Pharmacokinetic and pharmacodynamic interaction of Rosuvastatin calcium with guggulipid extract in rats

Background & objectivesRosuvastatin calcium (RC) is a potent and competitive synthetic inhibitor of HMG-CoA reductase used for the treatment of dyslipidemia. Guggulipid obtained from Commiphora mukul is used in the treatment of a wide variety of diseases such as atherosclerosis, hypercholesterolemia, rheumatism, and obesity. The present study evaluates the pharmacokinetic and pharmacodynamic interactions between RC and the standardized guggulipid extract in rats.Materials and methodsThe guggulipid extract was standardized for the presence of guggulsterones. The pharmacokinetic interaction was determined after a single dose administration of RC alone or in combination with the guggulipid extract or after multiple-dose administration of RC alone or RC along with the guggulipid extract for 14 days. To determine the pharmacodynamic interaction, RC and guggulipid extract were administered to hyperlipidemic rats for 14 days. The level of significance was determined using unpaired student’s t-test, one way ANOVA, the post-ANOVA Tukey test.ResultsStandardization of guggulipid extract showed it contains 7.5%w/w of guggulsterones. Guggulipid extract increased the bioavailability of RC in both single-dose and multiple-dose studies. Guggulipid extract reduced the rate of absorption (Ka) of RC but showed an increase in maximum serum concentration (Cmax). An in-vitro study using isolated rat intestine revealed that guggulipid extract decreased the rate of absorption of RC in the intestinal lumen. The hypolipidemic activity of RC was augmented by the guggulipid extract in hyperlipidemic rats.Interpretation & conclusionTherefore it is concluded that guggulipid extract increases the bioavailability of RC by delaying its Ka and augments its hypolipidemic action. However, it is recommended that a combination of RC with guggulipid extract should be used only after an adverse effect(s) of this combination are determined.     

Natriuretic Peptides Inhibit Nicotine-Induced Whole-Cell Currents and Catecholamine Secretion in Bovine Chromaffin Cells: Evidence for the Involvement of the Atrial Natriuretic Factor R2 Receptors

Abstract: There is increasing evidence that members of the natriuretic peptide family display sympathoinhibitory activity, but it remains uncertain which receptor pathway is implicated. We performed cyclic GMP production studies with chromaffin cells treated with either atrial natriuretic factor (ANF) or C-type natriuretic peptide (CNP) and found that these cells specifically express the ANF-R_1C but not the ANF-R_1A receptor subtype. Evidence for the existence of ANF-R₂ receptors was obtained from patch-clamp experiments where C-ANF, an ANF-R₂-specific agonist, inhibited nicotinic currents in single isolated chromaffin cells. Involvement of ANF-R₂ receptors in the modulation of nicotinic currents was further supported by the significant loss of this inhibitory activity after the cleavage of the disulfide-bridged structure of C-ANF. This linearized form of C-ANF also displayed a lower binding affinity for ANF-R₂ receptors. Like the patch-clamp studies, secretion experiments demonstrated that both CNP and C-ANF are equally effective in reducing nicotine-evoked catecholamine secretion by cultured chromaffin cells, raising the possibility that this effect of CNP is predominantly mediated by the ANF-R₂ and not the ANF-R_1C receptors. Finally, this response appears to be specific to nicotinic agonists because neither histamine- nor KCI-induced secretions were affected by natriuretic peptides. In the present study, we report (1) the presence of ANF-R_1C and ANF-R₂ receptor subtypes in bovine chromaffin cells, (2) the inhibition by natriuretic peptides of nicotinic whole-cell currents as well as nicotine-induced catecholamine secretion, (3) the possible mediation of these effects by the ANF-R₂ class of receptors, and (4) the specificity of this inhibition to nicotinic agonists. Because bovine chromaffin cells release ANF, BNP, and CNP together with catecholamines, all three peptides might exert negative feedback regulation of catecholamine secretion in an autocrine manner by interacting with the nondiscriminating ANF-R₂ receptor subtype.     

Natural inspired piperine-based ureas and amides as novel antitumor agents towards breast cancer

In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides (5a–i) and ureas (8a–y) as potential anticancer agents. The anticancer action was assessed against triple negative breast cancer (TNBC) MDA-MB-231, ovarian A2780CP and hepatocellular HepG2 cancer cell lines. In particular, 8q stood out as the most potent anti-proliferative analogue against TNBC MDA-MB-231 cells with IC₅₀ equals 18.7 µM, which is better than that of piperine (IC₅₀ = 47.8 µM) and 5-FU (IC₅₀ = 38.5 µM). Furthermore, 8q was investigated for its possible mechanism of action in MDA-MB-231 cells via Annexin V-FITC apoptosis assay and cell cycle analysis. Moreover, an in-silico analysis has proposed VEGFR-2 as a probable enzymatic target for piperine-based derivatives, and then has explored the binding interactions within VEGFR-2 active site (PDB:4ASD). Finally, an in vitro VEGFR-2 inhibition assay was performed to validate the in silico findings, where 8q showed good VEGFR-2 inhibitory activity with IC₅₀ = 231 nM.     

Association between Gestational Weight Gain and Postpartum Diabetes: Evidence from a Community Based Large Cohort Study

We have investigated the prospective association between excess gestational weight gain (GWG) and development of diabetes by 21 years post-partum using a community-based large prospective cohort study in Brisbane, Australia. There were 3386 mothers for whom complete data were available on GWG, pre-pregnancy BMI and self-reported diabetes 21 years post-partum. We used The Institute of Medicine (IOM) definition to categorize GWG as inadequate, adequate and excessive. We found 839 (25.78%) mothers gained inadequate weight, 1,353 (39.96%) had adequate weight gain and 1,194 (35.26%) had gained excessive weight during pregnancy. At 21 years post-partum, 8.40% of mothers self-reported a diagnosis of diabetes made by their doctor. In the age adjusted model, we found mothers who gained excess weight during pregnancy were 1.47(1.11,1.94) times more likely to experience diabetes at 21 years post-partum compared to the mothers who gained adequate weight. This association was not explained by the potential confounders including maternal age, parity, education, race, smoking, TV watching and exercise. However, this association was mediated by the current BMI. There was no association for the women who had normal BMI before pregnancy and gained excess weight during pregnancy. The findings of this study suggest that women who gain excess weight during pregnancy are at greater risk of being diagnosed with diabetes in later life. This relationship is likely mediated through the pathway of post-partum weight-retention and obesity. This study adds evidence to the argument that excessive GWG during pregnancy for overweight mothers has long term maternal health implications.     

Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain

Sprouty (Spry) was first identified in a genetic screen in Drosophila to be an antagonist of fibroblast growth factor and epidermal growth factor (EGF) signaling, seemingly by inhibiting the Ras/MAP kinase pathway. Data base searches lead to the identification and cloning of, to date, four mammalian sprouty genes. The primary sequences of the mammalian sprouty gene products share a well conserved cysteine-rich C-terminal domain with the Drosophila protein. The N-terminal regions, however, do not exhibit significant homology. This study aimed at determining the disposition of Spry proteins in intact cells before and after stimulation of the EGF receptor tyrosine kinase. Full-length or deletion mutants of Spry, tagged at the N termini with the FLAG-epitope, were expressed in COS-1 cells by transient transfection and analyzed by immunofluorescence microscopy before and after EGF stimulation of the cells. In unstimulated cells, the Spry proteins were distributed throughout the cytosol except for human Sprouty2 (hSpry2), which, although generally located in the cytosol, co-localized with microtubules. In all cases, the Spry proteins underwent rapid translocation to membrane ruffles following EGF stimulation. The optimal translocation domain was identified by deletion and immunofluorescence analysis to be a highly conserved 105-amino acid domain in the C-terminal half of the hSpry2 protein. The translocation of this conserved domain, based on hSpry2 data, was independent of the activation of phosphatidylinositol-3 kinase.     

The efficacy of a video-based marker-less tracking system for gait analysis

Most clinical gait analyses are conducted using motion capture systems which track retro-reflective markers that are placed on key landmarks of the participants. An alternative to a three-dimensional (3D) motion capture, marker-based, optical camera system may be a marker-less video-based tracking system. The aim of our study was to investigate the efficacy of the use of a marker-less tracking system in the calculation of 3D joint angles for possible use in clinical gait analysis. Ten participants walked and jogged on a treadmill and their kinematic data were captured with a marker and marker-less tracking system simultaneously. The hip, knee and ankle angles in the frontal, sagittal and transverse planes were computed. Root Mean Square differences (RMS_diff) between corresponding angles for each participant’s support phase were calculated and averaged to derive the mean within-subject RMS_diff. These within-subject means were averaged to obtain the mean between-subject RMS_diff for the relevant joint angles in the two gait conditions (walking and jogging). The RMS_diff between the two tracking systems was less than 1° for all rotations of the three joint angles of the hip and knee. However, there were slightly larger differences in the ankle joint angles. The results of this study suggest a potential application in gait analysis in clinical settings where observations of anatomical motions may provide meaningful feedback.     

31P and19F NMR studies of glycophorin-reconstituted membranes: Preferential interaction of glycophorin with phosphatidylserine

Summary Glycophorin A, a major glycoprotein of the erythrocyte membrane, has been incorporated into small unilamellar vesicles composed of a variety of pure and mixed phospholipids. Nuclear spin labels including³¹P and¹⁹F have been used at natural abundance or have been synthetically incorporated in lipids to act as probes of lipid-protein interaction. Interactions produce broadening of resonances in several cases and it can be used to demonstrate preferential interaction of certain lipids with glycophorin.³¹P and¹⁹F probes show a strong preferential interaction of glycophorin with phosphatidylserine over phosphatidylcholine. There is some evidence that interactions are more pronounced at the inner surface of the bilayer and these results are rationalized in terms of the asymmetric distribution of protein and lipid.     

Protecting the heart: a practical review of the statin studies

The aim of this review of the landmark HMG-CoA reductase inhibitors (statins) studies is to enable the clinician to draw practical lessons from these trials. The Scandinavian Simvastatin Survival Study (4S) established the importance of treating the hypercholesterolemic patient with established cardiovascular heart disease. The West of Scotland Coronary Prevention Study (WOSCOPS) showed the benefit of treating healthy hypercholesterolemic men who were nevertheless at high risk of developing cardiovascular heart disease in the future. The Cholesterol and Recurrent Events (CARE) study, a secondary prevention trial, proved the benefit of treating patients with myocardial ischemia and cholesterol levels within normal limits. This conclusion was confirmed by the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) study, another secondary prevention study that enrolled patients with a wide range of cholesterol levels (4-7 mmol/dL), into which the large majority of patients would belong. The importance of treating patients with established ischemic heart disease (IHD), and those at high risk of developing cardiovascular heart disease, regardless of cholesterol level, was being realized. The Air Force/Texas Coronary Artery Prevention Study (AFCAPS/TexCAPS) then showed that treatment can reduce adverse cardiovascular events even in the primary prevention of patients with normal cholesterol levels. The Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) trial showed that hypocholesterolemic therapy is useful in the setting of an acute coronary syndrome, while the Atorvastatin Versus Revascularisation Treatment (AVERT) study showed that aggressive statin therapy is as good as angioplasty in reducing ischemic cardiac events in patients with stable angina pectoris. Finally, the Heart Protection Study (HPS) randomized more than 20,000 patients, and the value of statins in reducing adverse cardiovascular events in the high-risk patient, including the elderly, women, and even in those with low cholesterol levels, is beyond doubt. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not be dependent on the actual cholesterol level of the patient. It is interesting to compare the large amount of data on the value and safety of the statins with the much more limited and less convincing data on antioxidant vitamins.     

Effect of medium composition,genotype and age of explant on the regeneration of hexaploid plants from endosperm culture of tetraploid kiwiberry (Actinidia arguta)

Plant Cell, Tissue and Organ Culture (PCTOC) - Endosperm, an ephemeral and storage tissue, serves as a source of nutrition and protection during embryo development and germination. It can be used...