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We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose.One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR.R-warfarin clearance was 32% higher in carriers of CYP2C19*17 than in carriers of CYP2C19*2 (mean 2.5 mL/min, 95% confidence interval (CI) 2.3-2.8 vs. 1.9 mL/min, 95% CI 1.7-2.2; P post hoc = 0.01). Patients with CYP2C19*1/*1 genotype had an intermediate clearance (mean 2.1 mL/min, 95% CI 1.8-2.4). The genotypes of VKORC1, CYP2C9, and CYP2C19, together with non-genetic factors (age, sex, and body weight) explained 52% of the variability in warfarin INR/daily dose, of which CYP2C19 genotypes accounted for 7%.This is the first study to include the gain-of-function CYP2C19*17 allele when assessing the impact of CYP2C19 polymorphisms on the clearance of warfarin enantiomers. CYP2C19 genotypes influenced the clearance of R-warfarin and contributed significantly to the variability in INR/daily dose, indirectly indicating a clinical relevance of R-warfarin.

To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas.One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods.Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks.CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide.

Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS.Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients.Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped.Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04).Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients.

The aims of this study were to evaluate the impact of the CYP2D6 polymorphism on both the steady-state plasma concentrations (Cp) and the clinical outcome of donepezil, a selective acetylcholinesterase inhibitor used in the treatment of Alzheimer’s disease (AD). Forty-two patients of Caucasian ethnicity affected by probable AD were included in the study. All had been receiving therapy with donepezil for at least 3 months: 31 patients with 5 mg/day and 11 patients with 10 mg/day. The CYP2D6 genotype was analysed, and donepezil Cp was measured by using high-performance liquid chromatography. On the basis of their CYP2D6 genotype, 30 patients could be classified as homozygous extensive metabolizers (EM), 10 as heterozygous EM and 2 as ultrarapid metabolizers (UM). No poor metabolizer was found. The dose and body weight-corrected median donepezil Cp were slightly, though not significantly, lower in homozygous than in heterozygous EM (0.33 vs. 0.41 ng/ml/mg/kg, respectively). The latter group consistently showed a better clinical response to treatment, as measured by change in Mini-Mental State Examination score (median: 1.40 vs. −1.30, respectively). UM patients had lower Cp than EM patients and showed no clinical improvement. Our preliminary data suggest that the CYP2D6 polymorphism influences both donepezil metabolism and therapeutic outcome and that a knowledge of a patient’s CYP2D6 genotype together with donepezil concentration measurements might be useful in the context of improving the clinical efficacy of donepezil therapy.

Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs.Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D(2) receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D(3) receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT(2A) receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene.The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P = 0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P = 0.030; OR 1.9; 95% CI 1.1-3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P = 0.040; OR 4.0; 95% CI 1.05-15.2) No significant differences in allele frequencies were found for the other polymorphisms.Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs.

Sirs, Despite large interindividual differences in dose requirement and a narrow therapeutic range, warfarin is still the most widely prescribed anticoagulant for thromboembolic therapy. However, the problems with dose titration, especially during the initial phase of treatment, lead to a high risk of either severe bleeding or the failure to prevent thromboembolism [1]. A working knowledge of warfarin interactive pathways and of the human genome will facilitate the determination of genetic factors that cause variable response to this drug. Warfarin acts through the inhibition of vitamin K reductase in the vitamin K cycle, thereby preventing the activation of clotting factors II, VII, IX and X and proteins C, S and Z [2, 3]. However, vitamin K1 can be reduced through another pathway, and a high intake of vitamin K1 may reverse the anticoagulant effect of warfarin [3–5]. Vitamin K1 is absorbed from the small intestine together with dietary fat, transported by chylomicrons in the blood and subsequently cleared by the liver through an apolipoprotein E (APOE) receptorspecific uptake [3, 6]. The major isoforms of apolipoprotein E are encoded by the three APOE alleles E2, E3 and E4 [7]. Individuals carrying the APOE*E4 allele have a more rapid uptake of chylomicron remnants following a meal than those that do not [8], and they also have lower serum concentrations of vitamin K1 following an overnight fast [6, 9, 10]. These findings suggest that carriers of APOE*E4 have a more rapid uptake of vitamin K1, leading to an enhanced availability of reduced vitamin K for the activation of clotting factors and proteins in the liver. Warfarin is administered as a racemate of Rand Senantiomers [11]. Cytochrome P450 2C9 (CYP2C9) is the main enzyme responsible for the metabolism of the more active S-warfarin [12], and genetic variability in CYP2C9 has a significant effect on warfarin dose requirement [13]. We have recently published a study on warfarin-treated Swedish patients showing that CYP2C9*1/*1 extensive metabolisers that are homozygous for APOE*E4 require higher warfarin doses than patients carrying other APOE alleles [14]. This study was repeated using 145 Italian patients, most of whom had participated in a previously published study on warfarin pharmacokinetics [15]. The local Ethics Committee (Comitato Etico dell’Azienda Ospedaliera di Padova) gave permission for the APOE genotyping. The warfarin patients had stable prothrombin time international normalised ratios (PT INR), and no interfering drugs were allowed during the study. Two APOE single nucleotide polymorphisms (SNPs) at nucleotide positions 334 and 472 were investigated using TaqMan (Applied Biosystems, Foster City, Calif.), and the ABI PRISM 7000 Sequence Detection System (Applied Biosystems) [14]. Twenty patients carried one APOE*E4 allele (E2/E4, n=1 and E3/E4, n=19), 105 were homozygous for E3 and 20 were heterozygous E2/E3. No one was homozygous for APOE*E4. There were no significant differences in age, gender, bodyweight or PT INR among the APOE genotype groups. We found that the weekly warfarin dose requirement did not vary between patients with different APOE genotypes (analysis of variance: p=0.5937; Fig. 1a). To test the contribution of other important factors, we combined the POE genotype with the CYP2C9 genotype, age, bodyweight and PT INR in a multiple regression model and found that CYP2C9 H. Kohnke AE M. G. Scordo AE M. Wadelius (&) Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden E-mail: mia.wadelius@medsci.uu.se Tel.: +46-18-6114945