Effect of tolvaptan on acute heart failure with hyponatremia--a randomized, double blind, controlled clinical trial.

OBJECTIVES: To assess the efficacy of tolvaptan in acute heart failure with hyponatremia using a randomized double-blinded placebo-controlled study design. BACKGROUND: Tolvaptan is a selective vasopressin receptor 2 antagonist. There are no published clinical trials on the utility of tolvaptan in acute heart failure with hyponatremia in the Indian population. METHODS: After screening and informed consent, 51 HF patients with hyponatremia were randomized using computer-generated randomization sequence to receive placebo or 15mg of tolvaptan for 5 days along with conventional medical therapy. The patient's perception of dyspnea using Likert score and the plasma sodium was measured at baseline and for the next 4 days. RESULTS: There was a mean improvement in sodium concentration by 5mEq/L (p=0.001) in patients receiving tolvaptan, whereas no significant improvement was seen in the placebo group (p=0.33). Significant improvement in Likert score was observed in both the groups (p=0.001), even though there was no difference between both the groups. Dry mouth and thirst were the most commonly occurring adverse effects observed in both the groups. There were no significant hemodynamic changes with tolvaptan therapy. CONCLUSION: Tolvaptan at a dose of 15mg is effective in reversing hyponatremia in acute heart failure and may be a suitable option in these patients.

Value of pentraxin-3 and galectin-3 in acute coronary syndrome: a short-term prospective cohort study.

BACKGROUND: Acute coronary syndrome (ACS) continues to be a leading cause of morbidity and mortality worldwide. Galectin-3 and pentraxin-3 are two prognostic biomarkers that have been studied in heart failure (HF). However, there are limited data on these biomarkers in the ACS population. The objective of the study was to determine the variables that are most affected by high concentrations of pentraxin-3 and galectin-3, and the influence they have on outcomes of all-cause mortality in patients with ACS. METHODS: We included a total of 160 patients [ST elevation myocardial infarction (STEMI),n = 64; non STEMI/unstable angina (NSTEMI/UA), n = 38; and control subjects with chronic stable angina (CSA)/microvascular angina (MVA) n = 58]. Plasma pentraxin-3 and galectin-3 levels were assessed from these patients at the time of hospital admission. Major adverse cardiovascular events including all-cause mortality, rehospitalizations and coronary artery bypass graft surgery (CABG) were assessed at 6 months. RESULTS: The median concentration of pentraxin-3 and galectin-3 were significantly higher in STEMI than in NSTEMI patients (p < 0.005) or controls (p < 0.005). Greater numbers of deaths (4 versus 0) were observed in STEMI patients with higher levels of these biomarkers. In addition, ACS patients with high levels of pentraxin-3 and galectin-3 had lower left ventricular ejection fraction (LVEF) (p < 0.005), and a moderate correlation was observed between LVEF and pentraxin-3 levels (r = -0.45, p < 0.005). Patients with higher galectin-3 levels were also observed to have a lower estimated glomerular fraction rate (eGFR), and a moderate correlation was observed between them (r = -0.34, p < 0.005). CONCLUSION: Pentraxin-3 and galectin-3 hold much promise in the ACS population as prognostic biomarkers.

Riociguat: Something new in pulmonary hypertension therapeutics?

Pulmonary hypertension (PH) continues to be a disease that is associated with woeful outcomes. The search for an ideal drug molecule for PH led to the discovery of riociguat, which is a first-in-class drug molecule that activates soluble guanylate cyclase. We conducted a systematic literature search using databases such as PubMed, Science Direct, Springer, Cochrane Reviews and Google Scholar to gather evidence generated from published clinical trials on the efficacy, safety, pharmacokinetics and regulatory status of riociguat. CHEST-1 and the PATENT-1 were phase-3 pivotal clinical trials that showed that riociguat was able to significantly improve the 6-min walk distance with 16 weeks of therapy as compared with the placebo arm. The drug also showed improvement in secondary outcome measures such as improvement in the pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide levels, World Health Organization functional class, time to clinical worsening and Borg dyspnea score. The drug had a modest safety profile, with hypotension being the most bothersome adverse effect. These findings led to various regulatory agencies around the world granting approval for riociguat for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The entry of a new class of drug for PAH and CTEPH therapy portends some hope for patients with a disease that is traditionally linked with a poor prognosis.

Evaluation of Endothelial and Platelet Derived Microparticles in Patients with Acute Coronary Syndrome.

BACKGROUND: Microparticles (MP) are a nuclear fragments of membrane released by the damaged cell during stress. Elevated levels of MP have been found in patients with acute coronary syndrome (ACS) owing to the damage in the endothelium. AIM: To determine if the levels of endothelial and platelet microparticles (EMP & PMP) in patients with ACS influenced the severity of the disease. MATERIALS AND METHODS: This was a prospective cohort study performed in 63 ACS patients (ST elevation myocardial infarction- STEMI-28, non ST elevation myocardial infarction -NSTEMI-35). After obtaining consent, blood samples were collected from the patients and processed by flow cytometry. RESULTS: The NSTEMI group had higher levels of EMP {792.11(327.59-1661.49) vs 300.35 (176.3-550.46), p=0.001} and PMP {218.87(86.65-439.77) vs 114.45(50.34-196.75), p= 0.007} as compared to the STEMI group. However, it was found that the EMP (r=-0.438, p=0.001) and PMP (r= -0.316, p=0.024) negatively correlated with Global Registry of Acute Coronary Events score (GRACE in-hospital score) for the entire cohort. CONCLUSION: The levels of microparticles are elevated in ACS patients and may reflect a protective effect in patients with acute coronary syndrome.

Utility of galectin-3 as a prognostic biomarker in heart failure: where do we stand?

BACKGROUND: Heart failure (HF) continues to be an illness of daunting proportions with a four- year mortality touching 50%. Biomarkers for prognosticating patients with heart failure have generated immense interest. Several studies have been conducted on a novel biomarker, galectin-3 to assess its prognostic effect in heart failure populations. However, the studies have generated conflicting results. Hence a systematic review was done to assess the utility of galectin-3 as a prognostic biomarker in HF. DESIGN: This study was a systematic review. METHODS: A literature search was done using terms 'galectin-3 and heart' and 'galectin-3 and heart failure' in MEDLINE, Science Direct, Scopus, Springer Link, Cochrane Library and Google Scholar for original articles using a predefined inclusion/exclusion criteria. RESULTS: Altogether 27 original articles were selected for the systematic review. Multivariate analysis showed galectin-3 to be ineffective in predicting all-cause mortality and cardiovascular mortality especially under the influence of factors such as estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF) and N-terminal pro-B-type natriuretic peptide (NTproBNP). Galectin-3 was not found to be superior to NTproBNP, sST2, GDF-15 or C-reactive protein (CRP) as a predictor of mortality. However the combination of natriuretic peptides and galectin-3 has been observed to be superior in predicting mortality compared to either of the biomarkers alone. The role of galectin-3 in remodelling has not been conclusively proven as seen in earlier pre-clinical studies. CONCLUSION: The current weight of evidence does not suggest galectin-3 to be a predictor of mortality. However, assessment of galectin-3 in a multi-biomarker panel may have a distinct advantage in prognosticating patients with heart failure.

Novel drug targets in clinical development for heart failure.

BACKGROUND: Heart Failure continues to be a leading cause of mortality and morbidity worldwide. The dismal prognosis of patients in acute heart failure (AHF) can be altered only by exploring novel drug molecules. Although the treatment for chronic heart failure (CHF) has seen remarkable progress, there is still a need to develop molecules that could improve the long-term survival outcomes. PURPOSE: To review the drug targets for acute and chronic heart failure and the molecules acting on these targets. METHODS: The article discusses on the mechanism of how the potential drug targets can be modulated to alter the pathophysiological processes in heart failure. Current evidence on molecules acting on these targets has also been described from published literature using the PubMed and Clinical Trials.gov databases. RESULTS: Some of the molecules that are currently being explored for AHF includeomecamtiv mecarbil which activates cardiac myosin ATPase, istaroxime an ionotropicagent that activates SERCA2a pump activity, ularitide and carperitide which are ANP(atrial natriuretic peptide) analogues and recombinant relaxin. Some of the targets forCHF include stabilization of ryanodine receptors, renin inhibition, neprilysin inhibition, neuregulins and SERCA2a gene therapy. CONCLUSION: Clinical trials in heart failure must be designed to minimize the risk of "drug failures." Nevertheless, it is hoped that in the days to come, drugs with superior efficacy and safety will eventually be produced from the surge of molecules that are in the pipeline.

New and emerging drug molecules against obesity.

Obesity has become a growing pandemic of alarming proportions in the developed and developing countries over the last few decades. The most perturbing fact regarding obesity is the increased predisposition for coronary artery disease, congestive heart failure and sudden cardiac death. The modest efficacy of current anti-obesity agents such as orlistat and the increasing withdrawals of several anti-obesity agents such as sibutramine, rimonabant have led to huge gaps in the pharmacotherapy of obesity. Lorcaserin and Phentermine-topiramate combination (phen-top) are two drugs approved by US FDA in 2012. Lorcaserin, a 5HT2C agonist has moderate efficacy with an acceptable safety profile. Clinical trials with Phen-top have shown a reasonable efficacy but at the cost of risks such as teratogenicity and psychiatric disturbances. Cetilistat, a lipase inhibitor is claimed to have superior safety profile to orlistat and is in phase 3 clinical trials. Other promising anti-obesity molecules acting on the gut which are in clinical trials include exenatide and liraglutide. Drugs which act on the monoaminergic and opioid systems include bupropion-naltrexone and bupropion-zonisamide. Other novel first-in-class drugs which have been explored and have limited success in early clinical development include velneperit, tesofensine, and beloranib. Tesofensine is a triple monoamine re-uptake inhibitor, velneperit acts as a neuropeptide Y5 receptor antagonist and beloranib is a methionine amino peptidase 2 inhibitor. Novel targets such as histamine H3 receptor, VEGF, matrix-metalloproteinase, sirtuin receptors are also being investigated. This review is an attempt to describe the new and emerging molecules that are in clinical development for obesity.