Orange juice substantially reduces the bioavailability of celiprolol, but the mechanism of this interaction remains to be resolved. For example, modulation of intestinal pH and of function of transporters implicated in the absorption of celiprolol may be involved. Because of the great extent of the orange juice-celiprolol interaction and a wide use of orange juice, this interaction is likely to have clinical importance in some patients, although hemodynamic consequences were not seen in young healthy subjects.

The role of adverse drug reactions (ADRs) as a cause of hospital visits varies depending on the type of hospitals. Our aim was to determine the incidence of drug-related emergency department visits to a district hospital, and to identify the drugs and patient groups involved. All patient visits to the emergency department of a Finnish district hospital were evaluated prospectively for 6 months. The physician on duty and a clinical pharmacologist selected all possibly drug-related visits for further scrutinising. The causality assessment (drug-related or not) was judged according to WHO criteria, based on the patients' files, including laboratory and other data. Of the 7113 evaluated visits, 167 (2.3%) were ''certainly'' or ''probably'' drug-related; 102 (1.4% of all) were related to ADRs and 65 (0.9%) to intentional overdoses. The most common ADRs were gastrointestinal symptoms (nΩ17) caused by antibiotics, opioids, nonsteroidal antiin-flammatory or cytostatic drugs. The International Classification of Disease (ICD-10) codes on patients' files were insensitive to disclose ADRs. The ADR patients were older (mean age 57 years) than the intentional overdose patients (38 years; P0.001). Males predominated in the intentional overdose group (38 males, 27 females) but not in the ADR patients. The majority of intentional overdoses was caused by psychotropics. The ADRs lead to hospitalisation in a higher frequency (51%) than did the intentional overdoses (35%). In conclusion, the incidence of ''certainly'' or ''probably'' drug-related visits to the district hospital emergency room was relatively low. The ICH-10 codes on patients' files were found to be insensitive to disclose the ADRs, even when they lead to hospital admission, casting doubts on the usefulness of ICH codes alone in ADR evaluation.

Background and aimsGemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, • )] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro , gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. MethodsIn a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. ResultsDuring the gemfibrozil-itraconazole phase, the AUC(0, • ) and C max of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range -8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t max and t 1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. ConclusionsThe combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.

Also poorly metabolized drugs, including certain b-blocking agents, can be susceptible to drug interactions caused by transporter inhibitors and inducers. Thus, our aim was to investigate the effect of rifampicin on the pharmacokinetics of atenolol in healthy people. In a randomized cross-over study with two phases, nine healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 100 mg dose of atenolol was administered orally. The plasma concentrations of atenolol and its excretion into urine were measured up to 33 hr after dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the intake of atenolol and 2, 4, 6, and 10 hr later. During the rifampicin phase, the mean area under the plasma concentration-time curve (AUC 0-≤ ) of atenolol was decreased to 81% and renal clearance increased to 109% of the placebo phase values (PϽ0.05). Rifampicin pretreatment reduced, albeit not statistically significantly, also the peak plasma concentration (C max ), AUC 0-33 hr , and amount of atenolol excreted to 85% (PΩ0.139), 81% (PΩ0.053), and 86% (PΩ0.12) of the respective placebo phase values. The average heart rate and diastolic blood pressure were slightly higher during the rifampicin phase compared with the placebo phase (PϽ0.05). To conclude, although the inducing effect of rifampicin may not have been at its maximum by day 6, rifampicin has only a minor effect on the pharmacokinetics of atenolol evidenced by a slight reduction in its bioavailability.Atenolol is a cardioselective b-adrenoceptor-blocking agent used in the treatment of coronary heart disease, hypertension, and certain cardiac arrhythmias. The oral bioavailability is about 50%, mainly due to incomplete absorption (Dollery 1999). Metabolism only plays a negligible role in its elimination, and over 90% of the absorbed atenolol dose can be found as unchanged drug in urine. The mean elimination half-life of atenolol is approximately 6 hr (Wan et al. 1979).Also poorly metabolized compounds can be susceptible to pharmacokinetic drug-drug interactions. For instance, plasma concentrations of digoxin and celiprolol can be increased by concomitant itraconazole ingestion (Partanen et al. 1996;Lilja et al. 2003), and reduced by pretreatment with rifampicin (Greiner et al. 1999;Lilja et al. 2004). A previous study suggests that verapamil can increase plasma concentrations of atenolol (Keech et al. 1988). Furthermore, in a case report, blood pressure lowering effect of atenolol was found to be decreased during concomitant rifampicin (Goldberg et al. 2003).Rifampicin is a potent inducer of several cytochrome P450 enzymes and some transporters, and concomitant use of rifampicin with other drugs can reduce their absorption and increase their elimination (Greiner et al. 1999;Fromm et al. 2000;Niemi et al. 2003). The present study was conducted to investigate possible effects of rifampicin on the pharmacokinetics of atenolol in healthy persons.Author for corresponden...

Fluconazole raised the plasma concentrations and reduced the systemic elimination of nateglinide probably by inhibiting its cytochrome P4502C9-mediated biotransformation. Concomitant use of fluconazole with nateglinide may prolong its blood glucose-lowering effect.

Adverse drug reaction is a significant cause of death. Most of the deaths occurred in seriously ill patients with high-risk medication and they are seldom preventable. Incidence figures based on death certificates only may seriously underestimate the true incidence of fatal adverse reactions.