RESUMO
Single nucleotide polymorphisms in six genes were investigated for an association between diastolic blood pressure change and duloxetine treatment. Nominally significant within-gene association was found with SLC6A2 rs4436775 and rs4564560 and HTR2A rs6313, but after adjusting for multiple comparisons, these associations were no longer significant.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Tiofenos/farmacologia , Inibidores da Captação Adrenérgica/uso terapêutico , Pressão Sanguínea/genética , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/tratamento farmacológico , Diástole/efeitos dos fármacos , Diástole/genética , Cloridrato de Duloxetina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Dor/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Receptores Dopaminérgicos/genética , Receptores de Serotonina/genética , Tiofenos/uso terapêuticoRESUMO
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.
Assuntos
Alelos , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/genética , Adulto , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno da Personalidade Borderline/tratamento farmacológico , Transtorno da Personalidade Borderline/genética , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/genética , Feminino , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Olanzapina , Farmacogenética , Risperidona/efeitos adversos , Risperidona/uso terapêuticoRESUMO
Single-nucleotide and diplotype associations with 17-item Hamilton Depression Rating Scale (HAMD(17)) total score changes were examined, based on catechol-O-methyltransferase (COMT) rs165599 status in duloxetine-treated, self-identified white patients with major depressive disorder. COMT rs165737 and a diplotype containing COMT rs165599 and COMT rs165737 were associated with HAMD(17) total score changes.
Assuntos
Antidepressivos/uso terapêutico , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Tiofenos/uso terapêutico , Adulto , Cloridrato de Duloxetina , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica , Fatores SexuaisRESUMO
Porcine models have become increasingly popular in cardiovascular research. The standard farm pig rapidly increases in body weight and size, potentially confounding serial measurements of cardiac function and morphology. We developed an adult porcine model that does not show physiologic increases in heart mass during the study period and is suitable for long-term study. We compared adult minipigs with the commonly used adolescent Yorkshire swine. Myocardial infarction was induced in adult Göttingen minipigs and adolescent Yorkshire swine by occlusion of the left anterior descending coronary artery followed by reperfusion. At 8 wk after infarction, the left ventricular ejection fraction was 34.1 +/- 2.3% in minipigs and 30.7 +/- 2.0% in Yorkshire swine. The left ventricular end-diastolic mass in Yorkshire pigs assessed by magnetic resonance imaging increased 17 +/- 5 g, from 42.6 +/- 4.3 g at week 1 after infarction to 52.8 +/- 6.6 g at week 8, whereas it remained unchanged in minipigs. Cardiac anatomy and physiology in adult minipigs were evaluated invasively by angiography and noninvasively by Multidetector Computed Tomography and by Magnetic Resonance Imaging at 1.5 T and 3 T prior to myocardial infarction and during folow-up. This porcine heart failure model is reproducible, mimics the pathophysiology in patients who have experienced myocardial infarction, and is suitable for imaging studies. New heart failure therapies and devices can be tested preclinically in this adult animal model of chronic heart failure.
