Chronic administration of DSP‐7238, a novel,potent, specific and substrate‐selective DPP IV inhibitor,improves glycaemic control and β‐cell damage in diabetic mice

Aims: The purpose of this study is to assess the in vitro enzyme inhibition profile of DSP‐7238, a novel non‐cyanopyrrolidine dipeptidyl peptidase (DPP) IV inhibitor and to evaluate the acute and chronic effects of this compound on glucose metabolism in two different mouse models of type 2 diabetes. Methods: The in vitro enzyme inhibition profile of DSP‐7238 was assessed using plasma and recombinant enzymes including DPP IV, DPP II, DPP8, DPP9 and fibroblast activation protein α (FAPα) with fluorogenic substrates. The inhibition type was evaluated based on the Lineweaver–Burk plot. Substrate selectivity of DSP‐7238 and comparator DPP IV inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin) was evaluated by mass spectrometry based on the changes in molecular weight of peptide substrates caused by release of N‐terminal dipeptides. In the in vivo experiments, high‐fat diet‐induced obese (DIO) mice were subjected to oral glucose tolerance test (OGTT) following a single oral administration of DSP‐7238. To assess the chronic effects of DSP‐7238 on glycaemic control and pancreatic β‐cell damage, DSP‐7238 was administered for 11 weeks to mice made diabetic by a combination of high‐fat diet (HFD) and a low‐dose of streptozotocin (STZ). After the dosing period, HbA1c was measured and pancreatic damage was evaluated by biological and histological analyses. Results: DSP‐7238 and sitagliptin both competitively inhibited recombinant human DPP IV (rhDPP IV) with K_i values of 0.60 and 2.1 nM respectively. Neither vildagliptin nor saxagliptin exhibited competitive inhibition of rhDPP IV. DSP‐7238 did not inhibit DPP IV‐related enzymes including DPP8, DPP9, DPP II and FAPα, whereas vildagliptin and saxagliptin showed inhibition of DPP8 and DPP9. Inhibition of glucagon‐like peptide‐1 (GLP‐1) degradation by DSP‐7238 was apparently more potent than its inhibition of chemokine (C‐X‐C motif) ligand 10 (IP‐10) or chemokine (C‐X‐C motif) ligand 12 (SDF‐1α) degradation. In contrast, vildagliptin and saxagliptin showed similar degree of inhibition of degradation for all the substrates tested. Compared to treatment with the vehicle, single oral administration of DSP‐7238 dose‐dependently decreased plasma DPP IV activity and improved glucose tolerance in DIO mice. In addition, DSP‐7238 significantly decreased HbA1c and ameliorated pancreatic damage following 11 weeks of chronic treatment in HFD/STZ mice. Conclusions: We have shown in this study that DSP‐7238 is a potent DPP IV inhibitor that has high specificity for DPP IV and substrate selectivity against GLP‐1. We have also found that chronic treatment with DSP‐7238 improves glycaemic control and ameliorates β‐cell damage in a mouse model with impaired insulin sensitivity and secretion. These findings indicate that DSP‐7238 may be a new therapeutic agent for the treatment of type 2 diabetes.     

Successful treatment of a disseminated infection with extensively drug‐resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin‐based multidrug regimen

Donor‐derived infections with multidrug‐resistant gram‐negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor‐derived, disseminated infection with colistin‐resistant, carbapenemase‐producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug‐resistant infections in immunocompromised hosts.     

重型乙型肝炎患者外周血细胞促凝血活性及新型促凝血因子hfgl2的表达

目的：了解各种临床类型乙型肝炎患者外用血细胞的促凝血活性（PCA）及新型促凝血因子人纤堆介素（human fibfinogen like protein 2，hfgl2）的表达情况，及其与疾病进展的关系。方法：病毒性乙型肝炎慢性重型25例。健康对照25例，分离外周血单个核细胞（PBMC）；病毒性乙型肝炎慢性重度和重型患者标本33例，病毒性乙型肝炎慢性轻度、中度共25例，健康对照25例分离其外周血白细胞（WBC）。用一期冻融法测量其PCA。采用免疫组化的方法检测hfgl2的表达。结果：病毒性乙型肝炎慢性重型患者PBMC的PCA较健康对照南出20倍。WBC的PCA在以下各组（健康对照组、病毒性乙型肝炎慢性轻中度组、病毒性乙型肝炎慢性重度和重型组）呈避步上升过程，但组间差异无显著性意义。PCA在病毒性乙型肝炎慢性重型组患者PBMC中的表达显著高于其在WBC的表达。PCA在健康对照组PBMC和喊的表达无显著差异，hfgl2在病毒性乙型肝炎慢性重型患者PBMC中的表达水平显著高于其在健康对照组中的表达。结论：病毒性乙型肝炎慢性重型患者PBMC中的PCA和hfgl2表达均显著升高，且其表达与疾病严重程度相关，hfgl2表达的强度（阳性细胞数）与PCA的升高呈正比相关。     

Wandering coronary stenoses: Adrenaline‐induced coronary artery spasm in a patient resuscitated from cardiac arrest

A 68‐year‐old ex‐smoker man with history of allergy, presented to the emergency department with progressive dyspnea one hour following self‐medication with aspirin for troublesome headache. Examination revealed diffuse sibilant rhonchi over both lungs. Electrocardiogram showed signs of ischemia. In the intensive care unit, he received bronchodilators, nitroglycerin, and aspirin. Bronchospasm increased, and then the patient was shocked, and developed cardiac arrest. After resuscitation, he was kept on mechanical ventilation and adrenaline infusion. He was sceduled for coronary angiography. The left system demonstrated stenosis of the mid‐segment of the left anterior descending artery (LAD), which was totally occluded distally, stenosis of the left circumflex (LCx) with a mild plaque in its marginal branch. The right system demonstrated stenosis of the mid‐segment of the right coronary artery (RCA), with diffusely diseased posterior descending artery (PDA) and posterolateral left ventricular branch (PLLV). Successful direct stenting was performed to the RCA. Angiography demonstrated worsening of the distal stenosis in the PLLV and complete occlusion of the PDA. Balloon dilatation of the PLLV was adequate, but dilatation of the PDA failed. Repeat angiography of the left system revealed an occluded LCx with critical stenosis of its marginal branch; nevertheless, the LAD was as before. Balloon dilatation of the distal LAD was attempted without improvement, yet, angiography therein, demonstrated “migration” of the stenoses in the LCx. The procedure was halted, adrenaline infusion discontinued, and an intra‐aortic balloon pump inserted. The patient was discharged one day later. Follow‐up angiography 6 months later demonstrated mild atherosclerotic coronary irregularities. © 2010 Wiley‐Liss, Inc.     

Endocannabinoids and liver disease--review.

AIMS: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. METHODS: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. RESULTS: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. CONCLUSIONS: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.     

Efficacy and safety of bucillamine,a d-penicillamine analogue,in patients with active rheumatoid arthritis

Abstract

Japanese rheumatologists consider bucillamine (Buc) to be a useful disease-modifying antirheumatic drug (DMARD) and often give Buc to patients with rheumatoid arthritis (RA) prior to administering methotrexate (MTX). However, no large studies on the efficacy and safety of Buc in RA patients have been published in English to date. We therefore investigated the clinical course of RA patients treated with Buc and compared the results with those for patients treated with MTX to evaluate and confirm the place of Buc in therapeutic strategies for RA in Japan. Our results suggested that Buc should be given to patients with moderately active RA either before or after the administration of MTX because its efficacy can be judged within 3 months and because serious adverse events are rare. Issues like the ability of Buc to prevent joint destruction and its efficacy and safety when combined with agents like etanercept require future study.     

Efficacy and safety of bucillamine, a d-penicillamine analogue, in patients with active rheumatoid arthritis

Japanese rheumatologists consider bucillamine (Buc) to be a useful disease-modifying antirheumatic drug (DMARD) and often give Buc to patients with rheumatoid arthritis (RA) prior to administering methotrexate (MTX). However, no large studies on the efficacy and safety of Buc in RA patients have been published in English to date. We therefore investigated the clinical course of RA patients treated with Buc and compared the results with those for patients treated with MTX to evaluate and confirm the place of Buc in therapeutic strategies for RA in Japan. Our results suggested that Buc should be given to patients with moderately active RA either before or after the administration of MTX because its efficacy can be judged within 3 months and because serious adverse events are rare. Issues like the ability of Buc to prevent joint destruction and its efficacy and safety when combined with agents like etanercept require future study.     

Apheresis in coronary heart disease with elevated Lp (a): a review of Lp (a) as a risk factor and its management

Lipoprotein (a) (Lp (a)) increases global cardiovascular risk, especially when LDL cholesterol is concomitantly elevated. Epidemiologic data show that Lp (a) concentration in plasma can be used to predict the risk of early atherogenesis in a dose-dependent manner and late stages of atherosclerosis are accelerated by elevated Lp (a). Therapeutic means to lower Lp (a) are limited. The most effective method to reduce plasma Lp (a) concentration significantly is therapeutic apheresis. Because apheresis is laborious and expensive, patients considered for this procedure should suffer from high Lp (a) concentrations, well beyond 50 mg/dL, and have manifested and progressive coronary heart disease despite maximal drug therapy. Experimental data and therapeutic results will be discussed in the present paper.     

Decreased 5‐HT2cR and GHSR1a interaction in antipsychotic drug‐induced obesity

Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5‐HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5‐HT2cR in ghrelin‐mediated appetite signalling. The 5‐HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5‐HT2cR antagonism reduces dimerization and increases GHSR1a‐induced food intake. Dimerization is specific to the unedited 5‐HT2cR isoform. 5‐HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5‐HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA‐induced obesity.     

TNF,TNF inducers,and TNFR2 agonists: A new path to type 1 diabetes treatment

In the past decade, interest in the century‐old tuberculosis vaccine, bacillus Calmette‐Guerin (BCG), has been revived for potential new therapeutic uses in type 1 diabetes and other forms of autoimmunity. Diverse clinical trials are now proving the value of BCG in prevention and treatment of type 1 diabetes, in the treatment of new onset multiple sclerosis and other immune conditions. BCG contains the avirulent tuberculosis strain Mycobacterium bovis, a vaccine originally developed for tuberculosis prevention. BCG induces a host response that is driven in part by tumour necrosis factor (TNF). Induction of TNF through BCG vaccination or through selective agonism of TNF receptor 2 (TNFR2) has 2 desired cellular immune effects: (1) selective death of autoreactive T cells and (2) expansion of beneficial regulatory T cells (Tregs). In human clinical trials in both type 1 diabetes and multiple sclerosis, administration of the BCG vaccine to diseased adults has shown great promise. In a Phase I trial in advanced type 1 diabetes (mean duration of diabetes 15 years), 2 BCG vaccinations spaced 4 weeks apart selectively eliminated autoreactive T cells, induced beneficial Tregs, and allowed for a transient and small restoration of insulin production. The advancing global clinical trials using BCG combined with mechanistic data on BCGs induction of Tregs suggest value in this generic agent and possible immune reversal of the type 1 diabetic autoimmune process.