Double blind, placebo-controlled dose escalating, multiple dose study with two groups of 30 volunteers with type II diabetes to assess efficacy on glucose-profile, triglycerides and blood pressure and pharmacokinetics of two different doses of BLX-1002

开始日期2006-11-21

申办/合作机构

Bexel Pharmaceuticals, Inc.

100 项与 BLX-1002 相关的临床结果

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100 项与 BLX-1002 相关的转化医学

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100 项与 BLX-1002 相关的专利（医药）

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项与 BLX-1002 相关的文献（医药）

2014-05-01·Physiological Reports

BLX-1002 restores glucose sensitivity and enhances insulin secretion stimulated by GLP-1 and sulfonylurea in type 2 diabetic pancreatic islets

Article

作者: Sjöholm, Åke ; Zhang, Qimin ; Zhang, Fan

BLX-1002 is a novel thiazolidinedione with no peroxisome proliferator-activated receptor (PPAR) activity that has been shown to improve glycemia in type 2 diabetes without weight gain. We previously found that BLX-1002 selectively augments glucose-sensitive (but not basal) insulin secretion in normal mouse β-cells. We have now extended these observations to other insulin secretagogues and to diabetic rat islets. To this end, dynamics of insulin secretion stimulated by glucose, GLP-1, and the sulfonylurea tolbutamide were examined in pancreatic islets from nondiabetic Wistar and type 2 diabetic Goto-Kakizaki rats ex vivo. BLX-1002 restored normal glucose-sensitive insulin secretion in otherwise "glucose-blind" islets from GK rats, but did not affect basal or glucose-stimulated secretion in normal Wistar rat islets. The stimulatory effect of BLX-1002 on insulin secretion at high glucose required Ca(2+) and involved phosphatidylinositol 3-kinase (PI3K) activity. Consistent with its effects on insulin secretion, BLX-1002 also augmented insulin secretion and cytoplasmic-free Ca(2+) concentrations ([Ca(2+)]i) stimulated by high glucose, GLP-1, and tolbutamide in islets from GK, but not Wistar, rats. The inactive analog BLX-1237 had no effects. In conclusion, our findings suggest that BLX-1002 potentiates insulin secretion by different stimuli in diabetic β-cells only, in a Ca(2+)-dependent manner and involving PI3K.

2012-12-01·Cardiovascular Diabetology1区 · 医学

Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells

1区 · 医学

ArticleOA

作者: Qimin Zhang ; Åke Sjöholm ; Thomas Nyström ; Özlem Erdogdu ; Linnéa Eriksson

AbstractBackgroundThe leading cause of death for patients suffering from diabetes is macrovascular disease. Endothelial dysfunction is often observed in type 2 diabetic patients and it is considered to be an important early event in the pathogenesis of atherogenesis and cardiovascular disease. Many drugs are clinically applied to treat diabetic patients. However, little is known whether these agents directly interfere with endothelial cell proliferation and apoptosis. This study therefore aimed to investigate how anti-diabetic and cardioprotective agents affect human coronary artery endothelial cells (HCAECs).MethodsThe effect of anti-diabetic and cardioprotective agents on HCAEC viability, proliferation and apoptosis was studied. Viability was assessed using Trypan blue exclusion; proliferation in 5 mM and 11 mM of glucose was analyzed using [3H]thymidine incorporation. Lipoapoptosis of the cells was investigated by determining caspase-3 activity and the subsequent DNA fragmentation after incubation with the free fatty acid palmitate, mimicking diabetic lipotoxicity.ResultsOur data show that insulin, metformin, BLX-1002, and rosuvastatin improved HCAEC viability and they could also significantly increase cell proliferation in low glucose. The proliferative effect of insulin and BLX-1002 was also evident at 11 mM of glucose. In addition, insulin, metformin, BLX-1002, pioglitazone, and candesartan significantly decreased the caspase-3 activity and the subsequent DNA fragmentation evoked by palmitate, suggesting a protective effect of the drugs against lipoapoptosis.ConclusionOur results suggest that the anti-diabetic and cardioprotective agents mentioned above have direct and beneficial effects on endothelial cell viability, regeneration and apoptosis. This may add yet another valuable property to their therapeutic effect, increasing their clinical utility in type 2 diabetic patients in whom endothelial dysfunction is a prominent feature that adversely affect their survival.

2011-06-01·American Journal of Physiology-Cell Physiology3区 · 生物学

Lipophilicity as a determinant of thiazolidinedione action in vitro: findings from BLX-1002, a novel compound without affinity to PPARs

3区 · 生物学

Article

作者: Luger, Anton ; Bolten, Charles W. ; Dey, Debendranath ; Staniek, Katrin ; Stadlbauer, Karin ; Lehner, Zsuzsanna ; Brunmair, Barbara ; Fürnsinn, Clemens

The pharmacology of thiazolidinediones (TZDs) seems to be driven not only by activation of peroxisome proliferator-activated receptor-γ (PPARγ), but also by PPARγ-independent effects on mitochondrial function and cellular fuel handling. This study portrayed such actions of the novel hydrophilic TZD compound BLX-1002 and compared them to those of conventional TZDs. Mitochondrial function and fuel handling were examined in disrupted rat muscle mitochondria, intact rat liver mitochondria, and specimens of rat skeletal muscle. BLX-1002 was superior to most other TZDs as an inhibitor of respiratory complex 1 in disrupted mitochondria, but had less effect than any other TZD on oxygen consumption by intact mitochondria and on fuel metabolism by intact tissue. The latter finding was obviously related to the hydrophilic properties of BLX-1002, because high potentials of individual TZDs to shift muscle fuel metabolism from the aerobic into the anaerobic pathway were associated with high ClogP values indicative of high lipophilicity and low hydrophilicity (e.g., % increase in lactate release induced by 10 μmol/l of respective compound: BLX-1002, ClogP 0.39, +10 ± 8%, not significant; pioglitazone, ClogP 3.53, +68 ± 12%, P < 0.001; troglitazone, ClogP 5.58, +157 ± 14%, P < 0.001). The observed specific properties of BLX-1002 could result from relatively strong direct affinity to an unknown mitochondrial target, but limited access to this target. Results suggest 1) that impairment of mitochondrial function and increased anaerobic fuel metabolism are unlikely to account for PPARγ-independent glucose lowering by BLX-1002, and 2) that higher lipophilicity of an individual TZD is associated with stronger acceleration of anaerobic glycolysis.

100 项与 BLX-1002 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
2型糖尿病	临床2期	-	Orchid Website Design Ltd.	-
2型糖尿病	临床2期	欧洲	Bexel Pharmaceuticals, Inc.	-
多发性硬化症	临床2期	美国	Bexel Pharmaceuticals, Inc.	-