Synthesis and ocular antihypertensive activity of new imidazolidine derivatives containing a beta-blocking side chain.

The syntheses of new phenylimidazolidine derivatives (3-6)1 containing a propanolamine oxime or an oxypropanolamine moiety attached either to the aromatic or to the imidazolidine ring are described. These compounds were evaluated for potential ocular antihypertensive activity in alpha-chymotrypsin-induced ocular hypertension in rabbits. These compounds represent a unique series of effective ocular antihypertensive agents that despite possessing structural characteristics of beta-blockers and of imidazolidine derivatives, exhibit weak alpha- and beta-adrenergic agonist and antagonist activities.

Pharmacokinetics of falintolol II. Absorption, distribution and elimination from tissues and organs following ocular administration and intravenous injection of falintolol in albino rabbits.

The absorption, distribution and elimination of falintolol maleate was studied in various ocular and extraocular tissues and organs following ocular instillation, intravenous injection of a 0.5% 14C-falintolol ophthalmic solution and repeated ocular instillations of a 1% non-labeled falintolol ophthalmic solution into albino New Zealand rabbits. Falintolol was distributed in all studied tissues and organs after both routes of administration.

Beta-adrenoceptor binding potencies of new aliphatic and alicyclic oxime ethers and their relevance to intraocular pressure control.

The selectivity and binding potency of a series of alkyliminoxypropanolamines characterized by the lack of an aromatic nucleus are studied using a new non-selective radioligand, (-)-(125I)-Iodocyanopindolol. The relationship between the effectiveness in lowering the intraocular pressure (IOP) in experimental hypertensive rabbit eyes and their capacity to bind to ciliary processes beta 2-adrenoceptors is discussed. The inhibition constant (Ki) and beta 2/beta 1 ratios indicate a beta 2-selectivity for the tested drugs.

Effects of adrenergic agents on alpha-chymotrypsin-induced ocular hypertension in albino and pigmented rabbits: a comparative study.

Alpha-chymotrypsin-induced ocular hypertension in albino rabbits is widely used as an experimental model to screen potential antiglaucoma drugs. The present study compares the intraocular pressure (IOP) response following the ocular application of single or repeated adrenergic agents in conscious albino and pigmented rabbits. A single instillation of clonidine was not as effective in lowering the IOP in pigmented hypertensive rabbit eyes as in albino hypertensive eyes.

Characterization of alpha 2-adrenergic receptors, negatively coupled to adenylate cyclase, in rabbit ciliary processes.

Inhibition of ciliary process adenylate cyclase was studied on rabbit membrane preparations. When considered individually, epinephrine, GTP and NaCl did not inhibit adenylate cyclase activity. On the other hand, when present together, epinephrine, GTP (10(-5) M) and NaCl (200 mM) acted synergistically to cause a 27% inhibition of basal activity.

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.

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.

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.

Topical and bioavailability of benzoyl peroxide.

Synopsis Benzoyl peroxide has been used for over 20 years to treat youthful acne. The aim of this study is to determine its release rate from the vehicle that allows it to reach and treat the skin (topical availability) and its ability to pass through the skin and reach the general circulation (bioavailability), in order to bring about good topical availability, linked to bioavailability or, an 'abioavailability'. Three preparations containing 10% of benzoyl peroxide were administered to the back of shaven New Zealand rabbits.

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.

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.

Simultaneous determination of neopynamine and piperonyl butoxide by capillary column gas-liquid chromatography.

A method is developed for the simultaneous determination of neopynamine and piperonyl butoxide by chromatography on a quartz capillary column using flame ionization detection. Benzyl mandelate is used as an internal standard. Calibration graphs are linear down to at least 3.

[Demonstration of the effects on the corneal epithelium of a mucomimetic collyrium. Study using scanning microscopy].

Ocular surface drying was studied in rabbits using an experimental model of blinking interruption. This model produces a discontinuity in the pre-corneal tear film after a few minutes of exposure to air. Changes in superficial epithelial cell structure were studied using a scan microscope.

Are local tolerance tests in animals always necessary?

The Draize test was introduced in 1944 as a toxicological standardization method to study irritation and toxicity of substances applied to the eye (and the skin). It has been considered, from that time on, as a routine toxicological protocol by most regulatory agencies to test eye-tolerance of chemicals. The authors think that for ethical and scientific reasons, this test is obsolete and should be changed or eliminated.

[Determination of free and conjugated cis-3,3,5-trimethylcyclohexanol in plasma and urine].

A gas chromatographic procedure was developed to determine free and conjugated cis-3,3,5-trimethylcylcohexanol in plasma and urine. The sample is extracted with dichloromethane when free cis-3,3,5-trimethylcyclohexanol is determined, or with hexane after enzymatic hydrolysis, when conjugated cis-3,3,5-trimethylcyclohexanol is determined. An aliquot of the organic extract is injected into a stainless-steel column (packed with Carbowax 20M, 15% on Chromosorb W AW 100-120 mesh) and detected with a flame ionization detector.

The bioavailability and pharmacokinetics of three zinc salts: zinc pantothenate, zinc sulfate and zinc orotate.

In this study the authors compared the pharmacokinetics of three zinc salts after parenteral and oral administration to rabbits: zinc sulfate, a soluble mineral salt; zinc pantothenate, a soluble organic salt; and zinc orotate, an insoluble organic salt. The results obtained with the two soluble salts were not significantly different (p less than 0.05).