TRENDS IN THE DEVELOPMENT OF CHEMOTHERAPY FOR PARASITIC DISEASES ~ I I KEITH ARNOLD I Roche Far East Research Foundation, Hong Kong. I

INTRODUCTION progress has been made in some areas, the disease has not yet been controlled, let alone The predominant trend in the chemotherapy eradicated in malarious regions of Africa, of parasitic diseases is a re-emphasis of the South America and Southeast Asia. In fact, need to continue to search for and develop malaria is returning in India where it had new drugs. The importance of chemotherapy almost been eliminated several years ago in the management of parasitic diseases is (Bruce-Chwatt, 1974). The World Health obvious. The need to continue to look for Organization (WHO), although continuing more effective and less toxic drugs is accepted to emphasize the absolute necessity for mos­ even by those who correctly maintain that quito control, also insists that antimalarial control or eradication of these diseases will drugs will be of great importance in the ma­ only result from measures such as vector nagement of this disease in the near and even control, immunization and improvement in distant future (W.H.O., 1976). public health and sanitation practices. The overall trend is therefore to support There are a large number of parasitic di­ research that is directed to the finding of new seases and it is not possible to mention them chemotherapeutic agents, which is made all individually nor is it appropriate to dis­ even more necessary by the emerging resist­ cuss them under the all embracing term ance throughout the world of P. Jalciparum "parasitoses". Therefore, attention will be to chloroquine. This problem of chloroquine directed first to malaria since this disease resistance has increased the intensity of the still represents the greatest problem among search for more effective and less toxic agents .. the tropical illnesses and is a significant pro­ since quinine is the only drug presently avai­ blem in Southeast Asia. Reference will then lable for serious and complicated cases of be made to amoebiasis which has been esti­ chloroquine resistant faIciparum malaria. mated to affect up to 10 %ofthe world's popu­ It is also the only parenteral drug readily lation; to and filariasis which available in this situation. affect over 400 million people; and to the The trend in chemotherapy of malaria was intestinal helminths such as Ascaris lumbri­ therefore away from the use of chloroquine coides, Trichuris trichiura and hookworm (except in Africa), and instead a complex and which together affect probably more than often toxic regimen was used. This consisted 1,400 million people throughout the world. of quinine three times daily for 10-14 days with pyrimethamine daily for 3 days plus MALARIA dapsone daily for as long as one month It is now apparent that the hope firmly (Sheehy et al., 1967). A much more simple held for many years that malaria would be and less toxic regimen of four doses of qui­ eradicated by programmes involving the nine and a single dose of either a single drug elimination of the anopheline mosquito vec­ (mefloquine) or a combination product, tor has not been realized. Although obvious pyrimethamine with sulfadoxine (Fansidar)

Vol. 9 No.2 June 1978 177 SOUTHEAST AsIAN J. TROP. MED. PuB. HLTH. has recently been mentioned as the treatment which included the screening of all available of choice (Hall, 1976). This regimen has chemicals from various sources as well as the resulted from basic research and clinical synthesis of new compounds. With the emer­ studies performed under the direction of the gence of chloroquine resistance in Southeast U.S. Army Antimalarial Drug Development Asia, more specifically in Vietnam, the U.S. Programme. Army faced a serious military problem and Other studies have shown that combining the Drug Programme received an added an antibiotic, such as tetracycline or clin­ impetus. Well over 200,000 compounds have damycin, with quinine is also effective in been tested. About 3 %were active in primary treating chloroquine resistant falciparum ma­ screening tests and 170 of the most active laria, but the response is slow and recrudes­ compounds went on for advanced testing in cence occurs (Hall, 1975b). monkeys. Pre-clinical pharmacological and toxicological studies were performed on 36 Several institutes are involved in the syn­ selected compounds. Investigational new thesis and testing of new anti-malarial com­ drug applications were submitted to the U.S. pounds, such as the WHO Collaborating Food and Drug Administration for 27 ofthese. Centre in Liverpool, England; a few phar­ Thirteen compounds have been or are being maceutical companies and the U.S. Army studied in clinical trials and several have also Antimalarial Drug Development Programme undergone field evaluation (Canfield and at the Walter Reed Army Institute of Re­ Rozman, 1974). search in Washington D.C. The testing of new drugs will be carried out at the clinical The most promising of all these compounds facilities of WHO Tropical Diseases Re­ was WR 142,490 or, as it is now called, me­ search Centre at Ndola, Zambia, within the floquine. The history of this drug is interest­ framework of the Special Programme for ing. Over 30 years ago a large number of Research and Training in Tropical Diseases; 4-quinolinemethanols were investigated for and in many other centres in countries through their antimalarial activity. The agent with -out the world. One of the most important the greatest activity, SN 10,275, was tested and productive field trial centres is in Thai­ in volunteers. Phototoxic side-effects pre­ land, namely, the U.S. Army Medical Com­ vented its general use although it was an ponent of the Armed Forces Research In­ effective blood schizonticidal agent with a stitute of Medical Sciences (formerly the long duration of activity. A derivative of medical research laboratory of the South this compound, WR 30,090, was recently East Asia Treaty Organization). found to be highly effective in man against both chloroquine-sensitive and chloroquine­ Since the U.S. Army effort is the most resistant strains of P. Jalciparum. This 4­ ambitious and productive and many of the quinolinemethanol showed only slight evi­ actual field studies are done in Thailand it dence of phototoxicity but demonstrated a is appropriate to describe their programme short duration of action. Mefloquine hy­ in more detail. drochloride (WR 142,490) is an analogue of The U.S. Army Antimalarial Drug Deve­ SN 10,275 and WR 30,090. Preclinical studies lopment Programme was organized in 1963 revealed that this drug was more effective with the aim of developing drugs for the than WR 30,090, had the long duration of prevention and treatment of malaria due to action characteristic ofSN 10,275 and showed chloroquine resistant strains of P. Jalciparum. no evidence of phototoxicity (Trenholme et The approach was a comprehensive one al., 1975).

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Extensive clinical testing of the drug under to single agents (Peters, 1975). Hence there I r field conditions has been done and it has been was the initial concurrent use of three drugs, concluded by Hall (1977) that mefioquine in quinine, pyrimethamine and dapsone or a association with quinine is the most effective sulphonamide (Sheehy et al., 1967). This I treatment for patients with chloroquine­ combination was also used because it was resistant falciparum malaria, including those more effective than any of the drugs used with severe or complicated disease. Mefio­ alone in preventing recrudescence. This com­ It I quine has also been shown to be effective plex approach has been much simplified by I when used alone as a single-dose treatment the sequential use of quinine with the fixed of mild falciparum malaria; moreover, it has drug combination of pyrimethamine and sul­ a prophylactic suppressant action against fadoxine. P. vivax and P. jalciparum, but relapse occurs The combination of pyrimethamine with with P. vivax several weeks after cessation the long acting sulphonamide, sulfadoxine, of treatment (Clyde et al., 1976). Unfortu­ is effective when given alone as a single-dose nately, the drug is not commercially avai­ treatment,especially in mild cases, but because lable. A parenteral form of mefioquine would there are some cases of recrudescence and be a very useful alternative to quinine but concern about resistance developing, it is local intolerance to the injection is delaying recommended that quinine be given as well. development of this formulation at the mo­ ment. There is a parenteral form of the pyrimetha­ A few pharmaceutical companies have mine sulfadoxine combination available and been involved in the search for new antima­ studies have shown this to be of value in se­ larials and the combination of pyrimethamine vere malaria, including the cerebral form, with sulfadoxine (Fansidar) is now widely but comparative studies with quinine have accepted and used for the treatment and pro­ not been done. However, Fansidar, is clearly phylaxis of falciparum malaria. In fact, the an important and useful alternative to paren­ combination of this product with quinine teral quinine. maybe the best available treatment for mo­ Although the major emphasis and trend derate and severe chloroquine resistant fal­ has been to develop drugs against P. jalci­ ciparum malaria presently available (Hall et parumthere has been a recent shift ofemphasis al., 1975 a). Fansidar is also recommended to the development of drugs with exoery­ for prophylaxis (WHO, 1976) and is an advan­ throcytic activity, since the only one available tage over presently available drugs since it at present is primaquine. A compound, WR can be given either weekly, every two weeks 171,952, from the U.S. Army Antimalarial or even monthly. Drug Programme, found to be effective in WHO (1976) has recommended that parti­ animal studies, was not successful in human cualr attention should be given to the deve­ volunteers infected with P. vivax (Canfield lopment of long-acting formulations provid­ and Rozman, 1974). New drugs with exoery­ ing optimum bio-availability of the drugs. throcytic activity in animal models are being This therefore is another trend and a promis­ discovered but it will be several years before ing compound of this sort, cycloguanil embo­ clinical trials in humans will be completed. nate, has been developed by Parke-Davis. AMOEBIASIS As regards resistance, the trend now is to use more than one drug at a time in the hope This parasitic is common in many of preventing the development of resistance parts of the world and although the intestinal

Vol. 9 No.2 June 1978 179 SOUTHE.. .sT AsIAN J. TROP. MED. PUB. HLTH. form appears to be a less serious disease in first successfully used in the mid 1960s (Po­ Southeast Asia than in Africa, it causes a well et al., 1966) and until recently was the significant amount of morbidity. drug of choice if given for a period of 5-10 days. Ornidazole (Tiberal) and tinidazole The trend in chemotherapy for amoebiasis (Fasigyn) are newer nitroimidazole deriva­ has been away from the complicated use of tives and studies have shown that ornidazole, a combination of several drugs given at the for example, given only for 3 days is effective same time. This treatment approach was not in treating intestinal amoebiasis (Lasserre, an attempt at preventing the development of 1978; Adjung et al., 1978). For amoebic liver resistance, as in the case of malaria, but was abscess the single dose or single day therapy necessary because of the varying degrees of first shown to be effective with metronidazole effectiveness of the available drugs at the (Aswapokee et al., 1974; Bunnag et al., 1975), sites where the amoebae may be located. That is also true with ornidazole, but at a lower is, in the bowel lumen, the wall of the bowel dosage of 2 gm instead of 2.4 gm (Lasserre, or in the liver. The development of new drugs 1978). Concurrent aspiration of the abscess that are highly active at all these sites is simp­ is recommended. lifying treatment and changing the belief that complete cure of amoebiasis requires In the Western world where metronidazole several drugs and often repeated courses of is mainly used for the treatment of trichomo­ treatment. niasis, a non-serious, non-fatal disease, the recent concern about the carcinogenicity of Previously it was necessary to think of metronidazole in rodents and its mutageni­ drugs as belonging to different categories, city in bacteria has led to a restriction of its such as those that act on amoebae in the bo­ use. In amoebiasis it has been suggested that wel lumen (direct-acting or luminal), those the drug be reserved for the moderate to se­ acting on amoebae in the lumen and in the riously ill patient and that diiodohydroxyquin bowel wall (indirect acting), and those that with paromomycin or tetracycline be used act on the amoebae in the liver and the bowel for the asymptomatic or mild case (Medical wall (tissue amoebicides). Direct-acting or Letter, 1976). In those parts of the world luminal amoebicides include the hydroxy­ where amoebiasis is a serious problem it be­ and the arsenical derivatives. In­ comes a matter of balancing priorities and direct-acting drugs comprise the tetracycline risks and most people treating the disease group of antibiotics; while tissue amoebicides would not hesitiate to use the nitroimidazole include emetine and dehydroemetine and derivatives in the management of all cases of chloroquine which is effective only on amoe­ amoebiasis. bae in the liver. In the past, therefore, for liver and intestinal involvement it was necessary to give emetine and chloroquine for the liver SCHISTOSOMIASIS amoebae, diiodohydroxyquinoline for the luminal amoebae and tetracycline for amoe­ Schistosomiasis, like malaria, presents bae in the bowel wall and lumen. enormous problems to be overcome in order to bring about its eradication. While inten­ New drugs effective at all sites are now sive efforts at vector control must be con­ available and the present trend in the chemo­ tinued there is also an obvious need to find therapy of amoebiasis is to use a single drug better drugs to treat patients who have the for a very short period of time. Metronida­ disease. The trend in chemotherapy is to find zole (Flagyl), a nitroimidazole derivative was more effective and less toxic drugs which can

180 Vol. 9 No. 2 June 1978 CHEMOTHERAPY FOR PARASITIC DISEASES

be used for individual and mass treatment. japonicum There is also a current trend to use drugs f The antimonial drugs given parenterally prophylactically since re-infestation is fre­ are effective although severe side-effects and I quent in areas where the disease is prevalent 1 and transmission is high. The development the parenteral mode of administration re-' strict these drugs to individual treatment. of new schistosomicidal drugs has been slow l due to the marked interspecies variation in can be used for S. japonicum, es­ susceptibility to infection and to the poor pecially for children since the severe side­ correlation between in vitro and in vivo tests effects of this drug are less frequent in pa­ (McMahon, 1976). tients under 14 years of age (BIas, 1978), and its administration is less complicated than Schistosoma haematobium that of the compounds. A new drug, (Bilarcil) an or­ An isoquinoline-pyrazoline derivative, pra­ ganophosphorous compound, is safe and ziquantel (Embay) is presently undergoing effective in treating with S. haema­ clinical trials and appears to be effective tobium but is ineffective against S. mansoni. against all three schistosomes. Roche has When given as a single, spaced-dose oral me­ two new compounds, Ro 11-0761 and Ro 11­ dication (every two weeks) it has also been 3128, which are being tested in phase I clinical found in initial studies in children to be an trials in schistosomiasis. However, it will be effective prophylactic drug since it protected several years before these drugs could be ge­ them against S. haematobium infection (Jews­ nerally available. bury and Cooke, 1976). The treatment of S. haematobium is also With the older more standard drugs there successful with niridazole (Ambilhar) which are certain difficulties, mainly related to side­ acts against S. mansoni and S. japonicum as effects, but a recent long-term follow-up (13 well, but less effectively. This drug given in a years) of antimony-treated S. mansoni infected low dose may inhibit egg production thereby patients showed that 23 % (7 of 30) still had limiting pathological changes and transmis­ active infections (Hedman and Bengtsson, sion while maintaining immunity. If mass 1977). Whether this will also be a problem treatment is given every 3 or 4 years to the with the newer drugs is impossible to say at population affected transmission of the this stage. disease may cease (Roux et al., 1975). Hycanthone has been shown to be a useful drug and in a single intramuscular dose is a convenient treatment for mass campaigns The recent drug of choice for S. mansoni was (Fuadin) but as with other against S. mansoni if the dose is kept low antimony agents such as antimony potassium since large doses cause toxicity and possible tartrate, it must be given parenterally in a liver damage (Cook et al., 1976). But the complicated schedule for several weeks. The known mutagenicity of hycanthone in bac­ trend in chemotherapy therefore, is to use a terial tests and in cytogenetic assays is of new drug, (Mansil) a hydroxy­ concern, especially when a metabolite with tetrahydroquinoline derivative. This drug three times the mutagenic activity of hycan­ when given as a single oral dose treatment thone has been found at the site of an intra­ has fewer side-effects than when given in­ muscular injection eight months later (Bued­ tramuscularly (Katz et al., 1977). ing, 1975).

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FILARIASIS the world. This number is probably increas­ There is little to report concerning trends ing rather than decreasing as a result of the in the chemotherapy of filariasis. The stan­ increased agricultural use of land and artifi­ . dard drug (Hetrazan) is cial irrigation . still the best one available although it is Effective drugs are available that will bring expensive, not completely effective and has about a cure in most instances. Considerable troublesome side-effects. Early clinical trials advances have been made in the last few years with are encouraging (Moreau in discovering drugs that are an improvement et at., 1975) but late relapse occurs with short on older remedies both in selectivity of action treatment courses (Mak, pers. comm.). The and in relative lack of toxicity. The trend mode of action of levamisole is a direct effect has been away from drugs such as aspidium, against the microfilariae and adult worms, hexylresorcinol and gentian violet, which are but whether it works also through its T-cell now obsolete and also away from more recent immunopotentiating properties is not yet discoveries such as pirvinium pamoate and known. tetrachlorethylene in favour of more broad­ A new compound Radanil, a nitroimida­ spectrum activity drugs such as pa­ zole derivative, is effective in Chagas disease moate (Combantrin) and (Ver­ (Trypanosoma cruzi). It has also shown in mox) (Hutchison et at., 1975). Although vitro micro and macro filaricidal activity. At tetrachlorethylene is still considered an effec­ the moment this drug is being tested in animal tive low-cost treatment for hookworm (Se­ models of filariasis at the Institute of Medical newiratne et al., 1975). Research in Kuala Lumpur. If the results Pyrantel is a depolarizing neuromuscular are encouraging, clinical studies in patients blocking agent which causes spastic paralysis will be carried out in Malaysia and Indonesia. of the worm. It is effective against Ascaris Two trends, however, using diethylcarba­ lumbricoides, Enterobius vermicularis, Ancy­ mazine are of interest. A recent study con­ lostoma duodenale and Necator american us. cluded that mass treatment of the population Mebendazole acts by irreversibly inhibiting in highly endemic areas is better than selec­ glucose uptake by the nematode. It is effec­ tive treatment of only those with microfi­ tive against the above and also Trichuris laraemia (Partono and Borahima, 1978). trichiura, and has few side effects (Davis, This is in keeping with another study that 1973). showed in a closed population that the use of common salt medicated with diethylcar­ A methyl-thienyl analogue of pyrantel, bamazine resulted in clinical cure or impro­ moran tel, has been introduced as a veterinary vement in patients with filariasis and in the nematocide with claims of greater tolerabi­ control of the disease in the rest of the popu­ lity. Since pyrantel pamoate was first intro­ lation. This was demonstrated by a signifi­ duced as a veterinary drug several years be­ cant reduction in the microfilarial rate and fore it was studied in man it is probable that microfilarial density in patients and a reduc­ will also undergo human trials. tion in the infection rate and larval density in the mosquito vector (Fan et at., 1978). FUTURE TRENDS Trends in the chemotherapy of parasitic diseases which are as yet little explored, in­ Parasitic worms or helminths are estimated clude the use of compounds to stimulate the to affect a very large number of people around cellular and humoral defence mechanisms of

182 Vol. 9 No.2 June 1978 CHEMOTHERAPY FOR PARASITIC DISEASES the human host. Also under consideration is Research on Malaria. Tech. Report. the use of antibodies as pure substances; but ERO-5-74: 259. the "purification" of large protein molecules, BUEDING, E., (1975). Dissociation of muta­ which is necessary to reduce further antigen­ genic and other toxic properties from antibody production and consequent side­ schistosomicides, in long-term toxicity effects, is extremely difficult. of antischistosomal drugs. J. Toxicol. Since chemical synthesis ofnew compounds Envir. Hlth., 1 : 173. is becoming increasingly more difficult and BUNNAG, D., HARINASUTA, T., VIRAVAN, c., more expensive and the obtaining of useful VANIJANONTA, S. and JAVANAVEJ, A., products from plants has already been ex­ (1975). Clinical trial of metronidazole plored, the search for new chemotherapeutic low dosage in amoebic liver abscess. agents has turned to the sea. The Roche In­ Southeast AsianJ. Trop. Med. Pub. Hlth., stitute of Marine Pharmacology in Australia 6: 99. ~ i is looking at substances isolated from living CANFIELD, C.J. and ROZMAN, R.S., (1974). I organisms found in the ocean. A compound Clinical testing of new antimalarial com­ I kainic acid obtained from a red alga, digenea pounds. Bull. w.H.O. 50 : 203. simplex, has shown anthelminthic activity CLYDE, D .F., MCCARTHY, V.C., MILLER, and this may be the beginning of a new era in R.M. and HORNICK, R.B., (1976). Sup­ the never-ending search for improved drugs pressive activity of mefioquine in sporo­ in man's struggle against disease. zoite-induced human malaria. Antimi­ crobial. Agents Chemother., 9: 384. REFERENCES COOK, J.A., JORDAN, P. and ARMITAGE, P., (1976). Hycanthone dose-response in ADJUNG, S.A., RASAD, R. and RUKMONO, B., treatment of schistosomiasis mansoni (1978). Tiberal in the treatment ofamoe­ in St. Lucia. Amer. J. Trop. Med. Hyg., bic dysentry. In: Proc. 18th SEAMEO­ 25 : 602. TROPMED Seminar: Current Concepts in Diagnosis and Treatment of Parasitic DAVIS, A., (1973). Drug treatment in in­ and other Tropical Diseases. Kuala testinal helminthiasis. w.H.O. Geneva. Lumpur. (in press). FAN, P.C., WANG, Y.C. and KING, M.L., ASWAPOKEE, N ., JAROONVESAMA, N., MUANG­ (1977). Follow-up observations on con­ MANEE, L. and CHAROENLARP, K., (1974). trol of Bancroftian filariasis by common Clinical trial of single course, low dosage salt medicated with diethylcarbamazine regimen of metronidazole in amoebic (DEC) on little Kinmen (Leihyu Dis­ liver abscess. Siriraj Hosp. Gaz., 26: 371. trict), Kinmen (Quemoy) Islands, Repu­ BLAS, B.L., (1978). Further trials with sup­ blic of China. In: Proc. 18th SEAMEO­ pressive dose ofAmbilhar for mass treat­ TROPMED Seminar: Current Concepts ment of Schistosoma japonicum infection. in the Diagnosis and Treatment ofParasitic In: Proc. 18th SEAMEO-TROPMED and other Tropical Diseases. Kuala Seminar: Current Concepts in the Diag­ Lumpur. (in press). nosis and Treatment ofParasitic and other HALL, A.P., (1976). The treatment of mala­ Tropical Diseases. Kuala Lumpur. (in ria. Brit. Med. J., 1 : 323. press). HALL, A.P., DOBERSTYN, E.B., KARNCHANA­ BRUCE-CHWATT, L.J., (1974). Remarks on CHETANEE, C., SAMRANSAMRUAJKIT, S., global malaria eradication. In : Basic LAIXUTHAI, B., PEARLMAN, E.J., LAMPE,

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R.M., MILLER, C.F. and PHINTUYOTHIN, MEDICAL LETTER, (1976). Drugs for parasitic P., (1977). Sequential treatment with infections. In: Handbook of Antimi­ quinine and mefloquine or quinine and crobial Therapy. Revised edition. 53. pyrimethamine-sulfadoxine for falcipa­ MOREAU, J.P., RADANIFLlNA, R. and BAR­ rum malaria. Brit. Med. J., 1 : 1626. BIER, P., (1975). Therapeutic activity of HALL, A.P., DOBERSTYN, E.B., METTAPRA­ levamisole in Bancroftian filariasis. A KONG, V. and SONKOM, P., (1975a). Fal­ follow-up control of microfilaraemia ciparum malaria cured by quinine fol­ during 45 days after 13 days' treatment. lowed by sulfadoxine-pyrimethamine. Med. Trop., 35 : 451. Brit. Med. J., 2 : 15. PARTONO, F. and BORAHIMA, S., (1978). Mass HALL, A.P., DOBERSTYN, E.B., NANAKORN, and selective treatment of Malayan A. and SONKOM, P., (1975b). Falciparum filariasis in two small villages in South malaria semi-resistant to clindamycin. Sulawesi, Indonesia. In: Proc.18th SEA­ Brit. Med. J., 2 : 12. MEO-TROPMED Seminar: Current Con­ HEDMAN, P. and BENGTSSON, E., (1977). A cepts in the Diagnosis and Treatment of 13-year follow-up of antimony-treated Parasitic and other Tropical Diseases. Schistosoma mansoni-infected patients. Kuala Lumpur. (in press). Amer. J. Trop. Med. Hyg., 26 : 693. PETERS, W., (1975). Editorial. J. Trop. Med. HUTCHISON, J.G.P., JOHNSTON, N.M., Hyg., 78 : 169. PLEVEY, M.V.P., THANGKHIEW, I. and POWELL, S.J., MACLEOD, I., WILNOT, A.J. AIDNEY, C., (1975). Clinical trial of and ELSDON-DEW. R., (1966). Metroni­ mebendazole, a broad-spectrum anthel­ dazole in amoebic dysentery and amoe­ minthic. Brit. Med. J., 2 : 309. bic liver abscess. Lancet, 2: 1239. JEWSBURY, J.M. and COOKE, M.J., (1976). Roux, J., PICQ, J.J., LAFAYE, A. and SELLIN, Prophylaxis of schistosomiasis - field B., (1975). Brief immunizing courses of trial of metrifonate for the prevention of niridazole as a protective treatment in human infection. Ann. Trop. Med. Para­ endemic S. haematobium schistosomiasis sit., 70 : 361. areas. A new procedure of mass treat­ KATZ, N., ZICKER, F. and PEREIRA, J.P., ment. Med. Trop., 35: 377. (1977). Field trials with oxamniquine in a schistosomiasis mansoni endemic SENEWIRATNE, B., HETTIARACHI, J. and area. Amer. J. Trop. Med. Hyg., 26: 234. SENEWIRATNE, K., (1975). Acomparative LASSERRE R., (1978). Short treatment of study of the relative efficacy of pyrantel amoebiasis with ornidazole. A review pamoate, bephenium hydroxynaphthoate paper. In: Proc. 18th SEAMEO-TROP­ and tetrachlorethylene in the treatment MED Seminar: Current Concepts in the of Necator american us infection in Cey­ Diagnosis and Treatment of Parasitic and lon. Ann. Trop. Med. Parasit., 69: 233. other Tropical Diseases. Kuala Lumpur. SHEEHY, P.J., REBA, R.C., NEFF, T.A., GAINT­ (in press). NER, J.R. and TIGERTT, W.D., (1967). MCMAHON, J.E., (1976). History of chemo­ Supplemental sulfone (Dapsone) therapy: therapy of bilharziasis, I. Development Use in treatment of chloroquine-resist­ of schistosomicides, II. Approaches to ant falciparum malaria. Arch. Intern. chemotherapy. E. Afr. Med. J., 53 : 295. Med., 119: 561.

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TRENHOLME, G.M., WILLIAM, R.L., DESJAR­ W.H.O., (1976). Malaria situation 1975. DIN, R.E., FRISCHER, H., CARSON, P.E., WHO Chron., 30: 492. RIECKMANN, K.H. and CANFIELD, c.J., (1975). Mefloquine (WR 142,490) in the W.H.O., (1976). Information on malaria treatment of human malaria. Science, risk for international travellers. WHO 190: 792. Wkly. Epidem. Rec., 24 : 200.

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