Faculty Bibliography

Oral rifaximin is a nonabsorbed antibiotic with broad-spectrum antimicrobial activity. Rifaximin 400 mg 3 times daily for 14 days was prospectively investigated in an outpatient setting for the treatment of mild hepatic encephalopathy (HE) in patients with cirrhosis due to hepatitis C virus (HCV). Patients were assessed 24 hours before and 14 days posttreatment Thirty-seven consecutive patients were treated. Twenty-three patients were receiving pegylated interferon (IFN) plus ribavirin, and 12 patients had type 2 diabetes mellitus (DM). Overall, rifaximin improved HE symptoms and lowered serum ammonia to normal levels. Rifaximin was well tolerated, and no hypo/hyperglycemic episodes were reported. Because systemic antibiotics are associated with nephrotoxicity, and lactulose administration in DM patients is not ideal, rifaximin may be a more appropriate treatment for DM patients. Hepatic encephalopathy symptoms can be mistaken for pegylated IFN plus ribavirin adverse effects, and patients treated with these medications should be periodically evaluated for HE

PURPOSE: A prospective randomized trial was undertaken to test the efficacy of low and standard doses of pegylated interferon alpha-2b in combination with ribavirin for the initial treatment of chronic hepatitis C. By nature of its design the study also provided data on response to therapy over a spectrum of doses of both pegylated interferon alpha-2b and ribavirin calculated on a body weight basis. SUBJECTS AND METHODS: Fifty micrograms of pegylated interferon alpha-2b or 100 microg for patients weighing<75 kg or 150 microg for patients>or=75 kg were administered weekly with 1000 mg ribavirin daily for 48 wk if serum hepatitis C virus (HCV) RNA was undetectable after the first 24 wk of therapy. RESULTS: Overall sustained viral response (SVR) was 45% for standard dose and 33% for low dose, p=0.02. For genotypes 2 and 3 SVR was 65% for standard dose, and 56% for low dose, p=0.51. For genotype 1 SVR was 38% for standard dose, and 24% for low dose, p=0.03. For genotype 1 patients whose doses exceeded the 1-2-5 threshold, that is >or=1.25 microg/kg body weight pegylated interferon alpha-2b weekly and >or=12.5 mg/kg body weight ribavirin daily, SVR was 51%. CONCLUSION: The results of this study underscore the importance of adequate dosing of ribavirin as well as pegylated interferons in achieving an SVR when treating genotype 1 chronic hepatitis C patients with combination therapy

Human lung epithelial (Calu-3) cells were used to investigate the effects of protease-activated receptor (PAR) stimulation on Cl(-) secretion. Quantitative RT-PCR (QRT-PCR) showed that Calu-3 cells express PAR-1, -2, and -3 receptor mRNAs, with PAR-2 mRNA in greatest abundance. Addition of either thrombin or the PAR-2 agonist peptide SLIGRL to the basolateral solution of monolayers mounted in Ussing chambers produced a rapid increase in short-circuit current (I(sc): thrombin, 21 +/- 2 microA; SLIGRL, 83 +/- 22 microA), which returned to baseline within 5 min after stimulation. Pretreatment of monolayers with the cell-permeant Ca(2+)-chelating agent BAPTA-AM (50 microM) abolished the increase in I(sc) produced by SLIGRL. When monolayers were treated with the cyclooxygenase inhibitor indomethacin (10 microM), nearly complete inhibition of both the thrombin- and SLIGRL-stimulated I(sc) was observed. In addition, basolateral treatment with the PGE(2) receptor antagonist AH-6809 (25 microM) significantly inhibited the effects of SLIGRL on I(sc). QRT-PCR revealed that Calu-3 cells express mRNAs for CFTR, the Ca(2+)-activated KCNN4 K(+) channel, and the KCNQ1 K(+) channel subunit, which, in association with KCNE3, is known to be regulated by cAMP. Stimulation with SLIGRL produced an increase in apical Cl(-) conductance that was blocked in cells expressing short hairpin RNAs designed to target CFTR. These results support the conclusion that PAR stimulation of Cl(-) secretion occurs by an indirect mechanism involving the synthesis and release of prostaglandins. In addition, PAR-stimulated Cl(-) secretion requires activation of CFTR and at least two distinct K(+) channels located in the basolateral membrane

P2Y receptor regulation of anion secretion was investigated in porcine endometrial gland (PEG) epithelial cells. P2Y2, P2Y4, and P2Y6 receptors were detected in monolayers of PEG cells and immunocytochemistry indicated that P2Y4 receptors were located in the apical membrane. Apical membrane current measurements showed that Ca2+-dependent and PKC-dependent Cl- channels were activated following treatment with uridine triphosphate (UTP) (5 microM). Current-voltage relationships comparing calcium-dependent and PKC-dependent UTP responses under biionic conditions showed significant differences in selectivity between Cl-)and I- for the PKC-dependent conductance (P(I)/P(Cl) = 0.76), but not for Ca2+-dependent conductance (PI/P(Cl) = 1.02). The I-/Cl- permeability ratio for the PKC-dependent conductance was identical to that measured for 8-cpt cAMP. Furthermore, PKC stimulation using phorbol 12-myristate 13-acetate (PMA) activated an apical membrane Cl- conductance that was blocked by the CFTR selective inhibitor, CFTRinh-172. CFTR silencing, accomplished by stable expression of small hairpin RNAs (shRNA), blocked the PKC-activated conductance associated with UTP stimulation and provided definitive evidence of a role for CFTR in anion secretion. CFTR activation increased the initial magnitude of Cl- secretion, and provided a more sustained secretory response compared to conditions where only Ca2+-activated Cl- channels were activated by UTP. Measurements of [cAMP]i following UTP and PMA stimulation were not significantly different than untreated controls. Thus, these results demonstrate that UTP and PMA activation of CFTR occurs independently of increases in intracellular cAMP and extend the findings of earlier studies of CFTR regulation by PKC in Xenopus oocytes to a mammalian anion secreting epithelium