Treatment of uncomplicated malaria in Africa: evaluation of randomized clinical trials.

BACKGROUND: Malaria is a major devastating infectious diseases in tropical countries. The resistance of P. falciparum to the traditional antimalarial drugs is believed to be contributing to increased malaria mortality. OBJECTIVE: The purpose of this study is to evaluate randomized clinical trials of uncomplicated P. faciparum malaria with the hope of providing recent scientific evidence on the current antimalarial drugs that would be effective, safe, affordable and available in Africa. METHODS: We reviewed articles based only on data collected between 2005 and 2009 and randomized clinical trials of uncomplicated P. faciparum malaria in Africa published between January 2006 and August 2009. Relevant articles were sourced using data available from PubMed Central, NCBI, NEJM, BMJ, Google, and Biomed Central. Data were analysed to determine the best outcomes of treatment. RESULTS: Sixty-two articles were identified as relevant. Twenty of these, involving 2967 patients, met our inclusion criteria. Three (3), 4, 3, 1, 3, 2 and 4 of the articles were based on chloroquine, sulphadoxine/pyrimethamine, amodiaquine, quinine, artemether-lumefantrine, artesunate plus sulphadoxine/pyrimethamine, and artesunate plus amodiaquine, respectively. The respective mean cure rates for these drugs were 66.7 +/- 28.4%, 72.0 +/- 35.6%, 83.0 +/- 24.3%, 64.0%, 95.4 +/- 0.56%, 97.4%, and 88.2 +/- 13.0%. While artemisinin combination therapy (ACT) remained highly effective across countries, there was no evidence of the effectiveness of chloroquine in most parts of the continent. No serious side effects was reported by ACT. CONCLUSION: ACT remains the best antimalarial for the treatment of uncomplicated P. falciparum malaria in Africa. Clinical trials on current state of the effectiveness of chloroquine in the various countries of the continent is recommended to be able to understand whether chloroquine needs to be returned for the effective treatment of uncomplicated malaria in the region.

The effect of protein binding and lipophilicity of penicillins on their in-vitro flux across gastric mucosa.

Delivery of amoxycillin across the human gastric mucosa to Helicobacter pylori is poor compared with that of metronidazole and clarithromycin, limiting the clinical effectiveness of this penicillin. To investigate the physicochemical properties of penicillins that influence their flux across gastric mucosa, the fluxes of metronidazole and eight penicillins were measured in vitro across rat gastric mucosa. The lipophilicity of these drugs was also measured using potentiometric titration. The mean fluxes of monobasic penicillins (range 0.66-0.89 nmol/cm2/h) were significantly lower than those of the aminopenicillins (range 1.94-2.80 nmol/cm2/h) (P < 0.005). Penicillin flux was not significantly correlated with lipophilicity as measured, but was significantly correlated with published protein binding data (rs = 0.9048, P < 0.002). Metronidazole flux was significantly higher than that of any penicillin at 22.6 (+/-0.9) nmol/cm2/h (P < 0.001). Therefore, the in-vitro gastric delivery of penicillins can be predicted from protein binding which may in turn predict activity against H. pylori in vivo.

Reversed-phase high-performance liquid chromatographic assay methods for the analysis of a range of penicillins in in vitro permeation studies.

Simple, rapid and selective HPLC methods have been developed for the analysis of amoxycillin, ampicillin, epicillin, mecillinam and propicillin. A Hypersil ODS 5 microm (150x4.6 mm I.D.) column was used with mobile phases containing aqueous phosphate buffers, pH 3-4.6 and either methanol or acetonitrile as the organic modifier. Samples were detected by their optimal UV absorption (210-230 nm). The lower limits of quantitation of the compounds (100 microl injection volume) were 0.1 microg/ml. The assays were linear in the range of 0.1-100 microg/ml with r2 values greater than 0.99. The methods have been applied successfully for the measurement of the flux of the compounds across Caco-2 cells monolayers.

The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection.

Although omeprazole is an important component in anti-Helicobacter pylori therapeutic regimes using clarithromycin, amoxycillin and metronidazole, the mechanism by which it enhances antimicrobial action is unknown. One potential explanation for this effect is increased antibiotic chemical stability resulting from gastric pH changes induced by co-administration of omeprazole. The chemical stability of clarithromycin, amoxycillin and metronidazole was investigated in aqueous solutions and in human gastric juice collected before and after a 7-day course of omeprazole. Amoxycillin, clarithromycin and metronidazole were prepared in buffered aqueous solutions of pH 1.0 to 8.0 and in gastric juice of pH 2.0 and 7.0. The gastric juice samples were obtained from fasted H. pylori-negative volunteers before and after they had received a 7-day course of omeprazole. All the samples were incubated at 37 degrees C and analysed at intervals by HPLC. Amoxycillin, clarithromycin and metronidazole were stable in aqueous solutions of pH 4.0-7.0, pH 5.0-8.0 and pH 2.0-7.0, respectively. At pH 2.0, the degradation half-lives were 19.0 +/- 0.2 h, 1.3 +/- 0.05 h and 2200 +/- 1100 h, respectively. In gastric juice samples of pH 2.0, the degradation half-lives were 15.2 +/- 0.3 h, 1.0 +/- 0.04 h and > or = 800 h, respectively. The half-lives of the drugs in the gastric juice samples of pH 7.0 were all > 68 h. The co-administration of omeprazole with amoxycillin or clarithromycin is likely to increase the chemical stability of amoxycillin and clarithromycin in gastric juice. Clarithromycin degrades rapidly at normal gastric pH (1.0-2.0) but amoxycillin and metronidazole are sufficiently stable at this pH to maintain an antibacterial concentration in the stomach.

Ion-pair high-performance liquid chromatographic assay method for the assessment of clarithromycin stability in aqueous solution and in gastric juice.

A simple and selective ion-pair HPLC method has been developed for the analysis of clarithromycin in aqueous solutions and in gastric juice. A Hypersil ODS 5-microns (150 x 4.6 mm I.D.) column was used with a mobile phase consisting of acetonitrile-aqueous 0.05 M phosphate buffer (pH 4.6) containing 5 mM l-octanesulphonic acid (50:50, v/v). The column temperature was 50 degrees C and detection was by UV absorption (210 nm). The limits of detection of 50-microliters samples were 0.4 microgram/ml (aqueous) and 0.78 microgram/ml (0.5 ml gastric juice) or better. The assay was linear in the range of 1.56 to 100 micrograms/ml with r2 values greater than 0.99. The recovery from the gastric juice samples was 98.5 +/- 2.9%. The method was applied successfully to determine the stability of clarithromycin in 0.01 M HCl and gastric juice.