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41.
Brian J Dean Steve Chang Maria Victoria Silva Elipe Yuan-Qing Xia Matt Braun Eric Soli Yuming Zhao Ronald B Franklin Bindhu Karanam 《Drug metabolism and disposition》2007,35(2):283-292
(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The major in vitro and in vivo metabolite of MK-0524 is the acyl glucuronic acid conjugate of the parent compound, M2. To compare metabolism of MK-0524 across preclinical species and humans, studies were undertaken to determine the in vitro kinetic parameters (K(m) and V(max)) for the glucuronidation of MK-0524 in Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human liver microsomes, human intestinal microsomes, and in recombinant human UDP glucuronosyltransferases (UGT). A comparison of K(m) values indicated that UGT1A9 has the potential to catalyze the glucuronidation of MK-0524 in the liver, whereas UGT1A3 and UGT2B7 have the potential to catalyze the glucuronidation in the intestine. MK-0524 also was subject to phase I oxidative metabolism; however, the rate was significantly lower than that of glucuronidation. The rate of phase I metabolism was ranked as follows: rat approximately monkey > human intestine > dog > human liver with qualitatively similar metabolite profiles across species. In all the cases, the major metabolites were the monohydroxylated epimers (M1 and M4) and the keto-metabolite, M3. Use of inhibitory monoclonal antibodies and recombinant human cytochromes P450 suggested that CYP3A4 was the major isozyme involved in the oxidative metabolism of MK-0524, with a minor contribution from CYP2C9. The major metabolite in hepatocyte preparations was the acyl glucuronide, M2, with minor amounts of M1, M3, M4, and their corresponding glucuronides. Overall, the in vivo metabolism of MK-0524 is expected to proceed via glucuronidation, with minor contributions from oxidative pathways. 相似文献
42.
Sekhar RV Jahoor F Pownall HJ Ballantyne CM Balasubramanyam A 《Current atherosclerosis reports》2004,6(3):173-179
The emergence of a new metabolic syndrome in patients with HIV infection, termed “HIV-associated dyslipidemic lipodystrophy”
(HADL), is characterized by central fat redistribution, severe dyslipidemia, and insulin resistance and predisposes to an
increased risk of cardiovascular disease. The factors promoting the development of cardiovascular disease in this condition
are not well understood and may involve contributions from antiretroviral drugs and components of the HIV virus, as well as
inflammatory cytokines, leading to accelerated lipolysis, dyslipidemia, lipotoxic insulin resistance, and vascular inflammation.
In this article, we review HADL in terms of metabolic, molecular, and cytokine derangements leading to cardiovascular disease. 相似文献
43.
Beauford RB Goldstein DJ Sardari FF Karanam R Luk B Prendergast TW Burns PG Garland P Chen C Patafio O Saunders CR 《The Annals of thoracic surgery》2003,76(1):12-7; discussion 17
BACKGROUND: Octogenarians are increasingly being referred for coronary artery revascularization. However, the prevalence of comorbid events and the propensity for neurologic dysfunction place octogenarians at higher risk for cardiopulmonary bypass-induced morbidity and mortality. Therefore, octogenarian patients represent a particularly attractive target for application of off-pump coronary artery bypass grafting. METHODS: From January 1999 to August 2001, 113 octogenarians had off-pump coronary artery bypass grafting. Their data were prospectively entered into the cardiac surgery database and analyzed retrospectively. Follow-up information was obtained through telephone survey. RESULTS: The mean age of the patients was 83 +/- 2.5 years, and the mean number of grafts per patient was 3.3 +/- 1. The most prevalent postoperative complication was atrial fibrillation (43%). Postoperative neurologic complications were seen in 5 patients (4%). There was one postoperative death (30-day mortality rate, 0.9%). The mean follow-up was 13.2 +/- 7 months and was complete for 90% of the patients. At the time of telephone survey, 85 (87%) of 98 patients were free from angina, and 91 (88%) were free from cardiac-related readmission. There were three late deaths. The majority of octogenarians (66%) reported that in retrospect, they would have the operation again. CONCLUSIONS: Off-pump multivessel revascularization in octogenarians is associated with excellent early and intermediate outcomes and provides a satisfactory quality of life. 相似文献
44.
Balasubramanyam M Balaji RA Subashini B Mohan V 《International journal of experimental diabetes research》2001,1(4):275-287
Altered cytosolic Ca2+ is implicated in the aetiology of many diseases including diabetes but there are few studies on the mechanism(s) of the altered Ca2+ regulation. Using human lymphocytes, we studied cytosolic calcium (Cai) and various Ca2+ transport mechanisms in subjects with Type 2 diabetes mellitus and control subjects. Ca2+-specific fluorescent probes (Fura-2 and Fluo-3) were used to monitor the Ca2+ signals. Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was used to study Ca2+-store dependent Ca2+ fluxes. Significant (P<0.05) elevation of basal Ca, levels was observed in lymphocytes from diabetic subjects. Cai levels were positively correlated with fasting plasma glucose and HbA1c. There was also a significant (P<0.05) reduction in plasma membrane calcium (PMCA) ATPase activity in diabetic subjects compared to controls. Cells from Type 2 diabetics exhibited an increased Ca2+ influx (as measured both by Fluo-3 fluorescence and 45Ca assays) as a consequence of thapsigargin-mediated Ca2+ store depletion. Upon addition of Mn2+ (a surrogate of Ca2+), the fura-2 fluorescence decayed in an exponential fashion and the rate and extent of this decline was steeper and greater in cells from type 2 diabetic patients. There was also a significant (P<0.05) difference in the Na+/Ca2+ exchange activity in Type 2 diabetic patients, both under resting conditions and after challenging the cells with thapsigargin, when the internal store Ca2+ sequestration was circumvented. Pharmacological activation of protein kinase C (PKC) in cells from patients resulted in only partial inhibition of Ca2+ entry. We conclude that cellular Ca2+ accumulation in cells from Type 2 diabetes results from (a) reduction in PMCA ATPase activity, (b) modulation of Na+/Ca2+ exchange and (3) increased Ca2+ influx across the plasma membrane. 相似文献
45.
Reddy S Karanam M Robinson E 《International journal of experimental diabetes research》2001,1(4):299-313
Spontaneous diabetes in the NOD mouse can be prevented by nicotinamide or by an infant formula diet in which the protein source is replaced with casein hydrolysate (Pregestimil) or soy protein (Prosobee). NOD mice maintained on the standard diet (chow and water) and given cyclophosphamide (Cy) at day 95 develop accelerated and synchronised diabetes within 14 days. Here, we compared the ability of oral nicotinamide or Prosobee, either given alone or concurrently, from weaning, in preventing diabetes in the Cy model. The resulting insulitis and the expression of intra-islet inducible nitric oxide synthase (iNOS) were examined at days 0, 4, 7, 11 and 14 following Cy administration. Intra-islet CD4 and CD8 cells and macrophages were also enumerated at day 11. In mice given the standard diet and injected with Cy at day 95 (group 5), diabetes developed in 7/11 mice, 14 days later. Mice exposed to oral nicotinamide (group 2), Prosobee (group 3) or both (group 4), did not develop the disease during this period and until a further 30 days (p = 0.03). In mice exposed to the standard diet and without Cy treatment (group 1) the insulitis scores increased slowly until day 11 and then declined slightly at day 14 whereas mice exposed to the same diet but given Cy at day 95, showed a sharp decline at day 4 followed by a rapid increase between day 7-14. However, in mice given either nicotinamide, Prosobee or both, the insulitis scores at most time-points were generally lower than in Cy-treated animals on the standard diet. In the latter group, CD4 and CD8 cells and macrophages were also higher at day 11 than all other 4 groups (CD4: p < 0.05; CD8: p< 0.05; macrophages: p<0.0001). The number of iNOS labelled cells increased progressively in mice on the standard diet and given Cy and were significantly higher at days 4, 7 and 11 than in the 3 dietary groups. Thus, oral nicotinamide or Prosobee, either alone or together, prevents Cy induced diabetes in the NOD mouse. The protective diets suppress Cy-induced intra-islet immune cell influx and iNOS expression. 相似文献
46.
The thiazolidinediones (TZDs) rosiglitazone and pioglitazone are newer additions to the antidiabetic armamentarium and are indicated for the treatment of type 2 diabetes mellitus (T2DM) in the United States. The TZDs are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists that provide clinically effective glycemic control and unique pharmacologic effects on multiple risk factors for T2DM-related morbidity, including improvement of insulin sensitivity and endothelial dysfunction, reduction of blood pressure, and amelioration of dyslipidemia. Weight gain and fluid retention occur with TZD therapy, especially when they are administered in higher doses and in combination with insulin. Although fluid retention associated with the use of TZDs is generally mild and reversible, these agents should not be used in patients with New York Heart Association Class III or IV heart failure symptoms. The findings of ongoing, long-term, prospective studies will clarify the role of the TZDs in the treatment of T2DM, particularly in terms of the durability of improvements in glycemic control, insulin sensitivity, pancreatic beta- cell function, and cardiovascular health. 相似文献
47.
Kaushik Kavya S. Ananthasivan Rupa Acharya Ullas V. Rawat Sudarshan Patil Uday Damodar Shankar Balasubramanyam Jose Abin 《Emergency radiology》2021,28(6):1097-1106
Emergency Radiology - Rhino-orbito-cerebral mucormycosis (ROCM) has regained significance following its resurgence in the second wave of the COVID-19 pandemic in India. Rapid and progressive... 相似文献
48.
Abdelmalek MF Lazo M Horska A Bonekamp S Lipkin EW Balasubramanyam A Bantle JP Johnson RJ Diehl AM Clark JM;and the Fatty Liver Subgroup of the Look AHEAD Research Group 《Hepatology (Baltimore, Md.)》2012,56(3):952-960
Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low- versus high-fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130-item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low- (<15 g/day) versus high-fructose (≥15 g/day) consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/ inorganic phosphate (Pi) ratio (0.08 versus 0.03; P = 0.05) and γ-ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06; P = 0.06). Patients with high UA (≥5.5 mg/dL) showed a lower minimum liver ATP/Pi ratio postfructose challenge (4.5 versus 7.0; P = 0.04). Conclusions: High-fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD. (HEPATOLOGY 2012;56:952-960). 相似文献
49.
Neda Rasouli Naji Younes Kristina M. Utzschneider Silvio E. Inzucchi Ashok Balasubramanyam Andrea L. Cherrington Faramarz Ismail-Beigi Robert M. Cohen Darin E. Olson Ralph A. DeFronzo William H. Herman John M. Lachin Steven E. Kahn the GRADE Research Group 《Diabetes care》2021,44(2):340
OBJECTIVEWe investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA1c) and the associations with selected phenotypic characteristics.RESEARCH DESIGN AND METHODSThis is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed <10 years earlier and were on metformin monotherapy. Insulin sensitivity and β-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI).RESULTSThe cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m2, HbA1c 7.5 ± 0.5%, and type 2 diabetes duration 4.0 ± 2.8 years. Women had higher DI than men but similar insulin sensitivity. DI was the highest in Black/African Americans, followed by American Indians/Alaska Natives, Asians, and Whites in descending order. Compared with Whites, American Indians/Alaska Natives had significantly higher HbA1c, but Black/African Americans and Asians had lower HbA1c. However, when adjusted for glucose levels, Black/African Americans had higher HbA1c than Whites. Insulin sensitivity correlated inversely with BMI, waist-to-hip ratio, triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and the presence of metabolic syndrome, whereas DI was associated directly with age and inversely with BMI, HbA1c, and TG/HDL-C.CONCLUSIONSIn the GRADE cohort, β-cell function differed by sex and race and was associated with the concurrent level of HbA1c. HbA1c also differed among the races, but not by sex. Age, BMI, and TG/HDL-C were associated with multiple measures of β-cell function and insulin sensitivity. 相似文献
50.
Michael P. Bancks Haiying Chen Ashok Balasubramanyam Alain G. Bertoni Mark A. Espeland Steven E. Kahn Scott Pilla Elizabeth Vaughan Lynne E. Wagenknecht the Look AHEAD Research Group 《Diabetes care》2021,44(5):1203
OBJECTIVEWe reevaluated the Action for Health in Diabetes (Look AHEAD) intervention, incorporating diabetes subgroups, to identify whether intensive lifestyle intervention (ILI) is associated with differential risk for cardiovascular disease (CVD) by diabetes subgroup.RESEARCH DESIGN AND METHODSIn the Look AHEAD trial, 5,145 participants, aged 45–76 years, with type 2 diabetes (T2D) and overweight or obesity were randomly assigned to 10 years of ILI or a control condition of diabetes support and education. The ILI focused on weight loss through decreased caloric intake and increased physical activity. To characterize diabetes subgroups, we applied k-means clustering to data on age of diabetes diagnosis, BMI, waist circumference, and glycated hemoglobin. We examined whether relative intervention effects on the trial’s prespecified CVD outcomes varied among diabetes subgroups.RESULTSWe characterized four subgroups related to older age at diabetes onset (42% of sample), poor glucose control (14%), severe obesity (24%), and younger age at diabetes onset (20%). We observed interactions (all P < 0.05) between intervention and diabetes subgroups for three separate composite cardiovascular outcomes. Randomization to ILI was associated with increased risk for each cardiovascular outcome only among the poor-glucose-control subgroup (hazard ratio >1.32). Among the three other diabetes subgroups, ILI was not associated with increased risk for CVD.CONCLUSIONSAmong overweight and obese adults with T2D, a lifestyle intervention was associated with differential risk for CVD that was dependent on diabetes subgroup. Diabetes subgroups may be important to identify the patients who would achieve benefit and avoid harm from an ILI. 相似文献