TREATMENT OF OPHTHALMOLOGICAL CONDITIONS WITH ACETYLCHOLINESTERASE INHIBITORS

Abstract

Embodiments of the invention involve treating ophthalmology conditions by the topical or oral use of acetylcholinesterase inhibitors. By effectively reducing or eliminating the population of demodex mites in affected areas and areas where demodex mites may exist, this treatment achieves a more complete remission of clinical signs and symptoms of the ophthalmological afflictions than any previously described method. Embodiments of the invention are useful for treating ocular afflictions caused by demodex-induced inflammatory eye conditions, including meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia, blepharitis and dry eye disease.

Claims

1. A method of treating an ophthalmological affliction, the method comprising the step of topically-applying to a human individual having the ophthalmological affliction an acetylcholinesterase inhibitor in a dosage sufficient to inactivate demodex brevis and/or demodex folliculorum mites from hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual, resulting in amelioration or cessation of the manifestations of allergic and/or inflammatory responses to the mites that cause symptoms and signs of the ophthalmological affliction in the individual; wherein the acetylcholinesterase inhibitor is selected from the group consisting of: physostigmine, demecarium, donepezil, tacrine, echothiophate, diisopropyl fluorophosphate, lactucopicrin, boswellia, Celastrus paniculatus, coumarins, galantamine, huperzine A, a prodrug thereof, and a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein said ophthalmological affliction is a demodex-induced inflammatory eye condition.

3. The method of claim 2, wherein said demodex-induced inflammatory eye condition is one or more of: Meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia, dry eye, and blepharitis.

4. (canceled)

5. The method of claim 1, wherein said acetylcholinesterase inhibitor is selected from the group consisting of: physostigmine, galantamine, demacarium, donepezil, tacrine, diisopropyl fluorophosphate, and echothiophate.

6. The method of claim 1, wherein said acetylcholinesterase inhibitor is efficiently transported into the epidermis or a subdermal region upon contact with said hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual.

7.-8. (canceled)

9. The method of claim 1, wherein the ophthalmological affliction is one or more of meibomian gland dysfunction, blepharitis, dry eye disease.

10. The method of claim 1, wherein the ophthalmological affliction affects the eye or eyelids, or both.

11.-21. (canceled)

22. The method of claim 1, wherein the topically-applied acetylcholinesterase inhibitor is formulated in a saline solution, carrier lotion, cream, soap, wash, shampoo or gel, with 0.001% to 5% by weight of the acetylcholinesterase inhibitor.

23.-25. (canceled)

26. The method of claim 22, wherein a dosage of the acetylcholinesterase inhibitor in the topically-applied lotion, cream, soap, wash, shampoo or gel is a lowest dose effective for killing the demodex mites.

27. The method of claim 22, wherein the topically-applied acetylcholinesterase inhibitor is encapsulated inside microliposomes before being formulated into the carrier lotion, cream, soap, wash, shampoo or gel.

28. The method of claim 22, wherein the topically-applied acetylcholinesterase inhibitor is applied to said hair follicles, skin, eyes, eyelids, eyelashes, or Meibomian Gland areas affected by the ophthalmological affliction.

29.-32. (canceled)

33. The method of claim 1, wherein the topically-applied acetylcholinesterase inhibitor is applied to an eye region corresponding to hair follicles, skin, eyes, eyelids, eyelashes, and/or meibomian gland areas at least once daily for a period of two to six weeks.

34.-42. (canceled)

43. The method of claim 1, wherein the acetylcholinesterase inhibitor is orally-administered or topically-applied in a continued intermittent regime sufficient for prophylactic control of demodex mite population in the said hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual.

44.-50. (canceled)

51. The method of claim 1, wherein the inactivation of the demodex brevis and/or demodex folliculorum mites from the said hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual results in a reduction in population of one or more bacteria from the genus staphylococcus or from the genus bacillus in the said hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual.

52.-56. (canceled)

57. A method of treating an ophthalmological affliction, the method comprising a step of topically-applying to an eye region of an individual having the ophthalmological affliction that is a demodex-induced inflammatory eye condition an active ingredient comprising an acetylcholinesterase inhibitor in a dosage sufficient to inactivate demodex brevis and/or demodex folliculorum mites from said eye region, wherein said eye region comprises hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual, resulting in amelioration or cessation of one or more manifestations of allergic and/or inflammatory responses to the mites that cause symptoms and signs of the ophthalmological affliction in the individual, wherein the topically-applied active ingredient is applied to the eye region areas affected by the ophthalmological affliction and to eye and/or facial areas not affected by the ophthalmological affliction; wherein the individual is a human and the active ingredient is selected from the group consisting of: physostigmine, demecarium, donepezil, tacrine, echothiophate, diisopropyl fluorophosphate, lactucopicrin, boswellia, celastrus paniculatus, coumarins, galantamine, huperzine A, a prodrug thereof, and a pharmaceutically acceptable salt thereof.

58.-70. (canceled)

71. The method of claim 57, wherein the ophthalmological affliction comprises one or more of Meibomian Gland Dysfunction, blepharitis, conjunctivitis, keratoconjunctivitis, hyperemia, or dry eye disease.

72.-87. (canceled)

88. The method of claim 1, further comprising the step of applying the acetylcholinesterase inhibitor with one or more of a spray bottle, impregnated swab/qtip, impregnated wipes, eye drops or spoolie brush.

89.-92. (canceled)

93. The method of claim 57, wherein the eye region corresponds to an area of between at least 1 cm and 10 cm around an outermost perimeter defined by the eye, eyelid, eyebrow and eyelashes.

94. The method of claim 1, wherein the acetylcholinesterase inhibitor is provided as a formulation containing 5% or less of the acetylcholinesterase inhibitor.

95. The method of claim 94, wherein the formulation further comprises a dimethyl sulfoxide.

96. The method of claim 1, further comprising the step of applying to the eye or eye region a conventional ophthalmological medication selected from the group consisting of: artificial tear substitutes, ointments, gels, warm compresses, environmental modification, topical cyclosporine, omega-3 fatty acid supplements, punctal plugs, and moisture chamber goggles.

97. The method of claim 1, further comprising the step of treating the individual with one or more of: punctal cautery, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, PROSE scleral contact lenses, or tarsorrhaphy.

98. The method of claim 1, further comprising the step of applying a full facial topical application of the acetylcholinesterase inhibitor to the individual.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1 summarizes a topical administration method to an eye region of an individual in need of treatment.

[0045] FIG. 2 is an illustration of Demodex folliculorum and Demodex brevis mites, including relative sizes and locations in the skin, hair follicles and glands.

[0046] FIG. 3 illustrates Demodex mites in the eye region, including eye lash and meibomian glands.

[0047] FIG. 4 is a table summary of Demodex survival time for various acetylcholinesterase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

[0048] In general, the terms and phrases used herein have their art-recognized meaning, which can be found by reference to standard texts, journal references and contexts known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of the invention.

[0049] “Inactivate” is used broadly herein to refer to the functional ability to decrease the impact of demodex brevis and/or demodex folliculorum mites. For example, the inactivation may be by death of the mite. Alternatively, the inactivation may refer to the inability of the mite to reproduce, so that the mite die off occurs as the mites age and die without reproduction. So long as the treatment leads to an adverse effect on the demodex brevis and/or demodex folliculorum mites that corresponds to improved clinical outcome, such as symptom improvement, the treatment is considered herein to inactivate demodex brevis and/or demodex folliculorum mites.

[0050] “Efficiently transported” refers to the ability of the treatment agent to act against mites that are located beneath the skin surface, such as into an epidermal or subdermal region so that the mites are timely inactivated.

[0051] “Substantially all” refers to, unless defined in the contrary, at least 90%, at least 95% or at least 99% of the relevant population, so in the context of demodex mites, it refers to inactivation (e.g., killed or eliminated or otherwise unable to propagate) and/or application to hair (number) or skin (surface area).

[0052] As used herein, “Demodex” refers to D. folliculorum and D. brevis mites, including Demodex mites in humans that may contribute to a demodex-induced inflammatory eye condition in humans.

[0053] D. folliculorum and D. brevis mites may play a role in ophthalmological conditions. An increased demodex population has been observed in patients with ophthalmological afflictions. For most people, demodex mites live harmlessly in the hair follicles, skin, eyelids, eyelashes, or meibomian glands as a result of either down-regulating host immunity or simply dodging host immune defenses. There is continual debate within the ophthalmology community as to whether or not they are the causative agents of such ophthalmological diseases as meibomian gland dysfunction, dry eye disease and blepharitis (inflammation of the eyelids).

[0054] Human beings are the one and only host of these ubiquitous mites [1]. In fact, these two mites are considered to be the most common ectoparasite of humans [6]. Women tend to have a higher rate of demodex infections [5]. The rate of infestation also seems to be correlated with age, with 84% of people at age 60 harboring mites and increasing to 100% in those 70 years and older [7]. Whether those that are immunocompromised are more susceptible to higher infestation rates is unknown, though some studies indicate that AIDs and leukemia patients may be more prone to greater than average numbers [5].

[0055] The mites are most commonly found in the scalp, face and upper chest area, with D. folliculorum exhibiting a predilection for the hair follicles and D. brevis for the sebaceous ducts and meibomian glands at the rim of the eyelids (the sebaceous ducts transfer the waxy sebum that lubricates the skin and hair from the sebum glands; the meibonmian glands are a special type of such gland) [4][5]. D. folliculorum are a communal bunch, tending to congregate in the follicle area of the hair or eyelashes with their posterior ends protruding from the follicular pores. D. brevis, on the other hand, tend to be more solitary and will occupy the sebaceous glands singly [6]. Both species are tiny, less than 0.4 mm, with elongated, clear bodies and four pairs of stout legs. D. brevis is usually a tad shorter, ˜0.1 mm, than D. folliculorum. They both have ridged scales along their cephalothorax and sharp, piercing teeth [6].

[0056] Short-lived creatures, a mite's life cycle from egg to larva to adult lasts from 14-18 days. Adults emerge from the follicles and ducts to reproduce at the surface of the skin where females will then deposit eggs in the sebaceous glands. Larva will mature via two nymphal stages in the glands until entering the follicles and ducts as adults to begin the cycle anew [6]. It is hypothesized that both species of mites feed upon sebum as a primary food source but may also munch on follicular and glandular epithelia. They are thought to be obligate ectoparasites, incapable of living outside their human host.

[0057] Some studies have discovered a greater than average mite density, greater than five mites per cm.sup.2, do seem to play a role in skin diseases for patients [6]. Researchers have suggested that blockage of the hair follicles and sebaceous ducts by mites may result in epithelial hyperplasia, elicit a phagocytic, granulomatous reaction or bring about an inflammatory response due to their waste products [5]. The fact that treatment with certain antibiotics can reduce the severity of meibomian gland dysfunction, blepharitis, dry eye disease strongly suggests a microbial component to mite-related diseases.

[0058] In 2007, researchers isolated from D. folliculorum a bacterium Bacillus oleronium that provoked inflammatory responses in 73% of rosacea patients but only 29% of controls [21]. These results suggest that patients with rosacea including ocular rosacea were sensitized to the bacteria and may be immunologically sensitive to the mites, bacteria or both [21].

[0059] Two antigenic proteins found on the bacterium's cell surface in particular appeared to be responsible for the inflammatory response by stimulating peripheral blood mononuclear cell proliferation; one 83 kDa protein showed similarity with heat-shock proteins while the other 62 kDa protein shared amino acid sequence homology with a protease enzyme found to be involved signal transduction as well as carbohydrate metabolism [21]. Stronger proof of the pathogenic role of B. oleroniusin ocular rosacea may also be found in the sensitivity of the bacterium to many antibiotics proven to be effective in the treatment of rosacea, specifically tetracycline, doxycycline and minocycline [21].

[0060] In an exemplary embodiment, an acetylcholinesterase inhibitor is administered topically to a patient with an active ophthalmological condition in which the underlying cause is a demodex mite. Because the target organisms, demodex brevis and demodex folliculorum, are ectoparasites in the mite family, an effective treatment must be capable of eradicating the entire lifecycle of such a microscopic insect, including egg, larval, and adult stages. For this reason, this embodiment treats such patients with several doses. Such spacing allows time for demodex eggs to hatch into immature mites that are killed before they can mature into egg-producing adults. After the acetylcholinesterase inhibitor carries out its miticidal activity on demodex brevis and demodex folliculorum organisms, inflammatory responses to them begin to diminish but remnants of the dead mites still elicit some flushing and lesion formation until the cleanup processes of the body remove them, a process requiring six to twelve weeks. During this initial phase of acetylcholinesterase inhibitor administration, conventional ophthalmological medications such as artificial tear substitutes, ointments, gels, warm compresses, environmental modification, topical cyclosporine, omega-3 fatty acid supplements, punctal plugs and moisture chamber goggles can be utilized in combination treatment with acetylcholinesterase inhibitor compounds. Patients with severe disease may further be treated with punctal cautery, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, PROSE scleral contact lenses and tarsorrhaphy can optionally be employed to suppress early flareups and to give early clinical response. No such medications are needed to treat manifestations of the ophthalmological condition after six to twelve weeks have elapsed. After prolonged intervals of freedom from symptoms, should classic signs begin to reappear, treatment can be repeated. The acetylcholinesterase inhibitor is formulated into a cosmetically-acceptable topical saline solution, lotion, cream, shampoo, or gel and applied especially to hair follicles, skin, eyes, eyelids, eyelashes, surrounding the eyes and any area possibly inhabited by demodex brevis and demodex folliculorum. Because of the well-known barrier effect the skin presents to the penetration of topical medications, such a route of treatment with acetylcholinesterase inhibitor is anticipated to require once or twice daily applications for as long as twelve to six weeks to achieve sufficient follicle penetration and effective miticidal activity. A topical formulation that could achieve this effect would contain about 5% or less of the acetylcholinesterase inhibitor. The lesser the percentage of the acetylcholinesterase inhibitor that can be used while still receiving the miticidal effect and successfully treating the ocular condition is ideal for limiting any possible side effects of the chemical. Further, full facial treatment is optionally useful for preventing reintroduction of the mites onto facial skin and glands.

[0061] Referring to FIG. 1, a method of treating an individual 10 having a demodex-induced ophthalmological affliction of Meibomian gland dysfunction, the method comprising the steps of: applying to the individual in need thereof an acetylcholinesterase inhibitor (indicated by arrow 20) in a dosage sufficient to inactivate demodex brevis mites and/or demodex folliculorum mites from hair follicles 100, eyelids 110, eyebrows 120, eyelashes 130 and Meibomian glands 140 in and around an eye region. In this manner, a sufficient amount of demodex brevis mites and/or demodex folliculorum mites are inactivated to ameliorate or cease manifestations of allergic and/or inflammatory responses to the mites that cause symptoms or signs of Meibomian gland dysfunction.

[0062] The allergic and/or inflammatory responses may be manifested by dry eye or blepharitis, and the symptoms related thereto. The application may be by a topical administration of acetylcholinesterase inhibitor 20 to an eye region 205 of the individual 10. Optionally, the eye region may be quantifiably defined, such as corresponding to an area of the eye region 205, including a distance 210, such as between at least 1 cm and 10 cm around an outermost perimeter 200 defined by the eye, eyelid, eyebrow and eyelashes. For clarity, the eye region 205 is illustrated as rectangular in shape, but the invention provided herein is compatible with any shape and region size, although it is preferable to control mite population in the area around the glands 140 so as to avoid relatively fast natural mite migration back to the glands 140 (or region adjacent thereto) with corresponding manifestation of unwanted clinical system. Accordingly, the methods provided herein, upon completion, may be characterized as ameliorating or cessation of symptoms and signs of the ophthalmolgical affliction of at least 30 days-6 months, and any range therein.

[0063] FIGS. 2-3 illustrate the demodex brevis and folliculorum mites in the skin area generally and the eye region, respectively, demonstrating the need to ensure treatment applications are able to achieve sub-dermal penetration.

Medical Use of Carbamates:

[0064] Urethane (ethyl carbamate) was once produced commercially in the United States as an antineoplastic agent and for other medicinal purposes. It was found to be toxic and largely ineffective. It is occasionally used as a veterinary medicine.

[0065] In addition, some carbamates are used in human pharmacotherapy, for example, the cholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine. Other examples are meprobamate and its derivatives like carisoprodol, felbamate, and tybamate, a class of anxiolytic and muscle relaxant drugs widely used in the 60s before the rise of benzodiazepines, and still used nowadays in some cases.

[0066] The cholinesterase inhibitors neostigmine and rivastigmine may be efficacious if they have similar miticidal capabilities compared to many other carbamate compounds.

[0067] Drug class and mechanism: Rivastigmine is an oral medication used to treat patients with Alzheimer's disease. Rivastigmine is in a class of drugs called cholinesterase inhibitors that also includes tacrine (Cognex), donepezil (Aricept), and galantamine (Razadyne—formerly known as Reminyl). Cholinesterase inhibitors inhibit (block) the action of acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine. Acetylcholine is one of several neurotransmitters in the brain, chemicals that nerve cells use to communicate with one another. Reduced levels of acetylcholine in the brain are believed to be responsible for some of the symptoms of Alzheimer's disease.

[0068] In vitro efficacy and mite lifetimes: Relative efficacy of various formulations are evaluated with a demodex survival time experiments. FIG. 4 tabulates demodex survival time, expressed in terms of LT50 (time at which 50% of demodex mites are killed) and/or average minutes to death for various inhibitors.