Bimatoprost: Mechanism of Ocular Surface Hyperemia Associated with Topical Therapy

Abstract

Bimatoprost is a safe and well-tolerated intraocular pressure (IOP) lowering drug that was approved in the United States in 2001 for the treatment of glaucoma and ocular hypertension. It is highly efficacious and produces greater mean reductions in IOP than other currently available antiglaucoma drugs. Conjunctival hyperemia is a common side effect of bimatoprost, but the hyperemia is typically mild and transient. No association has been found between signs of inflammation and the presence of hyperemia in bimatoprost-treated patients. Preclinical studies have elucidated the pharmacological mechanism of bimatoprost-related hyperemia and have examined the possible involvement of inflammation. Bimatoprost, as well as the free acid of latanoprost, elicited endothelium-dependent vasorelaxation in the rabbit jugular vein preparation, a quantitative in vitro model for ocular surface hyperemia (OSH). The vasorelaxant responses to either bimatoprost or latanoprost free acid were significantly inhibited by L-NAME, a nitric oxide synthase inhibitor. Similarly, the in vivo OSH responses to topically applied bimatoprost or latanoprost in dog eyes were significantly inhibited by L-NAME. As predicted, prostaglandin E(2) (PGE(2))-induced conjunctival hyperemia was not inhibited by L-NAME, since PGE(2) has a direct relaxant effect on the vascular smooth muscle. In-life observations and histopathological assessment of ocular surface tissues following bimatoprost treatment were performed for multiple-dose one month, 6 month, or 12 month safety studies in rabbits, dogs, and non-human primates. Results of these studies showed no evidence of bimatoprost-related inflammation in the ocular surface tissues. In summary, OSH related to bimatoprost treatment in laboratory animals occurs by endothelial-derived nitric oxide-mediated vasodilatation and is not associated with inflammation. These studies suggest that conjunctival hyperemia, a side effect of bimatoprost treatment, results from non-inflammatory, pharmacologically based vasodilatation.

Bimatoprost 0.01% vs bimatoprost 0.03%: a 12-month prospective trial of clinical and in vivo confocal microscopy in glaucoma patients

“…[13][14][15][16][17] However, bimatoprost 0.03% eye drop is burdened with some side effects. Conjunctival congestion, which is believed to result from nitric oxide-mediated vasodilatation in the conjunctiva, 18,19 is the most frequent adverse effect, accounting for discontinuation of therapy in about 3% of patients. 20 Also, increased ocular discomfort is typically associated with long-term use of prostaglandin analogs.…”

Study Design and Methodologies for Evaluation of Anti-glaucoma Drugs

“…Although ADME studies typically will indicate whether the test article actually gets into the eye in some instances additional endpoints may be used to confirm that pharmacologically active drug is reaching the eye. Secondary biomarkers that may be easily and noninvasively observed include alterations in pupil size and conjunctival hyperemia [143].…”

Síndrome glaucomatosa em cães: parte 2

“…Estudo recente demonstrou que a hiperemia conjuntival é decorrente da liberação de óxido nitroso endotelial e não por eventos inflamatórios relacionados à ação mediadora da inflamação pelas prostaglandinas (CHEN et al, 2005). Outros efeitos colaterais, como hiperpigmentação palpebral e da íris, não foram observados em animais (WILLIS, 2004).…”