With timolol maleate, 300 mg/kg/day in rats (equivalent to about 42,000 times systemic exposure following the maximum recommended ocular dose in human [MRHOD]) was associated with significantly increased incidence of adrenal pheochromocytomas in a two-year study; in a lifetime study in mice, 500 mg/kg/day (equivalent to about 71,000 times systemic exposure following the MRHOD) but not 5 or 50 mg/kg/day (about 700 or 7,000 times systemic exposure following the MRHOD) of timolol maleate was associated with significantly increased incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas. Neither brimonidine tartrate nor timolol maleate was mutagenic in in vitro and in vivo studies. Reproduction and fertility studies in rats did not reveal any adverse effects on male or female fertility with brimonidine tartrate or timolol maleate. Clinical trials
Two prospective, randomized, double-blinded, phase III clinical trials were conducted at 53 sites in the United States to compare the IOP-lowering efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol maleate fixed combination twice daily with 0.2% brimonidine tartrate three times daily or 0.5% timolol maleate twice daily in patients aged 18 or older who had ocular hypertension or glaucoma. When assessed over a 3-month period, pooled results from a total of 1159 patients showed significantly greater mean IOP decrease from baseline with the brimonidine/timolol combination (4.9-7.6 mmHg) than with brimonidine monotherapy (3.1-5.5 mmHg) or timolol monotherapy (4.3-6.2 mmHg) across all follow-up visits.
Cogan syndrome (also Cogans syndrome) is a rare disorder characterized by recurrent inflammation of the front of the eye (the cornea) and often fever, fatigue, and weight loss, episodes of vertigo (dizziness), tinnitus (ringing in the ears) and hearing loss. It can lead to deafness or blindness if untreated. The classic form of the disease was first described by D. G. Cogan in 1945. Signs and symptoms
Cogan syndrome is a rare, rheumatic disease characterized by inflammation of the ears and eyes. Cogan syndrome can lead to vision difficulty, hearing loss and dizziness. The condition may also be associated with blood-vessel inflammation (called vasculitis) in other areas of the body that can cause major organ damage in 15% of those affected or, in a small number of cases, even death. It most commonly occurs in a persons 20s or 30s. The cause is not known. However, one theory is that it is an autoimmune disorder in which the bodys immune system mistakenly attacks tissue in the eye and ear. Causes
It is currently thought that Cogan syndrome is an autoimmune disease. The inflammation in the eye and ear are due to the patients own immune system producing antibodies that attack the inner ear and eye tissue. Autoantibodies can be demonstrated in the blood of some patients, and these antibodies have been shown to attack inner ear tissue in laboratory studies.