The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1'-hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients. After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1'-hydroxymidazolam, and 1'-hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1'-hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration. For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 +/- 0.18. For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 +/- 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different (p = 0.009). Collectively, these results show that the small intestine contributes significantly to the first-pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first-pass metabolism may be a general phenomenon for all high-turnover CYP3A4 substrates.
Hepatic steatosis is a recognized problem in patients after orthotopic liver transplant (OLT). However, de novo development of nonalcoholic fatty liver disease (NAFLD) has not been well described. The aim of this study was to determine the prevalence and predictors of de novo NAFLD after OLT. A retrospective analysis was performed on 68 OLT patients with donor liver biopsies and posttransplantation liver biopsies. Individual medical charts were reviewed for demographics, indication for OLT, serial histology reports, genotypes for hepatitis C, comorbid conditions, and medications. Liver biopsies were reviewed blindly and graded according to the Brunt Scoring System. Multivariate logistic regression analysis was used to study the risk factors for developing NAFLD. The interval time from OLT to subsequent follow-up liver biopsy was 28 +/- 18 months. A total of 12 patients (18%) developed de novo NAFLD, and 6 (9%) developed de novo NASH. The regression model indicated that the use of angiotensin-converting enzyme inhibitors (ACE-I) was associated with a reduced risk of developing NAFLD after OLT (odds ratio, 0.09; 95% confidence interval, 0.010-0.92; P = 0.042). Increase in body mass index (BMI) of greater than 10% after OLT was associated with a higher risk of developing NAFLD (odds ratio, 19.38; 95% confidence interval, 3.50-107.40; P = 0.001). In conclusion, de novo NAFLD is common in the post-OLT setting, with a significant association with weight gain after transplant. The use of an ACE-I may reduce the risk of developing post-OLT NAFLD.
Hypothesis: Radiocephalic fistulas for maintenance hemodialysis access are not feasible in all patients with endstage renal disease. Our aim was to review our experience with 3 types of upper arm arteriovenous fistula (AVF) to ascertain whether they are reasonable alternatives to radiocephalic fistulas and which, if any, have superior performance. Patients and Methods: Patient medical records were retrospectively reviewed. The main outcomes were maturation rate, time to maturation, assisted maturation rate, complication rates, reintervention rates, primary and assisted primary patency rates, and effects of comorbidities. Results: Eighty-six patients with end-stage renal disease underwent creation of a brachiocephalic, brachiobasilic, or brachial artery-to-median antecubital vein AVF. Overall, 80% matured, with 23% requiring an intervention to achieve maturity. The mean time to maturation was 3.8 months; 47% had a complication (inability to access, thrombosis, and so on), and 43% required additional interventions. The overall primary patency and assisted primary patency rates at 12 months were 50% and 74%, respectively. Brachiobasilic AVFs not superficialized immediately often needed a second operation. There were no significant differences in patency rates among the 3 AVF types. The AVFs in patients with diabetes took 2 months longer to mature than did those in patients without diabetes. Conclusions: An upper arm AVF is a reasonable alternative for maintenance hemodialysis access when a radiocephalic AVF is not possible. There are 3 valid options from which to choose to best accommodate each patient's antecubital anatomy. Diabetes may adversely affect outcomes. Our data suggest that brachiobasilic AVFs should be superficialized at the initial procedure, if feasible.
Sirolimus, a potent new immunosuppressant, has been anecdotally associated with surgical wound complications. We studied postoperative surgical wound complications in 15 kidney recipients receiving sirolimus, prednisone, and tacrolimus or cyclosporine (study group) compared with 15 recipients receiving tacrolimus, prednisone, and mycophenolate mofetil who were pair-matched for surgical wound complication risk factors. Surgical wound complications were defined as any complication related to the surgical transplant wound requiring reintervention. Fifty-three percent of the study group and 7% of the control group experienced more than one surgical wound complication (P=0.014), and the relaparotomy incidence was 33% and 7%, respectively. Four graft losses have occurred since the beginning of the study: one chronic rejection and two deaths with function in the study group, and one death with function in the control group. At 1 year, graft survival for study recipients compared with control recipients was 87% and 93%, respectively; patient survival was 93% in both groups. Recipients receiving sirolimus demonstrated a significantly higher surgical wound complication rate, but graft and patient survival were not affected. Peritransplant immunosuppression with sirolimus and steroids warrants careful consideration, particularly in recipients with surgical complication risk factors.
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