The bioavailability of the topical drugs at the receptor site depends on the drug kinetics in the conjunctival cul-de-sac, corneal penetration, and the distribution and rate of drug elimination in the eye. In the conjuntival cul-de-sac, the drug is diluted by the tears and a major part is lost through the lacrimal drainage system. Only a small amount mixes with precorneal tear film and is absorbed by cornea. Prolonging the drug contact time with the surface of the eye increases its penetration across the cornea. Timolol in gel-forming solution (GFS) is timolol maleate in combination with a heteropolysaccharide derived from gellan gum. It is a liquid at room temperature and becomes a gel after reacting with cations in the tears. This property of the formulation increases the corneal contact time allowing greater corneal penetration and these requires less frequent administration. The drug has recently been launched in India as Timolet GFS (0.25% and 0.5% Milmet Pharmaceutical, Baroda, India) as a once-daily dose. The primary objective of the present crossover study was to compare the ocular hypotensive effect and side effects of 0.5% timolol in gel forming solution administered once daily, with 0.5% timolol solution (Milmet Pharmaceutical, Baroda, India) administered twice daily in open angle glaucoma in Indian subjects.
Materials and Methods
We screened all the patients of open angle glaucoma (OAG) on timolol maleate monotherapy registered in the Glaucoma Services of Dr. Rajendra Prasad Centre, All India Institute of Medical Sciences, New Delhi between July and December 2000.
A total of 70 patients fulfilled our criteria and were selected for the purpose of the study. The inclusion criteria included age over 40 years, clinical diagnosis of OAG in both eyes substantiated by Humphrey visual fields examination, patients on treatment with timlol maleate 0.5% solution, intraocular pressure (IOP) less than or equal to 21 mm of Hg in diurnal curve, and visual acuity >6/60. The exclusion criteria were any abnormality preventing applanation tonometry, patient resistance that restricted adequate examination of the ocular fundus or anterior chamber; or past conventional intraocular or laser surgery to lower the IOP, pregnant and lactating females, and patients taking other systemic and ocular medications that could affect IOP. Patients with any of the following were also excluded: concurrent uveitis in either of the eyes, history of allergic hypersensitivity or poor tolerance to any components of the preparations used in this study, patients with a clinically serious medical and psychiatric condition, risk of worsening of visual fields due to discontinuation of drug for washout period; contraindication to beta blockers; and progressive retinal or optic nerve disease other than glaucoma. All the patients were on treatment with timolol maleate 0.5% twice a day for more than a month. Informed consent was taken from all patients before enrollment. Ten patients refused the switchover citing inability to come for frequent follow-ups.
All the patients who met our inclusion/ exclusion criteria underwent a thorough ophthalmological examination including ocular examination, medical history, gonioscopy, slitlamp biomicroscopy, Snellen's visual acuity, Goldmann applanation tonometry, dilated fundoscopic examination, and Humphrey 30-2 visual field testing. Patients went through a washout period of 4 weeks before starting timolol-GFS. A detailed review was done of their past medical treatment, ocular side-effects and IOP control. A 3-hourly diurnal IOP was performed by applanation tonometry starting at 7 a.m. to assess 24-hour variation with 0.5% glucomol twice a day. The IOP was recorded by the resident on duty, who was masked to the study. Patients were given a detailed questionnaire detailing the compliance and side effects before they were shifted to timolol GFS 0.5% once daily. After 6 weeks on timolol GFS 0.5%, IOP measurement was taken. In addition, patients were asked to complete a questionnaire regarding compliance and side effects.
The results were analysed using sample paired 't' test and Friedman non-parametric analysis of variance (AOV) for various parameters as and when considered appropriate by the statistician. Patients who failed to comply with the investigations were excluded from the final results.
Of the 60 patients included in the study, 26 were females and 34 were males. The average age of female patients was 56.4 years (48-63 years), and male patients 58.7 years (47-68 years). Fifty-two patients completed a follow-up of 6 weeks. The two medications were compared in terms of diurnal IOP variation, peak values during 24 hours as well as IOP values at the same time of day. The results were analysed using sample paired 't' test comparing baseline IOP on timolol 0.5% solution administered twice daily and IOP on Timolol 0.5% GFS given once a day. [Table - 1] illustrates the mean decrease from the baseline pressures for two treatments at 7am to 4am at 3-hourly intervals The figure depicts comparison of mean IOP. These results show that there was no statistically significant difference in the ocular hypotensive effect of the two treatments.
The only ocular symptom that showed a difference between the two medications was the incidence of blurring of vision, but this too was statistically not significant. Eight of 52 patients (15.38%) on Timolol GFS experienced blurred vision after the medication compared to 3 patients (5.77%) on Timolol maleate solution treatment. Incidentally, these same three patients complained that this symptom worsened after switching over to timolol maleate GFS solution.
Compliance was compared between Timolol maleate solution and Timolol maleate GFS in terms of the number of times the drug was reported missed over a 6-week period. Ten patients reported to have missed Timolol maleate once or more in 6 weeks as compared to three patients on Timolol maleate GFS [Table - 2]. This difference was not significant statistically. No systemic adverse effect was noted in any of our patients on Timolol-GFS over a short follow-up period of 6 weeks. The ocular side-effect profile of both treatment groups was similar [Table - 3].
Timolol maleate has been established as the first line drug in the treatment of open angle glaucoma. Timolol maleate in gel form increases the corneal contact time thereby increasing the bioavailability, thus permitting a convenient once-daily dosage. The lower systemic absorption also decreases the incidence of systemic side-effects.
The results of the study indicate that the hypotensive effect of Timolol 0.5% in gel-forming solution administered once daily is equivalent to that of 0.5% Timolol administered twice daily. This observation corresponds with the earlier reports comparing these two drugs. The tolerance to both drugs was similar except for a higher incidence of blurred vision immediately after administration of Timolol gel forming solution [Table - 3]. This however was a complaint expressed by the patients and was not verified by visual acuity testing. Up to 16% of blurring of vision has been reported in earlier studies. In a study by Stewart et al, visual acuity reduction was recorded immediately after instillation (one minute after instillation), but it was statistically equal at 5 and 30 minutes after administration. Higher viscosity of gel-forming solution is responsible for this effect. In our patients blurring was temporary, lasting for no more than a few minutes and it did not lead to cessation of the drug in any of them. The study did not show any statistical difference of compliance between the two drugs. This however, is expected in view of the short follow-up. Since the compliance is influenced by the drug regimen, lowering the drug frequency may improve compliance in the long run.
Our observations from this study suggest that the more convenient 0.5%Timolol in gel-forming solution can be offered as an equally efficacious and well-tolerated alternative to twice daily 0.5% timolol solution in open angle glaucoma in Indian eyes. No systemic adverse effect was noted in any of the study patients on Timolol-gel forming solution over the 6-week period. However, longterm efficacy and ocular and systemic safety of Timolol 0.5% in gel solution needs to be further evaluated.
The small power is a shortcoming of this study. The power of the study was calculated at 22.89%. This value of power is explained by the nearly similar pressure-lowering effect of the two drugs. A very large sample size is required with these readings to raise the power to 80%. This was not feasible considering the short duration of the study.
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Conflict of Interest:
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