TRENDS in the DEVELOPMENT of CHEMOTHERAPY for PARASITIC DISEASES ~ I I KEITH ARNOLD I Roche Far East Research Foundation, Hong Kong
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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 schistosomiasis 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). 178 Vol. 9 No.2 June 1978 CHEMOTHERAPY FOR PARASITIC DISEASES 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.