Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-02
2003-03-11
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S912000
Reexamination Certificate
active
06531480
ABSTRACT:
The present invention relates to the topical ocular use of non-peptide bradykinin receptor antagonists for the treatment of human ocular pain, neovascularization, corneal haze, allergy and inflammatory diseases.
BACKGROUND OF THE INVENTION
Inflammation from cellular stress can cause excessive tissue damage. Numerous biochemical pathways are known to lead to inflammation. In general, these include the generation of locally produced or inflammatory cell derived proinflammatory cytokines (e.g., IL
1
, IL
6
, IL
8
and TNF
&agr;
), as well as products from the cyclooxygenase system, such as prostaglandins, and the lipoxygenase system, such as leukotrienes, “HETEs” and “HPETEs.” Other pro-inflammatory mediators released by mast cells (e.g., histamine, platelet activating factor) cause vascular permeability increases which in turn lead to the presence of yet more pro-inflammatory agents (e.g., bradykinin) at the site of trauma/allergic reaction. See generally,
Goodman and Gilman's The Pharmacological Basis of Therapeutics,
pages 600-617, Pergman Press, NY (1990). Therapies designed to inhibit the production of these types of agents and/or the blockade of the receptors mediating their effects are therefore of great interest.
Ocular allergic inflammation is a condition which generally causes patient discomfort including red eye, conjunctival edema and congestion, ocular discharge as well as scratchiness and itchiness. Ocular inflammation can be initiated by various insults. For example, ocular inflammation can result from allergic response to various allergens, bacterial infections, trauma to the eye, dry eye and surgical complications. Various anti-inflammatory therapies are currently in use for the treatment of ocular inflammation including the topical administration of diclofenac.
Allergic conjunctivitis affects over 25% of the general population (Friedlander,
Ann. Allergy,
volume 67, pages 5-13 (1991)). Human ocular allergic pathophysiology is mediated via several cellular and molecular mechanisms involving mast cells (Abelson and Schaefer,
Survey Ophthalmology,
volume 38, pages 115-132 (1993)). Once the conjunctival mast cells are activated by allergens, pollutants, airborne chemicals or pathogens, they rapidly liberate numerous inflammatory mediators (e.g., histamine and prostanoids) into the tear-film. These released agents, in turn, increase conjunctival vascular permeability and permit infiltration of additional pro-inflammatory agents such as bradykinin and inflammatory cells on the ocular surface (Abelson and Schaefer,
Survey Ophthalmology
). The net result of these events is generalized inflammation, edema, redness and itching—the cardinal signs of allergic conjunctivitis (Abelson and Schaefer,
Survey Ophthalmology
). Proud et al. (
J. Allergy Clin. Immunol.,
volume 85, pages 896-905 (1990)) have shown that 0.2 &mgr;M bradykinin is present in the tear-film of ocular allergic patients exposed to allergens, and that bradykinin can mimic the symptoms of allergic conjunctivitis.
Antihistamines (alone or in combination with alpha-adrenergic vasoconstrictors) and corticosteroids are currently used to treat some of the symptoms of allergic conjunctivitis and corneal/conjunctival inflammation. These drugs, however, have serious disadvantages and side-effects (e.g., low potency, short duration of action, discomfort and increases in intraocular pressure) which limit their clinical utility. Thus, new anti-allergy agents with improved efficacy and fewer side-effects are still needed.
Ocular surgery can result in various post-surgical inflammatory complications of the eye. Such complications generally include: 1) loss of vascular blood barrier function; 2) neutrophil accumulation; 3) tissue edema including conjunctiva swelling, conjunctiva congestion and corneal haze; 4) cataract formation; 5) cellular proliferation; and 6) loss of membrane integrity including decrease in docosahexaenoic acid levels in membrane phospholipids.
Another pathology which can affect the eye is neovascularization or angiogenesis. Angiogenesis is a term used to describe the development of new blood vessels or neovascularization (L. Diaz-Flores et al.,
Angiogenesis: an Update, Histology and Histopathology,
volume 9, pages 807-843 (1994)). Though angiogenesis is a normal process for the development or maintenance of the vasculature, pathological conditions (i.e., angiogenesis dependent diseases) arise where blood vessel growth is actually harmful. Such pathologies include diabetic retinopathies, proliferative vitreoretinopathies, psoriasis, artritis and tumor development. The progression of angiogenesis occurs in several phases which include: elaboration of the angiogenic signal; dissolution of the blood vessel basement membrane; endothelial cell proliferation; endothelial cell migration; and formation and differentiation of capillary tubules and loops.
Recently, BK has been shown to be a potent cell proliferating stimulator in several cell types and tissues (Hall,
Pharmacol. Rev.,
Wiernas et al.,
British J. Pharmacol.,
volume 123, pages 1127-1137 (1998)). As stated above, cellular proliferation is a critical component of the angiogenic response.
Angiogenesis is also associated with other important diseases of ocular tissue, especially in older patients and diabetics. Any abnormal growth of blood vessels in the eye can scatter and block the incident light prior to reaching the retina. Neovascularization can occur at almost any site in the eye and significantly alter ocular tissue function. Some of the most threatening ocular neovascular diseases are those which involve the retina. For example, many diabetic patients develop a retinopathy which is characterized by the formation of leaky, new blood vessels on the anterior surface of the retina and in the vitreous causing proliferative vitreoretinopathy. A subset of patients with age related macular degeneration develop subretinal neovascularization which leads to their eventual blindness.
Current therapy for the treatment of ocular neovascular disease is not very effective. Retinal neovascularization is often treated with multiple laser burns to the retina to remove the pathological vasculature. Patients with neovascular diseases of the anterior chamber (e.g. corneal neovascularization, iritis rubeosis) are treated with potent topical ocular glucocorticoids. These therapies are only partially effective and generally only slow neovascularization and the progress of the overall disease. In addition, they can cause severe side effects, including raising of intraocular pressure, if used over a relatively long period of time.
Other areas of ocular trauma relate to pain. Pain is a perceived nociceptive response to local stimuli in the body. The perception of pain at the level of the central nervous system requires the transmission of painful stimuli by peripheral sensory nerve fibers. Upon stimulation of tissue (i.e., thermal, mechanical or chemical), electrochemical signals are transmitted from the sensory nerve endings to the spinal column, and hence to the brain where pain is perceived.
The cornea is highly innervated with sensory afferents which transmit various painful stimuli to the central nervous system. Pain conditions involving the eye, therefore, can arise in numerous instances such as, foreign body stimulus, inflammation, dry eye syndrome, accidental trauma, surgical procedures and post-surgical recovery. For example, ocular pain can result from photorefractive keratotomy (PRK), a vision correcting, surgical procedure whereby a laser is used to shape the cornea. This process involves the photoablation of Bowman's membrane and the stromal levels of the cornea. As a result, the denuding of the nerve-containing epithelial layers of the cornea can cause some patients to experience pain following laser surgery until the epithelium regenerates.
Various therapies have been attempted for the alleviation of pain. The use of non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, have been developed to treat pain. These agents inh
Alcon Manufacturing Ltd.
Fay Zohreh
Yeager Sally S.
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