John D. Mccracken

Clinical Implications of Hepatic Steatosis in Patients with Chronic Hepatitis C: A Multicenter Study of U.S. Veterans

Studies have indicated a high prevalence of hepatic steatosis in patients with chronic hepatitis C (CHC). To address the impact of steatosis on the clinical course of CHC and treatment response requires large multicenter studies. The present study analyzed hepatitis C virus (HCV)-infected veterans enrolled in a U.S. Veteran Administration multicenter study of the epidemiology and response to interferon α-2b and ribavirin treatment. Of the 357 patients, 97.1% were males, with a mean age of 48.7±6.4 years, and 184 (51.5%) had hepatic steatosis. The mean body mass index (BMI) was 29.3±5.2xa0kg/m2, including 37.1% who were obese (BMI, ≥30xa0kg/m2). Stage III–IV fibrosis was present in 111 of 334 (33.3%) of the patients. After adjusting for age, race, and history of alcohol use in the past 12 months, only stage III–IV fibrosis was independently and significantly associated with hepatic steatosis (P=0.03). There was a trend of association between obesity and steatosis independent of the other factors. Only HCV genotype was independently associated with a sustained virological response (SVR) to interferon α-2b and ribavirin treatment after adjusting for age, alcohol use, steatosis, BMI, stage III–IV fibrosis, serum AFP, and HCV load. In conclusion, analyses of our multicenter trial data demonstrated that the prevalence of hepatic steatosis is 51.5% in HCV-infected U.S. veterans. We found that steatosis is independently associated with stage III–IV fibrosis. However, only HCV genotype, and not steatosis, obesity, or stage III–IV fibrosis, was associated with SVR to interferon α-2b and ribavirin treatment.

Mechanism of Enhancement of Intestinal Ulcerogenicity of S-Aryl Propionic Acids by Their R-Enantiomers in the Rat

We previously observed a marked increase ingastrointestinal toxicity of rac -flurbiprofen comparedto the therapeutically equivalent dose of the Senantiomer. This paper quantitates these observations and examines the mechanism by which thisparadoxical toxicity occurs. We have evaluated the ulcerscores, mucosal neutrophil infiltration, byimmunostaining of CD11/18 antigen, and mucosalneutrophil activity by myeloperoxidase measurement at two doselevels of (R)-, (S)-, and rac-flurbiprofen, administeredover 30 days. Dose-response for intestinal ulcerproduction was observed for rac- and (S)-flurbiprofen; animals given (R)flurbiprofen exhibited noulcers. Yet rac-flurbiprofen proved to be twice asulcerogenic as (S)-flurbiprofen. The mechanism of theexacerbation of gastrointestinal toxicity of(S)flurbiprofen by the noncyclooxygenase inhibiting(R)-flurbiprofen is believed to be associated with itseffect on ICAM-1 up-regulation. This is followed byneutrophil adhesiveness to ICAM-1 via the LFA-1 antigenon its surface and the extravasation ofneutrophils into the tissue. We also examined the effectof high dose (R)-flurbiprofen vs vehicle over 15 days inanimals in which ulcers had been produced by treatment with (S)-flurbiprofen for the previous 15 days.(R)-flurbiprofen did not sustain induced ulcers. Theresults of this study suggest that human studies beconducted to determine if enhanced gastrointestinal toxicity occurs in man. This is at issue sincerac compounds of this class are available over thecounter and others may be introduced.