Shinji Hidaka

Protective Effects of Dithiocarbamates against Renal Toxicity of cis-Diamminedichloroplatinum in Rats

Sodium diethyldithiocarbamate (DDTC), sodium N-benzyl-D-glucamine dithiocarbamate (BGD), sodium N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD), and sodium N-p-carboxybenzyl-D-glucamine dithiocarbamate (CBGD) were evaluated for efficacy as inhibitors of cis-diamminedichloroplatinum (DDP)-induced nephrotoxicity in a rat model. Treatments with 2.0 mmol/kg of BGD, HBGD, and CBGD immediately after DDP (20 mumol/kg) injection effectively prevented the nephrotoxic effects of DDP, but administration of DDTC immediately after DDP injection afforded a small protection. Concurrent treatment with 0.5 or 1.0 mmol/kg of HBGD, or 1.0 mmol/kg of CBGD could prevent DDP-induced renal damage. A significant decrease in weight loss was also observed in these dithiocarbamate-rescued rats. The platinum concentrations in liver and kidney were significantly decreased by BGD, HBGD, and CBGD treatments, respectively. The antitumor efficacy of DDP in the Walker 256 carcinoma-bearing rats was not affected by administration of HBGD (1.0 mmol/kg) or CBGD (1.0 mmol/kg). The results of this study indicated that the injection of HBGD or CBGD to rats treated with DDP can protect against DDP-induced nephrotoxicity more effectively than DDTC or BGD.

Involvement of an Influx Transporter in the Blood-Brain Barrier Transport of Naloxone

Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood–brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [3H]naloxone exhibited saturability in a concentration‐dependent manner (concentration range 0.5 µM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier‐mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, Kt, was 2.99±0.71 mM; the maximum uptake rate, Jmax, was 0.477±0.083 µmol/min/g brain; and the nonsaturable first‐order rate constant, Kd, was 0.160±0.044 ml/min/g brain. The uptake of [3H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H1‐antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [3H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L‐carnitine or substrates for organic anion transport systems such as p‐aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH‐dependent and saturable influx transport system that is a selective transporter for cationic H1‐antagonists is involved in the BBB transport of naloxone in the rat. Copyright

Protection against cis-diamminedichloroplatinum-induced nephrotoxicity in rats by N-benzyl-D-glucamine dithiocarbamate

Sodium N-benzyl-D-glucamine dithiocarbamate (BGD) was evaluated for its efficacy as an inhibitor of cis-diamminedichloroplatinum (DDP)-induced nephrotoxicity in a rat model. Treatment with 2.0 mmol/kg of BGD immediately after DDP injection effectively prevented nephrotoxic effects of DDP, but administration of BGD -1 or 1 h after DDP afforded a small protection. Concurrent treatment with 0.5 mmol/kg of BGD could not prevent renal damage. The platinum concentrations in liver and kidney were significantly decreased by BGD treatment. The antitumor efficacy of DDP in the Walker 256 carcinoma-bearing rats was not affected by administration of BGD (2.0 mmol/kg).

Protection against cis-diamminedichloroplatinum-induced nephrotoxicity by 2,3-dimercaptosuccinic acid in rats.

The present study was designed to examine the usefulness of 2,3-dimercaptosuccinic acid (DMSA) for the purpose of reducing cis-diamminedichloroplatinum (DDP)-induced nephrotoxicity and effective clinical use of DDP and safe. The effectiveness of DMSA on the DDP-excretion in rat kidney was observed by measuring the platinum concentration using Atomic Absorption Instrument. Co-administration of DMSA (1.0 or 2.0 mmol/kg) 1 hour after DDP injection (20 mumol/kg) showed more decrease in the platinum concentration than that immediately after DDP injection. The alleviating effect of DMSA on DDP toxicity was evaluated by lipid peroxidation, enzymatic antioxidants, and glutathione levels. The administration of DDP alone caused a significant increase in lipid peroxidation and significant decreases in enzymatic antioxidants and glutathione levels in the kidney. Co-administration of DMSA (2.0 mmol/kg) 1 hour after DDP injection showed the most effective reduction of these enzymatic damages caused by DDP. These findings suggested that the co-administration of DMSA (2.0 mmol/kg) 1 hour after DDP injection leads DDP to effective excrete from renal tissue and suppresses the lipid peroxide reaction and results in reduction of nephrotoxicity.

Protective Effect of N-Benzyl-D-glucamine Dithiocarbamate Against Renal Toxicity in Rats During Repeated cis-Diamminedichloroplatinum Administrations

The protective effects of N-benzyl-D-glucamine dithiocarbamate (BGD) against the renal toxicity caused by repeated injections of cis-diamminedichloroplatinum (DDP) were studied in rats. The rats were injected i.p. with BGD (2.0 mmol/kg) immediately after i.v. injection of DDP (20 mumol/kg), and after 10 and 20 days they received repeated treatments with the same doses of DDP and BGD. Treatment with BGD prevented nephrotoxicity after repeated DDP administrations. Repeated DDP injections increased lipid peroxidation in the kidney and decreased GSH concentration in the kidney at 5 days after the third injection of DDP. BGD treatment prevented the increase in lipid peroxidation and the decrease in the GSH concentration caused by repeated administration of DDP. The determination of activities of antioxidant enzymes in the kidney showed that catalase activity decreased after repeated DDP administrations and that superoxide dismutase activity tended to decrease. Changes in activities of these enzymes were prevented by BGD treatment. The platinum concentrations in kidney and liver were decreased by BGD treatment. These results indicate that BGD treatment prevents the accumulation of platinum in the kidney after repeated administrations of DDP, resulting in protection against the DDP-induced renal toxicity.

Comparative effect of clopidogrel plus aspirin and aspirin monotherapy on hematological parameters using propensity score matching

Background Clopidogrel and aspirin are antiplatelet agents that are recommended to reduce the risk of recurrent stroke and other cardiovascular events. Dual antiplatelet therapy with clopidogrel and aspirin has been shown to increase the risk of hemorrhage, but the effects of the drugs on laboratory parameters have not been well studied in real-world clinical settings. Therefore, we evaluated and compared the effects of combination therapy with clopidogrel plus aspirin and aspirin monotherapy on laboratory parameters. Methods We used data from the Nihon University School of Medicine Clinical Data Warehouse obtained between November 2004 and May 2011 to identify cohorts of new users (n = 130) of clopidogrel (75 mg/day) plus aspirin (100 mg/day) and a propensity score matched sample of new users (n = 130) of aspirin alone (100 mg/day). We used a multivariate regression model to compare serum levels of creatinine, aspartate aminotransferase, and alanine aminotransferase, as well as hematological parameters including hemoglobin level, hematocrit, and white blood cell, red blood cell, and platelet counts up to 2 months after the start of administration of the study drugs. Results There were no significant differences for any characteristics and baseline laboratory parameters between users of clopidogrel plus aspirin and users of aspirin alone. Reductions in white blood cell and red blood cell counts, hemoglobin levels, and hematocrit in users of clopidogrel plus aspirin were significantly greater than those in users of aspirin alone. Conclusion Our findings suggest that adverse hematological effects may be greater with combination clopidogrel plus aspirin therapy than with aspirin monotherapy.

Anticholinergic load negatively correlates with recovery of cognitive activities of daily living for geriatric patients after stroke in the convalescent stage

Anticholinergic drugs are associated with risks of falls, confusion and cognitive dysfunction. However, the effect of anticholinergic drug use on rehabilitation outcomes after a stroke is poorly documented. We therefore aimed to establish whether the anticholinergic load was associated with functional recovery among geriatric patients convalescing after stroke.

Utilization of the Bridging Strategy for the Development of New Drugs in Oncology to Avoid Drug Lag

Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early‐initiation BG strategy, late‐initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style. Comparison of the differences in SL among the strategies also indicated that the SL in the GT strategy and that in the early‐initiation BG strategy were significantly shorter than that in the late‐initiation BG strategy. The findings in our study suggest that the late‐initiation BG strategy may not contribute to shortening drug lag. Because the number of late‐initiation BG studies has not decreased, we propose first that pharmaceutical companies should initiate clinical development as early as possible in Japan so that they can choose the GT strategy as a first option at the next step, and second when they cannot choose the GT strategy after investigating differences in exposure between Japanese and non‐Japanese in a phase 1 study, they should select the early BG strategy to avoid future drug lag. It is also important for the regulatory authorities to provide reasonable guidance to have a positive impact on strategic decisions, even for foreign‐capital companies.

Assessment of the Relationship between Hypnotics and Delirium Using the Japanese Adverse Drug Event Report (JADER) Database

　The Japanese Adverse Drug Event Report (JADER) database was used to examine the risk of delirium and the time of its onset with various hypnotics, including 10 benzodiazepines (BZDs), 3 non-benzodiazepines (non-BZDs), 1 melatonin receptor agonist (MRTA), and 1 orexin receptor inhibitor (OXRI). Data entered in the JADER database between April 1, 2004 and February 1, 2016 were analyzed. The index for safety signal detection, the reporting odds ratio (ROR), was the odds ratio for adverse drug reaction reporting. The ROR for each drug was calculated; a signal was considered present if the lower bound of the 95% confidence interval of the ROR was greater than 1. The time to onset of delirium was calculated for drugs for which the number of days from the start of drug administration to delirium onset was reported. During the period examined in the analysis, a total of 621114 adverse drug reaction reports were seen, and the total number of delirium reports was 1417 after redundant cases were excluded. A signal was detected for 5 of the 10 BZDs and all 3 non-BZDs, with no signal for the MRTA and the OXRI. The time of delirium onset varied widely even for drugs classified as being in the same action duration group, and no correlation was seen for delirium onset time. The results of this study suggested that delirium risk varies depending on the hypnotic. Thus, hypnotics can be selected according to their delirium risk.

ALTERATION OF SMALL INTESTINAL ABSORPTION OF SACCHARIDES IN CIS-DIAMMINEDICHLOROPLATINUM-ADMINISTERED MICE

Abstract The effect of cis-diamminedichloroplatinum (DDP) on small intestinal absorption of saccharides, and the protective effect of n-p-hydroxymethylbenzyl-d-glucamine dithiocarbamate (HBGD) on DDP-induced intestinal toxicity were studied. The small intestinal absorption of d-glucose and d-galactose, which are actively absorbed, decreased 2 days after DDP administration. The activity of Na + ,K + -ATPase in the intestinal tissue was not inhibited by DDP administration. The small intestinal absorption of maltose and sucrose decreased 2 and 4 days after DDP administration. The activities of maltase and sucrase in the intestinal mucosa decreased after DDP administration, but these enzyme activities in control mice were not inhibited by DDP in the in vitro experiments. A scanning electron micrograph of the jejunum after DDP showed damage in the villi. These results indicate that the inhibitory effect of DDP on the small intestinal absorption of saccharides results from the DDP-induced mucosal damage. Treatment with HBGD (1 mmol/kg) 5 min after DDP injection prevented the decreases in the intestinal absorption of d-glucose, d-galactose, maltose, and sucrose. Platinum (Pt) concentrations in the small intestine after DDP administration decreased following HBGD treatment. Biliary and urinary excretions of Pt after DDP administration were remarkably increased by HBGD treatment. These results indicate that the administration of DDP to mice causes the decrease in the intestinal absorption of saccharides, and that HBGD can effectively remove Pt from the intestine through biliary and urinary excretions, resulting in protection against the intestinal toxicity induced by DDP.