Lack of effect of norfloxacin on hyperdynamic circulation in bile duct‐ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho‐kinase?

Hennenberg, Martin; Trebicka, Jonel; Buecher, D.; Heller, J.; Sauerbruch, Tilman

doi:10.1111/j.1478-3231.2009.02010.x

Cited by 13 publications

(10 citation statements)

References 49 publications

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“…For example, some antibiotics have been shown to reduce complications in cirrhosis and thereby improve patient survival [23]. Other antibiotics have also been shown to attenuate the progression of liver fibrosis in experimental models of fibrosis although results have varied based on the specific antibiotic that was tested [6, 38, 39]. However, antibiotic side effect and resistance remain a concern that prevents broader utilization of antibiotics in cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice

Zhu

Zou

Jagavelu

et al. 2012

Journal of Hepatology

123

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Background/Aims Liver fibrosis is associated with angiogenesis and leads to portal hypertension. Certain antibiotics reduce complications of liver failure in humans, however, effect of antibiotics on the pathologic alterations of the disease are not fully understood. The aim of this study was to test whether the non-absorbable antibiotic rifaximin could attenuate fibrosis progression and portal hypertension in vivo, and explore potential mechanisms in vitro. Methods Effect of rifaximin on portal pressure, fibrosis, and angiogenesis was examined in wild type and toll like receptor 4 (TLR4) mutant mice after bile duct ligation (BDL). In vitro studies were carried out to evaluate the effect of the bacterial product and TLR agonist, lipopolysaccharide (LPS) on paracrine interactions between hepatic stellate cells (HSC) and liver endothelial cells (LEC) that lead to fibrosis and portal hypertension. Results Portal pressure, fibrosis, and angiogenesis were significantly lower in BDL mice receiving rifaximin compared to BDL mice receiving vehicle. Studies in TLR4 mutant mice confirmed that the effect of rifaximin was dependent on LPS/TLR4 pathway. Fibronectin (FN) was increased in BDL liver and was reduced by rifaximin administration and thus was explored further in vitro as a potential mediator of paracrine interactions of HSC and LEC. In vitro, LPS promoted FN production from HSC. Furthermore, HSC-derived FN promoted LEC migration and angiogenesis. Conclusion These studies expand our understanding of the relationship of intestinal microbiota with fibrosis development by identifying FN as a TLR4 dependent mediator of the matrix and vascular changes that characterize cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice

Zhu

Zou

Jagavelu

et al. 2012

Journal of Hepatology

123

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“…Nevertheless, a combination of Rifaximin and Propanolol seem to be promising, probably due to additive effects of Rifaximin compared with NSBB monotherapy with decreased incidence of side effects due to lower NSBB dose than used normally as shown by an open-label randomized (2:1) trial in 73 patients [31]. Treatment with Norfloxacin, a synthetic broad-spectrum antibiotic active against Gram-positive and Gram-negative bacteria, reversed the hyperdynamic state, but effects on portal pressure were neglectable [32,33]. However, Norfloxacin seems to improve survival in some cirrhotic patients, especially those with low ascitic fluid protein concentrations, probably due to decreased incidence of bacterial infection [34••].…”

Section: Current Concepts In the Clinicsmentioning

confidence: 99%

Novel Targets and Drug Development in Portal Hypertension

Schierwagen

Klein

Uschner

et al. 2019

Curr Hepatology Rep

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Purpose of the Review This review aims to introduce animal models of portal hypertension in which targets and drugs can be tested and presents current advances in the field of preclinical and early clinical settings. Recent Findings The interest in this field has risen in recent years and many promising targets and potential drugs have been tested in preclinical and early clinical studies. Most of these targets are intrahepatic and aim to decrease hepatic stellate cell activity, as this cell type mediates both fibrosis and portal hypertension. Summary Liver cirrhosis with portal hypertension is a global health burden due to their complications. Besides that, there are only a few therapies available, those are ineffective in a large part of the patients. Therefore, novel targets and treatment options are vastly needed.

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“…A prospective double-blind study investigating Rifaximin and propranolol combination therapy versus propranolol monotherapy is currently ongoing [98]. In contrast, treatment with norfloxacin had no effect on HVPG [99–101]. Another approach is to restore intestinal bacterial diversity by supplementing probiotics.…”

Section: Inflammation and Bacterial Translocationmentioning

confidence: 99%

Novel treatment options for portal hypertension

Schwabl

Laleman

2017

Gastroenterology Report

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Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.

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Lack of effect of norfloxacin on hyperdynamic circulation in bile duct‐ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho‐kinase?

Abstract: Short-term treatment of BDL rats with norfloxacin does not change hyperdynamic circulation or vascular contractility, despite reduction of PKG activity.

Cited by 13 publications

References 49 publications

Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice

Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice

Novel Targets and Drug Development in Portal Hypertension

Novel treatment options for portal hypertension

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