Alan S. Rosman

Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase

BACKGROUND/AIMS Chronic ethanol consumption results in the induction of hepatic cytochrome P4502E1 (CYP2E1) in man, which is believed to play an important role in the pathogenesis of alcoholic liver disease. However, the amount and duration of alcohol intake associated with CYP2E1 induction is not known but limited information is available on the disappearance of CYP2E1 following alcohol withdrawal. METHODS To study these questions, five healthy male volunteers received ethanol daily (40 g/day) over 4 weeks. CYP2E1 induction was monitored by using the chlorzoxazone test before and every week following the start of alcohol ingestion. In addition, CYP2E1 was also determined in five alcoholics 1, 3, 8 and 15 days following ethanol withdrawal and in five patients with non-alcoholic liver disease. RESULTS A significant CYP2E1 induction occurred 1 week following the ingestion of 40 g ethanol per day and increased further after 4 weeks. The disappearance of CYP2E1 was found to be significant 3 days following ethanol withdrawal and further decreased up to day 8. Thereafter, no significant change occurred and CYP2E1 activities were comparable with those in patients with non-alcoholic liver disease. CONCLUSIONS These data show a significant and quick induction of CYP2E1 activity, already at moderate alcohol consumption, which may be of importance in the pathogenesis of alcoholic liver disease, of ethanol, drug and vitamin A interactions and in alcohol associated carcinogenesis.

Metaanalysis of trials comparing laparoscopic and open surgery for Crohn’s disease

Background:Several studies in the literature have suggested that laparoscopic surgery for Crohn’s disease is associated with faster postoperative recovery and a morbidity and recurrence rate similar to that for open surgery. Most of these studies have been limited by a small sample size and a short follow-up period.Methods:To clarify whether open or laparoscopic resection results in a better outcome, a metaanalysis of studies was performed comparing the two procedures for Crohn’s disease. Pooled effects were estimated using a random-effects model.Results:Laparoscopic surgery required more operative time than open surgery (26.8 min; 95% confidence interval [CI], 6.4–47.2 min), but resulted in a shorter duration of ileus and a decreased hospital stay (−2.62 days; 95% CI, −3.62 to −1.62). Laparoscopic surgery also was associated with a decreased rate for postoperative bowel obstruction and surgical recurrences.Conclusions:Laparoscopic surgery for Crohn’s disease is feasible, safe, and associated with shorter duration of ileus and a shorter hospital stay.

Metaanalysis of trials comparing minimally invasive and open distal pancreatectomies

BackgroundThe current literature suggests that minimally invasive distal pancreatectomy (MIDP) is associated with faster recovery and less morbidity than open surgery. However, most studies have been limited by a small sample size and a single-institution design. To overcome this problem, the first metaanalysis of studies comparing MIDP and open distal pancreatectomy (ODP) has been performed.MethodsA systematic literature review was conducted to identify studies comparing MIDP and ODP. Perioperative outcomes (e.g., morbidity and mortality, pancreatic fistula rates, blood loss) constituted the study end points. Metaanalyses were performed using a random-effects model.ResultsFor the metaanalysis, 10 studies including 349 patients undergoing MIDP and 380 patients undergoing ODP were considered suitable. The patients in the two groups were similar with respect to age, body mass index (BMI), American Society of Anesthesiology (ASA) classification, and indication for surgery. The rate of conversion from full laparoscopy to hand-assisted procedure was 37%, and that from minimally invasive to open procedure was 11%. Patients undergoing MIDP had less blood loss, a shorter time to oral intake, and a shorter postoperative hospital stay. The mortality and reoperative rates did not differ between MIDP and ODP. The MIDP approach had fewer overall complications [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27–0.89], major complications (OR, 0.57; 95% CI, 0.34–0.96), surgical-site infections (OR, 0.32; 95% CI, 0.19–0.53), and pancreatic fistulas (OR, 0.68; 95% CI, 0.47–0.98).ConclusionsThe MIDP procedure is feasible, safe, and associated with less blood loss and overall complications, shorter time to oral intake, and shorter postoperative hospital stay. Furthermore, the minimally invasive approach reduces the rate of pancreatic leaks and surgical-site infections after ODP.

Chronic xerostomia increases esophageal acid exposure and is associated with esophageal injury

OBJECTIVE To assess the effects of chronic xerostomia on parameters of gastroesophageal reflux and esophagitis. DESIGN Observational study of a cohort of male patients with xerostomia and age-matched control subjects. SETTING Tertiary-care Veterans Affairs Medical Center. SUBJECTS Sixteen male patients with chronic xerostomia secondary to radiation for head and neck cancers or medications. Nineteen age-matched male control subjects with comparable alcohol and smoking histories. MEASUREMENTS AND MAIN RESULTS Esophageal motility was similar in patients with xerostomia and controls. Clearance of acid from the esophagus and 24-hour intraesophageal pH were markedly abnormal in patients with xerostomia. Symptoms and signs of esophagitis were significantly more frequent in subjects with xerostomia. CONCLUSIONS Chronic xerostomia may predispose to esophageal injury, at least in part, by decreasing the clearance of acid from the esophagus and altering 24-hour intraesophageal pH. Esophageal injury is a previously unreported complication of long-term salivary deficiency.

Efficacy of a high and accelerated dose of hepatitis B vaccine in alcoholic patients: a randomized clinical trial.

PURPOSE A randomized, double-blind trial was conducted to compare the efficacy of a high-dose versus standard-dose hepatitis B vaccine in alcoholic patients. PATIENTS AND METHODS One hundred ten alcoholic patients were randomized to either receive the standard dose (20 micrograms at 0.1, and 6 months) or a high dose (40 micrograms at 0, 1, 2, and 6 months) of recombinant hepatitis B vaccine (Engerix-B). Patients were monitored for relapse of drinking using self-report, serial serum carbohydrate deficient transferrin, and collateral verification. The final titer of antibody to hepatitis B surface antigen (anti-HBs) was obtained 12 months after the first vaccine dose; a seroconversion was defined as a titer greater than 10 mlU/ml. RESULTS One hundred subjects completed the study; 10 of these had clinical or pathological evidence of cirrhosis. Thirty-six out of 48 (75%) of patients administered the high-dose regimen seroconverted compared with 24 of 52 (46%) in the standard dose group (P < 0.005). The mean anti-HBs titer of the high dose group was significantly greater than of the standard dose group (76.4 versus 39.4 mlU/ml, P < 0.01). Logistic regression demonstrated a significant effect on seroconversion for the vaccine dose (P < 0.005) and serum albumin (P = 0.05) but not for the other variables such as race, age, drinking during the study, serum creatinine, arm muscle circumference, and cirrhosis. CONCLUSIONS A high- and accelerated-dose regimen of hepatitis B improves the serological response in alcoholic patients. This regimen (currently recommended for hemodialysis patients) should now also be considered for patients with a history of alcoholism.

Meta-Analysis of Trials Comparing Minimally-Invasive and Open Liver Resections for Hepatocellular Carcinoma

BACKGROUND Recent literature suggests that minimally-invasive hepatectomy (MIH) for hepatocellular carcinoma (HCC) is associated with better perioperative results and similar oncologic outcomes compared to open hepatectomy (OH). However, previous reports have been limited by small sample size and single-institution design. METHODS To overcome these limitations, we performed a meta-analysis of studies comparing MIH and OH in patients with HCC using a random-effects model. RESULTS Nine eligible studies were identified that included 227 patients undergoing MIH and 363 undergoing OH. Patients were similar respect to age, gender, rates of cirrhosis, hepatitis C infection, tumour size, and American Society of Anesthesiology classification. The MIH group had lower rates of hepatitis B infection. There were no differences in type of resection (anatomic or non-anatomic), use of Pringles maneuver, and operative time. Patients undergoing MIH had less blood loss [difference -217 mL; 95% confidence interval (CI), -314 to -121], lower rates of transfusion [odds ratio (OR), 0.38; 95% CI, 0.24 to 0.59], shorter postoperative stay (difference -5 days; 95% CI, -7.84 to -2.25), lower rates of positive margins (OR, 0.30; 95% CI, 0.12 to 0.69) and perioperative complications (OR, 0.45; 95% CI, 0.31 to 0.66). Survival outcomes were similar in the two groups. CONCLUSIONS Although patient selection might have influenced some of the observed outcomes, MIH was associated with decreased blood loss, transfusions, rates of positive resection margins, overall and specific morbidity, and hospital stay. Survival outcomes did not differ between MIH and OH, although further studies are needed to evaluate the impact of MIH on long-term results.

Meta-analysis of trials comparing laparoscopic transperitoneal and retroperitoneal adrenalectomy

BACKGROUND Laparoscopic adrenalectomies are being performed increasingly, either with transperitoneal or retroperitoneal approaches. Studies comparing the 2 approaches have not shown the superiority of either technique, but these studies are limited by small sample sizes and single-institution designs. To overcome these limitations, we performed a meta-analysis of studies comparing lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy. METHODS A systematic review of studies comparing lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy was conducted. Study endpoints included perioperative outcomes and measures of postoperative recovery. Meta-analysis was performed using a random effects model, pooling variables evaluated by more than 3 studies. RESULTS Twenty-one studies comparing a total of 1,205 lateral transperitoneal adrenalectomies and 688 retroperitoneal adrenalectomies were suitable for meta-analysis. Patients in the 2 groups were similar in term of age, sex, body mass index, lesion size and location, and rates of malignancy. There were no statistically significant differences between lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy in terms of operative time, blood loss, hospital stay, time to oral intake, overall and major morbidity, and mortality. CONCLUSION Both lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy are associated with very low rates of perioperative complications. According to our meta-analysis, clinical outcomes after either technique are similar. For most adrenal lesions requiring operation, minimally invasive adrenalectomy can be performed safely and effectively with either transperitoneal or the retroperitoneal approach. Additional studies may be needed to analyze if any difference in long-term results exist.

The renal safety of bowel preparations for colonoscopy : a comparative study of oral sodium phosphate solution and polyethylene glycol

Background  Rare cases of nephrotoxicity have been reported with oral sodium phosphate solution (OSPS).

Infusion of Neostigmine–Glycopyrrolate for Bowel Evacuation in Persons with Spinal Cord Injury

Defecatory complications are common after spinal cord injury (SCI) and have been attributed, in part, to an imbalance of the autonomic nervous system between parasympathetic and sympathetic effects on the colon. Because parasympathetic (i.e., cholinergic) input to the bowel may be downregulated after SCI, it was hypothesized that neostigmine, a medication that increases cholinergic tone by blocking the metabolism of acetylcholine, might promote bowel evacuation in these persons. Since neostigmine is known to cause bradycardia and bronchoconstriction, we also assessed whether these side-effects could be prevented by coadministration of neostigmine with glycopyrrolate, an anticholinergic agent that has limited activity on the muscarinic receptors of the colon. The hypothesis was tested in 13 persons with SCI in whom videofluoroscopy was carried out after instillation of a barium oatmeal paste into the rectum and descending colon. On separate days, subjects received, in a randomized, blinded design, one of three intravenous infusates (normal saline, 2 mg neostigmine, or 2 mg neostigmine + 0.4 mg glycopyrrolate). The effect of these infusates on bowel evacuation of the barium paste, heart rate, and airway resistance was determined. Both neostigmine and neostigmine + glycopyrrolate resulted in prompt bowel evacuation. The nadir heart rate was lower after neostigmine alone than with the combination. Neostigmine administration increased both total and central airway resistance, an effect that was not observed with the coadministration of glycopyrrolate. Other side-effects of neostigmine and the combination of drugs included muscle fasciculations and dry mouth, both of which were mild and short-lived. Abdominal cramping was noted in subjects with spinal cord lesions below thoracic level 10. These results indicated that neostigmine/glycopyrrolate administration is safe and well tolerated in persons with chronic SCI.

Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans.

Objective:Previous in vitro studies have demonstrated that hepatic P4502E1 metabolizes chlorzoxazone (CZX, a commonly used muscle relaxant) to 6-hydroxychlorzoxazone (6-OH-CZX). We thus assessed whether measurement of the plasma 6-OH-CZX/CZX ratio after a CZX challenge could serve as a marker of hepatic P4502E1 content.Methods:Three subject groups were included: recently drinking alcoholics (N = 6), abstinent alcoholics (N = 5), and nonalcoholic subjects with liver disease (N = 5) undergoing liver biopsy. Excess tissue was procured for immunochemical determination of hepatic P4502E1 content. Within an hour of the biopsy, 750 mg CZX was administered orally and serial plasma samples were collected for 6 h.Results:Recently drinking alcoholic subjects had a higher area under the curve for plasma 6-OH-CZX (1.354 ± 0.258 μg · min · ml−1) then abstinent alcoholic subjects (0.296 ± 0.080 μg · min · ml−1, p < 0.005) and subjects with nonalcoholic liver disease (0.428 ± 0.061 μg · min · ml−1, p < 0.005). The use of the plasma 6-OH-CZX/CZX ratio at 90, 120, and 180 min discriminated between recently drinking alcoholic and nondrinking subjects. Hepatic P4502E1 content significantly correlated with the maximal 6-OH-CZX concentration (r = 0.76, p= 0.001) and other pharmacokinetic parameters. In the recently drinking group, the area under the curve for plasma 6-OH-CZX significantly decreased after 8 days of abstinence.Conclusions:Measurement of plasma 6-OH-CZX after administration of a CZX challenge can serve as a marker of hepatic P4502E1 activity and thus help avoid adverse drug reactions secondary to P4502E1 induction, particularly in heavy drinkers.