Br. J. clin. Pharmac. (1992), 33, 573-574
Methods in tropical pharmacology Introduction
That scientists and clinicians should wish to coin the phrase 'Tropical Pharmacology' may in itself be an indictment of the neglect by pharmacologists and others of a subject area which covers a range of debilitating infections which are a threat to millions. Drug treatment of parasitic infections has a long history. Cinchona bark has been used in amoebiasis and malaria for nearly 400 years and in the early years of this century, the arsenicals were introduced for the chemotherapy of trypanosomiasis after the observations of Paul Ehlich showed that these substances had pharmacological activity. Subsequently it was shown that suramin was effective as a macrofilaricide against Onchocerca volvulus. Several of these compounds remain in the front line of the antiparasitic armamentarium even though their toxicological profile renders them wholly inappropriate for mass chemotherapy. A rational strategy for chemotherapy demands that the correct drug is administered to the patient by the most suitable route in the right amount for an appropriate period. The vast majority of antiparasitic agents were introduced before modem techniques for drug evaluation and before the development of sensitive and selective analytical methods for the assay of drugs and metabolites in biological fluids. Thus, regimens used today are often empirically derived. However, by means of improved analytical methodology it is now possible to measure drugs and their metabolites with specificity and sensitivity and, particularly in the treatment of severe malaria, these advances together with the successful application of pharmacokinetic analysis, have enabled a more rational approach to be adopted to the design of dosage regimens. In the tropical regions, the measurement of a drug concentration in the plasma can prove problematic if the most suitable equipment is unavailable. In their article, Peter Winstanley and Bill Watkins, working in Kenya, will outline the difficulties facing clinical pharmacologists under these circumstances, and how their aim of optimization of treatment of severe malaria by attempting to associate measurements of plasma concentrations in vivo to pharmacological responses in vivo and drug action in vitro is being achieved. Clearly, given that populations of malaria parasites may exhibit a range of sensitivities to a given concentration of a particular antimalarial agent, it is reasonable to assume that an optimal therapeutic regimen in, say, East Africa may be entirely inappropriate for South East Asia. The work of Nick White and his colleagues at the Wellcome Unit in Bangkok, Thailand, has been preeminent in the application of the principles of clinical pharmacokinetics to the design of treatment regimens in severe malaria. In his review in this series, Dr White will describe how, by obtaining fundamental information relating to the disposition of key antimalarials, judicious use of pharmacokinetic modelling techniques can generate dosage regimens suitable for evaluation in the field.
Indeed, many of these regimens are now in place as part of treatment schedules for severe malaria in Thailand. Turning to some other tropical diseases of worldwide significance the picture is not one of unqualified success. There have been advances in our understanding of the pharmacology of older drugs and, particularly in the treatment of schistosomiasis the antiparasitic armamentarium is relatively impressive. In onchocerciasis too, the introduction of ivermectin promises to revolutionize the chemotherapy of this disease, offering single-dose treatment with minimum adverse effect. However, we still lack a safe and effective macrofilaricide. Recent developments in this area will be reviewed by Dr Kwablah Awadzi from the Onchocerciasis Chemotherapeutic Research Centre in Ghana, where clinical trials and clinical pharmacological studies have been performed over the last fifteen years under the auspices of the World Health Organisation. While not strictly a 'tropical' disease - since cases are reported within the European continent, including the United Kingdom - echinococcosis or human hydatid disease, poses particular problems for chemotherapy. Until the advent of the broad spectrum anthelmintics, mebendazole and albendazole, surgical removal of hydatid cysts was the only remedy for this infection. However, these anthelmintics, originally introduced for the treatment of worms whose habitat is the gastrointestinal tract, are relatively poorly absorbed and improved formulation and delivery of these compounds is clearly a major issue here, together with an improved ability to diagnose the infection. Philip Craig has worked extensively on hydatid disease in the Peoples Republic of China, and, in association with his colleagues in that country, will highlight current problems and advances. Finally, a great deal of effort has been dedicated to improving our understanding of parasite biochemistry with the aim of identifying putative targets for chemotherapeutic agents. It must be said at the outset that this approach has not entirely been successful even if much important information relating to parasite intermediary metabolism has been generated. A notable discovery has been trypanothione, a compound formed by condensation of glutathione and spermidine which is central to the detoxification mechanisms which operate within trypanosomatid protozoa. These parasites are responsible for severe disease in Europe, Africa and South America and their chemotherapy is most unsatisfactory. Treatment of Trypanosoma cruzi infection is virtually impossible while treatment of Leishmania sp. and Trypanosoma brucei (T. b) gambiense and T. b rhodensiense is, at best, difficult - often involving the administration of toxic drugs based on heavy metals such as antimony and arsenic. Alan Fairlamb and Simon Croft of the London School of Hygiene and Tropical Medicine, will focus on research which has attempted to define the
573
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G. Edwards & S. A. Ward
metabolic differences between parasite and host that might represent good targets for chemotherapy. Again, the emphasis will be on how the tools and methods of biochemistry and pharmacology are being used to further our knowledge which, hopefully, will lead to the development of safer and more effective drugs to be placed at the service of the clinician.
GEOFFREY EDWARDS1'2 & STEPHEN A. WARD' Series Editors 1Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, L69 3BX, UK and 2Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K.
Methods in tropical pharmacology Introduction
That scientists and clinicians should wish to coin the phrase 'Tropical Pharmacology' may in itself be an indictment of the neglect by pharmacologists and others of a subject area which covers a range of debilitating infections which are a threat to millions. Drug treatment of parasitic infections has a long history. Cinchona bark has been used in amoebiasis and malaria for nearly 400 years and in the early years of this century, the arsenicals were introduced for the chemotherapy of trypanosomiasis after the observations of Paul Ehlich showed that these substances had pharmacological activity. Subsequently it was shown that suramin was effective as a macrofilaricide against Onchocerca volvulus. Several of these compounds remain in the front line of the antiparasitic armamentarium even though their toxicological profile renders them wholly inappropriate for mass chemotherapy. A rational strategy for chemotherapy demands that the correct drug is administered to the patient by the most suitable route in the right amount for an appropriate period. The vast majority of antiparasitic agents were introduced before modem techniques for drug evaluation and before the development of sensitive and selective analytical methods for the assay of drugs and metabolites in biological fluids. Thus, regimens used today are often empirically derived. However, by means of improved analytical methodology it is now possible to measure drugs and their metabolites with specificity and sensitivity and, particularly in the treatment of severe malaria, these advances together with the successful application of pharmacokinetic analysis, have enabled a more rational approach to be adopted to the design of dosage regimens. In the tropical regions, the measurement of a drug concentration in the plasma can prove problematic if the most suitable equipment is unavailable. In their article, Peter Winstanley and Bill Watkins, working in Kenya, will outline the difficulties facing clinical pharmacologists under these circumstances, and how their aim of optimization of treatment of severe malaria by attempting to associate measurements of plasma concentrations in vivo to pharmacological responses in vivo and drug action in vitro is being achieved. Clearly, given that populations of malaria parasites may exhibit a range of sensitivities to a given concentration of a particular antimalarial agent, it is reasonable to assume that an optimal therapeutic regimen in, say, East Africa may be entirely inappropriate for South East Asia. The work of Nick White and his colleagues at the Wellcome Unit in Bangkok, Thailand, has been preeminent in the application of the principles of clinical pharmacokinetics to the design of treatment regimens in severe malaria. In his review in this series, Dr White will describe how, by obtaining fundamental information relating to the disposition of key antimalarials, judicious use of pharmacokinetic modelling techniques can generate dosage regimens suitable for evaluation in the field.
Indeed, many of these regimens are now in place as part of treatment schedules for severe malaria in Thailand. Turning to some other tropical diseases of worldwide significance the picture is not one of unqualified success. There have been advances in our understanding of the pharmacology of older drugs and, particularly in the treatment of schistosomiasis the antiparasitic armamentarium is relatively impressive. In onchocerciasis too, the introduction of ivermectin promises to revolutionize the chemotherapy of this disease, offering single-dose treatment with minimum adverse effect. However, we still lack a safe and effective macrofilaricide. Recent developments in this area will be reviewed by Dr Kwablah Awadzi from the Onchocerciasis Chemotherapeutic Research Centre in Ghana, where clinical trials and clinical pharmacological studies have been performed over the last fifteen years under the auspices of the World Health Organisation. While not strictly a 'tropical' disease - since cases are reported within the European continent, including the United Kingdom - echinococcosis or human hydatid disease, poses particular problems for chemotherapy. Until the advent of the broad spectrum anthelmintics, mebendazole and albendazole, surgical removal of hydatid cysts was the only remedy for this infection. However, these anthelmintics, originally introduced for the treatment of worms whose habitat is the gastrointestinal tract, are relatively poorly absorbed and improved formulation and delivery of these compounds is clearly a major issue here, together with an improved ability to diagnose the infection. Philip Craig has worked extensively on hydatid disease in the Peoples Republic of China, and, in association with his colleagues in that country, will highlight current problems and advances. Finally, a great deal of effort has been dedicated to improving our understanding of parasite biochemistry with the aim of identifying putative targets for chemotherapeutic agents. It must be said at the outset that this approach has not entirely been successful even if much important information relating to parasite intermediary metabolism has been generated. A notable discovery has been trypanothione, a compound formed by condensation of glutathione and spermidine which is central to the detoxification mechanisms which operate within trypanosomatid protozoa. These parasites are responsible for severe disease in Europe, Africa and South America and their chemotherapy is most unsatisfactory. Treatment of Trypanosoma cruzi infection is virtually impossible while treatment of Leishmania sp. and Trypanosoma brucei (T. b) gambiense and T. b rhodensiense is, at best, difficult - often involving the administration of toxic drugs based on heavy metals such as antimony and arsenic. Alan Fairlamb and Simon Croft of the London School of Hygiene and Tropical Medicine, will focus on research which has attempted to define the
573
574
G. Edwards & S. A. Ward
metabolic differences between parasite and host that might represent good targets for chemotherapy. Again, the emphasis will be on how the tools and methods of biochemistry and pharmacology are being used to further our knowledge which, hopefully, will lead to the development of safer and more effective drugs to be placed at the service of the clinician.
GEOFFREY EDWARDS1'2 & STEPHEN A. WARD' Series Editors 1Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, L69 3BX, UK and 2Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K.
