Chen June, Dinh Tim, Woodward David F, Holland Michael, Yuan Yang-Dar, Lin Tsung-Hua, Wheeler Larry A
Department of Biological Sciences (RD3), Allergan Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
Cardiovasc Drug Rev. 2005 Fall;23(3):231-46. doi: 10.1111/j.1527-3466.2005.tb00168.x.
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.
比马前列素是一种安全且耐受性良好的降低眼压药物，于2001年在美国获批用于治疗青光眼和高眼压症。它疗效显著，与其他现有抗青光眼药物相比，能使眼压均值降低得更多。结膜充血是比马前列素的常见副作用，但这种充血通常较轻且为一过性。在接受比马前列素治疗的患者中，未发现炎症迹象与充血存在之间的关联。临床前研究阐明了比马前列素相关充血的药理机制，并研究了炎症可能的参与情况。比马前列素以及拉坦前列素的游离酸，在兔颈静脉制备实验中引发了内皮依赖性血管舒张，这是一种用于眼表充血（OSH）的定量体外模型。一氧化氮合酶抑制剂L-NAME可显著抑制对比马前列素或拉坦前列素游离酸的血管舒张反应。同样，L-NAME可显著抑制在犬眼中局部应用比马前列素或拉坦前列素后的体内OSH反应。正如所预测的，L-NAME并未抑制前列腺素E2（PGE2）诱导的结膜充血，因为PGE2对血管平滑肌有直接舒张作用。在兔子、狗和非人灵长类动物中进行了多剂量1个月、6个月或12个月的安全性研究，对比马前列素治疗后的眼表组织进行了活体观察和组织病理学评估。这些研究结果显示，眼表组织中没有比马前列素相关炎症的证据。总之，实验动物中与比马前列素治疗相关的OSH是由内皮源性一氧化氮介导的血管舒张引起的，与炎症无关。这些研究表明，比马前列素治疗的副作用结膜充血是由非炎症性、基于药理学的血管舒张导致的。
