CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.

Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers. This study compared safety and tolerability among the different CYP2D6 metabolizer groups in the 12-week open-label phase of an atomoxetine study in adult patients with ADHD. Genotyping identified 1039 patients as extensive/ultrarapid metabolizers, 780 patients as intermediate metabolizers, and 117 patients as poor metabolizers. Common (≥5% frequency) treatment-emergent adverse events did not significantly differ between extensive/ultrarapid and intermediate metabolizers (odds ratios were <2.0 or >0.5). Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. There were no significant differences between extensive/ultrarapid and intermediate metabolizers in changes from baseline in vital signs. These results suggest that data from CYP2D6 intermediate and extensive/ultrarapid metabolizers can be combined when considering safety analyses related to atomoxetine.

A phase 2, placebo-controlled study of the opioid receptor antagonist LY2196044 for the treatment of alcohol dependence.

BACKGROUND: Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients. METHODS: This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period. Patients (N = 375) were alcohol-dependent, treatment-seeking adults. Patients were randomly assigned to once-daily LY2196044 (final doses of 125 or 250 mg/d) or placebo. DNA samples were collected at baseline. At each visit, patients underwent safety assessments, laboratory testing, efficacy measures, and medical management. Blood samples were also obtained for pharmacokinetic testing. The primary measure was the change from baseline in the percent heavy drinking days (HDD). Secondary efficacy measures were percent days abstinent per month and number of drinks per day. RESULTS: The treatment difference in change from baseline in % HDD between LY2196044 and placebo was not statistically significant (-43.02 vs. -38.72%, respectively; p = 0.12). There was a trend toward greater change from baseline in the percent days abstinent per month for the LY2196044 group compared with the placebo group (33.49 vs. 28.12%, respectively; p = 0.051). The decrease from baseline for mean number of drinks per day was statistically significantly greater in the LY2196044 group compared with the placebo group (-5.37 vs. -4.66 drinks per day, respectively; p = 0.013). LY2196044-treated patients who were dopamine receptor type 4-variable number tandem repeat L carriers had greater reductions in % HDD (p = 0.0565), increased percent days abstinent (p = 0.0496), and reduced drinks per day (p = 0.0069) than placebo-treated L carriers. The safety profile for LY2196044 appeared similar to that of other opioid antagonists. CONCLUSIONS: The results from this proof-of-concept clinical trial warrant further evaluation of LY2196044 for the treatment of alcohol dependence.

Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia.

OBJECTIVE: Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. METHOD: The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. RESULTS: The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. CONCLUSIONS: Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups.

Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis.

OBJECTIVE: To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination. METHOD: A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments. CONCLUSIONS: Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2. TRIAL REGISTRATION: Parent study registered at ClinicalTrials.gov identifier: NCT00035321.

Analysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone.

OBJECTIVE: We examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy. METHOD: Patients with schizophrenia (DSM-IV) were assessed during 2006 and 2007 for response/nonresponse (defined as ≥ 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks. Associations between change in PANSS total (primary outcome measure), positive, and negative scores and the 6 SNPs were examined in risperidone-treated patients (N = 145). Genotype frequencies and improvement in PANSS total scores were analyzed for those SNPs significantly associated with change in PANSS total score. RESULTS: The SNPs XKR4 rs9643483 and GRIA4 rs2513265 were significantly associated with change in PANSS total response (adjusted P < .05 for both), with the same direction of effect as reported for iloperidone. For patients with nonresponsive genotypes for these SNPs, mean improvement in PANSS total score for African Americans was two-thirds that seen for whites (XKR4: -13.9 versus -21.4; GRIA4: -12.5 versus -20.9). CONCLUSIONS: In this retrospective pharmacogenomic analysis, we found that 2 SNPs previously linked to iloperidone response were also associated with response to risperidone. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00337662.

A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study.

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.

Analysis of mutational spectra: locating hotspots and clusters of mutations using recursive segmentation.

Mutations within different regions of disease-causing genes can vary in their impact on disease initiation and progression. Determining how individual mutations within such genes affect disease risk and progression can improve the accuracy of prognoses and help guide treatment selection. Estimates of mutation-specific risks can be poor, however, when genes have a large number of distinct mutations, and data for any given mutation is sparse. To address this problem, we present here a method of analysing the spectrum of mutations observed across a gene that pools together mutations that appear to have similar effects on disease. One of the assumptions underlying the analysis of mutational spectra created in this manner is that the frequency of the mutation in the sample reflects the degree of its effect on disease development. Additionally, mutations that disrupt the same functionally important region of the gene are expected to have a similar impact on disease development. These mutations tend to form a cluster within the spectrum. Therefore, we developed an algorithm that segments a spectrum into regions containing sites with similar mutational frequencies, and have derived by simulation equations that allow one to evaluate whether segmentation is needed. We used this approach to investigate the spectrum of mutations observed in the p53 tumour suppressor gene in colorectal cancer tumours. Here, recursive segmentation identified the boundaries of apparent clusters better than did other methods, and this approach could identify clusters of mutations which corresponded to biologically important regions of the p53 protein.

A common promoter polymorphism in the hepatic lipase gene (LIPC-480C>T) is associated with an increase in coronary calcification in type 1 diabetes.

Type 1 diabetes is associated with coronary heart disease (CHD) and coronary artery calcification (CAC), a measure of subclinical CHD. The hepatic lipase gene promoter polymorphism (LIPC-480C>T) is a common variant affecting lipid metabolism. This study examined the relation between the LIPC-480C>T and CAC in type 1 diabetes. In the type 1 diabetic patients studied, 56% had CAC >0 Agatston units (AU). These subjects had a longer duration of diabetes (26.2 +/- 1.3 vs. 17.8 +/- 1.4 years; P < 0.001), lower HDL cholesterol levels (55.7 +/- 2.4 vs. 61.0 +/- 2.5 mg/dl; P = 0.05), higher triglyceride levels (101 +/- 17.3 vs. 66 +/- 7.6 mg/dl; P < 0.05), and higher diastolic blood pressure (79.7 +/- 1.0 vs. 76.0 +/- 1.4 mmHg; P < 0.05). The LIPC-480 T allele was more common in subjects with CAC (frequency = 0.31 +/- 0.05 vs. 0.14 +/- 0.04; P = 0.006). The proportion with CAC was 44% in LIPC-480CC subjects, 71% in heterozygotes, and 83% in LIPC-480TT subjects (P < 0.01). LIPC-480 T allele frequency increased as the amount of CAC increased (P = 0.007). LIPC-480 genotype was independently associated with the CAC (odds ratio = 2.90, 95% CI 1.22-6.92, P < 0.05) after adjusting for duration of diabetes, age, sex, diastolic blood pressure, HDL cholesterol, and triglyceride levels. In conclusion, the LIPC-480C>T polymorphism was associated with subclinical CHD in type 1 diabetes. This genetic variant may identify subjects in which early intervention to prevent CHD may be appropriate.

Gluconic Acid as a Fresh Beef Decontaminant.

Effectiveness of 0, 1.5 and 3.0% gluconic acid (G) and/or 0 and 1.5% lactic acid (L) solutions in reducing aerobic psychrotrophic bacteria plate counts (PPCs) and lactic acid bacteria counts (LACs) on vacuum-packaged beef was investigated at 0, 14, 28 and 56 days of storage. Instrumental and visual color changes were evaluated up to 28 days. Steaks treated with 1.5% L, plus 1.5% G or 3.0% G, solutions showed 2.0 and 2.5 log reductions (P<0.05) in PPCs compared to nontreated samples, respectively, at days 28 and 56. At 1.5%, G or L intervention for 0 and 14 days PPCs did not differ (P>0.05). However, PPCs were lower (P