Attenuation of serum lipid abnormalities and cardiac oxidative stress by eicosapentaenoate-lipoate (EPA-LA) derivative in experimental hypercholesterolemia

BACKGROUND: Dietary cholesterol plays an important role in development of atherogenesis and cardiovascular disease. We explored the lipemic-oxidative injury in the hypercholesterolemic atherogenic animals. The effects of eicosapentaenoic acid (EPA), dl-alpha-lipoic acid (LA) and eicosapentaenoate-lipoate derivative (EPA-LA) were tested for their efficacy in controlling the atherogenic disturbances. METHODS: Four groups of male Wistar rats were fed with a high cholesterol diet (rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. Of these groups, 3 groups of rats were treated with either EPA (oral gavage, 35 mg/kg body weight/day), LA (oral gavage, 20 mg/kg body weight/day) or EPA-LA derivative (oral gavage, 50 mg/kg body weight/day) from 16th day to 30th day of the experimental period. RESULTS: HCD induced abnormal increase in lipid peroxidation and serum cholesterol, triglyceride, LDL and VLDL, and a decreased HDL concentration. Altered activity of cardiac and serum creatine kinase, accompanied by a depressed cardiac enzymatic and nonenzymatic antioxidants defense system were observed in HCD fed rats. These changes were partially restored in the EPA and LA treated groups, however, their combined derivative EPA-LA more effectively restored the altered parameters near to that of control (P<0.05). CONCLUSION: Lipid abnormalities and oxidative injury were induced by a hypercholesterolemic diet. Administration of the combination treatment of EPA-LA afforded protection against the lipemic-oxidative injury.     

Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease

We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.     

Social cognitive variables as correlates of physical activity in persons with multiple sclerosis: findings from a longitudinal, observational study

There is a lack of data regarding the associations among changes in social cognitive variables and physical activity over time in persons with multiple sclerosis (MS). To that end, the current study adopted a panel design and analysis for examining hypothesized relationships among changes in social cognitive variables and physical activity over time in persons with MS, and this is necessary for designing effective behavioral interventions. On two occasions separated by an 18-month period, persons (N = 218) with relapsing-remitting MS (RRMS), who were initially recruited by telephone for a cross-sectional study, completed a battery of questionnaires that assessed social cognitive variables and physical activity. Those study materials were delivered and returned via the United State Postal Service. The 18-month changes in self-efficacy (path coefficient = .25, p < .01) and goal setting (path coefficient = .26, p < .01) had direct effects on residual change in physical activity. The change in self-efficacy further had an indirect effect on residual change in physical activity that was accounted for by change in goal setting (path coefficient = .05, p < .05). This longitudinal study suggests that self-efficacy and goal setting represent plausible targets for changing physical activity behavior in persons with RRMS.     

Vascular stiffness and genetic variation at the endothelial nitric oxide synthase locus: the Framingham Heart study

Arterial stiffness is a moderately heritable trait that is affected by alterations in the bioavailability of NO. Previous studies have found associations between variants in the gene for endothelial NO synthase (NOS3) and arterial properties. We previously identified a linkage peak for forward pressure wave amplitude in the immediate vicinity of NOS3. Therefore, we evaluated relations between arterial stiffness measures and common genetic variants at this locus. Eighteen single nucleotide polymorphisms capturing approximately 90% of underlying common variation in NOS3 were genotyped in unrelated Framingham Heart Study participants (N=1157; 52.2% women; mean age: 62 years) with routinely ascertained tonometry data that provided 5 arterial phenotypes (forward and reflected pressure wave amplitude, central pulse pressure, carotid-femoral pulse wave velocity, and mean arterial pressure). In women but not men, the genotype for the common NOS3 missense mutation (Glu298Asp, rs1799983) was related to central pulse pressure (women: GG=53+/-0.9, GT=54+/-0.9, and TT=47+/-2.0 mm Hg, P=0.0047; men: GG=50+/-1.0, GT=49+/-0.9, and TT=47+/-1.8 mm Hg, P=0.30) and forward wave amplitude (women: GG=41+/-0.7, GT=42+/-0.7, and TT=38+/-1.6 mm Hg, P=0.029; men: GG=42+/-0.9, GT=41+/-0.8, and TT=39+/-1.5 mm Hg, P=0.47). The only other nominally significant sex-specific association in men but not women was between an intronic polymorphism (rs1800781) and reflected wave amplitude (women: AA=10.4+/-0.4, AG=11.1+/-0.6, and GG=8.9+/-2.2 mm Hg, P=0.50; men: AA=6.1+/-0.3, AG=7.3+/-0.5, and GG=11.3+/-2.3 mm Hg, P=0.014). After adjusting for multiple testing (18 polymorphisms and 5 phenotypes), these nominal associations were no longer significant. The present study was suggestive of modest relations between common genetic variants at the NOS3 locus and arterial stiffness.     

Red clover Trifolium pratense (Linn.) isoflavones extract on the pain threshold of normal and ovariectomized rats – a long‐term study

Depletion of estrogens occurs in women during menopause, while in experimental animals, oophorectomy is a common method to deplete the animals of their gonadal hormones. Recently, phytoestrogens derived from plants have been tried as estrogen substitutes during menopause. In the present study an isoflavones methanol extract from red clover Trifolium pratense (Linn.) was administered orally (500 mg/kg of body weight) to ovariectomized (OVX) and normal (controls) rats for 90 and 180 days. Their pain threshold was monitored using tail flicking and formalin test methods. Observations showed that the OVX rat pain threshold was reduced due to estrogen deprivation, whereas the pain threshold levels in OVX rats treated with isoflavones extract was similar to the control animals. The present study demonstrated the influence of phytoestrogen on long‐term OVX rats in pain perception in the absence of ovarian estrogen and without toxic side effects. However, the actions of gonadal hormones on nociceptive axis are myriad and complex, so further studies on the exact physiological mechanism of the phytoestrogen action on nociceptive axis is warranted. Copyright © 2010 John Wiley & Sons, Ltd.     

Development of ultra fast liquid chromatographic method for simultaneous determination of nitrendipine and carvone in skin diffusate samples

A simple and sensitive reverse phase ultra fast liquid chromatographic (UFLC) method for simultaneous determination of nitrendipine and carvone in skin diffusate samples and microemulsions was developed and validated. The separation was achieved using a gradient mobile phase, on an Onyx column. The eluents were monitored by photodiode array detection. The linearity ranges of proposed method were 0.125–50 μg mL⁻¹ and 0.125–30 μg mL⁻¹ for nitrendipine and carvone respectively. The intra-day and inter-day coefficient of variation and percent error values of the assay method were less than 10%. The method was found to be precise, accurate, and specific during the study. The method was successfully applied for simultaneous estimation of nitrendipine and carvone in ex vivo skin diffusate samples and microemulsions.     

The effect of different meal types on the pharmacokinetics of darunavir (TMC114)/ritonavir in HIV-negative healthy volunteers

This open-label, randomized, crossover study investigated the bioavailability, short-term safety, and tolerability of darunavir (TMC114) coadministered with low-dose ritonavir under fasted conditions and after different meal types in HIV-negative healthy volunteers. All volunteers received ritonavir 100 mg twice daily on days 1 to 5, with a single darunavir 400-mg tablet given on day 3 (darunavir/rtv). Pharmacokinetic parameters for darunavir and ritonavir were determined under fasted conditions and following a standard breakfast, a high-fat breakfast, a nutritional protein-rich drink, or a croissant with coffee. Administration of darunavir/rtv in a fasting state resulted in a decrease in darunavir C(max) and AUC(last) of approximately 30% compared with administration after a standard meal. No significant differences in darunavir plasma concentrations were observed between different fed states. Darunavir/rtv should therefore be administered with food, but exposure to darunavir is not affected by the type of meal.