Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-12-06
2002-04-23
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C514S913000, C424S085100, C424S085200
Reexamination Certificate
active
06376541
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods of lowering intraocular pressure (IOP), such as in the treatment of glaucoma. The invention particularly relates to the upregulation of the endogenous synthesis of prostaglandins in the eye to effect such treatment.
BACKGROUND OF THE INVENTION
Glaucoma
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior segment of the eye. The anterior segment of the eye consists of anterior and posterior chambers. The anterior chamber lies in front of the iris and contains aqueous humor which helps support the cornea. The posterior chamber lies behind the iris and encompasses the crystallin lens of the eye.
The causes of aqueous humor accumulation in the anterior segment are not fully understood. It is known that elevated intraocular pressure (“IOP”) can be at least partially controlled by administering drugs such as beta-blockers and carbonic anhydrase inhibitors, which reduce the production of aqueous humor within the eye, or agents such as miotics and sympathomimetics, which increase the outflow of aqueous humor from the eye.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers, have been associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension.
Prostaglandins
Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G
2
, which is subsequently converted to prostaglandin H
2
. Other naturally occurring prostaglandins are derivatives of prostaglandin H
2
. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Two naturally-occurring prostaglandins which have been shown to lower IOP are PGF
2&agr;
, (an F-series prostaglandin) and PGE
2
(an E-series prostaglandin) which have the following chemical structures:
The relationship of PGF
2&agr;
, receptor activation and IOP lowering effects is not well understood. It is believed that PGF
2&agr;
, receptor activation leads to increased outflow of aqueous humor. Regardless of the mechanism, PGF
2&agr;
, and certain of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F
2&agr;
the Human Eye,
Graefe's Archive Ophthalmology
222:139-141 (1985); and Kerstetter et al., Prostaglandin F
2&agr;
-1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow,
American Journal of Ophthalmology
105:30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF
2&agr;
, analogs with IOP lowering efficacy.
Synthetic PGF
2&agr;
-type analogs have been pursued in the art (
Graefe's Archive Ophthalmology
229:411-413 (1991)). Though PGF
2&agr;
type molecules lower IOP, a number of these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (AIm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy,
Current Opinion in Ophthalmology
, 4(11):44-50 (1993)).
The relationship between EP receptor activation and IOP lowering effects is not well understood. There are currently four recognized subtypes of the EP receptor: (EP
1
, EP
2
, EP
3
, and EP
4
(Ichikawa, Sugimoto, Negishi, Molecular aspects of the structures and functions of the prostaglandin E receptors,
J. Lipid Mediators Cell Signaling
, 14:83-87 (1996)). It is known in the art that ligands capable of EP
2
receptor activation, such as PGE
2
and synthetic analogs (Flach, Eliason, Topical Prostaglandin E
2
Effects on Normal Human Intraocular Pressure
Journal of Ocular Pharmacology
4(1):13-18 (1988); Woodward, et al., Molecular Characterization and Ocular Hypotensive Properties of the Prostaglandin EP2 Receptor
Journal of Ocular Pharmacology and Therapeutics
11(3):447-454 (1995)), or EP
3
receptor activation (Woodward, et al., Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies,
Journal of Lipid Mediators
, 6:545-553 (1993); Waterbury, et al., EP
3
but not EP
2
FP or TP Prostanoid-Receptor Stimulation May Reduce Intraocular Pressure,
Investigative Ophthalmology and Visual Science
, 31(12):2560-2567 (1990)) lower IOP. However, some of these molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing, including an initial increase in IOP, photophobia, and eye ache (see for example Flach, Eliason, Topical Prostaglandin E
2
Effects on Normal Human Intraocular Pressure,
Journal of Ocular Pharmacology
4(1):13-18 (1988)).
It has now been postulated that ocular hyperemia, such as that attendant to the topical administration of the prostaglandins described above, is mediated by a sensory nerve response on the surface of the eye [1]. The prostaglandins PGF
2&agr;
and PGE
2
are naturally formed by different tissues in the eye and are components of normal aqueous humor. Nevertheless, both are associated with acute inflammation and are considered early mediators of an induced inflammatory response. Still, co-administration of these natural prostaglandins to reduce IOP has been proposed. See, U.S. Pat. No. 5,565,492.
Many synthetic prostaglandins purporting to avoid or reduce one or more of the side effects attributable to the natural prostaglandins have also been shown to lower IOP by varying degrees. See, for example, U.S. Pat. Nos. 5,321,128; 5,698,733; 5,700,835; and 5,721,273.
The cornea, which is reportedly capable of producing both PGF
2&agr;
, and PGE
2
, appears also to have the ability to convert topically applied PGF
2&agr;
, into PGE
2
to elevate aqueous humor levels of this important prostaglandin. In fact, prostaglandins are believed to be produced in all tissues surrounding the anterior chamber of the human eye including the iris/ciliary body, lens epithelial pocket and trabecular meshwork. Constitutive prostaglandin synthesis (non-inducible and providing relatively constant prostaglandin levels in normal aqueous humor) by these tissues may be an important factor in the normal control of IOP, and the loss of prostaglandin synthetic capability at or near the anterior chamber could result in an increase in IOP. Based in part on these observations, it is suggested that tissues in contact with the anterior chamber are likely accustomed to rapid changes in, and probably accommodate to, elevated levels of prostaglandins in aqueous humor.
Since prostaglandins, bot
David Karen C.
Nixon Jon C.
Alcon Manufacturing Ltd.
Copeland Barry L.
Mertz Prema
Prasad Sarada C
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