Peter A. G. M. De Smet

Health risks of herbal remedies: An update

m The use of herbal remedies has become a common orm of alternative therapy. A 1997 survey in the nited States estimated that 12.1% of the adult popuation had used herbal medicines in the past 12 months compared with 2.5% in 1990), costing

A genome-wide association study of acenocoumarol maintenance dosage

5.1 billion in ut-of-pocket expenses. Among herbal users, 15.1% ad seen an alternative medicine practitioner, resulting n 10.5 million office visits, 19.8% of which had been ompletely or partially covered by insurance. Parallel o this increased popularity, clinical pharmacologic inerest in the efficacy and safety of herbal remedies has lso grown. In the wake of this interest, this review iscusses concerns about herbal remedies from a clincal pharmacologic perspective. Building on an earlier

The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon

Several genome-wide association studies have been performed on warfarin. For acenocoumarol, the most frequently used coumarin in many countries worldwide, pharmacodynamic influences are expected to be comparable. Pharmacokinetics however might differ. We aimed to confirm known or identify new genetic variants contributing to interindividual variation on stabilized acenocoumarol dosage by a GWAS. The index population consisted of 1451 Caucasian subjects from the Rotterdam study and results were replicated in 287 subjects from the Rotterdam study extended cohort. Both cohorts were genotyped on the Illumina 550K Human Map SNP array. From polymorphisms tested for association with acenocoumarol dosage, 35 single nucleotide polymorphisms (SNPs) on chromosome 16 and 18 SNPs on chromosome 10 reached genome-wide significance. The SNP with the lowest P-value was rs10871454 on chromosome 16 linked to SNPs within the vitamin K epoxide reductase complex subunit 1 (VKORC1) (P = 2.0 x 10(-123)). The lowest P-value on chromosome 10 was obtained by rs4086116 within cytochrome P450 2C9 (CYP2C9) (P = 3.3 x 10(-24)). After adjustment for these SNPs, the rs2108622 polymorphism within cytochrome P450 4F2 (CYP4F2) gene on chromosome 19 reached genome-wide significance (P = 2.0 x 10(-8)). On chromosome 10, we further identified genetic variation in the cytochrome P450 2C18 (CYP2C18) gene contributing to variance of acenocoumarol dosage. Thus we confirmed earlier findings that acenocoumarol dosage mainly depends on polymorphisms in the VKORC1 and CYP2C9 genes. Besides age, gender, body mass index and target INR, one polymorphism within each of the VKORC1, CYP2C9, CYP4F2 and CYP2C18 genes could explain 48.8% of acenocoumarol dosage variation.

The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon.

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

Allelic Variants of Cytochrome P450 2C9 Modify the Interaction Between Nonsteroidal Anti‐inflammatory Drugs and Coumarin Anticoagulants

Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarin anticoagulant metabolism. The variant alleles CYP2C9*2 and CYP2C9*3 are associated with an increased response to warfarin. However, an effect on acenocoumarol dose requirements appears to be absent for the CYP2C9*2 allele and the consequences for the metabolism of phenprocoumon have not yet been established. We investigated CYP2C9 polymorphisms in relation to the international normalized ratio (INR) during the first 6 weeks of treatment and its effect on the maintenance dose in a cohort of 1124 patients from the Rotterdam Study who were treated with acenocoumarol or phenprocoumon. There was a statistically significant difference in first INR between patients with variant genotypes and those with the wild-type. Almost all acenocoumarol-treated patients with a variant genotype had a significantly higher mean INR and had a higher risk of an INR > or = 6.0 during the first 6 weeks of treatment. A clear genotype-dose relationship was found for acenocoumarol-treated patients. For patients on phenprocoumon, no significant differences were found between variant genotypes and the wild-type genotype. Individuals with one or more CYP2C9*2 or CYP2C9*3 allele(s) require a significantly lower dose of acenocoumarol compared to wild-type patients. Phenprocoumon appears to be a clinically useful alternative in patients carrying the CYP2C9*2 and *3 alleles.

Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment.

Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti‐inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction.

Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes

In the Netherlands, several reports have described a potentiation of acenocoumarol‐induced anticoagulation by co‐medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR) ≥ 6, until death, end of treatment, or end of the study period. The Andersen–Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55–2·55) and lansoprazole (HR 1·49, 95% CI 1·05–2·10). There was also a lower and non‐significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co‐medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs.

Contribution of Renal Impairment to Potentially Preventable Medication-Related Hospital Admissions

Background Genome-wide association studies (GWAS) on warfarin and acenocoumarol showed that interindividual dosage variation is mainly associated with single nucleotide polymorphisms (SNPs) in VKORC1 and to a lesser extent in CYP2C9 and CYP4F2. For phenprocoumon dosage, the genes encoding CYP3A4 and ApoE might play a role. Objective To assess the association between common genetic variants within VKORC1, CYP2C9, CYP4F2, CYP3A4, and ApoE and phenprocoumon maintenance dosage, and to identify novel signals using GWAS. Methods We selected all participants from the Rotterdam study who were treated with phenprocoumon. For each SNP, we tested the association between the above-mentioned genotypes and age, sex, body mass index, and target INR adjusted-phenprocoumon maintenance dosage. Results Within our study population (N=244), VKORC1, CYP2C9, CYP4F2 genotypes together explained 46% of phenprocoumon maintenance dosage variation. Each additional VKORC1 variant allele reduced phenprocoumon maintenance dosage by 4.8 mg/week (P<0.0001) and each additional CYP2C9 variant allele by 2.2 mg/week (P=0.002). Each additional variant allele of CYP4F2 increased phenprocoumon dosage by 1.5 mg/week (P=0.022). Variant alleles of CYP3A41*B and ApoE showed no association with phenprocoumon dosage. Genome-wide significant SNPs were all related to VKORC1 activity. Best associated were two SNPs in complete linkage disequilibrium with each other and with SNPs within VKORC1: rs10871454 [Syntaxin 4A (STX4A)] and rs11150604 (ZNF646), each with a P value of 2.1×10−22. Each reduced phenprocoumon maintenance dosage weekly by 4.9 mg per variant allele. Conclusion Similar to earlier findings with warfarin and acenocoumarol, phenprocoumon maintenance dosage depended on polymorphisms in the VKORC1 gene. CYP2C9 and CYP4F2 were of modest relevance.

Discontinuation of β-Blockers and the Risk of Myocardial Infarction in the Elderly

Background: Medication errors and renal impairment contribute to severe adverse drug events, which may lead to hospital admission. Objective: To determine whether medication errors and renal impairment contribute to hospital admission and examine these errors for strategies to prevent admissions. Methods: The 714 medication-related hospital admissions reported in the prospective multicenter study HARM (Hospital Admissions Related to Medication) were analyzed. The patients were divided into 3 groups based on the availability of creatinine levels: group A, the home-monitored group (n = 227); group B, the hospital-monitored group (n = 420); and group C, the unmonitored group (n = 67). Results: After assessment, 70 admissions (10%) were considered to be related to a medication error and renal impairment (A, 29; B, 41; C, none). In these 70 patients, 85 errors occurred in group A, 66 errors in group B, and none in group C. Dosing errors were identified in 46 patients (A, 14; B. 32), a drug-drug interaction in 22 patients (A. 13; B, 9), and a drug-disease interaction in 17 patients (A, 10; B, 7). Conclusions: Renal impairment and medication errors may lead to medication-related hospital admissions. Monitoring renal function and adjusting pharmacotherapy according to renal function might help to prevent hospital admissions. This can be a strategy for research on how to decrease the number of medication-related hospital admissions.

The use of opioids at the end of life: knowledge level of pharmacists and cooperation with physicians

AbstractBackground: It has been shown that the abrupt cessation of treatment with β-adrenoceptor antagonists (β-blockers) increases the risk of myocardial infarction in patients with hypertension. As β-blockers differ in their pharmacokinetic and pharmacodynamic properties, this risk of discontinuation might also differ between subgroups of β-blockers. Objective: To determine whether discontinuation of β-blockers is associated with an increased risk of myocardial infarction in elderly patients and whether the effects of recent cessation differs between subgroups of β-blockers, categorised according to their selectivity, lipophilic profile and intrinsic sympathomimetic activity (ISA). Design: A cohort study in users of β-blockers within the Rotterdam Study, which was a prospective population-based follow-up study of 7983 individuals aged ≥55 years. Patients: We identified 2588 individuals who had been treated with a β-blocker for at least 30 days at any time during the study period of 1 January 1991 to 1 January 2002. In this group, 148 subjects developed incident myocardial infarction. Methods: Detailed information on the medication use and clinical characteristics of all patients were collected from the files of pharmacies, general practices and hospitals. Myocardial infarction was diagnosed on the basis of internationally accepted criteria and verified by a cardiologist. The duration of β-blocker use was calculated from computerised pharmacy records on the basis of the number of dispensed tablets or capsules and the prescribed daily number.For every individual, on the index date (date of myocardial infarction in cases, the same date in controls [defined as any patient who had not experienced a myocardial infarction up to that timepoint]) the usage of β-blockers was determined and classified as either current or as past use. Past use was classified into three different periods: cessation of β-blockers less than 30 days; between 30 and 180 days; and more than 180 days before the index date. The risk of myocardial infarction in the three periods of cessation of exposure were analysed using a Cox proportional hazards model that included potential confounders and cardiac comedication. These analyses were performed for the whole group and for subgroups of β-blockers. Results: Discontinuation of any β-blocker was not associated with an increased risk of myocardial infarction compared with current use of a β-blocker. Analyses within subgroups showed that discontinuation of selective β-blockers was associated with an increased risk of myocardial infarction compared with current use of any β-blocker within the first 30 days (relative risk [RR] 2.70; 95% CI 1.06, 6.89) and also between 30 and 180 days after discontinuation (RR 2.44; 95% CI 1.07, 5.59). No increased risk was demonstrated in the other β-blocker subgroups. Conclusion: Overall, discontinuation of β-blockers was not associated with an increased risk of myocardial infarction. However, when analysed by β-blocker subgroup, cessation of selective β-blockers was associated with an increased risk of myocardial infarction during the first 180 days after discontinuation.