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Biomedical subjects

Bernard Masereel

Publications and source records attributed to Bernard Masereel.

28 records · Page 2Linked to original sources
PubMed2003

Effects of endotoxic shock on right ventricular systolic function and mechanical efficiency.

OBJECTIVE: To investigate the effects of endotoxin infusion on right ventricular (RV) systolic function and mechanical efficiency. METHODS: Six anesthetized pigs (Endo group) received a 0.5 mg/kg endotoxin infusion over 30 min and were compared with six other anesthetized pigs (Control group) receiving placebo for 5 h. RV pressure-volume (PV) loops were obtained by the conductance catheter technique and pulmonary artery flow and pressure were measured with high-fidelity transducers. RESULTS: RV adaptation to increased afterload during the early phase of endotoxin-induced pulmonary hypertension (T30) was obtained by both homeometric and hetereometric regulations: the slope of the end-systolic PV relationship of the right ventricle increased from 1.4+/-0.2 mmHg/ml to 2.9+/-0.4 mmHg/ml (P<0.05) and RV end-diastolic volume increased from 56+/-6 ml to 64+/-11 ml (P<0.05). Consequently, right ventricular-vascular coupling was maintained at a maximum efficiency. Ninety minutes later (T120), facing the same increased afterload, the right ventricle failed to maintain its contractility to such an elevated level and, as a consequence, right ventricular-vascular uncoupling occurred. PV loop area, which is known to be highly correlated with oxygen myocardial consumption, increased from 1154+/-127 mmHg/ml (T0) to 1798+/-122 mmHg/ml (T180) (P<0.05) while RV mechanical efficiency decreased from 63+/-2% (T0) to 45+/-5% (T270) (P<0.05). CONCLUSIONS: In the very early phase of endotoxinic shock, right ventricular-vascular coupling is preserved by an increase in RV contractility. Later, myocardial oxygen consumption and energetic cost of RV contractility are increased, as evidenced by the decrease in RV efficiency, and right ventricular-vascular uncoupling occurs. Therefore, therapies aiming at restoring right ventricular-vascular coupling in endotoxic shock should attempt to increase RV contractility and to decrease RV afterload but also to preserve RV mechanical efficiency.

Animals↗
PubMed2002

In vitro and in vivo effects of new insulin releasing agents.

The present study aimed at characterizing in vitro and in vivo the effects of BM 208 (N-[4-(5-chloro-2-methoxybenzamidoethyl)benzenesulfonyl]-N'-cyano-N"-cyclohexylguanidine) and BM 225 (1-[4-(5-chloro-2-methoxybenzamidoethyl)benzene sulfonamido]-1-cyclohexylamino-2-nitroethylene); two new isosteres of the hypoglycemic sulfonylurea glibenclamide. In rat pancreatic islets perifused at close to normal (8.3mM) D-glucose concentration, both BM 208 and BM 225 (10 and 25 microM) increased 45Ca outflow and insulin release. The compounds did not affect the 45Ca outflow rate from islets exposed to Ca(2+)-free media. In single pancreatic islet cells loaded with the fluorescent Ca(2+) indicator fura-2 and incubated in the presence of 8.3mM glucose, BM 208 and BM 225 raised the [Ca(2+)](i). All these findings indicate that, in islet cells exposed to a physiological concentration of D-glucose, the secretory capacity of the new glibenclamide isosteres is related to a facilitation of Ca(2+) entry. The potency and duration of action of BM 225 was, however, more pronounced than that of BM 208. Successive additions of BM 208 provoked repeated increments in 45Ca outflow and insulin release, without evidence of tachyphylaxis. Lastly, intraperitoneal injection of BM 208 and BM 225 to fed rats lowered plasma glucose concentration in a dose-dependent manner. BM 225 was more potent and acting faster than BM 208. Our results indicate that appropriate structural modification can generate isosteres of glibenclamide with different features and activity profiles.

Animals↗
PubMed2002

Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties.

A series of aromatic/heterocyclic sulfonamides incorporating valproyl moieties were prepared to design antiepileptic compounds possessing in their structure two moieties known to induce such a pharmacological activity: valproic acid, one of the most widely used antiepileptic drugs, and the sulfonamide residue included in acetazolamide and topiramate, two carbonic anhydrase inhibitors with antiepileptic properties. Some of these derivatives showed very high inhibitory potency against three carbonic anhydrase (CA) isozymes, such as CA I, CA II, and CA IV, involved in important physiological processes. Topiramate, a recently developed antiepileptic drug possessing a sulfamate moiety, also shares this property, although earlier literature data reported this compound to be a weak-moderate CA I, II, and IV inhibitor. The valproyl derivative of acetazolamide (5-valproylamido-1,3,4-thiadiazole-2-sulfonamide, 6M) was one of the best hCA I and hCA II inhibitor in the series and exhibited very strong anticonvulsant properties in an MES test in mice. In consequence, other 1,3,4-thiadiazolesulfonamide derivatives possessing potent CA inhibitory properties and substituted with different alkyl/arylcarboxamido/sulfonamido/ureido moieties in the 5 position have been investigated for their anticonvulsant effects in the same animal model. It was observed that some lipophilic derivatives, such as 5-benzoylamido-, 5-toluenesulfonylamido-, 5-adamantylcarboxamido-, and 5-pivaloylamido-1,3,4-thiadiazole-2-sulfonamide, show promising in vivo anticonvulsant properties and that these compounds may be considered as interesting leads for developing anticonvulsant or selective cerebrovasodilator drugs.

Acetazolamide↗
PubMed2002

Thromboxane A2 inhibition: therapeutic potential in bronchial asthma.

Bronchial asthma is a disease defined by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. In addition to histamine and acetylcholine, recent studies have emphasized the role of arachidonic acid metabolites (leukotrienes, prostaglandins and thromboxane A(2)) in the pathogenesis of asthma. Among these mediators, thromboxane A(2) (TXA(2)) has attracted attention as an important mediator in the pathophysiology of asthma because of its potent bronchoconstrictive activity. Thromboxane A(2) is believed to be involved not only in late asthmatic responses but also in bronchial hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA(2) include TXA(2) receptor antagonism and thromboxane synthase inhibition. Results of double-blind, placebo-controlled clinical trials have proven the efficacies of the thromboxane receptor antagonist seratrodast and the thromboxane synthase inhibitor ozagrel in the treatment of patients with asthma. Seratrodast and ozagrel are available in Japan for the treatment of asthma. Ramatroban, another thromboxane receptor antagonist, is currently under phase III clinical evaluation in Europe and Japan for the treatment of asthma. The pharmacological profiles of the thromboxane modulators may be improved by combination with leukotriene D(4) receptor antagonists. A multi-pathway inhibitory agent such as YM 158, which is a novel orally active dual antagonist for leukotriene D(4) and thromboxane A(2 )receptors, may have potent therapeutic effects in the treatment of bronchial asthma. Large scale clinical trials are necessary to further define the role of thromboxane modulators in the treatment of patients with asthma.

Anti-Asthmatic Agents↗
PubMed2002

Synthesis and biological evaluation of aroylguanidines related to amiloride as inhibitors of the human platelet Na(+)/H(+) exchanger.

Pyridine and benzene bioisosteres of amiloride were synthesized and evaluated for their inhibitory potency against the sodium-hydrogen exchanger (NHE) involved in intracellular pH regulation. The inhibition of NHE was determined by using the platelet swelling assay (PSA) in which the swelling of human platelets was induced by their incubation in an acid buffer (pH 6.7). Additionally, the inhibitory potency of the most active compounds was assessed by measuring the inhibition of the EIPA-sensitive (22)Na(+) uptake (UIA) by human platelets after intracellular acidosis. The results indicated that several benzene derivatives and compounds bearing an carbonylguanidine moiety in the meta position of the pyridine nitrogen were much more potent than amiloride (PSA:IC(50)=43.5 microM; UIA:IC(50)=100.1 microM), but less than EIPA, a pyrazine NHE inhibitor (PSA:IC(50)=0.08 microM; UIA:IC(50)=0.5 microM). In both biological assays (2-amino-5-bromo-pyridine-3-carbonyl)guanidine (32) was the most active molecule (PSA: IC(50)=0.8 microM, UIA : IC(50)=0.8 microM). Our investigations demonstrated that the replacement of the pyrazine ring of amiloride by a pyridine or a phenyl ring improved the NHE inhibitory potency (phenyl >pyridine >pyrazine).

Amiloride↗
PubMed2002

Therapeutic potential of thromboxane inhibitors in asthma.

This paper reviews the role of thromboxane A(2) (TXA(2)) in the pathogenesis of pulmonary allergies, particularly asthma. The potential of TXA(2) modifiers in the prevention and/or treatment of pulmonary allergies is also discussed. Bronchial asthma is characterised by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. Several studies have elucidated the role of arachidonic acid metabolites (leukotrienes, prostaglandins and TXA(2)) in the pathogenesis of asthma. Among those mediators, TXA(2) has attracted attention due to its strong physiological activity. Indeed, TXA(2) demonstrates not only potent bronchoconstrictive activity but is also believed to be involved both in late asthmatic responses and in bronchial hyperresponsiveness, a typical feature of this disease. Several thromboxane receptor antagonists (TXRAs) and thromboxane synthase inhibitors (TXSIs) have been studied with the aim of reducing or preventing asthma. As double-blind, placebo-controlled clinical trials have proven the efficiency of some TXA(2) modifiers in treating asthma, the TP receptor antagonist seratrodast (AA-2414) and the thromboxane synthase inhibitor ozagrel hydrochloride (OKY-046) are now available as anti-asthmatic agents in Japan. Moreover, seratrodast and ramatroban (BAY-U-3405), another thromboxane receptor antagonist, are currently under Phase III clinical evaluation in the US for the treatment of asthma.

Asthma↗
PubMed2002

Recent advances in antiplatelet agents.

Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.

Animals↗
PubMedDate not supplied

A pharmacophore model for sulphonyl-urea (-cyanoguanidine) compounds with dual action, thromboxane receptor antagonists and thromboxane synthase inhibitors.

A 3D pharmacophore model was developed for original sulphonyl-urea (-cyanoguanidine) compounds and known molecules which behave both as thromboxane receptor antagonists and as thromboxane synthase inhibitors. Five recognition sites appear to be essential for this dual activity: two hydrogen bond acceptors, an anionic site, a hydrophobic group and an aromatic ring. Such a model could be used to design new leads possessing the same pharmacological profile and to improve the activity of our compounds.

Binding Sites↗