimal bactericidal
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concentration (MBC) was 1.5 μM (Lee and Suh, 2016).
Sansanmycins are members of uridylpeptide family produced by the soil bacterium Streptomyces
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spp. These uridylpeptides are potents and selective anti-mycobacterials involved in inhibition of peptidoglycan biosynthesis (Tran et al., 2016). Teixobactin is a recently discovered anti-mycobacterial
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peptide isolated from Eleftheria terrae, a soil microorganism. The mechanism of action was identified as
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inhibition of peptidoglycan biosynthesis, though, noteworthy, teixobactin-resistant strains of M.
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3.9. Quinones and terpenes
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tuberculosis could not be generated (Ling et al., 2015).
In 2016, Jyoti et al. reported the effects of an extract of Artemisia capillaris on the in vitro
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susceptibility of MTb. This plant is native to Central and Southeast Asia, particularly Korea, and is used as an antimicrobial agent. Two compounds from this extract were identified as active against MTb strains using bioassay-guided fractionation, ursolic acid (UA) and hydroquinone (HQ), with a MIC of 12.5 μg/mL against the susceptible strains, and of 12.5-25 μg/mL against MDR/XDR strains. This group also investigated the mechanism by which UA may exert its anti-MTb activity (Jyoti et al., 2016). In strain MTb H37Ra, UA decreased mycolic acid biosynthesis in a dose-dependent manner as determined by quantitative LC/MS/MS. This compound is a branched long-chain fatty acid that makes up to 60% of the outer cell wall of Mycobacterium. By inhibiting biosynthesis of mycolytic acid the bacterial cell wall 43
ACCEPTED MANUSCRIPT cannot be formed and this causes Mycobacterium cell death. Electron microscopy further confirmed that UA had effects on both the cell wall and the intracellular content of H37Ra (Jyoti et al., 2015). In 2013, Metha et al. showed that extracts of Citrullus colocynthis (L.) Schrad. (Cucurbitaceae), known commonly as bitter apple, a medicinal plant from India used to treat bacterial infections, including tuberculosis and other respiratory diseases, had activity against MTb (Mehta et al., 2013). In this study, a
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methanol extract of the ripe fruits exhibited activity against MTb strains with a MIC ≤ 62.5 µg/ml. One
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fraction (FC III) of this extract showed a MIC of 31.2 µg/mL against strain MTb H37Rv, and other fractions also inhibited 16 clinical isolates of MTb, including 7 wild type, 8 MDR-TB, 1 XTB and 2 non-
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TB Mycobacterium strains with MICs in the range of 50-125, 31.2-125 and 62.5-125 µg/mL, respectively. Interestingly, the active compound identified from fraction FC III was UA, though other terpenes were
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also identified as cucurbitacin E 2-O-β-D-glucopyranoside and cucurbitacin I 2-O-β-D-glucopyranoside from fraction FC IX. Ursolic acid and cucurbitacin E 2-O-β-D-glucopyranoside were identified as the
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main chemical constituents active against MTb H37Rv (MICs 50 and 25 µg/ml, respectively), as well as
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against the clinical isolates (Mehta et al., 2013).
In a publication by Uc-Cachón et al. (2014), naphthoquinones with anti-MTb activity were
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isolated from Diospyros anisandra, a native plant from the Yucatan peninsula used in traditional Mayan
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medicine. These compounds have a naphthalene skeleton substituted by ketone groups in positions C1 and C2 (1,2-naphthoquinones) or positions C1 and C4 (1,4-naphthoquinones), and are found as
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monomers, dimers, trimers or tetramers (Uc-Cachón et al., 2014). Naphthoquinones have a wide variety of biological activities, including antibacterial, antifungal, antiparasitic, antiviral, antiinflammatory and cytotoxic effects. In this study, stem bark extracts of Diospyros anisandra were active against MTb strains, and 3 monomeric and 5 dimeric naphthoquinones were isolated, identified and tested. Plumbagin and its dimers maritinone and 3,30-biplumbagin showed the highest activity against both susceptible and MDR-TB strains with a MIC of 1.56-3.33 mg/mL. Only maritinone and 3,30-biplumbagin showed no toxicity against normal eukaryotic cells, and had 32 times more activity against MDR-TB strains. In terms of mechanism of action, it has been shown that naphthoquinones can target the electron transport chain of 44
ACCEPTED MANUSCRIPT Mycobacterium because they are structurally similar to menaquinone. In addition, they also may inhibit menaquinone biosynthesis thereby interfering with electron transport and cellular respiration (Uc-Cachón et al., 2013).
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4. Case study: traditional Chinese medicine In traditional Chinese medicine (TCM), many herbal formulas have been used as adjunctive
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therapy, along with conventional TB chemotherapy, to manage MDR-TB. Some clinical trials have
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shown that various TCM herbal formulas can enhance the immune system, reduce adverse events observed with conventional TB chemotherapy, improve the overall quality of life, and decrease the level
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of MTb in sputum culture (Jiang et al., 2015). One systematic review and meta-analysis analyzed 20 clinical trials involving 1823 TB patients from China (Jiang et al., 2015). This review concluded that
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adjunct therapy with TCM herbal formulas and TB chemotherapy significantly (p < 0.001) enhanced the
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treatment success and improved radiological findings. However, subjects who received TCM herbals in combination with chemotherapy had similar relapse rates; though the incidence of adverse events was
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lower (Jiang et al., 2015). These data suggest that TCM herbal medicines may improve the overall treatment and recovery of TB.
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A second systematic review and meta-analysis assessed the effects of TCMs in combination with
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TB chemotherapy in 30 randomized clinical trials (RCTs) involving 3374 participants with a diagnosis of MDR-TB (Wang et al., 2015). This review concluded that the quality of the clinical trials in the analysis was generally poor in terms of risk of bias. It further suggested again that TCM plus chemotherapy was more effective on the conversion rate of sputum as compared with chemotherapy alone. The study showed that, when compared with chemotherapy only, a benefit in MDR-TB patients was observed on the rate of reduction of lung lesions (in 7 studies), cavity closure rate (5 studies), reduced relapse rate (4 studies) and reduced abnormal liver function tests (14 studies) when TCM plus chemotherapy was used.
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ACCEPTED MANUSCRIPT No serious adverse event was reported in any of the study. The authors further suggested that, considering the positive results, further robust clinical trials are warranted (Wang et al., 2015). Beyond the clinical trials, one rodent study by Lu et al. (2013) investigated the effects of the traditional Chinese herbal medicines Radix Ranunculi Ternati, Radix Sophorae Flavescentis, Prunella vulgaris L. and Stellera chamaejasme L. on immunity in a rat model of MDR-TB. Treatment of the
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animals with the TCM herbal remedies significantly changed the levels of serum IFN-γ (p < 0.05). RT-
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PCR analysis showed a statistically significant increase in the mRNA levels of IFN-γ and IL-12, and a significant decrease in the mRNA levels of IL-4 and IL-10 (p < 0.05). In summary, this study showed that
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treatment with TCM herbs increased cellular-mediated immunity in a MDR-TB rodent model (Lu et al., 2013).
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In addition, an in vitro study performed by Nam et al. showed that (-)-deoxypergularine (DPX), an alkaloid extracted from the dried roots of the plant Cynanchum atratum (known as Bai Wei in TCM)
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showed activity against MDR-TB (Nam et al., 2016). The compound inhibited the growth of both
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susceptible and MDR-TB strains with a MIC of 12.5 µg/mL, with excellent activity against XDR-TB at 12.5 µg/mL. In a checkerboard assay, the combination of DPX and rifampin was synergistic in the MTb
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strain H37Ra, as was isoniazid plus DXP. In combination with streptomycin or ethambutol, the results
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(Nam et al., 2016).
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were equivocal. Unfortunately, no checkerboard assays were performed on the XDR-resistant strains
4.1. In vitro evidence
Tuberculosis or ’the white plague’, as people named it due to high fatal rate, even today presents one of the leading cause of motality with 9 million cases of active TB and 1.3 million deaths occurring every year (Hussain at al., 2014). Significant factors such as specific cell wall composition, dormant cells, long lasting therapy and inproper use of the first- and second-line drugs are related to continously increasing incidence of the multi-drug resistant (MDR) strains. Therefore, modern science is in constant
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ACCEPTED MANUSCRIPT search for novel alternatives in treating this infectious disease, especially those from natural sources which may have shorter treatment regimes and be effective with fewer side-effects. In these investigations, researchers mostly rely on the data obtained from traditional medicine practitioners. One of the first known studies in this route was the efficacy of garlic as antitubercular therapy, carried out in
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1912 by Dr. Minchin. He performed anti-TB treatments on his patients by an inhaler mask containing a
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sponge soaked in garlic juice and reported that, in certain individuals, the drug was active against the
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pathogen (Dini et al., 2011). In the last decades, the studies have focused to the efficacy of phytochemicals against multi-drug resistant isolates of Mycobacterium tuberculosis, thus providing
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promising results on the effectiveness of plant products against Mycobacterium. Garlic was demonstrated to possess antimycobacterial activity in many studies, where allicin was
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confirmed to be the carrier of this activity in the study of Gupta and Viswanathan (Gupta and Viswanathan, 1955). They found that this compound acts in synergistic manner with antibiotics
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streptomycin and chloramphenicol against M. tuberculosis. The same synergism was not detected when
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antitubercular drugs were combined with garlic extract, thus pointing to the allicin efficacy (Abbruzzese et al., 1987). Further studies on this subject confirmed garlic efficiency against various MTb strains,
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including MDR ones (Delaha and Garagusi, 1985; Ratnakar and Murthy, 1996; Gupta et al., 2010;
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Hannan et al., 2011). The most recent study of (Rajani et al., 2015), who investigated ethanol extract of garlic against 48 MDR and one reference strains (H37Rv) of MTb showed MIC values in the range of 0.5-
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2.0 mg/ml. Another plant of the Allium genus, shallot (Allium ascalonicum L.), was investigated for activity against MTb in the study of (Mansour et al., 2009). Its ethyl acetate extract exhibited activity against all of the ten tested clinical isolates of MTb at concentration of 500 µg/mL. Nine plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases were used for making hexane, methanol, chloroform and water extracts, which were further evaluated for antimycobacterial activity (Camacho‐Corona et al., 2008). Among the tested extracts, the activity was shown by hexane (Citrus aurantifolia, C. sinensis, Foeniculum vulgare, Olea europaea), two chloroform (Larrea tridentata, Nasturtium officinale) and one methanol (Musa acuminata) extracts. 47
ACCEPTED MANUSCRIPT Nasturtium officinale chloroform extract exhibited the most prominent activity against both reference and MDR strains (MICs were 100 µg/mL and < 100 µg/mL, respectively). Other extracts showing activity against these strains were Foeniculum vulgare and Olea europaea hexane extracts, which exhibited efficacy against all the resistant MTb variants at concentrations lower than 100 µg/mL.
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Study by León-Díaz (2010) showed that hexane extract of Aristolochia taliscana, the herb used in
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Mexican traditional medicine, presents an important source of antimycobacterial compounds. This extract
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was tested against a wide range of mycobacteria including standard strain (H37Rv), four mono-resistant H37Rv variants and 12 clinical MDR isolates, as well as against five non-tuberculous mycobacteria.
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Bioguided fractionation of the obtained extract led to the isolation of the neolignans licarin A, licarin B and eupomatenoid-7, which all demonstrated antimycobacterial activity at very low concentrations (3.25-
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50.00 µg/mL). Among them, the most prominent action was observed for licarin A, which was active at 6.25 µg/mL even against MDR isolate resistant to first- and second-line antibiotics (León-Díaz et al.,
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2010). Gupta et al. (2010) investigated activity of aqueous extracts of Acalypha indica and Adhatoda
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vasica leaves, bulbs of Allium cepa, cloves of Allium sativum and pure gel of Aloe vera leaves against MDR strains of MTb. All extracts were be effective against MDR isolates and drug-susceptible reference
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strain H37Rv.
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Among the tested acetone, ethanol and aqueous extracts obtained from 5 plants (Acorus calamus L. rhizome, Andrographis paniculata Nees. leaves, Ocimum sanctum L. leaves, Piper nigrum L. seeds
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and Pueraria tuberosa DC. tuber), only P. nigrum acetone extract showed to possess antimycobacterial activity (Birdi et al., 2012). In the study of Anthony et al. (2012), butanol extracts of Alstonia scholaris fruits, flowers, bark and leaves were tested for efficacy against one standard strain (H37Rv), one clinical isolate sensitive to antibiotics, and one MDR clinical strain. The results pointed to significant efficacy of bark and leaf extracts against MDR strain at 100 µg/mL, while at 500 µg/mL all extracts showed inhibitory action against all tested strains. Among them, the highest activity was reported for bark extract of Alstonia scholaris, which showed inhibition of 47.40, 51.46 and 73.09% against standard, clinical sensitive and clinical MDR strains, respectively. 48
ACCEPTED MANUSCRIPT Seven mangrove plants (Ceriops decandra, Aegiceras corniculatum, Excoecaria agollacha, Avicennia officinalis, Rhizophora mucronata, Suaeda monoica and Sesuvium portulacastrum) were collected and their hexane and methanol extracts were tested for antimycobacterial activity (Prabhu, 2014). The assys were carried against one standard, one clinical strain sensitive to drugs and one strain of
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Mycobacterium tuberculosis resistant to streptomycin, isoniazid, rifampicin and ethambutol. Hexane
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extracts of all plants failed to exert antimycobacterial activity, while methanol extracts of E. agollacha,
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followed by those extracted from A. corniculatum and A. officinalis exhibited significant activity at concentrations of 500 µg/mL.
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In another study, fresh leaves of Taxus baccata, Senna alata, Andrographis paniculata, Adhatoda vasica, Acalypha indica and Aloe vera were extracted with water (ratio 1:1) and investigated against three
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MTb strains, including one MDR strain (DKU-156). The results showed inhibition of the treated MDR strain by all tested extracts at concentrations 2, 4 and 6% (Bernaitis et al., 2013). Among the tested
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extracts, T. baccata showed the highest potency considering percentage of bacterial growth reduction on
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LJ (Lowenstein Jensen) agar.
In the study of Deveci et al. (2013), a total of 57 isolates including 17 MDR strains were
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investigated for sensitivity to Ankaferd Blood Stopper®, a mixture of plant extracts prepared from
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Alpinia officinarum, Glycyrrhiza glabra, Thymus vulgaris, Urtica dioica and Vitis vinifera. The mixture showed very significant antimycobacterial activity, with inhibitory concentrations ranging from < 1.37
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µg/mL to 21.88 µg/mL. Singh et al. (2013) investigated different solvent extracts of two plants, Urtica dioica and Cassia sophera, for antimycobacterial activity. They determined that the hexane extract of U. dioica and methanol extract of C. sophera possessed this activity. Further testing of semi-purified fractions of these two extracts showed significant inhibition of clinical MDR strains of MTb. Gupta et al. (2014) investigated antimycobacterial activity of Alpinia galanga (L.) Willd. under intracellular and in axenic (aerobic and anaerobic) conditions. Intracellular assay represented a model for investigating the activity of the extracts against non-replicating dormant bacilli, characterized by the switch from aerobic/microaerophilic to anaerobic respiratory pathways. Among the tested extracts 49
ACCEPTED MANUSCRIPT (obtained by water, acetone and ethanol Soxhlet extraction), acetone and etanolic extracts were active in all tested conditions at low concentrations (25, 50 and 100 µg/ml). Recently, similar investigation (in axenic and intracelluler conditions) was carried out by Bhatter et al. (2016) who tested the efficacy of acetone, ethanol and aqueous extracts of four plant species (Acorus calamus L. rhizome, Ocimum
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sanctum L. leaves, Piper nigrum L. seeds and Pueraria tuberosa DC. tuber) against MTb H37Rv.
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Acetone extract of P. nigrum showed the highest antimycobacterial activity by inhibiting the tested strain
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in aerobic, microaerophilic and anaerobic conditions. Also, water extract of P. tuberosa showed significant activity under reduced oxygen conditions, which pointed to the importance of anaerobiosis for
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its efficacy.
Antimycobacterial activity of aqueous extracts of selected Indonesian medicinal plants
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(Andrographis paniculata, Annona muricata, Centella asiatica, Pluchea indica and Rhoeo spathacea) was investigated in the study of Radji et al. (2015). Their results showed that Pluchea indica and Rhoeo
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spathacea ehxibited promising antimycobacterial activity against a MDR strain of Mycobacterium
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tuberculosis, by inhibiting its growth at concentrations of 2.5 and 5 mg/mL. Another recent study on the plant efficacy against mycobacteria was the one performed by
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Johanpour et al. (2015). They tested antimycobacterial activity of the ethanol extract from six Iranian
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medicinal plants against six clinical isolates (2 of them were MDR). The results pointed to significant activity of Peganum harmala and Punica granatum extracts. Owing to the fact that the assay was carried
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out using disc diffusion method, high concentrations (100 and 200 mg/mL) were determined to be active. Considering sensitive isolates, the inhibition zones of the P. harmala extract at higher concentration corresponded to those obtained by rifampin and isoniazid. Another study showed the activity of methanol, ethyl acetate and n-hexane extracts from plant material of Euphorbia hirta, a medicinal plant used in India for the treatment of many respiratory disorders (asthma, cough and various acute/chronic respiratory infections). Among the tested extracts, ethyl acetate extract showed the highest activity against MTb H37Rv, with concentration of 500 µg/mL reducing microbial growth to 35.27% in comparison with the untreated, control value (Rajasekar et al., 2015). 50
ACCEPTED MANUSCRIPT Finally, four clinical isolates including two MDR and two sensitive strains to rifampin and isoniazid were used to investigate the antimycobacterial activity of the Peganum harmala hydro-alcoholic seed extract. All tested strains, including the MDR ones, showed sensitivity to this extract (Davoodi et al., 2015).
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5. Conclusions
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The urgent need for development of new drugs to reduce the global burden of TB has greatly
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stimulated the exploration of traditional knowledge as source of novel and effective phytotherapeutic agents. Worldwide, many plant species have been and continue to be used in various traditional healing
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systems, as well as marine organisms and fungi, thus representing a nearly unlimited source of active
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ingredients.
Noteworthy, besides their antimycobacterial activity, natural products can be useful in adjuvant
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therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their adverse effects and to reverse mycobacterial multi drug-resistance, the latter an emerging and very critical topic
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because of the genetic plasticity and environmental adaptability of Mycobacterium. Probably, the wide
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use of some traditional herbal remedies in the treatment of tuberculosis may be indicative of their efficacy and, above all, safety. Not least, natural products can also be used as a template for the development of
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new scaffolds of drugs.
In any case, crude natural product extracts are complex mixtures of hundreds of different
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compounds that may be synergistically active once administered. Therefore, discovery and development of new pure products involve isolation, purification and identification of target compounds from complex crude extracts is sometimes a major drawback in natural products research. Not least, even if some natural products have still been investigated in clinical trials, the validation of their efficacy and safety as antituberculosis agents is far from being reached, and, hence, according to an evidence-based approach, more high-level randomized clinical trials are urgently needed.
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Pulmonary tuberculosis is a human disease. Multi-drug-resistant tuberculosis cause to an urgent need for discovery and development of new drugs to reduce the global burden of this disease. Many plant species have been and continue to be used in various traditional healing systems around the world to treat tuberculosis. Evidence-based approach, suggested for more high-level randomized clinical trials.
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Javad Sharifi-Rad, Bahare Salehi, Zorica Z. Stojanović-Radić, Patrick Valere Tsouh Fokou, Marzieh Sharifi-Rad, Gail B. Mahady, Majid Sharifi-Rad, Mohammad-Reza Masjedi, Temitope O. Lawal, Seyed Abdulmajid Ayatollahi, Javid Masjedi, Razieh Sharifi-Rad, William N. Setzer, Mehdi Sharifi-Rad, Farzad Kobarfard, Atta-ur Rahman, Muhammad Iqbal Choudhary, Athar Ata, Marcello Iriti PII: DOI: Reference:
S0734-9750(17)30077-0 doi: 10.1016/j.biotechadv.2017.07.001 JBA 7134
To appear in:
Biotechnology Advances
Received date: Revised date: Accepted date:
29 December 2016 22 June 2017 5 July 2017
Please cite this article as: Javad Sharifi-Rad, Bahare Salehi, Zorica Z. Stojanović-Radić, Patrick Valere Tsouh Fokou, Marzieh Sharifi-Rad, Gail B. Mahady, Majid Sharifi-Rad, Mohammad-Reza Masjedi, Temitope O. Lawal, Seyed Abdulmajid Ayatollahi, Javid Masjedi, Razieh Sharifi-Rad, William N. Setzer, Mehdi Sharifi-Rad, Farzad Kobarfard, Atta-ur Rahman, Muhammad Iqbal Choudhary, Athar Ata, Marcello Iriti , Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches, Biotechnology Advances (2017), doi: 10.1016/j.biotechadv.2017.07.001
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ACCEPTED MANUSCRIPT Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches Javad Sharifi-Rada,*, Bahare Salehib*, Zorica Z. Stojanović-Radićc, Patrick Valere Tsouh Fokoud,e, Marzieh Sharifi-Radf, Gail B. Mahadyg, Majid Sharifi-Radh, Mohammad-Reza Masjedii, Temitope O. Lawalg,j, Seyed Abdulmajid Ayatollahia,k, Javid Masjedil, Razieh Sharifi-
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Radm, William N. Setzern, Mehdi Sharifi-Rado,*, Farzad Kobarfarda,p , Atta-ur Rahmanq,
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Muhammad Iqbal Choudharyq, Athar Atar, Marcello Iritis,*
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
b
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Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases
(NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran c
Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš,
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Višegradska 33, Niš, Serbia d
Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health
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Sciences, University of Ghana, Accra LG 581, Ghana
Antimicrobial Agents Unit, LPMPS, Department of Biochemistry, Faculty of Science, University of
f
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Yaoundé 1, Yaoundé 812, Cameroon
Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran
g
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Department of Pharmacy Practice, Clinical Pharmacognosy Laboratories, University of Illinois at
Chicago, USA h
Zabol, Iran i
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Department of Range and Watershed Management, Faculty of Natural Resources, University of Zabol,
Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung
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Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran j
Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Nigeria
k
Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences
Tehran, Iran l
Tobacco Control Strategic Research Center, Shahid Beheshti University of Medical Sciences Tehran,
Iran m
Department of Biology, Faculty of Science, University of Zabol, Zabol, Iran
n
Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA
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Department of Medical Parasitology, Zabol University of Medical Sciences, 61663335 Zabol, Iran
p
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Iran q
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi 75270, Pakistan r
Department of Chemistry, Richardson College for the Environmental Science Complex The University
Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan
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of Winnipeg, Winnipeg, Canada
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20133, Italy
* Corresponding authors at: Phytochemistry Research Center, Shahid Beheshti University of Medical
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Sciences, Tehran, Iran. E-mail address: [email protected] (J. Javad Sharifi-Rad). Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases
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(NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail address: [email protected] (B. Salehi).
Department of Medical Parasitology, Zabol University of Medical Sciences, 61663335 Zabol, Iran. E-
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mail address: [email protected] (M. Sharifi-Rad). Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan
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ABSTRACT
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20133, Italy. E-mail address: [email protected] (M. Iriti).
Tuberculosis is a highly infectious disease declared a global health emergency by the World Health Organization, with approximately one third of the world’s population being latently infected with Mycobacterium tuberculosis. Tuberculosis treatment consists in an intensive phase and a continuation phase. Unfortunately, the appearance of multi drug-resistant tuberculosis, mainly due to low adherence to prescribed therapies or inefficient healthcare structures, requires at least 20 months of treatment with second-line, more toxic and less efficient drugs, i.e., capreomycin, kanamycin, amikacin and fluoroquinolones. Therefore, there exists an urgent need for discovery and development of new drugs to 2
ACCEPTED MANUSCRIPT reduce the global burden of this disease, including the multi-drug-resistant tuberculosis. To this end, many plant species, as well as marine organisms and fungi have been and continue to be used in various traditional healing systems around the world to treat tuberculosis, thus representing a nearly unlimited source of active ingredients. Besides their antimycobacterial activity, natural products can be useful in
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adjuvant therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their
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adverse effects and to reverse mycobacterial multi-drug resistance due to the genetic plasticity and
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environmental adaptability of Mycobacterium. However, even if some natural products have still been investigated in preclinical and clinical studies, the validation of their efficacy and safety as
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antituberculosis agents is far from being reached, and, therefore, according to an evidence-based
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approach, more high-level randomized clinical trials are urgently needed.
Keywords:
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Mycobacterium
Traditional healing systems
Antimycobacterial agents
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Evidence-based medicine
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Herbal medicine
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Multi drug-resistance
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ACCEPTED MANUSCRIPT 1. Introduction Pulmonary tuberculosis (TB) is a humankind disease. Available evidence shows that some pharaohs in ancient Egypt suffered from TB and recent radiological studies using computerized tomography revealed spinal involvement in some cases. Therefore, TB is a historical disorder that had centuries of history
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accompanied with human life. Since the detection of tubercle bacilli as the causal agent by Robert Koch
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in 1882, and after the introduction of first anti-TB drugs by Schatz and Waksman in 1940, great
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developments have transpired in the fields of biology, microbiology, pathogenesis, immunology, drug therapy and, recently, molecular genetics of this disease and its etiological agent. However, TB is still a
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worldwide problem. It has been estimated, that almost one billion people have died from TB during the last 200 years (Paulson, 2013). According to the latest report, World Health Organization (WHO)
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declared that, in 2014, nearly 1,400,000 people had died from TB, from this number, 890,000 were men, 480,000 women and 140,000 were children. Currently, TB with HIV are the main killers globally. In the
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year 2014, almost 9,600,000 people had TB, 5,400,000 of whom were men, 3,200,000 women and 1
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million children. Around 12% of these people were HIV positive. At the same time, 6,000,000 new cases of TB were reported by WHO, that is 63% of the total estimated figures. This means that almost 37% of
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patients with TB were undiagnosed and/or unreported (WHO, 2015). In 2014, 480,000 cases of multi
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drug-resistant (MDR) TB were estimated, while only one quarter of this number, around 123,000 were diagnosed and treated worldwide. According to the sustainable development goals (SDG), all countries
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are obliged to reduce the number of death from TB, 90% by the year 2030, and to reduce the number of new cases to 80%, simultaneously. In addition, all countries should plan in a manner that no family will be compromised because of this disease. Following the Oslo meeting in 1995, WHO defined two major targets as success criteria of national TB programs. First, at least 70% of patients should be diagnosed (case finding), and at least 80% of smear positive cases should be cured (cure rate). After a vast struggle and hard work at the national, regional and global level, and following the discovery of new rapid and applicable molecular diagnostic techniques and affordable therapeutic regimens, WHO has modified its strategy from ”Stop TB” to ”End TB“ strategy. 4
ACCEPTED MANUSCRIPT MDR TB is defined as cases infected with tubercle bacilli that are resistant to the major essential drugs, rifampin (RIF) and isoniazid (INH), while XDR (Masjedi et al., 2006; Masjedi et al., 2008; Velayati et al., 2012; Masjedi et al., 2013) (extensively drug-resistant) refers to cases which are MDR and resistant to fluoroquinolone and two injectable drugs (amikacin and capreomycin). Recently TDR (totally drug-
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resistant) patterns were reported which include cases resistant to all antibiotics. These resistant cases raise
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difficult issues in the subject of successful control and management of tuberculosis. Although 2-3 billion
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of currently living people are infected with tubercle bacilli, only 5-15% of them will develop active disease during their lifetime, which is mainly pulmonary tuberculosis (Talavera et al., 2001; Tiemersma et
subject of different branches of research (Smith, 2003).
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al., 2011). This fact explains the complicated interaction between the microbe and the host, which is the
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Tuberculosis bacilli are mycobacteria related to the actinomycete group (the mycobacterium TB complex) which include human and bovine types, Mycobacterium africanum, M. microtti and M. canetti. These
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aerobic bacilli in 80 to 90% of cases invade the lungs, and in 5 to 20% colonize other extra-pulmonary
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organs, mainly lymph nodes, bones and joints, and genitourinary system 9 (Tiemersma et al., 2011). The main route of entrance of tubercle bacilli into the body is in form of aerosol droplets via the lung. As
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these microbes reach the alveoli, they face and are engulfed by alveolar macrophages, and may infect type
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II pneumocytes. Later, dendritic cells, T lymphocytes, cytokines and many other mediators and biologic factors interfere and appear in the scene and lead to the development of typical granulomatas and necrosis
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which we are not described in detail in this introduction (Mehta et al., 1996; Tascon et al., 2000). The main strategy of TB treatment was focused on DOT‘s strategy, that is “Directly Observed Treatment short course“, which is 6 months treatment. In the initial two months, the patient receives 4 major drugs (RIF, INH, pyrazinamide, ethambutol) under close observation by health worker or defined volunteer person, and the following 4 months will continue with two drugs (RIF and INH). This six months regimen is recommended to all cases of pulmonary and extra-pulmonary cases including children and older patients. As mentioned earlier, MDR TB which includes cases resistant to both RIF and INH, was reported in 1990 by WHO and is a real obstacle in the general control of this disease worldwide. In the 5
ACCEPTED MANUSCRIPT year 2006, XDR types were reported and it seems that 3.2% of all new cases of TB and 20% of those who received treatment were MDR (Holtz and Cegielski, 2007; Chiang et al., 2010; Millardet al., 2015; Ghanashyam, 2016). In the year 2014, almost 190,000 patients with MDR had died and only 50% of those with MDR were treated successfully. With the introduction of linezolid (Farshidpour et al., 2013;
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Lee et al., 2015) in 2000, and bedaquiline (Diacon et al., 2009; WHO, 2013) in 2009, WHO
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recommended new therapeutic regimens to deal with MDR and XDR cases. A relevant issue in the field
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of tuberculosis is vaccine use. Historically, the extensively used vaccine worldwide is BCG (Bacillus Calmette-Guérin) vaccine. This vaccine, made from a weak strain of Mycobacterium bovis, was
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introduced 80 years ago and is still recommended by WHO to be used in early childhood as one of the 6 essential vaccines, particularly in prevalent areas. BCG vaccine is effective in preventing development of
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severe forms of TB in children, mainly biliary tuberculosis and meningitis. This vaccine is less effective in preventing tuberculous disease among adults (Bedi, 2005).
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Recent advances in the molecular biology and immunopathogenesis of mycobacterial diseases have led to
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extensive research in these fields and different vaccines have been introduced to be used as a preventive or therapeutic (Lalvani et al., 2013; Mangtani et al., 2014; Kaufmann et al., 2015). However, we should
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wait for affordable and effective vaccines in the coming years. The complex scenario is the interaction
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between the immune system and tubercle bacilli after the preliminary infection, which, in most cases, leads to latent tuberculosis infection (LTI). As mentioned earlier, in more than 80% of cases, the human
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body is able to contain the infection and the bacilli remain dormant through the whole life of infected people. This phenomenon is a subject of extensive research (Parrish et al., 1998; Wayne et al., 2001; Cardona, and Ruiz-Manzano, 2004). It is worthwhile to mention that WHO, international organizations, research institutions, charities and supporters altogether are working very hard to tackle different aspects of this problem and to achieve the projected targets in the coming decades.
2. Traditional knowledge on plants used against tuberculosis
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ACCEPTED MANUSCRIPT Medicinal plants have been in use for centuries to cure various ailments including tuberculosis. Infusions, macerations, tinctures and decoctions of medicinal plant parts such as leaves, roots, stem bark, stem, flowers and fruits have been used for centuries as traditional treatments of TB by native people worldwide. Commercial preparations of some of these remedies are available and continue to be used considerable
success
in
affected
communities.
Even
though
ethnobotanical
and
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with
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ethnopharmacological studies confirmed their wide use in the treatment of TB, the therapeutic and safe
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doses are still to be established for most of them. Most of the studies also failed to provide scientific evidence to traditional beliefs and therapeutic practices. Therefore, this work is an attempt to document
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medicinal plants traditionally used to control TB. Different traditional healing systems have been applied to cure TB, ranging from the poor documented oral African medicine to the well documented Asian or
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Chinese, Ayurveda and so on.
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2.1. Indigenous knowledge on tuberculosis
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The unique and exclusive indigenous knowledge in Africa is orally transferred to the next generation especially in rural communities (Lawal et al., 2014). Tuberculosis is believed to be a contagious disease
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transmitted mainly through sharing contaminated food and eating-utensils, and droplet infection is known by the African traditional system by signs and symptoms that include cough, wheezing cough, labored
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breathing and weight loss (Tabuti et al., 2010). However, some of these symptoms are not specific and
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can be related to other pulmonary diseases such as asthma, different infections, cancer and ordinary cough. In Ayurveda (Indian traditional medicine system), TB is aptly referred as Rajayakshma, a disease of grave prognosis, along with ascites and marasmus, that spreads from one person to another (Jayana) like the flight of birds. It is attributable to tissue emaciation or loss (Dhatukshaya) involved in pathogenesis accompanied by metabolic dysfunction (Dhatwagninasana): fluid, blood, muscle, adipose tissue and generative tissue are lost leading to immunosuppression (Debnath et al., 2012; Samal, 2016). Conventional anti-TB medications have been prescribed to control symptoms, but they result in side effects and, therefore, the use of herbal medicine has been promoted (Arya, 2011). Finally, traditional 7
ACCEPTED MANUSCRIPT Chinese medicine cure TB by combining antibacterial treatments, strengthening QI (vital energy) and administering herbs to protect the liver (Liu et al., 2008). 2.2. Medicinal plants used in African traditional medicine for the management of tuberculosis A total of 222 plant species used in Africa for TB treatment were recorded, belonging to 71 families
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(Table 1). The families with the most species of plants used to cure TB are Leguminosae (or Fabaceae, 28 species) and Compositae (or Asteraceae, 20 species) (Table 1). Overall, the most frequently used plant
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parts are leaves, whole root and stem bark (Tabuti et al., 2010). The most frequently cited species are
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Erythrina abyssinica Lam. ex DC. and Allium sativum L. (4 occurrences), Ficus platyphylla Delile, Bidens pilosa L., Asparagus africanus Lam., Carissa edulis (Forssk.) Vahl. and Allium cepa L. (3
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occurrences) (Table 1). The anti-TB activity of E. abyssinica and A. sativum have been demonstrated extensively. E. abyssinica crude methanol extract showed antimicrobial activity on the sensitive strain
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H37Rv and the rifampicin resistant strain TMC-331, with MIC values of 0.39 mg/ml and 2.35 mg/ml,
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respectively (Bunalema, 2010). A. sativum extract inhibited both non-MDR and MDR M. tuberculosis isolates, with MIC values ranging from 1000 to 3000 μg/mL (Hannan et al., 2011). The leaf ethanol
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extract of B. pilosa exhibited activity against M. tuberculosis at 100 μg/mL (Gautam et al. 2007). C. edulis showed antibacterial activity against slow (M. tuberculosis, M. kansasii) and fast (M. fortuitum and
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M. smegmatis) growing mycobacteria (Mariita, 2006). A. cepa anti-mycobacterial activities have
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previously been reported (Arya, 2011).
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ACCEPTED MANUSCRIPT Table 1. Common medicinal plants in African traditional medicine for tuberculosis treatment. Plant family Botanical name Mode of preparation/administration Acanthaceae
Acanthus pubescens (Thomson ex Oliv.) Engl. Brillantaisia owariensis P. Beauv.
Roots are used to treat TB and related diseases Leaves are used to treat TB and related diseases Leaves and whole plant are used to treat TB and related diseases
Hygrophila auriculata (Schumach.) Heine Acanthus montanus (Nees) T.Anderson Aizoaceae
Carpobrotus edulis (L.) N.E.Br.
Amaranthaceae
Chenopodium ambrosioides L.
U N
A
Achyranthes aspera L.
M
Uganda
(Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010; Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Nguta etl al., 2015; Lall aand Meyer, 1999) (Tabuti et al., 2010) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Lawal et al., 2014; Nguta etl al., 2015) (Faleyimu et al., 2009; Greene et al., 2010; Tabuti et al., 2010; Nguta etl al., 2015) (Madikizela, 2014) (Lawal et al., 2014)
Uganda
Uganda, Ghana Nigeria
South Africa South Africa, Ghana
Flowers are used to treat TB and related diseases Leaves are used to treat TB and related diseases Leaves and bulbs are used in the treatment of TB
Uganda
Allium sativum L.
Bulbs, tubers and leaves are used for the treatment of TB and related symptoms
South Africa, Nigeria, Ghana
Brunsvigia grandiflora Lindl.
Bulbs against coughs and colds
South Africa
Haemanthus albiflos Jacq.
Used for the treatment of TB
South Africa
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Amaranthus spinosus L. Amaryllidace
C S
References
T P
I R
Leaf infusion is used in the treatment of TB Leaf decoction is used orally for the treatment of TB Leaves are used in curing TB and related symptoms
Locations
T P
Allium cepa L.
E C
C A
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Uganda Ghana, Nigeria, South Africa
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Anacardiaceae
Tulbaghia acutiloba Harv.
Used for the treatment of TB
South Africa
Tulbaghia violacea Harv.
Used for the treatment of TB
South Africa
Mangifera indica L.
Stem bark is used to treat TB and related diseases
Uganda
Pistacia aethiopica Kokwaro Rhus rogersii Schönland
Leaves are used to treat TB Used in the treatment of TB-related diseases or their symptoms Bark is used in the treatment of TBrelated diseases or their symptoms Leaf infusion is used in the treatment of TB Leaves or roots are pound, boiled and filtered for drinking Dried pound bark is boiled in water for drinking Used for the treatment of TB
Sclerocarya birrea (A Rich) Hochst. Spondias mombin L. Annonaceae
Annona senegalensis Pers.
Apiaceae
Centella asiatica (L.) Urb.
Daucus carota L.
U N
D E
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South Africa Nigeria Nigeria Nigeria South Africa
Used for the treatment of TB
South Africa
Leaf decoction and bark maceration are used in the treatment of TB
Nigeria
Araujia sericifera Brot.
Used for the treatment of TB
South Africa
Carissa edulis (Forssk.) Vahl.
Leaves, roots and root bark are used in the treatment of TB-related diseases or their symptoms
South Africa, Uganda, Kenya
Cryptolepis sanguinolenta (Lindl.) Schltr.
Root bark is used for the treatment of TB symptoms and lung infections
Uganda
Cocos nucifera L.
Husk decoction is used in the treatment
Nigeria,
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Alstonia boonei De Wild
E C
C A
Arecaceae
C S
A
Centella coriacea Nannf.
Apocynaceae
I R
T P
Kenya South Africa
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(Lawal et al., 2014) [ (Lawal et al., 2014) (Tabuti et al., 2010; Orodho et al., 2014) (Mariita, 2006) (Greene et al., 2010) (Greene et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Lawal et al., 2014) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Mariita, 2006; Tabuti et al., 2010; Greene et al., 2010) (Bunalema, 2010; Orodho et al., 2014) (Ogbole and
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Asclepiadaceae
of TB
Ghana
Elaeis guineensis Jacq.
Oil soup is used in the treatment of TB
Nigeria
Asclepias fruticosa L.
Roots are used in the treatment of TBrelated diseases or their symptoms Leaves are used to treat TB and related symptoms Shoots and stem (wood) are used for the treatment of TB
South Africa
Gomphocarpus physocarpus E. Mey. Asparagaceae
Asparagus africanus Lam.
I R
T P
C S
U N
Uganda
South Africa, Uganda
Asparagus falcatus (L.) Oberm.
Leaves and roots are used to treat TB
Balanophoraceae
Thonningia sanguinea Vahl.
Nigeria
Bignoniaceae
Stereospermum kunthianum Cham.
Burseraceae
Boswellia dalzielii Hutch.
Fruit decoction is used in the treatment of TB Boiled leaves or bark or roots in water to drink for TB or their symptoms Bark is pounded, powdered and mixed with porridge for the treatment of TB or their symptoms Bark boiled in water for the treatment of TB or their symptoms Leaves and stem bark are used for the treatment of TB or symptoms
Warburgia ugandensis Sprague
Used for the treatment of TB or their symptoms
Cannabaceae
Cannabis sativa L.
Used for the treatment of TB
Uganda, Kenya, Tanzania South Africa
Capparaceae
Capparis erythrocarpos Isert.
Roots are used for the treatment of TB
Uganda
A
D E
T P
E C
Commiphora africana (A.Rich.) Endl. Canellaceae
Warburgia salutaris (G. Bertol.) Chiov.
C A
M
11
South Africa
Nigeria Nigeria
Nigeria South Africa, Uganda
Ajaiyeoba, 2010; Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Greene et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010; Lawal et al., 2014; Madikizela, 2014) (Madikizela, 2014) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Tabuti et al., 2010; Greene et al., 2010; Greene et al., 2010) (Orodho et al., 2014) (Lawal et al., 2014) (Tabuti et al.,
ACCEPTED MANUSCRIPT or symptoms Used for the treatment of TB or symptoms Tubers are used for the treatment of TB or symptoms Used for the treatment of TB
Capparis tomentosa Lam.
Uganda
Caprifoliaceae
Maerua edulis (Gilg & Gilg-Ben.) DeWolf. Scabiosa albanensis R.A. Dyer
Caricaceae
Carica papaya L.
Caryophyllaceae
Silene undulata Aiton
Leaves and seeds are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
Celastraceae
Cassine papillosa (Hochst.) Kuntze
Used to cure TB-related symptoms
South Africa
Maytenus senegalensis (Lam.) Excell
Roots and root bark are used to cure TBrelated symptoms Leaf decoction is used in the treatment of TB
South Africa
Clusiaceae
Colchicaceae Combretaceae
Uganda
T P
I R
C S
Garcinia kola Heckel; Garcinia spp.
U N
A
D E
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South Africa South Africa, Uganda South Africa
Nigeria, Uganda, Kenya Nigeria
Anogeissus leiocarpus (DC.) Guill. & Perr.
Leaf decoction is used in the treatment of TB Roots boiled in water for drinking in the treatment of TB
Anogeissus schimperi Hochst. ex Hutch. & Dalziel
Bark socked or boiled in water to drink for the treatment of TB
Nigeria
Combretum apiculatum Sond.
Dried leaves boiled for drinking in the treatment of TB Leaves used in the treatment of TBrelated diseases or their symptoms Used in the treatment of TB-related symptoms Bark boiled in salted water for drinking in the treatment of TB
Nigeria
Gloriosa superba L.
T P
E C
C A
Combretum erythrophyllum (Burch) Sond. Combretum molle R. Br. Ex G. Don. Terminalia brownii Fresen.
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Nigeria
South Africa South Africa Nigeria
2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010; Greene et al., 2010) (Lawal et al., 2014) (Lall aand Meyer, 1999) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Faleyimu et al., 2009; Ofukwu et al., 2008) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Greene et al., 2010) (Lall aand Meyer, 1999) (Ofukwu et al., 2008)
ACCEPTED MANUSCRIPT Terminalia phanerophlebia Engl. & Diels Terminalia sericea Burch ex D.C. Asteraceae
Artemisia afra Jacq. ex Willd. Aspilia africana (Pers.) C. D. Adams
Roots are used for the treatment of TB
South Africa
Bark are used in the treatment of TBrelated diseases or their symptoms Used for the treatment of TB
South Africa
Roots are used for the treatment of TB and related symptoms Flowers or whole plant are used to treat TB
South Africa
I R
T P
Bidens pilosa L.
C S
Conyza ivifolia Burm.f.
Conyza sumatrensis (Retz.) E. Walker (syn. C. floribunda) Gutenbergia cordifolia Benth. ex Oliv. Helichrysum appendiculatum (L.f.) Less.
T P
D E
Helichrysum caespititium (DC.) Sond. ex Harv.
E C
Helichrysum imbricatum (L.) Less.
C A
Helichrysum krausii Sch.Bip.
Helichrysum leiopodium DC.
Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Leaves are used in the treatment of TB or related symptoms Roots and leaves are used for the treatment of TB and related symptoms Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Exudates are used against TB and related disorders, such as bronchopneumonial diseases, and symptoms such as cough, fever, blood in the sputum The tea and infusion are used as a demulcent in coughs and in pulmonary affections The smoke of dried flowers and seeds in a pipe is used for the relief of cough and as a remedy for TB Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum
A
U N
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13
Uganda
Uganda, Ghana, South Africa South Africa
Uganda Uganda South Africa
(Madikizela, 2014) (Greene et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Tabuti et al., 2010; Lawal et al., 2014) (Meyer et al., 2002) (Tabuti et al., 2010) (Tabuti et al., 2010) (Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
South Africa
(Meyer et al., 2002)
ACCEPTED MANUSCRIPT Helichrysum melanacme DC. Helichrysum nudifolium (L.) Less.
Helichrysum odoratissimum (L.) Sweet Microglossa pyrifolia (Lam.) Kuntze Nidorella anomala Steetz.
Senecio serratuloides DC. var. serratuloides Vernonia amygdalina Delile
D E
T P
Ipomoea batatas (L.) Lam.
U N
A
Vernonia woodii O.Hoffm.
E C
Ipomoea involucrata P.Beauv.
C A
South Africa South Africa
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Uganda, South Africa Uganda
T P
I R
C S
Nidorella auriculata DC.
Convolvulaceae
Used in the treatment of TB-related symptoms Tea and infusion are used as a demulcent in coughs and in pulmonary affections Leaves are used in the treatment of TBrelated symptoms Roots are used in the treatment of TBrelated symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Pounded fresh leaves fresh and squeezed for drinking are used in the treatment of TB-related symptoms. Root barks used to treat TB and asthma Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Peeling maceration is used in the treatment of TB Leaf infusion is used to cure TB
South Africa South Africa South Africa Nigeria, Uganda, Kenya South Africa
Nigeria Nigeria
Costaceae
Costus afer Ker Gawl.
Stem decoction and leaf infusion are used in the treatment of TB
Nigeria
Crassulaceae
Kalanchoe spp.
Leaves are used in the treatment of TBrelated symptoms Leaf infusion is used in the treatment of TB
Uganda
Bryophyllum pinnatum (Lam.) Oken
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Nigeria
(Lall aand Meyer, 1999) (Meyer et al., 2002) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lall aand Meyer, 1999) (Lall aand Meyer, 1999) (Lall aand Meyer, 1999) (Mariita, 2006; Ofukwu et al., 2008; Tabuti et al., 2010) (Meyer et al., 2002) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010)
(Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010)
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Momordica foetida Schum. Lagenaria sphaerica (Sond.) Naudin Momordica charantia L.
Cyperaceae
Cyperus articulatus L.
Roots are used in the treatment of TBrelated symptoms Roots are used in the treatment of TBrelated symptoms Leaves/bark are used in the treatment of TB-related diseases or their symptoms
C S
Cyperus rotundus L. ssp. rotundus Diospyros mespiliformis Hochst
U N
A
Euclea natalensis A. DC.
Uganda Kenya
T P Ghana
Uganda Uganda
South Africa
Used in the treatment of TB-related symptoms Roots are used in the treatment of TBrelated symptoms Bark is used in the treatment of TBrelated diseases or their symptoms Stem bark is used to treat TB, asthma, and coughs Leaves are used to treat TB
South Africa
Croton pseudopulchellus Pax
(Tabuti et al., 2010) (Tabuti et al., 2010) (Mariita, 2006) (Nguta etl al., 2015) (Tabuti et al., 2010) (Tabuti et al., 2010) (Greene et al., 2010)
Kenya
(Lall aand Meyer, 1999) (Tabuti et al., 2010) (Greene et al., 2010) (Mariita, 2006)
Kenya
(Mariita, 2006)
Used to treat TB-related symptoms
South Africa
Euphorbia scarlatica (L) O. Kuntz
Stems are used to treat common cold and TB
Kenya
(Lall aand Meyer, 1999) (Mariita, 2006)
Euphorbia schimperiana Scheele
Leaves are used in the treatment of TBrelated symptoms Stems are used to treat TB and asthma Roots are used in the treatment of TB-
Uganda
Euclea divinorum Hiern. Euphorbiaceae
Uganda
I R
Cyperus latifolius Poir.
Ebanaceae
Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Whole plant is used to treat asthma, TB, and pneumonia Roots are used to treat TB
D E
Bridelia micrantha (Hochst.) Baill.
T P
Croton macrostachyus Hochst. ex Ferret et Galinier Croton megalocarpus Hutch.
E C
C A
Euphorbia tirucalli L. Tragia brevipes Pax
M
15
Uganda South Africa
Kenya Uganda
(Tabuti et al., 2010) (Mariita, 2006) (Tabuti et al.,
ACCEPTED MANUSCRIPT related symptoms Tragia subsessilis Pax Geraniaceae
Pelargonium sidoides DC. Pelargonium reniforme Curtis
Gunneraceae
Gunnera perpensa L.
Hypoxidaceae
Hypoxis argentea Harv. ex Baker
Hypericaceae
Hypericum revolutum Vahl
Iridaceae
Zygotritonia bongensis (Pax) Mildbr
Lamiaceae
Achyrospermum carvalhoi Gürke
T P
E C
C A
Leonotis nepetifolia (L.) R. Br. Mentha longifolia (L.) L. Ocimum gratissimum L.
Uganda
Roots are used in the treatment of coughs and tuberculosis Used in the treatment of TB-related symptoms Used for the treatment of TB
T P
South Africa South Africa
I R
C S
Used for the treatment of TB or symptoms Bulb tincture is used to cure TB
U N
South Africa South Africa Uganda Nigeria
Leaves are used in the treatment of TBrelated symptoms Leaf decoction is used in the treatment of TB Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Leaves and stem (wood) are used in the treatment of TB-related symptoms Leaves and stems are used in the treatment of colds, coughs, bronchitis, asthma and TB Leaves are used in the treatment of TBrelated symptoms Used for the treatment of TB
Uganda
Bulb is boiled in water for drinking and used in the treatment of TB-related symptoms.
Nigeria
D E
Iboza multiflora (Benth.) E. A. Bruce
Leonotis intermedia Lindl.
Roots are used in the treatment of TBrelated symptoms Roots are used to treat coughs and TB
A
Clerodendrum capitatum (Willd.) Schum. & Thonn Hoslundia opposita Vahl
Iboza riparia (Hochst.) N. E. Br.
2010)
M
16
Nigeria Uganda Uganda Uganda South Africa
Uganda South Africa
(Tabuti et al., 2010) (Mativandlela et al., 2006) (Mativandlela et al., 2006) (Lall aand Meyer, 1999) (Lawal et al., 2014) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Madikizela, 2014) (Tabuti et al., 2010) (Lawal et al., 2014) (Ofukwu et al., 2008; Ogbole and Ajaiyeoba,
ACCEPTED MANUSCRIPT
Rosmarinus officinalis L.
Leaf tincture is used in the treatment of TB Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TBrelated symptoms Used for the treatment of TB
Cryptocarya latifolia Sond.
Used to cure TB-related symptoms
Persea americana Mill.
Leaves, stem (wood) and seeds are used in the treatment of TB-related symptoms
Abrus precatorius L.
Leaves and roots are used to treat TB, bronchitis, whooping cough, chest complaints and asthma. Seed decoction is used in TB treatment Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Stem bark, stem (wood) and fruits are used in the treatment of TB-related symptoms Used for the treatment of TB
South Africa, Nigeria
Stem bark is used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Stem bark is used in the treatment of TB-related symptoms
Uganda
Ocimum suave Willd. Plectranthus barbatus Andr. Pycnostachys erici-rosenii R.E.Fr.
Lauraceae
Leguminosae (Fabaceae)
D E
T P
Acacia hebecladoides Harms Acacia hockii De Wild.
U N
A
E C
C A
Acacia karroo Hayne
Acacia mearnsii De Wild. Acacia nilotica (L.) Delile Acacia polyacantha Willd.
M
17
Uganda Uganda
T P
I R
C S
Acacia albida Delile
2010)
Uganda
South Africa South Africa Uganda
Nigeria Nigeria Uganda
South Africa
Nigeria Uganda
(Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Lall aand Meyer, 1999) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Madikizela, 2014) (Faleyimu et al., 2009) (Faleyimu et al., 2009) (Tabuti et al., 2010; Orodho et al., 2014) (Lawal et al., 2014) (Tabuti et al., 2010) (Faleyimu et al., 2009) (Tabuti et al., 2010)
ACCEPTED MANUSCRIPT Acacia xanthophloea Benth.
Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Bark infusion is used to cure TB
Albizia coriaria Oliv. Baphia nitida Lodd. Cassia alata L.
South Africa Uganda Nigeria
Fairly dried leaves boiled for drinking in the treatment of TB-related symptoms Dried leaves boiled for drinking in the treatment of TB-related symptoms Bark is used in the treatment of TBrelated diseases or their symptoms Leaves are used for the treatment of TB symptoms and pulmonary infections
I R
T P
Cassia occidentalis L.
C S
Cassia petersiana Bolle Desmodium repandum (Vahl) DC.
U N
A
Nigeria Nigeria
South Africa Uganda
(Lall aand Meyer, 1999) (Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Greene et al., 2010) (Tabuti et al., 2010)
Entada abbysinica A.Rich.
Used in the treatment of TB-related symptoms
Kenya, Tanzania
(Orodho et al., 2014)
Erythrina abyssinica Lam. ex DC.
Root and stem barks are used for the treatment of TB symptoms and pulmonary infections
Uganda, Kenya, Tanzania
Roots are used in the treatment of TBrelated symptoms Leaf infusion is used in the treatment of TB Leaves are used in the treatment of TBrelated symptoms Roots are used in the treatment of TBrelated symptoms Bark is used in the treatment of TBrelated diseases or their symptoms
South Africa
(Mariita, 2006; Tabuti et al., 2010; Bunalema, 2010; Orodho et al., 2014) (Madikizela, 2014) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Greene et al., 2010)
Used in the treatment of TB-related symptoms
Nigeria
D E
T P
Indigofera arrecta Benth. ex Harv. & Sond. Lonchocarpus cyanescens (Schumach. & Thonn.) Benth. Mucuna pruriens (L.) DC.
E C
C A
Ormocarpum trichocarpum (Taub.)Harms Peltophorum africanum Sond Piliostigma reticulatum (DC.) Hochst.
M
18
Nigeria Uganda Uganda South Africa
(Faleyimu et al., 2009)
ACCEPTED MANUSCRIPT Piliostigma thonningii (Schumach.) Milne-Redh. Schotia brachypetala Sond Senna siamea (Lam.) Irwin & Barneby Tamarindus indica L.
Stem (wood) is used in the treatment of TB-related symptoms Bark used in the treatment of TB-related diseases or their symptoms Stem bark is used in the treatment of TB-related symptoms Leaves are used in the treatment of TBrelated symptoms
Uganda South Africa Uganda
I R
T P Uganda, Nigeria
Loranthaceae
Tapinanthus dodoneifolius (DC.) Danser
Leaves, Bark boiled in water for drinking in the treatment of TB
Malvaceae
Adansonia digitata L.
Dried leaves boiled in water for drinking 2 times for 24 days only in the treatment of TB Fresh leaves is boils in water for drinking and are used in the treatment of TB Roots are used in the treatment of TBrelated diseases or their symptoms Fruit infusion is used in the treatment of TB Leaf decoction is used in TB treatment
Nigeria
Leaf is used in the treatment of TB
Nigeria
Antherotoma senegambiensis (Guill. & Perr.) Jacq.-Fél. Dissotis rotundifolia (Sm.) Triana
Leaves are used in the treatment of TBrelated symptoms Leaves are used in the treatment of TB
Uganda
Azadirachta indica A. Juss.
Seeds, leaves, stem (wood) and stem bark are used in the treatment of TB
Ghana, Uganda
Ekebergia capensis Sparm.
Used in the treatment of TB-related symptoms
South Africa
C S
Ceiba pentandra (L.) Gaertn.
A
Grewia villosa Willd.
D E
Cola acuminata (P.Beauv.) Schott & Endl.
T P
Glyphaea brevis (Spreng.) Monach.
E C
Hibiscus sabdariffa L. Melastomataceae
Meliaceae
C A
U N
M
19
Nigeria
Nigeria
South Africa Nigeria Nigeria
Ghana
(Tabuti et al., 2010) (Greene et al., 2010) (Tabuti et al., 2010) (Faleyimu et al., 2009; Tabuti et al., 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008; Faleyimu et al., 2009) (Ofukwu et al., 2008) (Greene et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Nguta etl al., 2015) (Tabuti et al., 2010; Nguta etl al., 2015) (Lall aand Meyer, 1999)
ACCEPTED MANUSCRIPT Menispermaceae Moraceae
Jateorhiza macrantha (Hook.f.) Exell & Mendonça Ficus asperifolia Miq.
Leaf infusion is used in the treatment of TB Leaf maceration is used in TB treatment
Nigeria
Ficus platyphylla Delile
Stem bark, squeezed fresh leaves or boiled for drinking in the treatment of TB-related symptoms
Nigeria, Uganda, South Africa
Nigeria
I R
T P
Ficus sur Forssk
Bark and roots are used to treat TB and lung ulceration
Moringaceae
Moringa oleifera Lam.
Seeds are used in the treatment of TBrelated symptoms
Musaceae
C S
South Africa
Musa nana Lour.
U N
Uganda, Nigeria
Leaf meal is used in the treatment of TB
Myristicaceae
Pycnanthus angolensis (Welw.) Warb.
Bark maceration is used in TB treatment
Nigeria
Myrsinaceae
Maesa lanceolata Forssk.
Myrtaceae
Callistemon citrinus (Curtis) Skeels
D E
T P
E C
Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson Eucalyptus spp.
C A
Psidium guajava L. Syzygium cordatum Hochst. ex Krauss Olacaceae
Ximenia caffra Sond. var. caffra
A
M
Nigeria
Roots are used in the treatment of TBrelated symptoms
Uganda
Leaves are used in the treatment of TBrelated symptoms Used for the treatment of TB
Uganda
Leaves and stem bark are used in the treatment of TB-related symptoms
Uganda, Kenya, Tanzania Nigeria
Bark maceration is used in the treatment of TB Used for the treatment of TB Leaves are used in the treatment of TBrelated diseases or their symptoms 20
South Africa
South Africa South Africa
(Ogbole and Ajaiyeoba, 2010) (Hannan et al., 2011) (Ofukwu et al., 2008; Tabuti et al., 2010; Lawal et al., 2014) (Lawal et al., 2014) (Madikizela, 2014) (Faleyimu et al., 2009; Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010; Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Greene et al., 2010)
ACCEPTED MANUSCRIPT Orobanchaceae
Alectra sessiliflora (Vahl) Kuntz
Leaf infusion is used in TB treatment
Nigeria
Phyllanthaceae
Phyllanthus fraternus G.L. Webster
Leaves are used in the treatment of TB
Ghana
Piperaceae
Piper capense L.f.
South Africa
Poaceae
Coix lacryma-jobi L.
Roots used in the treatment of TBrelated diseases or their symptoms Glumes are used in the treatment of TB
Cymbopogon giganteus Chiov.
Leaves are used in the treatment of TB
Cymbopogon citratus (DC.) Stapf.
Leaf infusion is used in TB treatment
Nigeria
Polygala fruticosa P.J.Bergius
Whole plant is used in TB treatment
Polygala myrtifolia L.
U N
South Africa
Used in the treatment of TB-related symptoms Roots are used in the treatment of TBrelated diseases or their symptoms
South Africa
Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Bark/leaves are used in the treatment of TB-related diseases or their symptoms Leaves and stem (wood) are used in the treatment of TB-related diseases or their symptoms Bark, leaves and roots are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
South Africa
Leaves are used in the treatment of TBrelated diseases or their symptoms
Uganda
Polygalaceae
I R
T P
C S
Securidaca longipedunculata Fresen.
A
D E
Polygonaceae
Rumex crispus L.
Primulaceae
Rapanea melanophloeos (L.) Mez.
Rhamnaceae
Berchemia discolor (Klotzsch) Hemsl.
T P
E C
Rhamnus prinoides L’Herit.
C A
Ziziphus mucronata Willd.
Rosaceae
Prunus africana (Hook.f.) Kalkman
Rubiaceae
Coffea spp.
M
21
Ghana Ghana
South Africa, Uganda
South Africa South Africa Uganda
South Africa
South Africa
(Ogbole and Ajaiyeoba, 2010) (Nguta etl al., 2015) (Greene et al., 2010) (Nguta etl al., 2015) (Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Madikizela, 2014) (Lall aand Meyer, 1999) (Tabuti et al., 2010; Greene et al., 2010) (Lall aand Meyer, 1999) (Lall aand Meyer, 1999) (Greene et al., 2010) (Tabuti et al., 2010) (Greene et al., 2010; Lawal et al., 2014) (Lawal et al., 2014) (Tabuti et al., 2010)
ACCEPTED MANUSCRIPT Gardenia ternifolia Schumach. & Thonn. ssp. jovis-tonantis (Welw.) Hiern. Pentanisia prunelloides Schinz Rubia cordifolia L. Rubia petiolaris DC. Rutaceae
Uganda
(Tabuti et al., 2010)
Roots are used to treat TB and chest disorders Used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
South Africa
(Madikizela, 2014) (Orodho et al., 2014) (Lawal et al., 2014) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Mariita, 2006) (Madikizela, 2014; Orodho et al., 2014) (Mariita, 2006)
Used for the treatment of TB
Citrus medica L.
Fruit infusion is used in TB treatment
Clausena anisata (Willd.) Hook.f. ex Benth. Harrisonia abyssinica Oliv.
Used for the treatment of TB
E C
Toddalia asiatica (L.) Lam. Zanthoxylum chalybeum Engl.
C A
Zanthoxylum gillettii De Wild. Waterm. Dodonaea angustifolia L. f. Haplocoelum foliolosum (Heirn) Bullock Hippobromus pauciflorus Radlk.
U N
A
M
South Africa Nigeria Nigeria South Africa
Root bark is used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
Uganda
Leaves are used in the treatment of TBrelated diseases or their symptoms Roots are used to treat TB Roots are used in the treatment of TBrelated diseases or their symptoms
Uganda
Stem bark is used to treat TB and asthma Leaves are used in the treatment of TBrelated diseases or their symptoms Stem bark is used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB
Kenya
D E
T P
Teclea nobilis Del.
C S
Fruit infusion is used in TB treatment
Uganda, Kenya South Africa
T P
I R
Agathosma betulina (P.J.Bergius) Pillans Citrus aurantifolia (Christm.) Swingle
Ptaeroxylon obliquum (Thunb.) Radlk.
Sapindaceae
Roots are used in the treatment of TBrelated diseases or their symptoms
22
South Africa
Kenya Uganda, Kenya
Uganda Uganda South Africa
(Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014)
ACCEPTED MANUSCRIPT Sapotaceae
Vitellaria paradoxa C.F.Gaertn
Oil decoction is used in TB treatment
Nigeria
Solanaceae
Capsicum frutescens L.
Used for the treatment of TB
South Africa
Solanum incanum L.
Fruits are used in the treatment of TB symptoms and chest-related infections
Kenya
Solanum torvum Sw.
Unripe fruits/leaves are used to treat TB
Withania somnifera (L.) Dunal
Used for the treatment of TB
Clerodendrum myricoides (Hochst)Vatke Lantana trifolia L.
Roots are used to treat TB and chest disorders Leaves are used for the treatment of TB and related symptoms Leaves are used to treat TB, pneumonia, and chest pains Leaves are used to treat TB and cough Stem (wood), leaves and tubers are used in the treatment of TB-related diseases or their symptoms Tubers, leaves and stem (wood) are used in the treatment of TB-related diseases or their symptoms Leaves are used in the treatment of TB
Kenya
Verbenaceae
C S
Lantana camara L.
Vitaceae
Lantana trifolia L. Cyphostemma cyphopetalum (Fresen.) Desc. Ex Wild & Drumm.
E C
U N
A
D E
T P
Rhoicissus tridentata (L.f.) Wild & R.B.Drumm.
I R
M
T P Ghana
South Africa
Uganda Kenya
(Mariita, 2006) (Tabuti et al., 2010)
South Africa, Uganda
(Tabuti et al., 2010; Greene et al., 2010) (Nguta etl al., 2015) (Tabuti et al., 2010; Nguta etl al., 2015) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010)
Aloe vera var. barbadensis
Zingiberaceae
Zingiber officinale Roscoe
Rhizomes are used in TB treatment
Ghana, Uganda
Fruit tincture is used in TB treatment
Nigeria
Zygophyllaceae
Aframomum melegueta (Roscoe) K.Schum. Balanites aegyptiaca (L.) Delile
Stem bark and roots are used in the treatment of TB-related diseases or their symptoms
Uganda
23
(Tabuti et al., 2010) (Mariita, 2006)
Kenya Uganda
Xanthorrhoeaceae
C A
(Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Bunalema, 2010; Orodho et al., 2014) (Nguta etl al., 2015) (Lawal et al., 2014) (Mariita, 2006)
Ghana
ACCEPTED MANUSCRIPT 2.3. Medicinal plants used in Asian traditional medicine for the management of tuberculosis From Asian traditional medicine including Ayurveda, 84 plant species have been recorded, belonging to 44 plant families. The most represented families are Leguminosae (or Fabaceae, 8 species), Lamiaceae (6 species) and Compositae (4 species) (Table 2). The most cited species are
T P
Adhatoda vasica (5 occurences), Tinospora cordifolia (3 occurences), Allium sativum, Acalypha indica, Asparagus racemosus, Cedrus deodara,
I R
Pinus contorta, Piper longum, Rubus occidentalis, Aloe vera, Glycyrrhiza glabra, Vitex negundo and Vitex trifolia (2 occurences) (Table 2).
C S
Adhatoda vasica oil from leaves, roots and flowers significantly inhibited the growth of M. tuberculosis B19-4 at a concentration of 4 µg/mL
U N
(Gautam et al., 2012). As well, the anti-TB activity of Tinospora cordifolia, Allium sativum, Acalypha indica, Aloe vera, Vitex negundo and Vitex trifolia have been documented (Arya, 2011).
A
D E
M
Table 2. Common medicinal plants used in Asia for tuberculosis treatment.
Plant family
Botanical name
Acanthaceae
C A
E C
T P
Adhatoda vasica Nees
Mode of preparation/administration
Leaves, flowers and roots are used for the treatment of asthma, gasping cough, bronchitis, cold and TB. Leaf juice (30 ml) with honey removes mucus from lungs
24
Locations Ayurveda
References (Ayyanar and Ignacimuthu, 2008; Arya, 2011; Debnath et al., 2012; Gautam et al., 2012; Alvin et al., 2014;
ACCEPTED MANUSCRIPT Tewari et al., 2015)
Amaranthaceae Amaryllidaceae
Andrographis paniculata (Burm.f.) Nees Spinacia oleracea L.
Ground leaves with mortar and pestle, served with honey for TB treatment Leaf decoction is taken orally against weight loss and TB Bulbs are used for the treatment of asthma, cough, bronchitis and TB
T P
I R
Allium cepa L.
Bulbs are used for the treatment of asthma, cough, bronchitis and TB Decoction of bulbs is used orally to treat TB
C S
Allium sativum L.
Apiaceae
Centella asiatica (L.) Urb.
U N
Whole plant is used for leprosy, bronchitis, asthma and TB. Boiled water extract of ground plant (all aerial parts) is used for TB treatment
A
D E
Hemidesmus indicus R.Br Apocynaceae
Arecaceae
Root is used in Rasayana as adjuvant therapy for TB
T P
Tabernaemontana coronaria (L.) Willd.
E C
Borassus flabellifer L.
C A
Licuala spinosa Thunb.
Berberidaceae
Berberis aristata DC.
Boraginaceae
Heliotropium indicum L.
M
Leaves are used to treat TB Old cane jaggery is used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Leaves are used to treat TB Hydroalcoholic extract is used as part of 200 mg Liv600 capsule administer thrice a day as adjuvant therapy for TB (hepatoprotective properties) Leaves, flowers or roots decoctions to treat TB 25
Indonesia Iraq Ayurveda Iraq, Ayurveda
Ayurveda, Indonesia
Ayurveda Malaysia Ayurveda
Malaysia Ayurveda
Arabian Peninsula
(Ahmed, 2016) (Arya, 2011) (Arya, 2011; Viswanathan et al., 2014; Ahmed, 2016) (Ayyanar and Ignacimuthu, 2008; Alvin et al., 2014) (Samal, 2016) (Mohamad et al., 2011) (Samal, 2016)
(Mohamad et al., 2011) (Samal, 2016) (Saganuwan, 2010)
ACCEPTED MANUSCRIPT Brassicaceae
Nasturtium indicum (L.) DC.
Burseraceae
Commiphora mukul (Hook. ex Stocks) Engl.
Calophyllaceae
Boiled water extract of all aerial parts is used for TB treatment Used for centuries. Commercial products are promoted for use in TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Roots are used to treat TB
T P
Mesua ferrea L.
I R
Pseudostellaria heterophylla (Miq.) Pax Caryophyllaceae
Whole plant juice rich in vitamin C is used in treatment of weakness after illness, lung congestion and TB
A
Terminalia chebula Retz
Commelinaceae
Rhoeo spathacea (Sw.) Stearn
Eclipta prostrata L.
D E
T P
E C
Pluchea indica (L.) Less.
C A
Saussurea lappa (Decne.) Sch.Bip. Taraxacum officinale F.H. Wigg
Crassulaceae
U N
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months
Combretaceae
Compositae (Asteraceae)
C S
Stellaria rubra Scop.
Kalanchoe integra (Medik.) Kuntze Benincasa hispida (Thunb.) Cogn.
M
Boiled water leaf extract is used for TB treatment Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Boiled water leaf and root extracts are used for TB treatment Roots are used in Rasayana capsules as ½ part in adjuvant therapy for TB Leaf decoction is taken orally against TB Leaves are used in the treatment of TB Remedy against TB 26
Indonesia Ayurveda Ayurveda
Ayurveda
Ayurveda
Ayurveda
Indonesia Ayurveda
Indonesia Ayurveda Iraq Ayurveda Philippine
(Alvin et al., 2014) (Dhanabal et al., 2015) (Samal, 2016)
(Chandra and Rawat, 2015) (Chandra and Rawat, 2015) (Samal, 2016)
(Alvin et al., 2014) (Samal, 2016)
(Alvin et al., 2014) (Samal, 2016) (Ahmed, 2016) (Arya, 2011) (Batugal et al., 2004)
ACCEPTED MANUSCRIPT
Euphorbiaceae
Trichosanthes dioica Roxb.
Roots and fruits are used in the treatment of TB
Acalypha indica L.
Leaves are used as expectorant, diuretic, respiratory disease, pneumonia, asthma and TB
Jatropha curcas L.
Stem bark decoction (30-50 ml) is taken orally thrice a day for TB treatment
T P
I R
Mallotus philippensis (Lam.) Müll.Arg. Ricinus communis L.
Glandular trichomes and hairs of fruit are used in the treatment of TB
C S
Boiled water extract of leaves and roots are used for TB
Flacourtiaceae
Hydnocarpus anthelminthica Pierre ex Laness
Seeds are used against leprosy and TB
Gentianaceae
Canscora decussata (Roxb.) Schult. & Schult.f.
Roots are used in the treatment of TB
U N
A
M
Leaves, fruits and roots are used in the treatment of TB Colebrookea oppositifolia Sm.
Ocimum sanctum L.
T P
Lamiaceae
D E
E C
Vitex negundo L.
C A
Leaves, flowers and seeds are used in the treatment of TB
Cinnamomum cassia (Nees & T.Nees) J.Pres
Ayurveda
Ayurveda Indonesia Chinese Ayurveda
Ayurveda
Ayurveda
Ayurveda Leaves and seeds as well as a decoction of the stem bark is used to treat TB
Vitex trifolia L.
Lauraceae
Ayurveda Ayurveda
Leaves, roots and fruits are used in the treatment of TB. Boiled water extract of leaves is used for TB treatment
Powder of stem bark is used against cough and TB
27
Ayurveda, Indonesia
Iraq
(Arya, 2011) (Arya, 2011; Dhanabal et al., 2015) (Poonam and Singh, 2009) (Arya, 2011) (Alvin et al., 2014) (Wang et al., 2010) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012; Ahuja et al., 2015) (Batugal et al., 2004; Arya, 2011; Alvin et al., 2014) (Ahmed, 2016)
ACCEPTED MANUSCRIPT
Cinnamomum tamala (Buch.Ham.) T.Nees & Eberm.
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Leaves are used to treat cough, respiratory tract infections, bronchitis Leaves and flowers are used in the treatment of TB
T P
Cinnamomum zeylanicum Blume
I R
Acacia senegal (L.) Willd.
C S
Caesalpinia pulcherrima (L.) Sw. Caesalpinia sappan L.
Leguminosae (Fabaceae)
U N
Boiled water extract of chopped pieces is used for TB
Flemingia strobilifera (L.) W.T. Aiton
Leaves are used to treat respiratory diseases including symptoms of TB
Glycyrrhiza glabra L.
Roots to treat TB. Roots are used in Rasayana capsules as 1 parts in adjuvant therapy for TB
A
D E
T P
Mimosa pudica L.
Trigonella foenum-graecum L.
E C
M
(Samal, 2016)
Ayurveda
(Samal, 2016)
Ayurveda
(Gautam et al., 2012) (Arya, 2011)
Ayurveda Indonesia Malaysia Chinese, Ayurveda
Leaves and roots are used in the treatment of TB
Ayurveda
Oil, leaves, roots and seeds are used as cough suppressant, to treat asthma, pneumonias and TB
Arabian Peninsula Ayurveda
Liliaceae
Asparagus racemosus Willd.
Malvaceae
Hibiscus tilliaceus L.
Menispermaceae
Tinospora cordifolia (Willd.) Miers
Stem and leaves benefit the general weakness and TB. Used in Rasayana capsules as 1 parts in adjuvant therapy of TB
Tinospora crispa (L.) Miers ex
Leaves are used to treat TB
C A
Ayurveda
Roots are useful in TB, cough and bronchitis Boiled water extract of leaves is used for TB treatment
28
Indonesia Ayurveda
Malaysia
(Alvin et al., 2014) (Mohamad et al., 2011) (Namita and Mukesh, 2012; Samal, 2016) (Arya, 2011) (Saganuwan, 2010) (Nair, 1998; Warrier, 2002) (Alvin et al., 2014) (Dhanabal et al., 2015; Samal, 2016) (Mohamad
ACCEPTED MANUSCRIPT Hook. f. & Thoms.
et al., 2011) Ayurveda
(Poonam and Singh, 2009) (Samal, 2016)
Azadirachta indica Juss. A.
Leaf paste is used against TB, 1 tea spoon twice a day by oral route.
Ayurveda
Myristica fragrans Houtt.
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months
Myrtus communis L.
Fruits are used in the treatment of TB
Ayurveda
(Arya, 2011)
Myrtaceae
Ayurveda
Syzygium aromaticum (L.) Merr. & L.M.Perry
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months
(Samal, 2016)
Ophioglossaceae
Helmintostachys zeylanica (L.) Hook.
Used to treat TB
Philippines
(Batugal et al., 2004) (Samal, 2016) (Samal, 2016)
Meliaceae
Myristicaceae
T P
C S
Phyllanthus fraternus G.L. Webster
Piperaceae
D E
T P
M
Pericarp is used in Rasayana capsules as 1 parts in adjuvant therapy for TB Freshly prepared decoction of aerial parts is used as part of 10 mg and administered thrice a day as adjuvant therapy of TB
Emblica officinalis Gaertn.
Fruit juice is useful for cough, asthma and TB
Cedrus deodara Roxb.
Leaves are used in the treatment of TB
E C
Pinaceae
U N
A
Emblica officinalis Gaertn. Phyllanthaceae
I R
C A
Ayurveda Ayurveda
Ayurveda Ayurveda
Ayurveda
Pinus contorta Douglas. ex Loudon.
The inner bark to treat TB
Pinus pinea L.
Leaves, roots and stem are used to treat TB
Piper longum L.; Piper spp.
Fruit is used in Rasayana capsules as ½ parts in adjuvant therapy of TB 29
Arabian Pennisula Ayurveda
(Tewari et al., 2015) ( Nair, 1998; Warrier, 2002) (Nair, 1998; Warrier, 2002) (Saganuwan, 2010) (Arya, 2011; Samal,
ACCEPTED MANUSCRIPT
Plantaginaceae Poaceae
Polygonaceae
Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Fruits and leaves are used to treat TB, hemorrhage and pneumonia
Plantago major L. Imperata cylindrical (L.) Raeuschel Saccharum spontaneum L.
Rhizome decoction is used to treat TB To treat TB
Rumex hastatus D. Don
Root and bark are used in the treatment of TB
Ranunculus ternatus Thunb.
Roots are used alone or combined with other herbal remedies in the treatment of TB. Radix Ranunculi Ternati is now the only commercially available medicine for the treatment of TB Leaves, oil and flowers are used to treat TB and cough
D E
T P
E C
Ixora chinensis Lam.
C A
U N
A
Prunus amygdalus Batsch
Rubus occidentalis L.
Salicaceae
C S
Seeds, flowers and leaves are used to treat cough and TB
Prunus armeniaca L.
Rubiaceae
I R
Sorghum bicolor (L.) Moench
Ranunculaceae Rosaceae
T P
M
Kernels are used in the treatment of TB
Arabian Peninsula Philippine Philippine Arabian Peninsula Ayurveda
Remedy against incipient TB, hemorrhage and headache
(Zhang et al., 2015)
Arabian Pennisula Ayurveda
(Saganuwan, 2010) (Arya, 2011)
Ayurveda
(Nair, 1998; Warrier, 2002) (Batugal et al., 2004) (Arya, 2011; Tewari et al., 2015) (Alvin et al., 2014) (Arya, 2011)
Philippine Ayurveda
Leaves, roots and fruits are used in the treatment of TB
Morinda citrifolia L.
Boiled water extract of aerial parts are used for TB treatment Leaves, roots, bark and fruits are used in TB treatment
30
(Saganuwan, 2010) (Batugal et al., 2004) (Batugal et al., 2004) (Saganuwan, 2010) (Arya, 2011)
Chinese
A decoction of the roots is used in the treatment of TB
Morinda citrifolia L.
Flacourtia ramontchi L'Hér.
2016)
Indonesia Ayurveda
ACCEPTED MANUSCRIPT Simaroubaceae
Brucea javanica (L.) Merr.
Ground fruits with mortar and pestle for TB treatment
Solanum nigrum L. Solanaceae
T P
Withania somnifera L. Verbenaceae
Hydroalcoholic extract is used as part of 200 mg capsules Liv-600 administered thrice a day as adjuvant therapy of TB Root is used in Rasayana capsules as 1 parts in adjunct treatment of TB Boiled water extract of leaves and flowers are used for TB treatment Rhizome is used in Rasayana capsules as ¼ part in adjuvant therapy of TB Rhizome is used in Rasayana capsules as ½ part in adjuvant therapy of TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6-8 months Whole plant is used as remedy for common cold, bronchitis and TB
I R
Lantana camara L.
C S
Alpinia galanga (L.) Willd. Curcuma longa L. Zingiberaceae
U N
Indonesia Ayurveda
Ayurveda Indonesia Ayurveda Ayurveda Ayurveda
A
Elettaria cardamomum (L.) Maton Kaempferia galanga L.
D E
M
Philippine
(Alvin et al., 2014) (Samal, 2016) (Samal, 2016) (Alvin et al., 2014) (Samal, 2016) (Samal, 2016) (Samal, 2016)
(Batugal et al., 2004)
T P
E C
2.4. Medicinal plants used in South Pacific and American traditional medicine for the management of tuberculosis From American traditional medicine, which, in some cases, is a mixture of African and Asian knowledges, we recorded 52 plant species,
C A
belonging to 27 families, used to treat TB and related symptoms (Table 3). The most represented families are Compositae (12 species), Leguminosae (or Fabaceae, 5 species) and Lamiaceae (4 species) (Table 3). Most cited species is Chenopodium ambrosiodes L., whose anti-TB activity has been reported previously (Ahmad et al., 2016).
31
ACCEPTED MANUSCRIPT Table 3. Medicinal plants used against tuberculosis in Americas. Plant family
Botanical name
Mode of preparation/administration
Locations
References
Amaranthaceae
Chenopodium ambrosiodes L.
Brazil, Amazonia
Aspidosperma carapanauba Pichon.
1 bunch of fresh leaves in 500 ml water as juice/syrup/condensed milk/tea, daily dosage 200/400 ml, for the treatment of lung problems, cough and TB Used in the treatment of TB-related symptoms
Parahancornia amapa (Huber) Ducke
Used in the treatment of TB-related symptoms
Amazonia
Aspidosperma carapanauba Pichon
Used in the treatment of TB-related symptoms
Amazonia
Aloe arborescens Mill.
Syrup and juice are indicated for the treatment of lung problems, cough and TB
Brazil
(Storey and Salem,1997; Leitão et al., 2013) (Storey and Salem,1997) (Storey and Salem,1997) (Storey and Salem,1997) (Leitão et al., 2013)
Leaves and gel from leaves are used in the treatment of TB. Hydroalcoholic extract as parts of 200 mg capsule Liv-600 administered thrice a day as adjuvant therapy for TB Stem bark is used in treating TB
Ayurveda
(Arya, 2011; Samal, 2016)
South Pacific Amazonia
(WHO,1998)
Apocynaceae
Asphodelaceae
T P
I R
C S
U N
A
D E
Aloe vera (L.) Burm.f.
Barringtoniaceae Bignoniaceae
T P
Barringtonia asiatica (L.) Kurz
E C
Arrabidaea chica (H.B.K.) Verlot.
M
Used in the treatment of TB-related symptoms
Amazonia
(Storey and Salem,1997) (Leitão et al., 2013)
Brassicaceae
Nasturtium officinale R. Br
Syrup and juice are indicated for the treatment of lung problems, cough and TB
Brazil
Combretaceae
Terminalia catappa L.
Leaves are used to treat bronchitis and TB
Tahiti
(WHO,1998)
Compositae
Artemisia spp.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Bidens pilosa L.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
C A
32
ACCEPTED MANUSCRIPT Elephantopus mollis Kunth.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Heterocondylus alatus (Vell.) R.M.King and H.Rob.
Tea and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Hypochaeris brasiliensis (Less.) Hook. and Arn.
Tea and juice are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Mikania laevigata Sch. Bip. ex Baker
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Solidago chilensis Meyen
Juice is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Vernonia phaeoneura Toledo
Juice is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Vernonia polyanthes Less.
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Syrup is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Tea and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
A handful of fresh leaves and flowers in 500 ml water as juice/condensed milk, daily dosage ad libitum Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Amazonia
(Storey and Salem,1997)
Amazonia Brazil
South Pacific South Pacific
(Storey and Salem,1997; Leitão et al., 2013) (WHO,1998)
U N
A
D E
T P
E C
Spilanthes acmella (L.) L. Crassulaceae
I R
C S
Vernonia westiniana Less. Vernonia spp.
T P
C A
Kalanchoe brasiliensis Cambess.
M
Euphorbiaceae
Euphorbia fidjiana Boiss.
Leaf is used in treating TB
Goodeniaceae
Scaevola taccada (Gaertner) Roxb.
Leaves, stem bark and roots are used to treat coughs and TB 33
(WHO,1998)
ACCEPTED MANUSCRIPT Lamiaceae
Leguminosae (Fabaceae)
Mentha pulegium L.
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Mentha x piperita L.
Tea is indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Ocimum campechianum Mill.
Used in the treatment of TB-related symptoms
Brazil
(Leitão et al., 2013)
Ocimum gratissimum L.
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Hymenaea spp.
Tea and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Acacia cochliacantha Humb. & Bonpl. ex Willd.
Shoots are used to treat TB and cold
Mexico
Bowdichia virgilioides Η.Β.Κ.
Used in the treatment of TB-related symptoms
Amazonia
Used in the treatment of TB-related symptoms
Amazonia
2 dry pods in 1 liter water as infusion/tea, daily dosage ad libitum Syrup are indicated for the treatment of lung problems, cough and TB
Amazonia
(CoronadoAceves et al., 2016) (Storey and Salem,1997) (Storey and Salem,1997) (Storey and Salem,1997) (Leitão et al., 2013)
T P
I R
D E
Hymenaea courbaril L. Caesalpinia ferrea Mart. Loranthaceae
T P
Struthanthus concinnus Mart.
E C
C S
U N
A
M
Brazil
Struthanthus marginatus (Desr.) G. Don
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
(Leitão et al., 2013)
Lythraceae
Punica granatum L.
Amazonia
Malvaceae
Hibiscus tiliaceus L. var. tiliaceus
Treatment of TB, pulmonary diseases or symptoms of these disorders Stem bark is used to prepare a remedy against cough which is also used for TB. Leaves are used in treating cough, sore throat and open wounds In the Solomon Islands, parts of the plant are used in treating cuts, TB and conjunctivitis.
(Storey and Salem,1997) (WHO,1998)
C A
34
South Pacific
ACCEPTED MANUSCRIPT In New Guinea, the bark is used to make a cough remedy which is also used for TB Syrup is indicated for the treatment of lung problems, cough and TB
Malva spp.
Brazil
(Leitão et al., 2013) (Storey and Salem,1997) (CoronadoAceves et al., 2016) (WHO,1998)
Meliaceae
Carapa guianensis Aubl.
Used in the treatment of TB-related symptoms
Amazonia
Myrtaceae
Eucalyptus camaldulensis Dehnh.
Leaves are used to treat TB, bronchitis and cough
Mexico
Syzygium malaccense (L.) Merr. & Perry
Leaves are used to treat bronchitis and TB. Stem bark infusion is used to treat TB and digestive tract problems. Tea is indicated for the treatment of lung problems, cough and TB
South Pacific
Eugenia uniflora L.
T P
I R
C S
U N
A
Orbiaceae
Bischofia javanica Blume
The cambium of the plant is used to treat TB
Piperaceae
Potomorphe peltata ( L ) Miq.
Used in the treatment of TB-related symptoms
Poaceae
Cymbopogon citratus (DC.) Stapf
Rhamnaceae
Ampelozizyphus amazonicus Ducke.
Rubiaceae
Morinda citrifolia L.
Rutaceae
D E
T P
E C
C A
Citrus limon (L.) Osbeck Citrus aurantium L.
M
Brazil
(Leitão et al., 2013)
South Pacific Amazonia
(WHO,1998)
Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB
Brazil
Used in the treatment of TB-related symptoms
Amazonia
Liquid pressed from young fruit is used in the treatment of TB. Used for the treatment of TB, pulmonary disease or symptoms of these diseases Indicated for the treatment of lung problems, cough and TB
South Pacific South Pacific Brazil South Pacific South Pacific
Solanaceae
Capsicum frutescens L.
Used as a remedy for TB
Urticaceae
Dendrocnide harveyi (Seemann) Chew
A preparation made from scrapings of the stem bark is used in treating illnesses described as pain in the lungs with vomiting 35
(Storey and Salem,1997) (Leitão et al., 2013) (Storey and Salem,1997) (WHO,1998) (WHO,1998) (Leitão et al., 2013) (WHO,1998) (WHO,1998)
ACCEPTED MANUSCRIPT of blood (TB) Zingiberaceae
Used in the treatment of TB-related symptoms
Zingiber officinale Roscoe.
Amazonia
(Storey and Salem,1997)
T P
To summarize, most of plant species belongs to Leguminosae (Fabaceae) and Compositae families. Amongst all the identified species, only few
I R
are shared across continents. Allium cepa, Allium sativum, Aloe vera, Azadirachta indica, Lantana camara, Centella asiatica and Withania somnifera were recorded in Asia and Africa (Fig. 1). On the other hand, Bidens pilosa, Capsicum frutescens, Chenopodium ambrosiodes, Hibiscus
C S
tiliaceus, Cymbopogon citratus and Zingiber officinale were recorded in South Pacific-Americas and Africa, while only Morinda citrifolia was
U N
identified both in Asia and South Pacific-Americas (Fig. 1). In general, very little uniformity has been observed in the plants mentioned,
A
highlighting the low consensus regarding TB remedies among the different traditional healing systems. This is likely due to the poor
M
experimentation or evidence of efficacy for TB treatment, as well as the limited availability and accessibility of some endangered medicinal
D E
species.
T P
E C
C A
36
ACCEPTED MANUSCRIPT
T P
Africa 6
222
South PacificAmericas
I R
52
0
C S
1
7
U N
Asia
A
84
D E
M
Fig. 1. Distribution of medicinal plants identified in the traditional treatment of tuberculosis across continents.
T P
E C
C A
37
ACCEPTED MANUSCRIPT 3. Targeting multidrug resistance in tuberculosis: management with phytochemicals and medicinal plants
3.1. Impact of MDR- and XDR-TB on public health Despite significant advances in treating the disease, tuberculosis continues to be a serious global
IP
T
health threat, with over 10.4 million cases, and 1.8 million deaths reported in 2015 (Smith et al., 2004; WHO, 2015; Nguyen, 2016; WHO, 2016). Mycobacterium tuberculosis (MTb), the etiologic agent of
CR
tuberculosis, is now considered one of the most successful pathogens among those causing infectious
US
diseases, and the incidence of MTb infections is on the rise globally due, in part, to the advent of HIV/AIDS. The continued prevalence of MTb is due to the fact that this pathogen has an innate ability to
AN
survive host defense mechanisms, as well as the lack of new therapies, the inappropriate use of anti-TB drugs, disease states that complicate treatment such as diabetes mellitus and HIV, as well as the
M
emergence of multi-drug resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains (WHO,
ED
2015).
Over the last two decades, there has been a focus on the research and development of novel
PT
therapies for TB and several drugs have been evaluated in clinical trials (WHO, 2016). However, the number of effective drugs for TB is still very small, and treatment is complicated and very lengthy,
CE
leading to patient non-compliance and an increase in drug resistance. Over the past 40 years, the
AC
resistance of MTb has moved from mono-drug to multidrug resistance (MDR), extensively drug resistant (XDR), and eventually totally drug resistant (TDR), through sequential accumulation of resistance mutations as reported by Nguyen et al., (2016). MDR-TB strains are resistant to both isoniazid and rifampicin, and these strains were responsible for over 480,000 reported cases and approximately 210,000 deaths in 2013(Nguyen, 2016). Extensively drug-resistant (XDR) MTb strains are also resistant to the quinolones and other second-line drugs and have been reported in at least 100 countries (WHO, 2015). The morbidity of XDR is 40-50% and poses a serious public health threat, especially in areas with high HIV prevalence. Antibiotic resistance of MTb strains continues to be a serious global health threat as 38
ACCEPTED MANUSCRIPT some clinical strains have developed the means to evade all available antibiotics (Adhvaryu and Vakharia, 2011; Mishra et al., 2015; WHO, 2016). As a consequence, there is an urgent need to develop novel anti-tuberculosis agents, particularly adjunct treatments that may be used to reverse antibiotic resistance, treat MDR- and XDR-TB, and to
T
enhance the immune system to improve MTb recovery rates. In addition, most of the anti-TB drugs
IP
currently target metabolic reactions and proteins that are critical for the proliferation of M. tuberculosis
CR
(Adhvaryu and Vakharia, 2011). Future studies should focus on research and development of new drugs based on novel molecular targets related to the establishment of mycobacterial dormancy in human
US
macrophages or inhibition of bacterial virulence factors that interfere with the signaling pathways of host
3.2. Natural products for MDR- and XDR-TB
AN
cells and affect immunity, leading to the persistence of the disease (Koul et al., 2011).
M
Medicinal plants have been used since the beginning of time to treat all diseases, including
ED
infectious diseases, and have been excellent leads for the development of new drugs. In fact, over the past 25 years, almost 50% of new drugs reviewed and approved by the US Food and Drug Administration
PT
have been derivatives of natural products (Newman and Cragg, 2007; Kinghorn et al., 2011; Cragg and
CE
Newman, 2013; Atanasov et al., 2015). Reviews of recently published scientific literature show that there are more than 350 species of plants used for the treatment of TB, from countries around the world, and
AC
many naturally occurring compounds have been isolated and identified with activity against MTb, MDRTB and XDR-TB (Camacho‐Corona et al., 2008; Samad et al., 2008). The following is an overview of some of the classes of natural products showing some promising activity against MDR- and XDR-TB.
3.3. Bisbenzylisoquinolone alkaloids In a study by Sureram et al. (2012) bisbenzylisoquinoline alkaloids including tiliacorinine, 20nortiliacorinine and tiliacorine isolated from roots of the edible plant Tiliacora triandra, as well as one synthetic derivative, 130-bromotiliacorinine, were active against MDR-TB strains. The 59 strains of M. 39
ACCEPTED MANUSCRIPT tuberculosis included 12 isolates resistant to isoniazid (INH) and rifampin (RMP); five isolates resistant to INH, RMP, and ethambutol (EMB); 23 isolates resistant to INH, RMP, and streptomycin (SM); nine isolates resistant to INH, RMP, EMB, and SM; one isolate resistant to INH, RMP, EMB, and ofloxacin (OFX); one isolate resistant to INH, RMP, SM, and OFX; and eight isolates resistant to INH, RMP, EMB,
T
SM, and OFX. The results of this study showed that tiliacorinine, 20-nortiliacorinine, tiliacorine, and 130-
IP
bromotiliacorinine were active against MDR-MTB strains with median inhibitory concentration (MIC)s
CR
ranging from 0.7 to 6.2 µg/mL. Cytotoxicity in normal MRC-5 (human fetal lung fibroblast) cell line was also determined. The alkaloids were cytotoxic in this cell line with median inhibitory concentration (IC50)
US
of 3.13-20.0 µg/mL (Sureram et al., 2012).
AN
3.4. Cinnamic acid derivatives
M
In a 2011 study by Lakshmanan et al., (2012) a compound isolated from the rhizomes of Kaempferia galanga and identified as ethyl p-methoxycinnamate (EPMC) was tested against MTb strains.
ED
Antimycobacterial activity of EPMC was evaluated in MTb strains H37Ra (ATCC 25177) and H37Rv
PT
(ATCC 25618). Eight MTb clinical isolates, six of which from patients with MDR-TB, were obtained from the Swedish National Strain Collection at the Swedish Institute for Infectious Disease Control
CE
(SMI), Solna, Sweden. The results of this study showed that EPMC inhibited the growth of all MTb strains tested, with a MIC of 0.485 mM. Four strains, irrespective of their drug resistance profiles (fully
AC
susceptible or MDR), were inhibited at 0.242 mM. EPMC toxicity was also tested on the human macrophage cell line THP-1 cells. An IC50 value of 3.8 mM was reported, indicating that EPMC was not toxic to macrophage cells at concentrations that could inhibit M. tuberculosis (Lakshmananet al., 2011). Interestingly, the study also showed that the MDR strains did not exhibit higher MIC value than the susceptible ones, suggesting that the mechanism of action may be different from the target of any of the current anti-TB drugs (Lakshmananet al., 2011).
40
ACCEPTED MANUSCRIPT 3.5. Fungal metabolites Ganihigama et al. (2015) evaluated the anti-MTb activity of 27 naturally occurring compounds from fungi against MDR-TB isolates. Many of these natural products included anthraquinones, diterpenoids, alkaloids and flavonoids. The fungal metabolites were tested against a non-virulent H37Ra
T
strain of M. tuberculosis and showed MIC values ranging from 3.1 µg/mL to > 100µg/mL. Among the
IP
compounds tested, vermelhotin exhibited activity with MIC of 3.1 mg/mL (Ganihigama et al., 2015).
CR
Vermelhotin, a tetramic acid isolated from an unidentified marine fungus (CRI247-01) demonstrated antimycobacterial activity towards five reference strains (MIC 3.1 - 6.2 µg/mL) and exhibited activity
US
against the MDR-TB strains with MIC ranging between 1.5 µg/mL and 12.5 µg/mL (Ganihigama et al., 2015). Unfortunately, this compound was also cytotoxic in normal cells, MRC-5 cell line (human lung
AN
fibroblast cells), with IC50 value of 6.97 µg/mL.
M
3.6. Iridoids
ED
Plants used in the Ayurvedic system of medicine containing iridoids, terpenes and other compounds have been shown to exert anti-MTb activities (Kumar et al., 2013). In one study on tree bark
PT
from Plumeria bicolor, a plant from India commonly known as Champa, several iridoids have been
CE
isolated and identified (Kumar et al., 2013). A methanol extract of the dried bark of P. bicolor, plumericin and isoplumericin were tested against susceptible MTb and four MDR-TB strains (Kumar et al.,
AC
2013).The extract showed a MIC between 20-25 µg/mL for all strains tested. Plumericin was very active against all strains with a MIC between 1.3 and 2.1 µg/mL, with higher activity against the MDR strains. Isoplumericin was also active with MICs between 2.0-2.6 µg/mL for all strains tested. No cytotoxicity was reported for other cell lines.
3.7 Marine natural products New interesting marine natural products have also been discovered with relevant activity against MTb and MDR-TB. From marine Streptomyces spp., cyclomarin A, a novel anti-inflammatory cyclic 41
ACCEPTED MANUSCRIPT peptide, was isolated and showed high activity against MTb with MIC of 0.3 µg/mL (Lee and Suh, 2016). The MIC90 of the drug was 2.5 μM after 5 days of treatment, suggesting a high efficacy within short treatment times. The occurrence of anti-mycobacterial metabolites from marine invertebrates, namely sponges, corals and gorgonians has been recently investigated (Daletos et al., 2016; Sansinenea and Ortiz,
T
2016). The compound (–)-8,15-diisocyano-11(20)-amphilectene, a diterpene isolated from the Carribean
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sponge Svenzea flava, showed a promising activity with MIC value of 3.2 µg/mL; the calculated
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selectivity index (SI; i.e., IC50/MIC) of compound was equal to 10.2, suggesting that amphilectane-type diterpenes are important anti-tuberculosis pharmacophores (Nieves et al., 2016). Agelasines, purine
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diterpenes isolated from Agelasidae (Agelas spp.) marine sponges, were found to exhibit biological activity against the dormant state of MTb, which plays an important role in latent tuberculosis infection
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(Arai et al., 2014). Very recently, three haliclocyclamines, dimeric 3-alkyl piridinium alkaloids isolated from the Indonesian marine sponge Haliclona spp., showed a dose-dependent anti-mycobacterial activity,
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with the highest inhibition zone (10 mm) at 5 µg/disc (Maarisit et al., 2017).
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3.8. Peptides
Anti-mycobacterial peptides have been recently reviewed (Silva et al., 2016; Dong et al., 2017),
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though they have been investigating since many decades. In the 1960’s, a cyclic peptide named
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griselimycin (GM) was discovered from Streptomyces spp.; it was effective against MTb, though its pharmacokinetic properties were poor (Holzgrabe, 2015). In 2015, Rolf Müller and colleagues retested GM after they increased the metabolic stability of the peptide by alkylating a proline residue in position 8. A novel metabolically stable cyclohexyl derivative was obtained with improved penetration of the mycobacterial cell wall, with a MIC of 0.06 μg/mL. The activity against MDR-TB was similar. Investigation on the mechanism of action showed that there was an amplification of the dnaN gene. This gene encodes for DnaN, a DNA polymerase sliding clamp that anchors the DNA to DNA polymerase, thus enhancing the replicatory strength of the enzyme and accelerating DNA replication and repair in 42
ACCEPTED MANUSCRIPT prokaryotes. DnaN is a molecular target of GM, and GM derivatives appear to bind to a hydrophobic pocket of the DNA polymerase sliding clamp, making it an extremely novel mechanism of action (Lee and Suh, 2016). Lassomycin, a peptide composed of 16 amino acids, was identified from Lentzea kentuckyensis IO0009804, another actinomycete. This peptide had activity against MDR and XDR MTb, with MICs
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ranging from 0.41 to 1.65 μM (Lee and Suh, 2016). Another peptide named ecumicin, produced by Nonomuraea spp. MJM5123 and composed of 13 amino acids, also showed promising anti-TB activity
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against MDR and XDR MTb, with MIC values ranging from 0.16 to 0.62 μM. The minimal bactericidal
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concentration (MBC) was 1.5 μM (Lee and Suh, 2016).
Sansanmycins are members of uridylpeptide family produced by the soil bacterium Streptomyces
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spp. These uridylpeptides are potents and selective anti-mycobacterials involved in inhibition of peptidoglycan biosynthesis (Tran et al., 2016). Teixobactin is a recently discovered anti-mycobacterial
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peptide isolated from Eleftheria terrae, a soil microorganism. The mechanism of action was identified as
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inhibition of peptidoglycan biosynthesis, though, noteworthy, teixobactin-resistant strains of M.
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3.9. Quinones and terpenes
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tuberculosis could not be generated (Ling et al., 2015).
In 2016, Jyoti et al. reported the effects of an extract of Artemisia capillaris on the in vitro
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susceptibility of MTb. This plant is native to Central and Southeast Asia, particularly Korea, and is used as an antimicrobial agent. Two compounds from this extract were identified as active against MTb strains using bioassay-guided fractionation, ursolic acid (UA) and hydroquinone (HQ), with a MIC of 12.5 μg/mL against the susceptible strains, and of 12.5-25 μg/mL against MDR/XDR strains. This group also investigated the mechanism by which UA may exert its anti-MTb activity (Jyoti et al., 2016). In strain MTb H37Ra, UA decreased mycolic acid biosynthesis in a dose-dependent manner as determined by quantitative LC/MS/MS. This compound is a branched long-chain fatty acid that makes up to 60% of the outer cell wall of Mycobacterium. By inhibiting biosynthesis of mycolytic acid the bacterial cell wall 43
ACCEPTED MANUSCRIPT cannot be formed and this causes Mycobacterium cell death. Electron microscopy further confirmed that UA had effects on both the cell wall and the intracellular content of H37Ra (Jyoti et al., 2015). In 2013, Metha et al. showed that extracts of Citrullus colocynthis (L.) Schrad. (Cucurbitaceae), known commonly as bitter apple, a medicinal plant from India used to treat bacterial infections, including tuberculosis and other respiratory diseases, had activity against MTb (Mehta et al., 2013). In this study, a
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methanol extract of the ripe fruits exhibited activity against MTb strains with a MIC ≤ 62.5 µg/ml. One
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fraction (FC III) of this extract showed a MIC of 31.2 µg/mL against strain MTb H37Rv, and other fractions also inhibited 16 clinical isolates of MTb, including 7 wild type, 8 MDR-TB, 1 XTB and 2 non-
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TB Mycobacterium strains with MICs in the range of 50-125, 31.2-125 and 62.5-125 µg/mL, respectively. Interestingly, the active compound identified from fraction FC III was UA, though other terpenes were
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also identified as cucurbitacin E 2-O-β-D-glucopyranoside and cucurbitacin I 2-O-β-D-glucopyranoside from fraction FC IX. Ursolic acid and cucurbitacin E 2-O-β-D-glucopyranoside were identified as the
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main chemical constituents active against MTb H37Rv (MICs 50 and 25 µg/ml, respectively), as well as
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against the clinical isolates (Mehta et al., 2013).
In a publication by Uc-Cachón et al. (2014), naphthoquinones with anti-MTb activity were
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isolated from Diospyros anisandra, a native plant from the Yucatan peninsula used in traditional Mayan
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medicine. These compounds have a naphthalene skeleton substituted by ketone groups in positions C1 and C2 (1,2-naphthoquinones) or positions C1 and C4 (1,4-naphthoquinones), and are found as
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monomers, dimers, trimers or tetramers (Uc-Cachón et al., 2014). Naphthoquinones have a wide variety of biological activities, including antibacterial, antifungal, antiparasitic, antiviral, antiinflammatory and cytotoxic effects. In this study, stem bark extracts of Diospyros anisandra were active against MTb strains, and 3 monomeric and 5 dimeric naphthoquinones were isolated, identified and tested. Plumbagin and its dimers maritinone and 3,30-biplumbagin showed the highest activity against both susceptible and MDR-TB strains with a MIC of 1.56-3.33 mg/mL. Only maritinone and 3,30-biplumbagin showed no toxicity against normal eukaryotic cells, and had 32 times more activity against MDR-TB strains. In terms of mechanism of action, it has been shown that naphthoquinones can target the electron transport chain of 44
ACCEPTED MANUSCRIPT Mycobacterium because they are structurally similar to menaquinone. In addition, they also may inhibit menaquinone biosynthesis thereby interfering with electron transport and cellular respiration (Uc-Cachón et al., 2013).
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4. Case study: traditional Chinese medicine In traditional Chinese medicine (TCM), many herbal formulas have been used as adjunctive
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therapy, along with conventional TB chemotherapy, to manage MDR-TB. Some clinical trials have
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shown that various TCM herbal formulas can enhance the immune system, reduce adverse events observed with conventional TB chemotherapy, improve the overall quality of life, and decrease the level
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of MTb in sputum culture (Jiang et al., 2015). One systematic review and meta-analysis analyzed 20 clinical trials involving 1823 TB patients from China (Jiang et al., 2015). This review concluded that
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adjunct therapy with TCM herbal formulas and TB chemotherapy significantly (p < 0.001) enhanced the
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treatment success and improved radiological findings. However, subjects who received TCM herbals in combination with chemotherapy had similar relapse rates; though the incidence of adverse events was
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lower (Jiang et al., 2015). These data suggest that TCM herbal medicines may improve the overall treatment and recovery of TB.
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A second systematic review and meta-analysis assessed the effects of TCMs in combination with
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TB chemotherapy in 30 randomized clinical trials (RCTs) involving 3374 participants with a diagnosis of MDR-TB (Wang et al., 2015). This review concluded that the quality of the clinical trials in the analysis was generally poor in terms of risk of bias. It further suggested again that TCM plus chemotherapy was more effective on the conversion rate of sputum as compared with chemotherapy alone. The study showed that, when compared with chemotherapy only, a benefit in MDR-TB patients was observed on the rate of reduction of lung lesions (in 7 studies), cavity closure rate (5 studies), reduced relapse rate (4 studies) and reduced abnormal liver function tests (14 studies) when TCM plus chemotherapy was used.
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ACCEPTED MANUSCRIPT No serious adverse event was reported in any of the study. The authors further suggested that, considering the positive results, further robust clinical trials are warranted (Wang et al., 2015). Beyond the clinical trials, one rodent study by Lu et al. (2013) investigated the effects of the traditional Chinese herbal medicines Radix Ranunculi Ternati, Radix Sophorae Flavescentis, Prunella vulgaris L. and Stellera chamaejasme L. on immunity in a rat model of MDR-TB. Treatment of the
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animals with the TCM herbal remedies significantly changed the levels of serum IFN-γ (p < 0.05). RT-
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PCR analysis showed a statistically significant increase in the mRNA levels of IFN-γ and IL-12, and a significant decrease in the mRNA levels of IL-4 and IL-10 (p < 0.05). In summary, this study showed that
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treatment with TCM herbs increased cellular-mediated immunity in a MDR-TB rodent model (Lu et al., 2013).
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In addition, an in vitro study performed by Nam et al. showed that (-)-deoxypergularine (DPX), an alkaloid extracted from the dried roots of the plant Cynanchum atratum (known as Bai Wei in TCM)
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showed activity against MDR-TB (Nam et al., 2016). The compound inhibited the growth of both
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susceptible and MDR-TB strains with a MIC of 12.5 µg/mL, with excellent activity against XDR-TB at 12.5 µg/mL. In a checkerboard assay, the combination of DPX and rifampin was synergistic in the MTb
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strain H37Ra, as was isoniazid plus DXP. In combination with streptomycin or ethambutol, the results
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(Nam et al., 2016).
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were equivocal. Unfortunately, no checkerboard assays were performed on the XDR-resistant strains
4.1. In vitro evidence
Tuberculosis or ’the white plague’, as people named it due to high fatal rate, even today presents one of the leading cause of motality with 9 million cases of active TB and 1.3 million deaths occurring every year (Hussain at al., 2014). Significant factors such as specific cell wall composition, dormant cells, long lasting therapy and inproper use of the first- and second-line drugs are related to continously increasing incidence of the multi-drug resistant (MDR) strains. Therefore, modern science is in constant
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ACCEPTED MANUSCRIPT search for novel alternatives in treating this infectious disease, especially those from natural sources which may have shorter treatment regimes and be effective with fewer side-effects. In these investigations, researchers mostly rely on the data obtained from traditional medicine practitioners. One of the first known studies in this route was the efficacy of garlic as antitubercular therapy, carried out in
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1912 by Dr. Minchin. He performed anti-TB treatments on his patients by an inhaler mask containing a
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sponge soaked in garlic juice and reported that, in certain individuals, the drug was active against the
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pathogen (Dini et al., 2011). In the last decades, the studies have focused to the efficacy of phytochemicals against multi-drug resistant isolates of Mycobacterium tuberculosis, thus providing
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promising results on the effectiveness of plant products against Mycobacterium. Garlic was demonstrated to possess antimycobacterial activity in many studies, where allicin was
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confirmed to be the carrier of this activity in the study of Gupta and Viswanathan (Gupta and Viswanathan, 1955). They found that this compound acts in synergistic manner with antibiotics
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streptomycin and chloramphenicol against M. tuberculosis. The same synergism was not detected when
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antitubercular drugs were combined with garlic extract, thus pointing to the allicin efficacy (Abbruzzese et al., 1987). Further studies on this subject confirmed garlic efficiency against various MTb strains,
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including MDR ones (Delaha and Garagusi, 1985; Ratnakar and Murthy, 1996; Gupta et al., 2010;
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Hannan et al., 2011). The most recent study of (Rajani et al., 2015), who investigated ethanol extract of garlic against 48 MDR and one reference strains (H37Rv) of MTb showed MIC values in the range of 0.5-
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2.0 mg/ml. Another plant of the Allium genus, shallot (Allium ascalonicum L.), was investigated for activity against MTb in the study of (Mansour et al., 2009). Its ethyl acetate extract exhibited activity against all of the ten tested clinical isolates of MTb at concentration of 500 µg/mL. Nine plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases were used for making hexane, methanol, chloroform and water extracts, which were further evaluated for antimycobacterial activity (Camacho‐Corona et al., 2008). Among the tested extracts, the activity was shown by hexane (Citrus aurantifolia, C. sinensis, Foeniculum vulgare, Olea europaea), two chloroform (Larrea tridentata, Nasturtium officinale) and one methanol (Musa acuminata) extracts. 47
ACCEPTED MANUSCRIPT Nasturtium officinale chloroform extract exhibited the most prominent activity against both reference and MDR strains (MICs were 100 µg/mL and < 100 µg/mL, respectively). Other extracts showing activity against these strains were Foeniculum vulgare and Olea europaea hexane extracts, which exhibited efficacy against all the resistant MTb variants at concentrations lower than 100 µg/mL.
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Study by León-Díaz (2010) showed that hexane extract of Aristolochia taliscana, the herb used in
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Mexican traditional medicine, presents an important source of antimycobacterial compounds. This extract
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was tested against a wide range of mycobacteria including standard strain (H37Rv), four mono-resistant H37Rv variants and 12 clinical MDR isolates, as well as against five non-tuberculous mycobacteria.
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Bioguided fractionation of the obtained extract led to the isolation of the neolignans licarin A, licarin B and eupomatenoid-7, which all demonstrated antimycobacterial activity at very low concentrations (3.25-
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50.00 µg/mL). Among them, the most prominent action was observed for licarin A, which was active at 6.25 µg/mL even against MDR isolate resistant to first- and second-line antibiotics (León-Díaz et al.,
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2010). Gupta et al. (2010) investigated activity of aqueous extracts of Acalypha indica and Adhatoda
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vasica leaves, bulbs of Allium cepa, cloves of Allium sativum and pure gel of Aloe vera leaves against MDR strains of MTb. All extracts were be effective against MDR isolates and drug-susceptible reference
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strain H37Rv.
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Among the tested acetone, ethanol and aqueous extracts obtained from 5 plants (Acorus calamus L. rhizome, Andrographis paniculata Nees. leaves, Ocimum sanctum L. leaves, Piper nigrum L. seeds
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and Pueraria tuberosa DC. tuber), only P. nigrum acetone extract showed to possess antimycobacterial activity (Birdi et al., 2012). In the study of Anthony et al. (2012), butanol extracts of Alstonia scholaris fruits, flowers, bark and leaves were tested for efficacy against one standard strain (H37Rv), one clinical isolate sensitive to antibiotics, and one MDR clinical strain. The results pointed to significant efficacy of bark and leaf extracts against MDR strain at 100 µg/mL, while at 500 µg/mL all extracts showed inhibitory action against all tested strains. Among them, the highest activity was reported for bark extract of Alstonia scholaris, which showed inhibition of 47.40, 51.46 and 73.09% against standard, clinical sensitive and clinical MDR strains, respectively. 48
ACCEPTED MANUSCRIPT Seven mangrove plants (Ceriops decandra, Aegiceras corniculatum, Excoecaria agollacha, Avicennia officinalis, Rhizophora mucronata, Suaeda monoica and Sesuvium portulacastrum) were collected and their hexane and methanol extracts were tested for antimycobacterial activity (Prabhu, 2014). The assys were carried against one standard, one clinical strain sensitive to drugs and one strain of
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Mycobacterium tuberculosis resistant to streptomycin, isoniazid, rifampicin and ethambutol. Hexane
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extracts of all plants failed to exert antimycobacterial activity, while methanol extracts of E. agollacha,
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followed by those extracted from A. corniculatum and A. officinalis exhibited significant activity at concentrations of 500 µg/mL.
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In another study, fresh leaves of Taxus baccata, Senna alata, Andrographis paniculata, Adhatoda vasica, Acalypha indica and Aloe vera were extracted with water (ratio 1:1) and investigated against three
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MTb strains, including one MDR strain (DKU-156). The results showed inhibition of the treated MDR strain by all tested extracts at concentrations 2, 4 and 6% (Bernaitis et al., 2013). Among the tested
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extracts, T. baccata showed the highest potency considering percentage of bacterial growth reduction on
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LJ (Lowenstein Jensen) agar.
In the study of Deveci et al. (2013), a total of 57 isolates including 17 MDR strains were
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investigated for sensitivity to Ankaferd Blood Stopper®, a mixture of plant extracts prepared from
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Alpinia officinarum, Glycyrrhiza glabra, Thymus vulgaris, Urtica dioica and Vitis vinifera. The mixture showed very significant antimycobacterial activity, with inhibitory concentrations ranging from < 1.37
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µg/mL to 21.88 µg/mL. Singh et al. (2013) investigated different solvent extracts of two plants, Urtica dioica and Cassia sophera, for antimycobacterial activity. They determined that the hexane extract of U. dioica and methanol extract of C. sophera possessed this activity. Further testing of semi-purified fractions of these two extracts showed significant inhibition of clinical MDR strains of MTb. Gupta et al. (2014) investigated antimycobacterial activity of Alpinia galanga (L.) Willd. under intracellular and in axenic (aerobic and anaerobic) conditions. Intracellular assay represented a model for investigating the activity of the extracts against non-replicating dormant bacilli, characterized by the switch from aerobic/microaerophilic to anaerobic respiratory pathways. Among the tested extracts 49
ACCEPTED MANUSCRIPT (obtained by water, acetone and ethanol Soxhlet extraction), acetone and etanolic extracts were active in all tested conditions at low concentrations (25, 50 and 100 µg/ml). Recently, similar investigation (in axenic and intracelluler conditions) was carried out by Bhatter et al. (2016) who tested the efficacy of acetone, ethanol and aqueous extracts of four plant species (Acorus calamus L. rhizome, Ocimum
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sanctum L. leaves, Piper nigrum L. seeds and Pueraria tuberosa DC. tuber) against MTb H37Rv.
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Acetone extract of P. nigrum showed the highest antimycobacterial activity by inhibiting the tested strain
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in aerobic, microaerophilic and anaerobic conditions. Also, water extract of P. tuberosa showed significant activity under reduced oxygen conditions, which pointed to the importance of anaerobiosis for
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its efficacy.
Antimycobacterial activity of aqueous extracts of selected Indonesian medicinal plants
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(Andrographis paniculata, Annona muricata, Centella asiatica, Pluchea indica and Rhoeo spathacea) was investigated in the study of Radji et al. (2015). Their results showed that Pluchea indica and Rhoeo
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spathacea ehxibited promising antimycobacterial activity against a MDR strain of Mycobacterium
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tuberculosis, by inhibiting its growth at concentrations of 2.5 and 5 mg/mL. Another recent study on the plant efficacy against mycobacteria was the one performed by
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Johanpour et al. (2015). They tested antimycobacterial activity of the ethanol extract from six Iranian
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medicinal plants against six clinical isolates (2 of them were MDR). The results pointed to significant activity of Peganum harmala and Punica granatum extracts. Owing to the fact that the assay was carried
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out using disc diffusion method, high concentrations (100 and 200 mg/mL) were determined to be active. Considering sensitive isolates, the inhibition zones of the P. harmala extract at higher concentration corresponded to those obtained by rifampin and isoniazid. Another study showed the activity of methanol, ethyl acetate and n-hexane extracts from plant material of Euphorbia hirta, a medicinal plant used in India for the treatment of many respiratory disorders (asthma, cough and various acute/chronic respiratory infections). Among the tested extracts, ethyl acetate extract showed the highest activity against MTb H37Rv, with concentration of 500 µg/mL reducing microbial growth to 35.27% in comparison with the untreated, control value (Rajasekar et al., 2015). 50
ACCEPTED MANUSCRIPT Finally, four clinical isolates including two MDR and two sensitive strains to rifampin and isoniazid were used to investigate the antimycobacterial activity of the Peganum harmala hydro-alcoholic seed extract. All tested strains, including the MDR ones, showed sensitivity to this extract (Davoodi et al., 2015).
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5. Conclusions
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The urgent need for development of new drugs to reduce the global burden of TB has greatly
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stimulated the exploration of traditional knowledge as source of novel and effective phytotherapeutic agents. Worldwide, many plant species have been and continue to be used in various traditional healing
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systems, as well as marine organisms and fungi, thus representing a nearly unlimited source of active
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ingredients.
Noteworthy, besides their antimycobacterial activity, natural products can be useful in adjuvant
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therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their adverse effects and to reverse mycobacterial multi drug-resistance, the latter an emerging and very critical topic
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because of the genetic plasticity and environmental adaptability of Mycobacterium. Probably, the wide
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use of some traditional herbal remedies in the treatment of tuberculosis may be indicative of their efficacy and, above all, safety. Not least, natural products can also be used as a template for the development of
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new scaffolds of drugs.
In any case, crude natural product extracts are complex mixtures of hundreds of different
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compounds that may be synergistically active once administered. Therefore, discovery and development of new pure products involve isolation, purification and identification of target compounds from complex crude extracts is sometimes a major drawback in natural products research. Not least, even if some natural products have still been investigated in clinical trials, the validation of their efficacy and safety as antituberculosis agents is far from being reached, and, hence, according to an evidence-based approach, more high-level randomized clinical trials are urgently needed.
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Abbruzzese, M.R., Delaha, E.C., Garagusi, V.F., 1987 Absence of antimycobacterial synergism between garlic extract and antituberculosis drugs. Diagn. Microbiol. Infect. Dis. 8 (2), 79-85. Adhvaryu, M., Vakharia, B., 2011. Drug-resistant tuberculosis: emerging treatment options. Clin. Pharmacol. 3, 51-67. Ahmad, I., Aqil, F., Owais, M., 2006. Modern Phytomedicine: Turning Medicinal Plants into Drugs. USA: Wiley. Ahmed, H.M., 2016. Ethnopharmacobotanical study on the medicinal plants used by herbalists in Sulaymaniyah Province, Kurdistan, Iraq. J. Ethnobiol. Ethnomed. 12, 8. Ahuja, S., Ahuja, S., Ahuja, U., 2015. Nirgundi (Vitex negundo) – Nature’s Gift to Mankind. Asian Agrihist. 19, 5-32. Alvin, A., Miller, K.I., Neilan, B.A., 2014. Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds. Microbiol Res. 169 (7-8), 483-95. Antony, M., James, J., Misra, C.S., Sagadevan, L.D.M., Veettil, A.T., Thankamani, V., 2012. Anti mycobacterial activity of the plant extracts of Alstonia scholaris. Int. J. Curr. Pharm. Res. 4, 40422. Arai, M., Yamano, Y., Setiawan, A., Kobayashi, M., 2014. Identification of the Target Protein of Agelasine D, a Marine Sponge Diterpene Alkaloid, as an Anti-dormant Mycobacterial Substance. Chem. Bio.Chem. 15(1), 117-123 Arya, V., 2011. A Review on Anti-Tubercular Plants. Int. J. Phar.Tech Res. 3 (2), 872-880. Atanasov, A.G., Waltenberger, B., Pferschy-Wenzig, E.M., Linder, T., Wawrosch, C., Uhrin, P., Temml, V., Wang, L., Schwaiger, S., Heiss, E.H., Rollinger, J.M., Schuster, D., Breuss, J.M., Bochkov, V., Mihovilovic, M.D., Kopp, B., Bauer, R., Dirsch, V.M., Stuppner, H., 2015. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol. Adv. 33(8), 1582-614. Ayyanar, M., Ignacimuthu, S., 2008. Medicinal uses and pharmacological actions of five commonly used Indian medicinal plants: a mini-review. Iran. J. Pharmacol. Ther. 7,107-14. Batugal, P.A., Kanniah, J., Young, L.S., Oliver, J.T., 2004. Medicinal Plants Research In Asia. Serdang, Selangor DE, Malaysia: International Plant Genetic Resources Institute – Regional Office for Asia, the Pacific and Oceania (IPGRI-APO); Bedi, R.S., 2005. Management of tuberculosis in special situations. Lung India 22, 138-41. Bernaitis, L., Shenoy, V.P., Ashok, M., Nath, M., Shenoy, R.P., 2013. Effects of selective medicinal plants against multi drug resistance Mycobacterium tuberculosis strains. Res. J. Pharm. Biol. Chem. Sci. 4 (3), 812-7. Bhatter, P.D., Gupta, P.D., Birdi, T.J., 2016. Activity of Medicinal Plant Extracts on Multiplication of Mycobacterium tuberculosis under Reduced Oxygen Conditions Using Intracellular and Axenic Assays. Int. J. Microbiol. 2016, 8073079. Birdi T, D'souza D, Tolani M, Daswani P, Nair V, Tetali P, Toro J.C. Hoffner S., 2012. Assessment of the activity of selected Indian medicinal plants against Mycobacterium tuberculosis: a preliminary screening using the Microplate Alamar Blue Assay. European J. Med. Plants. 2 (4), 308-323. Bunalema, L., 2010. Anti-mycobacterial activity and acute toxicity of Erythrina abyssinica, Cryptolepis sanguinolenta and Solanum incanum Uganda: Makerere University Kampala. Camacho‐Corona, M.R., Ramírez‐Cabrera, M.A., Santiago, O.G., Garza‐González, E., Palacios, I.P., Luna‐Herrera, J., 2008. Activity against drug resistant‐tuberculosis strains of plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases. Phytother. Res. 22 (1), 82-5.
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Pulmonary tuberculosis is a human disease. Multi-drug-resistant tuberculosis cause to an urgent need for discovery and development of new drugs to reduce the global burden of this disease. Many plant species have been and continue to be used in various traditional healing systems around the world to treat tuberculosis. Evidence-based approach, suggested for more high-level randomized clinical trials.
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