- Email: [email protected]
Antischistosomal therapy: Current status and recent developments
Arab Journal of Gastroenterology 10 (2009) 1–3
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Editorial
Antischistosomal therapy: Current status and recent developments
Historical background and distribution The Nile River has been an epicenter for schistosomiasis since ancient Egypt. In 1980, an estimated 10% of the 200 million persons infected with Schistosoma were Egyptians [1,2]. Two of the three most important human species of Schistosoma are endemic in Egypt: Schistosoma haematobium, which primarily causes disease in the urinary tract, and Schistosoma mansoni, which principally causes morbidity in the gut and liver. Schistosoma japonicum is restricted to the Pacific region [3]. The first effective therapy for schistosomiasis, using multiple intravenous injections of tartar emetic, was introduced in 1918. This was the treatment of choice for American troops infected with S. japonicum during the re-invasion of the Philippines in 1944; tartar emetic remained the standard therapy for S. mansoni and S. japonicum for over 60 years [4]. From the 1950s until the 1980s, the Egyptian Ministry of Health (MOH) undertook large control campaigns using intravenous tartar emetic. Unfortunately, this effort to control a major health problem was accompanied by local side effects [5]. Moreover, it established a very large reservoir of hepatitis C virus (HCV) in the country. By the mid-1980s, the effective oral drug, praziquantel, replaced tartar emetic as treatment for schistosomiasis in the entire country. This reduced both schistosomal transmission and disease [6]. Antischistosomal drugs Schistosome infections can be cured with inexpensive drugs, but people living in endemic countries usually become reinfected. Currently, three effective schistosomicidal drugs are in use [7,8]: Metrifonate (for S. haematobium), oxamniquine (for S. mansoni) and praziquantel (for all human species). Metrifonate: It is an organophosphorus compound with anticholinesterase activity. It acts by blocking the worm’s acetyl cholinesterase causing temporary paralysis of S. haematobium worms. Worms are swept from the vesical plexus into the vena cava to the pulmonary vasculature where they are unable to return to their habitat and are destroyed by the immune response. The dose is 3– 10 mg/kg of body weight given at 2 weeks intervals. This gives a cure rate of 70–80%. It is well tolerated and side effects are mild and rare including colicky abdominal pain, nausea, vomiting, diarrhoea, sweating and bronchospasm. Requiring multiple administrations, it is therefore operationally less convenient in community based control programmes [9]. Oxamniquine: Is a tetrahydroquinolone compound effective against S.mansoni. Its exact mode of action is unknown. It is given as 15 mg/kg of body weight orally in a single dose. This dose results in a cure rate of 60–90% for infections in the Caribbean and South
America. North and East African strains of S. mansoni are less sensitive to this compound and require a dose of 60 mg/kg divided over 3 days. This high dose raises the cost of treatment making it difficult to use in control programs in areas like Egypt, Sudan and Kenya. The only contraindication is tendency to convulsions or epilepsy. Side effects are minor and relatively common (7–15%) in the form of dizziness, drowsiness, headache, abdominal pain, vomiting and diarrhoea. These may last for few hours and disappear spontaneously. Fever may occur on the third or fourth day after therapy and may be associated with eosinophilia and Loffler’s pneumonitis, which is probably related to worms’ death and disintegration [8]. Praziquantel (PZQ): It is an isoquinoline compound and is the drug that is used to treat human schistosomiasis on a large scale. It is given orally and is nontoxic and highly effective against all human schistosomes. It is given in a single dose of 40 mg/kg of body weight. Children and patients infected with japonicum species are given 60 mg/kg in two divided doses. The cure rates are 80–90% and are higher in those with mild infections. However, egg counts are markedly reduced in patients with heavy infection who are not cured by the drug. Cure rates are reported to decrease in the last decade. It was found to be very low in an area in Senegal that is recently invaded by S. mansoni. Oxamniquine could cure patients not responding to praziquantel [10]. Use of PZQ will increase in the foreseeable future, whether given alone or in combination with other anthelminthics in integrated control programmes [10]. PZQ produces instantaneous contraction of the muscles of the parasite followed by spastic paralysis of the worm and rapid vacuolization of its tegument. This occurs due to increased influx of calcium. The changes are maximal in the dorsal membrane tubercles of the male worms. This leads to loss of the attachment of the worms to the endothelium of the vessel wall. They are swept to the liver where they are attached by the phagocytes, granulocytes and cell-mediated immune cells. Thus, the host’s immune response appears strongly implicated in the mode of action of PZQ, [11]. The drug is safe and nontoxic. Minor side effects may occur in the form of epigastric discomfort, abdominal colic, nausea, vomiting, headache, dizziness, pruritis and transient skin eruption. Efficacy and safety of PZQ are similar in patients with and without liver cell failure [12]. In addition to the chemical side effects of antischistosomal drugs, worm death, relocation and degeneration may result in harmful effects, particularly in the presence of a heavy worm load. Worms are swept to the liver, lungs and rarely to the central nervous system where large granulomas may form. A large amount of soluble antigens is released over a short period of time and may be the cause of fever and Loffler’s-like pneumonitis which may be seen after treatment in some patients. Symptoms are usually mild but may be severe in heavy infections when they may be treated
1687-1979/$ - see front matter Arab Journal of Gastroenterology. Published by Elsevier B.V. doi:10.1016/j.ajg.2009.03.002
2
Editorial / Arab Journal of Gastroenterology 10 (2009) 1–3
with a short course of corticosteroids [4]. On an experimental basis, PZQ has been suggested to reverse hepatic fibrosis in schistosomiasis [13]. Drug resistance The chemotherapeutic armamentarium against an important disease such as schistosomiasis consists mainly of just one drug, namely PZQ. Thus, development of drug resistance is an impending danger with serious implications for the health protection of millions of people. This rationale and legitimate concern is reflected by the recent proposal of a new class of compounds that could represent a novel source of drugs against schistosomiasis [14]. Resistance to schistosomicides was first reported against hycanthane in Brazil then in Kenya. As a rule, all hycanthane-resistant strains are also resistant to oxamniquine, but still sensitive to other drugs. Resistance to PZQ has been reported to be induced by heavy drug pressure on the parasite in S. mansoni infected mice. Resistance of human parasite is still a rare occasion in S. mansoni and not in S. haematobium infections. A recent work in Egypt has shown that three out of each 1000 patients harbor parasites that should be treated and can tolerate high doses of PZQ [15]. Failure of PZQ in Senegal was also suggested to be due to resistance [16,17]. Other antischistomal drugs Amoscanate [18]and oltipraz [19] showed good schistosomicidal effects but their clinical evaluation has been suspended in the 1980s because of their toxicity. In general, the safety and efficacy of PZQ proven in its wide scale usage may have retarded development of other drugs. However, the recent reports about PZQ resistance may encourage again research for new antischistosomal drugs [20]. Mirazid is a herbal drug derived from myrrh (purified Commiphora molmol Engier) developed in Egypt. It is available in the local Egyptian market since 2001. It is formulated in soft gelatin capsules each containing 300 mg of purified extract. The adult dose is two capsules daily on an empty stomach for three consecutive days. The drug is safe and no serious side effects have been reported in large scale clinical trials conducted in Egypt. Some patients had giddiness, somnolence or abdominal pain after treatment. Myrrh causes separation of the male and female coupled worms by permanent loss of musculature. This leads to shift of the female worms to the liver where their phagocytosis takes place. The efficacy as an antischistosomal drug has been debated; some studies showed a high efficacy in the treatment of schistosomiasis and fascioliasis [21] in which a cure rate of 91.7% was observed after a dose of 10 mg/kg for three days. In their study, the authors did not report the method of stool analysis used to diagnose schistosomiasis and monitor cure nor the number of stool samples before or after treatment. Although they did report the cure rate, no mention was made of the egg count before or after treatment. Moreover, they stated that the majority of the S. mansoni infected patients treated with Mirazid were previously treated with repeated courses of PZQ, but they did not report the time interval between both treatments. Other authors came to a different opinion when they found a much lower cure rate compared to that of PZQ in their studies [22,23]. These investigators showed a cure rate for Mirazid of 8.9% among S. mansoni infected villagers receiving two doses at a three week interval (each treatment was two capsules taken on an empty stomach for three consecutive days) [18], the cure rate in the other study for Mirazid-reated household members and school children was 8.9% and 9.1% compared with cure rates of 62.5% and 79.7%, in those treated with PZQ, respectively. Therefore, the authors do not recommend mirazid as an agent to control schistosomiasis [23].
A problem with PZQ is that it does not kill schistosomula that are 3–12 days old. Artemeter (an antimalarial drug) can kill these organisms and it can prevent new infection in a dose given every two weeks. It has been tried in S. japonicum-endemic areas in Southern China to prevent new infections during the transmission season [24]. Artemeter is also active against other human schistosomes and it appears to be synergistic to PZQ in killing adult worms. It should not be used in malaria-endemic areas to prevent the selection of artemeter-resistant Plasmodium falciparum [25]. Future therapies Aminoalkanethiols, aminoalkanethiosulfuric acids and the corresponding disulfides: These are sulfur containing compounds that show an interesting in vivo activity against infection by Schistosoma mansoni. These substances include the aminoalkanethiols, aminoalkanethiosulfuric acids and aminoalkyl disulfides, among others. Although the aminoethanethiols and their disulfide derivatives have presented a relatively high toxicity for the host animal, the aminoalkanethiosulfuric acids have a low toxicity and a high specificity for the adult female S. mansoni worms. In vitro studies with schistosomula, lung-phase schistosomula and adult worms have demonstrated effects on the tegument and the metabolism on these different stages of S. mansoni worms. The encapsulation of these drugs in a nanoemulsion has resulted in an increase in the in vitro activity [26]. Artemisinins and the related 1,2,4-trioxolanes are new promising antischistosomal compounds, as are inhibitors of a schistosomespecific bifunctional enzyme, thioredoxin–glutathione reductase [27]. Prevention and control Schistosomiasis cannot be eradicated on a worldwide scale at present although certain foci have been cleared successfully (e.g., in Japan) [28]. Schistosomiasis control is the realistic goal of the present and the near future [4]. In the 1990s, WHO/TDR created a product development program and initiated collaborations with other major international donors to promote rapid vaccine development and other tools for the control of endemic diseases. With regard to schistosomiasis, more than 10 important antigens with strong potential as vaccines candidates were developed; however, most of them have been difficult to move forward [29]. Chemotherapy is the most cost effective form of control as it reduces transmission (by reducing the number of ova in the excreta) and morbidity (by reducing the number of ova retained in the tissues and by lowering the body burden of parasites). Current schistosomicidal drugs are safe and cure at least 75% of infected subjects and reduce ova excretion by 90–95% in those not cured. Treatment may be offered to the whole population (mass chemotherapy) without prior testing, or given only to individuals identified to harbor moderate or severe infections (targeted population chemotherapy). The former approach is suitable for populations with high prevalence (>30%). Savings in time, effort and money to diagnose and evaluate cure in individual patients outweigh the cost and the relatively small risk of a safe drug being administered to the non infected community members. Children and adolescents, especially those out of school, should be the major target population for chemotherapy. Repeated cycles of mass chemotherapy have been effective in many endemic areas in decreasing the overall population morbidity and transmission [30,31]. Preclinical studies demonstrating the antischistosomal activity of artemisinins, and clinical trials showing the safety and efficacy
Editorial / Arab Journal of Gastroenterology 10 (2009) 1–3
of these drugs were published. Given its activity against immature stages of the worm artemisin is promising as a chemopreventive agent [32]. Conclusion Despite the existence of the highly effective antischistosome drug PZQ, schistosomiasis is spreading into new areas, and although it is the cornerstone of current control programs, PZQ chemotherapy does have limitations. In particular, mass treatment does not prevent reinfection. Furthermore, there is increasing concern about the development of parasite resistance to PZQ. Consequently, vaccine strategies represent an essential component for the future control of schistosomiasis as an adjunct to chemotherapy. References [1] Abdel Wahab MF. Schistosomiasis in Egypt. Boca Raton, Florida, USA: CRC Press, Inc.; 1982. [2] Abdel Wahab MF, Strickland GT, El Sahly A, et al. Schistosomiasis mansoni in an Egyptian village in the Nile Delta. Am J Trop Med Hyg 1980;29(5):868–74. [3] Chen Z, Zhou XN, Yang K, et al. Strategy formulation for Schistosomiasis japonica control in different environmental settings supported by spatial analysis: a case study from China. Geospat Health 2007;1(2):223–31. [4] Strickland GT, Ramirez BL. Schistosomiasis. In: Hunter GW, Thomas SG, Strickland GT, et al., editors. Hunter’s tropical medicine and emerging infectious diseases. W.B. Saunders Company; 2000. p. 804–31. [5] Scott JA. The incidence and distribution of the human schistosomes in Egypt. Am J Hyg 1937;25(3):566–614. [6] Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000;355(9207):887–91. [7] Shekhar KC. Schistosomiasis drug therapy and treatment considerations. Drugs 1991;42(3):379–405. [8] Cioli D. Chemotherapy of schistosomiasis: an update. Parasitol Today 1998;14(10):418–22. [9] McMahon JE. A comparative trial of praziquantel, metrifonate and niridazole against Schistosoma haematobium. Ann Trop Med Parasitol 1983;77(2):139–42. [10] Picquet M, Vercruysse J, Shaw DJ, et al. Efficacy of praziquantel against Schistosoma mansoni in Northern Senegal. Trans R Soc Trop Med Hyg 1998;92(1):90–3. [11] Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 2008;21(6):659–67. [12] El Guiniady MA, el Touny MA, Abdel Bary MA, et al. Clinical and pharmacokinetic study of praziquantel in Egyptian schistosomiasis patients with and without liver cell failure. Am J Trop Med Hyg 1994;51(6):809–18. [13] Helmi AH, Abdel Hadi AA, El Shanawani F, et al. The pharmacological approach to reverse portal hypertension and hepatic schistosomal fibrosis in Egypt. J Egypt Soc Parasitol 2005;35(3):731–50. [14] Cioli D, Valle C, Angelucci F, et al. Will new antischistosomal drugs finally emerge? Trends Parasitol 2008;24(9):379–82.
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[15] Ismail M, Botros S, Metwally A, et al. Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. Am J Trop Med Hyg 1999;60(6):932–5. [16] Danso Appiah A, Utzinger J, Liu J, et al. Drugs for treating urinary schistosomiasis. Cochrane Database Syst Rev 2008(3):CD000053. [17] Gryseels B, Mbaye A, De Vlas SJ, et al. Are poor responses to praziquantel for the treatment of Schistosoma mansoni infections in Senegal due to resistance? An overview of the evidence. Trop Med Int Health 2001;6(11): 864–73. [18] Kohler P, Davies KP, Zahner H. Activity, mechanism of action and pharmacokinetics of 2-tert-butylbenzothiazole and CGP 6140 (amocarzine) antifilarial drugs. Acta Trop 1992;51(3–4):195–211. [19] Benson 3rd AB. Oltipraz: a laboratory and clinical review. J Cell Biochem Suppl 1993;17F:278–91. [20] Doenhoff MJ, Kusel JR, Coles GC, et al. Resistance of Schistosoma mansoni to praziquantel: is there a problem? Trans R Soc Trop Med Hyg 2002;96(5): 465–9. [21] Sheir Z, Nasr AA, Massoud A, et al. A safe, effective, herbal antischistosomal therapy derived from myrrh. Am J Trop Med Hyg 2001;65(6):700–4. [22] Barakat R, Elmorshedy H, Fenwick A. Efficacy of myrrh in the treatment of human Schistosomiasis mansoni. Am J Trop Med Hyg 2005;73(2):365–7. [23] Botros S, Sayed H, El Dusoki H, et al. Efficacy of mirazid in comparison with praziquantel in Egyptian Schistosoma mansoni-infected school children and households. Am J Trop Med Hyg 2005;72(2):119–23. [24] Xiao SH, Booth M, Tanner M. The prophylactic effects of artemether against Schistosoma japonicum infections. Parasitol Today 2000;16(3):122–6. [25] Utzinger J, N’Goran EK, N’Dri A, et al. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet 2000;355(9212):1320–5. [26] De Oliveira Penido ML, Zech Coelho PM, de Mello RT, et al. Antischistosomal activity of aminoalkanethiols, aminoalkanethiosulfuric acids and the corresponding disulfides. Acta Trop 2008;108(2-3):249–55. [27] Utzinger J, Xiao SH, Tanner M, et al. Artemisinins for schistosomiasis and beyond. Curr Opin Invest Drugs 2007;8(2):105–16. [28] Ebisawa I. Epidemiology and eradication of Schistosomiasis japonica in Japan. J Travel Med 1998;5(1):33–5. [29] McManus DP, Loukas A. Current status of vaccines for schistosomiasis. Clin Microbiol Rev 2008;21(1):225–42. [30] Butterworth AE, Sturrock RF, Ouma JH, et al. Comparison of different chemotherapy strategies against Schistosoma mansoni in Machakos District, Kenya: effects on human infection and morbidity. Parasitology 1991;103 Pt 3:339–55. [31] Olveda RM, Daniel BL, Ramirez BD, et al. Schistosomiasis japonica in the Philippines: the long-term impact of population-based chemotherapy on infection, transmission and morbidity. J Infect Dis 1996;174(1):163–72. [32] El Bassiouni EA, Helmy MH, Saad EI, et al. Modulation of the antioxidant defence in different developmental stages of Schistosoma mansoni by praziquantel and artemether. Br J Biomed Sci 2007;64(4):168–74.
Gamal Esmat * Maissa El Raziky Tropical Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt * Tel.: +20 2236847524; fax: +20 223682774 E-mail address: [email protected] (Gamal Esmat)
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Editorial
Antischistosomal therapy: Current status and recent developments
Historical background and distribution The Nile River has been an epicenter for schistosomiasis since ancient Egypt. In 1980, an estimated 10% of the 200 million persons infected with Schistosoma were Egyptians [1,2]. Two of the three most important human species of Schistosoma are endemic in Egypt: Schistosoma haematobium, which primarily causes disease in the urinary tract, and Schistosoma mansoni, which principally causes morbidity in the gut and liver. Schistosoma japonicum is restricted to the Pacific region [3]. The first effective therapy for schistosomiasis, using multiple intravenous injections of tartar emetic, was introduced in 1918. This was the treatment of choice for American troops infected with S. japonicum during the re-invasion of the Philippines in 1944; tartar emetic remained the standard therapy for S. mansoni and S. japonicum for over 60 years [4]. From the 1950s until the 1980s, the Egyptian Ministry of Health (MOH) undertook large control campaigns using intravenous tartar emetic. Unfortunately, this effort to control a major health problem was accompanied by local side effects [5]. Moreover, it established a very large reservoir of hepatitis C virus (HCV) in the country. By the mid-1980s, the effective oral drug, praziquantel, replaced tartar emetic as treatment for schistosomiasis in the entire country. This reduced both schistosomal transmission and disease [6]. Antischistosomal drugs Schistosome infections can be cured with inexpensive drugs, but people living in endemic countries usually become reinfected. Currently, three effective schistosomicidal drugs are in use [7,8]: Metrifonate (for S. haematobium), oxamniquine (for S. mansoni) and praziquantel (for all human species). Metrifonate: It is an organophosphorus compound with anticholinesterase activity. It acts by blocking the worm’s acetyl cholinesterase causing temporary paralysis of S. haematobium worms. Worms are swept from the vesical plexus into the vena cava to the pulmonary vasculature where they are unable to return to their habitat and are destroyed by the immune response. The dose is 3– 10 mg/kg of body weight given at 2 weeks intervals. This gives a cure rate of 70–80%. It is well tolerated and side effects are mild and rare including colicky abdominal pain, nausea, vomiting, diarrhoea, sweating and bronchospasm. Requiring multiple administrations, it is therefore operationally less convenient in community based control programmes [9]. Oxamniquine: Is a tetrahydroquinolone compound effective against S.mansoni. Its exact mode of action is unknown. It is given as 15 mg/kg of body weight orally in a single dose. This dose results in a cure rate of 60–90% for infections in the Caribbean and South
America. North and East African strains of S. mansoni are less sensitive to this compound and require a dose of 60 mg/kg divided over 3 days. This high dose raises the cost of treatment making it difficult to use in control programs in areas like Egypt, Sudan and Kenya. The only contraindication is tendency to convulsions or epilepsy. Side effects are minor and relatively common (7–15%) in the form of dizziness, drowsiness, headache, abdominal pain, vomiting and diarrhoea. These may last for few hours and disappear spontaneously. Fever may occur on the third or fourth day after therapy and may be associated with eosinophilia and Loffler’s pneumonitis, which is probably related to worms’ death and disintegration [8]. Praziquantel (PZQ): It is an isoquinoline compound and is the drug that is used to treat human schistosomiasis on a large scale. It is given orally and is nontoxic and highly effective against all human schistosomes. It is given in a single dose of 40 mg/kg of body weight. Children and patients infected with japonicum species are given 60 mg/kg in two divided doses. The cure rates are 80–90% and are higher in those with mild infections. However, egg counts are markedly reduced in patients with heavy infection who are not cured by the drug. Cure rates are reported to decrease in the last decade. It was found to be very low in an area in Senegal that is recently invaded by S. mansoni. Oxamniquine could cure patients not responding to praziquantel [10]. Use of PZQ will increase in the foreseeable future, whether given alone or in combination with other anthelminthics in integrated control programmes [10]. PZQ produces instantaneous contraction of the muscles of the parasite followed by spastic paralysis of the worm and rapid vacuolization of its tegument. This occurs due to increased influx of calcium. The changes are maximal in the dorsal membrane tubercles of the male worms. This leads to loss of the attachment of the worms to the endothelium of the vessel wall. They are swept to the liver where they are attached by the phagocytes, granulocytes and cell-mediated immune cells. Thus, the host’s immune response appears strongly implicated in the mode of action of PZQ, [11]. The drug is safe and nontoxic. Minor side effects may occur in the form of epigastric discomfort, abdominal colic, nausea, vomiting, headache, dizziness, pruritis and transient skin eruption. Efficacy and safety of PZQ are similar in patients with and without liver cell failure [12]. In addition to the chemical side effects of antischistosomal drugs, worm death, relocation and degeneration may result in harmful effects, particularly in the presence of a heavy worm load. Worms are swept to the liver, lungs and rarely to the central nervous system where large granulomas may form. A large amount of soluble antigens is released over a short period of time and may be the cause of fever and Loffler’s-like pneumonitis which may be seen after treatment in some patients. Symptoms are usually mild but may be severe in heavy infections when they may be treated
1687-1979/$ - see front matter Arab Journal of Gastroenterology. Published by Elsevier B.V. doi:10.1016/j.ajg.2009.03.002
2
Editorial / Arab Journal of Gastroenterology 10 (2009) 1–3
with a short course of corticosteroids [4]. On an experimental basis, PZQ has been suggested to reverse hepatic fibrosis in schistosomiasis [13]. Drug resistance The chemotherapeutic armamentarium against an important disease such as schistosomiasis consists mainly of just one drug, namely PZQ. Thus, development of drug resistance is an impending danger with serious implications for the health protection of millions of people. This rationale and legitimate concern is reflected by the recent proposal of a new class of compounds that could represent a novel source of drugs against schistosomiasis [14]. Resistance to schistosomicides was first reported against hycanthane in Brazil then in Kenya. As a rule, all hycanthane-resistant strains are also resistant to oxamniquine, but still sensitive to other drugs. Resistance to PZQ has been reported to be induced by heavy drug pressure on the parasite in S. mansoni infected mice. Resistance of human parasite is still a rare occasion in S. mansoni and not in S. haematobium infections. A recent work in Egypt has shown that three out of each 1000 patients harbor parasites that should be treated and can tolerate high doses of PZQ [15]. Failure of PZQ in Senegal was also suggested to be due to resistance [16,17]. Other antischistomal drugs Amoscanate [18]and oltipraz [19] showed good schistosomicidal effects but their clinical evaluation has been suspended in the 1980s because of their toxicity. In general, the safety and efficacy of PZQ proven in its wide scale usage may have retarded development of other drugs. However, the recent reports about PZQ resistance may encourage again research for new antischistosomal drugs [20]. Mirazid is a herbal drug derived from myrrh (purified Commiphora molmol Engier) developed in Egypt. It is available in the local Egyptian market since 2001. It is formulated in soft gelatin capsules each containing 300 mg of purified extract. The adult dose is two capsules daily on an empty stomach for three consecutive days. The drug is safe and no serious side effects have been reported in large scale clinical trials conducted in Egypt. Some patients had giddiness, somnolence or abdominal pain after treatment. Myrrh causes separation of the male and female coupled worms by permanent loss of musculature. This leads to shift of the female worms to the liver where their phagocytosis takes place. The efficacy as an antischistosomal drug has been debated; some studies showed a high efficacy in the treatment of schistosomiasis and fascioliasis [21] in which a cure rate of 91.7% was observed after a dose of 10 mg/kg for three days. In their study, the authors did not report the method of stool analysis used to diagnose schistosomiasis and monitor cure nor the number of stool samples before or after treatment. Although they did report the cure rate, no mention was made of the egg count before or after treatment. Moreover, they stated that the majority of the S. mansoni infected patients treated with Mirazid were previously treated with repeated courses of PZQ, but they did not report the time interval between both treatments. Other authors came to a different opinion when they found a much lower cure rate compared to that of PZQ in their studies [22,23]. These investigators showed a cure rate for Mirazid of 8.9% among S. mansoni infected villagers receiving two doses at a three week interval (each treatment was two capsules taken on an empty stomach for three consecutive days) [18], the cure rate in the other study for Mirazid-reated household members and school children was 8.9% and 9.1% compared with cure rates of 62.5% and 79.7%, in those treated with PZQ, respectively. Therefore, the authors do not recommend mirazid as an agent to control schistosomiasis [23].
A problem with PZQ is that it does not kill schistosomula that are 3–12 days old. Artemeter (an antimalarial drug) can kill these organisms and it can prevent new infection in a dose given every two weeks. It has been tried in S. japonicum-endemic areas in Southern China to prevent new infections during the transmission season [24]. Artemeter is also active against other human schistosomes and it appears to be synergistic to PZQ in killing adult worms. It should not be used in malaria-endemic areas to prevent the selection of artemeter-resistant Plasmodium falciparum [25]. Future therapies Aminoalkanethiols, aminoalkanethiosulfuric acids and the corresponding disulfides: These are sulfur containing compounds that show an interesting in vivo activity against infection by Schistosoma mansoni. These substances include the aminoalkanethiols, aminoalkanethiosulfuric acids and aminoalkyl disulfides, among others. Although the aminoethanethiols and their disulfide derivatives have presented a relatively high toxicity for the host animal, the aminoalkanethiosulfuric acids have a low toxicity and a high specificity for the adult female S. mansoni worms. In vitro studies with schistosomula, lung-phase schistosomula and adult worms have demonstrated effects on the tegument and the metabolism on these different stages of S. mansoni worms. The encapsulation of these drugs in a nanoemulsion has resulted in an increase in the in vitro activity [26]. Artemisinins and the related 1,2,4-trioxolanes are new promising antischistosomal compounds, as are inhibitors of a schistosomespecific bifunctional enzyme, thioredoxin–glutathione reductase [27]. Prevention and control Schistosomiasis cannot be eradicated on a worldwide scale at present although certain foci have been cleared successfully (e.g., in Japan) [28]. Schistosomiasis control is the realistic goal of the present and the near future [4]. In the 1990s, WHO/TDR created a product development program and initiated collaborations with other major international donors to promote rapid vaccine development and other tools for the control of endemic diseases. With regard to schistosomiasis, more than 10 important antigens with strong potential as vaccines candidates were developed; however, most of them have been difficult to move forward [29]. Chemotherapy is the most cost effective form of control as it reduces transmission (by reducing the number of ova in the excreta) and morbidity (by reducing the number of ova retained in the tissues and by lowering the body burden of parasites). Current schistosomicidal drugs are safe and cure at least 75% of infected subjects and reduce ova excretion by 90–95% in those not cured. Treatment may be offered to the whole population (mass chemotherapy) without prior testing, or given only to individuals identified to harbor moderate or severe infections (targeted population chemotherapy). The former approach is suitable for populations with high prevalence (>30%). Savings in time, effort and money to diagnose and evaluate cure in individual patients outweigh the cost and the relatively small risk of a safe drug being administered to the non infected community members. Children and adolescents, especially those out of school, should be the major target population for chemotherapy. Repeated cycles of mass chemotherapy have been effective in many endemic areas in decreasing the overall population morbidity and transmission [30,31]. Preclinical studies demonstrating the antischistosomal activity of artemisinins, and clinical trials showing the safety and efficacy
Editorial / Arab Journal of Gastroenterology 10 (2009) 1–3
of these drugs were published. Given its activity against immature stages of the worm artemisin is promising as a chemopreventive agent [32]. Conclusion Despite the existence of the highly effective antischistosome drug PZQ, schistosomiasis is spreading into new areas, and although it is the cornerstone of current control programs, PZQ chemotherapy does have limitations. In particular, mass treatment does not prevent reinfection. Furthermore, there is increasing concern about the development of parasite resistance to PZQ. Consequently, vaccine strategies represent an essential component for the future control of schistosomiasis as an adjunct to chemotherapy. References [1] Abdel Wahab MF. Schistosomiasis in Egypt. Boca Raton, Florida, USA: CRC Press, Inc.; 1982. [2] Abdel Wahab MF, Strickland GT, El Sahly A, et al. Schistosomiasis mansoni in an Egyptian village in the Nile Delta. Am J Trop Med Hyg 1980;29(5):868–74. [3] Chen Z, Zhou XN, Yang K, et al. Strategy formulation for Schistosomiasis japonica control in different environmental settings supported by spatial analysis: a case study from China. Geospat Health 2007;1(2):223–31. [4] Strickland GT, Ramirez BL. Schistosomiasis. In: Hunter GW, Thomas SG, Strickland GT, et al., editors. Hunter’s tropical medicine and emerging infectious diseases. W.B. Saunders Company; 2000. p. 804–31. [5] Scott JA. The incidence and distribution of the human schistosomes in Egypt. Am J Hyg 1937;25(3):566–614. [6] Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000;355(9207):887–91. [7] Shekhar KC. Schistosomiasis drug therapy and treatment considerations. Drugs 1991;42(3):379–405. [8] Cioli D. Chemotherapy of schistosomiasis: an update. Parasitol Today 1998;14(10):418–22. [9] McMahon JE. A comparative trial of praziquantel, metrifonate and niridazole against Schistosoma haematobium. Ann Trop Med Parasitol 1983;77(2):139–42. [10] Picquet M, Vercruysse J, Shaw DJ, et al. Efficacy of praziquantel against Schistosoma mansoni in Northern Senegal. Trans R Soc Trop Med Hyg 1998;92(1):90–3. [11] Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 2008;21(6):659–67. [12] El Guiniady MA, el Touny MA, Abdel Bary MA, et al. Clinical and pharmacokinetic study of praziquantel in Egyptian schistosomiasis patients with and without liver cell failure. Am J Trop Med Hyg 1994;51(6):809–18. [13] Helmi AH, Abdel Hadi AA, El Shanawani F, et al. The pharmacological approach to reverse portal hypertension and hepatic schistosomal fibrosis in Egypt. J Egypt Soc Parasitol 2005;35(3):731–50. [14] Cioli D, Valle C, Angelucci F, et al. Will new antischistosomal drugs finally emerge? Trends Parasitol 2008;24(9):379–82.
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Gamal Esmat * Maissa El Raziky Tropical Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt * Tel.: +20 2236847524; fax: +20 223682774 E-mail address: [email protected] (Gamal Esmat)