Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus.

Sitagliptin is an oral, potent, highly selective, once-daily DPP-4 inhibitor indicated for the treatment of type 2 diabetes mellitus (T2DM). To assess the dose-ranging efficacy and safety/tolerability profile of once-daily sitagliptin 25, 50, 100, and 200 mg in Japanese patients with T2DM. In this randomized, double-blind, placebo-controlled study, 363 Japanese patients with inadequate glycemic control (HbA(1c)=6.5-10%; FPG< or =270 mg/dL) were randomized (1:1:1:1:1) to placebo, sitagliptin 25, 50, 100, or 200 mg q.d. for 12 weeks. The primary endpoint was change from baseline in HbA(1c) at Week 12. At Week 12, treatment with sitagliptin at all doses tested provided significant (p<0.001) reductions in HbA(1c) (-0.69 to -1.04%) from baseline (7.49 to 7.65%) relative to placebo. Sitagliptin significantly (p<0.001) reduced fasting plasma glucose (FPG; -15.9 to -23.2 mg/dL) and 2-hour postprandial glucose (2-hr PPG; -40.3 to -65.0 mg/dL) relative to placebo, in a dose-dependent manner. At doses > or =50 mg, differences in HbA(1c), FPG, and 2-hr PPG between the sitagliptin groups were not statistically significant. Sitagliptin was generally well tolerated with a low and similar incidence of hypoglycemia and minimal weight gain relative to placebo. Treatment with sitagliptin for 12 weeks provided significant and clinically meaningful reductions in HbA(1c), FPG, and 2-hr PPG across the dose range studied and was generally well tolerated in Japanese patients with T2DM.

An autopsy case of combined drug intoxication involving verapamil, metoprolol and digoxin.

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 microg/ml, 3.6 microg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.

[Effects of chronic alcohol administration on changes of extracellular dopamine and serotonin concentration induced by methamphetamine--comparison of two different alcohol preference rat lines].

We have investigated the effects of single administration of methamphetamine (MAP) (1.0 mg/kg, i.p.), and of combined administration of ethanol (EtOH) (2.0 g/kg, i.v.) and MAP (1.0 mg/kg, i.p.) on striatal extracellular dopamine (DA) and serotonin (5-HT) levels in chronic alcohol treated rats using a brain-microdialysis method. We used two different lines of rats with high and low alcohol preferences, (high alcohol preference rat (HAP) and low alcohol preference rat (LAP), respectively), which were chronically fed an alcohol containing liquid diet for 6 to 8 weeks. The percent change in DA and 5-HT in striatum following single administration of MAP was significantly higher in control-fed LAP than HAP. However, in the alcohol-fed group, the percent changes in DA and 5-HT were significantly elevated in the alcohol-fed HAP compared to LAP. There were no significant increases in striatal extracellular DA and 5-HT in alcohol-fed LAP. In combined administration of MAP and EtOH, extracellular DA and 5-HT levels increased slightly following EtOH administration in chronic alcohol-fed rats, especially in HAP. Dramatic increases of DA and 5-HT levels were observed in alcohol-fed HAP following EtOH and MAP administration. The percent change in DA and 5-HT in alcohol-fed HAP was further elevated to 4667.7 +/- 1095.5% and 3116.9 +/- 1162.7% of the maximal change, respectively. These percent changes ware higher than that observed with a single administration of MAP. Meanwhile, LAP were less sensitive to the influence of chronic EtOH administration and to single administration of MAP. These results demonstrate that a chronic treatment of EtOH enhances the sensitivity to MAP in a high alcohol preference rat line, when two drugs were administrated simultaneously, and that a significant difference of responsiveness to abused drugs was indicated between these two lines. It is necessary to consider the alcohol preference when investigating the interaction of alcohol and/or other abused drugs.

Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52 weeks.

AIMS/INTRODUCTION: The efficacy and safety of sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, when added to metformin monotherapy was examined in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: In this 52-week, add-on to metformin study, 149 patients were randomly assigned to receive sitagliptin 50 mg or placebo once daily in a double-blind fashion for 12 weeks. Thereafter, all patients who completed the double-blind period of the study received open-label sitagliptin 50 mg once daily for 40 weeks, with the investigator option of increasing sitagliptin to 100 mg once daily for patients who met predefined glycemic thresholds. RESULTS: After 12 weeks of treatment, the mean change from baseline in glycated hemoglobin (HbA1c) significantly decreased with sitagliptin relative to placebo (between-group difference [95% confidence interval] = -0.7% [-0.9 to -0.5] P < 0.001). At week 12, the mean changes in 2-h post-meal glucose (-2.6 mmol/L [-3.5 to -1.7]) and fasting plasma glucose (-1.0 mmol/L [-1.3 to -0.6]) also decreased significantly with sitagliptin relative to placebo (P < 0.001 for both). Significant improvements from baseline in glycemic control were also observed in the open-label period through to week 52. There were no differences between treatment groups in the incidence of adverse events (AEs), including hypoglycemia and predefined gastrointestinal AEs (nausea, vomiting and diarrhea) during the double-blind period, with similar findings in the open-label period. CONCLUSIONS: Over a period of 52 weeks, the addition of sitagliptin once-daily to ongoing metformin therapy was efficacious and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT00363948).

Sitagliptin added to treatment with ongoing pioglitazone for up to 52 weeks improves glycemic control in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: Patients with type 2 diabetes mellitus often require treatment with more than one oral antihyperglycemic agent to achieve their glycemic goal. The present study was carried out to assess the efficacy and safety of sitagliptin as add-on therapy in Japanese patients with type 2 diabetes mellitus inadequately controlled (HbA1c ≥ 6.9% and <10.4%) on pioglitazone monotherapy (15-45 mg/day). MATERIALS AND METHODS: In the initial 12-week, double-blind treatment period, patients were randomized (1:1) to sitagliptin 50 mg/day (n = 66) or placebo (n = 68), followed by a 40-week open-label treatment period in which all patients received sitagliptin 50 mg/day that could have been increased to 100 mg/day for patients meeting predefined glycemic parameters. RESULTS: After 12 weeks, mean changes from baseline in HbA1c (the primary end-point), fasting plasma glucose and 2-h post-meal glucose were -0.8%, -0.9 mmol/L and -2.7 mmol/L, respectively, in the sitagliptin group compared with placebo (all P < 0.001). The incidence of adverse experiences during the double-blind treatment period was similar in both treatment groups, and the incidences of hypoglycemia and gastrointestinal adverse experiences were low. In the open-label period, improvements in glycemic parameters with sitagliptin treatment were maintained and sitagliptin was generally well tolerated. CONCLUSIONS: Sitagliptin as add-on therapy provided significant improvements in glycemic parameters and was well tolerated in Japanese patients with type 2 diabetes mellitus inadequately controlled on pioglitazone monotherapy. This trial was registered with ClinicalTrials.gov (no. NCT00372060). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00120.x, 2011).

An autopsy case of imipramine poisoning.

We present a fatal imipramine poisoning. Quantitative analysis of imipramine and its metabolite, desipramine, was performed by high-performance liquid chromatography. The concentrations of imipramine and desipramine were 18.67 microg/mL and 6.21 microg/mL in heart blood and 6.90 microg/mL and 1.77 microg/mL in the femoral venous blood, respectively. We concluded that the cause of death was due to imipramine poisoning.

Therapeutic effects of alendronate 35 mg once weekly and 5 mg once daily in Japanese patients with osteoporosis: a double-blind, randomized study.

The efficacy and safety of treatment with oral alendronate (ALN) 35 mg once weekly for 52 weeks were compared with those of ALN 5 mg once daily in a double-blind, randomized, multicenter study of Japanese patients with involutional osteoporosis. The primary efficacy end point was the percent change from baseline in the lumbar spine (L1-L4) bone mineral density (BMD) after 52 weeks of treatment. In this study, 328 patients were randomized to ALN 5 mg once daily (160 patients) or ALN 35 mg once weekly (168 patients). The adjusted mean percent change from baseline in lumbar spine (L1-L4) BMD after 52 weeks of treatment was 5.8% and 6.4% in the once-daily group and the once-weekly group, respectively (both P < 0.001). The 95% confidence interval for the difference in spine BMD change between the two treatment groups was -0.31% to 1.48%, indicating that the two regimens were therapeutically equivalent, since the confidence interval fell entirely within the predefined equivalence criterion (+/-1.5%). The time course of the spine BMD increase was also similar for both regimens. Regarding total hip BMD, mean changes from baseline at 52 weeks were 2.8% and 3.0% in the once-daily group and the once-weekly group, respectively. In addition, the bone markers (urinary deoxypyridinoline, urinary type-I collagen N-telopeptides, and serum bone-specific alkaline phosphatase) were reduced to a similar level by either treatment throughout the treatment period. The tolerability and safety profiles were also similar between the treatment groups. Taken together, we conclude that the efficacy and safety of the ALN 35-mg once-weekly regimen are therapeutically equivalent to those of the ALN 5-mg once-daily regimen.

Different blood acetaldehyde concentration following ethanol administration in a newly developed high alcohol preference and low alcohol preference rat model system.

A significant difference in blood-acetaldehyde concentration was observed between high alcohol-preference (HAP) rats and low alcohol-preference (LAP) rats, newly developed different alcohol preference lines. This difference of acetaldehyde accumulation may be due to cytosolic aldehyde dehydrogenase (ALDH1) polymorphism, which has been reported previously. As the doses of ethanol we employed are higher than that of voluntary drinking, there may be little direct relationship between acetaldehyde accumulation and alcohol preference. We suggest therefore that the ALDH1 polymorphism is associated with alcohol preference in HAP/LAP lines through some other unidentified mechanism.