64 research outputs found
Omeprazole ameliorates aspirin-induced gastroduodenal injury
Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) damage the gastroduodenal epithelium by two mechanisms: direct toxic effects and effects related to the depletion of endogenous prostaglandins. The prostaglandin-depleted mucosa has increased suceptibility to luminal aggressive factors, yet the role of acid in the pathogenesis of the NSAID ulcer is controversial. In humans, standard doses of H 2 -receptor antagonists prevent only duodenal injury and provide no protection for the gastric mucosa. It is not known whether more potent suppression of acid can prevent NSAID damage. Twenty healthy volunteers were randomized to a double-blind, placebo-controlled, crossover study to determine if omeprazole, 40 mg/day prevents gastroduodenal injury due to two weeks of aspirin administration (650 mg four times a day). The severity of mucosal injury was quantitated by endoscopy and stratified by a scale from 0 (normal) to 4 (ulcer). Fourteen of the 20 subjects had less gastric injury during cotherapy with omeprazole. All six with no difference received aspirin plus omeprazole in the first treatment period. Omeprazole significantly decreased aspirin-induced gastric mucosal injury ( P <0.001, Wilcoxon signed-rank test). Omeprazole protected 85% of subjects from extensive gastric erosions (often associated with evidence of intraluminal bleeding) or ulceration, whereas 70% of the subjects developed aspirin-induced grades 3 and 4 gastric injury on placebo ( P <0.01 by X 2 ). No subject taking omeprazole developed duodenal injury of any grade, while 50% taking placebo developed erosions and 15% had ulcer ( P <0.001). Medication side effects were mild in the majority of subjects. Heartburn occurred in seven subjects on aspirin and placebo vs one on aspirin and omeprazole ( P <0.01). Salicylate levels were 7.39±4.72 mg/dl (535±340 µmol/liter) in the placebo group and 6.95±4.3 mg/dl (503±311 µmol/liter) in the omeprazole group. We conclude that omeprazole, 40 mg/day eliminates duodenal injury and markedly ameliorates gastric injury due to administration of aspirin 2600 mg/day. Omeprazole prophylaxis of NSAID injury deserves further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44420/1/10620_2005_Article_BF02090067.pd
Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment
Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni
The influence of food on the pharmacokinetics of ketoconazole following oral doses of 200, 400, 600 and 800 mg
Absence of a food associated reduction in ketoconazole absorption at 200, 400, 600 and 800 mg doses in man
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