Clinical pharmacokinetics of ticlopidine

Platelets contribute significantly to arterial-occlusive thrombosis, one of the major causes of death and disease throughout the world. Consequently, inhibiting platelet function is a potentially important therapeutic goal. Among agents that inhibit platelet function, ticlopidine shows a wide spectrum of antiplatelet activity. There have been a limited number of studies investigating the pharmacokinetic profile of the drug. However, it has been demonstrated that absorption of ticlopidine after oral administration is rapid, is improved when the drug is administered with food, but reduced by the coadministration of antacid. Ticlopidine is extensively metabolised, with little unchanged drug present in the plasma. After administration of a single dose, unchanged ticlopidine can be detected for up to 96 hours postdose. Repeated administration of ticlopidine 250mg twice daily results in 3- to 4-fold accumulation of the drug after 2 weeks. The terminal elimination half-life is between 20 and 50 hours. Dosage selection is not determined by the pharmacokinetic profile of the drug, but rather by determination of the effect of the drug on bleeding time. The clearance of theophylline and phenazone (antipyrine) are reduced by ticlopidine, resulting in increased plasma drug concentrations. In contrast, the plasma concentration of cyclosporin is reduced. Aspirin (acetylsalicylic acid) increases the bleeding time in patients receiving ticlopidine concurrently, while corticosteroids reduce bleeding time. Ticlopidine use is discouraged in patients with severe organ failure. Furthermore, ticlopidine should be discontinued 2 weeks before surgery and dental intervention. Most importantly, the blood cell count should be monitored regularly during the 3 first months of treatment with ticlopidine because 1% of patients receiving ticlopidine may experience agranulocytosis

Synthèse de 6,7-dihydro-imidazo(1,2-a)-s-triazines

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Synthèse de 6,7-dihydro-imidazo(1,2-a)-s-triazines

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Oral bioavailability of nizatidine and ranitidine concurrently administered with antacid.

This four-way crossover open-label study on eight healthy subjects was designed to investigate the effect on bioavailability of orally administered nizatidine given concurrently with an antacid (magnesium hydroxide-aluminium hydroxide mixture). Ranitidine was used as a comparison. Subjects were hospitalized overnight for each drug application which was given as a single dose [nizatidine or ranitidine (300 mg) or antacid (20 ml) of a neutralizing capacity of 50 mmol hydrochloric acid]. Plasma nizatidine or ranitidine concentrations were measured by high performance liquid chromatography. No statistically significant difference occurred in the kinetic profile of nizatidine after antacid administration although it took longer to reach maximum concentration in plasma. The area under the concentration-time curve was also reduced (by less than 10%) and there was a longer lag between administration and absorption. Bioequivalence (Westlake test) for ranitidine in the presence or absence of antacid was confirmed (difference less than 12%). For nizatidine, with or without antacid, the value of the Westlake test was just above the limit for bioequivalence (21.4%), whereas the Student's t-test for related means (one-tailed distribution) gave P = 0.045. There was no clinically relevant nizatidine-antacid interaction at the doses used in this study

Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of cholesterol synthesis. HMG-CoA reductase inhibitors are potent reversible inhibitors of this enzyme, which act by competing for the substrate HMG-CoA. This review is mainly devoted to the 4 main HMG-CoA reductase inhibitors used today: lovastatin, simvastatin, pravastatin and fluvastatin. Depending upon the dosage, these drugs are able to reduce plasma cholesterol levels by more than 40%. After absorption, each undergoes extensive hepatic first-pass metabolism. Up to 5 primary metabolites are formed, some of which are active inhibitors. The elimination half-lives vary from 0.5 to 3.5 hours and excretion is mainly via the faeces. A limited number of drug interactions has been reported. Increases in liver enzymes and muscle creatine kinase activity are among the most severe adverse effects. These powerful drugs should be reserved for patients with high plasma cholesterol levels and/or those with cardiovascular disease. New therapeutic approaches to atherosclerosis are currently under investigation. HMG-CoA reductase inhibitors are the cornerstone of this research