The safety and efficacy of switching timolol maleate 0.5% solution to timolol hemihydrate 0.5% solution given twice daily.

This study was undertaken to evaluate the safety and efficacy of switching patients treated with timolol maleate to timolol hemihydrate. In patients with ocular hypertension or chronic open-angle glaucoma treated with beta-blockers for at least three months, we prescribed timolol maleate solution 0.5% given twice daily for one month. We then switched each patient to timolol hemihydrate solution 0.5% (Betimol, Ciba Vision Ophthalmics) given twice daily for three months. This study found over the first three months in 30 completed subjects, using a worse eye analysis, that the intraocular pressure changed from 18.3+/-2.1 mm Hg on timolol maleate to 18.8+/-2.3 mm Hg on timolol hemihydrate (P=0.10) 12 hours after dosing. There was no difference in the overall incidence of unsolicited anterior segment side effects between timolol maleate (4 cases) versus timolol hemihydrate (3 cases) (P=0.69). One patient exited the study because of pain and burning in both eyes while on timolol maleate. No patient was discontinued due to loss of intraocular pressure control after switching to timolol hemihydrate. It was concluded that switching from timolol maleate to timolol hemihydrate is safe and effective in maintaining control of the intraocular pressure.

Ocular-specific delivery of timolol by sequential bioactivation of its oxime and methoxime analogs.

S-(-)- Timolol maleate was oxidized, using the modified Pfitzner-Mofatt method, to the corresponding keto analog, which was then coupled with either hydroxylamine or methoxyamine in the same reaction medium. The products separated, timolone oxime (TO) or timolone methoxime (TMO), were found to be a mixture of both E and Z isomers with the Z isomer in higher concentration. Both isomers could be separated on silica column. No isomerization of any of the isomers could be detected whether in buffers or biological fluids. TMO salts were found to be stable in slightly acidic buffer. The Z isomer of TMO is more stable than the E isomer. Both TO and TMO showed pronounced reduction of the intraocular pressure (IOP) in normotensive rabbits, when instilled into the conjunctival sac. Reduction of IOP caused by either TO or TMO was higher than the reduction produced with the same dose of timolol maleate. Equal doses of any of the TMO isomers or the mixture of isomers gave almost the same percent reduction of IOP. TMO and TO did not show cardiovascular effects when administered intravenously to rabbits or rats. Both are good candidates to be used for topical management of glaucoma without producing systemic side effects.

Preliminary evaluation of a series of amphiphilic timolol prodrugs: possible evidence for transscleral absorption.

A series of amphiphilic esters of timolol malonate (octanoyl, decanoyl, dodecanoyl, myristoyl and palmitoyl timolol) were tested in rabbits for their capacity to antagonise the isoproterenol-induced ocular hypotension, using timolol maleate as reference standard. The most active prodrug, palmitoyl timolol malonate (PTM) was also evaluated for its capacity: (a) to decrease IOP in a model of bethamethasone-induced ocular hypertension, and (b) to permeate "in vitro" through rabbit corneal tissues. PTM, the prodrug with the longest aliphatic chain and therefore the greatest amphiphilic/lipophilic character, showed "in vivo" significant activity differences with respect to timolol maleate: the beta-antagonism was more important at earlier and later experimental times, and the IOP decrease was more marked at longer times. The prodrug, however, showed "in vitro" an inferior corneal permeability when compared with timolol maleate. The significant differences observed for the beta-antagonism of PTM at earlier times of the test might be attributed to transscleral absorption, due to the physicochemical characteristics of the prodrug, while the prolonged action (also observed in the IOP-depression test) might be due to sustained release, resulting from accumulation of the prodrug in the corneal epithelium. The present preliminary results are indicative of the potentiality of amphiphilic properties in a prodrug molecule.

Improved delivery through biological membranes. 26. Design, synthesis, and pharmacological activity of a novel chemical delivery system for beta-adrenergic blocking agents.

Novel ketoxime analogues of known beta-blockers (propranolol, timolol, carteolol) were synthesized and tested as potential site-specific chemical delivery systems. It was assumed that a hydrolysis-reduction sequence could produce the active beta-blockers in the iris-ciliary body. It was found that some of these bioprecursors are remarkably active in reducing intraocular pressure in rabbits. The ketoxime derivative of propranolol is more effective and much less irritant than its parent beta-blocker. While the ketoximes also displayed activity on isoprenaline-induced tachycardia after iv administration, they were void of activity when given orally. Propranolol was found for a prolonged time and in significant concentrations in the rabbit's eye following topical administration of its ketoxime precursor; however, the inactive ketoximes apparently were not converted to the corresponding beta-blockers in the eye. A correlation was found between the physicochemical properties of the ketoximes and their conversion to the amino alcohol and thus their subsequent activity. The results suggest that at least some of the ketoxime precursors could have a use as antiglaucoma agents without systemic side effects.

Relative effectiveness of prodrug and viscous solution approaches in maximizing the ratio of ocular to systemic absorption of topically applied timolol.

The effectiveness of the prodrug approach in maximizing the ratio of ocular to systemic absorption of topically applied timolol was compared with that based on viscous solutions. The pigmented rabbit was the experimental animal. o-Butyryl timolol, a lipophilic ester prodrug of timolol, was found to be twice as effective as hyaluronic acid and poly(vinyl alcohol) solutions in enhancing the ocular absorption of timolol. In addition, it was slightly more effective than retaining the instilled dose in the conjunctival sac for 240 min via nasolacrimal blockade. On the other hand, due to its inability to minimize contact of the instilled dose with the nasal mucosa, o-butyryl timolol was less capable than the viscous solutions in reducing systemic drug absorption. But this could be corrected by reducing the instilled solution volume from 25- to 5 microliter, resulting in a nine-fold reduction in plasma timolol levels while still providing the same amount of drug in the aqueous humor as a five times higher dose of timolol. The net result was a 15-fold improvement in the ratio of ocular to systemic drug absorption, which was also achieved upon retaining the instilled dose in the conjunctival sac for 240 min. It thus appears that the approach based on improved corneal absorption would be as effective as that based on improved retention in the conjunctival sac in maximizing the ratio of ocular to systemic drug absorption, so long as a smaller instilled dose volume of the prodrug is used.

Improved corneal penetration of timolol by prodrugs as a means to reduce systemic drug load.

A major problem in the use of timolol in glaucoma therapy is its relatively high incidence of cardiovascular and respiratory side effects. This report presents preliminary evidence for the feasibility of a prodrug approach to minimize systemic absorption of timolol using a reduced topical dose made possible by improved corneal drug penetration. The results indicate that the O-acetyl, propionyl, butyryl, and pivalyl ester prodrugs of timolol were virtually completely hydrolyzed between 30 and 150 min when incubated with plasma, aqueous humor, and ocular tissue homogenates of pigmented rabbits. Moreover, the in vitro corneal penetration of all but the O-pivalyl prodrug was 2-3 times higher than timolol. This was accompanied by a four- to sixfold increase in aqueous humor concentration at 5 and 30 min post-instillation of 15 mM solutions, although the plasma timolol concentration at the same time points was either unaltered or slightly reduced. Collectively, these preliminary findings suggest that at least a twofold reduction in the topical dose of timolol is possible by using prodrugs, thereby reducing timolol concentration in the systemic circulation and possibly the incidence of cardiovascular and respiratory side effects.

Urinary metabolites of timolol from humans and laboratory animals. Syntheses and beta-adrenergic blocking activities.

Syntheses are reported for three metabolites (2-4) of timolol (1) formed by oxidative metabolism of the morpholine ring. GLC-MS comparisons are presented which establish that the two metabolites whose structures were previously in question are identical with their synthetic counterparts 2 and 3. In 2, metabolic oxidation of the 4-morpholinyl group of 1 had occurred at the carbon next to oxygen to give the 2-hydroxy-4-morpholinyl moiety, whereas in 3, the morpholine of 1 has been oxidized one step further and then ring opened to produce the N-(2-hydroxyethyl)glycine substituent. Biological testing of synthetic samples of the three major metabolites from human urine (3, 4, and 6) indicated that only 4, in which the morpholine moiety has been degraded to a 2-hydroxyethylamino group, had significant beta-adrenergic blocking activity (one-seventh that of timolol in anesthetized dogs).

[A new beta-blocking agent in the treatment of chronic open-angle glaucoma: timolol maleate. Effect of instillation of 1 drop on the intraocular pressure]. / Un nouveau béta-bloquant dans le traitement du glaucome chronique à angle ouvert: le maléate de timolol. Effet tensionnel de l'instillation d'une goutte.

A total of 45 patients with chronic open-angle glaucoma were divided randomly into three groups of fifteen. Each patient in each group was given one drop into one eye (the other eye serving as a control), of either placebo, timolol 0,5%, or timolol 1,5%. The patients were observed for a period of seven hours, and results showed that timolol was effective in reducing ocular tension when compared to placebo. It was also rapid in action (one to two hours after instillation), and no side-effects were noted. Timolol 0,5% appears to be as equally effective as the 1,5% strength.

[Results of a double-blind medium-term study comparing effects of timolol maleate and epinephrine in 120 patients with chronic open-angle glaucoma]. / Résultat d'une étude à moyen terme en double aveugle comparant le maléate de timilol à l'épinéphrine sur 120 patients porteurs d'un glaucome chronique à angle ouvert.

A double-blind medium term study of the activity of timolol in chronic open-angle glaucoma was conducted in four French ophthalmological centers, using the same protocol. A total of 119 patients were treated: --60 with timolol; --59 with épinéphrine, for comparison. Results showed a significantly superior efficacy for timolol over épinéphrine, after in weeks of treatment. Good tonometric control was obtained in 81.6% of the patients treated with timolol, against 52.5% of those receiving épinéphrine. In 68% of the glaucomatons patients treated with timolol, good tonometric control was obtained with the lowest dose preparation containing 0.1%. No side-effects were noted during the study, either locally or generally (particularly blood pressure changes).

[Timolol maleate: results of its long-term action in the treatment of chronic primary open-angle glaucoma]. / Le maléate de timilol: résultat de son action à long terme dans le traitement du glaucome chronique primitif à angle ouvert.

Three groups of patients with chronic open-angle glaucoma, who had ineluded in the previous study, had been treated with timolol twice daily for more than a year. The long-term results confirm the efficacity noted in the medium-term survey, and the absence of side-effects, especially those related to the pulse rate and blood pressure in some of the patients. Drug associations had been necessary:--pilocarpin,--acetazolamid, seem to have the best synergic action with timolol.

[A single dose of maleate of timolol given orally: the effect on the ocular pressure (author's transl)]. / Le timolol per os en dose unique: effet sur la tension oculaire.

A single dose of 5 mg of maleate of timolol given orally to glaucomatous patients, considerably lowers their I.O.P. during a period of time of at least 6 hours. It causes only a slight decrease in blood pressure and pulse rate.