OBJECTIVETo assess whether HTR1A and HTR1B polymorphisms are associated with the predisposition, gender, PUMC Classification and/or severity of adolescent idiopathic scoliosis (AIS).

METHODSRs6294 (HTR1A) and rs6296 (HTR1B) were genotyped in 103 AIS patients treated from January 2006 to March 2007, and 108 controls with matched gender and age. The data were analyzed by the allelic and genotypic association analysis, and the genotype-phenotype (gender, PUMC Classification, and Cobb angle) association analysis.

RESULTSThe distributions of the alleles of all the 2 SNPs met Hardy-Weinberg equilibrium in the controls (goodness-of-fit chi(2) test, P > 0.05). The allele A of rs6294 was related with the occurrence of AIS (P = 0.041), but differences of the allele frequencies of rs6296 and the genotype frequencies of both SNPs between 2 groups had no statistical significance (P > 0.05). The genotype A/A + A/G of rs6294 was associated with AIS PUMC type III, and there was no other positive results in genotype-phenotype association analysis.

CONCLUSIONThese results suggest that HTR1A may be a predisposition gene of AIS PUMC type III, and PUMC Classification may has its genetic basis.

Adolescent ; Gene Frequency ; Genetic Association Studies ; Genotype ; Humans ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Receptor, Serotonin, 5-HT1A ; genetics ; Receptor, Serotonin, 5-HT1B ; genetics ; Scoliosis ; genetics

BACKGROUNDRecent studies have suggested that susceptibility to major depressive disorder (MDD) might be related to the serotonin 1A receptor (5-HTR1A) C (-1019) G polymorphism. In this study, we aimed to assess the association between 5-HTR1A C (-1019) G polymorphism and MDD in the Northern Han ethnic group of China.

METHODSThe C (-1019) G of 5-HTR1A was detected with polymerase chain reaction (PCR) in 400 patients with MDD and 400 unrelated age- and sex-matched healthy control subjects. Association between the C (-1019) G and MDD was statistically analyzed.

RESULTSThere was a statistically significant difference between MDD patients and controls in both the genotype distribution (Chi(2) = 10.913, df = 2, P = 0.004) and the allele frequency (Chi(2) = 10.379, df = 1, P = 0.001), and a significant difference in the genotype distribution and the allele frequency was found both in the female subjects (Genotype distribution: Chi(2) = 15.406, df = 2, P = 0.000; allele frequency: Chi(2) = 15.552, df = 1, P = 0.000) and the late-onset subjects (Genotype distribution: Chi(2) = 7.771, df = 2, P = 0.021; allele frequency: Chi(2) = 8.007, df = 1, P = 0.005) in the two groups.

CONCLUSIONThese results suggest that 5-HTR1A C (-1019) G polymorphism is probably associated with MDD and it is likely to be the susceptible gene locus for the female and late-onset MDD.

Adult ; Asian Continental Ancestry Group ; genetics ; China ; Depressive Disorder, Major ; ethnology ; genetics ; pathology ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Receptor, Serotonin, 5-HT1A ; genetics

Compounds with serotonin reuptake inhibition/5-HT(1A) dual activity were used to build 3D pharmacophore model as a training molecules by Discover Studio. Based on the model, 8 novel aryl piperazine benzo[b][1,4] oxazine derivatives were designed and synthesized, and their structures were confirmed by 1H NMR and HR-MS. Biological evaluation illustrated that compounds VI(1) and VI(7) showed potent functional activities at both 5-HT transporter and 5-HT(1A) receptor, which can be used as lead compounds to guide future research of design and synthesis of potent novel compounds.
Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Drug Design ; Genetic Vectors ; Molecular Structure ; Oxazines ; chemical synthesis ; chemistry ; pharmacology ; Piperazines ; chemical synthesis ; chemistry ; pharmacology ; Plasmids ; Protein Binding ; Receptor, Serotonin, 5-HT1A ; genetics ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; genetics ; metabolism ; Serotonin Uptake Inhibitors ; metabolism ; Structure-Activity Relationship ; Transfection

PURPOSE: Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. MATERIALS AND METHODS: Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. RESULTS: Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. CONCLUSIONS: Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.
Adolescent ; Adult ; Aged ; Body Mass Index ; Cytochrome P-450 CYP2D6/genetics ; Humans ; Leptin/blood ; Male ; Middle Aged ; Mutation ; Paroxetine/*administration & dosage/blood ; Polymorphism, Genetic ; Premature Ejaculation/*drug therapy/genetics ; Receptor, Serotonin, 5-HT1A/genetics ; Risk Factors ; Serotonin Uptake Inhibitors/*administration & dosage ; Time Factors ; Treatment Outcome ; Young Adult

PURPOSE: Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. MATERIALS AND METHODS: Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. RESULTS: Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. CONCLUSIONS: Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.
Adolescent ; Adult ; Aged ; Body Mass Index ; Cytochrome P-450 CYP2D6/genetics ; Humans ; Leptin/blood ; Male ; Middle Aged ; Mutation ; Paroxetine/*administration & dosage/blood ; Polymorphism, Genetic ; Premature Ejaculation/*drug therapy/genetics ; Receptor, Serotonin, 5-HT1A/genetics ; Risk Factors ; Serotonin Uptake Inhibitors/*administration & dosage ; Time Factors ; Treatment Outcome ; Young Adult