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Biomedical subjects

Peter Winstanley

Publications and source records attributed to Peter Winstanley.

11 recordsLinked to original sources
PubMed2006

Malaria chemotherapy.

Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.

Africa↗
PubMed2006

Beyond registration--measuring the public-health potential of new treatments for malaria in Africa.

Malaria claims over one million lives a year in some of the poorest countries of the world. Affected populations and governments cannot afford to pay for expensive new therapies. Most antimalarial treatments are purchased from local shops and administered in the home. These factors make for a complex set of requirements for any new treatment for malaria if a substantial reduction in mortality is ever to be achieved. Thankfully there are several treatments being developed, mostly within public-private partnerships. Typically, the goal of public-private partnerships is the granting of a product license, so work plans end after phase III trials. As these drugs will ultimately be used unsupervised, malaria control programme managers will require further data on safety and whether the drug is as efficacious when used outside of controlled clinical trials before allowing widespread use of these new products. These data need to be collected in highly specific phase IV programmes. We explain why public-private partnerships should extend their development plans well beyond drug registration, and set out the requirements of such a programme. We aim to generate debate and discussion so that guidelines that are internationally accepted and adhered to can be developed not only for antimalarials but for all drugs that are being developed specifically for use in resource-poor settings.

Africa↗
PubMed2006

Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsone.

AIMS: To determine the population pharmacokinetics of chlorproguanil, dapsone and the active metabolite of chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. METHODS: Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n=48) and adults (n=65) and children (n=68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg-1 of chlorproguanil and 2.5 mg kg-1 of dapsone. RESULTS: The population pharmacokinetic parameter estimates for chlorproguanil were ka=00.09 h-1 (intersubject variability was 44%), CL/F=51.53 l h-1 (57%), CLD/F=54.67 l h-1, V1/F=234.40 l (50%) and V2/F=1612.75 l; for dapsone were ka=00.93 h-1, CL/F=1.99 l h-1 (72%) and V/F=76.96 l (48%); and for chlorcycloguanil were CLm/Fm=3.72 l h-1 kg-1 (67%) and Vm/Fm=12.76 l kg-1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. CONCLUSIONS: Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa.

Adolescent↗
PubMed2005

Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet?

Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalarial drug, is associated with selection of point mutations in dihydrofolate reductase and dihydropteroate synthase. Among these mutations, the leucine 164 dihydrofolate reductase mutation (Leu-164) is associated with higher levels of SP resistance; this mutation is also associated with a decrease in the efficacy of chlorproguanil/dapsone, a newly developed antifolate antimalarial drug. Leu-164 has been detected in Southeast Asia and South America, regions where SP is no longer effective. Surprisingly, this mutation has not yet been detected in Africa, using the standard protocol based on PCR-RFLP, despite high SP resistance. In this paper, we discuss briefly the reasons why Leu-164 has not yet been selected in Africa and we propose a means that may slow down the selection of this mutation.

Africa↗
PubMed2004

Current issues in the treatment of uncomplicated malaria in Africa.

Sub-Saharan Africa is faced with a crisis of rising levels of resistance to antimalarial drugs and few available and affordable alternatives. Combination chemotherapy, using two or more drugs with different mechanisms and sites of action together, is proposed as a mechanism for slowing the process of development of resistance. In Thailand, this approach has resulted in a sustained increase in the cure rate. Whether such an effect would be seen in Africa is not known. This article reviews the rationale behind combination therapy, the drugs available and the available evidence from combination therapy trials in Africa. Treatment of uncomplicated malaria in pregnancy and infants is also discussed.

Adult↗
PubMed2004

Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit.

The artemisinins are playing an increasingly important role in treating multidrug-resistant malaria. The artemisinin, artesunate, is currently in use in Southeast Asia and is advocated for use in Africa. In these areas, more than one million people die of malaria each year, with the highest mortality occurring in children and pregnant women. To test the developmental toxicity in ICH-compliant animal studies, embryofetal development studies were conducted in rats and rabbits treated with artesunate alone or a three-drug combination (CDA) consisting of chlorproguanil hydrochloride, Dapsone, and artesunate in the ratio 1.00:1.25:2.00. Developmental toxicity seen with CDA could be attributed to the administered dose of artesunate. The hallmark effect of artesunate exposure was a dramatic induction of embryo loss, apparent as abortions in rabbits and resorptions in both rats and rabbits. In addition, low incidences of cardiovascular malformations and a syndrome of skeletal defects were induced at or close to embryolethal doses of artesunate in both rats and rabbits. The cardiovascular malformations consisted of ventricular septal and vessel defects. The skeletal syndrome consisted of shortened and/or bent long bones and scapulae, misshapen ribs, cleft sternebrae, and incompletely ossified pelvic bones. These developmental effects were observed largely in the absence of any apparent maternal toxicity. The no or low adverse effect levels were in the range of 5 to 7 mg/kg/day artesunate. Encouragingly, no adverse drug-related developmental effects have been observed in a limited number of pregnant women (more than 100 first trimester and 600 second and third trimester) treated with artemisinins, primarily artesunate. Investigations of the mechanism of developmental toxicity are ongoing to attempt to determine whether rats and rabbits are more sensitive to artemisinins than humans.

Abnormalities, Drug-Induced↗
PubMed2004

Therapy of falciparum malaria in sub-saharan Africa: from molecule to policy.

The burden of falciparum malaria remains as great as ever, and, as has probably always been the case, it is carried mainly by tropical Africa. Of the various means available for the control of malaria, the use of effective drugs remains the most important and is likely to remain so for a considerable time to come. Unfortunately, the extensive development of resistance by the parasite threatens the utility of most of the affordable classes of drug: the development of novel antimalarials has never been more urgently needed. Any attempt to understand the vast complexities of falciparum malaria in Africa requires an ability to think "from molecule to policy." In consequence, the review ambitiously tries to examine the current pharmacopeia, the process by which new drugs are developed and the ways in which drugs are actually used, in both the formal and informal health sectors. The informal sector is particularly important in Africa, where around half of all antimalarial treatments are bought from informal outlets and taken at home without supervision by health care professionals: the potential impact of adherence on clinical outcome is discussed. Given that the full costs are carried by the patient in a large proportion of cases, the importance of drug affordability is explored. The review also discusses the splicing of new drugs into national policy. The various parameters that feed into deliberations on changes in drug policy are discussed.

Adolescent↗
PubMed2003

The contribution of clinical pharmacology to antimalarial drug discovery and development.

Unlike human immunodeficiency virus (HIV) disease or tuberculosis, both of which are also major threats to public health throughout the tropics, uncomplicated falciparum malaria is relatively cheaply and rapidly cured, usually in Outpatients. However, in common with both HIV and TB (but to varying degrees), control of malaria is threatened by inadequate resources and drug resistance. Worldwide, it is Africa that carries the greatest burden of falciparum malaria mortality and morbidity; by no coincidence, it is also Africa that is most resource-limited. The drugs for severe disease (quinine and the artemisinins) are largely unaffected by resistance so far, but the 'first-line' drugs, mostly used by outpatients (mainly chloroquine and sulfadoxine-pyrimethamine) are a major cause for concern. Although effective drugs are available, they are largely too expensive for routine use. The present article reviews the ways in which clinical pharmacology has contributed to the identification of new drugs and strategies for malaria.

Africa↗
PubMed2003

Chemosensitization of Plasmodium falciparum by probenecid in vitro.

Resistance to drugs can result from changes in drug transport, and this resistance can sometimes be overcome by a second drug that modifies the transport mechanisms of the cell. This strategy has been exploited to partly reverse resistance to chloroquine in Plasmodium falciparum. Studies with human tumor cells have shown that probenecid can reverse resistance to the antifolate methotrexate, but the potential for reversal of antifolate resistance has not been studied in P. falciparum. In the present study we tested the ability of probenecid to reverse antifolate resistance in P. falciparum in vitro. Probenecid, at concentrations that had no effect on parasite viability alone (50 microM), was shown to increase the sensitivity of a highly resistant parasite isolate to the antifolates pyrimethamine, sulfadoxine, chlorcycloguanil, and dapsone by seven-, five-, three-, and threefold, respectively. The equivalent effects against an antifolate-sensitive isolate were activity enhancements of approximately 3-, 6-, 1.2-, and 19-fold, respectively. Probenecid decreased the level of uptake of radiolabeled folic acid, suggesting a transport-based mechanism linked to folate salvage. When probenecid was tested with chloroquine, it chemosensitized the resistant isolate to chloroquine (i.e., enhanced the activity of chloroquine). This enhancement of activity was associated with increased levels of chloroquine accumulation. In conclusion, we have shown that probenecid can chemosensitize malaria parasites to antifolate compounds via a mechanism linked to reduced folate uptake. Notably, this effect is observed in both folate-sensitive and -resistant parasites. In contrast to the activities of antifolate compounds, the effect of probenecid on chloroquine sensitivity was selective for chloroquine-resistant parasites (patent P407595GB [W. P. Thompson & Co., Liverpool, United Kingdom] has been filed to protect this intellectual property).

Animals↗