Naoyuki Okuyama

Stimulation of Adenylyl Cyclase and Induction of Brain-Derived Neurotrophic Factor and TrkB mRNA by NKH477, a Novel and Potent Forskolin Derivative

Abstract: The present study was undertaken to examine whether NKH477, a novel and potent water‐soluble forskolin derivative, stimulates adenylyl cyclase and regulates brain‐derived neurotrophic factor (BDNF) and TrkB expression in the rat brain. Administration of NKH477 at a dose of 1.0 mg/kg, but not 0.1 mg/kg, increased levels of cyclic AMP (cAMP) in a time‐dependent manner in frontal cortex and hippocampus. Repeated administration of NKH477 (1.0 mg/kg) for 7 or 14 days also increased levels of cAMP in these two brain regions, indicating that the response does not desensitize with chronic treatment. In addition, administration of NKH477 at the 1 mg/kg dose increased the expression of BDNF and TrkB mRNA in frontal cortex and hippocampus. This effect was observed after single, as well as repeated (7 or 14 days), administration of NKH477. These results demonstrate that NKH477 administration rapidly increases cAMP levels in brain and provides evidence that stimulation of this second messenger system increases the expression of BDNF and TrkB mRNA.

Possible association between delusional disorder, somatic type and reduced regional cerebral blood flow

1. A 78-year-old female with DDST and pain disorder was treated by clomipramine 20-100 mg/day. The hypochondriacal delusion was completely resolved, while the pains were partially resolved. 2. The SPECT using Xe-133 taken at the early stage of clomipramine treatment, when she still had hypochondriacal delusions, showed markedly reduced rCBF in the temporal and parietal lobes, with predominance on the left hemisphere. Meanwhile, the SPECT taken after resolution of the hypochondriacal delusions showed a marked improvement in the reduced rCBF. 3. This report suggests that DDST has some association with reduced rCBF in the temporal and parietal lobes.

Clomipramine treatment of delusional disorder, somatic type.

Four patients of delusional disorder, somatic type, were treated with clomipramine 60-120 mg/day. All patients showed marked clinical improvement after 27-57 days of clomipramine treatment. In one case, previous treatments by various antipsychotic drugs including pimozide had been unsuccessful. This report suggests that clomipramine is effective at least for some patients with delusional disorder, somatic type, including pimozide-resistant cases. It is also suggested that there is some association between delusional disorder, somatic type, and serotonergic dysfunction.

Occipital hypoperfusion in a patient with psychogenic visual disturbance

A patient with bilateral diminished visual acuity and blurred vision was given the diagnosis of psychogenic visual disturbance after extensive psychiatric and ophthalmological examinations. Single photon emission computed tomography with Tc-99m-ethylcysteinate dimer demonstrated remarkably reduced regional cerebral blood flow (rCBF) in the bilateral occipital lobes. More specifically, rCBF was reduced in the visual association areas, but not in the primary visual areas. These findings suggest that functional suppression of the visual association area is associated with the development of psychogenic visual disturbance.

Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam

The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

Enhancement of 5-hydroxytryptamine-stimulated phosphoinositide hydrolysis in the rat cerebral cortex by repeated immobilization stress.

The present study was undertaken to investigate the influence of repeated immobilization stress on phosphoinositide hydrolysis induced by 5-hydroxytryptamine (5-HT) and noradrenaline in the rat cerebral cortex. Three groups of rats subjected to stress intervention were immobilized for 2 h per day for 3, 7, and 14 days. The stress intervention of any duration did not alter noradrenaline-stimulated phosphoinositide hydrolysis. The 3- and 7-day repeated immobilization enhanced 5-HT-stimulated phosphoinositide hydrolysis, whereas the characteristics of 5-HT2 receptor binding did not change. Chronic treatment with imipramine partially, but significantly, suppressed the increase in 5-HT-stimulated phosphoinositide hydrolysis, induced by the 3-day repeated immobilization. These findings imply that modulation of 5-HT-stimulated phosphoinositide hydrolysis occurs in stressful situations and that the therapeutic effects of tricyclic antidepressant drugs might be related to the modulation of phosphoinositide hydrolysis mediated by 5-HT receptors.

No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.

Nucleotide sequence analysis of the binding site on the inositol 1,4,5-trisphosphate type-1 receptor in bipolar disorder — a negative study

Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder.