A post hoc analysis of Dupuytren contracture treated with collagenase Clostridium histolyticum across disease stages.

This post hoc analysis from a multicenter study (NCT01674634) was designed to evaluate the efficacy of collagenase Clostridium histolyticum (CCH) treatment in patients with different stages of Dupuytren contracture. Previously untreated patients who received two concurrent injections of CCH in two affected joints in the same finger were assessed by disease severity (Tubiana stage). The mean (SD) improvement in total fixed flexion contraction (FFC) 31 days post-CCH treatment in 181 patients was: 71.1 (36.5)% for Tubiana I, 77.0 (21.0)% for Tubiana II, 72.0 (20.4)% for Tubiana III and 66.4 (22.2)% for Tubiana IV. Treatment of metacarpophalangeal and proximal interphalangeal joints in the same finger resulted in a mean (SD) improvement of 82.5 (24.8)% and 66.4 (27.9)%, respectively. In conclusion, CCH is an effective treatment alternative for all stages of Dupuytren contracture and it provides a less invasive treatment alternative to surgery with similar short-term efficacy in patients with more severe disease.

A truncated analogue of CCL2 mediates anti-fibrotic effects on murine fibroblasts independently of CCR2.

The truncated [1+9-76] CCL2 analogue, also known as 7ND, has been described in numerous reports as an anti-inflammatory and anti-fibrotic agent in a wide spectrum of animal models, e.g. models of cardiovascular disease, graft versus host disease and bleomycin-induced pulmonary fibrosis. 7ND has been reported to function as a competitive inhibitor of CCL2 signaling via CCR2 in human in vitro systems. In contrast, the mechanistic basis of 7ND action in animal models has not been previously reported. Here we have studied how 7ND interacts with CCL2 and CCR2 of murine origin. Surprisingly, 7ND was shown to be a weak inhibitor of murine CCL2/CCR2 signaling and displaced murine CCL2 (JE) from the receptor with a K(i)>1 µM. Using surface plasmon resonance, we found that 7ND binds murine CCL2 with a K(d) of 670 nM, which may indicate that 7ND inhibits murine CCL2/CCR2 signaling by a dominant negative mechanism rather than by competitive binding to the CCR2 receptor. In addition we observed that sub-nanomolar levels of 7ND mediate anti-fibrotic effects in CCR2 negative fibroblasts cultured from fibrotic lung of bleomycin-induced mice. Basal levels of extracellular matrix proteins were reduced (collagen type 1 and fibronectin) as well as expression levels of α-smooth muscle actin and CCL2. Our conclusion from these data is that the previously reported effects of 7ND in murine disease models most probably are mediated via mechanisms independent of CCR2.

Inhibition of 11betaHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice.

BACKGROUND: A substantial body of evidence indicates that reduced plasma adiponectin levels may be key in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. Glucocorticoids decrease the levels of adiponectin in animals and humans. Cortisone is transformed to its active form cortisol, via 11beta-hydroxysteroid dehydrogenase (HSD) type 1. This study sought to ascertain if inhibition of 11beta HSD1 with a new selective inhibitor, BVT116429, affects the concentrations of circulating adiponectin with concomitant effects on glucose homeostasis in diabetic mice. RESULTS: KKAy mice were treated with BVT116429 (3, 10, 30 mg/kg), rosiglitazone (5 mg/kg) or vehicle once daily for ten days. Plasma adiponectin levels rose in mice treated with BVT116429 and this was found to be both the hexameric and the high molecular weight multimeric forms of adiponectin. Seven days of treatment with the 11beta HSD1-inhibitor BVT116429 decreased basal insulin levels but no changes in glucose tolerance were seen. After ten days of treatment, fasting blood glucose level was decreased by BVT116429 comparable to the effects of rosiglitazone. Another 11beta HSD1 inhibitor, BVT2733, improved HbA1c but had no effect on adiponectin. CONCLUSION: Inhibition of 11beta HSD1 can be expected to be beneficial for treating the pathology of type 2 diabetes mellitus. The differences seen in adiponectin between BVT116429 and BVT2733 could be explained by different pharmacodynamics exerted by the compounds in different tissues in the body. Increases in adiponectin concentrations may be an integral component in the mechanism of action of this new11beta HSD1 inhibitor and may be a useful marker of efficacy during the clinical development of 11beta HSD1 inhibitor compounds.

A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects.

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPARalpha/gamma modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.