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Br J Ophthalmol 2000;84:293–299 293 EVects of topical nipradilol, a â blocking agent Br J Ophthalmol: first published as 10.1136/bjo.84.3.293 on 1 March 2000. Downloaded from with á blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans Mikiko Kanno, Makoto Araie, Hiroshi Koibuchi, Kanjiro Masuda Abstract nitroglycerin-like vasodilating activity is ap- Aims—To study the eVects of topical proximately one fifth that of nitroglycerin.2 nipradilol, a non-selective â blocker with á Some á1 blockers and nitroglycerin are re- blocking and nitroglycerin-like activities, ported to reduce intraocular pressure (IOP) in on intraocular pressure (IOP) and aque- experimental animals or normal humans by ous humour dynamics in normal humans increasing uveoscleral outflow or tonographic and in patients with ocular hypertension. outflow for at least a short period of time.5–13 A Methods—Nipradilol (0.06%, 0.125%, highly selective á1 blocker, bunazosin, reduced 0.25%, 0.5%) was applied to normal IOP in glaucoma patients by about 4 mm Hg volunteers (n = 12) to test for IOP lowering for 1 year without producing tachyphylaxis.14 eVects. In a second group of normal The á1 blocking and nitroglycerin-like activi- volunteers (n = 11), nipradilol (0.125% and ties of nipradilol might further enhance the 0.25%) and timolol (0.5%) were compared ocular hypotensive eVect owing to its â for IOP lowering eVects. After a single blocking activity, which is expected to reduce administration of 0.25% nipradilol, IOP, aqueous production. Further, the á1 blocking flare intensity in the anterior chamber, and nitroglycerin-like vasodilating activities of aqueous flow, uveoscleral outflow, tono- nipradilol might provide an advantage over graphic outflow facility, and episcleral other â blockers that do not have such eVects venous pressure were either directly on ocular circulation. In a previous study, we measured or mathematically calculated. found that the hypotensive eVect of a single Topical nipradilol (0.25%) was adminis- instillation of 0.25% nipradilol was signifi- tered to 24 patients with ocular hyper- cantly greater than that of 0.5% timolol in rab- tension twice daily for 8 weeks. bit eyes. In rabbit eyes, the IOP lowering eVect Results—Administration of 0.25% ni- is attributed to both a decrease in aqueous pradilol decreased IOP with a maximum humour production and an increase in uveo- http://bjo.bmj.com/ reduction of 4.2 mm Hg lasting 12 hours. A scleral outflow, and 2 weeks twice daily admin- single instillation of both 0.25% nipradilol istration of 0.25% nipradilol might have and 0.5% timolol reduced the IOP in nor- beneficial eVects on optic nerve head tissue 15 motensive human subjects to the same circulation. degree. A single instillation of 0.25% To further evaluate the potential of topical nipradilol decreased the aqueous flow rate nipradilol as a new antiglaucoma drug, we examined the eVect of topical nipradilol on in the treated eye by 20%. Nipradilol pro- on September 30, 2021 by guest. Protected copyright. duced no significant eVect in tonographic IOP and aqueous humour dynamics in normal outflow facility or episcleral venous pres- human eyes. We also performed a preliminary sure, but uveoscleral outflow was in- clinical study in a group of patients with ocular Department creased. In patients with ocular hypertension to examine the clinical potential Opthalmology, hypertension, twice daily instillation of of nipradilol. University of Tokyo 0.25% nipradilol decreased IOP without School of Medicine, tachyphylaxis for the 8 week test period. Japan Material and methods M Kanno Conclusion—Topical nipradilol (0.25%) M Araie reduced IOP by decreasing the aqueous NORMAL HUMAN VOLUNTEERS K Masuda flow rate and probably also by increasing The study population consisted of a total of 23 uveoscleral outflow. Nipradilol should be normal volunteers ranging in age from 31 to 49 Section of further investigated as a new antiglau- years without a history of ocular disease. Ophthalmology, JR coma drug. Before admission into the study, written Tokyo General ( 2000;84:293–299) consent was obtained from each subject after Hospital, Japan Br J Ophthalmol H Koibuchi the nature of the study was fully explained. Before treatment, a medical history was taken Correspondence to: Nipradilol is a non-selective â blocker with á1 and a complete ophthalmological examination Makoto Araie, Department blocking and nitroglycerin-like vasodilating was performed on each patient. Inclusion of Ophthalmology, University of Tokyo School activities that are attributed to its nitroxyl criteria included IOP measurements in one eye 1–3 of Medicine, 7-3-1 Hongo, moiety. It has been registered as a systemic within 2 mm Hg of the other eye, IOP in both Bunkyou-ku, Tokyo 113, hypotensive drug.4 The in vitro â blocking eyes less than 21 mm Hg, gonioscopy demon- Japan activity of nipradilol is approximately twice strating an open angle of grades 3–4, normal 1 Accepted for publication that of propranolol, the á1 blocking activity indirect ophthalmoscopic findings, and a nor- 1 October 1999 about one fifth that of phentolamine,2 and the mal appearance of the optic nerve head. 294 Kanno, Araie, Koibuchi, et al Subjects wearing contact lenses were not after drug administration. At the same time, Br J Ophthalmol: first published as 10.1136/bjo.84.3.293 on 1 March 2000. Downloaded from included in the study. blood pressure and heart rate were also measured. The results were analysed as the dif- PATIENTS WITH OCULAR HYPERTENSION ference between the change from pretreatment A preliminary study population consisted of a values in the nipradilol treatment study and total of 24 subjects with ocular hypertension that in the vehicle treatment (control) study, (14 women and 10 men; mean age 50.1 (SE because the baseline IOP was diVerent among 3.2) years) who had a documented IOP of 22 these subjects. mm Hg or higher in at least one eye on two (IOPnipradilol,t−IOPnipradilol,0)−(IOPvehicle,t separate occasions during the follow up and −IOPvehicle,0) (1) had normal visual field (Humphrey Perimeter in which represents the time of IOP measure- 30-2 program) and normal appearance of the t ments and represents the pretreatment meas- optic disc. The study was approved by the eth- 0 urements. Subjects were questioned about spe- ics committee of the University of Tokyo cific ocular and systemic symptoms such as School of Medicine. Exclusion criteria in- cluded any ocular disease except ocular hyper- discomfort, burning on instillation, or blurred tension. vision. Comparison with 0.5% timolol ophthalmic —Normal volunteers (n = 11) were DRUGS solution Nipradilol ophthalmic solutions of 0.06%, used. Vehicle of nipradilol ophthalmic solution 0.125%, 0.25%, 0.5%, and the vehicle solution (0%), 0.125% and 0.25% nipradilol, and 0.5% were supplied by Kowa (Tokyo, Japan). timolol were tested for their IOP lowering Timolol maleate ophthalmic solution (0.5%) eVects on 4 separate days, with a washout was purchased from Banyu Pharmaceutical period of 2 weeks. The order of application of (Tokyo, Japan). the four sets of solutions was randomly assigned in each subject. INSTRUMENTS At 0800 of each experimental day, an inves- The IOP was measured with either a Gold- tigator blind to the treatments administered 50 mann applanation tonometer or applanation µl of one of these drugs or the vehicle topically pneumatonograph (Alcon, Fort Worth, TX, to one eye and vehicle to the other eye. USA) under topical anaesthesia (0.4% oxybu- Intraocular pressure was measured with a procaine hydrochloride). Fluorophotometric Goldmann applanation tonometer and slit measurements were made with a scanning lamp examinations were performed immedi- fluorophotometer (Fluotron Master, Coherent ately before and 1, 2, 4, 6, 8, and 12 hours after Radiation Inc, Palo Alto, CA, USA) aqueous drug administration. Before and after drug flare intensity measurements with a laser flare instillation, blood pressure and heart rate were cell meter (Kowa, Tokyo, Japan), tonographic measured in all subjects. The results were ana- measurements with an electronic tonometer lysed as the diVerence between the change (Handaya, Tokyo, Japan), episcleral venous from pretreatment values in the nipradilol or http://bjo.bmj.com/ pressure measurements with a Zeimer ven- timolol treatment study and that in the vehicle omanometer (Eyetech, Skokie, IL, USA), and treatment study, using equation (1). anterior chamber depth measurements with an anterior chamber depth meter (Haag Streit, Bern, Switzerland). All measurements were Mechanism of IOP reduction performed by investigators blind to the treat- EVects of a single application of 0.25% ment. nipradilol on aqueous humour dynamics was investigated. Subjects included 12 normal vol- on September 30, 2021 by guest. Protected copyright. EXPERIMENTAL PROCEDURES unteers. Those who participated in the former EVect of topical nipradilol on IOP in normal experiments were not included in this study. volunteers A drug-placebo pair was allocated to each Dose response study—Twelve normal volunteers subject as a right/left eye pair and the subject’s were randomly assigned to two six subject right or left eye always received the same solu- groups. In one group 0% (vehicle), 0.06%, or tion of the paired solutions. Studies were 0.25% nipradilol was applied and in another performed on four separate occasions, with 1 group 0% (vehicle), 0.125%, or 0.5% ni- week intervals. In the first experiment, IOP, pradilol was applied to test for the eVects on aqueous protein flare intensity, and pupillary IOP on 3 separate days, with a washout period diameter were measured hourly from 0900 to of 2 weeks. Each solution was instilled in one 1100. Immediately after the 1100 measure- randomly chosen eye and each subject received ment, 50 µl of one of the paired solutions the test solution in the same eye during this (0.25% nipradilol or placebo) was applied to series of experiments.

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