Quantitative determination of oxytocin receptor antagonist atosiban in rat plasma by liquid chromatography-tandem mass spectrometry.

A kinetic study of atosiban was conducted following repeated intravenous administration in Wistar rats. Sample analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) following full validation of an in-house method. Eptifibatide, a cyclic peptide, was used as an internal standard (IS). The analyte and internal standard were extracted using solid phase extraction (SPE) method. Chromatographic separation was carried out using an ACE C18 5 microm 50 mm x 4.6 mm column with gradient elution. Mass spectrometric detection was performed using TSQ Quantum ultra AM. The lower limit of quantification was 0.01 microg/ml when 100 microl rat plasma was used. Plasma concentrations of atosiban were measured at 0 (pre-dose), 2, 15, 30, 45, 60, 120 min at the dosage levels of 0.125 mg/kg (low dose), 0.250 mg/kg (mid dose), and 0.500 mg/kg (high dose), respectively. Atosiban plasma concentration measured at Day 1 showed mean peak atosiban concentration (C(max)) 0.40, 0.57, 1.95 microg/ml for low, mid and high dose treated animals and mean peak concentration on Day 28 was 0.41, 0.88, 1.31microg/ml on Day 28 for low, mid and high dose treated animals.

Ameliorative effect of combination of fenofibrate and rosiglitazone in pressure overload-induced cardiac hypertrophy in rats.

The present study has been designed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor (PPAR)alpha agonist, rosiglitazone, a PPARgamma agonist and the combination of both fenofibrate and rosiglitazone in partial abdominal aortic constriction (PAAC)-induced pathological cardiac hypertrophy in rats. Rats were subjected to PAAC for 4 weeks to produce pathological cardiac hypertrophy. The fenofibrate (3 mg/kg day(-1), p.o.), rosiglitazone (3 mg/kg day(-1), p.o.) and the combination of both fenofibrate (3 mg/kg day(-1), p.o.) and rosiglitazone (3 mg/kg day(-1), p.o.) were administered 3 days before PAAC and continued for 4 weeks after PAAC. The development of cardiac hypertrophy was assessed in terms of measuring ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content and LV collagen content. Further, the collagen accumulation in left ventricle was analyzed using picrosirius red staining. Moreover, the cross-sectional area (CSA) of cardiomyocytes was assessed using hematoxylin and eosin staining and measured using a NIH Scion image analyzer. The PAAC produced cardiac hypertrophy by increasing LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. However, treatment with fenofibrate and rosiglitazone either alone or in combination significantly attenuated PAAC-induced increase in LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. The combination of fenofibrate and rosiglitazone was more effective in attenuating the PAAC-induced cardiac hypertrophy than either drug alone. Thus, it may be concluded that dual activation of PPARalpha and PPARgamma may provide synergistic benefits in preventing the development of pathological cardiac hypertrophy.

PPAR ligands: are they potential agents for cardiovascular disorders?

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. The PPAR subfamily consists of three members: PPARalpha, PPARgamma, and PPARbeta/delta. Fibrates are acting via PPARalpha, and they are used as lipid-lowering agents. PPARgamma agonists reduce insulin resistance and have been used in the treatment of type 2 diabetes. As the knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including a novel role in the management of cardiovascular disorders (CVD). PPARalpha/gamma dual agonists are currently under development and hold considerable promise in the management of type 2 diabetes and provide an effective therapeutic option for treating the multifactorial components of CVD. Several experimental and clinical evidences elucidated the beneficial effects of PPAR ligands in prevention and treatment of various CVD. However, PPARalpha and PPARgamma agonists have been shown to be proinflammatory and proatherogenic in a few studies. Further, PPARgamma ligands have been noted to be involved in the pathogenesis of congestive heart failure. These controversial results obtained from a few studies created further complication in understanding the role of PPARs. The function of PPARdelta and its potential as a cardiovascular therapeutic target are currently under investigation. The present review focuses on the merits and limitations of PPAR agonists with regard to their use in CVD.

PPAR dual agonists: are they opening Pandora's Box?

Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in diabetic cardiovascular complications. Moreover, the newly developed PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future.