Background and purpose: Extrahepatic vasodilation and increased intrahepatic vascular resistance represent attractive targets for the medical treatment of portal hypertension in liver cirrhosis. In both dysfunctions, dysregulation of the contractionmediating Rho kinase plays an important role as it contributes to altered vasoconstrictor responsiveness. However, the mechanisms of vascular Rho kinase dysregulation in cirrhosis are insufficiently understood. They possibly involve mitogenactivated protein kinase/extracellular signal-regulated kinase (ERK)-dependent mechanisms in extrahepatic vessels. As the multikinase inhibitor sorafenib inhibits ERK, we tested the effect of sorafenib on haemodynamics and dysregulated vascular Rho kinase in rats with secondary biliary cirrhosis. Experimental approach: Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Sorafenib was given orally for 1 week (60 mg·kg). Messenger RNA levels were determined by quantitative real time polymerase chain reaction, protein expressions and protein phosphorylation by Western blot analysis. Aortic contractility was studied by myographic measurements, and intrahepatic vasoregulation by using livers perfused in situ. In vivo, haemodynamic parameters were assessed invasively in combination with coloured microspheres. Key results: In BDL rats, treatment with sorafenib decreased portal pressure, paralleled by decreases in hepatic Rho kinase expression and Rho kinase-mediated intrahepatic vascular resistance. In aortas from BDL rats, sorafenib caused up-regulation of Rho kinase and an improvement of aortic contractility. By contrast, mesenteric Rho kinase remained unaffected by sorafenib. Conclusions and implications: Intrahepatic dysregulation of vascular Rho kinase expression is controlled by sorafenib-sensitive mechanisms in rats with secondary biliary cirrhosis. Thus, sorafenib reduced portal pressure without affecting systemic blood pressure.
Portal hypertension in cirrhosis depends on increased intrahepatic vascular resistance, which is explained by fibrosis and intrahepatic hyperresponsiveness to vasoconstrictors. Both are caused by activation and proliferation of hepatic stellate cells (HSCs). Portal hypertension of cirrhotic rats can be reduced by the multikinase inhibitor sorafenib, due to a reduction of intrahepatic vascular resistance. Therefore, the hepatic effects of sorafenib require further understanding. Here, we investigated hepatic and HSC-specific sorafenib effects in cirrhotic rats. Animal models of bile duct ligation-induced secondary biliary cirrhosis in rats were studied. The rats were treated with sorafenib (60 mg/kg/day) for 1 week, starting after established cirrhosis. Histological evaluation was carried out using hemalaun and eosin (HE) staining. Apoptosis was studied by PARP cleavage, colorimetric caspase-3 assay, and electrophoretic DNA detection. HSC activation was studied by hepatic Sirius red and immunohistochemical aSMA (a-smooth muscle actin) staining, and by in vitro experiments with culture-activated primary HSCs. Biochemical serum parameters suggested the occurrence of sorafenib-induced liver damage. HE staining revealed histological changes in livers of sham-operated and bile duct-ligated (BDL) rats in response to sorafenib, which were different in both groups. In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic aSMA and procollagen-1a mRNA expression. As shown by immunohistochemical staining, perisinusoidal aSMA expression was reduced by sorafenib in BDL rats. This was associated with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care.
Fourteen patients with Helicobacter pylori infection were treated with omeprazole capsules 20 mg and amoxycillin capsules 1000 mg twice daily for 14 days and 14 patients with omeprazole capsules 20 mg and placebo twice daily for 14 days. Samples from saliva, dental plaque and faeces and biopsies from antrum and corpus were analysed in order to determine the ecological changes in the normal microflora. Several microorganisms were affected by both treatment regimens. Two patients were colonised with enterobacteria in the oral cavity and stomach during the omeprazole plus amoxycillin treatment. A general increase in the number of microorganisms from gastric mucosa was observed in both treatment groups. A selection of resistant enterobacteria and an increase in beta-lactamase production was observed in the faecal samples during the omeprazole plus amoxycillin treatment. Eradication of H. pylori in the omeprazole-amoxycillin group was 50% and in the omeprazole placebo group 0% four weeks after treatment. No viable H. pylori were cultivated in the saliva, dental plaque or faecal samples. Treatment with omeprazole 20 mg and amoxycillin 1000 mg twice daily for 14 days altered the normal microflora in the oral, gastric and intestinal tract and antibiotic resistant microorganisms increased in numbers in the intestinal microflora.
Forty-four healthy volunteers were given either amoxycillin (ten subjects), cefpodoxime proxetil (ten subjects), ceftibuten (14 subjects) or cefuroxime axetil (ten subjects) orally for 7-10 days, in order to study the ecological effects on the intestinal microflora. In all three groups receiving oral cephalosporins there was a significant increase in beta-lactamase activity during administration (P < 0.05). There was also an inverse correlation between enzyme activity in faeces during administration compared with the concentration of drug in the intestines and the level of ecological disturbance in the normal intestinal microflora. In volunteers given amoxycillin, only small alterations in the faecal microflora were observed although overgrowth by new amoxycillin resistant enterobacteria occurred in all volunteers. There was an overgrowth of enterococci and yeasts during treatment with cefpodoxime proxetil, ceftibuten or cefuroxime axetil, whereas the numbers of enterobacteria were reduced. Colonization with resistant enterobacteria did not occur, but 14 of 34 subjects receiving oral cephalosporins were colonized by Clostridium difficile. Side-effects were mild and not associated with the ecological alterations in the intestinal microflora.
In the present study we determined the resistance patterns of anaerobic bacteria from human saliva and stool specimens and investigated whether there were significant differences in resistance between outpatients and hospitalized patients, regardless of whether they had received antimicrobial agents. No bacterial strains resistant to ampicillin, piperacillin, cefoxitin, cefuroxime, imipenem, clindamycin, doxycycline, chloramphenicol, or metronidazole were isolated from the saliva samples. However, resistance to ampicillin, cefoxitin, and cefuroxime was found in strains from 70%o of the fecal samples (mainly Bacteroides thetaiotaomicron, Clostridium innocuum, and Bacteroides ovatus). Resistance to both ampicillin and cefuroxime was frequently found in 19%o of the isolated strains (mainly B. thetaiotaomicron, B. ovatus, and Bacteroides vulgatus). No strains that were resistant to imipenem, chloramphenicol, or metronidazole were found. Hospitalization and/or intake of antimicrobial agents was associated with an increase in the relative number of resistant anaerobic intestinal bacteria. The percentage of resistant anaerobic strains encountered, compared with the total number of anaerobic bacteria in the normal fecal microflora, was between 5.2 and 14.8%, with the lower value associated with the outpatient group. Two-thirds of the resistant strains from this group had a relative frequency of less than 1% of the total anaerobic flora, while one-third of the strains were present at a level of greater than 1%; for the hospitalized patients, two-thirds of the strains were present at a level of greater than 1%, and one-third of the strains were present at a level of less than 1% (P < 0.001). Patients who had received antimicrobial agents for 6 days or more (n = 20) had an average of 1.6 resistant anaerobic strains each, while patients treated for 3 to 5 days (n = 30) had a mean number of 0.87 resistant strains each (P < 0.05).
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