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Biomedical subjects

P Winstanley

Publications and source records attributed to P Winstanley.

At least 19 recordsLinked to original sources
PubMed2001

Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania.

BACKGROUND: Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine. METHODS: Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase (dhfr) and dyhydropteroate synthetase (dhps). FINDINGS: 360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (7%) of 44 [corrected] children retreated with chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations. INTERPRETATION: Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.

Adolescent↗
PubMed2001

Modern chemotherapeutic options for malaria.

Unlike HIV disease or tuberculosis, both of which are also major threats to public health throughout the tropics, uncomplicated malaria of whatever species can be cheaply and rapidly cured, usually in outpatients. However, in common with both HIV and tuberculosis, control of malaria is threatened by inadequate resources and by drug resistance. Africa carries the greatest burden of malaria mortality and morbidity; by no coincidence, Africa is also the most resource-limited. The drugs for severe disease (quinine and the artemisinins) are largely unaffected by resistance so far, but the "first-line" drugs, mainly used by outpatients (eg, chloroquine and sulfadoxine-pyrimethamine), are a major cause for concern. Although effective drugs are available they are mostly too expensive for routine use. This article reviews the main drugs for malaria and outlines the therapeutic use of these drugs for uncomplicated and severe disease. The article then examines the challenges faced in the processes of changing policy, and the implementation of that policy shift.

Africa↗
PubMed2001

Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria.

The synergistic antifolate combination of chlorproguanil with dapsone (CPG-DDS; LAPDAP) is being developed by a public-private partnership as a low-cost treatment for uncomplicated falciparum malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this. A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency and African licencing authorities. The team working on LAPDAP has also started to develop the triple combination of chlorproguanil-dapsone-artesunate (CDA) as a low-cost combination therapy for uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and development of CDA is at an early stage), the development team is keen to communicate with public health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated public health issues.

Antimalarials↗
PubMed2000

Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study.

BACKGROUND: Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae. We undertook a randomised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria. METHODS: Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly assigned a single intramuscular dose of phenobarbital (20 mg/kg) or identical placebo. Clinical tolerance was assessed at the start of the trial, with particular reference to respiratory depression and hypotension. Seizures were timed and recorded, and treated in a standard way. Plasma phenobarbital concentrations were measured. Analyses were by intention to treat. FINDINGS: 440 children with cerebral malaria were admitted to the hospital; 100 were not recruited to the study. Of the remaining 340, 170 received phenobarbital and 170 placebo. The drug was adequately absorbed and well tolerated. Seizure frequency was significantly lower in the phenobarbital group than in the placebo group (18 [11%] vs 46 [27%] children had three or more seizures of any duration; odds ratio 0.32 [95% CI 0.18-0.58]) but mortality was doubled (30 [18%] vs 14 [8%] deaths; 2.39 [1.28-4.64]). The frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group, and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam (odds ratio 31.7 [1.2-814]). INTERPRETATION: In children with cerebral malaria, phenobarbital 20 mg/kg provides highly effective seizure prophylaxis but is associated with an unacceptable increase in mortality. Use of this dose cannot, therefore, be recommended.

Adolescent↗
PubMed1999

Comparative bioavailability of three different preparations of rifampicin.

OBJECTIVE: To study the relative bioavailabilities of two generic rifampicin preparations with Rimactane. METHOD: Each of nineteen healthy volunteers received a single oral dose of 600 mg of rifampicin in an open cross-over randomised three-way single-dose design with a washout period of 7 days between each doses. Plasma concentrations of rifampicin were determined by HPLC. In vitro dissolution profiles of the same drugs were determined and compared with human bioavailability study results. RESULTS: No statistically significant difference was found in main bioavailability parameters between Rimactane and generic preparations studied. Both generic preparations also fulfilled the bioequivalence criteria based on the 90% confidence intervals. There was a good correlation between in vivo and in vitro results: faster dissolution time corresponded to the lower Tmax value; lower percentage of released compound to the lower AUC value. Significant intersubject variations were found in main bioavailability parameters; significant negative correlation was found between average AUC values and body weight of the volunteer. CONCLUSION: All three products were bioequivalent. Our results also suggest the suitability of one-compartmental model with lag time, first order input and first order output to describe the kinetics of rifampicin.

Administration, Oral↗
PubMed1998

Clinical trials of chemotherapy for falciparum malaria.

Plasmodium falciparum remains one of the World's most prevalent and devastating pathogens. Mainly for economic reasons, the parasite's ability to develop resistance to drugs has not been matched by the rate at which new compounds are developed. Even so, there are new drugs (or new combinations of old drugs) currently under investigation, or in the process of development (at the moment): Pyronaridine, a well-tolerated, synthetic drug that may have utility for multi-resistant falciparum malaria in many parts of the world; however,problems remain over the formulation of this drug (which is a major determinant of its bioavailability) and its eventual cost. Chlorproguanil-dapsone (lap dap) is being studied as a possible low-cost'successor' to pyrimethamine-sulfadoxine; the utility of chlorproguanil-dapsone as 'salvage' therapy for clinical cases of pyrimethamine-sulfadoxine failure has yet to be tested in clinical trials. Atovaquone-proguanil (malarone) has utility against multi-resistant parasites; however, it is likely to be expensive (but is currently being provided free-of-charge in certain areas of Africa). Artemether-benflumetol (coartemether) combines the advantages of artemether (a rapid reduction in parasite load) with a second drug that reduces the risk of recrudescence; the cost of this combination is unclear. Rectal artesunate is being studied as an intervention to reduce the proportion of children with falciparum malaria who deteriorate to severe disease; the formulation is appropriate for use in rural health centres.

Journal Article↗
PubMed1997

New prospects for the treatment of malaria.

This update focuses on drugs for both uncomplicated and severe falciparum malaria. Chloroquine, long the mainstay of therapy, is no longer reliable because of widespread resistance, but is still attractive because of its very low cost. The following strategies for the future use of 4-aminoquinolines in uncomplicated malaria are discussed: the use of other existing 4-aminoquinolines such as amodiaquine, drug-induced reversal of chloroquine resistance, and the development of new 4-aminoquinolines with activity against resistant isolates. Pyrim- ethamine-sulfadoxine is now the drug of first-choice in much of Africa, but resistance to this antifolate combination is expected to become clinically apparent within the next five years. Research into the utility of novel antifolate combinations is described. Mefloquine and halofantrine are drugs which are extensively used in Southeast Asia, but are too expensive for general use in most African countries. The possible roles for artemisinine derivatives (alone and in combination with either mefloquine or benflumitol), pyronaridine and atovaquone-proguanil are described. The absolute importance of drug cost as a determinant of its utility in poorer countries is emphasised.

Journal Article↗
PubMed1997

Infection with Plasmodium berghei alters benzodiazepine receptor in rat brain.

The purpose of this study was to assess the effect of malaria infection on benzodiazepine binding in rat brain. Young male Wistar rats were infected with the rodent parasite Plasmodium berghei, while age-matched control rats (n = 5) received normal saline intraperitoneally. Parasitemia was determined in blood of infected animals. Animals were killed after two weeks, and synaptosomal brain membrane homogenate was prepared from cerebral cortex. Membrane homogenate was incubated in duplicate with 3H-flunitrazepam (0.2-10 nM in buffer, pH 7.4) and binding parameters determined. The number of receptors (Bmax) was decreased marginally but significantly (P = 0.047) in malaria-infected (MI) rats (MI rats: 1.12 +/- 0.1 pmol.mg-1 protein; control rats: 1.42 +/- 0.08 pmol.mg-1 protein) while binding affinity (Kd) was not altered (MI rats: 1.18 +/- 0.3 nM; control rats: 1.02 +/- 0.15 nM). These results suggest that malaria may be associated with decreased benzodiazepine activity.

Animals↗
PubMed1995

Indicators of life-threatening malaria in African children.

BACKGROUND: About 90 percent of the deaths from malaria are in African children, but criteria to guide the recognition and management of severe malaria have not been validated in them. METHODS: We conducted a prospective study of all children admitted to the pediatric ward of a Kenyan district hospital with a primary diagnosis of malaria. We calculated the frequency and mortality rate for each of the clinical and laboratory criteria in the current World Health Organization (WHO) definition of severe malaria, and then used logistic-regression analysis to identify the variables with the greatest prognostic value. RESULTS: We studied 1844 children (mean age, 26.4 months) with a primary diagnosis of malaria. Not included were 18 children who died on arrival and 4 who died of other causes. The mortality rate was 3.5 percent (95 percent confidence interval, 2.7 to 4.3 percent), and 84 percent of the deaths occurred within 24 hours of admission. Logistic-regression analysis identified four key prognostic indicators: impaired consciousness (relative risk, 3.3; 95 percent confidence interval, 1.6 to 7.0), respiratory distress (relative risk, 3.9; 95 percent confidence interval, 2.0 to 7.7), hypoglycemia (relative risk, 3.3; 95 percent confidence interval, 1.6 to 6.7), and jaundice (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.3). Of the 64 children who died, 54 were among those with impaired consciousness (n = 336; case fatality rate, 11.9 percent) or respiratory distress (n = 251; case fatality rate, 13.9 percent), or both. Hence, this simple bedside index identified 84.4 percent of the fatal cases, as compared with the 79.7 percent identified by the current WHO criteria. CONCLUSIONS: In African children with malaria, the presence of impaired consciousness or respiratory distress can identify those at high risk for death.

Anemia↗
PubMed1995

Marked variation in pyrimethamine disposition in AIDS patients treated for cerebral toxoplasmosis.

We have characterized the disposition of pyrimethamine in 20 adults with advanced AIDS. After the first dose, the area under concentration versus time curves (corrected for dose-size) varied 13-fold. This marked variation in drug levels was also noted during accumulation towards steady-state: pyrimethamine levels were consistently below the suggested lower end of the therapeutic range (750 mg/L) in three severely ill patients with perturbed consciousness (two of whom received the drug by nasogastric tube). Possible mechanisms for these observations are discussed. Pyrimethamine levels may be an important determinant of the rate of response to treatment by AIDS patients with toxoplasmosis: therapeutic drug monitoring may have a role.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Drug treatment of toxoplasmic encephalitis in acquired immunodeficiency syndrome.

Toxoplasma gondii is a ubiquitous parasite, which causes several serious diseases. Until the AIDS pandemic, toxoplasmic encephalitis was largely confined to the pharmacologically immune-suppressed and to cases of congenital transmission. T gondii is now one of the more commonly encountered opportunistic pathogens of advanced AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1990

Adverse effects of captopril in hospital outpatients with hypertension.

Hypertensive patients prescribed captopril while attending a hospital hypertension clinic were studied, to identify the benefits of the drug, its adverse effects and factors predisposing to them. One hundred and eighty two patients were followed for a mean of 18 months; 24 received captopril alone, and 158 combinations of captopril and other antihypertensive drugs, especially loop diuretics (91/158), or thiazide diuretics (57/158), or other vasodilators (57/158). The mean final dose of captopril was 67 mg/day. Blood pressure (BP) was effectively controlled in 73% of patients (mean fall in systolic BP 29 mmHg, CI 24 to 34, P less than or equal to 0.001; mean fall in diastolic BP 18 mmHg, CI 16 to 20, P less than or equal to 0.001). Blood urea and creatinine rose slightly in all patients (urea by 0.9 mmol/l [13%], CI 0.5-1.3, P less than or equal to 0.001 and creatinine by 9 mumols/l [8%], CI 4-13, P less than or equal to 0.001). Twenty six patients were withdrawn from captopril therapy: 6 because of poor control of their blood pressure, two because it was no longer necessary and 12 (7.7%) because of extrarenal adverse effects--10 for rashes, one each for gastric upset and impotence. Captopril was withdrawn in a further 6 patients, because of deteriorating renal function. Factors discriminating those at risk of renal dysfunction were high doses of captopril, concomitant high dose diuretic therapy and undiagnosed renovascular disease.

Adult↗
PubMed1987

The disposition of amodiaquine in man after oral administration.

A method is described for the simultaneous determination of amodiaquine (AQ) and desethylamodiaquine (AQm) in plasma, urine, whole blood and packed red cells. After oral administration of AQ (600 mg) to seven healthy subjects, absorption of AQ was rapid, reaching peak concentrations in plasma, whole blood, and packed cells at 0.5 +/- 0.03, 0.5 +/- 0.1 and 0.5 +/- 0.1 h respectively (mean +/- s.e. mean). The apparent terminal half-life of AQ was 5.2 +/- 1.7 h. AQ was detectable for no longer than 8 h. AQ underwent rapid conversion to AQm, which reached peak concentrations in plasma, whole blood and packed cells at 3.4 +/- 0.8, 2.3 +/- 0.5 and 3.6 +/- 1.1 h respectively. AQm was still detectable at the end of the sampling period (96 h) when the plasma concentration was 29 +/- 8 ng ml-1. The area under the plasma concentration vs time curve (AUC(0, infinity] for AQ was 154 +/- 38 ng ml-1 h; the corresponding value for AQm was 8037 +/- 1383 ng ml-1 h. There were no significant differences in the values for AUC of AQ between plasma, whole blood, or packed cells. The whole blood to plasma concentration ratio for AQm was 3.1 +/- 0.2, and the AUC (0.24) for AQm in whole blood (6811 +/- 752 ng ml-1 h) was significantly greater than that in plasma (2304 +/- 371 ng ml-1 h), P less than 0.001. The recovery of AQm from urine collected 0-24 h was 6.8 +/- 0.8 mg (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗