The latest medical research on Gastroenterology

Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs.

Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters.

Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4 mm Hg, p<0.001) and carvedilol+placebo (18.9±3-to-16.9±3 mm Hg, p<0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6 mm Hg, p=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; p=0.021). With test-meal, HVPG increased in both groups (p<0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, p<0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (p<0.01). Incidence of adverse events was similar.

In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines.

Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults have been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when over-activated. The aim of this study is to explore the role of hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP.

CP was induced in mice by repeated injections of L-arginine or Caerulein in two separate models. Mice were administered with the FDA approved pharmacological hedgehog pathway inhibitor, Vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease.

Our study shows that hedgehog signaling was over-activated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already established fibrosis. Additionally, inhibition of hedgehog signaling resulted in reversal of pancreatic stellate cell activation ex vivo. Conclusions: Findings from our study justify conducting clinical trials using Vismodegib against CP and thus, could lead to development of novel therapeutic strategy for the treatment of CP.