Entity

Time filter

Source Type

Genève, Switzerland

Carter N.,Glaxosmithkline | Pamba A.,Glaxosmithkline | Duparc S.,International Center Cointrin | Waitumbi J.N.,Kenya Medical Research Institute
Malaria Journal | Year: 2011

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is common in populations living in malaria endemic areas. G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone- artesunate (CDA) phase III clinical trial programme. Methods. Study participants, aged > 1 year, with microscopically confirmed uncomplicated Plasmodium falciparum malaria, and haemoglobin 70 g/L or haematocrit 25%, were recruited into two clinical trials conducted in six African countries (Burkina Faso, Ghana, Kenya, Nigeria, Tanzania, Mali). G6PD genotype of the three most common African forms, G6PD*B, G6PD*A (A376G), and G6PD*A- (G202A, A542T, G680T and T968C), were determined and used for frequency estimation. G6PD phenotype was assessed qualitatively using the NADPH fluorescence test. Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration, temperature, asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg (both given once daily for three days) or six-dose artemether-lumefantrine. Results: Of 2264 malaria patients enrolled, 2045 had G6PD genotype available and comprised the primary analysis population (1018 males, 1027 females). G6PD deficiency prevalence was 9.0% (184/2045; 7.2% [N = 147] male hemizygous plus 1.8% [N = 37] female homozygous), 13.3% (273/2045) of patients were heterozygous females, 77.7% (1588/2045) were G6PD normal. All deficient G6PD*A- genotypes were A376G/G202A. G6PD phenotype was available for 64.5% (1319/2045) of patients: 10.2% (134/1319) were G6PD deficient, 9.6% (127/1319) intermediate, and 80.2% (1058/1319) normal. Phenotype test specificity in detecting hemizygous males was 70.7% (70/99) and 48.0% (12/25) for homozygous females. Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin (p = 0.154), adjusted mean baseline temperature (p = 0.9617), or adjusted log mean baseline parasitaemia (p = 0.365). There was no effect of G6PD genotype (p = 0.490) or phenotype (p = 0.391) on the rate of malaria recrudescence, or reinfection (p = 0.134 and p = 0.354, respectively). Conclusions: G6PD deficiency is common in African patients with malaria and until a reliable and simple G6PD test is available, the use of 8-aminoquinolines will remain problematic. G6PD status did not impact baseline haemoglobin, parasitaemia or temperature or the outcomes of anti-malarial therapy. Trial registration. Clinicaltrials.gov: NCT00344006 and NCT00371735. © 2011 Carter et al; licensee BioMed Central Ltd. Source


Saha N.,Ranbaxy Laboratories | Moehrle J.J.,International Center Cointrin | Zutshi A.,Ranbaxy Laboratories | Sharma P.,Clinical Pharmacology and PharmacokineticsHaryana | And 2 more authors.
Journal of Clinical Pharmacology | Year: 2014

Arterolane (RBx11160, OZ277) maleate is a rapidly acting synthetic trioxolane anti-malarial. This randomized, placebo controlled study was a phase I study to evaluate the clinical safety and tolerability as well as pharmacokinetics (PKs) of arterolane maleate including food effect. Eight single rising oral doses of arterolane (25, 50, 100, 150, 200, 300, 400, 600 mg), food effect under fed and fasting conditions at 100 mg dose and four multiple oral dose regimens (25, 50, 100, 200 mg) were administered once daily for 7 days in 64 healthy young males (Caucasian). A randomized, placebo-controlled study was also conducted in healthy elderly males and females (Caucasian) to investigate PKs, safety and tolerability of single oral dose (100 mg) of arterolane. All doses were well tolerated after oral administration. The initial peak of arterolane was apparent at 2-3 hours post-dose followed by a secondary peak at approximately 5 hours post-dose. Thereafter, plasma arterolane concentration declined with a geometric mean t1/2 of approximately 2-4 hours. The PKs of arterolane appeared to be time-invariant after repeated once-daily dosing. The incidence of adverse events was similar for placebo and active treatments. Arterolane had similar PKs and tolerability in elderly and younger subjects and between elderly males and females. © 2013, The American College of Clinical Pharmacology. Source


Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Plattner J.J.,Anacor Pharmaceuticals Inc. | Easom E.E.,Anacor Pharmaceuticals Inc. | Waterson D.,International Center Cointrin | And 4 more authors.
Tetrahedron Letters | Year: 2011

Efficient synthesis is essential for antimalarial therapeutics. A four-step route has been established for the synthesis of 7-(2-carboxyethyl)-1,3-dihydro- 1-hydroxy-2,1-benzoxaborole 1 that is a potent new class boron-containing antimalarial agent in preclinical development with IC50 = 26 nM against the malaria parasite Plasmodium falciparum. © 2011 Elsevier Ltd. All rights reserved. Source


Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Plattner J.J.,Anacor Pharmaceuticals Inc. | Freund Y.R.,Anacor Pharmaceuticals Inc. | Easom E.E.,Anacor Pharmaceuticals Inc. | And 13 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

A series of boron-containing benzoxaborole compounds was designed and synthesized for a structure-activity relationship investigation surrounding 7-(HOOCCH 2CH 2)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1) with the goal of discovering a new antimalarial treatment. Compound 1 demonstrates the best potency (IC 50 = 26 nM) against Plasmodium falciparum and has good drug-like properties, with low molecular weight (206.00), low ClogP (0.86) and high water solubility (750 μg/mL at pH 7). © 2010 Elsevier Ltd. All rights reserved. Source


Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Plattner J.J.,Anacor Pharmaceuticals Inc. | Freund Y.R.,Anacor Pharmaceuticals Inc. | Easom E.E.,Anacor Pharmaceuticals Inc. | And 11 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure-activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC 50 0.026-0.209 μM) against Plasmodium falciparum. © 2011 Elsevier Ltd. All rights reserved. Source

Discover hidden collaborations