Formulation and development of novel control release transdermal patches of carvedilol to improve bioavailability for the treatment of heart failure.

The main aim of this study is to optimize and evaluate transdermal patch of Carvedilol by the use of different polymer and different permeation enhancers which help to release drug in controlled action and thereby increase the bioavailability of the drug. Main objective was to avoid first pass metabolism of Carvedilol. Transdermal patches were developed by solvent evaporation method. The combination of Eudragit RS-100 as rate controlling polymer and Span 80 as a permeation enhancer was found to be ideal formulation (Formulation F7) with maximum drug release i.e. 100.29 ± 0.44 % within 12 h. Formulation F7 showed maximum bioavailability and showed maximum drop of BP at 6 h. From this study the conclusion was, transdermal patch of Carvedilol which contains Eudragit RS-100 polymer and Span 80 as penetration enhancer produced sustained and continued drug release.

The proliferation and migration of atherosclerosis-related HVSMCs were inhibited by downregulation of lncRNA XIST via regulation of the miR-761/BMP9 axis.

Atherosclerosis (AS) is a chronic inflammatory disease that can be caused by the proliferation and migration of human vascular smooth muscle cells (HVSMCs). Here, we found that lncRNA XIST was related to the abnormal proliferation and migration of HVSMCs, and thus, the mechanism by which XIST regulated HVSMCs was further investigated. HVSMCs were treated with oxidized low-density lipoprotein (ox-LDL, 100 µg/ml) as AS models. CCK8 assays, flow cytometry, Transwell assays and wound healing assays were applied to evaluate cell viability, cell cycle analysis, and cell migration, respectively. A dual-luciferase reporter assay was employed to verify the binding relationships between XIST and miR-761, miR-761, and BMP9. Ox-LDL induced the proliferation and migration of HVSMCs, upregulated the expression of XIST, downregulated miR-761 expression, and activated the BMP9/ALK1/endoglin pathway. Luciferase assays revealed that XIST sponged miR-761. XIST knockdown ameliorated ox-LDL-mediated effects in HVSMCs, which were largely abolished by miR-761 silencing. BMP9 was targeted-inhibited by miR-761. MiR-761 overexpression alleviated ox-LDL-mediated effects in HVSMCs. However, BMP9 overexpression abolished miR-761-mediated effects in HVSMCs treated with ox-LDL. Our findings suggested that XIST knockdown suppressed the proliferation and migration of HVSMCs by promoting miR-761, which targeted-inhibited the BMP9/ALK1/endoglin pathway.

Relationship of postprandial nonesterified fatty acids, adipokines, and insulin across gender in human immunodeficiency virus-positive patients undergoing highly active antiretroviral therapy.

BACKGROUND: Metabolic derangements are common in human immunodeficiency virus (HIV)-positive subjects undergoing antiretroviral therapy, but little is known about postprandial conditions. METHODS: We investigated the relationship between leptin, adiponectin, nonesterified fatty acids (NEFA), and insulin in response to a day-long meal pattern and evaluated gender differences in HIV-positive men (n = 12) and women (n = 13) undergoing highly active antiretroviral therapy (HAART). RESULTS: For both men and women, a significant decrease in postprandial NEFA levels was observed following breakfast (0.53 vs. 0.22 mmol/L, P < 0.001, baseline and at 3 hours, respectively), whereas day-long postprandial leptin and adiponectin levels showed small nonsignificant oscillations. In contrast to NEFA and adiponectin, postprandial leptin levels were significantly higher among women compared to men (P < 0.05). Postprandial NEFA levels correlated positively with fasting insulin levels (r(2) = 0.25, P = 0.016), and the postbreakfast decrease in NEFA levels correlated significantly with the postbreakfast increase in insulin levels (r(2) = 0.17, P = 0.038). No significant association between postprandial adipokines and insulin was observed. CONCLUSIONS: In HAART-treated, HIV-infected men and women, levels of NEFA, but not adipokines, showed significant postprandial variation. Furthermore, food intake resulted in significant NEFA suppression in proportion to the food-stimulated insulin increase.

Plasma levels of myeloperoxidase are not elevated in patients with stable coronary artery disease.

BACKGROUND: Plasma and serum levels of myeloperoxidase (MPO), a redox-active hemoprotein released by polymorphonuclear neutrophils (PMN) upon activation, is now recognized as a powerful prognostic determinant of myocardial infarction in patients suffering acute coronary syndromes. However, there is limited information on whether systemic MPO levels are also elevated and of discriminating value in patients with stable coronary artery disease (CAD) representing different ethnic groups. METHODS: Plasma levels of MPO and traditional CAD risk factors were quantified in African American and Caucasian patients (n=557) undergoing elective coronary angiography. RESULTS: MPO levels did not differ significantly between patients with or without CAD [421 pM (321, 533) vs. 412 pM (326, 500), p>0.05]. MPO levels were similar across ethnicity and gender, and correlated positively with CRP and fibrinogen levels (r=0.132, p=0.002 and r=0.106, p=0.011, respectively). CONCLUSION: In conclusion, plasma MPO levels were not elevated in patients with stable CAD, suggesting that systemic release of MPO is not a characteristic feature of asymptomatic CAD.

Increased lipoprotein remnant cholesterol levels in HIV-positive patients during antiretroviral therapy.

Increased levels of postprandial triglycerides (TG) and remnant like particles (RLP) are associated with cardiovascular disease. We evaluated whether postprandial lipemia differed in HIV-positive patients with or without different antiretroviral regimens. A standardized high fat load was administered to 28 subjects: 11 HIV-positive subjects receiving protease inhibitors (PI), 10 HIV-positive subjects receiving non-nucleoside reverse transcriptase inhibitors (NNRTI) and 7 HIV-positive subjects not receiving highly active antiretroviral therapy, HAART (Naïve). Baseline TG levels and TG area under the curve (AUC) did not differ among the three groups. The postprandial TG concentration curves were similar in the NNRTI and Naïve groups, peaking at 3-5-h. Baseline RLP cholesterol was higher in the NNRTI group compared to other two groups (P=0.035). Both HAART groups (NNRTI and PI) had higher postprandial RLP cholesterol AUC than the Naïve group (P=0.024, ANOVA). In conclusion, during HIV conditions, HAART resulted in a pro-atherogenic pattern with accumulation of remnant lipoproteins.

Adiponectin levels are associated with coronary artery disease across Caucasian and African-American ethnicity.

The hypothesis was tested that plasma levels of adiponectin would be associated with coronary artery disease (CAD) across African-American and Caucasian ethnicity and gender. Adiponectin levels, cardiovascular risk factors, and extent of CAD were measured in 453 subjects (173 African-American and 280 Caucasian men and women). The distribution of adiponectin levels differed significantly between African-Americans and Caucasians (P<0.0001). Among African-Americans, the adiponectin distribution was skewed toward lower levels. For women, adiponectin levels were higher among Caucasians compared with African-Americans (P<0.001), whereas no interethnic difference was observed for men. Irrespective of ethnic group, subjects with CAD had lower levels of adiponectin than did subjects without CAD. Adiponectin was negatively and significantly associated with waist-hip ratio, body mass index, diastolic blood pressure, insulin level, and homeostasis model assessment-insulin resistance in both ethnic groups. Among lipid parameters, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels were negatively correlated with adiponectin, whereas the high-density lipoprotein cholesterol level correlated positively for both African-Americans and Caucasians. In a multiple regression model, controlling for gender, ethnicity, and other CAD risk factors, adiponectin levels were negatively associated with CAD (P<0.05). The results indicate that, across gender and ethnicity, low adiponectin levels may be an independent risk factor for CAD.

ApoE genotype affects allele-specific apo[a] levels for large apo[a] sizes in African Americans: the Harlem-Basset Study.

The genetic variability of apolipoprotein E (apoE) influences plasma lipoprotein levels, and allele frequencies differ between African Americans and Caucasians. As African Americans have higher lipoprotein [a] (Lp[a]) levels than Caucasians, we investigated the effects of the apoE gene on allele-specific apolipoprotein [a] (apo[a]) levels across ethnicity. We determined apo[a] sizes, allele-specific apo[a] levels (i.e., levels associated with alleles defined by size), and the apoE gene polymorphism in 231 African Americans and 336 Caucasians. African Americans, but not Caucasians, with the apo E2 genotype had lower levels of Lp[a] compared with those with the apo E4 genotype (9.6 vs. 11.2 nmol/l; P = 0.034, expressed as square root levels). Distribution of apo[a] alleles across apoE genotypes were similar between African Americans and Caucasians. Among African Americans with large apo[a], the allele-specific apo[a] level was significantly lower among epsilon2 carriers compared with epsilon3 or epsilon4 carriers (5.4 vs. 6.6 and 7.4 nmol/l, respectively; P < 0.005, expressed as square root levels). In contrast, there was no significant difference in allele-specific apo[a] levels across apoE genotypes among Caucasians. For large apo[a] sizes, apoE genotype contributed to the observed African American-Caucasian differences in allele-specific apo[a] levels.

Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol.

We studied the relationship of apolipoprotein E (apoE) isoforms and coronary artery disease (CAD) in 224 African Americans and 326 Caucasians undergoing diagnostic coronary angiography. The presence of CAD was defined as >50% stenosis in at least one artery. ApoE allele frequencies were 0.12, 0.62, and 0.26 for epsilon 2, epsilon 3, and epsilon 4, respectively, in African Americans and 0.08, 0.78, and 0.14 for epsilon 2, epsilon 3, and epsilon 4, respectively, in Caucasians. Among African Americans, CAD was present in 9 of 34 epsilon 2 carriers (26%), significantly smaller (P < 0.05) in proportion compared with 39 of 82 epsilon 3 carriers and 43 of 92 epsilon 4 carriers (48% and 47%, respectively), suggesting a protective effect of the epsilon 2 allele. No such difference was seen in Caucasians. In African Americans but not Caucasians, LDL cholesterol was lower in epsilon 2 carriers than in epsilon 3 and epsilon 4 carriers (106 vs. 127 and 134 mg/dl, respectively; P < 0.005). After adjusting for lipid levels, the association between apoE2 and CAD was no longer significant. Thus, the protective effect of apoE2 seen in African Americans could be explained by a favorable lipid profile in epsilon 2 carriers, whereas in Caucasians, the absence of such a protective effect could be attributable to the lack of effect of apoE2 on the lipid profile.