Evidence based traditional anti-diarrheal medicinal plants and their phytocompounds

Biomedicine & Pharmacotherapy 96 (2017) 1453–1464

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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Review

Evidence based traditional anti-diarrheal medicinal plants and their phytocompounds

T

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Pooja Rawat, Pawan Kumar Singh , Vipin Kumar Value Addition Research and Development-Human Health, National Innovation Foundation-India, Grambharti, Mahudi Road, Gandhinagar, Gujarat, 382650, India

A R T I C L E I N F O

A B S T R A C T

Keywords: Diarrhea Traditional medicines Phytomolecule Clinical trial Mechanism of action

Traditional medicines are an integral component of alternative health care systems used by millions of the people worldwide. Traditionally used herbals are multi-constituent medications, safety and efficacy of which is based on experiences of the practitioners, whereas modern drugs are single molecules, rigorously tested, structurally optimized and toxicologically cleared. Plants are being recognized as potential source of drug discovery and more than 80% of modern drugs are derived directly from natural sources (plants, microbes, cells etc.) or their molecules/compounds. A large number of traditional medicinal plants are used for the treatment of diarrhea and related gastrointestinal disorders. Many of these plants have been scientifically validated in animal models of diarrhea. However, very few of these have been clinically tested through controlled trials. The article highlights various traditional anti-diarrheal medicinal plants, which are shown to have high efficacy in in-vivo models. It was noticed that few active phytomolecules have been also identified from these plants however these have not been substantially explored in terms of their clinical efficacy and safety. This review also describes the potential herbal extracts which may be investigated for identification of novel active molecules against diarrhea and other gastrointestinal disorders. Robust clinical trials of lead plants/phyto-molecules will be needed to develop novel, effective and safe phyto-medicines for combating diarrhea and associated disorders.

1. Introduction Diarrhea is a gut disorder characterized by passage of three or more loose or liquid stools per day and is one of the leading cause of child mortality and morbidity. Three clinical types namely acute watery, acute bloody and persistent diarrhea have been defined depending upon the duration and symptoms [1]. Globally, one in ten deaths (about 8,00,000) of those under five are due to diarrhea [2]. Among developing world, higher prevalence of diarrhea related deaths occur among children in sub-saharan and south Asian countries (78%) [3]. More than 2.8 billion episodes of diarrhoea per year have been estimated in adolescents, adults and children aged above 5 years [4]. Pathophysiology of diarrheal disease is multifactorial involving poor absorption, intestinal microbiota, gut motility, hypersensitivity, microbial infection, metabolism error, chemical irritation, immune system, genetic factors and various secretory stimuli such as, bacterial enterotoxins, hormones generated by endocrine neoplasms, dihydroxy bile acids, hydroxylated fatty acids and inflammatory mediators [5]. Prevention and treatment strategies for diarrheal diseases include exclusive breastfeeding, zinc supplementation, better hygiene, immunization, oral rehydration therapy and antibiotics [6]. Despite the global decline in mortality

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(> 50%) from 2000 till 2013, the disease still carries a high burden of morbidity. Treatment of acute infectious diarrhea includes antibiotics such as tetracycline, ciprofloxacin, norfloxacin, fleroxacin, cinoxacin, erythromycin, metronidazole, ampicillin, amoxycyline, doxycycline, vancomycin, and paromomycin [1]. However, use of antibiotics is often associated with depletion of beneficial gut and mucosal micro-organism [7], immuno-suppression [8] and allergic reactions [9]. Emergence of antibiotic resistant pathogenic strains is also observed over long-term use which results in spread and stabilization of resistant bacteria and resistance genes [10]. This may sometimes also lead to overgrowth of enteropathogens such as Clostridium difficile, termed as antibiotic-associated diarrhea [11]. Increasing resistance to currently used therapeutic agents in many common pathogens has revitalized the interest of scientists in natural product-based drug discovery. Medicinal plants have been used as traditional treatment options for various human diseases for thousands of years. Many of today's drugs are plant-derived natural products or their derivatives [12,13]. Traditionally, use of plants and their preparations for the treatment of diarrhea and associated symptoms is well reported [14,15,16]. Several validation studies have highlighted the therapeutic potential of traditional medicinal plants, their extracts and

Corresponding author. E-mail address: pawan@nifindia.org (P.K. Singh).

https://doi.org/10.1016/j.biopha.2017.11.147 Received 25 October 2017; Received in revised form 21 November 2017; Accepted 29 November 2017 0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved.

Biomedicine & Pharmacotherapy 96 (2017) 1453–1464

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3.1. Croton lechleri (Sangre de drago)

phytochemicals. For some ethnomedicinal plants, mode of action has also been investigated. Castor oil induced diarrhea is the most commonly used animal model. Besides Magnesium sulphate, Barium sulphate and Vibrio cholerae-induced diarrhea model are also used for studying the efficacy of anti-diarrheal drugs. Castor oil is known to induce diarrhea by three different mechanisms. First one is by releasing nitric oxide and thereby increasing permeability of gastrointestinal membrane for calcium. Second is by stimulating prostaglandin synthesis and thereby increasing fluid and electrolytes into the lumen of the bowel. Increasing peristalsis is another mechanism through which castor oil works. Magnesium sulfate is known to induce diarrhea by promoting cholecytokinin release from the duodenal mucosa thereby preventing the reabsorption of sodium chloride and water from the lumen. In anti-diarrheal studies of drugs, charcoal meal test is often employed to test gastrointestinal propulsive motility. This test is based on the intestinal transport of a charcoal meal along the small intestine and calculation of charcoal evacuation time [17]. Loperamide, Bismuth subsalicyclate and Diphenoxylate are few of the synthetic anti-diarrheal drugs used for symptomatic relief of diarrhea [18]. Loperamide is known to act by prolonging the transit time of intestinal content, thereby allowing absorption of more water from the fecal matter [19]. Bismuth subsalicylate shows anti-diarrheal activity through multiple mechanisms [20], the drug is known to slow down the expulsion of fluids in intestinal lumen by coating the tissues. It also displays antisecretory, anti-microbial action and stimulates the absorption of fluids and electrolytes by the intestinal cells [21,22]. Anti-diarrheal action of Diphenoxylate is due to effect on circular muscle activity of the intestine, thereby slowing the intestinal transit [23]. Several traditional plants have been evaluated for their anti-diarrheal potential using charcoal meal test and castor oil induced diarrhea. The review aims to highlight traditional anti-diarrheal medicinal plants and the scientific studies supporting their traditional uses. Potential medicinal plants based on the validation outcomes have been suggested for further exploration and identification of active molecules. Very few plant based preparations have been tested through randomized controlled trials. Detailed investigation of few traditional medicinal plants have revealed several active phytomolecules. This study also summarizes these active molecules and their therapeutic potential.

Croton lechleri, also known as sangre de drago, is an ethnomedicine from South America, frequently used for the treatment of diarrhea. SP303 is an oligomeric proanthocyanidin prepared from the latex of Croton lechleri [46]. SP-303 (Provir) was clinically investigated in patients of traveler’s diarrhea through a double blind, randomized, placebo-controlled study. A total of 184 persons (> 17 yr) were selected and doses of 125 mg, 250 mg, 500 mg of SP-303 or a matching placebo were administered four times a day for 2 days. Enterotoxigenic Escherichia coli was found to be the etiologic agent in 19% of the cases. Duration of diarrhea was markedly shortened (21%) during 48 h of therapy. SV-303 at a dose of 125 mg and 250 mg was found to be most effective resulting in 85–91% partial or complete improvement [24]. In phase II, safety and efficacy of orally administered SP-303 was investigated in patients with AIDS and diarrhea using randomized, double blind, placebo-controlled study. The study involved a total of 26 subjects receiving SP-303, and 25 receiving placebo. 500 mg of SP-303 or placebo was administered every 6 h for 96 h (4 days). The formulation was found to be safe. Significant reduction in stool weight and abnormal stool frequency was also observed in the intervention group in comparison to placebo-treated subjects [26]. 3.2. Camellia sinensis Camellia sinensis, also known as black tea, is one of the most consumed global beverage. The effect of Camellia sinensis consumption on nonbacterial diarrhea in paediatrics patients, evaluating different parameters (such as effect on stool consistency, volume, and frequency of defecation) was studied through single-blind randomized clinical trial. The study involved 140 pediatric patients (2–12 yrs) with acute nonbacterial diarrhea. Patients in the test group received tablets containing 500 mg dry black tea along with standard treatment, while control group received standard treatment only. Significant differences in the stool volume, frequency of defecation was observed between intervention group and control group, after 24 h of treatment [39]. The effect of black tea on diarrhea was found to be comparable with that of standard drug, loperamide. Several phytoconstituents such as; 4HPyran-4-One, 1-methyl-5-mercaptotetrazole, n-hexa decanoic acid, nDecanoic acid, Phytol, Octadecanol, and Tetradecanol, have been identified from the leaves of Camellia sinensis. The plant is also reported to show anti-microbial activity against Salmonella typhi, Staphylococcus aureus and Pseudomonas aeruginosa, though detailed investigation against pathogenic organisms responsible for diarrhea and other gastrointestinal disorders has not been carried out till date [47]. The plant extracts and its phytomolecules may further be explored for their probable role in anti-diarrheal activity, using both infectious and noninfectious study models.

2. Methodology For this review, the literature published on anti-diarrheal traditional medicinal plants during January, 2015 till October, 2017 were explored using search engine Google Scholar, Pubmed and Science Direct. The keywords used for conducting searches included herbal, plant, castor oil, diarrhea, and gastrointestinal.

3. Clinical trials on plant preparations with anti-diarrheal activity

3.3. Mentha piperita

Very few plant based medicinal preparations have been subjected to clinical trials (Table 1). Assessment of anti-diarrheal efficacy of these preparations have been carried out through randomized controlled trials in different conditions of diarrhea such as traveler’s diarrhea, HIV associated diarrhea, Inflammatory Bowel Syndrome (IBS) associated diarrhea and acute diarrheic disease (ADD). Several clinical studies were conducted using plant based medicinal preparations, which are complex mixtures containing multiple phyto-constituents. The rationale of using these mixtures may be the synergistic action of several components present in the herb, with probable role of some inactive constituents as enhancers, in the pharmacokinetics of the active component. This may possibly be responsible for observed therapeutic benefits of the herbal formulations. Additionally, it is also important to address the issues of herbal drug standardization recommended in regulatory guidelines, to achieve consistency in the quality and efficacy.

Mentha piperita, also known as peppermint, was tested for its efficacy against diarrhea in a randomized, double blind, placebo-controlled clinical study. Peppermint was administered to the intervention group in form of enteric-coated peppermint-oil formulation (Colpermin). The trial involved a total of 110 subjects, including 66 men and 44 women (18–70 yr) with symptoms of IBS. One capsule of either Colpermin (containing 187 mg peppermint oil) or placebo was given to subjects three to four times a day. The trial was conducted for a period of one month. Out of 52 patients on Colpermin tablet, 43 (83%) had reduced stool frequency, whereas among 49 subjects on placebo, only 16 (32%) had reduced stool frequency. Improvement in other symptoms of IBS was also observed in subjects on Colpermin tablet in comparison to placebo group [30]. Essential oil from M. piperita displays anti-microbial activity against number of microbes including bacteria (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus), 1454

Randomized, double blind, placebo- controlled trial

Single-blind randomized clinical trial

–

Role of the opioid system

Gut stimulant and relaxant activities, Anti-microbial effect

–

Black tea extract- 4H-Pyran-4-One, 1-methyl-5mercaptotetrazole, n-hexa decanoic acid, n-Decanoic acid, Phytol, Octadecanol, Tetradecanol

Karachine, aromoline, oxyberberine, oxyacanthine, berbamine, and berberine chloride, Cis-p-mentha -1(7),8-dien-2-ol, 3-Nonynoic acid, Urea, N,N´-bis(2hydroxyethyl)-, 3-Trifluoroacetoxypentadecane, Pterin -6-carboxylic acid, 2,2-Difluoroheptacosanoic acid, y-Sitosterol, Spirost-8-en-11-one, 3-hydroxy-, (3ß,5α,14ß,20ß,22ß,25R)-, Curan,16,17-didehydro-, (20xi.)-, 17.alfa.21ß-28,30-Bisnorhopane, Ethyl isoallocholate, Milbemycin B,6,28-anhydro-15-chloro25-isopropyl-13-dehydro-5-

Tong-xie-ning [Paeonia lactiflora (root), Atractylodes macrocephala (rhizome), Citrus reticulate (green unripe exocarp), Allium macrostemon (bulb)]

Camellia sinensis

Entoban [Holarrhena antidysenterica, Berberis aristata, Symplocos racemosa, Querecus infectoria and Helicteres isora]

1455 Randomized trial

Randomized, double blind, placebo- controlled trial

Anti-spasmodic, Anti-microbial effect

Phytodrug (QG-5), quercetin 3-O-alpha-L-arabinoside (guajavarin); quercetin 3-O-beta-D-glucoside (isoquercetin); quercetin 3-O-beta-D-galactoside (hyperin); quercetin 3-O-beta-L-rhamnoside (quercitrin) and quercetin 3-O-gentobioside.

Psidium guajava

5 days

Reduction in daily bowel frequency, relief from abdominal pain, distention, stool consistency and sensation of incomplete evacuation

Reduction in defecations frequency

24 h Acute Nonbacterial Diarrhea Chronic diarrhea

Improvement in IBS-related diarrhea in the TXNG group compared to placebo

Anti-spasmodic effect, no difference in other major symptoms, anti-bacterial activity 10 months

3 days

Diarrhea predominant- IBS

Acute diarrheic disease (ADD)

Reduction in abnormal stool frequency

1 month

Diarrhea associated with IBS

Randomized, double blind, placebo-controlled study

Antimicrobial activity, antispasmodic activity, reduction in gastric motility

Essential oil containing 47 constituents. Major constitutents include menthol (19.1%), isomenthone (14.8%), limonene (10.6%), iso-menthanol (8.8%), menthyl acetate (6.6%), b-pinene (5.6%), a-pinene (4.8%), 1,8-cineole (3.5%), isopulegol (3%), pulegone (2.3%), piperitone (2.1%), and bphellandrene (2.8%)

Mentha piperita

Reduction in abnormal stool frequency

4 days

HIV associated diarrhea

Shortening of duration of diarrhea

2 days

Traveler’s diarrhea

Randomized, double blind, placebo-controlled trial Randomized, double blind, placebo-controlled study

Inhibition of intestinal cystic fibrosis transmembrane regulator (CFTR) Cl− channel and calcium-activated Cl− channel

Crofelemer, a purified proanthocyanidin oligomer extracted from the bark latex

Croton lechleri

Outcomes

Study Duration

Type of Diarrhea

Type of clinical trial

Mechanism of action

Phytochemicals

Plant

Table 1 Clinical trials of plant based preparations against diarrhea.

[40,41,42,43,44,45]

[37,38,39]

[36]

[32,33,34,35]

[28,29,30,31]

[24,25,26,27]

Reference (s)

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Sedative and Muscle Relaxant activity [61] [53]

Cancer [62], anti-Alzheimer [63], Inflammation [54], Arthritis [64]; Nephrotoxicity [65]; Osteoporosis [66]

Gastric ulcer [52]; Hypolipidemic activity[55]; cancer [56]; anti-venom [57]; Anti-nociceptive activity [58]; Antioxidant, free radical scavenging, hepatoprotective activity [59] – [52]

Leaves of Psidium guajava are traditionally used for the treatment of diarrhea, dysentery, gastroenteritis, stomach aches, and indigestion. In an attempt to test the scientific basis of its anti-diarrheal activity, safety and efficacy of a phytodrug (QG-5®, with a standardized concentration of flavonoids, estimated as quercetin 1 mg/500 mg), developed from guava leaves, was tested in a randomized, double blind, placebo controlled clinical study. Capsules containing 500 mg of the product were administered to 50 patients (20–59 yrs) every 8 h during 3 days. Intake of guava product resulted in significant reduction in the duration of abdominal pain in these patients [34]. In another study, effect of aqueous leaf extract of P. guajava prepared through hot extraction method was evaluated on parameters associated with pathogenicity of infectious diarrhea. Remarkable anti-bacterial activity was observed towards S. flexneri and Vibrio cholerae. An inhibition in the adherence of enteropathogenic E. coli and invasion by both Enteroinvasive E. coli and S. flexneri to HEp-2 cells was observed [32]. Antimicrobial activity of P. guajava was observed against the pathogens of enteric fever, and suggested to be one of the mechanism of anti-diarrheal activity [35]. Antimicrobial activity of various phytoconstituents found in P. guajava leaves (quercetin, quercetin-3-O-α-L-arabinofuranoside, quercetin-3-Oβ-D-arabinopyranoside, quercetin-3-O-β-D-glucoside and quercetin-3-Oβ-D-galactoside, Quercetin-3-O-β-D-arabinopyranoside), may be one of the mechanism of its anti-diarrheal action. This has been tested against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, however detailed studies against diarrhea causing pathogens may be carried out further to identify the exact mechanism of action [49]. Guajanoic acid, β-sitosterol, uvaol, oleanolic acid, and ursolic acid are other phytoconstituents present in the plant and may be investigated to identify their possible involvement in anti-diarrheal efficacy, by integrating computed prediction and wet lab models [50].

Inhibition of Diarrhea: 89% Intestinal motility Inhibition: 69% Anti-secretory and anti-motility properties

Protection from diarrhea: 69%; Inhibition of Intestinal fluid accumulation: 33%; Antisecretory and antioxidant potential Stachysrosane (1): 100% Protection from Diarrhea; Stachysrosane (2): 70% protection from Diarrhea Delay in onset of diarrhea: 32%

20 mg/Kg

10 mg/Kg

10 mg/Kg

LD50: 1280 mg/Kg Increase in time of onset of diarrhea: 37%; Enteropooling inhibition: 44% Anti-spasmodic and Anti-secretory activities 120 mg/Kg

Aromatic plants, such as Mentha longifolia L., Artemisia dracunculus L., Coriandrum sativum L., Origanum vulgare L., Rosmarinus officinalis L., Thymus vulgaris L., and Zingiber officinale Rosc. Azima tetracantha- Leaves

45 mg/Kg

3.4. Psidium guajava

[54]

Insecticidal activity [51]

Anti-diarrheal activity Maximum Effective dose Source

[60]

Other Reported Pharmacological activities References

fungi and yeast. About 47 phyto-components have been identified in peppermint oil. The major constituents are menthol (19.1%), isomenthone (14.8%), limonene (10.6%), iso-menthanol (8.8%), menthyl acetate (6.6%), b-pinene (5.6%), a-pinene (4.8%), 1,8-cineole (3.5%), isopulegol (3%), pulegone (2.3%), piperitone (2.1%), and b-phellandrene (2.8%) [48]. These phyto-compounds are the subject of further investigation to identify the activities along with their mode of action against diarrhea.

Tong-xie-ning (TXNG) is a Chinese polyherbal formulation composed of four herbs, namely, Paeonia lactiflora (root), Atractylodes macrocephala (rhizome), Citrus reticulate (green unripe exocarp) and Allium macrostemon (bulb). A randomized, placebo-controlled, double blind clinical trial was conducted on a total of 60 subjects with diarrhea-predominant IBS during a 10-month period to evaluate the safety and efficacy of TXNG. Significant improvement in stool form, appearance and decrease in stool frequency was observed. Diarrhea alleviation time in the TXNG group was also reduced by 47% in treatment group (7.6 ± 4.6 days) in comparison to the placebo group (14.4 ± 4.3 days) [36].

Dracocephalum kotschyi- Aerial parts

Stachys parviflora- whole plant

Eriosema chinense- Roots

3.5. Tong-xie-ning

Entoban is a polyherbal formulation composed of Holarrhena antidysenterica, Berberis aristata, Symplocos racemosa, Querecus infectoria and Helicteres isora. In a randomized clinical trial, safety and efficacy of Entoban was evaluated in 150 chronic diarrhea patients (18–60 yrs). The effect of treatment was compared with synthetic drug Metronidazole. The treatment group was administered Entoban capsule (400 mg) every 8 h for five days, whereas control group received Metronidazole tablet (400 mg) for same time duration. Patients were

Stachysrosane (1) and Stachysrosane (2), Diterpenoids Apigenin

Eriosematin E, a prenylated flavanone,

Friedelin

1,8-cineole, a terpenoid oxide

3.6. Entoban

Phytocompounds

Table 2 Active Phytomolecules with anti-diarrheal efficacy.

P. Rawat et al.

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Fig. 1. Molecular structures of anti-diarrheal phytomolecules isolated from traditional medicinal plants.

diarrheal efficacy [42,43,44,45].

evaluated for daily bowel frequency; abdominal pain, distention, stool consistency and sensation of incomplete evacuation. Relief from diarrhea symptoms was observed with complete improvement in 84.78% patients in test group and 78.72% in control group. The herbal formulation was also found to be safer in comparison to synthetic drug, Metronidazole (NCT02642250). Observed anti-diarrheal efficacy of Entoban may be the outcome of synergistic effect of herbal mixture. Holarrhena antidysenterica is known to exhibit gut stimulant and relaxant activities, mediated through activation of histamine receptors and Ca2+ channel blockade [40] and also through anti-microbial activity [41]. Other components of Entoban such as Berberis aristata, Symplocos racemosa, Querecus infectoria and Helicteres isora may possibly be having role as anti-microbials, thereby contributing towards its anti-

4. Potent phytomolecules with proven anti-diarrheal efficacy Several phytochemicals isolated from the plants were identified and tested for their efficacy against diarrhea (Table 2). 1,8-Cineole is a major or minor constituent occurring in a number of biologically active aromatic plants and spice oils, such as Mentha longifolia, Artemisia dracunculus, Coriandrum sativum, Origanum vulgare, Rosmarinus officinalis, Thymus vulgaris, and Zingiber officinale. Effect of intake of different doses of this compound (20, 60, 80, 120 mg/Kg) was investigated in castor oil induced diarrhea model. The study demonstrated significant anti-spasmodic and anti-secretory activity with delay observed in onset 1457

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Table 3 Recently identified traditional medicinal plants with anti-diarrheal properties (in-vivo studies). Plant

Plant part

Type of Extracts

Effective Maximum dose tested

% Inhibition of symptoms

References

Mentha longifolia Maranta arundinacea

Aerial parts Leaves

Essential oil Methanolic

80 mg/Kg 400mg/Kg

[80] [81]

Linum usitatissimum

Seeds

Aqueous methanolic

500 mg/Kg

Holarrhena antidysenterica Musa paradisiaca Anacardium occidentale Psidium guajava Codiaeum variegatum Gmelina arborea Mangifera indica Lagerstroemia speciosa Vernonia amygdalina Cymbopogon citratus Dalbergia sissoo Matricaria chamomilla Alpinia oxyphylla Manihot esculenta

Seeds

Ethanolic

[83]

Stem – Leaves Leaves Root Leaf Roots Leaf Leaf Leaf Aerial parts Fructus Leaves

Sap Cashew gum, a complex heteropolysaccharide Ethanolic extract Ethanolic extract Ethanol Aqueous Methanolic Methanolic Methanolic Ethanolic Aqueous- Methanolic Ethanolic Ethanolic

54% (defecation); 52% (intestinal content) 52% (diarrhea); 31% (enteropooling) 63% (defecation); 37% (intestinal motility) 59% (defecation) 77% (defecation) 100% (defecation); 66% (enteropooling) 51% (diarrhea) 88% (fecal spots)

[84] [85] [86] [87] [88] [89] [90] [91]

66% (faeces); 79% (watery stools) 61% (diarrhea) 23.53% (wet faeces proportion) 44% (fluid accumulation); 58% (intestinal transit)

[92] [72] [93] [94]

– – – – – Rhizome

Methanolic Methanolic Methanolic Methanolic Methanolic Methanolic

200 mg/Kg and 400 mg/Kg 1.0 ml 60 mg/Kg 750 mg/Kg 500 mg/Kg 400 mg/Kg 100 mg/Kg 400 mg/Kg 400 mg/Kg 400 mg/Kg 400 mg/Kg 300 mg/Kg 20000 mg/Kg 100 mg/Kg and 200 mg/Kg 500 mg/Kg 500 mg/Kg 500 mg/Kg 500 mg/Kg 500 mg/Kg 1000 mg/Kg

68% (fluid accumulation) 57% (diarrhea); 40% (enteropooling); 43% (intestinal transit) 68% (diarrhea); 38% (enteropooling); 56% (gut motility) 54% (defecation)

12% (diarrhea); 4% (intestinal transit) 38% (diarrhea); 24% (intestinal transit) 47% (diarrhea); 26% (intestinal transit) 12% (diarrhea); 10% (intestinal transit) 4% (diarrhea); 2% (intestinal transit) 80% (protection)

[95]

Leaves Seeds – Root

Ethanolic Aqueous Ethyl acetate Aqueous

500 mg/Kg 100 mg/Kg 300 mg/Kg 75 mg/Kg

Dichloromethane

200 mg/Kg

Solanum paniculatum

Leaves, Stem, Flowers Root

500 mg/kg

Polypodium vulgare Ajuga remota Adiantum capillus-veneris Idigofera spicata

Rhizome Aerial parts Leaves Root

Successive extract of Dichloromethane and Ethanol Hydro-alcoholic extracts Methanolic Aqueous- Methanolic Methanolic

Detarium senegalense

Stem Bark

Aqueous

400 mg/Kg

Croton macrostachyus

Leaves

Chloroform and Methanol

500 mg/Kg

Chebulae Fructus

Fruits

Aqueous

800 mg/Kg

Morinda citrifolia Oxalis barrelieri

Roots Whole plant

Ethanol Aqueous

Mikania cordata Litsea monopetala Murraya koenigii Acacia nilotica Microcos paniculata Pistia stratiotes

Leaves Leaves Leaves Root Stem Bark Leaves and Roots

Ethanolic Ethanolic Hydro-alcoholic Methanolic Methanolic Petroleum ether& Methanol

400 mg/Kg 25 mg/Kg 250 mg/Kg 400 mg/Kg 400 mg/Kg 400 mg/Kg 400 mg/Kg 400 mg/Kg 400 mg/Kg

Pseudocedrela kotschyi

Leaves

Ethanol

400 mg/Kg

Aphanamixis polystachya Cordia africana Gaultheria trichophylla Syzygium cordatum

Leaves Root bark Whole plant Fruit pulp Seeds Root Aerial parts Leaves

Ethanolic Mathanol Methanol Methanol

500 mg/Kg 400 mg/Kg 1000 mg/Kg 400 mg/Kg 400 mg/Kg 300 mg/Kg 1 g/Kg 400 mg/Kg

Rhanterium epapposum Achillea fragrantissima Artemisia herba alba Echinops spinosus Echinops hussoni Polygonatum verticillatum Mimosa diplotricha Myrtus communis Trichilia emetica Pelargonium luridum Calea zacatechichi

Rhus tripartita Cynodon dactylon Salacia lehmbachii

500 mg/Kg 800 mg/Kg 500 mg/Kg 400 mg/Kg

Methanolic Ethanolic Ethanolic

1458

89% (defecation) 77% (protection); 68% (intestinal fluid volume) 79% (defecation) 85% (diarrhea) (75 mg/Kg); 50% (enteropooling) (600 mg/Kg); 71% (intestinal transit) (300 mg/Kg) Percentage increase in time of onset of diarrhea – 140% 50% (diarrhea); 26% (enteropooling); 44% (intestinal motility) 40% (protection) 79% (defecation); 63% (intestinal transit) 60% (protection) 53% (diarrhea); 11% (fluid accumulation); 11% (intestinal motility) 57% (protection); 87% (enteropooling); 44% (intestinal transit) with Ethyl acetate fraction 96% (defecation) (Chloroform extract); 82% (defecation) (Methanolic extract); 68% (enteropooling) (chloroform extract); 65% (enteropooling) (chloroform extract); 58% (diarrhea); 64% (enteropooling); 35% (intestinal motility) 68% (protection) 100% (diarrhea) at 250 mg/kg; 46% (intestinal transit) at 100 mg/Kg 48% (defecation) 60% (defecation) 36% (wet faeces); 48% (intestine transit) 41% (defecation) 63% (diarrhea) Leaves- 52% (defecation) for methanolic extracts; 59% (defecation) for pet. ether extracts; Roots- 16% (defecation) for Methanolic extract and 34% (defecation) for Pet. ether extract 91% (diarrhea); 82% (intestinal fluid accumulation); 66% (transit time) No activity 61% (diarrheal drops); 56% (defecation) 77% protection 49% (Motility) 41% (Motility) 50% (anti-diarrheal index) 27% (defecation); 19% (Motility) 81% (diarrhea); 63% (motility); 56% (enteropooling) (continued

[82]

[71] [96] [97] [98] [73] [99] [100] [78] [101] [79] [102] [103] [104]

[105] [106] [107] [108] [109] [110] [111] [112]

[113] [114] [115] [69] [116] [117] [118] [119] on next page)

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Table 3 (continued) Plant

Plant part

Type of Extracts

Effective Maximum dose tested

% Inhibition of symptoms

References

Sesbania grandiflora Manilkara zapota Alchornea cordifolia

Leaves Leaves Bark

Ethanolic Ethanolic Aqueous

400 mg/Kg 400 mg/Kg 400 mg/Kg

[120] [121] [122]

Caladium bicolor Alsotinia scholoris Tridax procubens Rumex maritimus Ageratum Conyzoides

Leaf Leaf Leaf Whole plant Leaf

Aqueous Ethanolic Aqueous & Ethanolic Methanolic Aqueous

1 mg/Kg 500 mg/Kg 400 mg/Kg 500 mg/Kg 1000 mg/Kg

Byrsocarpus coccineus Artemisia indica Curcuma zedoaria Picralima nitida Setaria italica Cistus salviifolius Rumex vesicarius

Root Bark Leaf Rhizome Seed Seeds Aerial parts Leaf

Aqueous Ethanolic Ethanolic Ethanolic Ethanolic Aqueous Methanolic

100 mg/Kg 500 mg/Kg 750 mg/Kg 180 mg/Kg 400 mg/Kg 600 mg/Kg 400 mg/Kg

Jatropha curcas Caesalpinia decapetala Leptadenia pyrotechnica Urena sinuata

Leaf Leaf Aerial parts Leaves

400 mg/Kg 300 mg/Kg 1200 mg/Kg 200 mg/Kg

Tamarindus indica Bambusa bambos Juglans regia Blumea densiflora Ziziphus oenoplia Calamus rotang Oroxylum indicum

Seed Leaf Leaf Whole plant Root Seeds Bark and Fruit

Polygonum bistorta Salvia schimperi Aganosma dichotoma Morinda pubescens Celtis integrifolia Byrsocarpus coccineus Spondias mombin Elephantorrhiza elephantina Oncoba spinosa Amaranthus tricolor Croton grewioides Wikstroemia indica

Rhizome Leaves Leaves Roots Leaves Root Bark Stem Bark Root

Aqueous Ethanolic Defatted Methanolic Methanolic extract, Chloroform fraction; nhexane fraction; Ethyl acetate, Hydromethanol fraction Ethanolic Methanolic Hydroethanolic Ethanolic Methanol Methanolic Methanolic extract, Hexane soluble fraction, carbon tetrachloride fraction, Dichloromethane and Ethylacetate soluble fraction Ethanolic Methanol Methanolic Ethanolic Aqueous Aqueous Ethyl acetate Aqueous

41% (defecation) 60% (diarrhea) 70% (diarrhea) (aqueous extract); 55% (transit time) (ethanolic extract) 47% (diarrhea) 52% (diarrhea); 51% (Intestinal content) 61% (Transit time) (Aqueous); 20% (Ethanolic) 48% (stool count) 20% (Transit time); 58% (diarrheal feaces); 37% (Intestinal volume) 74% (Percent protection); 53% (intestinal content) 51% (diarrhea); 43% (intestinal transit) 22% (stool weight) 96% (diarrhea); 44% (fluid accumulation); 18% (diarrhea) 91% (diarrhea) 66% (defecation); 49% (intestinal content weight); 45% (intestinal transit) 56% (diarrhea) 59% (protection from diarrhea) 68% (diarrhea) 37% (diarrhea) (Ethyl acetate fraction); 56% (enteropooling) (hexane fraction); 32% (intestinal transit) (Hexane fraction) 78% (faeces weight) 55% (diarrhea) 94% (diarrhea); 75% (defecation) 35% (defecation) 47% (fluid accumulation) 66% (diarrhea) Bark- 53% (CCl4 fraction); 50% (methanolic extract) Fruit- 51% (CCl4 fraction); 46% (methanolic extract)

1000 mg/Kg 400 mg/Kg 400 mg/Kg 300 mg/Kg 750 mg/Kg 100 mg/Kg 500 mg/Kg 400 mg/Kg

60% 80% 68% 63% 77% 74% 83% 64%

Root Leaves Aerial parts Leaves

Ethanol Ethyl acetate Ethanolic Methanolic

400 mg/Kg 200 mg/Kg 250 mg/Kg 400 mg/Kg

Tecurium oliverianum Bombax buonopozense Harungana Madagascariensis Khaya senegalensis Commelina benghalensis

– Leaves Stem bark

Methanolic Methanolic Ethanolic

1000 mg/Kg 400 mg/Kg 200 mg/Kg

74% (diarrhea) 90% (diarrhea); 52% 81% (defecation) 28% (diarrhea); 30% (intestinal transit) 61% (diarrhea); 33% 56% (diarrhea); 53% 69% (diarrhea); 55%

Stem Bark Leaves

Butanolic fraction Methanol

150 mg/Kg 400 mg/Kg

Calophyllum inophyllum Alchornea laxiflora Maytenus erythroxylon Bidens biternata Citrus limon

Leaves Leaves Leaves Aerial parts Fruit Peel

Ethanolic Aqueous Ethanolic Aqueous Hexane

500 mg/Kg 125 mg/Kg 500 mg/Kg 400 mg/Kg 20 mg/Kg

Hopea Odorata

Leaves

Ethanol

400 mg/Kg

Cenchrus ciliaris

Whole plant

Dichloromethane

100-500 mg/Kg

Hygrophila spinosa Triumfetta pilosa Symplocos paniculata Quercus ilex Persicaria orientalis Phrynium imbricatum

Whole plant Leaves Bark Fruit Leaves Leaves

Ethanol Ethanol Methanol Aqueous Methanol Ethanol

500 mg/Kg 400 mg/Kg 500 mg/Kg 500 mg/Kg 400 mg/Kg 400 mg/Kg

Nymphaea lotus

Methanol

Rhizome

800 mg/kg

1459

400 mg/Kg 400 mg/Kg 2000 mg/Kg 500 mg/Kg 400 mg/kg 500 mg/Kg 400 mg/Kg

(protection from diarrhea) (number of fecaes) (diarrhea) (defecation) (protection) (protection) (diarrhea) (diarrhea)

[123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [77] [134] [135] [136] [137]

[138] [139] [140] [141] [142] [143] [144]

[145] [146] [147] [148] [149] [128] [150] [151]

(enteropooling); 35%

[152] [153] [154] [155]

(intestinal transit) (intestinal transit) (intestinal transit)

[156] [157] [158]

(enteropooling)

87% (diarrhea); 30% (intestinal trasit) 55% (diarrhea); 45% (enteropooling); 35% (intestinal transit) 62% (diarrhea) 70% (defecation frequency) 81% (diarrhea) 63% (fecal output) 34% (diarrhea); 68% (enteropooling); 37% (intestinal transit) 58% (diarrhea); 46% (enteropooling); 35% (intestinal transit) 77% (protection) (500 mg/Kg); 63% (intestinal transit)(200mg/Kg) 30% (diarrhea) 63% (diarrhea) 67% (protection) 49% (transit) 75% (diarrhea) 44% (diarrhea) (Petroleum ether fraction); 33% (enteropooling); 26% (intestinal Transit) 68% (diarrhea)

[159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [68] [170] [171] [172] [173]

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Fig. 2. Mechanisms of action of different anti-diarrheal medicinal plant.

secretory activity, enhanced intestinal absorption, anti-motility or antiperistaltic effect, anti-microbial effect and anti-spasmodic action. These effects have been well demonstrated in numbers of in-vivo studies wherein treatment with herbal extracts (of various plant parts prepared in different solvents) resulted in inhibition of enteropooling/ intestinal fluid accumulation, gastrointestinal transit and also reduction in frequency and volume of faecal output (Table 3). Specific mechanisms through which traditional medicinal plants act include blockage of calcium channel [67,68], anti-muscarinic mechanism, inhibition of butyrylcholinesterase [69], inhibition of phosphodiesterase enzyme [70], activation of adenosine triphosphate-sensitive K+ channels [71,72], improved activity of Na+-K+ ATPase in the small intestine, and attenuation of nitric oxide concentration [73]. Alterations in smooth muscle contractility are among the key mechanisms involved in the pathophysiology of gastrointestinal disorders including diarrhea (Fig. 2). Smooth muscle contraction is mainly mediated through influx of Ca2+ via voltage-dependent channels located in the plasma membrane and regulated through modulation of the membrane potential. K+ channel activation is mostly associated with outward K+ currents that hyperpolarize the membrane and thereby reduces cell excitability and contractility. The closure of K+ channels induces membrane depolarization and smooth muscle contraction. Calcium channels blockers are one of the class of anti-diarrheal drugs. Depressant effects of Calcium channel blockage is either due to their direct effect on contraction of smooth muscles of intestine or due to interference in cholinergic neurotransmission [74]. Several plants extracts show spasmolytic effects

of diarrhea by 37% in treatment group in comparison to control group. The administeration of compound also showed 20% decrease in peristaltic index. LD50 of 1,8-Cineole was observed to be 1280 mg/Kg [51]. Anti-diarrheal efficacy of Friedelin, isolated from leaves of Azima tetracantha (Salvadoraceae), was evaluated in castor oil induced and Magnesium sulphate induced diarrhea models. The compound was tested at different doses (5, 10, 20 mg/Kg). The compound, at a dose of 20 mg/kg, showed 89% inhibition in castor oil induced diarrhea, whereas in case of Magnesium sulphate induced diarrhea, inhibition was 83%. Reduction of gastrointestinal motility by 69% was also observed [52]. Two diterpenoids, Stachysrosane (1) and Stachysrosane (2), were isolated from Stachys parviflora (Lamiaceae) and tested for their anti-diarrheal potential. In case of Stachysrosane (1), 100% protection from castor oil induced diarrhea was observed at 45 mg/Kg, whereas Stachysrosane (2) was found to show 70% protection from diarrhea [53]. Apigenin is a multifunctionl phytomolecule with multiple pharmacological activities such as, anti-metastatic, anti-osteoporotic, anti-inflammatory, anti-arthritis effects, etc. The compound isolated from Dracocephalum kotschyi (Lamiaceae) was observed to have anti-diarrheal effect causing delay in onset of diarrhea by 32% in treatment group in comparison to control group [54]. Structures of these phytomolecules are shown in Fig. 1. 5. Mechanism of action of anti-diarrheal medicinal plants Most of the herbal extracts are known to exhibit anti-diarrheal activity through one or more of the following mechanisms viz. anti1460

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through their action as calcium channels blockers. These include Holarrhean antidysenterica [40], Elaeagnus umbellate, Buddleja polystachya [70], Morus nigra [67], Pistacia integerrima [75], Heliotropium strigosum and Trapa bicornis [76], Rumex vesicarius [77]. Whereas in others, anticholinergic mechanisms are involved. These plants extracts function through inhibition of either acetylcholinesterase (Polypodium vulgare, Morus nigra) or butylcholinesterase enzymes (Gaultheria trichophylla), thereby resulting into intestinal smooth muscle relaxation [67,69,78]. Plants such as, Adiantum capillus-veneris, Polygonatum verticillatum, Matricaria chamomilla, Symplocos paniculata display anti-spasmodic properties through opening of ATP dependent K+ channels [55,56,64,68].

[3] [4]

[5] [6]

[7]

6. Discussion [8]

Morbidity and mortality due to diarrhea has been a major global health challenge. Due to adverse effects of chemical medications, herbal approaches are being preferred by scientific community in combating diseases. Despite vast availability of the anti-diarrheal traditional plants with proven efficacy, not much attention has been directed towards utilizing these phyto- preparations for treatment of diarrhea and associated ailments. Several scientific reports indicate that these herbal extracts mediate their anti-diarrheal effects through their action as antisecretory agents, anti-peristaltic effects, anti-microbial and anti-spasmodic effects. Though some of the plants have been investigated in detail and active phytoconstituents have also been isolated and identified, however these studies are very few in numbers. Some of the antidiarrheal phytoconstituents such as Apigenin, Friedelin, are known to have multiple therapeutic effects besides their anti-secretory/ antimotility activity. Apigenin, isolated from aerial parts of Dracocephalum kotschyi, is a molecule with multiple pharmacological effects. This molecule has been well investigated for its effect against different types of cancer, arthritis, osteoporosis, inflammation and plays important role in neuronal system with efficacy against Alzheimer and other neural diseases. Certain phytochemicals such as, Eriosematin E (a prenylated flavanone), Stachysrosane and 1,8-cineole (a terpenoid oxide) have not been investigated much. The lead plants and phytomolecules may therefore be further explored for their other related pharmacological effects. Few of the traditionally reported medicinal plants have been demonstrated to possess excellent anti-diarrheal efficacy. Some of the extracts such as, Mangifera indica (leaf), herbal composition of Vernonia amygdalina (leaf) & Cymbopogon citratus (leaf), Polygonatum verticillatum (rhizome), Mimosa diplotricha (leaf), Pelargonium luridum (root), Croton macrostachyus (aerial parts), Oxalis barrelieri (whole plant), Pseudocedrela kotschyi (leaf), Maytenus erythroxylon (leaf), Khaya senegalensis (stem bark), Croton grewioides (aerial parts), Amaranthus trocolor (leaf), Spondias mombin (stem bark), Salvia schemperi (leaf), Cistus salviifolius (aerial parts) and Salacia lehmbachhi (leaf) depicted significant activity against diarrhea with 80%–100% inhibition observed for different tested parameters. These potential herbal extracts should be utilized as source of new herbal drug discovery, used for identification of active plant molecule(s), followed by stringent pre-clinical and clinical investigations for efficacy and safety.

[9]

[10]

[11]

[12] [13] [14]

[15]

[16] [17] [18]

[19]

[20]

[21]

[22]

[23]

[24]

Acknowledgments [25]

Authors are grateful to Prof Anil Gupta, Executive vice Chair, National Innovation Foundation India for his honorary guidance and encouragement for carrying out the research activities.

[26]

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