In primates, intraocular pressure is measured with a tonometer. A normal reading for a healthy, adult primate eye would be in the range 14 to 24 mm Hg. [See generally DeRousseau, C. J. and Bito, L. Z., EXP. EYE RES. 32:407-417 (1981); Kornblueth, W., et al., ARCH. OPHTHALMOL. 72: 489-490 (1964).] An increase of about 4 to 7 mm Hg. above the average reading for a specific subject would be indicative of ocular hypertension.
Glaucoma, an eye disorder afflicting various mammals, including primates, is characterized by increased intraocular pressure (ocular hypertension). In man, such ocular hypertension results from an imbalance between the rate of secretion of aqueous humor by the ciliary epithelium into the anterior and posterior chambers of the eye and the rate of outflow or drainage of the aqueous humor from the anterior and posterior chambers, primarily via the canal of Schlemm. It is generally believed that obstruction of aqueous humor drainage is the primary cause of the imbalance.
Chronic glaucoma typically results in slow, progressive loss of visual fields, and, if not controlled, ultimately in blindness. Initial treatment usually involves topical application of miotics, particularly pilocarpine and carbachol. If treatment with miotics is not effective, systemic administration of carbonic anhydrase inhibitors may be employed. If such approaches are unsuccessful, the glaucoma may have to be treated by surgery.
The treatment of human glaucoma with miotics is unsatisfactory for several reasons. The miotics may destroy a patient's night vision or cause ciliary muscle spasms. Moreover, long-term use of miotics may result in the development of tolerance (tachyphylaxis) to the miotics, necessitating the use of progressively higher doses. Finally, miotics may cause discomfort or other undesirable side effects. Long-term use of carbonic anhydrase inhibitors has likewise been found unsatisfactory. Such use may produce adverse systemic results or lead to the development of cataracts.
Eicosanoids and their derivatives include numerous biologically useful compounds. For example, the prostaglandins (PGs), a group of eicosanoids which contain cyclical fatty acids, are known to possess diverse biological activities. Originally isolated as lipid-soluble extracts from sheep seminal vesicles and human seminal fluid, prostaglandins have now been found in most mammalian tissue, although in lesser concentrations.
Activities of prostaglandins include stimulation of smooth muscle, dilation of small arteries, bronchial dilation, lowering of blood pressure, inhibition of gastric secretion, of lipolysis and of platelet aggregation, and induction of labor, abortion and menstruation.
It has been previously believed that administration of PGs, particularly PGE.sub.2, increases intraocular pressure based upon the results of studies involving intracameral and intravitreal injection of PGs into mammalian eyes. Accordingly, most research in this area focused on the use of prostaglandin antagonists rather than prostaglandins per se in the treatment of glaucoma.
More recently, studies of the effect of exogenous administration of PGs in cannulated and uncannulated rabbit eyes showed that topical aand intravitreal application of about 25 to 200 .mu.g. PGE.sub.2 or PGE.sub.2.alpha. per eye produced a short hypertensive phase, followed by hypotony. [Camras, C. B., Bito, L. Z. and Eakins, K. E., INVEST. OPHTHALMOL. VIS. SCI., 16:1125-1134 (1977)] However, a small dosage of PGF.sub.2.alpha., about 5 .mu.g, topically applied on rabbit eyes, produced a long period of hypotony, without any significant initial rise in intraocular pressure. Id. Other studies have shown that rabbits produce tolerance or tachyphylaxis to intracamerally or topically administered PGs. [Eakins, K. E., EXP. EYE RES., 10:87 (1970); Beitch, B. R. and Eakins, K. E., BRIT. J. PHARM., 37:158 (1969); Bito, L. Z. et al., ARVO, 22(No. 3):39 (1982)]
In addition, studies on species variations in ocular irritative and inflammatory response have shown that vertebrates such as primates and birds, which depend primarily on vision for sensory input, have more complex eye structures than rabbits, including more sophisticated ocular defense mechanisms. Accordingly, the eyes of primates and birds respond to topical application of chemical irritants in a manner unlike those of rabbits. This phenomenon may be due to the fact that the ciliary processes in rabbits are morphologically different from those of other species. In rabbits, there are abundant iridial ciliary processes which are uniquely susceptible to breakdown, e.g., by neuronal irritation or paracentesis, and deterioration of the blood-aqueous barrier. This propensity for breakdown appears to have an important protective function for rabbits which have highly exposed eye globes. Because of its exaggerated ocular irritative response, the rabbit has been widely used in studies of the role of PGs in ocular inflammation. In contrast, primates show a qualitatively different response to paracentesis: protein entry through the canal of Schlemm rather than breakdown of the ciliary processes. [Raviola, EXP. EYE RES. 25 (Supp.):27 (1977)]. Accordingly, use of the rabbit eye as a model for primates has been discredited except in ocular inflammation studies. [Bito, L. Z. and Klein, E. M., EXP. EYE RES. 33:403-412 (1981); Klein, E. M. and Bito, L. Z., PROC. INT. SOC. EYE RES. 1:65; Klein, E. M. and Bito, L. Z., INVEST. OPHTHALMOL. VIS. SCI. 20 (Supp.):33 (1981)].
USPTO Backgrounds
USPTO Backgrounds