PubMed Health⌕ Search

Biomedical subjects

G Leclerc

Publications and source records attributed to G Leclerc.

At least 73 records · Page 4Linked to original sources
PubMed1987

Effects of topically applied falintolol: a new beta-adrenergic antagonist for treatment of glaucoma.

Changes in intraocular pressure (IOP) following topical administration of falintolol (0.5%-0.25%), a new beta-blocking agent, were studied in conscious albino rabbits with alpha-chymotrypsin-induced ocular hypertension. The drug produced a reduction in IOP equal to that of timolol. A longer duration of activity was noted with falintolol. The rate of transport of topically applied falintolol through the isolated bovine cornea under conditions simulating normal physiology was linear up to three hours and twice as fast as timolol from 3 to 6 hours. Since topical ocular application of beta-adrenergic antagonists useful in glaucoma therapy can also cause a number of troublesome systemic side effects, several conclusive preclinical investigations were carried out with falintolol. Of major concern was the effect falintolol might have on the pupil, cornea, and heart rate when administered topically. The results show that falintolol does not produce any noteworthy side effects and is capable of being an effective beta-blocking agent in open-angle glaucoma therapy.

Administration, Topical↗
PubMed1987

Determination of falintolol, a new aliphatic beta-adrenergic antagonist, in whole blood by gas chromatography with electron-capture detection: geometric isomers resolution.

Falintolol oxalate, a new beta-adrenergic antagonist, is characterized by the presence of an oxime function and exists in a racemic form as a mixture of syn- and anti- isomers in a ratio of about 8:2. This article describes a selective gas chromatographic method for the resolution of the geometric isomers and the quantitation of the drug. The unchanged falintolol and internal standard, a related compound, are separated from blood by a solvent extraction under alkaline conditions, and then the drug is derivatized. The heptafluorobutyric derivatives are chromatographed on an SE-30 capillary quartz column and detected with a nickel-63 electron-capture detector. Because the syn- and anti- isomers of falintolol display comparable chromatographic responses, the sum of the two geometrical isomers is used for the quantitation of falintolol in blood. This method allows small serial blood samples in conscious rats, and 0.05 microgram of falintolol/0.1 mL of blood can be routinely determined. A calibration curve is prepared for the blood extracts. Linearity is observed in the study range (0.05 to 1 microgram/0.1 mL of blood). No interference by endogenous substances is observed. The procedure is applied successfully to drug absorption in rats when repeated oral doses are administered.

Adrenergic beta-Antagonists↗
PubMed1987

A novel positive inotropic series. 1st communication: in vitro studies of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolone derivatives.

A series of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolones and related compounds were evaluated for positive inotropic and vasodilatory activities in vitro. Most of them produced dose-related increases in myocardial contractility on guinea pig isolated atria and perfused heart. In guinea pig atria, the 6-pyridyl molecules were more active than the 5-pyridyl ones; the mean ED50 of compounds 14, 32 and 33 was 4.0 x 10(-7) mol/l i.e. 33 times that of sulmazole; that of compounds 6 and 7 was 2.0 x 10(-5) mol/l. The potencies of the 5- and the 6-pyridyl series also differed by 2 log units on perfused guinea pig heart. The 5- and 6-pyridyl series induced relaxation in precontracted pig coronary artery and coronary vasodilation on perfused guinea pig heart. Compounds 14, 32 and 33 also showed alpha-adrenolytic properties, which were by 0.7 log unit lower than that of phentolamine. These results indicate that this novel cardiotonic series exert positive inotropic and coronary vasodilatory effects.

Animals↗
PubMed1987

A novel positive inotropic series. 2nd communication: in vivo studies of 5- and 6-pyridyl-2(1H)-quinolone derivatives.

In the anaesthetized rabbits and dogs, the 6-pyridyl compounds 14, 32 and 33 (0.1-3 mg/kg) and the 5-pyridyl compounds 6 and 7 (1-10 mg/kg), administered i.v., produced dose-related increases in cardiac contractile force lasting more than 30 min. They also produced relatively minor and shorter-lasting increases in heart rate. Only the 6-pyridyl series decreased blood pressure. The effects were not blocked by propranolol. In the normal haemodynamic states, myocardial oxygen consumption did not increase. When the haemodynamic characteristics of heart failure were produced by propranolol in anaesthetized rabbits and dogs, compounds 14, 32 and 33 reversed these effects, increasing in particular cardiac output. These studies suggest that compounds of the 6-pyridyl series might be beneficial in patients with congestive heart failure.

Anesthesia↗
PubMed1986

Transient heart failure in an adult with Kawasaki disease.

Kawasaki disease is a mucocutaneous lymph node syndrome with important cardiovascular complications that usually afflicts young children. We describe a 31-year-old woman who developed transient heart failure during the acute phase of Kawasaki disease. The diagnosis was supported by the presence of all six criteria of the disease: fever, conjunctivitis, strawberry tongue, cervical lymphadenopathies, truncal exanthem, and periungual membranous desquamation. Related clinical and laboratory findings included heart failure, arthralgias, transverse nail grooves, thrombocytosis, and elevated serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and bilirubin. Alternative diagnoses were excluded. During her acute febrile illness, the patient developed tachycardia, hypotension, pulmonary rales, S3 gallop, and hepatojugular reflux. The chest roentgenogram showed new Kerley A and B lines. A first-pass isotopic ventriculography showed diffuse hypokinesia and decreased ventricular ejection fractions; spontaneous recovery occurred after a few days. A coronarography performed two months later showed no aneurysmal dilatation. Kawasaki disease is a cause, albeit rare, of myocardial dysfunction in the adult human, and should be sought for actively in a patient with heart failure during the course of an acute febrile illness, associated with mucocutaneous changes.

Adult↗
PubMed1986

Cardiotonic agents. 1. Synthesis and structure-activity relationships in a new class of 3-, 4-, and 5-pyridyl-2(1H)-quinolone derivatives.

A series of 3-, 4-, and 5-pyridyl-2(1H)-quinolone derivatives with H or HO or CH3O substituents in the 8-position were prepared and tested for positive inotropic activity. Several derivatives, especially 29, 9b, and 27 with a pyridyl ring in the 5-position, were ca. 2-10 times more potent on left guinea pig atria than sulmazole (ARL-115) and milrinone used as references. Some structure-activity relationships are discussed.

Animals↗
PubMed1986

Cardiotonic agents. 2. Synthesis and structure-activity relationships in a new class of 6-, 7-, and 8-pyridyl-2(1H)-quinolone derivatives.

A series of 6-, 7-, and 8-pyridyl-2(1H)-quinolone derivatives with various quinolone substitutents (CH3, Cl, OH, OCH3) was prepared by arylation of pyridine with quinolone via a diazotized aminoquinolone for positive inotropic activity. Several derivatives, especially those with a pyridyl ring in the 6-position, were from 28 to 50 times more potent on left guinea pig atria than ARL-115 and milrinone used as references. Intrinsic activities of the derivatives were almost equivalent to that of ARL-115. These results indicate that pyridyl-2(1H)-quinolone derivatives are a potent new class of positive inotropic agents.

Animals↗
PubMed1986

Candida folliculitis in heroin addicts.

Three heroin addicts had Candida folliculitis of the scalp, beard, and pubis associated with fever, chills, headache, and fatigue. In each case, pseudohyphae were found within a hair and yeasts around it and Candida was recovered from urine. These facts support a systemic dissemination. Since serious ocular and osteoarticular lesions have been described with this type of skin lesion, prompt diagnosis may be important to initiate treatment and prevent sequelae.

Adult↗
PubMed1985

Synthesis and irreversible beta-adrenergic blockade with a bromoacetamido derivative of betaxolol.

1-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-3-[1-p-(bromoacetamidophe nyl) -2-methyl-2-propylamine]-2-propranol (8), which is a derivative of the beta 1-adrenergic agent betaxolol, was synthesized. Compound 8 showed less potent beta-adrenergic blocking activity than betaxolol in an in vitro test with guinea pig tracheal muscle and left atrium but retained high beta 1-selectivity. Irreversible beta-adrenoceptor antagonism of 8 was assessed by the blockade of the isoproterenol response of the guinea pig atria and by ligand binding studies with rat cerebral cortex.

Adrenergic beta-Antagonists↗
PubMed1985

New chiral and isomeric cyclopropyl ketoxime propanolamine derivatives with potent beta-adrenergic blocking properties.

The synthesis of R-(+) and S-(-) isomers of O-[3-tert-butylamino)-2-hydroxypropyl] cyclopropyl methyl ketone oxime (falintolol) is described. The syn and anti isomers of falintolol were obtained in two different ways from cyclopropyl methyl ketoxime or from falintolol. For comparison purposes, the enantiomers of the dicyclopropyl ketone oxime derivatives were also prepared. Structure-activity relationships are described.

Adrenergic beta-Antagonists↗
PubMed1985

In vitro potential measurement, anaesthetic and antimicrobial effects as indicators of beta-blocker toxicity of the cornea.

Three tests were utilized to determine and compare the toxicity of timolol, propranolol and two new aliphatic and alicyclic oxime ethers with beta-blocking activity (falintolol and compound POS 7). Effects on the electrical potential difference across the in vitro bovine corneal epithelium. Local anaesthesia on in vivo rabbit cornea. Antimicrobial activity on bacterial and fungal suspensions. In addition, partition coefficients were determined as physicochemical properties of the drugs. Falintolol, as well as timolol produced a minor change in electrophysiology at clinical concentration. They had neither local anaesthetic, nor antimicrobial effects. Conversely, propranolol and compound POS 7 showed acute corneal toxicity in the present models. It was concluded that changes in the potential difference across a perfused cornea in vitro, local anaesthesia and bacterial inhibition, might be a demonstration of the cytotoxicity of certain topical agents in terms of acute eye tissue reaction. They might represent a valuable model for the acute corneal toxicity evaluation of topical beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1985

Derivatives related to betaxolol with alpha- and beta-adrenergic activities.

The paper describes the synthesis and the pharmacological evaluation of some derivatives of betaxolol, all with a N-aralkylamine instead of the tertiobutylamine. Their general formulas are: (Formula: see text). These compounds have been tested for beta 1-adrenergic receptors antagonism on guinea pig atria, beta 2-adrenergic receptor antagonism on guinea pig trachea and alpha-adrenergic blocking activity on rat aorta. Compound U12 with a marked alpha-blocking activity and compound R8 with a beta 1/alpha ratio = 1 were selected for a haemodynamic study in the dog. The decrease in cardiac work and the diminution of total peripheral resistance exhibited by U12 are consistent with a dual alpha/beta-blocking agent. Finally, structure-activity relationships are discussed.

Adrenergic alpha-Antagonists↗
PubMed1984

Postjunctional alpha-adrenoceptors. Alpha 1 and alpha 2 subtypes in rat vasculature in vitro and in vivo.

The postsynaptic alpha-adrenoceptors in rat aorta and in pithed rat were investigated according to their sensitivity to nine alpha-adrenergic agonists and to the selective antagonists yohimbine (alpha 2) and prazosin (alpha 1) and the nonselective one, phentolamine. In addition, in radioligand binding studies, the affinity and selectivity of the drugs were determined on rat cerebral cortex using [3H] yohimbine and [3H] prazosin. On rat aorta, prazosin is 1,000 times more potent than yohimbine against each alpha-adrenoceptor agonist, whether alpha 1- or alpha 2-selective. Rat aorta probably contains only alpha 1-adrenoceptors. Pressor effects in pithed rats are mediated by post-junctional alpha 1- and alpha 2-adrenoceptors. The dose-response curve for alpha-methylnorepinephrine in the presence of prazosin, using Hofstee's plots, revealed alpha 1- and alpha 2-adrenoceptors, respective proportions being 80.5 and 19.5%.

Adrenergic alpha-Agonists↗
PubMed1984

Synthesis and beta-adrenergic blocking activity of new aliphatic and alicyclic oxime ethers.

We describe the synthesis and pharmacological properties of two new series of aliphatic and alicyclic beta-adrenergic blockers, most of them containing a cyclopropyl ring. They belong either to 2-hydroxy-3-(tert-butylamino)propyl ether A or 2-hydroxy-3-tert-(butylamino)propyl ketoxime ether B derivatives. The O-[2-hydroxy-3-(tert-butylamino)propyl] dicyclopropyl ketoxime 5 exhibited a beta-adrenergic antagonist activity comparable to that of propranolol. It was found that ketoxime ethers B generally showed higher potency than the corresponding ethers A. We confirm that the presence of an aromatic nucleus is not crucial for the beta-adrenergic activity. Structure-activity relationships among these series are discussed.

Adrenergic beta-Antagonists↗
PubMed1983

Study of two alkylating derivatives: the p-isothiocyanato- and the p-methylisothiocyanato-clonidine.

Pharmacological experiments with isolated rat aorta and radioligand binding studies in rat cerebral membranes were performed with the p-isothiocyanato (p-NCS) and p-methylisothiocyanato (p-CH2-NCS) derivatives of clonidine in order to assess their selectivity for alpha 1- and alpha 2-adrenoceptors, and to characterize their ability to alkylate alpha-adrenoceptors. Preincubation of rat aortic strips with both derivatives produced non-parallel rightward shifts in the dose-response curves of noradrenaline and significantly depressed the maximum response in a manner characteristic of irreversible receptor antagonists. The p-CH2-NCS derivative was slightly more potent than the p-NCS derivative. Further analysis of the data indicated that treatment of rat aorta with a 30 microM concentration of the p-CH2-NCS derivative alkylated all but 2.4 percent of the alpha-adrenoceptors, whereas a 100 microM concentration of the p-NCS derivative was required to produce a similar degree of alpha-adrenoceptor alkylation. Radioligand binding studies indicate an apparent 2 fold alpha2-adrenoceptor selectivity for the p-NCS derivative. In contrast, the p-CH2-NCS derivative displayed 7 fold selectivity for alpha 1-adrenoceptors. Interestingly, both alkylating derivatives of clonidine produced dose-dependent contractile responses in rat aorta with pD2 values of 6.30 and 5.56 for the p-NCS and p-CH2-NCS derivatives, respectively, relative to a pD2 of 7.67 for clonidine. The order of potency of the two alkylating derivatives of clonidine for producing contraction of rat aorta is the opposite of that for antagonizing the contractile effects of noradrenaline. The results suggest that the p-NCS and p-CH2-NCS derivatives of clonidine non-competitively antagonize noradrenaline by irreversibly alkylating alpha-adrenoceptors.

Alkylating Agents↗
PubMed1982

Synthesis and cardiovascular activity of a new series of cyclohexylaralkylamine derivatives related to perhexiline.

A series of 24 cyclohexylaralkylamine derivatives related to perhexiline has been synthesized and screened for cardiovascular activity. All the compounds contained an exocyclic amine which was substituted either by an alkyl, cycloalkyl, or aralkyl group. In the hope of further reducing toxicity, the synthesis of p-tolyl- and p-hydroxyphenyl derivatives 23 and 24 was undertaken. The effect of separating the cyclohexylamine moiety with respect to the aromatic nucleus has been systematically examined. The pharmacological investigations were directed to a search for compounds having an activity better than perhexiline according to the following order of criteria: (1) alpha-adrenolytic activity; (2) increase of coronary blood flow; (3) calcium antagonism. Several compounds were more potent and exhibited lower toxicity than perhexiline. Further detailed pharmacological investigations (tension time index and decreased cardiac work) have led to the selection of N,2-dicyclohexyl-2-phenethylamine (3) for clinical trials, which are now under way.

Adrenergic alpha-Antagonists↗
PubMed1980

Synthesis and beta-adrenergic blocking activity of new aliphatic oxime ethers.

New beta-adrenergic blocking agents, most of which do not contain an aromatic nucleus, were synthesized. They were derived either from alkylamino-aliphatic oxime ethers or alkylamino-aliphatic ethers. Most active among these are O-[3-(tert-butylamino)-2-hydroxypropyl]acetoxime (8; trachea pA2 = 7.65) and 1-isobutoxy-3-(tert-butylamino)-2-propanol (15; trachea pA2 = 7.49), both of which displayed bronchoselectivity (beta 2/beta 1 ratio approximately 15). The role and importance of the aromatic nucleus in this class of compounds are discussed.

Adrenergic beta-Antagonists↗