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Unoprostone As Adjunctive Therapy to Timolol: a Double Masked

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Unoprostone As Adjunctive Therapy to Timolol: a Double Masked 592 CLINICAL SCIENCE Br J Ophthalmol: first published as 10.1136/bjo.87.5.592 on 1 May 2003. Downloaded from Unoprostone as adjunctive therapy to timolol: a double masked randomised study versus brimonidine and dorzolamide A Hommer, for The Unoprostone Adjunctive Therapy Study Group,* B Kapik, N Shams ............................................................................................................................. Br J Ophthalmol 2003;87:592–598 *Members listed at the end Aims: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjunc- of paper. tive therapy to timolol in patients with primary open angle glaucoma or ocular hypertension. Methods: This was a randomised, double masked, parallel group, multicentre (14) study. After using timolol maleate 0.5% monotherapy twice a day for 2 weeks, patients (n = 146) with an early morning intraocular pressure (IOP) between 22 and 28 mm Hg, inclusively, received unoprostone isopropyl 0.15% (n = 50), brimonidine tartrate 0.2% (n = 48), or dorzolamide hydrochloride 2.0% (n = 48) twice daily as adjunctive therapy to timolol maleate 0.5% for another 12 weeks. Safety was based on comprehensive ophthalmic examinations, adverse events, and vital signs. Efficacy was based on mean change from baseline in the 8 hour diurnal IOP at week 12. Baseline was defined as values obtained See end of article for after 2 weeks of timolol monotherapy. authors’ affiliations Results: Each drug was safe and well tolerated. Burning/stinging was the most common treatment ....................... emergent adverse event. No clinically relevant changes from baseline were observed for any ophthal- Correspondence to: mic examination or vital signs. At week 12, each adjunctive therapy produced statistically significant Naveed Shams, MD, PhD, (p<0.001) reductions from timolol treated baseline in the mean 8 hour diurnal IOP (−2.7 mm Hg, uno- Novartis Ophthalmics Inc, prostone; −2.8 mm Hg, brimonidine; −3.1 mm Hg, dorzolamide). The extent of IOP reduction did not 11695 Johns Crek Pkwy, Duluth, GA 30097, USA; differ significantly between unoprostone and either brimonidine (p = 0.154) or dorzolamide (p = mailto:naveed.shams@ 0.101). pharma.novartis.com Conclusion: Unoprostone was safe and well tolerated and provided a clinically and statistically sig- Accepted for publication nificant additional reduction in IOP when added to stable monotherapy with timolol. Furthermore, uno- 12 April 2002 prostone was not significantly different from brimonidine and dorzolamide as adjunctive therapy to ....................... timolol. http://bjo.bmj.com/ laucoma, a group of chronically progressive neuropa- tive effects on retinal and neuronal development and thies, is characterised by damage to the optic nerve and function.89 Furthermore, DHA delays photoreceptor loss of visual field, primarily due to the death of retinal apoptosis10 11 and maintains photoreceptor function and G 1 12–16 ganglion cells and cupping of the optic nerve head. Although survival. DHA is also recognised for its vasorelaxing effects the exact aetiology of glaucoma has not been fully elucidated, on the cardiovascular system.17–21 vascular factors that reduce ocular blood flow and dysfunction Unoprostone isopropyl, a 22 carbon analogue of the of neuroprotective mechanisms are considered to be impor- naturally occurring docosanoids, possesses numerous proper- on September 23, 2021 by guest. Protected copyright. tant factors in the development of the disease.2–6 Elevated ties of potential benefit in the physiological management of intraocular pressure (IOP), a main characteristic of glaucoma- glaucoma. Specifically, unoprostone has been shown to coun- tous disease, is also considered to be a significant aetiological teract endothelin-1 induced vasoconstriction in both animal factor, although its exact role is currently a subject of debate. and human models,22–25 increase ocular blood flow and blood Current treatment strategies for glaucoma and ocular flow velocity in rabbits and humans,22 26–30 and protect against hypertension (OH) are primarily aimed at lowering elevated ischaemia and photoreceptor damage in rats,31–33 as well as IOP.Topical β blockers such as timolol are usually the first line against glutamate mediated neuronal death in an in vitro of ocular hypotensive therapy. If target IOP is not reached after model.34 In addition to these properties, unoprostone signifi- an appropriate period of monotherapy, combination treat- cantly reduces IOP.35 36 Recent evidence suggests that unopros- ments are used to achieve the desired IOP lowering effect, tone exerts its effects by opening maxi-K+ channels, which especially combinations of drugs with differing modes of may lead to vascular relaxation and/or relaxation of the action.7 Since glaucoma is a multifaceted disease, there is sig- trabecular meshwork, resulting in increased conventional nificant research under way to develop combination regimens outflow.37 that not only lower IOP but address other physiological Since 1994, unoprostone isopropyl 0.12% ophthalmic solu- aspects of the disease, particularly neuroprotective mecha- tion has been approved in Japan and several other countries nisms and vascular dysfunction. Such an integrated approach around the world for the lowering of IOP in patients with to the physiological management of glaucoma holds great glaucoma and OH. Furthermore, the Japanese labelling for promise for advancing the field and treating patients with the unoprostone 0.12% contains information regarding its favour- disease. able effects on ocular blood flow. Unoprostone isopropyl 0.15% In light of this, docosahexanoic acid (DHA) and its oxygen- ophthalmic solution has been approved in the United States ated metabolites, the docosanoids, have gained recent and several other countries for use in the same patient popu- attention for their potentially beneficial effects on glaucoma- lation. The purpose of this study was to compare the IOP low- tous disease. DHA, the most abundant long chain polyunsatu- ering efficacy and safety of unoprostone isopropyl 0.15%, bri- rated fatty acid in the human body, is well known for its posi- monidine tartrate 0.2%, and dorzolamide hydrochloride 2.0% www.bjophthalmol.com Unoprostone as adjunctive therapy to timolol 593 as adjunctive therapy to timolol maleate 0.5% in patients with Patient population primary open angle glaucoma (POAG) or OH who are insuffi- The study population consisted of adult (>18 years) patients Br J Ophthalmol: first published as 10.1136/bjo.87.5.592 on 1 May 2003. Downloaded from ciently responsive to timolol alone. Unlike unoprostone, which (male or female, any ethnicity) with unilaterally or bilaterally lowers IOP by increasing aqueous humour outflow, particu- elevated IOP associated with a diagnosis of POAG, OH, larly conventional outflow,38–40 dorzolamide lowers IOP by pseudoexfoliation glaucoma, or pigmentary dispersion glau- reducing aqueous humour production,41 and brimonidine coma. Patients on β blocker monotherapy before entry must reduces aqueous humour flow and increases uveoscleral have used the drug for at least 4 weeks and had an IOP >22 outflow.42 To facilitate discussion, the three combination treat- mm Hg at screening. If patients were using more than one ments are identified only by the type of adjunctive therapy drug to lower IOP,their screening IOP had to be <22 mm Hg; employed. patients who used a β blocker as part of a multiple drug regi- men must have used the drug for >4 weeks. After 2 weeks of PATIENTS AND METHODS run-in monotherapy with timolol, patients had to have an Ethical considerations early morning IOP between 22 and 28 mm Hg, inclusively, This study was conducted in accordance with the ethical prin- withnomorethana5mmHgdifference between eyes (in ciples that have their origin in the Declaration of Helsinki as patients with bilateral disease). Patients also had to have an amended (Somerset West, South Africa, 1996). Before the angle of at least 30° at screening (according to the Shaffer study was initiated, an institutional review board or ethics scale) and a best corrected distance visual acuity >0.1 committee approved the protocol and informed consent form (20/200) at screening and baseline. in compliance with US regulations and applicable local regu- Patients were excluded from the study if they (1) had been lations. Each patient was informed of the investigational using a topical, ocular prostaglandin-type medication to con- nature of the study and gave written informed consent before trol elevated IOP for a period of >3 months before screening, any study related procedures were initiated. or had any history of its use that equalled 3 months in dura- tion; (2) had a contraindication to β blockers, sulfonamides, or Study design α This was a randomised, double masked, active controlled, par- agonists; (3) had laser or intraocular surgery within 3 allel group, multicentre study conducted at 14 investigational months of screening or filtration surgery within 6 months of sites in Europe and the United Kingdom. Aftera2week, open screening; or (4) were pregnant, lactating, or refused to use a label, monotherapy period with timolol maleate 0.5% (Timop- reliable form of contraception during the study (for women of tic), qualified patients were randomised by the sponsor in a childbearing potential only). Patients were also excluded if 1:1:1 ratio to receive unoprostone 0.15% (Rescula), brimoni- their dose or regimen of an existing chronic or systemic medi- dine tartrate 0.2% (Alphagan),
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