Field-adapted sampling of whole blood to determine the levels of amodiaquine and its metabolite in children with uncomplicated malaria treated with amodiaquine plus artesunate combination.

BACKGROUND: Artemisinin combination therapy (ACT) has been widely adopted as first-line treatment for uncomplicated falciparum malaria. In Uganda, amodiaquine plus artesunate (AQ+AS), is the alternative first-line regimen to Coartem(R) (artemether + lumefantrine) for the treatment of uncomplicated falciparum malaria. Currently, there are few field-adapted analytical techniques for monitoring amodiaquine utilization in patients. This study evaluates the field applicability of a new method to determine amodiaquine and its metabolite concentrations in whole blood dried on filter paper. METHODS: Twelve patients aged between 1.5 to 8 years with uncomplicated malaria received three standard oral doses of AQ+AS. Filter paper blood samples were collected before drug intake and at six different time points over 28 days period. A new field-adapted sampling procedure and liquid chromatographic method was used for quantitative determination of amodiaquine and its metabolite in whole blood. RESULTS: The sampling procedure was successively applied in the field. Amodiaquine could be quantified for at least three days and the metabolite up to 28 days. All parasites in all the 12 patients cleared within the first three days of treatment and no adverse drug effects were observed. CONCLUSION: The methodology is suitable for field studies. The possibility to determine the concentration of the active metabolite of amodiaquine up to 28 days suggested that the method is sensitive enough to monitor amodiaquine utilization in patients. Amodiaquine plus artesunate seems effective for treatment of falciparum malaria.

Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. * The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. * No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria. WHAT THIS STUDY ADDS: * This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria. * The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor. * The study proposes dose modification to improve response with the CQ + SDx/PYR combination. AIMS: To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination. METHODS: Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 microl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis. RESULTS: A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V(C)/F) values were estimated to be 2.84 l h(-1) and 230 l. The typical CL/F for SDx was 0.023 l h(-1), while the factor relating its V(C)/F to normalized body weight was 1.6 l kg(-1). Post hoc parameter estimates for both drugs showed lower maximum concentrations (C(max)) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome. CONCLUSIONS: The study results suggest that full-strength combination to all children would improve the cure rate.

Access and use of medicines information sources by physicians in public hospitals in Uganda: a cross-sectional survey.

BACKGROUND: Rational and cost-effective prescription of medicines requires up-to-date and readily accessible medicines information. There are several studies on availability and access to medicines information sources, but have been conducted only in high-income countries. OBJECTIVE: To assess medicines information sources accessed by physicians in public hospitals in Uganda, and physicians' opinion on establishment of a medicines information centre in the country. METHODS: A cross-sectional survey including 369 physicians from six district, six regional and two university hospitals. Data was collected using a semi-structured self-administered questionnaire. RESULTS: Response rate was 91%. This included 31, 136 and 168 physicians from the district, regional and university hospitals, respectively. In the district hospitals the source of medicines information reported to be most available was colleagues (100%), while in the regional and university hospitals it was literature from pharmaceutical companies (98%) and hard copy of research publications (99%) respectively. The most frequently used source in the district and regional hospitals was National Standard Treatment Guideline (90% and 73% respectively), and colleagues in university hospitals (89%). Accessibility problems with reported available sources were commonest with research publications in medical journals, both hard copy and through the internet, MIMS, pharmacists and pharmacologists. Need for a medicines information centre was indicated by 80% of the respondents. CONCLUSION: Majority of the physicians in public hospitals in Uganda have limited access to unbiased drug information. Therefore, there is need to assess the feasibility of establishing a drug information centre, and then assess its use during a trial period.

Access and use of medicines information sources by physicians in public hospitals in Uganda: a cross-sectional survey

Background :Rational and cost-effective prescription of medicines requires up-to-date and readily accessible medicines information. There are several studies on availability and access to medicines information sources, but have been conducted only in high-income countries. Objective:To assess medicines information sources accessed by physicians in public hospitals in Uganda, and physicians' opinion on establishment of a medicines information centre in the country. Methods:A cross-sectional survey including 369 physicians from six district, six regional and two university hospitals. Data was collected using a semi-structured self-administered questionnaire.Results :Response rate was 91%. This included 31, 136 and 168 physicians from the district, regional and university hospitals, respectively. In the district hospitals the source of medicines information reported to be most available was colleagues (100%), while in the regional and university hospitals it was literature from pharmaceutical companies (98%) and hard copy of research publications (99%) respectively. The most frequently used source in the district and regional hospitals was National Standard Treatment Guideline (90% and 73% respectively), and colleagues in university hospitals (89%). Accessibility problems with reported available sources were commonest with research publications in medical journals, both hard copy and through the internet, MIMS, pharmacists and pharmacologists. Need for a medicines information centre was indicated by 80% of the respondents.Conclusion : Majority of the physicians in public hospitals in Uganda have limited access to unbiased drug information. Therefore, there is need to assess the feasibility of establishing a drug information centre, and then assess its use during a trial period

Acute toxicity effects of the methanolic extract of Fagara zanthoxyloides (Lam.) root-bark.

BACKGROUND: Fagara zanthoxyloides is a well known medicinal plant in Uganda. It is used extensively in malaria and other infections. However nothing is known about its toxicity. OBJECTIVE: The objective of the study was to evaluate the acute toxicity of the methanolic extract of the root-bark of F. zanthoxyloides, in mice. METHODS: Methanolic extract of the root-bark of the plant was administered orally to mice at various dose levels to determine the acute toxic effects and the median lethal dose (LD50) in mice. RESULTS: The LD50 of the methanolic extract was found to be 5.0 g/Kg body weight within 95% confidence limits. The mice showed signs of cerebral irritation before dying. Histopathological examinations of the viscera showed congestion and focal necrosis of the liver and renal tubules. CONCLUSION: It was concluded that the extract of F. zanthoxyloides is safe, however the cerebral mechanism that lead to the death of the mice need to be investigated further.

Chloroquine in the Ugandan market fails quality test: a pharmacovigilance study.

BACKGROUND: Antimalaria treatment failure has been partly attributed to poor quality antimalarials in the drug market. A 1998 survey in Kampala showed that 55% of tablets and 62% of injection forms of chloroquine failed the quality test. OBJECTIVE: This study was carried out as a follow-up to establish the quality of chloroquine tablet and injection dosage forms in the Ugandan drug market from June - November 2001. METHODS: Chloroquine tablets and injection dosage forms, randomly purchased from pharmacies and drug shops in the four regions of Uganda, were assayed for content of the active ingredient according to the USP standard, using the HPLC method. RESULTS: Of the tablets samples surveyed, 39% failed the content test with 11% having sub-normal and 28% having supra-normal amounts, whilst 51% of the injection samples failed with 40% and 11% having sub-normal and supra-normal amounts respectively. CONCLUSION: There was overall improvement in the quality of chloroquine in Uganda compared with the 1998 figures, but the failure rates are still unacceptably high. The variations in the chloroquine amounts in both the tablet and injection forms may contribute to chloroquine toxicity or poor response during treatment. More vigorous pharmacovigilance on drugs entering the Ugandan drug market is needed.

Use of drugs and their effects during pregnancy

"Drugs are chemical compounds that act by interacting with body tissues and alter their activity. The most actively dividing cells are more susceptible. Pregnancy is a condition where cells multiply very rapidly during conception and formation of the fetus. When drugs are given to a pregnant mother; they may interfere with cell division; growth and development. The effect depends on the time of drug exposure. Drugs given in the early pregnancy (first trimester); when fetal parts are being formed; result in severe anatomical defects (teratogenic). After 12 weeks; most body parts are already formed and drugs given during this time would interfere with the normal growth and physiological functions of the fetus. Medicines can still reach the fetus after delivery when nursing mothers take certain drugs. The potential of harming the fetus by prescribing drugs to the mother is considerable; and this was demonstrated by the Thalidomide disaster. The only way to ensure that drugs are safe and efficacious is by a randomized and placebo controlled study. for obvious ethical reasons; there are few studies designed to evaluate the safety and efficacy of drugs in pregnancy. Some studies have; however; been done on the efficacy of aspirin in the prevention of pre-eclampsia and some antihypertensive agents. Information given on many drugs includes non-specific and unhelpful warnings like ""not to be used in pregnancy unless the benefits outweigh the risks"". But we know that the ""risks"" and ""benefits"" have neverand; because of ethical problems; cannot be evaluated in any large clinical trials. Also; the disease being treated may affect or be affected by pregnancy. Despite this fear and uncertainty; we have to prescribe drugs during pregnancy. This review is to summurize some of the important points that should be borne in mind when prescribing drugs for pregnant women."