Identification of potential novel bioaccumulative and persistent chemicals in sediments from Ontario (Canada) using scripting approaches with GC×GC-TOF MS analysis.

This work describes a single and fast approach using a filtering script as a means of prioritizing sample processing of data acquired by GC×GC-TOF MS for the identification of potentially novel persistent and bioaccumulative halogenated chemicals. The proposed script is based on the recognition of a generic halogenated isotope cluster pattern that allows for the simultaneous detection of chlorinated, brominated, or mixed halogen-substituted compounds in a single classification. Once developed, the script was applied to the identification of organohalogens in stream sediments collected across the southern region of Ontario (Canada).

IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels.

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.

Discontinued drugs in 2006: cardiovascular drugs translational medicine perspective.

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.

Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke.

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.

Why has R&D productivity declined in the pharmaceutical industry?

Productivity in pharmaceutical R&D has been on the decline for the past several years, and much has been written on the subject. The causes for the decline in productivity are many and complex. Some of the causes are external to R&D and therefore difficult to address, such as growing regulatory conservatism and lack of international regulatory harmonisation.

Carvedilol case history: the discovery and development of the first β-blocker for the treatment of congestive heart failure.

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.

Pharmacology of the angiotensin II receptor antagonist, eprosartan.

The non-peptide angiotensin II receptor antagonists represent a new class of drugs with demonstrated efficacy in the treatment of hypertension. Eprosartan is a potent, orally active AT(1) receptor antagonist which is chemically distinct from losartan and other non-peptide angiotensin II receptor antagonists. Eprosartan has a high affinity for the angiotensin II AT(1) receptor, but does not interact with the AT(2) receptor, adrenergic receptors or other receptors involved in cardiovascular regulation.

Known by the society he keeps: an interview with Robert Ruffolo.

By his own admission, Robert R. Ruffolo, Head of Research and Development at Wyeth-Ayerst, is a bit of a nerd. Opting to spend seven nights per week with his textbooks at the expense of all else, he earned his pharmacy degree summa cum laude, and his PhD in pharmacology in just over three years.

Rabbit alpha2-adrenoceptors: both platelets and adipocytes have alpha2A-pharmacology.

The recombinant alpha2-adrenoceptors, designated as alpha2a and alpha2d, have highly similar amino acid sequences, but distinct pharmacological properties. It has been suggested that these two receptor subtypes are species orthologs, since the alpha2-adrenoceptors of a given species have pharmacological characteristics corresponding to either the alpha2a- (human, pig) or alpha2d- (rat, mouse, guinea pig, cow) adrenoceptor. Radioligand binding assays in rabbit adipocyte suggest alpha2D-adrenoceptor pharmacology.

Variations in disparate regions of the murine coronavirus spike protein impact the initiation of membrane fusion.

The prototype JHM strain of murine hepatitis virus (MHV) is an enveloped, RNA-containing coronavirus that has been selected in vivo for extreme neurovirulence. This virus encodes spike (S) glycoproteins that are extraordinarily effective mediators of intercellular membrane fusion, unique in their ability to initiate fusion even without prior interaction with the primary MHV receptor, a murine carcinoembryonic antigen-related cell adhesion molecule (CEACAM). In considering the possible role of this hyperactive membrane fusion activity in neurovirulence, we discovered that the growth of JHM in tissue culture selected for variants that had lost murine CEACAM-independent fusion activity.

Comparison of bisoprolol and carvedilol cardioprotection in a rabbit ischemia and reperfusion model.

Carvedilol, a selective alpha(1) and non-selective beta-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 beta(1) selective adrenoceptor antagonist, bisoprolol. Carvedilol (1 mg/kg) or bisoprolol (1 mg/kg) was given intravenously 5 min before reperfusion.

A comparison of carvedilol and metoprolol antioxidant activities in vitro.

Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension. angina, and congestive heart failure. Metoprolol is a beta1-selective adrenoceptor antagonist.

Drug discovery in the next millennium.

Selection and validation of novel molecular targets have become of paramount importance in light of the plethora of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. This review addresses these technological advances as well as several new areas that have been created by necessity to deal with this new paradigm, such as bioinformatics, cheminformatics, and functional genomics.

Phosphorescent oxygen sensors utilizing sulfur-nitrogen-phosphorous polymer matrixes: synthesis, characterization, and evaluation of poly(thionylphosphazene)-b-poly(tetrahydrofuran) block copolymers.

We examine the use of thionylphosphazene-based block copolymers as matrixes for oxygen sensor applications. Poly(aminothionylphosphazene)-b-poly(tetrahydrofuran) (PATPy-PTHFx) block copolymers were prepared via reaction of ring-opened poly(chlorothionylphosphazene) with THF and subsequently with excess n-butylamine (to form PBATPy-PTHFx) or methylamine (to form PMATPy-PTHFx). The block copolymers were characterized by NMR, gel permeation chromatography, and differential scanning calorimetry.

Pharmacology of eprosartan, an angiotensin II receptor antagonist: exploring hypotheses from clinical data.

Selective blockade of the angiotensin II AT1 receptor represents a novel mechanism for interrupting the renin-angiotensin system without altering the potential benefits of AT2 receptor stimulation. This selective inhibition produces none of the disadvantages associated with reduced bradykinin metabolism and angiotensin II generated by non-angiotensin-converting enzyme pathways. Eprosartan is a potent (1.

Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure.

Systolic hypertension is a major risk factor for cardiovascular disease. The determinants of systolic blood pressure are peripheral resistance and arterial compliance. Arterial vasoconstriction, vascular growth and fluid retention, induced by the renin-angiotensin system directly or indirectly by enhancing sympathetic nervous system activity, are important factors in increasing peripheral resistance, decreasing arterial compliance and, consequently, elevating systolic blood pressure.

Apoptosis: a potential target for discovering novel therapies for cardiovascular diseases.

The realization that apoptosis is genetically programmed raises the exciting prospect that modulating apoptosis may provide novel approaches for treatment of cardiovascular diseases in which apoptosis has been demonstrated. Low molecular weight inhibitors of caspases and mitogen-activated protein kinases have been evaluated, with promising results in a variety of cardiovascular apoptotic models.

Effects of alpha1-adrenoceptor antagonists on agonist and tilt-induced changes in blood pressure: relationships to uroselectivity.

We evaluated the uroselectivity of a series of alpha1-adrenoceptor antagonists by comparing their potency against phenylephrine-induced increases in urethral perfusion pressure and diastolic blood pressure in the anesthetized rabbit and pithed rat. In the rabbit, Rec 15/2739 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl -4H-1-benzopyran-8-carboxamide) as well as analogs with a chlorine substituent on the methoxyphenyl ring (Rec 15/2869) or this substituent combined with the replacement of the phenyl substituent on the pyran ring by cyclohexyl (Rec 15/3011) were 2-6-fold more potent against the urethral vs. vascular response to phenylephrine.

Adrenoceptor pharmacology: urogenital applications.

Although the selective alpha1-adrenoceptor antagonists were initially developed as antihypertensive drugs, and they are still utilized for this indication, the alpha1-adrenoceptor blockers are now used extensively for the symptomatic treatment of benign prostatic hyperplasia (BPH). As a result, a number of new drugs in this class have been specifically developed for use in BPH. The utility of alpha1-adrenoceptor antagonists in BPH derives from the observation, made several decades ago, that the irreversible, alpha1- adrenoceptor selective antagonist phenoxybenzamine, blocked the contractile activity of norepinephrine in isolated strips of rat or human prostate.

In vitro and in vivo characterization of intrinsic sympathomimetic activity in normal and heart failure rats.

Clinical studies conducted with carvedilol suggest that beta-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many beta-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic sympathomimetic activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes.

Molecular basis for the stereoselective interactions of catecholamines with alpha-adrenoceptors.

The catecholamines were found to inhibit the binding of the alpha 2-adrenoceptor agonist, [3H]-clonidine, to the recombinant wild type alpha 2a-adrenoceptor (Table 1) with potencies that are consistent with their functional activity in alpha 2-adrenoceptor test systems [6,7]. Mutation of Ser165 to alanine had no significant effect (less than 2-fold) on the affinity of any of the catecholamines for the alpha 2a-adrenoceptor, and in particular, the ratios of affinities between the corresponding (-)- and (+)-enantiomers of the catecholamines were not altered by the point mutation at Ser165. These findings indicate clearly that Ser165, in contrast to predictions made by molecular modeling, plays little if any role in the binding of the catecholamines in general, and cannot be involved in the attachment of the beta-hydroxyl group to the alpha 2a-adrenoceptor.

Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure.

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.

SB 211475, a metabolite of carvedilol, reduces infarct size after myocardial ischemic and reperfusion injury in rabbits.

The aim of this study was to investigate the effect of SB 211475, a metabolite of carvedilol with weak alpha1-adrenoceptor antagonism and antioxidant effect, on myocardial reperfusion injury and infarct size in anesthetized rabbits. The rabbits were subjected to 60 min of regional myocardial ischemia and 180 min of reperfusion. SB 211475 was administered either as 0.