rifampin and Malaria--Falciparum

The effects of adding rifampin to quinine were assessed in adults with uncomplicated falciparum malaria. Patients were randomized to receive oral quinine either alone (n = 30) or in combination with rifampin (n = 29). Although parasite clearance times were shorter in the quinine-rifampin-treated patients (mean +/- standard deviation, 70 +/- 21 versus 82 +/- 18 h; P = 0.023), recrudescence rates were five times higher (n = 15 of 23; 65%) than those obtained with quinine alone (n = 3 of 25; 12%), P < 0.001. Patients receiving rifampin had significantly greater conversion of quinine to 3-hydroxyquinine and consequently considerably lower concentrations of quinine in their plasma after the second day of treatment (median area under the plasma drug concentration-time curve from day zero to day 7 = 11.7 versus 47.5 micro g/ml. day, P < 0.001). Rifampin significantly increases the metabolic clearance of quinine and thereby reduces cure rates. Rifampin should not be combined with quinine for the treatment of malaria, and the doses of quinine should probably be increased in patients who are already receiving rifampin treatment.

Topics: Adult; Area Under Curve; Drug Interactions; Drug Therapy, Combination; Humans; Malaria, Falciparum; Male; Quinine; Rifampin

The relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for > or = 28 days. All patients received a 7-day oral quinine regimen either alone (n = 22) or in combination with rifampin (n = 8). The median fever clearance time was 58.5 h, and the mean +/- standard deviation parasite clearance time was 73 +/- 24 h. After recovery, six patients had recrudescences of Plasmodium falciparum malaria and seven had delayed appearances of P. vivax infection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 microg.day/ml had a relative risk of 5.3 (95% confidence interval = 1.6 to 17.7) of having a subsequent recrudescence of infection (P = 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 microg/ml and an MIC of 0.7 microg/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).

Topics: Adult; Antibiotics, Antitubercular; Antimalarials; Area Under Curve; Drug Therapy, Combination; Half-Life; Humans; Malaria, Falciparum; Male; Prospective Studies; Quinine; Rifampin; Treatment Outcome

Malaria is one of the world's most devastating diseases, infecting well over 300 million people annually and killing between 2 and 3 million worldwide. Increasing parasite resistance to many existing drugs is exacerbating disease. Resistance to commonly used malarial drugs is increasing the need to develop new drugs urgently. Due to the slow pace and substantial costs of new drug development, repurposing of old drugs which is recently increasingly becoming an attractive proposition of highly efficient and effective way of drug discovery led us to study the drug rifampicin for this purpose. The present paper aims to investigate the route of

Topics: Antimalarials; Drug Design; Drug Repositioning; Humans; Malaria; Malaria, Falciparum; Molecular Docking Simulation; Mycobacterium tuberculosis; Plasmodium falciparum; Rifampin

Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC

Topics: Antimalarials; Antitubercular Agents; Dose-Response Relationship, Drug; Malaria, Falciparum; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Parasitic Sensitivity Tests; Plasmodium falciparum; Pyrvinium Compounds; Structure-Activity Relationship; Tuberculosis

A series of novel morpholinoquinoline based conjugates with pyrazoline moiety were synthesized under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. Most of them exhibited significant antibacterial activity as compared to the first line drugs. Compounds 6a and 9d were found to possess excellent antibacterial activity potency as compared to ampicillin (286 μM), chloramphenicol (154 μM) and ciprofloxacin (150 μM). In antifungal screening, against Candida albicans, compounds 6c, 7c, 8a, 8b, 8c and 9b showed significant activity as compared to griseofulvin (1147 μM). Compounds 8b, 6b, 9d, 6a, 9b, 7b and 8a displayed brilliant activity against P. falciparum strain as compared to chloroquine (IC50 0.062 μM) as well as quinine (IC50 0.826 μM). Compounds 6d, 7b, 8b, 9c and 9d exhibited superior antitubercular activity. Among them 8b was found to be equipotent to rifampicin with 95% inhibition. The cytotoxicity of the synthesized compounds was tested using bioassay of Schizosaccharomyces pombe cells at cellular level.

Topics: Anti-Infective Agents; Antimalarials; Antitubercular Agents; Bacteria; Bacterial Infections; Fungi; Humans; Malaria, Falciparum; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycoses; Plasmodium falciparum; Pyrazoles; Quinolines; Structure-Activity Relationship; Tuberculosis

Many anti-bacterial drugs inhibit growth of malaria parasites by targeting their bacterium-derived endosymbiotic organelles, the mitochondrion and plastid. Several of these drugs are either in use or being developed as therapeutics or prophylactics, so it is paramount to understand more about their target of action and modality. To this end, we measured in vitro growth and visualized nuclear division and the development of the mitochondrion and apicoplast in Plasmodium falciparum treated with five drugs targeting bacterial housekeeping pathways. This revealed two distinct classes of drug effect. Ciprofloxacin, rifampicin, and thiostrepton had an immediate effect: slowing parasite growth, retarding organellar development and preventing nuclear division. Classic delayed-death, in which the drug has no apparent effect until division and reinvasion of a new host by the daughter merozoites, was only observed for two drugs: clindamycin and tetracycline. These cells had apparently normal division and segregation of organelles in the first cycle but severe defects in apicoplast growth, subtle changes in the mitochondrion and a failure to complete cytokinesis during the second cycle. In two cases, the drug response in P. falciparum directly conflicted with reported responses for the related parasite Toxoplasma gondii, suggesting significant differences in apicoplast biology between the two parasites.

Topics: Animals; Anti-Bacterial Agents; Cells, Cultured; Ciprofloxacin; Clindamycin; DNA Replication; Malaria, Falciparum; Plasmodium falciparum; Protein Biosynthesis; Rifampin; Tetracycline; Thiostrepton; Time Factors; Transcription, Genetic