rifampin and Malaria

Topics: Animals; Antimalarials; Humans; Life Cycle Stages; Liver; Malaria; Plasmodium; Structure-Activity Relationship

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Chloramphenicol; Clindamycin; Erythromycin; Gentamicins; Humans; Leucomycins; Lincomycin; Malaria; Neomycin; Penicillins; Rifampin; Streptomycin; Tetracyclines

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

Phenyl- and bioisosteric ferrocenyl-derived aminoquinoline-benzimidazole hybrid compounds were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. All compounds were active against the two strains, generally showing enhanced activity in the K1 strain, with resistance indices less than 1. Cytotoxicity studies using Chinese hamster ovarian cells revealed that the hybrids were relatively non-cytotoxic and demonstrated selective killing of the parasite. Based on favourable in vitro antiplasmodial and cytotoxicity data, the most active phenyl (4c) and ferrocenyl (5b) hybrids were tested in vivo against the rodent Plasmodium berghei mouse model. Both compounds caused a reduction in parasitemia relative to the control, with 5c displaying superior activity (92% reduction in parasitemia at 4 × 50 mg/kg oral doses). The most active phenyl and ferrocenyl derivatives showed inhibition of β-haematin formation in a NP-40 detergent-mediated assay, indicating a possible contributing mechanism of antiplasmodial action. The most active ferrocenyl hybrid did not display appreciable reactive oxygen species (ROS) generation in a ROS-induced DNA cleavage gel electrophoresis study. The compounds were also screened for their in vitro activity against Mycobacterium tuberculosis. The hybrids containing a more hydrophobic substituent had enhanced activity (<32.7 μM) compared to those with a less hydrophobic substituent (>62.5 μM).

Topics: Animals; Anti-Bacterial Agents; Antimalarials; Benzimidazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Ferrous Compounds; Malaria; Mice; Molecular Structure; Mycobacterium tuberculosis; Parasitic Sensitivity Tests; Plasmodium falciparum; Quinolines; Structure-Activity Relationship

To predict the optimal chemoprophylactic dose of mefloquine in infants of 5-10 kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models.. The PBPK model was developed in Simcyp version 14.1 and verified against clinical pharmacokinetic data in adults; the final model, accounting for developmental physiology and enzyme ontogeny was then applied in the paediatric population. The clinical effectiveness model utilized real-world chemoprophylaxis data with stratification of output by age and including infant data from the UK population.. PBPK simulations in infant populations depend on the assumed fraction of mefloquine metabolized by CYP3A4 (0.47, 0.95) and on the associated CYP3A4 ontogeny (Salem, Upreti). However, all scenarios suggest that a dose of 62.5 mg weekly achieves or exceeds the exposure in adults following a 250 mg weekly dose and results in a minimum plasma concentration of 620 ng ml. The PBPK and clinical effectiveness models are mutually supportive and suggest a prophylactic dose of 62.5 mg weekly in the Caucasian 5-10 kg infant population travelling to endemic countries. This dual approach offers a novel route to dose selection in a vulnerable population, where clinical trials would be difficult to conduct.

Topics: Adult; Age Factors; Antimalarials; Child; Child, Preschool; Drug Dosage Calculations; Drug Interactions; Female; Humans; Infant; Ketoconazole; Malaria; Mefloquine; Middle Aged; Models, Biological; Rifampin; Treatment Outcome; White People; Young Adult

In this study, a structure-activity relationship (SAR) compound series based on the NDH-2 inhibitor diphenyleneiodonium (DPI) was synthesised. Compounds were evaluated primarily for in vitro efficacy against Gram-positive and Gram-negative bacteria, commonly responsible for nosocomial and community acquired infections. In addition, we also assessed the activity of these compounds against Mycobacterium tuberculosis (Tuberculosis) and Plasmodium spp. (Malaria). This led to the discovery of highly potent compounds active against bacterial pathogens and malaria parasites in the low nanomolar range, several of which were significantly less toxic to mammalian cells.

Topics: Animals; Bacteria; Community-Acquired Infections; Cross Infection; Gram-Negative Bacteria; Gram-Positive Bacteria; Malaria; Mycobacterium tuberculosis; Onium Compounds; Structure-Activity Relationship

Artemisinin-based combination therapy (ACT) remains the most effective chemotherapeutic strategy in the management of malaria. However, reports of reduced susceptibility of Plasmodium falciparum to the ACT justify the need for continued search for alternative anti-malarial drugs. The use of antibiotics with anti-malarial properties represents a potentially valuable chemotherapeutic option for the management of drug resistant infections. Thus, the intrinsic anti-malarial activity of the combination of clinical doses of rifampicin with amodiaquine and artemether was evaluated in an animal model using Plasmodium berghei.. A modification of the suppressive tests in vivo was employed. The anti-malarial activity of standard doses of amodiaquine (AQ) with or without artemether (ART) and combined with varying doses of rifampicin (RIF 15 mg/kg or RIF 30 mg/kg body weight) was evaluated in 40 mice sub-divided into eight groups and inoculated intraperitoneally with 1 × 10(7) red blood cells infected with chloroquine-resistant P. berghei ANKA strain. There were two control groups of animals, one group received amodiaquine alone while the other group received saline. Parasiticidal activity and survival of the animals were assessed over 21 days.. Parasitaemia in the control animals peaked at 38% on day 9 and all animals died by day 10. The combination of amodiaquine with rifampicin 15 mg/kg body weight was the most effective of all the combinations and more efficacious than amodiaquine alone. The order of superiority of anti-malarial efficacy of the combinations was as follows; AQ + RIF 15 > AQ > AQ + ART + RIF 30 > AQ + ART + RIF 15 > AQ +RIF 30.. The combination of the clinical dose of rifampicin (15 mg/kg) with amodiaquine represents a potentially valuable treatment option in management of drug resistant malaria. In addition, the role of pharmacokinetic interaction in multiple drug therapy cannot be over-emphasized.

Topics: Amodiaquine; Animals; Antimalarials; Artemether; Artemisinins; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Malaria; Male; Mice; Plasmodium berghei; Rifampin; Survival Analysis

The existing armament of drugs for the treatment and prevention of malaria is inadequate due to development of resistance. In addition to this due to lack of economic enticement the rate of new drug development and new drug discovery in the segment of parasitic diseases is very low as compared to the other segments. This has necessitated the better deployment and usage of existing antimalarial drugs as well as discovery of antimalarial activity of drugs which are well characterized for other diseases; these approaches help to reduce the time and cost required for new drug discovery. The present study evaluated the antimalarial activity of antituberculosis drugs rifampicin, isoniazide, and ethambutol in monotherapy and combination in Plasmodium berghei-infected mice. Animals were observed for mortality, parasite progression, and toxicity for a period of 1 month. Rifampicin + isoniazide and rifampicin + isoniazide + ethambutol treatment resulted in an overall survival rate of 60% compared to 0% in vehicle-fed animals by 4 weeks after post-infection without showing any toxicity.

Topics: Animals; Antimalarials; Drug Therapy, Combination; Ethambutol; Isoniazid; Malaria; Mice; Plasmodium berghei; Rifampin; Survival Analysis; Treatment Outcome

Chloroquine (CQ)-resistant Plasmodium falciparum appears to decrease CQ accumulation in its food vacuole by enhancing its efflux via an active membrane pump, which has been reported to be a P-glycoprotein-like transporter. Rifampicin (RIF) is a P-glycoprotein inhibitor and also has some antimalarial activity. It is hoped that a combination of choloroquine-rifampicin (CQ + RIF) would be advantageous in the treatment of CQ-resistant malaria. Swiss albino mice were inoculated with CQ-resistant P. berghei intraperitoneally, and studied for the effect of CQ versus the combination of CQ + RIF at various doses on the clearance of parasitemia, the survival of the mice, and the recrudescence of malaria. Paradoxically, RIF decreased the survival rate and rate of clearance of parasitemia and increased the rate of recrudescence significantly when combined with various doses of CQ. Our results indicated that RIF worsened the course of the disease, and we concluded that RIF should not be combined with CQ in the treatment of malaria.

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Drug Therapy, Combination; Malaria; Mice; Parasitemia; Plasmodium berghei; Rifampin

Topics: Acute Kidney Injury; Amebiasis; Antimalarials; Cholera; Drug Resistance, Microbial; Encephalitis; Glomerulonephritis; Helminthiasis; Hepatitis B Antigens; Humans; Leprosy; Malaria; Neurologic Manifestations; Parasitic Diseases; Pyrimethamine; Rifampin; Sulfonamides; Thiabendazole; Tropical Medicine; Trypanosomiasis, African

Topics: Animals; Antimalarials; Cephaloridine; Dapsone; Diet; Evaluation Studies as Topic; Injections, Subcutaneous; Kinetics; Leprosy; Malaria; Methods; Mice; Mycobacterium leprae; Oxadiazoles; Pyridines; Rifampin; Salicylates; Streptovaricin; Viomycin

Topics: Animals; Malaria; Mice; Rifampin; Rodent Diseases