[show abstract][hide abstract] ABSTRACT: The IUPHAR database (IUPHAR-DB) integrates peer-reviewed pharmacological, chemical, genetic, functional and anatomical information on the 354 nonsensory G protein-coupled receptors (GPCRs), 71 ligand-gated ion channel subunits and 141 voltage-gated-like ion channel subunits encoded by the human, rat and mouse genomes. These genes represent the targets of approximately one-third of currently approved drugs and are a major focus of drug discovery and development programs in the pharmaceutical industry. IUPHAR-DB provides a comprehensive description of the genes and their functions, with information on protein structure and interactions, ligands, expression patterns, signaling mechanisms, functional assays and biologically important receptor variants (e.g. single nucleotide polymorphisms and splice variants). In addition, the phenotypes resulting from altered gene expression (e.g. in genetically altered animals or in human genetic disorders) are described. The content of the database is peer reviewed by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR); the data are provided through manual curation of the primary literature by a network of over 60 subcommittees of NC-IUPHAR. Links to other bioinformatics resources, such as NCBI, Uniprot, HGNC and the rat and mouse genome databases are provided. IUPHAR-DB is freely available at http://www.iuphar-db.org.
Nucleic Acids Research 11/2008; 37(Database issue):D680-5. · 8.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial. The disappointment was heightened by the latter study being viewed as a most promising compound for stroke drug development program based on the preclinical data. Since the SAINT I/II development program included many of the STAIR (Stroke Therapy Academic Industry Round table) guidelines, yet have still failed to achieve the expected efficacy, there is a clear need to continue and analyze the path forward for stroke drug discovery. To this end, this review calls for a consortium approach including academia, government (FDA/NIH), and pharmaceutical industry partnerships to define this path. It is also imperative that more attention is given to the evolving discipline of Translational Medicine. A key issue in this respect is the need to devote more attention to the characteristics of the drug candidate nature-target interaction, and its relationship to pharmacodynamic treatment end points. It is equally important that efforts are spent to prove that phenotypic outcomes are linked to the purported mechanism of action of the compound. Development of technologies that allows a better assessment of these parameters, especially in in vivo models are paramount. Finally, rational patient selection and new outcome scales tailored in an adaptive design model must be evaluated.
[show abstract][hide abstract] ABSTRACT: This perspective on discontinued cardiovascular drugs is the first in a series of papers on drugs dropped from clinical development in 2006. The compounds described in this perspective have been removed from development in various stages and for different reasons. This paper hereby provides a translational medicine perspective on these compounds based on information available through the Pharmaprojects pipeline database. In particular, potential gaps in the pipeline, due to a lack of biomarkers and translational medicine perspectives are emphasized.
[show abstract][hide abstract] ABSTRACT: Carvedilol is a multiple action drug that blocks β1-, β2- and α1- adrenoceptors, and has potent antioxidant properties. Carvedilol is the first drug of its kind to be approved for the treatment of congestive heart failure, and is now the standard of care for this devastating disease. The discovery and development of carvedilol encountered an adverse regulatory climate, skepticism by the cardiology community and hesitance by the company, and in the early 1990s, the fate of the drug was uncertain. Nonetheless, in the largest heart failure study conducted up until that point, carvedilol produced marked reductions in morbidity and mortality, and has given new hope to patients afflicted with congestive heart failure. The story behind carvedilol contains important observations and lessons for scientists, regulators and physicians.
Expert Opinion on Drug Discovery 06/2006; 1(1):85-89. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Carvedilol, a selective α1 and non-selective β-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to the efficacy of carvedilol cardioprotection, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a β1 selective adrenoceptor antagonist, bisoprolol. Carvedilol (1 mg/kg) or bisoprolol (1 mg/kg) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (45 min) and reperfusion (240 min) resulted in significant increases in left ventricular end diastolic pressure, large myocardial infarction (64.7±2.6% of area-at-risk) and a marked increase in myeloperoxidase activity (64±14 U/g protein in area-at-risk). Carvedilol treatment resulted in sustained reduction of the pressure-rate-index and significantly smaller infarcts (30±2.9, P<0.01 vs. vehicle) as well as decreased myeloperoxidase activity (26±11 U/g protein in area-at-risk, P<0.01 vs. vehicle). Administration of bisoprolol at 1 mg/kg resulted in a pressure-rate-index comparable to that of carvedilol and also decreased infarct size (48.4±2.5%, P<0.001 vs. vehicle, P<0.05 vs. carvedilol), although to a significantly lesser extent than that observed with carvedilol. Treatment with bisoprolol failed to reduce myeloperoxidase activity in the ischemic myocardial tissue. In addition, carvedilol, but not bisoprolol, markedly decreased cardiac membrane lipid peroxidation measured by thiobarbituric acid formation. Taken together, this study suggests that the superior cardioprotection of carvedilol over bisoprolol is possibly the result of carvedilol's antioxidant and anti-neutrophil effects, not its hemodynamic properties.
European Journal of Pharmacology 10/2000; · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic heart failure (CHF) is a progressive disease of diverse origins, multiple mechanisms and complex therapeutic strategies. Contemporary drugs aimed to alleviate the progression of CHF attempt to improve volume/salt loads (edema), correct circulatory aberrations (vascular constriction, low cardiac output) and protect the heart from direct toxic effects of neurohormonal systems such as the renin-angiotensin-aldosterone and the sympathetic nervous system. Most recently (1997) carvedilol (Coreg), a vasodilating beta-adrenergic blocking agent was approved for treatment of heart failure thereby introducing the first beta-blocking agent to heart failure medicine. Carvedilol is a multiple action, non-specific - and 1-adrenergic receptor blocker and a potent antioxidant agent. Carvedilol has unique antioxidant properties confirmed in physico-chemical, biochemical, cellular and in vivo animal studies. In this paper, the role of oxidative stress in heart failure is reviewed in reference to the antioxidant actions of carvedilol and its possible contribution to the overall efficacy of the drug in reducing morbidity and mortality in heart failure patients.
[show abstract][hide abstract] ABSTRACT: Stress-activated protein kinase (SAPK/JNK) has been implicated in the signaling pathway that leads to cell death. Carvedilol, a new vasodilating β-adrenoceptor antagonist with potent antioxidant activity, has been shown to convey a high degree of cardioprotection in a variety of experimental models of myocardial ischemia as well as in patients with congestive heart failure. The present study was designed to explore whether the cardioprotective effects of carvedilol involve inhibition of SAPK activation. Ex vivo ischemia (30 min)–reperfusion (60–120 min) of the rabbit heart resulted in 67% reduction of pressure–rate product, 45% necrosis of left ventricular tissue and 62% loss of myocardial creatine kinase (P<0.01 vs. basal). SAPK levels in the perfused hearts increased markedly following reperfusion (5.6-fold increase, P<0.01 vs. basal). Carvedilol, at 10 μM, administered at time of reperfusion, enhanced recovery of pressure–rate product by 61%, reduced necrotic size by 65% and decreased myocardial creatine kinase loss by 62% (P<0.01 vs. vehicle). Carvedilol also inhibited reperfusion-induced activation of SAPK by 61% (P<0.01 vs. vehicle). Carvedilol, at 1 μM, displayed a trend of cardioprotection and inhibition of SAPK activation. Our results suggest that SAPK may play a role in ischemia/reperfusion-induced cardiac injury and inhibition of SAPK activation by carvedilol may contribute to its cardioprotective effects.
European Journal of Pharmacology 04/1998; · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Carvedilol is a third-generation vasodilating β-blocker initially approved for the treatment of hypertension. It lowers systemic arterial blood pressure without causing reflex tachycardia and preserves renal function. More recently, carvedilol has been shown to reduce morbidity and mortality in patients with congestive heart failure. This reduction may occur in part via β-blockade and α1-adrenoceptor blockade, the latter resulting in vasodilation. Importantly, carvedilol and several of its metabolites are potent antioxidants that may inhibit the oxidation of norepinephrine and the subsequent formation of toxic intermediates, such as reactive free radicals in the myocardium. As a result, carvedilol inhibits the expression of certain genes involved in myocardial damage, such as intracellular adhesion molecule-1, free-radical-induced activation of transcription factors, and programmed cell death or apoptosis. In this respect, carvedilol represents a new therapy for the treatment of hypertension and congestive heart failure and combines, in one molecule, a number of potentially beneficial properties.