Peak pulse blood volume in controlled modification of local perfusion parameters

BACKGROUND: Choroidal autoregulation is discussed controversially. The present study was designed to investigate for the effect of standardized manipulation of local perfusion parameters on choroidal hemodynamics in cynomolgus monkey eyes with lasersurgically induced glaucoma (CMG; German abbreviation: RA-LHDG). METHODS: CMG unilaterally received 2-3 laser treatments so as to develop the lasered-eye glaucoma model. Intraocular pressure (IOP; German abbreviation: IOD) and Ocular Pulse Amplitude (OPA) were measured and Peak Pulse Blood Volume (PPBV; German abbreviation: PGBV) was determined. RESULTS: In CMG PPBV was not significantly (sig., p > 0.05) altered in laser-treated eyes--despite a sig. (p < 0.05) increase in IOP. Untreated contralateral control eyes of monkeys with an IOP-increase > 5 mm Hg in laser-treated eyes showed a sig. (p < 0.05) increase in PPBV. CONCLUSION: Unchanged PPBV in laser-treated eyes of CMG and an increase in PPBV in control eyes point at a bilateral autoregulatory compensatory mechanism, which is more manifest in eyes with IOPs in the normal range.     

Ocular pulse amplitude, intraocular pressure and beta blocker/carbonic anhydrase inhibition in combined therapy of primary open-angle glaucoma

BACKGROUND: Beyond intraocular pressure (IOP, German abbreviation: IOD) ocular perfusion is increasingly discussed in the pathogenesis of the glaucomas. The present study was designed to investigate for ocular pulse amplitude (OPA) in primary open angle glaucoma patients with elevated intraocular pressure (POAG, German abbreviation: POWG) following application of timolol, a beta-blocker and dorzolamide a topical carbonic anhydrase inhibitor. METHODS: OPA (Ocular Blood Flow System, OBF Labs U.K.) IOP, heart rate, systolic and diastolic brachial artery pressures were measured before and 4 weeks following application of timolol and additional 4 weeks following application of a timolol/dorzolamide combination in 14 POAG patients. RESULTS: Following administration of timolol, IOP was highly significantly reduced in drug treated POAG eyes; this effect was additively enhanced by dorzolamide. Timolol did not affect OPA, whereas dorzolamide significantly increased OPA in drug treated POAG eyes. Systemic perfusion parameters were unchanged. CONCLUSION: Timolol and dorzolamide drastically reduced IOP, in addition dorzolamide increased OPA in POAG, an ocular microcirculatory effect which may further help to improve prognosis of POAG.     

Glaucoma treatment with timolol.

Thirty-two eyes from 19 patients with either capsular glaucoma, pigmentary glaucoma or primary open angle glaucoma were given topical timolol and followed through a 3--6 months period. Twelve eyes were previously out of control on full medication including pilocarpine, epinephrine and acetazolamide. Eight of these eyes could be adequately controlled throughout the follow-up period on topical timolol or a combination of timolol and pilocarpine, but without resorting to acetazolamide. One eye needed acetazolamide in combination with timolol, and three eyes had to be referred to surgery. Twelve eyes were adequately controlled either on pilocarpine or full medication, but could be equally well controlled on timolol alone, or timolol and pilocarpine in combination. Acetazolamide could be withheld from all of the six patients who used this drug. Eight eyes were previously untreated. They could all be adequately controlled either on timolol (5 eyes) or timolol and pilocarpine (3 eyes). The study indicates that the effect of timolol 0.5% X 2 may be stronger than the combined effect of epinephrine 1% X 2 and acetazolamide 500 mg a day. Topical timolol was well tolerated. No side reactions occurred and the pupillary size and reactions were not influenced by the timolol treatment.     

Topical antiglaucoma medications and lacrimal drainage system obstruction

PURPOSE: To evaluate the effect of topical antiglaucoma medications on the lacrimal drainage system. METHODS: In a prospective controlled blind observational case series, 627 eyes of 384 patients (219 males, 165 females) were screened. Data recording (demographics and history taking), allocation in case (on topical antiglaucoma medications) and control (no glaucoma) groups, and examinations (eye examination and dye disappearance test) were performed by a senior ophthalmology resident. Exclusion criteria were epiphora prior to onset of treatment with topical antiglaucoma medication (only for case group), history of long-term use of topical medications (other than antiglaucoma medications in the case group), and previous ocular and periocular disorders. Diagnostic probing and irrigation of the lacrimal drainage system were performed by an oculoplastic surgeon masked to a patient's status as case or control. RESULTS: After exclusion, there were 130 eyes from 98 patients and 280 eyes from 178 patients in the case and control groups, respectively. Case and control groups were matched. There was significantly more lacrimal drainage system obstruction in the case group (26 of 130, 20%) than in the control group (24 of 280, 8.57%) (p = 0.002). Upper lacrimal drainage system obstruction was significantly more in the case group (p = 0.018). Increasing age was associated with significantly more obstruction in the control group only (p = 0.029). Statistically significant obstruction was found in the patients taking timolol + dorzolamide (p = 0.021) and timolol + dorzolamide + pilocarpine (p = 0.017) with a duration of 2 weeks to 156 months. CONCLUSION: Patients taking a combination of topical antiglaucoma medications showed significantly increased risk of developing lacrimal drainage system obstruction. Both total and upper obstruction was significantly more frequent in patients on topical antiglaucoma medications.     

Effect of changing from concomitant timolol pilocarpine to bimatoprost monotherapy on ocular blood flow and IOP in primary chronic angle closure glaucoma.

The aim of the present prospective masked study was to assess the effect of bimatoprost monotherapy on ocular blood flow and intraocular pressure (IOP) in eyes of primary chronic angle closure glaucoma patients already on concomitant timolol and pilocarpine. Thirty two patients of bilateral primary chronic angle closure glaucoma (PCACG) on topical timolol 0.5% twice a day and pilocarpine 2% three times daily were switched over to bimatoprost 0.03% once daily in both eyes. Intraocular pressure (IOP) and pulsatile ocular blood flow (POBF) were recorded before and after starting bimatoprost and were followed up every four weeks for three months. Bimatoprost had statistically significant (p < 0.05) mean IOP reduction from 19.3 +/- 6.6 to 13.5 +/- 4.5 mmHg (30.5%) and there was improvement from 858 +/- 260 to 1261 +/- 321 microL/min (46.8%) in mean pulsatile ocular blood flow (p < 0.05). Conjunctival hyperemia (32%) was the most common adverse effect of bimatoprost. Bimatoprost 0.03% monotherapy improved ocular blood flow and provided a better diurnal IOP control than concomitant timolol-pilocarpine in eyes with primary chronic angle closure glaucoma and was found to be well tolerated.     

The long-term hypotensive effect of timolol maleate compared with the effect of pilocarpine in simple and capsular glaucoma.

The long-term intraocular pressure (IOP) lowering effect of a beta-adrenergic blocking agent, timolol maleate, in topical administration was compared with the effect of pilocarpine on simple and capsular glaucoma by means of diurnal pressure curves during a six-month follow-up. In simple glaucoma timolol was more effective than pilocarpine in lowering IOP. In the follow-up a significant but not marked increase of the IOP was observed. In capsular glaucoma timolol was not effective enough, but when it was co-administered with miotics the IOP lowering effect was better than with either substance alone. Timolol induced no accomodative myopia, miosis, reduction of tear flow or other side effects. It increased the outflow facility in simple glaucoma but not in capsular glaucoma. During the trial, the anterior chamber depth increased while the corneal thickness remained unchanged. Four out of the six eyes included in a previous report of secondary glaucoma due to chronic uveitis are still, after one year of therapy, controlled with timolol.     

Intraocular pressure-lowering effects of latanoprost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open-angle glaucoma. Italian Latanoprost Study Group

PURPOSE: To compare intraocular pressure (IOP) after adding either latanoprost or pilocarpine to timolol treatment or switching to latanoprost monotherapy in glaucomatous eyes in which IOP was inadequately controlled with timolol. METHODS: This 6-month randomized study comprised 148 patients with primary open-angle or pseudoexfoliation glaucoma, which was inadequately controlled with topical beta-adrenergic antagonists. After a 2- to 4-week run-in period with timolol 0.5% twice daily, patients were assigned in randomized fashion to three study groups: one group received add-on therapy of latanoprost 0.005% once daily, the second group received add-on therapy of pilocarpine 2% three times daily, and the third group switched to latanoprost 0.005% once daily. Mean diurnal IOP was measured at baseline and after 3 and 6 months of treatment. RESULTS: At 6 months, 128 patients had completed the study. Diurnal IOP was significantly reduced from baseline in all groups. Adding latanoprost to timolol treatment reduced diurnal IOP by 6.1+/-0.3 mmHg (-28%), adding pilocarpine to timolol treatment reduced diurnal IOP by 4.2+/-0.3 mmHg (-19%), and switching from timolol to latanoprost monotherapy reduced diurnal IOP by 5.5+/-0.3 mmHg (-25%). CONCLUSION: A significantly greater reduction in diurnal IOP was achieved after addition of latanoprost than after addition of pilocarpine in patients in whom IOP was not adequately controlled with timolol alone. Further, the results of this study indicate that a switch to latanoprost monotherapy can be attempted before combination treatment is initiated.     

Timolol increased retrobulbar flow velocities in untreated glaucoma eyes but not in ocular hypertension

PURPOSE: To investigate retrobulbar blood flow velocities and the effects of topical timolol treatment in eyes with newly detected, previously untreated open angle glaucoma or ocular hypertension. METHODS: Fifteen eyes with open angle glaucoma (OAG) and 12 eyes with ocular hypertension (OH), in the same number of patients, all untreated and newly detected, were examined with colour Doppler imaging of retrobulbar vessels before and after 1 month of topical timolol treatment (0.5% Timoptic BID). RESULTS: Baseline central retinal artery end diastolic velocity was lower (48%, p=0.0002) and resistive index higher (7.6%, p=0.018) in the OAG group than in the OH group. In the glaucoma group mean end diastolic velocity increased by 41%, (p=0.006) while resistive index decreased by 5.8%, (p=0.02) on treatment, while no significant changes were seen in the OH group. Blood flow velocities in the ophthalmic artery did not change with treatment. Baseline IOP and IOP reduction did not differ between OAG and OH group. CONCLUSION: Peripheral resistance to blood flow was found to be increased in untreated glaucoma eyes as compared to a similar group of eyes with ocular hypertension. Timolol treatment diminished resistance significantly in the glaucoma group, but not in the ocular hypertension group. Thus the two groups responded differently to timolol treatment. The reaction to IOP lowering treatment could indicate defective autoregulation in the glaucoma group.     

DROP ATTACK IN GLAUCOMA: THE MELBOURNE EXPERIENCE WITH TOPICAL MIOTICS, ADRENERGIC AND NEURONAL BLOCKING DROPS

We have considered the effectiveness of miotics (pilocarpine 2% and ecothiopate iodide (Phospholine Iodide) 0.125 or 0.25%), adrenaline (Eppy/N 1 %) or adrenaline precursors (dipivalyl epinephrine or dipivefrin hydrochloride (Propine) 0.1%) and neuronal blockers (timolol maleate (Timoptol) 0.5%) in 165 patients in the clinical situation. All drops were effective in lowering intraocular pressure with an average fall of 6.6 mmHg for timolol (160 eyes), 8.21 mmHg for pilocarpine (79 eyes), 5.77 mmHg for dipivalyl epinephrine (57 eyes), 7.23 mmHg for adrenaline (17 eyes) and 10.5 mmHg for ecothiopate iodide (16 eyes). In chronic simple open-angle glaucoma, ocular hypertension and pseudoexfoliative glaucoma, pilocarpine and timolol were almost equally effective while dipivalyl epinephrine and adrenaline were also effective, but more as additive therapy, though dipivalyl epinephrine may be useful on its own in ocular hypertension. In low-tension glaucoma timolol and dipivalyl epinephrine together seemed best, while in secondary glaucomas all were effective at times, but ecothiopate iodide was best in aphakic glaucoma and fluorometholone (FML Liquifilm) 0.1% was important in inflammatory glaucoma. Side effects were frequent with dipivalyl epinephrine and timolol, with respiratory disease a strong contraindication to timolol.     

Pharmacokinetic basis for nonadditivity of intraocular pressure lowering in timolol combinations

The authors determined whether the ocular absorption of topically applied timolol in the pigmented rabbit was affected significantly by coadministration with either pilocarpine or epinephrine in the same drop to explain the nonadditivity in intraocular pressure lowering (IOP) seen clinically. They instilled 25 microliters of 0.65% timolol maleate solution (equivalent to 0.5% timolol), both in the presence and absence of 2.6% pilocarpine nitrate or 1% epinephrine bitartrate, into pigmented rabbit eyes. The time course of timolol concentration in the conjunctiva, anterior sclera, corneal epithelium, corneal stroma, aqueous humor, iris-ciliary body, and lens was monitored for 360 min by using reversed-phase high-performance liquid chromatography. The area under the timolol concentration-time curve in all but one of the anterior segment tissues was reduced by 20-50% (mean, 40%) when timolol was coadministered with pilocarpine and by 20-70% (mean, 42%) when timolol was coadministered with epinephrine. Such an effect was not a result of alterations in corneal permeability or aqueous humor turnover rate, nor was it related to the extent of systemic absorption caused by pilocarpine and epinephrine. Rather, the reduction in ocular timolol absorption may have been caused by the accelerated washout of timolol by tears stimulated by the coadministered drugs and, to a lesser extent, by the loss of timolol through binding to the increased amount of tear proteins induced by the coadministered drugs. Thus, the nonadditivity in IOP lowering from timolol-pilocarpine and timolol-epinephrine combinations is probably caused by changes in precorneal timolol clearance.     

Effect of timolol versus pilocarpine on visual field progression in patients with primary open-angle glaucoma.

BACKGROUND: Relatively few studies have been conducted linking decreasing intraocular pressure (IOP) to preservation of visual field. This investigation was conducted to determine if this link could be made and to compare the long-term effect of two ocular hypotensive agents on preservation of visual field. METHODS: In an observer-masked study, 189 patients with primary open-angle glaucoma received either timolol or pilocarpine by random allocation. The dose of antiglaucoma agent was increased from 0.25% to 0.5% twice daily for timolol or from 2% to 4% four times daily for pilocarpine if the initial IOP response was inadequate. After an on-treatment baseline, visual fields were followed every 4 months for 2 years using the Octopus program 32. RESULTS: Compared with timolol, significantly more patients receiving pilocarpine discontinued use because of inadequate IOP control (P < or = 0.01). By comparing the mean visual field scores, it can be seen that the pilocarpine group had a significantly worse score at all timepoints from month 4 to month 24. The pilocarpine group also had a greater mean number of test loci with decreased sensitivity of 5 or more decibels (dB) at all timepoints. The mean within-patient regression slope for timolol was 0.01 dB/month and for pilocarpine was -0.06 dB/month (P < 0.01). The study has shown that over a 2-year period, patients treated with pilocarpine 2% or 4% four times daily experienced a significantly greater visual field deterioration than that seen in patients receiving either 0.25% or 0.5% timolol twice daily. CONCLUSION: Although these data do not support a link between lowering of IOP and visual field preservation, treatment with timolol was associated with significantly less visual field loss than treatment with pilocarpine.     

Experimental studies with timolol: a new ocular hypotensive agent (author's transl)]

The present report reviews the animal pharmacology supporting the clinical use of timolol maleate ophthalmic solution in the therapy of glaucoma and elevated intraocular pressure (IOP). The studies have included the effects of timolol upon normal IOP of rabbits and upon elevated IOP in two models of experimental ocular hypertension. Comparisons are made between the latter actions of timolol and those of the reference adrenergic antiglaucoma agent, epinephrine. The interaction of timolol and the beta-adrenergic stimulant, isoproterenol, was also studied to assess the ability of timolol to block beta-adrenergic receptors in the eye. Additionally, the penetration and distribution of timolol in ocular and extraocular tissues and fluids following local application to the eyes of rabbits is described and a resume of the toxicological studies with timolol are presented.     

An experimental study of the ocular hypotensive action of dopaminergic antagonists

The ocular hypotensive action of a group of dopaminergic antagonists was observed in the low intraocular pressure model of albino rabbits infused with 20% NaCl. It was found that haloperidol lowered IOP significantly in both eyes, though the drug was administered in one eye. Compared with timolol and pilocarpine, the strength in lowering IOP was in the order haloperidol greater than timolol greater than pilocarpine. Haloperidol did not affect the pupil. It may be a promising antiglaucoma agent.     

Two-year follow-up of latanoprost 0.005% monotherapy after changing from previous glaucoma therapies.

AIM: The aim of this study was to evaluate the long-term follow-up of patients who were changed to latanoprost from previous glaucoma therapies. METHODS: Primary open-angle, exfoliative or chronic angle-closure glaucoma, or ocular hypertensive patients who switched to latanoprost therapy with a 2-year follow-up, were evaluated for efficacy, safety, and continuance of therapy. RESULTS: In 1,571 patients, the intraocular pressure (IOP) across all treatment groups of 21.3 +/- 4.1 was reduced to 17.6 +/- 3.2 mm Hg after switching to latanoprost. Latanoprost reduced the IOP from previous monotherapies, including nonselective beta-adrenergic blockers, topical carbonic anhydrase inhibitors, alpha-adrenergic agonists and pilocarpine (p < 0.0001) and adjunctive therapies, including the fixed combinations of dorzolamide and timolol, pilocarpine and timolol, and pilocarpine and metipranolol, and the unfixed combination of dorzolamide and timolol and dorzolamide and clonidine (p < 0.0028). Latanoprost further reduced the IOP across all diagnostic groups (p < 0.0001). The most common ocular adverse event was ocular irritation (n = 25; 1.6%), which was also the most common reason given for patients who discontinued latanoprost because of an adverse event (n = 20; 1.3%). CONCLUSIONS: The mean IOP was maintained at an acceptable level throughout the 2-year follow-up period on latanoprost. Latanoprost generally provides further reduction of IOP when switched from previous mono- and adjunctive therapies, with a low rate of side effects and discontinuations.     

Ocular hypotensive effects of cholinergic and adrenergic drugs may be influenced by prostaglandins E2 in the human and rabbit eye

PURPOSE: Increased PGE2 production by the iris and ciliary body regulate intraocular pressure (IOP) in vivo. Various cholinergic and adrenergic compounds are traditionally used as antiglaucoma drugs, and their effect on IOP reduction is antagonised by cyclooxygenase inhibitors, indicating a role for eicosanoids in their hypotensive activity. One of the most potent antiglaucoma drugs, PG2 alpha (Latanoprost), reduces IOP by increasing uveoscleral outflow and also increases PGE2 production by the iris and ciliary body in vivo. We investigated whether cholinergic and adrenergic antiglaucoma drugs induce the production of prostaglandin E2 (PGE2) in vitro by: 1) the iris-ciliary body (ICB) of rabbits and, 2) irises of glaucoma patients. METHODS: Pilocarpine 2%, epinephrine 1% and echothiophate iodide 0.125% were applied topically to both eyes of Albino rabbits. Control groups were treated with the corresponding vehicles, or untreated completely. Human iris specimens were obtained from nine untreated cataract eyes, and five eyes under antiglaucoma medication undergoing surgery. PGE2 were determined by a radioimmunoassay. RESULTS: PGE2 production by the ICB of treated rabbits in vitro was twice that of vehicle-treated or untreated rabbit eyes (p<0.001, for either group). In vitro PGE2 production by treated glaucoma patients' irises was three times higher (p<0.001) than in cataract control patients. CONCLUSIONS: The study found an increase in in vitro production of PGE2 by the irises of eyes treated with cholinergic and adrenergic antiglaucoma medications. This suggests a role for endogenous PG production in the hypotensive effect of both classes of drug.     

Treatment of intraocular pressure elevation after photorefractive keratectomy

PURPOSE: To study the effect of timolol maleate, dorzolamide, or a combination of both in post photorefractive keratectomy (PRK) eyes with an elevated intraocular pressure (IOP) after topical steroid administration. SETTING: Refractive Surgery Outpatient Department, 1st Department of Ophthalmology, Semmelweis University, Budapest, Hungary. METHODS: Forty-five patients with elevated IOP were randomly enrolled in 3 groups: Group 1 received timolol maleate 0.5% twice a day; Group 2 received timolol maleate 0.5% twice a day and dorzolamide 2% 3 times a day; and Group 3 received only topical dorzolamide 2% 3 times a day. Intraocular pressure was measured 3 days and 1, 3, and 6 weeks after the antiglaucoma medication was started. RESULTS: The mean preoperative IOP was 15.25 mm Hg +/- 1.28 (SD). Following administration of topical fluorometholone, the IOP increased a mean of 27.39 +/- 2.88 mm Hg. Six weeks after the antiglaucoma therapy was started, the mean IOP reduction was 6.6 mm Hg in Group 1, 8.86 mm Hg in Group 2, and 4.64 mm Hg in Group 3. CONCLUSIONS: A combination therapy of timolol 0.5% and dorzolamide 2% was most effective in treating secondary IOP elevation after PRK. Dorzolamide alone did not adequately control secondary post-PRK IOP elevation.     

Timolol and aceclidine. A clinical study of interaction in the eye

In the Netherlands timolol maleate, probably the drug of first choice in antiglaucoma therapy, is often combined with other intraocular pressure lowering drugs. The efficacy of most combinations have been discussed in the literature several times, except the one with aceclidine, a parasympathetic drug, that has a reasonable popularity in Western Europe. Unlike pilocarpine, aceclidine does not seem to give a clinically significant additional pressure lowering effect in timolol pre-treated eyes. The decrease in IOP in aceclidine pre-treated eyes after single dose timolol seems to be an effect of timolol alone. Our results suggest that co-administration of timolol and aceclidine is not a rational action in antiglaucomatous therapy.     

The outcome of phacoemulsification in eyes after filtering glaucoma surgery

BACKGROUND: Our aim was to evaluate the outcome of phacoemulsification in eyes after filtering glaucoma surgery. PATIENTS AND METHODS: Thirty eyes of 30 patients with different forms of glaucoma in which phacoemulsification after filtering glaucoma surgery was done were included in this retrospective study. Intraocular pressure (IOP) was measured before and one week, 1, 3, 6, 12, 18, 24, 30, 36 and 42 months after phacoemulsification. The best corrected visual acuity (BCVA) and the number of antiglaucoma medications before phacoemulsification and at the end of follow-up were evaluated. Partial failure of IOP control was defined as the need for an increased number of antiglaucoma medications to maintain IOP < 21 mmHg or prevent a progression of visual field or optic disc damage. Complete failure of IOP control was defined as an IOP > 21 mmHg with an additional number of antiglaucoma medications or a progression of visual field or optic disc damage requiring filtering surgery. RESULTS: The mean interval between filtration surgery and phacoemulsification was 5.8 years (SD 3.8) and the mean follow-up after phacoemulsification was 23.4 months (SD 11.4). There were no differences between the mean IOP before and after phacoemulsification during the entire follow-up period (p > 0.05). The mean preoperative BCVA was 0.30 (SD 0.2), improving to a mean of 0.72 (SD 0.3) postoperatively at the end of follow-up (p < 0.0001). The mean number of antiglaucoma medications before phacoemulsification was 1.2 (SD 1.2), increasing after phacoemulsification to 1.5 (SD 1.2) at the end of follow-up (p > 0.05). In 9 eyes a partial failure of IOP control was assessed, so according to the Kaplan-Meier survival analysis the success rate after 12 months was 72 % and after 42 months 67 %. In 3 eyes a complete failure of IOP control was assessed, thus according to the Kaplan-Meier survival analysis the success rate after 22 months was 93 % and after 42 months 77 %. CONCLUSION: Phacoemulsification in eyes after filtering glaucoma surgery resulted in a stable IOP, a non-significant increase in the number of antiglaucoma medications and a significantly improved BCVA.     

Comparative effects of antiglaucoma drugs on voltage-dependent calcium channels

BACKGROUND: Experimental evidence suggests that substances able to interact with voltage-dependent Ca2+ channels (VDCCs) might be beneficial in glaucoma management. It was therefore of significance to show that beta-adrenoceptor antagonists used in glaucoma directly interact with L-type VDCCs. In the present study, the affinity of several antiglaucoma drugs (betaxolol, carteolol, levobunolol, timolol, brimonidine, dorzolamide, latanoprost and pilocarpine) for these and other VDCCs was investigated using radioligand binding assays. Experiments were also carried out to assess the effect of antiglaucoma drugs on the NMDA-stimulated Ca2+ influx into isolated rat retinas. METHODS: Competition radioligand binding studies to L-, N- and P/Q-type VDCCs were performed in rat cortical homogenates. The effects of antiglaucoma drugs on the NMDA-stimulated influx of 45Ca2+ were studied in isolated rat retinas. RESULTS: Only beta-adrenoceptor antagonists significantly interacted with radioligand binding to L-type VDCCs, with betaxolol displaying the highest potency. None of the antiglaucoma drugs tested showed any significant affinity for either N- or P/Q-type VDCCs. Only beta-adrenoceptor antagonists attenuated the NMDA-stimulated 45Ca2+ influx into isolated rat retinas, with betaxolol exhibiting at least 10 times higher potency than timolol. Brimonidine, dorzolamide, latanoprost and pilocarpine did not elicit any significant effect on the NMDA-stimulated 45Ca2+ influx. Additional experiments strongly suggested that the effect of betaxolol on the NMDA-stimulated 45Ca2+ resulted from inhibition of L-type VDCCs. CONCLUSION: Of the antiglaucoma drugs investigated, betaxolol displays the greatest L-type VDCC-blocking activity and this may be of clinical relevance. Such a characteristic could account for some of its described ocular actions.     

Combined therapy of pilocarpine or latanoprost with timolol versus latanoprost monotherapy

Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance.