Eye (1989) 3, 294-297
Otrivine-Antistin-Pupil, Corneal and Conjunctival Responses to Topical Administration
D. R. TREW, L. A. WRIGHT, S. E. SMITH London
Summary The ocular effects of Otrivine-Antistin eyedrops have been measured in a placebo controlled single-blind study in sixteen healthy volunteers. The drops produced mild sympathomimetic responses in the eye but had no effect on corneal sensitivity or on intraocular pressure. The evidence indicates that use of Otrivine-Antistin imposes no risk to the subject.
Otrivine-Antistin is a Pharmacy only eyedrop symptoms and a good tolerance to administra medication for the symptomatic relief of tion by patients.7.9 However, Otrivine-Anti allergic or irritative conjunctivitis. It contains stin eye drops have not been included in the a sympathomimetic decongestant (xylometa procedures. This study has been undertaken, zoline hydrochloride 0.05 per cent w/v) and an therefore, to record the effects of these drops antihistamine (antazoline sulphate 0.5 per on pupil diameter, palpebral height, con cent w/v) as active principles. Though it has junctival vessel diameter, corneal sensitivity also been in use for some years, the precise and intraocular pressure and to evaluate any nature of the local responses to its application possible risks associated with their use, has been poorly documented. A few studies have been conducted on the Materials and Methods clinical use of sympathomimetic agents as Subjects ocular decongestants but they have concen Sixteen healthy subjects (8 male, 8 female) trated on the subjective interpretation of aged 19-59 years took part. All were of effects on symptoms and signs.1,2 In addition, normal height and weight and none had sig most have employed oxymetazoline as the nificant abnormality on ocular, cardiovascular sympathomimetic agent and its actions have and general medical examination or in been observed in animals.3 Objective tests, haematological or biochemical profiles. Each such as pupillometry, have occasionally been gave written consent to participate and the used but the results were inconclusive or not study was approved by the Ethics Committee quoted.4,5 of West Lambeth Health Authority. The use of combination drops in allergic conjunctivitis has been widespread and well Treatments and Study Design accepted,6 Studies employing these prep Subjects attended on one occasion, in the arations have shown their use in controlling morning. Otrivine-Antistin and a matching
Correspondence to: Mr D, R, Trew FRCS, Lecturer in Ophthalmology, Department of Clinical Pharmacology, St Thomas' Hospital, London SE1 7EH,
From: The Division of Pharmacological Sciences and Toxicology, United Medical and Dental Schools, St Thomas's Campus, London SE1 7EH, OTRIVINE-ANTISIN-PUPIL 295
'vehicle only' solution were administered Yashica Dental-Eye camera under flash single blind as eyedrops. Two drops of drug illumination with the subject's gaze at solution were instilled 30 seconds apart to one infinity. The palpebral height was eye and the same procedure followed for the measured, on a projection, through the drug-free vehicle to the second eye. mid-point of the pupil. (3) Conjunctival vessel diameter was Measurements measured from 1: 1 photographs taken on Morning intraocular pressure values, for each the above camera. The negatives were subject, were recorded at a previous visit to viewed under a micruscope using a cali the department by applanation tonometry, brated eyepiece graticule. Corne'll sen under benoxinate 0. 4% local anaesthesia. sitivity was measured with a Cochet and This procedure was repeated at the conclusion Bonnet Aesthesiometer using a 0. 12 mm of the experiment, i. e. 4 hours after eyedrop filament. instillation. Adverse responses to the drops (stinging, irritation, misty vision, photo Statistical Analysis phobia) were sought by direct questioning at Values for pupil diameters, palpebral heights 1, 5 and 10 minutes after instillation. At the and conjunctival vessel diameter� were ana same time, tearing and redness of the eyes lysed by comparisons between the two eyes of were assessed by inspection. each subject using Student paired t-tests. The following measurements were per Analysis of variance was also performed for formed before and at 0. 5, 1, 1. 5, 2, 3 and 4 all post-treatment values using these sources: hours after eyedrop instillation: subjects, eyes (treatments), times and interac (1) Pupil diameters were measured by infra tion eyes-times. Intraocular pressure values red TV pupillography under bright were compared between eyes by paired t-tests illumination provided by two 30W fluor and occurrences of symptoms and signs by escent lamps placed 50 cm from the sub Chi-squared tests. ject. Six subjects were additionally evaluated under standard overhead light
ing only. Results (2) Eyelid positions were recorded with a Pupil Diameter Mean pupil diameters at the two lighting PUPIL DIAMETER levels are illustrated in Figure 1. A small mydriatic response to Otrivine-Antistin occurred which was detectable only under bright illumination and which appeared to be maximal (0. 24 mm) at 3 hours after instilla tion. Table I shows that the diameter differ a; 1ii ence was statistically significant but E '" represented only an approximately 5% '0 change over the control eye. '0. � :J D- g/':-
Palpebral Height Figure 2 shows the mean palpebral heights for each treatment. There was no inter-ocular time difference before instillation, but Otrivine l.!J Otr-Ant. bn a Dummy bri 0 Otr-Ant. dim • Dummy dim Antistin produced a small increase in pal pebral height compared to the dummy treat Fig. 1 Mean pupil di ameters (mm) for each treatment ment. The inter-ocular difference was at the two light levels. Open symbols represent Ot rivine detectable at 0. 5 hour, reached a maximum at Antistin, closed symbols represent vehicle only. The upper graphs represent values in dim light (n=6); the one hour (0.57±0.14mm, P<0. 001) and lower graphs represent values in bright light (n=16). declined thereafter. 296 D. R. TREW ET AL.
Table I Pupil diameter differences at each observation and redness were observed in 4/16 and 6/16 corrected for any initial differences, expressed as per subjects respectively. These effects had disap cent mydriatic response peared by 5 minutes. The dummy eyedrops
Time (hr) produced temporary stinging, lrntation after andlor redness in only one subject. Only the instillation Mean±SEM P difference in occurrence of stinging was statis tically significant (Chi-squared = 12. 955, O.S 0.4±1.6 0.227 NS P
4 h after Occasion At screening treatment PALPEBRAL HEIGHT 14 �------, Otrivine-Antistin lS.4±0.3 14.9 ±O.7 Dummy solution lS.2±0.4 14.9 ±0.6 Paired t 0.824 0.124 E P NS NS .s 12
Conjunctival Artery Diameter Figure 3 illustrates the mean diameters for single targeted arteries in each eye. Analysis of variance revealed that more than 50% of the variance was unidentifiable, which sug gests that the data have poor repeatability, 2 perhaps because the measurements were time done at the limit of microscopic resolution. o Otr-Ant. Pal • Dummy Pal However, it can be seen that there is a trend towards vasoconstriction in response to Fig. 2 Mean palpebral heights (mm) for each treat ment. Symbols as in Fig. I. Otrivine-Antistin, which was confirmed by CONJUNCTIVAL VESSEL DIAMETER analysis of variance. (F=6.005, P<0.05). 40 �------,
Intraocular Pressure
Table II shows that Otrivine-Antistin pro 35 duced no change in intraocular pressure by E 2- comparison with the dummy eyedrops. E '" 30 '0 a; Corneal Sensitivity U) U) '" Median corneal sensitivity values (full fila > 25 ment extension) were unchanged by the treatments and in no subject was sensitivity impaired by either one.
2 4 Symptoms and Signs time o Otr-Ant. Conj • Dummy Conj Otrivine-Antistin produced some mild sting ing, recorded at one minute after instillation, Fig. 3 Mean diameters (um) for single conjunctival in 12/16 and irritation in 5116 subjects; tearing arteries in each eye. Symbols as in Fig. 1. OTRIVINE-ANTlSIN-PUPIL 297 changes, comprising mydriasis, elevation of metazoline ophthalmic solution in patients with allergic and non-infectious conjunctivitis. Phar the upper eyelid and vasoconstriction, are matherape utica 198 0, 2: 35H. consistent with a sympathomimetic response 2 Rybicza R and Mauracher E: Oxymetazoline to the xylometazoline contained in the ophthalmic solution versus naphazoline solution in non-infectious conjunctivitis. Pharma product. The mydriatic response was too therape utica 1983, 3: 376-81. small to be of clinical significanceor to impose 3 Duzman E, Anderson J, Vita JB, Lue JC, Chen CC, any risk of pupil block or irido-corneal angle Leopold IH: Topically applied oxymetazoline. closure and thus of acute glaucoma, even in Ocular vasoconstrictive activity, pharmacokine tics and metabolism. Ar ch Ophthalmo ll983, 101: susceptible subjects. 1122-- 6. The eyedrops had "0 effect on corneal sen 4 Fox SL, Samson CR, Danzig MR: Oxymetazoline in sitivity or on intraocular pressure and pro the treatment of allergic and non-infectious con ] In t Me d Res 1979, 7: 528-30. duced some mild and transient irritation in junctivitis. 5Duzman E, Warman A, Warman R: Efficacy and some subjects, consistent with clinical safety of topical oxymetazoline in treating allergic experience. and environmental conjunctivitis. Ann We conclude that Otrivine-Antistin pro Ophthalmol 1986, 18: 28- 31. 6 duces mild sympathomimetic responses in the Abelson MB and Weston JH: Antihistamines. Ch 13 Clinical Ophthalmic Pharmacology. Ed. Lam eye but that in its use as a decongestant, these berts OW, Potter DE. Boston and Toronto, are harmless and impose no risk to the Little, Brown and Co. subject. 7 Miller J and Wolf EH: Antazoline phosphate and naphazoline hydrochloride, singly and in com bination for the treatment of allergic con We thank Dr J. Gregory of Dispersa Ltd for the gift of junctivitis-a controlled, double-blind clinical Otrivine-Antistin eyedrops and for financial support. trial. Ann Al lergy 1975, 35: 81--6. DRT is supported by the Iris Fund for Prevention of "Abelson MB, Allansmith MR, Friedlaender MH: Blindness. DRT and LAW are supported by the Effects of topically applied ocular decongestant Special Trustees of St Thomas' Hospital. and antihistamine. Am ] Ophthalmol 1972, 90: 254-7. References 9 Lanier BQ, Tremblay N, Smith JP, de Faller JM: A I Breakey AS, Cinotti AA, Hirshman M, Skowron double masked comparison of ocular deconges RA, Samson CR, Danzig MR: A double-blind, tants as therapy for allergic conjunctivitis. Ann multi-centre controlled trial of 0. 025 per cent oxy- Al le rgy 1983, 50: 174-7.