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P Gautheron

Publications and source records attributed to P Gautheron.

At least 19 recordsLinked to original sources
PubMed1997

IRAG working group 1. Organotypic models for the assessment/prediction of ocular irritation. Interagency Regulatory Alternatives Group.

The brief of the Organotypic Models Working Group was to review data submitted to the Interagency Regulatory Alternatives Group on the use of isolated eyes and components of the eye used to predict eye irritation potential. Data submissions were received on four test systems: the isolated rabbit eye (one submission), the isolated chicken eye (one submission), the bovine cornea (eight submissions) and the cultured bovine lens (one submission). On the basis of the data submitted on each test it was concluded that the isolated rabbit eye test as performed was capable of screening for severe eye irritants, but overall was of no practical value for determining irritation potential across the full range; that the isolated chicken eye test as performed showed promise as a method of predicting eye irritation potential, but the database was too small and needed expanding; that the bovine corneal opacity test had an extensive database and overall performed reasonably at screening out severe irritants and performed well for assigning relative potencies; and that the bovine lens test should be researched further to demonstrate its utility. The overall conclusion drawn was that the isolated eye tests and the bovine corneal opacity test can be used now to screen for severely irritating materials. However, it would be unwise to rely solely on these organotypic methods to provide evidence of lack of eye irritation hazard.

Animal Testing Alternatives↗
PubMed1992

Bovine corneal opacity and permeability test: an in vitro assay of ocular irritancy.

Most of the published in vitro tests of ocular irritancy investigate a single parameter, generally cytotoxicity, using different cell types in culture. Although good correlations with in vivo data have been reported by some investigators, many of these studies examined only limited classes of products, mainly surfactants and cosmetic ingredients. To predict the irritant potential of compounds in development and process intermediates (which include a wide variety of chemical classes with variable physical characteristics), an assay which would allow great flexibility was needed. A recently published model of corneal opacity was appropriate for this purpose and therefore investigated. The method was substantially modified and extended to study, in the same assay, two important components of irritation, i.e., opacity and permeability. For opacity alone, values obtained for 44 common chemicals showed a correlation of r = 0.73 with published in vivo data. However, compounds like sodium lauryl sulfate and some medium-chain alcohols gave false-negative results, apparently because they produced destruction of corneal epithelium. Such an effect was quantified by the measure of corneal permeability to fluorescein, and changes observed were found to be consistent with the known irritant potential of the compounds. In combination, the measurement of these two endpoints thus appeared to be sufficient to accurately predict ocular irritancy. This was further verified with 15 process intermediates. In short, the bovine corneal opacity and permeability assay allows investigation of two important components of eye irritation, in a one-day experiment, using an ocular tissue. It represents a useful approach to assess ocular irritation at least for our needs.

Animals↗
PubMed1990

Topically active carbonic anhydrase inhibitors. 3. Benzofuran- and indole-2-sulfonamides.

Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compounds for clinical use was precluded by the observation that they cause dermal sensitization in guinea pigs. A correlation between electrophilicity, as assessed by in vitro reactivity with reduced glutathione, and dermal sensitization potential was further documented.

Administration, Topical↗
PubMed1990

MK-927: a topically active ocular hypotensive carbonic anhydrase inhibitor.

MK-927 (dl-5,6-dihydro-4-(2-methylpropylamino)-4H-thieno(2,3b)thiopyra n-2-sulfonamide-7,7-dioxide hydrochloride) is a water soluble, carbonic anhydrase inhibitor (CAI) possessing a Ki of 12.0 nM against purified human carbonic anhydrase II in vitro. The acute instillation of one drop (50 microliters) of 0.5%, 1% and 2% solutions of MK-927 maximally decreased the intraocular pressure (IOP) of ocular hypertensive, cynomolgus monkeys by 4.7, 5.9 and 9.6 mm Hg, respectively. The decline of 9.6 mm Hg represented a reduction of 27% from the corresponding vehicle-treated value of 35.3 mm Hg. Peak reductions in IOP were present at 2 to 4 hr after the instillation of the three doses and the ocular hypotensive effect was waning at 6 hr. The IOP of normotensive, monkey eyes was significantly lowered by 1% and 2% solutions of MK-927 with the effect being more transient in these eyes than in hypertensive eyes. The elevated IOP of alpha-chymotrypsinized rabbits was dose-dependently decreased by 0.01%, 0.1% and 0.5% solutions of MK-927. MK-927 modestly bound to rabbit ocular pigment in vitro and the concentrations of MK-927 in the iris + ciliary body of pigmented rabbits were higher than those in the same tissue of albino rabbits after dosing with 0.5% MK-927. The ocular hypotensive effect of 2% MK-927 was greater in magnitude and longer in duration in normal pigmented than in albino rabbits. The IOP lowering action of MK-927 was local as evidenced by results of ocular distribution studies and the observation that the unilateral instillation of 0.5% MK-927 into the contralateral eye was devoid of effect on the untreated, hypertensive eye of alpha-chymotrypsinized rabbits. MK-927 has been selected for topical evaluation in glaucoma patients.

Administration, Topical↗
PubMed1990

L-662,583 is a topically effective ocular hypotensive carbonic anhydrase inhibitor in experimental animals.

1. L-662,583 was a potent inhibitor in vitro of purified, human erythrocyte carbonic anhydrase II, possessing an IC50 of 0.7 nM. The IC50 values for MK-927, acetazolamide and methazolamide were 13.0 nM, 10.8 nM and 21.2 nM, respectively. 2. A 1 h pretreatment with one 50 microliters drop of a 0.1% solution of L-662,583 blocked carbonic anhydrase activity in a homogenate of the iris + ciliary body of albino rabbits by 63%. Similar treatment with 0.1% suspensions of acetazolamide and methazolamide elicited inhibitions of 30% and 20%, respectively. This ex vivo model indirectly assesses the ability of an agent to enter the rabbit eye. 3. Concentrations of L-662,583 in the cornea, aqueous humour and iris + ciliary body of albino rabbits were determined by h.p.l.c. at predetermined times after the instillation (one drop of 50 microliters) of a 2% solution of L-662,583. Peak levels for cornea (47.4 micrograms g-1), aqueous humour (4.51 micrograms ml-1) and iris + ciliary body (9.61 micrograms g-1) occurred at 0.5, 2 and 1 h after instillation, respectively. 4. The experimentally elevated intraocular pressure of the right eye of rabbits, induced by prior intraocular injection of alpha-chymotrypsin, was maximally decreased by 4.5 mmHg, 6.2 mmHg and 9.8 mmHg after the instillation (one drop of 50 microliters) of 0.01%, 0.1% and 0.5% solutions of L-662,583, respectively. All three concentrations lowered intraocular pressure at all time points from 1 h up to and including 5 h, the last recorded time point. The unilateral instillation of L-662,583 (0.5%) into the contralateral, left eye failed to lower the elevated intraocular pressure of the untreated, right eye. This finding indicates that the site of action of topically applied L-662,583 in this paradigm is local. The ocular normotensive, albino rabbit was much less susceptible than the ocular hypertensive rabbit to the intraocular pressure lowering effect of topically applied L-662,583, with a 2% solution maximally decreasing intraocular pressure by 2.3 mmHg. 5. Unilateral ocular hypertension was elicited in the right eye of sedated, cynomolgus monkeys by argon laser-induced photocoagulation of the trabecular meshwork. The instillation (one drop of 50 microL) of L-662, 583 (2%) significantly lowered the elevated intraocular pressure of the right eye at all time points from 1 h up to and including 5 h. The maximum decline was 8.3 mmHg at 3 h and this represented a reduction of 23% from the corresponding baseline value of 36.8 mmHg. The intraocular pressure of the hypertensive, right eye was maximally decreased by 4.1 mmHg and 4.8 mmHg after the instillation of 0.5% and 1% solutions of L-662,583, respectively. Like the rabbit, the normotensive eye of cynomolgus monkeys was more resistant than the hypertensive eye to the ocular hypotensive action of L-662, 583, as indicated by the inability of 0.5% and 1% solutions of the agent to lower intraocular pressure. L-662,583 (2%) maximally reduced the intraocular pressure of normotensive monkey eyes by 2.4 mmHg at 2 h. 6. L-662,583 is structurally different from MK-927, a carbonic anhydrase inhibitor that lowers the intraocular pressure of glaucoma patients following the instillation of a 2% solution. These preclinical observations indicate that L-662,583, like MK-927, is a water-soluble carbonic anhydrase inhibitor which, on topical administration, lowers intraocular pressure by virtue of an action confined to within the eye.

Administration, Topical↗
PubMed1989

Topically active carbonic anhydrase inhibitors. 2. Benzo[b]thiophenesulfonamide derivatives with ocular hypotensive activity.

Derivatives of benzo[b]thiophene-2-sulfonamide were prepared to investigate their potential utility as topically active inhibitors of ocular carbonic anhydrase. Such an agent would be useful in the treatment of glaucoma. Among the compounds described are 6-hydroxybenzo[b]thiophene-2-sulfonamide (16) and its acetate ester (23), which are among the most potent ocular hypotensive agents in this class, as assessed in the alpha-chymotrypsinized rabbit. These compounds were selected for clinical evaluation.

Animals↗
PubMed1988

Ocular distribution studies of the topical carbonic anhydrase inhibitors L-643,799 and L-650,719 and related alkyl prodrugs.

The ocular distribution of the carbonic anhydrase inhibitors 6-hydroxybenzothiazide-2-sulphonamide (L-643,799) and 6-hydroxybenzothiophene-2-sulphonamide (L-650,719) has been investigated in albino rabbits after conjunctival administration of these compounds or related alkyl prodrugs. The ocular penetration of L-650,719 has been compared in ocular normotensive rabbits and in animals whose intraocular pressure has been experimentally elevated.

Administration, Topical↗
PubMed1988

L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity.

L-653,328 is the acetate ester of L-652,698 ((S)-3-tert-butylamino-1-[4-[2(hydroxy)ethyl]phenoxy]2-propanol). The penetration of L-652,698 into the albino rabbit eye was enhanced when the compound was instilled as its prodrug acetate ester. The instillation (one drop of 50 microliter) of 0.01, 0.05 and 0.1% solutions of L-653,328 significantly decreased in a dose-dependent manner the elevated intraocular pressure (IOP) of alpha-chymotrypsinized rabbits by 3.2, 4.7 and 6.1 mm Hg, respectively. A 0.01% solution of L-652,698 failed to significantly lower IOP, whereas this dose of timolol (3.8 mm Hg) and betaxolol (3.3 mm Hg) was effective. L-652,698 was active at 0.05% and 0.1%. Extraocular beta-adrenoceptor blockade was quantified in ganglion-blocked, conscious rabbits by determining effects on heart rate and blood pressure changes to i.v. isoproterenol (0.5 microgram/kg). Doses of timolol blocking isoproterenol-induced hypotension and tachycardia by 50% were 0.0065% and 0.03%, respectively. The corresponding doses for betaxolol were greater than 3% (43% inhibition) and 0.3%. Heart rate and blood pressure changes to isoproterenol were blocked by 18 and 36%, respectively, after the instillation of a 3% solution of L-653,328. The reduced propensity of L-653,328 for extraocular beta-adrenoceptor blockade stems from the modest affinity of L-652,698, its active moiety, for beta-adrenoceptors. The Ki values of L-652,698 for displacement of 125I-iodocyanopindolol binding to beta 1-(left ventricle) and beta 2-binding sites (iris + ciliary body) in the rabbit were 5.7 microM and 7.3 microM, respectively. In marked contrast, the corresponding values for timolol were 12 nM and 1.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

The ability of salbutamol and theophylline to suppress immediate allergic conjunctivitis in the guinea pig.

Topically administered salbutamol was extremely effective in suppressing immediate allergic conjunctivitis in the guinea pig; a dose as low as 0.1% elicited 98% inhibition. Topical pretreatment with 1% propranolol completely blocked the suppressant action of 0.1% salbutamol. This was also the case after systemic propranolol (1 mg/kg SC); the beta-adrenoceptor antagonist itself has no effect on antigen-induced inflammation. The effect of 0.1% salbutamol was unaltered by pretreatment with the specific beta 1-adrenoceptor antagonist betaxolol (1 mg/kg SC). In marked contrast, the suppressant action of 0.1% salbutamol was profoundly inhibited by pretreatment with the selective beta 2-adrenoceptor antagonist ICI-118,551 (0.5 mg/kg SC). The experiments employing beta-adrenoceptor antagonists unequivocally demonstrate that the salbutamol suppression of immediate allergic conjunctivitis in the guinea pig is mediated via the activation of beta 2-adrenoceptors. The methylxanthine phosphodiesterase inhibitor theophylline was active after oral administration, 50 mg/kg eliciting an 80% inhibition. Theophylline was inactive topically at 1% and 5%, but this could be due to the fact that the compound was insoluble at these concentrations. Thus, procedures that elevate cyclic-AMP levels suppress immediate hypersensitivity reactions in the guinea pig conjunctiva. Whether or nor this offers an alternative approach to treat allergic conjunctivitis in humans remains to be determined.

Administration, Oral↗
PubMed1985

A study on the ocular and extraocular pharmacology of metipranolol.

Metipranolol (Betamann) is a clinically efficacious ocular hypotensive drug and preclinical experiments were undertaken to characterize this beta-adrenoceptor antagonist. In vitro beta1- and beta2-adrenoceptor antagonism was evaluated using the guinea pig atrium and the rat uterus, respectively. The respective pA2 values were 8.3 and 8.4. Topical metipranolol, 0.3% and 0.6%, blocked both the hypotension (beta2-mediated) and the tachycardia (beta1-mediated) elicited in ganglion-blocked, conscious rabbits by isoproterenol, 0.5 microgram/kg, i.v. The Ki for displacement of 3H-dihydroalprenolol binding to rabbit iris + ciliary body homogenates was 34 nM. The effect of metipranolol, 0.3% and 0.6%, was not particularly striking on the intraocular pressure (IOP) of conscious, normotensive rabbits. However, the elevated IOP of the alpha-chymotrypsinized rabbit eye was significantly decreased (maximum reduction of 5.8 mm Hg) following the instillation of metipranolol, 0.3%. IOP recovery in conscious rabbits following hyperosmotic challenge (i.v. infusion of a 20% NaCl solution) was not decreased by a 1-h pretreatment with a 0.3% solution. In contrast, a significant reduction of 41% was elicited by a 0.6% solution. Hence, the ocular hypotensive effect of metipranolol may result from decreased aqueous humor inflow. Metipranolol, 0.6%, was devoid of effect on rabbit pupil diameter. However, corneal local anesthesia was elicited in the rabbit by both 0.3% and 0.6% solutions of the drug, the effect being more marked with the higher concentration.

Animals↗
PubMed1985

On the pharmacology of L-645,151: a topically effective ocular hypotensive carbonic anhydrase inhibitor.

L-645,151 [(2-sulfamoyl-6-benzothiazolyl)-2,2-dimethylpropionate] is the O-pivaloyl ester of L-643,799 (6-hydroxybenzothiazole-2-sulfonamide), topically administered L-645,151 being a substrate for ocular esterases with the resultant liberation of the active moiety, L-643,799, during penetration of the ocular surface. The minimum concentrations of topically administered suspensions (1 drop of 50 microliters into both eyes) of L-645,151, L-643,799, dichlorphenamide and methazolamide significantly lowering the elevated intraocular pressure (IOP) of the alpha-chymotrypsinized rabbit eye were 0.25, 2, 10 and 5%, respectively. IOP was not significantly decreased by 10% suspensions of acetazolamide or ethoxzolamide. The IOP lowering action of L-645,151 was local as the unilateral instillation of L-645,151 (0.25%) into the contralateral eye was devoid of effect in alpha-chymotrypsinized rabbits. L-645,151 (2%) decreased aqueous humor inflow in both the conscious rabbit and the anesthetized dog. Outflow facility in the conscious rabbit was unaltered by a 10% suspension of L-645,151. Low peak levels (0.52 microgram/g) of L-643,799 were present in rabbit renal cortex after the instillation of L-645,151 (2%) into both eyes; this treatment did not induce diuresis in the conscious rabbit. The corresponding maximum concentration in the iris + ciliary body was 4.01 micrograms/g. These preclinical studies reveal that L-645,151 is the most potent, topically effective ocular hypotensive carbonic anhydrase inhibitor described to date.

Administration, Topical↗
PubMed1984

R-enantiomer of timolol: a potential selective ocular antihypertensive agent.

Various studies were conducted to evaluate the effects of timolol, an S-enantiomer, relative to its R-enantiomer upon intraocular pressure and related ocular systems in the rabbit. The R-enantiomer was about one-third as potent as timolol in displacing 3H-dihydroalprenolol binding to iris-ciliary body tissue, reducing aqueous humor formation, and lowering intraocular pressure of alpha-chymotrypsin hypertensive eyes. In contrast, the R-enantiomer was 50 to 90 times less potent than timolol in antagonizing the effects of isoproterenol on pulmonary and atrial beta-adrenergic receptors. The data indicate that the R-enantiomer may lower intraocular pressure in man at concentrations less likely than timolol to block extraocular beta-adrenergic receptors. Finally, to account for the differential effect of the R-enantiomer upon ocular as opposed to extraocular beta-adrenergic receptors, it is tentatively suggested that this agent may also act upon a population of ocular beta-adrenergic receptors showing relatively poor stereoselectively.

Animals↗
PubMedDate not supplied

Influence of dietary fats on atherosclerosis, coagulation and platelet phospholipids in rabbits.

SUMMARY: Male rabbits were fed for six months diets comprising cholesterol (0.1%) and either butter alone (10%) or butter (5%) plus cacao butter, coconut oil, olive oil, or corn oil (4.5%). These fats could be classified according to their atherogenicity as follows, in decreasing order: butter, olive oil, coconut oil, cacao butter, and corn oil. The severity of the atherosclerotic lesions was correlated with the plasma cholesterol. By contrast, concerning their effect on the recalcification plasma (platelet-rich) clotting time (PCT), These fats could be classified in the following way: cacao butter, butter,, coconut oil, olive oil and corn oil. The values of the PCT were significantly correlated with the ratio stearic/linoleic acid in the dietary fats, the clotting activity and the fatty acid composition of the platelet phospholipid fractions examined (phosphatidyl serine plus phosphatidyl inositol), but not with the concentration of these fractions in platelets. Butter was the only fat able to induce severe alterations at the same time in coagulation (presumably through an increase in the activity of certain platelet phospholipids), lipemia and arterial wall morphology.

Animals↗