Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

Brain serotonin synthesis and metabolism (turnover), as indicated by CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), may depend on plasma concentrations of the essential amino acid L-tryptophan (TRP). We investigated the biochemical effects of acute plasma TRP depletion (ATD) in normal volunteers undergoing a 36-h CSF collection via lumbar drain. Six subjects who were in good health were put on a low-TRP diet (160 mg/day) 24 h before lumbar puncture; this diet was continued for the first 22 h of the CSF collection. At hour 22, subjects ingested a TRP-deficient 15-amino acid drink shown previously to deplete plasma TRP. Total plasma TRP, free plasma TRP, and CSF TRP subsequently decreased 86.3, 86.5, and 92.3%, respectively. CSF 5-HIAA decreased by 32.8%. Plasma total and free TRP concentrations were both decreased at ϳ2 h following ingestion of the TRP-free amino acid drink and were lowest ϳ6 h after ATD; CSF TRP and 5-HIAA were decreased at 2.5 h and ϳ4 h after ATD, respectively. CSF TRP was lowest 8.0 h later. CSF 5-HIAA continued to decrease 14 h after the TRP-deficient amino acid drink was given.

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

Two single-center, double-blind, randomized, placebo-controlled, sequentially enrolled studies were conducted. In study 1, 8 subjects (6 active/2 placebo) received 60-, 90-, 120-, 180-, or 240-mg tolvaptan/matching placebo. In study 2, 9 subjects (6 active/3 placebo) received 180-, 240-, 300-, 360-, 420-, or 480-mg tolvaptan/matching placebo. Increases in tolvaptan C(max) were less than dose-proportional and plateaued at doses greater than 240 mg; AUC(infinity) increased proportionally with dose. Changes in serum K(+), creatinine clearance, and Na(+), K(+), and osmolality urinary excretion were similar to the placebo group for the 0- to 24-hour interval following dosing. Changes were observed in plasma arginine vasopressin, serum aldosterone, and plasma renin activity but were not clinically significant. Increases were seen in mean serum Na(+) concentrations (4-6 mEq/L), plasma osmolality ( approximately 8 mOsm/kg), and free water clearance ( approximately 6 mL/min) throughout 0 to 24 hours; none of these increases was dose dependent. Only total urine volume excretion (0-72 hours postdose) increased linearly with dose. As plasma tolvaptan concentrations increased, the duration that the urine excretion rate remained above baseline rates also increased. The most frequent adverse events--excess thirst, frequent urination, and dry mouth--appeared to be related to the pharmacological action of tolvaptan. No dose-limiting toxicities were observed.

No abstract

Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C: <30 ml/min per 1.73 m(2). Measurements were performed before, after 3 weeks of tolvaptan (up titration to 90/30 mg/day, split dose), and 3 weeks after the last dose of tolvaptan. With tolvaptan, a minor, reversible decrease in GFR ((125)I-iothalamate clearance) was found that reached significance in groups A and B: -7.8 (interquartile range -13.7 to -1.3) and -4.3 (-9.7 to -0.9) ml/min per 1.73 m(2), respectively, but not in group C (GFR decrease -0.7 (-1.1 to 1.5) ml/min/1.73 m(2)). The percentage change in GFR, ERPF ((131)I-hippuran clearance), and filtration fraction with tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

Early maternal deprivation reduces CNS serotonin turnover, and individual differences in CSF 5-HIAA concentrations are trait-like and appear to stabilize in infancy.