＜Editors' Choice＞ Clinical impact of standardized creatinine on dose adjustment of capecitabine.

Although the Cockcroft-Gault equation is still used for the dose adjustment of many drugs that have been approved prior to creatinine standardization, the clinical impact of standardized creatinine in the dose adjustment of capecitabine is poorly understood. We focused on patients with borderline renal function and evaluated the tolerability and safety of capecitabine in patients who received capecitabine plus oxaliplatin (Cape-Ox). We retrospectively identified patients with resected colorectal cancer who had received adjuvant therapy with Cape-Ox regimen. Creatinine clearance (CrCL) was calculated by the Cockcroft-Gault equation with standardized creatinine measured using enzymatic methods, and adjusted CrCL was estimated by adding 0.2 (mg/dL) to the serum creatinine in the equation. We defined patients with "pseudo-normal" renal function as those who had an adjusted CrCL of ≤50 mL/min in patients with normal renal function (CrCL >50 mL/min). We evaluated the tolerability and grade 2 or severer adverse events of capecitabine treatment. One hundred four patients had normal and 10 had impaired renal function (CrCL <50 mL/min). Among the 104 patients with normal renal function, 23 (22.1%) had pseudo-normal renal function. Seventeen patients completed the eight cycles of Cape-Ox therapy without treatment delay or dose reduction, and all of them had truly normal renal function. The patients with pseudo-normal renal function were more likely to have grade 2 or severer thrombocytopenia than those with truly normal renal function. We should recognize correctly the clinical impact of standardized creatinine in the treatment of borderline renal function with Cape-Ox regimen in patients.

Plasma dehydroepiandrosterone sulfate levels in patients with major depressive disorder correlate with remission during treatment with antidepressants.

OBJECTIVE: We attempted to investigate whether dehydroepiandrosterone sulfate (DHEA-S) levels are associated with remission of major depressive disorder by assessing scores on the 17-Item Structured Interview Guide for the Hamilton Depression before and after antidepressant treatment. METHODS: Plasma DHEA-S levels in 24 patients diagnosed with major depressive disorder on the basis of Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) before and after antidepressant treatment, and 24 healthy, gender-matched, and age-matched controls were measured using a radioimmunoassay kit. RESULTS: Plasma DHEA-S levels in patients were significantly higher than those in healthy controls. In patients who achieved remission after antidepressant treatment, plasma DHEA-S levels significantly declined compared with the levels before treatment. A significant correlation was observed between changes in DHEA-S levels and Absence of Depressive and Anxious Mood scores, which are calculated from the 2-Item Structured Interview Guide for the Hamilton Depression rating as follows: severity of depressive mood and anxiety in patients before and after antidepressant treatment. CONCLUSIONS: These findings suggest that plasma DHEA-S levels can be used as a putative indicator of the state of remission in patients with major depressive disorder. Copyright © 2014 John Wiley & Sons, Ltd.

Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers.

Since most first-generation antihistamines have undesirable sedative effects on the central nervous systems (CNS), newer (second-generation) antihistamines have been developed to improve patients' quality of life. However, there are few reports that directly compare the antihistaminic efficacy and impairment of psychomotor functions. We designed a double-blind, placebo controlled, crossover study to concurrently compare the clinical effectiveness of promethazine, a first-generation antihistamine, and fexofenadine and olopatadine, second-generation antihistamines, by measuring their potency as peripheral inhibitors of histamine-induced wheal and flare. Further, we investigated their sedative effects on the CNS using a battery of psychomotor tests. When single therapeutic doses of fexofenadine (60 mg), olopatadine (5 mg) and promethazine (25 mg) were given in a double-blind manner to 24 healthy volunteers, all antihistamines produced a significant reduction in the wheal and flare responses induced by histamine. In the comparison among antihistamines, olopatadine showed a rapid inhibitory effect compared with fexofenadine and promethazine, and had a potent effect compared with promethazine. In a battery of psychomotor assessments using critical flicker fusion, choice reaction time, compensatory tracking, rapid visual information processing and a line analogue rating scale as a subjective assessment of sedation, promethazine significantly impaired psychomotor function. Fexofenadine and olopatadine had no significant effect in any of the psychomotor tests. Promethazine, fexofenadine and olopatadine did not affect behavioral activity, as measured by wrist actigraphy. These results suggest that olopatadine at a therapeutic dose has greater antihistaminergic activity than promethazine, and olopatadine and fexofenadine did not cause cognitive or psychomotor impairment.

Role of N-methyl-D-aspartate receptors in antidepressant-like effects of sigma 1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503) in olfactory bulbectomized rats.

In the present study, we aimed to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the antidepressant-like effects of a sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503), in the olfactory bulbectomized (OB) rat model of depression. A symptomatology-based behavioral investigation was made by reconstructing in OB rats the symptoms of depression, such as psychomotor agitation, loss of interest, and cognitive dysfunction, using a typical antidepressant, desipramine, as a positive control. Repeated treatment with SA-4503 ameliorated the behavioral deficits in OB rats resembling depression symptoms in the open-field test, sexual behavior test, and cued and contextual fear-conditioning test. SA-4503 displayed advantages over desipramine in the sexual behavior test. SA-4503 also reversed the decrease in the protein expression of NMDA receptor subunit (NR)1, but not NR2A or NR2B, in the prefrontal cortex, hippocampus, and amygdala of OB rats. The behavioral and neurochemical effects of SA-4503 were blocked by combined treatment with a specific sigma(1) receptor antagonist, N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride (NE-100). Furthermore, the effects of SA-4503 on the performance of OB rats in the behavioral tests were abrogated by acute treatment with an NMDA receptor antagonist, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). The present study indicated for the first time that the sigma(1) receptor agonist SA-4503 may have effects on depressive symptoms such as agitation, loss of interest, and impaired cognition, which are mediated by NMDA receptors.

Behavioural and neurochemical features of olfactory bulbectomized rats resembling depression with comorbid anxiety.

In order to probe the nature and validity of olfactory bulbectomized (OB) rats as a model of depression, we reevaluated their behavioural and neurochemical deficits in relation to the symptoms and neurochemical abnormalities of depression using our protocols, which distinguish anhedonia-resembling behaviour in sexual behavioural test, the hippocampus (Hip)-dependent long-term memory and anxiety-resembling behaviour specially. Besides exploratory hyperactivity in response to a novel environmental stress resembling the psychomotor agitation, OB rats showed a decrease of libido, and a deficit of long-term explicit memory, resembling loss of interest and cognitive deficits in depressive patients, respectively. OB rats also exhibited the anxiety symptom-resembling behaviour in social interaction and plus-maze tests. In the OB rats, we found degenerated neurons in the piriform cortex, decreased protein expression of NMDA receptor subunit 1 (NR1), but not NR2A or NR2B, in the prefrontal cortex (PFC), Hip and amygdala (Amg), and decreased phosphorylation of cAMP-response element-binding protein (CREB) in the PFC and Hip, but not Amg. The behavioural and neurochemical abnormalities in OB rats, except for the performance in the plus-maze task and neuronal degeneration, were significantly attenuated by repeated treatment with desipramine (10 mg/kg), a typical antidepressant. The present study indicated that OB rats may be a model of depression with comorbid anxiety, characterized by agitation, sexual and cognitive dysfunction, neuronal degeneration, decreased protein expression of NR1, and decreased phosphorylation of CREB.

Comparative study of acute effects of single doses of fexofenadine, olopatadine, d-chlorpheniramine and placebo on psychomotor function in healthy volunteers.

Since most classical (first-generation) antihistamines have undesirable sedative effects on the central nervous system (CNS), newer (second-generation) antihistamines have been developed to relieve the sedative effects and to improve the patient's quality of life. However, the psychomotor profiles of second-generation antihistamines are not fully elucidated. In this randomized, double-blind, crossover study, the acute effects of single doses of second-generation antihistamines, fexofenadine (120 mg) and olopatadine (10 mg), on cognitive and psychomotor performance were investigated in comparison with those of placebo and d-chlorpheniramine (4 mg), a first-generation antihistamine, using objective and subjective assessments, in 11 healthy Japanese volunteers. In a battery of psychomotor tests, d-chlorpheniramine impaired tracking ability in the compensatory tracking task and caused a reduction in behavioural activity as continuously measured by wrist actigraphy. Olopatadine, like d-chlorpheniramine, reduced the behavioural activity, while fexofenadine had no effect in any of the tests. No significant changes in the subjects' self-ratings of drowsiness were found with the three antihistamines. These results suggest that d-chlorpheniramine and olopatadine, but not fexofenadine, produce sedative effects on psychomotor performance, and that the CNS profile of fexofenadine is different from that of olopatadine.