[Liver Injury Risk Factors in Amyotrophic Lateral Sclerosis Patients Treated with Riluzole].

Riluzole, a drug used in the management of amyotrophic lateral sclerosis (ALS), is associated with a high incidence of liver failure. It is imperative to determine risk factors and severity of liver injury in patients taking riluzole to devise an appropriate treatment regimen. We, therefore, studied risk factors for liver injury in ALS patients who were prescribed riluzole at Kitasato University East Hospital from 1999 to 2015. Of the 222 patients enrolled in this study, 113 and 109 patients were diagnosed with mild to moderate (grade 1 or 2) and without (grade 0) liver injury, respectively. Prediction of risk factors was determined using binary logistical regression analyses. The results showed that 50.9% (n=113) of ALS patients developed mild to moderate liver injury; 71.7% and 53.1% of patients were concurrently using CYP1A2 inhibitors (p=0.005) and diclofenac (p=0.032), respectively; 55.8% of patients with liver injury had a history of smoking (p=0.011). Multivariate analyses revealed that the concurrent use of CYP1A2 inhibitors [odds ratio (OR) 2.152, 95% confidence interval (CI) 1.225-3.780, p=0.008] and history of smoking (OR 1.938, 95% CI 1.125-3.340, p=0.017) were independent risk factors for liver injury in patients receiving riluzole. In conclusion, treatment of ALS patients with riluzole, smoking habits, and concurrent use of CYP1A2 inhibitors are independent liver injury risk factors. Further studies on liver injury are warranted in ALS patients treated with riluzole to comprehensively understand the underlying mechanisms of riluzole-associated liver toxicity.

Anti-angiogenic effects of valproic acid in a mouse model of oxygen-induced retinopathy.

Pathological retinal angiogenesis contributes to the pathogenesis of several ocular diseases. Valproic acid, a widely used antiepileptic drug, exerts anti-angiogenic effects by inhibiting histone deacetylase (HDAC). Herein, we investigated the effects of valproic acid and vorinostat, a HDAC inhibitor, on pathological retinal angiogenesis in mice with oxygen-induced retinopathy (OIR). OIR was induced in neonatal mice by exposure to 80% oxygen from postnatal day (P) 7 to P10 and to atmospheric oxygen from P10 to P15. Mice were subcutaneously injected with valproic acid, vorinostat, or vehicle once a day from P10 to P14. At P15, retinal neovascular tufts and vascular growth in the central avascular zone were observed in mice with OIR. Additionally, immunoreactivity for phosphorylated ribosomal protein S6 (pS6), an indicator of mammalian target of rapamycin (mTOR) activity, was detected in the neovascular tufts. Both valproic acid and vorinostat reduced the formation of retinal neovascular tuft without affecting vascular growth in the central avascular zone. Valproic acid reduced the pS6 immunoreactivity in neovascular tufts. Given that vascular endothelial growth factor (VEGF) activates mTOR-dependent pathways in proliferating endothelial cells of the neonatal mouse retina, these results suggest that valproic acid suppresses pathological retinal angiogenesis by interrupting VEGF-mTOR pathways.

Effects of zolpidem/triazolam on cognitive performance 12 hours after acute administration.

OBJECTIVE: Most previous studies have concluded that decreased cognitive function and performance due to ultra-short acting hypnotics do not persist after 6-9 h post-administration. This study examined the effects of ultra-short acting hypnotics on cognitive function and performance 12 h after administration, ie, a time considered sufficient for the effects of hypnotics to disappear. METHODS: Thirteen healthy young male volunteers (mean age, 23.4 ± 3.2 years) participated in this study. Participants attended three sessions of polysomnography (PSG) recording preceded by oral administration of placebo for the first session, and 5 mg zolpidem or 0.25 mg triazolam for the second and third sessions, in a double-blinded, randomized manner at intervals of at least five days. A cognitive test battery was administered following each session, consisting of a psychomotor vigilance task (PVT), which reflects alertness and sleepiness, digit symbol substitution test (DSST), which reflects attention and working memory function, and assessment of subjective sleepiness and mental condition using a visual analog scale (VAS). RESULTS AND CONCLUSIONS: The administration of hypnotics significantly increased total sleep time, sleep efficiency, and sleep stages 2 and 4, and significantly decreased wake after sleep onset and sleep stage 1. PVT parameters were not affected by the administration of hypnotics, but DSST score was significantly lower, and "subjective alertness," "vigor," and "sadness" significantly deteriorated, after administration. In conclusion, while objective sleepiness disappeared 12 h after the administration of ultra-short acting hypnotics, their effects to decrease cognitive function persisted even after 12 h post-administration.

[The pharmacist's role in smoking cessation].

Since they have very good opportunities to aid smokers in quitting smoking at clinics or pharmacies, pharmacists play an important role in encouraging smoking cessation. They should be aware of the significance of tobacco abstinence. Therapeutic assistance for cessation includes drug treatment of nicotine dependence and counseling based on behavioral science for psychological dependence. Particularly in drug treatment, pharmacists are able to exercise their professional knowledge by assisting smoking cessation from a pharmaceutical viewpoint. It is possible for any pharmacist to provide a brief smoking cessation intervention, such as asking a patient whether or not they smoke and advising them, if they smoke, to stop smoking.

Bibliographical investigation (domestic and overseas) on the treatment of endogenous Candida endophthalmitis over an 11-year period.

A bibliographic search was conducted of cases of Candida endophthalmitis reported in Japan and overseas between 2000 and 2011, in the Japana Centra Revuo Medicina Website of Japan Medical Abstracts Society (domestic reports) and MEDLINE (overseas reports). The investigation yielded 42 reports in domestic journals (49 cases ; hereinafter referred to as domestic cases) and 39 reports in journals published overseas (46 cases ; hereinafter referred to as overseas cases). The isolation rate of Candida albicans in the domestic cases was 65.3%, and that in the overseas cases was 71.7%. The initial treatment for the Candida endophthalmitis was fluconazole (FLCZ) therapy in 51.0% of the domestic cases and 38.1% of the overseas cases. Domestic reports suggested the effectiveness of FLCZ therapy for stage II cases, and of vitrectomy for stage III and IV cases. Reports from overseas, on the other hand, suggested the effectiveness of amphotericin B (AMPH-B) or voriconazole (VRCZ) therapy for stage II cases, and of vitrectomy for stage III and IV cases.

Population pharmacokinetics of tazobactam/piperacillin in Japanese patients with community-acquired pneumonia.

The population pharmacokinetics on tazobactam/piperacillin (TAZ/PIPC; 1:8, 4.5 g x 3) was analyzed in Japanese patients with community-acquired pneumonia using the Nonlinear Mixed Effect Model version VI. Analysis by the one-compartment model yielded the following results for PIPC: total clearance (CL) = 8.22+(Ccr-71.4) x 0.0561 (L/hr), distribution volume (Vd) = 13.7 (L). The pharmacokinetic parameters for TAZ were: CL = 8.67 + (Ccr-71.4) x 0.0682 (L/hr), Vd = 14.4 (L). Of the pharmacokinetic parameters of PIPC, CL included Ccr as a variation factor, whereas the Vd included no variation factor. Because PIPC is excreted into the urine in the unchanged form, its pharmacokinetic factors seem to reflect the renal function status. In this study of patients with community-acquired pneumonia, the mean Vd per body weight was 0.26 L/kg, and the results suggested an increase of the Vd in patients with community-acquired pneumonia as compared with the value in healthy adults.

Evaluation of arbekacin anti-MRSA agents for adult in Japan.

There are a limited number of reports that compare the clinical efficacy of anti-MRSA agents such as arbekacin (ABK), vancomycin (VCM), teicoplanin (TEIC) and linezolid (LZD). There is a tendency for these four agents to show variation in the inflammatory response parameters, in C-reactive protein (CRP) and in white blood cell count (WBC), depending on the administration period. There was no significant difference among the agents in analysis of variance (ANOVA) in the group of days 1-3 (p = 0.0536) but there was some significant difference in the group of days 4-7, as well as days 8-14 (p < 0.001, p < 0.01) in relative variation rate of CRP. Furthermore, we compared in more detail the groups of LZD, VCM and ABK, with a significant decrease of CRP, each of which showed more decrease in comparison with the group of TEIC in the period days 4-7 (p < 0.01). We took 1-hr serum level after days 3-4, with the ABK treatment as the peak concentration (C(peak)). Having made nonlinear logistic regression analysis of CRP and C(peak)/MIC, we concluded that the decrease rate estimable by early inflammatory effect could be decreased to some 40%, assuming that C(peak)/MIC shows the high value within 4 days after ABK treatment.

Compatibility of carbapenem antibiotics with nafamostat mesilate in arterial infusion therapy for severe acute pancreatitis: stabilities of carbapenem antibiotics.

The effectiveness of continuous regional arterial infusion therapy using protease inhibitors and antibiotics for severe acute pancreatitis has been previously reported. Carbapenem antibiotics, which have a broad antibacterial spectrum, and nafamostat mesilate are often used for this therapeutic approach. We investigated the compatibility of various carbapenem antibiotics with nafamostat mesilate. Carbapenem antibiotics were dissolved in 30 mL of saline or 5% glucose and the appearance, pH, and stability of the solutions were determined. The changes in each carbapenem antibiotic solution after mixing with nafamostat mesilate were then investigated. Biapenem and doripenem showed a residual rate of > or = 90% at 8 hours after dissolution in saline or 5% glucose and exhibited an appropriate appearance and residual rate (> or = 90%). After mixing with nafamostat mesilate, biapenem maintained a residual rate of > or = 90% for the longest time period (8 hours) and exhibited a slight coloration, followed by doripenem (6 hours) and meropenem dissolved in saline. The other carbapenem antibiotics that were tested exhibited changes in appearance or their residual rate. Biapenem and doripenem, which exert their effects in a time-dependent manner, can be infused for prolonged periods for the treatment of not only severe acute pancreatitis, but also other severe infections.

Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis.

Voriconazole (VRCZ) reportedly possesses a broad spectrum of antifungal activity against Aspergillus spp. and Candida spp., and the blood concentration of VRCZ is correlated with both the efficacy and the adverse effects of this drug. Monitoring of the blood concentration target level of VRCZ has not yet been widely adopted in the medical field, and no evidence concerning this target level has been reported. Accordingly, we used a meta-analysis to investigate the optimal blood concentration of VRCZ. Using data from 12 reports, we found that the success rate for fungal infection treatment increased significantly at VRCZ levels greater than 1.0 µg/ml when a graded cutoff value within the range of 1.0-3.0 µg/ml was used as the VRCZ trough blood concentration [odds ratio (OR) 7.23, 95% confidence interval (CI) 2.84-18.37, P < 0.0001]. Concerning the safety evaluation, the incidence of adverse neurological effects increased significantly at a cutoff value of 4.0 µg/ml when a graded cutoff value within the range of 3.0-6.0 µg/ml was used (OR 2.23, 95% CI 1.12-4.46, P = 0.02). However, in all 12 literature sources, an increasing incidence of liver dysfunction was reported at higher blood concentrations, and no accurate cutoff values were obtained. Consequently, a VRCZ trough blood concentration more than 1.0 µg/ml from the perspective of efficacy and less than 4.0 µg/ml from the perspective of safety is recommended.

Clinical efficacy of arbekacin for Gram-negative bacteria.

In an analysis of methicillin-resistant Staphylococcus aureus (MRSA) infected patients treated with arbekacin (ABK) only, Gram-negative bacteria (GNB) that were inhibited by low minimal inhibitory concentrations (MICs) of amikacin (AMK) or gentamycin (GM) were eradicated by the end of the ABK treatment. On the other hand, GNB that were only inhibited by high MICs of AMK or GM persisted until the end of treatment with ABK only. Thus, ABK can be expected to be effective even in cases of mixed infection with GNB and MRSA.

Dose conversion in opioid rotation from continuous intravenous infusion of morphine hydrochloride injection to fentanyl patch in the management of cancer pain.

Opioid rotation has been proposed for management of cancer pain. No studies directly investigating dose equivalence between morphine injection (continuous IV administration) and the transdermal fentanyl patch have been reported. Therefore, we examined dose conversion ratios in patients undergoing opioid rotation from morphine injection to fentanyl patches. The subjects consisted of 45 patients admitted to Kitasato University East Hospital. Medical records were consulted to determine the "basic dose of morphine injection immediately prior to rotation" and the "basic dose of fentanyl patch after rotation". Equivalent doses and conversion ratios obtained with the expression of (daily dose of morphine injection (mg)/daily delivered dose of fentanyl patch (mg)) were determined from the relationship between the data by regression analysis. The regression equation obtained was Y=50.882X-13.96, r²=0.8922, where X and Y are daily doses of morphine injection and fentanyl patch, respectively. Equivalent doses and conversion ratios for daily dose of morphine injection (mg): daily delivered dose of fentanyl patch (mg) (patch dose mg/3 days) were 16.6 mg: 0.6 mg (2.5 mg)=28:1, 47.1 mg: 1.2 mg (5 mg) = 39:1 and 169.2 mg: 3.6 mg (15 mg)=47:1. In other reports, the ratio of morphine vs. fentanyl at 50:1 had no relation to the dose. While the present study suggested that in opioid rotation from low dose, 50:1 is not enough for the fentanyl patch. The dose conversion ratio of morphine injection to fentanyl patch was different at the low doses and high doses of morphine.