The Effect of AST-120 on Hepatic Metabolism and Transport in Chronic Kidney Disease

Chronic kidney disease (CKD) is characterized by a progressive and irreversible decline in renal function. Patients are at high risk for adverse drug events since they are typically administered multiple medications concurrently and pharmacokinetic changes in the diseased state are relatively unexplored. Recent studies point towards molecules known as uremic toxins for playing a mechanistic role in altering the expression and function of drug metabolizing enzymes and drug transporter proteins. To further investigate this hypothesis an adenine-induced model of CKD was used in male wistar rats. AST-120 was administered to remove uremic toxins in an attempt to recover metabolic enzyme as well as transporter protein function and activity. Animals were injected with rosuvastatin prior to sacrifice as a probe for transporter function. Impaired organic anion transporting polypeptide (OATP) and cytochrome P450 (CYP) function are important to acknowledge in a clinical setting since both of these protein superfamilies have broad substrate specificities. We have shown significant down regulation in CYP2B1 activity and expression in rats (

Predictors of repair and effect of gender on treatment of ruptured abdominal aortic aneurysm

AbstractObjectiveThe purpose of this study was to determine factors associated with increased likelihood of patients undergoing surgery to repair ruptured abdominal aortic aneurysms (AAAs). Specifically, we investigated whether men were more likely than women to be selected for surgery after rupture of AAAs.MethodsAll patients with a ruptured AAA who came to a hospital in Ontario between April 1, 1992, and March 31, 2001, were included in this population-based retrospective study. Administrative data were used to identify patients, patient demographic data, and hospital variables.ResultsCrude 30-day mortality for the 3570 patients who came to a hospital with a ruptured AAA was 53.4%. Of the 2602 patients (72.9%) who underwent surgical repair, crude 30-day mortality was 41.0%. Older patients (odds ratio [OR], 0.649 per 5 years of age; P < .0001), with a higher Charlson Comorbidity Index (OR, 0.848; P < .0001), were less likely to undergo AAA repair. Patients treated at high-volume centers (OR, 2.674 per 10 cases; P < .0001) and men (OR, 2.214; P < .0001) were more likely to undergo AAA repair.ConclusionMen are more likely to undergo repair of a ruptured AAA than women are, for reasons that are unclear. Given the large magnitude of the effect, further studies are clearly indicated

Survival after ruptured abdominal aortic aneurysm: effect of patient, surgeon, and hospital factors

AbstractObjectiveThe purpose of this study was to determine the effects of patient, surgeon, and hospital factors on survival after repair of ruptured abdominal aortic aneurysm (AAA) and to compare them with risk factors for survival after elective AAA repair. It was hypothesized that patients operated on by high-volume surgeons with subspecialty training would have better outcomes, which might argue for regionalization of AAA surgery.MethodsIn this population-based retrospective cohort study, surgeon billing and administrative data were used to identify all patients who had undergone AAA repair between April 1, 1992, and March 31, 2001, in Ontario, Canada. Demographic information was collected for each patient, as well as numerous variables related to the surgeons and hospitals.ResultsThere were 2601 patients with ruptured AAA repair, with an average 30-day mortality rate of 40.8%. Significant independent predictors of lower survival were older age, female gender, lower patient income quintile, performance of surgery at night or on weekends, repair in larger cities, surgeons with lower annual volume of ruptured AAA operations, and surgeons without vascular or cardiothoracic fellowship training. There were 13,701 patients with elective AAA repair, with an average 30-day mortality rate of 4.5%. Significant independent predictors of lower survival were similar, except gender was not significant, but the Charlson Comorbidity Index was. When the hazard ratios associated with predictive factors were compared, surgeon factors appeared to be more important in ruptured AAA repair, and patient factors appeared more important in elective AAA repair.ConclusionFor elective AAA repair, and even more so for ruptured AAA repair, high-volume surgeons with subspecialty training conferred a significant survival benefit for patients. Although this would seem to argue in favor of regionalization, decisions should await a more complete understanding of the relationship between transfer time, delay in treatment, and outcome

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes Mellitus in Mice.

Background Tetrahydrobiopterin is a cofactor of endothelial NO synthase ( eNOS ), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of tetrahydrobiopterin on eNOS uncoupling and congenital heart defects ( CHD s) induced by pregestational diabetes mellitus in mice. Methods and Results Adult female mice were induced to pregestational diabetes mellitus by streptozotocin and bred with normal male mice to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHD s were identified by histological analysis. Cell proliferation, eNOS dimerization, and reactive oxygen species production were assessed in the fetal heart. Pregestational diabetes mellitus results in a spectrum of CHD s in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHD s from 59% to 27%, and major abnormalities, such as atrioventricular septal defect and double-outlet right ventricle, were absent in the sapropterin-treated group. Lineage tracing reveals that pregestational diabetes mellitus results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes mellitus were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased eNOS dimerization and lowered reactive oxygen species levels in the fetal heart. Conclusions Sapropterin treatment in the diabetic mothers improves eNOS coupling, increases cell proliferation, and prevents the development of CHD s in the offspring. Thus, sapropterin may have therapeutic potential in preventing CHD s in pregestational diabetes mellitus