Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites.

BACKGROUND: The pharmacokinetic interactions of the widely used statin atorvastatin with fibrates and enzyme inducers are not known. Therefore we studied the effects of rifampin (INN, rifampicin) and gemfibrozil on the pharmacokinetics of atorvastatin. METHODS: Two randomized crossover studies were conducted. In study 1, 10 healthy volunteers took 600 mg rifampin or placebo once daily for 5 days. On day 6, they ingested a single 40-mg dose of atorvastatin. In study 2, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 5 days. On day 3, they ingested a single 20-mg dose of atorvastatin. Plasma concentrations of atorvastatin (in nanograms per milliliter) and its metabolites (in arbitrary units) were measured by liquid chromatography-tandem mass spectrometry up to 48 to 72 hours after dosing. RESULTS: Rifampin reduced the total area under the plasma concentration-time curve (AUC) of unchanged atorvastatin (acid) by 80% (95% confidence interval [CI], 73% to 84%; P < .001), that of the active metabolites 2-hydroxyatorvastatin acid by 43% (95% CI, 29% to 51%; P < .001) and 4-hydroxyatorvastatin acid by 81% (95% CI, 74% to 84%; P < .001), and that of their lactones by 93% (95% CI, 90% to 95%), by 61% (95% CI, 50% to 69%), and by 76% (95% CI, 70% to 81%), respectively (P < .001). The peak plasma concentration of 2-hydroxyatorvastatin acid was increased by 68% (95% CI, 21% to 127%; P = .005) by rifampin. Rifampin shortened (P < .001) the half-lives of atorvastatin (by 74%; 95% CI, 67% to 81%) and its metabolites, for example, atorvastatin lactone (by 82%; 95% CI, 80% to 85%) and 2-hydroxyatorvastatin acid (by 70%; 95% CI, 64% to 78%). Gemfibrozil increased the AUC of atorvastatin (by 24%; 95% CI, -1% to 50%; P =.059), 2-hydroxyatorvastatin acid (by 51%; 95% CI, 28% to 70%; P < .001) and its lactone (by 29%; 95% CI, 13% to 53%; P =.003), and 4-hydroxyatorvastatin acid (by 82%; 95% CI, 60% to 126%; P < .001) and its lactone (by 28%; 95% CI, 15% to 51%; P =.001). The half-lives of atorvastatin and its lactone metabolites were slightly shortened by gemfibrozil (P < .05). CONCLUSIONS: Rifampin markedly decreases and gemfibrozil moderately increases the plasma concentrations of atorvastatin and its metabolites. It is advisable to increase the dosage of atorvastatin and preferable to administer it in the evening to guarantee adequate concentrations during the nighttime rapid cholesterol synthesis when rifampin or other potent inducers of cytochrome P450 3A4 are coadministered. Care is warranted, and only low doses of atorvastatin should be used if coadministration with gemfibrozil is needed.

Accidental intravenous administration of racemic adrenaline: two cases associated with adverse cardiac effects.

Accidental intravenous administration of racemic adrenaline (epinephrine) is a rare but potentially lethal complication. We describe a case of a 68-year-old man with chronic obstructive pulmonary disease who developed severe dyspnoea at home, and a case of an 81-year-old woman who had an allergic reaction associated with severe dyspnoea. The paramedics accidentally administered racemic adrenaline intravenously in both cases. Both patients suffered from severe cardiac adverse effects but their outcome was eventually favourable. Previous reports of accidental intravenous administration of racemic adrenaline are also reviewed. We discuss the potential risks of using racemic adrenaline, especially in the treatment of geriatric patients, and the possibilities of reducing the risk of accidents in drug administration.

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol.

OBJECTIVES: Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking agent celiprolol in healthy volunteers. METHODS: In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. RESULTS: During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was 80% greater (P <.05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001). Hemodynamic variables did not differ between the phases. CONCLUSIONS: Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice-celiprolol interaction is probably of clinical relevance.

Warfarin and fibrinolysis--a challenging combination: an observational cohort study.

BACKGROUND: Patients presenting with ST-segment elevation myocardial infarction (STEMI) frequently use warfarin. Fibrinolytic agents and warfarin both increase bleeding risk, but only a few studies have been published concerning the bleeding risk of warfarin-prescribed patients receiving fibrinolysis. The objective of this study was to define the prevalence for intracranial haemorrhage (ICH) or major bleeding in patients on warfarin treatment receiving pre-hospital fibrinolysis. METHODS: This was an observational cohort study. Data for this retrospective case series were collected in Helsinki Emergency Medical Service catchment area from 1.1.1997 to 30.6.2010. All warfarin patients with suspected ST-segment elevation myocardial infarction (STEMI), who received pre-hospital fibrinolysis, were included. Bleeding complications were detected from Medical Records and classified as ICH, major or minor bleeding. RESULTS: Thirty-six warfarin patients received fibrinolysis during the study period. Fourteen patients had bleeding complications. One (3%, 95% CI 0-15%) patient had ICH, six (17%, 95% CI 7-32%) had major and seven (19%, 95% CI 9-35%) had minor bleeding. The only fatal bleeding occurred in a patient with ICH. Patients' age, fibrinolytic agent used or aspirin use did not predispose to bleeding complications. High International Normalized Ratio (INR) seemed to predispose to bleedings with values over 3, but no statistically significant difference was found. CONCLUSIONS: Bleedings occur frequently in warfarin patients treated with fibrinolysis in the real world setting, but they are rarely fatal.