Instillation Of Timolol Research Articles

Pharmacologic activity of mGLUR4 agonist in a model of primary open-angle glaucoma: A preclinical experimental study

Background. Worldwide, more than 67 million people suffer from glaucoma. In Russia, this number exceeds 1.08 million people. Annually, the number of primary cases increases by 3–4%. The increasing prevalence of glaucoma intensifies the search for neuroprotectants that can reduce the loss of retinal ganglion cells, thereby impeding the progression of the disease. Objective. To study of the pharmacological activity of mGLUR4 agonist, ZC64-0001 substance, on a model of primary open-angle glaucoma. Methods. The conducted preclinical study involved 60 sexually mature male Wistar rats, weighing 180–220 g. The observation period was 73 days. The animals were divided into 6 groups with 10 animals in each. Group 1 included intact animals (without any manipulations); Group 2 included negative control animals with the water injected in the anterior chamber of the eye; in Group 3–6, primary open-angle glaucoma was modelled by injecting 1% hyaluronic acid solution into the anterior chamber of the eye once every 7 days from day 1 to day 62 of the study. Animals in Group 4 were treated intragastrically with H-[(4-chlorophenyl)methyl]-1,6-dihydro-4-methoxy-1-(2-methylphenyl)-6-oxo-3-pyridazinecarboxamide under the laboratory code of ZC64-0001 at a dose of 10 mg/kg. Animals in Group 5 received Mexidol as a comparison drug intramuscularly at a dose of 25.7 mg/kg. Animals in Group 6 were treated with a Timolol instillation at a dose of 0.009 ml/kg. The studied compounds were administered from day 63 of the study once a day for 10 days. The evaluated indicators included the level of microcirculation in the retina, the amplitude of a-wave and b-wave of the electroretinogram, and the number of retinal ganglionic layer nuclei in the setting of the conducted treatment. Statistical processing of the data was performed using the Statistica 10.0 software (StatSoft, USA). Differences were determined at the significance level of p ˂ 0.05. Results. ZC64-0001 increased the level of microcirculation relative to the group with modelled glaucoma by 11.5%, with this indicator being statistically significantly different from that both in the group with modelled glaucoma and the intact group ( р < 0.05). In the group of animals receiving ZC64-0001, the amplitude of a-wave increased relative to the primary glaucoma group by 17.7%, with this index being statistically different from the groups of intact animals and negative control (р < 0.05). The b-wave amplitude increased by 34.4% relative to the group with modelled glaucoma, being statistically different from the intact group, negative control group, pathology modelled group, and comparison drug groups ( р < 0.05). Administration of ZC64-0001 increased the number of retinal ganglion cell nuclei relative to the group with modelled glaucoma by 41.0%, which had a statistically significant difference from all the studied groups ( р < 0.05). Conclusion. The ZC64-0001 compound demonstrated high neuroprotective properties in a model of primary open-angle glaucoma, leading to an improvement in retinal microcirculation, an increase in the wave amplitude according to the conducted electrophysiological study, and an increase in the number of ganglion cell nuclei.

Ocular and Systemic Pharmacokinetics of Brimonidine and Timolol After Topical Administration in Rabbits: Comparison Between Fixed-Combination and Single Drugs.

IntroductionThis study was aimed to compare ocular tissue distribution and systemic exposure of brimonidine and timolol after single topical administration to rabbits of fixed-combination ophthalmic solution of 0.1% brimonidine tartrate and 0.5% timolol and single drugs (0.1% brimonidine tartrate ophthalmic solution or 0.5% timolol ophthalmic solution) or concomitant administration of single drugs.MethodsRabbits were treated with a single topical administration of each ophthalmic solution or concomitant administration of single drugs. For concomitant administration, 0.1% brimonidine tartrate was administered after 0.5% timolol instillation successively within 10 s (without interval) or with 5-min intervals. Brimonidine and timolol concentrations in the aqueous humor, retina/choroid, vitreous body, and plasma were determined with liquid chromatography-tandem mass spectrometry.ResultsThe area under the curve values of both drugs in the aqueous humor after fixed-combination administration were comparable to those after concomitant administration. The value of brimonidine was comparable to that after 0.1% brimonidine tartrate administration, whereas the value of timolol was 1.6-fold higher than that after 0.5% timolol administration. The plasma area under the curve value of brimonidine did not differ between fixed-combination and single-drug administrations, but that of timolol was higher after fixed-combination administration than after single-drug administration. Similar concentration-time curves of brimonidine were observed in the posterior ocular tissues in all groups. For concomitant administration, both drug concentrations in the aqueous humor without an administration interval were lower than those with 5-min intervals.ConclusionThere was no difference in the effect of formulation compositions on ocular and systemic pharmacokinetics among the ophthalmic solutions, but brimonidine may alter the ocular and systemic absorption of timolol, which is possibly due to its pharmacologic action. We demonstrated the importance of an administration interval in the concomitant administration of these drugs. This concern could be avoided by using a fixed combination of brimonidine and timolol.

Omega-3 fatty acids protect retinal neurons in the DBA/2J hereditary glaucoma mouse model

The purpose of this study was to evaluate the neuroprotective effects of omega-3 polyunsaturated fatty acid (ω3-PUFA) supplementation, alone or in combination with timolol eye drops, in a mouse model of hereditary glaucoma. DBA/2J mice (8.5-month-old) were assigned to an ω3-PUFAs + timolol, ω3-PUFAs only, timolol only, or an untreated group. Treated mice received a daily gavage administration of eicosapentaenoic acid (EPA) and docosahexaenoic acid and/or topical instillation of timolol (0.5%) once a day for 3 months. Blood was analysed regularly to determine ω3-PUFA levels and retinas were histologically analysed. Real-time PCR and Western blot were performed for retinal pro-inflammatory cytokines and macrophages. Blood arachidonic acid/EPA ratio gradually decreased and reached the desired therapeutic range (1–1.5) after 4 weeks of daily gavage with ω3-PUFAs in the ω3-PUFAs + timolol and ω3-PUFAs only groups. Retinal ganglion cell densities were significantly higher in the ω3-PUFAs + timolol (1303.77 ± 139.62/mm2), ω3-PUFAs only (768.40 ± 52.44/mm2) and timolol only (910.57 ± 57.28/mm2) groups than in the untreated group (323.39 ± 95.18/mm2). ω3-PUFA supplementation alone or timolol alone, significantly increased protein expression levels of M1 macrophage-secreted inducible nitric oxide synthase and M2 macrophage-secreted arginase-1 in the retina, which led to significant decreases in the expression levels of tumour necrosis factor-α (TNF-α). ω3-PUFA supplementation alone also resulted in significantly reduced expression of interleukin-18 (IL-18). ω3-PUFA + timolol treatment had no effect on the expression level of any of the aforementioned mediators in the retina. Supplementation with ω3-PUFAs has neuroprotective effect in the retinas of DBA/2J mice that is enhanced when combined with timolol eye drops. The continued inflammation following ω3-PUFAs + timolol treatment suggests that downregulation of IL-18 and TNF-α may not be the only factors involved in ω3-PUFA-mediated neuroprotection in the retina.

Neuroprotective effects of EPA and DHA fatty acids in the DBA/2J hereditary glaucoma mouse model

PurposeTo determine whether omega‐3 (ω‐3) supplementation used alone or in combination with timolol, protect against inflammation and RGC loss in DBA/2J mouse modelMethodsDBA/2J mice were assigned to the following treatment groups (n = 20/group) with balanced sex:ω‐3 plus timolol, ω‐3,timolol and untreated. All treatments were started at the age of 8.5 months and continued until sacrifice at 11.5 months of age. Mice received daily gavage administration of fish oil (EPA/DHA = 2:1) and/or topical instillation of timolol (0.5%) once a day. The dosage of EPA/DHA was adjusted so that the AA/EPA blood ratio was within therapeutic range of 1–1.5 using Gas chromatography. RGC densities were counted using Brn3a antibody. Real‐time polymerase chain reaction was performed to determine the gene expression of TNF‐α, IL‐1β and IL‐18 inflammatory molecules in the retinas. Western blot analysis was used to test the protein expression of IL‐18 in the retinas.ResultsRGC densities were found significantly higher in the groups of ω‐3 plus timolol (p = 0.0041),ω‐3 (p = 0.0097) and timolol (p = 0.0011) compared to that of untreated group. No significant differences were seen in the gene expression levels of TNF‐α (p = 0.0790, p = 0.0742, p = 0.1006),IL‐1β (p = 0.1242, p = 0.4865, p = 0.5280) and IL‐18 (p = 0.6320, p = 0.3351, p = 0.3663) in the retinas between the groups of ω‐3 plus timolol, ω‐3 or timolol and the untreated group. Protein expression of IL‐18 was significantly reduced in the retinas of ω‐3 treatment group compared to that of untreated (p = 0.0367)ConclusionsOur findings suggest not only that ω‐3 supplementation (AA/EPA ratio <1.5) has a neuro‐protective effect in the DBA/2J, as demonstrated by the RGC density analysis, but also provide insight into the role of inflammation in the pathogenesis of glaucoma and indicate that ω‐3 administration could be beneficial in controlling inflammation in the retina.

Effect of prophylactic timolol 0.1% gel on intraocular pressure after an intravitreal injection of ranibizumab: a randomized study.

PurposeThe purpose of this study is to make a prospective evaluation of the effect of timolol 0.1% eye gel on short-term intraocular pressure (IOP) after an intravitreal injection (IVI) of ranibizumab.Participants and methodsOne hundred and fifty eyes of 150 IVI-naïve patients with macular edema caused by various pathological conditions (age-related macular degeneration, central or branch retinal vein occlusion, and diabetic retinopathy) were scheduled to undergo an IVI of ranibizumab (0.5 mg/0.05 cc). The patients were randomly divided into three groups: 50 were not treated with timolol before the IVI (group 1); 50 received an instillation of timolol 0.1% eye gel the evening before the IVI (group 2); and 50 received an instillation of timolol 0.1% eye gel 2 hours before the IVI (group 3). The incidence of clinically significant intraocular hypertensive spikes (>25 mmHg and >40 mmHg) was then assessed.ResultsOur findings showed that mean IOP at baseline was significantly higher than at both 5 and 60 minutes after IVI (P<0.01). Spikes of >25 mmHg were recorded at either time in 27 patients (54%) in group 1, 23 patients (44%) in group 2, and 24 patients (48%) in group 3. None of the between-group differences were significant. Spikes of >40 mmHg (which were only detected 5 minutes after IVI) were recorded in nine (18%), eight (16%), and one patient (2%) in groups 1, 2, and 3, respectively. The only significant difference was between the control and group 3 (P=0.012).ConclusionAn increase in IOP after antivascular endothelial growth factor IVI is a frequent complication. The prophylactic use of timolol 0.1% gel effectively reduced the mean IOP when administered 2 hours before IVI and was also effective in preventing dangerous IOP spikes of >40 mmHg. It is therefore recommended before IVIs as a means of preventing emergency procedures and preserving the health of the optic nerve.

Avaliação eletrocardiográfica de cães clinicamente hígidos sob tratamento com solução oftálmica de maleato de timolol 0,5%: estudo preliminar

&lt;p&gt;O maleato de timolol 0,5% é um fármaco recomendado para tratamento de glaucoma em cães. Após instilação, e absorvido para a circulação sistêmica e por ser um antagonista beta-adrenérgico pode promover efeitos colaterais sistêmicos importantes sobre a condução elétrica cardíaca. No presente estudo, foi avaliada a alteração causada pelo timolol 0,5% oftálmico no eletrocardiograma. Foram selecionados seis cães hígidos para participar de dois tratamentos oftálmicos diferentes: no primeiro foi instilado placebo (hipromelose 0,5%) e no segundo utilizou-se timolol 0,5%. O colírio foi instilado a cada 12 horas por 14 dias. Os parâmetros eletrocardiográficos foram mensurados nos tempos: zero, 10, 60, 120, 240, 360 e 720 minutos após instilação da solução ocular nos dias primeiro, sétimo e décimo quarto de cada tratamento. As alterações eletrocardiográficas foram mais evidentes entre 120 e 240 minutos pós-instilação de timolol 0,5% quando comparado com o tratamento placebo. O ritmo foi irregular, com momentos de arritmia sinusal e bradicardia sinusal. Os intervalos RR e PR prolongaram significativamente (p &amp;lt; 0,05) desde o primeiro dia de instilação de timolol, sendo o prolongamento mais expressivo no décimo quarto dia de tratamento. O intervalo QT demonstrou pouca variação, apenas prolongando significativamente (p &amp;lt; 0,05) no décimo quarto dia de aplicação de timolol. O intervalo QTc não demonstrou alteração significativa (p &amp;gt; 0,05). Apesar das alterações encontradas, não foram observadas manifestações clínicas relacionadas ao timolol nos animais estudados. Deve-se considerar, porém, que os animais em questão eram hígidos e, portanto, as alterações decorrentes do uso do timolol em animais com cardiopatias preexistentes poderiam promover sinais clínicos, sendo recomendada a avaliação cardíaca de pacientes previamente à prescrição do timolol oftálmico.&lt;/p&gt;

Timolol 0.1% Gel versus Timolol 0.5% Eyedrops in the Prophylaxis of Ocular Hypertension after Phacoemulsification Surgery

To determine the efficacy of timolol 0.1% gel in preventing increased intraocular pressure (IOP) after uncomplicated cataract surgery. In this prospective, double-blinded, randomized study were enrolled 70 patients who underwent uncomplicated cataract surgery with phacoemulsification and intraocular lens implantation. After cataract surgery, 25 patients received a single instillation of timolol 0.1% gel (group A); 20 a single instillation of timolol 0.5% eyedrops (group B); and 25 no treatment (group C). The IOP was measured before surgery (T0) and 5 minutes (T1), 2 hours ± 30 minutes (T2), 4 hours ± 30 minutes (T3), and 24 hours ± 180 minutes after surgery (T4). The patients in groups A and B had lower mean IOP values than those in group C at T2, T3, and T4; IOP was higher at T2 and T3 than at T1 in the control group. The IOP spikes in group C were higher than those observed in groups A and B: at T2, they were observed in 40% of the patients in group A, 30% in group B, and 76% in group C; and at T3, in respectively 20%, 10%, and 68%; and at T4, in respectively 4%, 0%, and 28%. Timolol 0.1% gel is as effective as timolol 0.5% eyedrops in reducing IOP and in limiting the occurrence of IOP spikes for up to 24 hours after phacoemulsification.

Intraocular Pressure-reducing Effects of Latanoprost Versus Timolol in Chinese Patients With Chronic Angle-closure Glaucoma

To compare the efficacy and safety of latanoprost and timolol in Chinese patients with chronic angle-closure glaucoma (CACG), who had undergone laser or surgical peripheral iridotomy but who continued to experience elevated intraocular pressure (IOP) levels. This 8-week, randomized, open-label, parallel, active-controlled study was conducted at 4 sites in China. Subjects were 18 to 75 years of age; had primary, unilateral, or bilateral CACG with an IOP between 21 and 35 mm Hg inclusive at screening; and had undergone peripheral iridotomy at least 1 month before study entry. Subjects were randomized (1:1) to receive 1 drop of latanoprost 0.005% (PM) or 1 drop of timolol 0.5% twice daily (AM and PM). Follow-up was at weeks 1, 2, 4, and 8. Primary efficacy endpoint: change in average IOP from baseline to week 8. One hundred forty-two subjects were randomized into the latanoprost and timolol group; the analysis population included 141 subjects (latanoprost, n=71; timolol, n=70). Mean baseline average IOP levels were 24 mm Hg in both groups. The least square mean change from baseline to week 8 was -6.7 mm Hg for latanoprost versus -4.9 mm Hg for timolol [least square mean difference=1.8 mm Hg (95% confidence interval, 0.7-2.9); P<0.001]. Latanoprost was associated with significantly lower mean average IOP levels at each visit (P<0.05). Both treatments were well tolerated and no treatment-emergent adverse event was considered by investigators to be severe. Once-daily administration of latanoprost 0.005% was significantly more effective in reducing IOP in Chinese patients with CACG than twice-daily instillation of timolol 0.5%. Both agents were well tolerated.

Sympathetic Inhibition of Accommodation after Sustained Nearwork in Subjects with Myopia and Emmetropia

The purposes of the present study were to assess the effect of a sympathetic inhibitory pharmacologic agent, timolol maleate, on the magnitude of nearwork-induced transient myopia (NITM) and its decay in different refractive groups for an extended near task duration and to determine the proportion of the young adult population manifesting effective sympathetic access under naturalistic closed-loop viewing conditions. Ten subjects with emmetropia and 10 with myopia were tested. They read binocularly for 1 hour at a distance of 35 to 40 cm. NITM was calculated as the difference in distance refractive state after task as compared with before task immediately after reading. All subjects received timolol maleate to block the sympathetic nervous system and betaxolol as a control agent in independent test sessions separated by at least 3 days. Forty minutes after drug instillation, the NITM measurement procedure was repeated. Initial NITM magnitude was larger in subjects with myopia than in subjects with emmetropia before and after timolol instillation. Furthermore, NITM magnitude in subjects with sympathetic access was increased after timolol instillation. In contrast, with the control agent betaxolol, there was no increase. NITM decay duration to baseline was increased after timolol instillation in the subjects with myopia only. Only 15% of the subjects (n = 3 subjects with myopia) demonstrated effective and significant access to sympathetic facility. Subjects with myopia demonstrated an increase in decay duration with timolol, thus suggesting impaired sympathetic inhibition of accommodation. This may be a precursor for myopia progression in some persons.

Success rates for switching to dorzolamide/timolol fixed combination in timolol responders who are insufficiently controlled by latanoprost monotherapy

We aimed to investigate the safety and efficacy of dorzolamide/timolol fixed combination (DTFC) in timolol responders with ocular hypertension or open-angle glaucoma who switched to DTFC because of insufficient control on latanoprost. We carried out a prospective, open-label cohort study with an active-historical control in which qualifying patients must have been treated with latanoprost monotherapy for at least 4 weeks, must have demonstrated insufficiently controlled intraocular pressure (IOP) (> or = 19 mmHg at 08.00 hours), and must have shown a decrease in IOP at 2 hours after timolol instillation of > or = 3 mmHg or > or = 15%. Patients then began DTFC dosed at 08.00 hours and 20.00 hours and discontinued latanoprost. Patients were evaluated again after 4 and 12 weeks. In 57 patients IOP was further reduced by 2.4 +/- 3.3 mmHg at 08.00 hours (p < 0.0001) and by 3.5 +/- 3.3 mmHg at 10.00 hours (p < 0.0001) after switching to DTFC. Responses to the Comparison of Ophthalmic Medications for Tolerability (COMTol) questionnaire showed no difference between DTFC and latanoprost for in terms of overall preference, typical daily activities, limitation of activities, compliance, satisfaction or quality of life (p > 0.05). However, greater frequency in burning and/or stinging (p < 0.0001) and bitter taste (p < 0.0001) were observed with DTFC, whereas unusual taste (p = 0.02) and itchy eyes (p = 0.05) were associated with latanoprost. This study suggests that patients who are insufficiently controlled on latanoprost monotherapy, and who are timolol responders, can generally achieve further IOP reduction and similar tolerance levels when changed to DTFC.

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

We have established an ocular pharmacokinetic/pharmacodynamic (PK/PD) model for a beta-adrenergic antagonist, timolol, after instillation into rabbits. Timolol concentrations were determined by HPLC in the tear fluid, aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber of the eye in rabbits. In addition, intraocular pressure (IOP) measurement was performed after instillation of timolol by a telemetry system, which was able to obtain detailed IOP data automatically. The PK/PD parameters were estimated by fitting the concentration-time profiles and the ocular hypotensive effect-time profiles using MULTI (RUNGE) program. The PK model consisted of six compartments and the PD model included aqueous humor dynamics based on an action mechanism of timolol, which causes lowering of IOP by suppressing aqueous humor production. The PK/PD model described well the concentration-time profiles and the ocular hypotensive effect-time profiles after instillation of timolol. This study is the first trial to develop an ocular PK/PD model for timolol after instillation. This model can predict both the drug concentrations in various ocular tissues and the ocular hypotensive effect after instillation of timolol.

Effects of topical carteolol and timolol on tissue circulation in the iris and choroid

Purpose. To evaluate the effects of topical carteolol or timolol on tissue circulation in the iris and posterior choroid. Methods. After a topical instillation of 20 µl of 2% carteolol, 0.5% timolol, or physiological saline (for control) into one eye, and physiological saline into the other eye of pento-barbital-anesthetized Dutch pigmented rabbits, normalized blur value; a quantitative index of tissue blood velocity in the iris (NB iris) and posterior choroid (NB cho) was obtained using the laser-speckle method. Intraocular pressure (IOP), blood pressure and pulse rate were serially monitored for 2 hours after instillation. Using separate groups of rabbits, NB iris and IOP were measured before and after 20-day twice-daily unilateral treatment of carteolol or timolol. Results. After a single instillation of carteolol, NB iris was significantly greater only in the treated eyes than control eyes (P = 0.0050, repeated measures two-way ANOVA), while NB cho showed no significant change. IOP in the treated eyes significantly reduced (P = 0.0005). Bilateral reductions of tissue vascular resistance in the iris were found after carteolol instillation (P = 0.0183 ~ 0.0322). After timolol instillation, serial changes in NB iris and NB cho in the treated eyes were significantly different from those in control eyes (P = 0.0129, 0.0031), while there were no significant differences at any of time points (Mann-Whitney test); IOP in both eyes was significantly reduced (P = 0.0096 ~ 0.0005); tissue vascular resistance in the iris and posterior choroid showed no significant changes. After 20-day treatment, NB iris in the both eyes of carteolol-treated rabbits significantly increased from the baseline (P = 0.0280, 0.0425, Wilcoxon signed rank test) and NB iris in timolol-treated eyes significantly decreased (P = 0.0280). Conclusions. A single instillation of topical carteolol significantly increased the iris tissue blood velocity in the treated eye and reduced the tissue vascular resistance in both eyes. Topical timolol tended to decrease tissue blood velocity in the iris and choroid of the treated eye, but showed no significant effects on tissue vascular resistance in the both tissues.

Effect of topical timolol on tissue circulation in optic nerve head

The effects of topical 0.5% timolol on tissue circulation in the albino rabbit optic nerve head (ONH) were investigated using a laser speckle tissue circulation analyzer. In the first experiment, the normalized blur (NB) value, a quantitative index of tissue blood flow velocity in the ONH, intraocular pressure (IOP), blood pressure, and pulse rate were measured under general anesthesia before, and 30, 60, 90, and 120 minutes after a 20 μL instillation of timolol in one eye and the vehicle in the other eye in a masked, randomized manner. In the second experiment, one eye of a rabbit received timolol twice daily for 20 days and the fellow eye received the vehicle in a masked, randomized manner. Every 5 days IOP was measured and the NB in the ONH and IOP were measured before treatment and 2 hours after the last instillation on the 20th day. After a single instillation of timolol, PR showed a maximum reduction of 12% and IOP in the timolol-treated eyes showed a maximum decrease in 25%. NB in the ONH and BP did not show any significant change during the experiment. After a 20-day treatment with timolol, IOP showed a maximum decrease of 25% in the timolol-treated eyes and 16% in the vehicle-treated eyes. The NB in the timolol-treated eyes increased significantly by 16% ( P < 0.01), whereas that in the vehicle-treated eyes showed no significant change. It was suggested that long-term topical timolol with a normal drug regimen caused a significant increase in the peripheral blood velocity in the ONH only in the timolol-treated eyes, at least partly, by local penetration of the drug. Ocular penetration of topically applied timolol is thought to be similar between rabbit and human eyes. Therefore, the present results may have clinical implications.

Sublingual timolol-an alternative to topical medication in glaucoma?

AIMS--To assess whether timolol drops lower a raised intraocular pressure (IOP) when given sublingually. This route of administration would be useful for glaucoma patients who are unable to instil their own drops--for example, because of stroke, poor vision, arthritis, poor coordination, or blepharospasm. METHODS--A placebo controlled randomised, double masked, crossover study was undertaken in the glaucoma clinic of a large teaching hospital. Twelve patients with ocular hypertension with IOPs over 21 mm Hg, normal optic discs, and full visual fields were examined by Humphrey perimetry. Single dose units of timolol maleate 0.5% drops and normal saline drops were given by instillation in one eye or sublingually. The IOP of both eyes, pulse rate, and blood pressure were all measured before and after each type of drop and route of administration. RESULTS--Two hours after instillation of timolol in one eye, the IOP in the treated eye was reduced by a mean of 8.5 mm Hg (p = 0.0000), and by 1.66 mm Hg in the fellow eye (p = 0.03). Two hours after sublingual instillation of timolol, the IOP was reduced by 7.55 mm Hg in the study eye (p = 0.0000) and by 7.7 mm Hg in the fellow eye (p = 0.0000). There was an equal amount of reduction in pulse rate by either route, but there was no significant change in blood pressure. CONCLUSIONS--The results show that, at least after 2 hours, sublingual treatment is almost as effective as topical treatment in lowering a raised IOP.

Sublingual timolol--an alternative to topical medication in glaucoma?

To assess whether timolol drops lower a raised intraocular pressure (IOP) when given sublingually. This route of administration would be useful for glaucoma patients who are unable to instil their own drops--for example, because of stroke, poor vision, arthritis, poor coordination, or blepharospasm. A placebo controlled randomised, double masked, crossover study was undertaken in the glaucoma clinic of a large teaching hospital. Twelve patients with ocular hypertension with IOPs over 21 mm Hg, normal optic discs, and full visual fields were examined by Humphrey perimetry. Single dose units of timolol maleate 0.5% drops and normal saline drops were given by instillation in one eye or sublingually. The IOP of both eyes, pulse rate, and blood pressure were all measured before and after each type of drop and route of administration. Two hours after instillation of timolol in one eye, the IOP in the treated eye was reduced by a mean of 8.5 mm Hg (p = 0.0000), and by 1.66 mm Hg in the fellow eye (p = 0.03). Two hours after sublingual instillation of timolol, the IOP was reduced by 7.55 mm Hg in the study eye (p = 0.0000) and by 7.7 mm Hg in the fellow eye (p = 0.0000). There was an equal amount of reduction in pulse rate by either route, but there was no significant change in blood pressure. The results show that, at least after 2 hours, sublingual treatment is almost as effective as topical treatment in lowering a raised IOP.

Topical timolol, corneal epithelial permeability and autofluorescence in glaucoma by fluorophotometry.

Corneal epithelial permeability and autofluorescence were measured by fluorophotometry in patients with open-angle glaucoma or ocular hypertension to quantify the epithelial function of the cornea and to evaluate its metabolic activity in 24 patients using daily timolol and 11 not using timolol. The findings were compared with those in age-matched healthy controls. Permeability values in patients using timolol were 1.9 times higher than in patients not using timolol and 2.5 times higher than in healthy controls (Mann-Whitney test P < 0.001). Values for patients not using timolol did not differ from those for healthy controls (P = 0.15). Corneal autofluorescence values in each patient group were higher than in healthy controls (P = 0.002). (1) open-angle glaucoma or ocular hypertension alone does not affect corneal epithelial permeability; (2) daily instillation of timolol causes impairment of the corneal epithelial barrier; (3) open-angle glaucoma or ocular hypertension are likely to induce an increase of corneal autofluorescence.

A Simple Method of Determining the Time Course of Timolol's Effects on Aqueous Flow in Humans

We have devised a simple method of determining the time course of the effects of timolol maleate on aqueous flow using changes in aqueous protein concentrations. Aqueous protein concentrations were measured with a laser flare-cell meter. First, the value of the coefficient of protein entry into the anterior chamber (kin) was determined in both eyes of 10 normal subjects. One week later, aqueous protein concentration changes were measured in both eyes of the same subjects before and after instillation of timolol in one eye. From these changes and the value of kin, changes in the aqueous flow rate were calculated using an equation formulating protein kinetics in the anterior chamber. Results of a separate experiment showed that instillation of topical timolol did not change the kin, justifying use of the kin as determined without considering timolol in the calculation. The calculated flow rate had a maximum decrease of 30% +/- 10% (mean +/- SEM, n = 10) 4 hours after instillation in treated eyes and of 10% +/- 6% 3 hours after instillation in fellow, untreated eyes.

The Glaucoma Laser Trial: 4. Contralateral Effects of Timolol on the Intraocular Pressure of Eyes Treated With ALT

ABSTRACT Several reports have documented a contralateral intraocular pressure (IOP) lowering effect after unilateral instillation of timolol. Data derived from the Glaucoma Laser Trial (GLT), a randomized trial of the efficacy and safety of argon laser trabeculoplasty (ALT) as compared with the efficacy and safety of topical medications as initial therapy for primary open-angle glaucoma (POAG), demonstrated an estimated mean pressure reduction of 0.5 mm Hg in the contralateral eye that had received ALT. This contralateral effect is smaller than that observed in other studies of POAG patients. Lower initial IOP, longer duration of treatment with timolol, and/or improved outflow facility modulation in the ALT-treated eyes may be responsible for the smaller contralateral effect of timolol observed in the GLT patients.

Effect of Coenzyme Q10 on Hemodynamic Response to Ocular Timolol

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial membrane and plays an important role in the maintenance of normal cardiac function. To evaluate the effects of ocular timolol on the cardiovascular system and determine the protective effect of CoQ10, 16 patients with glaucoma were studied using impedance cardiography. Following instillation of 1 mg timolol maleate in each eye, heart rate (HR) and stroke index (SI) decreased, and total peripheral resistance index (TPRI) increased significantly. Reexamination was performed after 6 weeks of 90 mg oral CoQ10. Despite decreases in HR, percent changes in HR were significantly less after CoQ10 at 120 min. Stroke index showed an initial increase which was not observed without CoQ10. These data suggest that CoQ10 delayed the appearance of inotropic blockade of timolol and hastened the disappearance of chronotropic blockade. Additional study of six normal volunteers with 6 weeks of oral CoQ10 showed a similar decrease of intraocular pressure after timolol instillation as compared to those without CoQ10. Thus, administration of oral CoQ10 in patients receiving ocular timolol may be useful in mitigating cardiovascular side effects without affecting intraocular pressure in the treatment of glaucoma.

Acute Closed-Angle Glaucoma After Arteriovenous Fistulas

Unilateral secondary acute closed-angle glaucoma was associated with a ciliochoroidal detachment in two patients. One patient, aged 17 years, had an orbital arteriovenous fistula. The other patient, aged 73 years, had a dural arteriovenous fistula that originated from branches of the right internal maxillary artery. In each patient there was increased intraocular pressure, a moderately shallow central anterior chamber, and a flat peripheral anterior chamber. The ciliochoroidal detachment was postulated to displace the iris-lens diaphragm, resulting in the closed angle. Closure of the orbital fistula in the 17-year-old patient reduced the ciliochoroidal detachment and relieved the glaucoma, but visual acuity was reduced to 20/200. The glaucoma in the 73-year-old patient was relieved with topical instillation of timolol 0.5%, homatropine 5%, and systemic administration of acetazolamide. The fistula closed spontaneously, with relief of other ocular signs of the arteriovenous fistula.