Wo 2010/019450 A2

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 18 February 2010 (18.02.2010) WO 2010/019450 A2

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/485 (2006.01) A61K 31/35 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61P 29/00 (2006.01) A61P 17/06 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/52 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/US2009/053040 NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, 6 August 2009 (06.08.2009) TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (30) Priority Data: ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/087,695 9 August 2008 (09.08.2008) US TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant and MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (72) Inventor: BAUER, Nyles [US/US]; 11 Woodcock Lane, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Ridgefield, CT 06877 (US). ML, MR, NE, SN, TD, TG). (74) Agents: ROSENMAN, Stephen, J . et al; Seed Intellec Published: tual Property Law Group PLLC, Suite 5400, 701 Fifth — without international search report and to be republished Avenue, Seattle, WA 98104-7064 (US). upon receipt of that report (Rule 48.2(g)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM,

(54) Title: SYNERGIZING ACTIVE COMPOUNDS FOR TREATING INFLAMMATION AND OTHER CONDITIONS (57) Abstract: Compositions and methods are

1 provided having unexpected anti-inflammatory and other properties based on unprecedented syn ergistic effects of administering two or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP -phosphodiesterase (PDE) in hibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phos phate) (NAD(P)H) oxidase inhibitor. Invention embodiments are useful for treating or reducing one or more of tissue inflammation, inflammation- associated cellular proliferation, oxidative stress or neuronal death or dysfunction, or for treating or preventing gray hair or restoring hair color.

G93A G93A+50uMN αl G93A+5uMNαl G93A+0.5uMN αl

FIG. 1 SYNERGIZING ACTIVE COMPOUNDS FOR TREATING INFLAMMATION AND OTHER CONDITIONS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 61/087,695 filed August 9, 2008, where this provisional application is incorporated herein by reference in its entirety.

STATEMENT REGARDING SEQUENCE LISTING The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 700153_401PC_SEQUENCE_LISTING.txt. The text file is 3 KB, was created on August 6, 2009, and is being submitted electronically via EFS-Web.

BACKGROUND

Technical Field The presently disclosed invention embodiments relate generally to compositions and methods for treating inflammation. More specifically, the present embodiments relate to formulations containing synergizing components for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction, and/or for treating or preventing gray hair or restoring hair color.

Description of the Related Art Maintenance of intact, functioning skin is significant to the health and survival of humans and other animals. The skin is the largest body organ in humans and other higher vertebrates (e.g., mammals), protecting against environmental insults through its barrier function, mechanical strength and imperviousness to water. As a significant environmental interface, skin provides a protective body covering that permits maintenance of physiological equilibria. Skin architecture is well known. Briefly, epidermis, the skin outer layer, is covered by the stratum corneum, a protective layer of dead epidermal skin cells (e.g., keratinocytes) and extracellular connective tissue proteins. The epidermis undergoes a continual process of being sloughed off as it is replaced by new material pushed up from the underlying epidermal granular cell, spinous cell, and basal cell layers, where continuous cell division and protein synthesis produce new skin cells and skin proteins (e.g., keratin, collagen). The dermis lies underneath the epidermis, and is a site for the elaboration by dermal fibroblasts of connective tissue proteins (e.g., collagen, elastin, etc.) that assemble into extracellular matrix and fibrous structures that confer flexibility, strength and elasticity to the skin. Also present in the dermis are nerves, blood vessels, smooth muscle cells, hair follicles and sebaceous glands. As the body's first line of defense, the skin is a major target for clinical insults such as physical, mechanical, chemical and biological (e.g. , xenobiotic, autoimmune) attack that can alter its structure and function. The skin is also regarded as an important component of immunological defense of the organism. In the skin can be found migrating, as well as resident, white blood cells (e.g., lymphocytes, macrophages, mast cells) and epidermal dendritic (Langerhans) cells having potent antigen-presenting activity, which contribute to immunological protection. Pigmented melanocytes in the basal layer absorb potentially harmful ultraviolet (UV) radiation. Disruption of the skin presents undesirable risks to a subject, including those associated with opportunistic infections, incomplete or inappropriate tissue remodeling, scarring, impaired mobility, pain and/or other complications. In humans and most animals inflammation is always present in skin and/or other tissues, even in a healthy body. Often arbitrarily, inflammation is divided into two gross types, acute and chronic. Acute inflammation, in general, is an appropriate bodily reaction to an insult (e.g., a clinical insult), whether a pathogen, parasite, or trauma. Ideally the inflammatory process ends soon after the insult has been dealt with or removed, and healing is complete. Chronic inflammation is normally viewed as an extended state of heightened immune system response which may, or may not, be an appropriate reaction to a bodily insult. Most, if not all, inflammation causes collateral damage to healthy tissue as well as targeting the appropriate clinical insult, and may be widely disseminated in the body or very localized. Redness (e.g., of the skin), increased heat, swelling, pain and loss of function are often, but not always, associated with the inflammatory response. There is mounting and very convincing evidence that inflammation, especially chronic, is linked to heart attacks, strokes, Alzheimer's Disease and other dementias, cancers, and additionally to many issues not currently thought of as being disease states such as cognitive decline, altered cognitive states, skin wrinkle formation, balding and many other "normal" aging processes including loss of hair color (e.g., US/2009/0 118203; D'Orazio et al, 2006 Nature 443:340; Michelet et al, 2009 Exp. Dermatol. 18:414) . But aging is not a necessary prerequisite for inflammation; asthma, atopic dermatitis, allergies, all on the rise in the United States, are all inflammatory diseases, and often occur in children. The inflammatory process involves the reaction of vascularized living tissues to local injury in which there is a series of changes in the terminal vascular bed, in blood, and in connective tissues, with the purpose of eliminating an offending irritant and repairing the damaged tissue. A great deal of this process is mediated by soluble circulating signaling molecules, typically polypeptides, referred to as cytokines, which orchestrate much of the cellular immune response and may operate locally or at some distance from their site of release by inflammatory cells. Under ideal conditions the source of the tissue injury is eliminated, the inflammatory response resolves, and normal tissue architecture and physiologic functions are restored. The nature of the acute inflammatory reaction can be intense and the affected area is walled off by a collection of inflammatory cells. This process results in destruction of tissue by metabolites of one or more inflammatory cell types, including polymorphonuclear leucocytes. Failure to eliminate the pathologic insult often results in the persistence of the inflammatory reaction. Multiple overlapping inflammatory response pathways have been described, as have multiple mechanisms for initiating an inflammatory pathway, and for feedback regulation to control such pathways, for example, by dampening or accelerating the response. Much of the inflammatory response is a "surface phenomenon" dependent on cell membrane perturbations. Acute inflammation generally takes a short and relatively severe course. It often begins within 4-6 hours of an insult and can last for 3-5 days. Active hyperaemia is usually noted, as is edema due to endothelial damage within the lymphatic system and small blood vessels. Occasionally fibrin thrombi within vessels can be noted. Leukocyte infiltration is variable. In general neutrophils usually predominate in acute inflammatory reactions, but sometimes mononuclear cells, lymphocytes, and/or plasma cells can be present. Clinical signs are most associated with the vascular changes and are stereotypical, including warmth, redness, swelling, pain, and loss of function. Lymphatic vessels have a role in moving away the exudate. The transportation of the exudate, the bulk being inflammatory cells and necrotic debris, can lead to acute regional lymphadenitis. The nature of chronic inflammation persists over a period of time as a result of a persistent inflammatory stimulus in which the host usually fails completely to eliminate the causative agent, but chronic inflammation may also be seen in improperly mounted immune responses, autoimmune disease, and aging. Chronic inflammation is characterized by the presence of mononuclear inflammatory cells (lymphocytes and macrophages) and fibroblasts, often with proliferating vasculature. This may follow an acute inflammatory phase or may develop as an insidious, low- grade, subclinical process without history of a prior acute inflammatory episode. Clinical signs are dependent upon duration of the illness, inflammatory lesions, cause and anatomical area affected (see, e.g., Kumar et al., Robbins Basic Pathology-S * Ed., 2009 Elsevier, London; Miller, LM, Pathology Lecture Notes, Atlantic Veterinary College, Charlottetown, PEI, Canada). Proliferative inflammation is an inflammatory process characterized by an increase in the number of tissue cells. These can encompass skin conditions such as psoriasis, seborrhea or eczema, or can also be thought of in terms of cancers and abnormal growths especially in light of accumulating evidence based on more efficient molecular methods to document even low grade chronic inflammation. Both inflammation and unregulated cellular proliferation remain a pressing biomedical and veterinary problem. Very few existing treatments are without side effect profiles that have potentially devastating effects on quality of life, and often carry a very real risk of a significant increase in morbidity and mortality. Because of the multiple biological and biochemical pathways involved, there is seldom a single solution for any given medical condition involving inflammation or cellular proliferation, hindering efforts to identify and implement effective treatments. Moreover, side effect profiles of most currently available treatments for inflammation are often potentially devastating, ineffective from the start, prone to development of tolerance (e.g., desensitization to escalating doses) with sustained use, and/or may significantly reduce the quality of life. Dermatological conditions such as eczema, seborrhea, and psoriasis are often chronic diseases that need lifelong treatment to be even partially controlled. Proliferative cellular diseases such as cancers, and diseases considered more benign such as excessive scar formation and benign tumors, abound in every society and age group. Disease states involving inflammation are generally addressed pharmacologically, though some can be managed by avoiding a known initiating cause such as a food, chemical or allergen. Often proliferative inflammatory diseases, such as eczema, seborrhea and psoriasis, are treated much the same way as non proliferative inflammatory states. Exceptions are diseases such as cancer, which are often treated surgically, with radiation, and/or chemotherapy, with the end goal being total destruction of the offending tissue. Although cancer is a proliferative inflammatory condition, it is still generally treated only as a cellular proliferative state and is certainly in need of a more targeted and benign treatment regimen. Symptomatic treatments, by definition, don't address the actual cause of the condition, but rather, treat the symptoms. Examples of such symptomatic treatments include, in asthma, the use of a bronchodilator; in eczema it may be the use of an occlusive cream. Despite such palliative treatments, generally the disease state remains, and may indeed progress as systemic damage continues, while the symptoms may be merely reduced or temporarily ameliorated. Generalized immunosuppressives such as corticosteroids are often used for a variety of inflammatory diseases because of their wide-ranging biological effects. Corticosteroids can be very effective and even lifesaving, however high dosages and long-term use inevitably result in side effects, often severe. Applied topically, corticosteroid side effects include skin damage, such as skin thinning, changes in pigmentation, easy bruising, stretch marks, redness and dilated surface blood vessels. Taken systemically, or absorbed through the skin, these steroids can cause side effects that may manifest in nearly every system within the body, and include Cushing's disease, osteoporosis, increased risk of infection, cataracts, and/or cognitive and psychological alterations, to name just a few. Generally, corticosteroids do not address the bulk of the disease process and are often used only to reduce symptoms by way of gross immunosuppression. Newer medications and treatments appear fairly regularly on the market as knowledge of the immune system advances. Monoclonal antibodies, cytokines, targeted immunosuppressives, etc. are all available, but at this time they are all regulated by prescription, and all are expensive. None of these medicines are without side effects, which include increased risk of infection and cancers, drug toxicity, and neurological problems. Additionally the long-term risks of using such recently developed therapeutics remains unknown, which is particularly problematic given that most serious inflammatory diseases, and autoimmune diseases (which all have a major inflammatory component), are long-term, and often lifelong, disease states. Clearly there remains a need for improved compositions and methods for treating inflammatory and proliferative cellular disease states and related conditions associated with inflammation, aging, oxidative stress, cancer and the like, which improved approaches would offer the potential for reduced side effects and could also address alternative biological pathways beyond those which are currently the targets of therapeutic intervention, so that a more diverse palette of treatments can be made available to all that suffer from these illnesses, and especially to those who have not responded well to available treatments. The presently disclosed embodiments address these needs and provide other related advantages. BRIEF SUMMARY According to certain embodiments of the invention that is disclosed for the first time herein, there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising administering to the subject a formulation that comprises an effective amount of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP- phosphodiesterase (PDE) inhibitor, and (iii) an adenylate cyclase activator. In certain embodiments the opiate antagonist is selected from naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist that is selected from D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-

Thr-NH 2 (CTP) [SEQ ID NO:1], D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2

(CTOP) [SEQ ID NO:2], D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) [SEQ ID NO:3], D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-

Lys-Thr-Pen-Thr-NH 2 (D-Tic-CTP) [SEQ ID NO:4], D-Tic-Cys-Tyr-D-Trp-Orn-Thr-

Pen-Thr-NH 2 (D-Tic-CTOP) [SEQ ID NO:5] and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-

Pen-Thr-NH 2 (D-Tic-CTAP) [SEQ ID NO:6], where Pen is penicillamine, Tic is D- tetrahydroisoquinoline carboxylic acid and Orn is ornithine; the PDE inhibitor is selected from a methylxanthine that is selected from caffeine, theobromine, paraxanthine, 3-isobutyl-1 -methylxanthine (IBMX) and theophylline; amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ 22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE2 selective inhibitor, a PDE3 selective inhibitor, a PDE4 selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine; and the adenylate cyclase activator is selected from forskolin, a forskolin derivative, an extract of Coleus forskohlii having adenylate cyclase activator activity, carbacyclin, isoproterenol, prostaglandin D2 , prostaglandin Ei and prostaglandin I2 (prostacyclin). In certain embodiments the opiate antagonist is naltrexone, the PDE inhibitor is caffeine and the adenylate cyclase activator is forskolin. In certain other embodiments there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator. In certain other embodiments there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator, wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype. In certain further embodiments the PDE inhibitor is caffeine and the adenylate cyclase activator is forskolin. In certain other embodiments the PDE inhibitor is selected from a methylxanthine that is selected from caffeine, theobromine, paraxanthine, 3-isobutyl-1-methylxanthine (IBMX) and theophylline; amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ 22536, GDPssS, clonidine, a

PDEi selective inhibitor, a PDE selective inhibitor, a PDE3 selective inhibitor, a

PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine, and the adenylate cyclase activator is selected from forskolin, a forskolin derivative, an extract of Coleus forskohlii {e.g., having adenylate cyclase activator activity), carbacyclin, isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I2 (prostacyclin). In another embodiment there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising administering to the subject a formulation that comprises an effective amount of (i) an opiate antagonist, partial antagonist, or reverse agonist, and (ii) an adenylate cyclase activator. In certain embodiments the opiate antagonist, partial antagonist, or reverse agonist is naltrexone, and the adenylate cyclase activator is forskolin. In certain other embodiments the opiate antagonist, partial antagonist, or reverse agonist is selected from naltrexone naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist that is selected from D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2

(CTP) [SEQ ID NO:1], D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP) [SEQ

ID NO:2], D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) [SEQ ID NO:3], D- tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2

(D-Tic-CTP) [SEQ ID NO:4], D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (D-Tic-

CTOP) [SEQ ID NO:5] and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic- CTAP) [SEQ ID NO:6]; and the adenylate cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin, isoproterenol, prostaglandin D2 , prostaglandin Ei and prostaglandin I2 (prostacyclin). In another embodiment there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising administering to the subject a formulation that comprises an effective amount of (i) an opiate antagonist, partial antagonist, or reverse agonist, and (ii) a cAMP-phosphodiesterase (PDE) inhibitor. In certain further embodiments the opiate antagonist, partial antagonist, or reverse agonist is naltrexone, and the cAMP- phosphodiesterase (PDE) inhibitor is caffeine. In certain other further embodiments the opiate antagonist, partial antagonist, or reverse agonist is selected from naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist that is selected from the group consisting of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP), D-Phe-

Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-

Thr-NH2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-

Lys-Thr-Pen-Thr-NH 2 (D-Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2

(D-Tic-CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic-CTAP); and the cAMP-phosphodiesterase (PDE) inhibitor is selected from a methylxanthine that is selected from caffeine, theobromine, paraxanthine, 3-isobutyl-1-methylxanthine (IBMX) and theophylline; amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ 22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE2 selective inhibitor, a PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine. According to certain other embodiments of the present invention there is provided a method of treating or preventing gray hair or restoring hair color, comprising administering to a subject a formulation that comprises an effective amount of an adenyl cyclase activator. In certain embodiments the adenyl cylcase activator is forskolin, while in certain other embodiments the adenyl cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii {e.g., having adenyl cyclase activator activity), carbacyclin, isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I2 (prostacyclin). In another embodiment of the present invention there is provided a method for treating or reducing one or more of tissue inflammation, inflammation- associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of two or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor. In certain further embodiments the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of- function phenotype, or a Smoothened gain-of-function phenotype. In certain embodiments of the present invention there is provided a method for treating or reducing one or more of tissue inflammation, inflammation- associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator, wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype. According to certain embodiments of the invention there is provided a method for treating or reducing one or more of tissue inflammation, inflammation- associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of three or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor. Certain embodiments of the invention provide a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of two or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) an adenylate cyclase activator, and (iii) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor. According to certain other embodiments there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of two or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, and (iii) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor. In certain further embodiments of the above described methods, the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist, and an adenylate cyclase activator. In certain other further embodiments of the above described methods the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist; a cAMP-PDE inhibitor; and an adenylate cyclase activator. In certain other further embodiments of the above described methods the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist; an adenylate cyclase activator; and an NAD(P)H oxidase inhibitor. In certain other further embodiments of the above described methods the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist; a c-AMP-PDE inhibitor; an adenylate cyclase activator; and an NAD(P)H oxidase inhibitor. In certain further embodiments of the above described methods, the step of administering comprises directly contacting a site of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress, neuronal death or dysfunction with said formulation. In certain other further embodiments of the above described methods, tissue inflammation, inflammation-associated cellular proliferation, oxidative stress or neuronal death or dysfunction is present at a site selected from skin, scalp, oral mucosa, genital mucosa, eye, conjunctiva, an internal organ and central nervous system. In certain further embodiments the site is (i) a central nervous system site that is selected from brain, spinal cord, meninges and cerebrospinal fluid, or (ii) an internal organ that is selected from heart, lung, liver, pancreas, gall bladder, spleen, kidney, small intestine, large intestine, thyroid, adrenal gland, stomach, diaphragm and bladder. In certain other further embodiments of the above described methods, the opiate antagonist is selected from naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist. In certain further embodiments the peptide opiate antagonist is selected from D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP), D-Phe-Cys-Tyr-

D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-

Pen-Thr-NH2 (D-Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (D-Tic-

CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic-CTAP). In certain other further embodiments of the above described methods, the cAMP-PDE inhibitor is selected from a methylxanthine, amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL

12330A, SQ 22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE2 selective

inhibitor, a PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine. In certain further embodiments the methylxanthine is selected from caffeine, paraxanthine, theophylline, 3-isobutyl-1-methylxanthine (IBMX) and theobromine. In certain other further embodiments of the above described methods the adenylate cyclase activator is selected from forskolin, a forskolin derivative, an extract of Coleus forskohlii {e.g., having adenylate cyclase activator activity),

carbacyclin, isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I2 (prostacyclin). In certain further embodiments the forskolin derivative has greater solubility than forskolin in a biocompatible solvent. In certain still further embodiments, the biocompatible solvent comprises a solvent selected from water, dimethylsulfoxide (DMSO), methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol and octanol. In certain other further embodiments of the above described methods, the NAD(P)H oxidase inhibitor is selected from apocynin, an apocynin active metabolite dimer, and chimeric peptide gp9 Ids-tat. In certain other further embodiments of the above described methods, the subject has a disease or condition selected from dermatitis, dandruff, poison oak exposure, poison ivy exposure, poison sumac exposure, exposure to an Anacardiaceae plant family member, gray hair, skin discoloration, vitiligo, an autoimmune disease, chronic inflammation, acute inflammation, cancer, skin wrinkling, cardiovascular disease, organ transplant, hair transplant, diabetic coma, excessive appetite, obesity, depression, erectile dysfunction, glaucoma, inhibition of scar formation, balding, cosmetic skin peeling, ablation or abrasion, asthma, chronic obstructive pulmonary disease and pneumonia. In certain other further embodiments of the above described methods, the formulation is for at least one of topical administration, administration, colonic administration, intravenous administration, subcutaneous administration, intraperitoneal administration and central nervous system administration. In certain further embodiments, central nervous system administration comprises administration to at least one of brain, spine and cerebrospinal fluid. In certain other embodiments there is provided a method for treating or reducing dermatitis in a subject, comprising administering to the subject a topical formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator. In certain further embodiments the PDE inhibitor is caffeine and the adenylate cyclase activator is forskolin. In certain other further embodiments the subject has psoriasis. In certain embodiments the cAMP- PDE inhibitor is caffeine and the adenylate cyclase activator is selected from forskolin, a forskolin derivative, an extract of Coleusforskohlii {e.g., having adenylate cyclase activator activity), carbacyclin, isoproterenol, prostaglandin D , prostaglandin

Ei and prostaglandin I2 (prostacyclin). In certain embodiments the dermatitis is selected from psoriasis, irritant dermatitis, seborrheic dermatitis, atopic dermatitis (eczema), allergic contact dermatitis, thermal-induced dermatitis, drug-induced dermatitis, dyshidrotic dermatitis, urticaria, autoimmune dermatitis, and bullous dermatitis. According to certain embodiments of the herein described invention there is provided a method for treating or reducing psoriasis in a subject, comprising administering to the subject a topical formulation that comprises an effective amount of caffeine and forskolin.

These and other aspects and embodiments of the invention will be evident upon reference to the following detailed description and attached drawings. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference in their entirety, as if each was incorporated individually. Aspects of the invention can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments of the invention. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figure 1 shows levels of reactive oxygen species in a cultured glial cell model of amyotrophic lateral sclerosis. Normal M059J glial cells or M059J harboring the G93A SODl mutation were cultured, and reactive oxygen species (ROS) determinations were made, essentially as described by Harraz et al, 2008 J. Clin. Invest. 118(2):659-670. Compounds were added to cultures as indicated. Left to right: First bar represents ROS levels in normal M059J cell line without added compounds; second bar shows ROS levels in G93A mutant glial cells without added compounds —these cells produced high levels of (ROS) and are regarded as a model for amyotrophic lateral sclerosis (ALS) with no additions. Third bar shows ROS levels in G93A mutant glial cells cultured in the presence of 50µM naltrexone. Fourth bar: G93A cells with 5µM naltrexone. Fifth bar: G93A cells with 0.5 µM naltrexone.

" Figure 2 shows the rate of NADPH-dependent O2 production in total endomembranes isolated from SH-SY (neuronal) or MO59J (glial) cells at 48 hours

following infection with adenoviral vectors expressing LacZ, SOD1 WT, SOD1 L8( , or SOD1 G93A . Cells, cell culture conditions and assay methods were as described in Harraz et al, 2008 J. Clin. Invest. 118(2):659-670. Relative oxygen generation was assessed as indicated in the presence or absence of apocynin (100 µM). Values are mean ± SEM (n = 6 per group).

DETAILED DESCRIPTION Certain embodiments of the invention disclosed herein are based on the surprising discovery that particular combinations may be made of certain known

compounds, which combinations as presently disclosed provide far superior anti inflammatory and other benefits than would be expected from any previous characterization of each compound's activity when used individually. The presently disclosed combinations of such compounds may exhibit desired anti-inflammatory, anti-aging, anti-oxidative, or anti-proliferative effects, or other clinically or cosmeceutically desired effects. In particular, and as described in greater detail below, it is disclosed for the first time herein that administration of a formulation that comprises an effective amount of specified combinations of at least two, three or four of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor, results in surprisingly synergistic and beneficial effects in the treatment of inflammatory, proliferative, aging-related and other conditions. The present embodiments will therefore find use in providing improved compositions and methods for the treatment of one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction, or for hair color loss or restoration, by offering unexpectedly synergistic effects, by providing surprisingly improved efficacies, and by presenting the ability to administer lower dosages of certain active compounds than was previously thought sufficient to beneficially provide a therapeutic effect, including the ability thereby to reduce the likelihood of undesired detrimental side- effects. Certain preferred embodiments thus provide, for example, surprisingly advantageous formulations and methods for the treatment of inflammatory conditions, including inflammation that is manifest in the skin and/or scalp, such as various types of dermatitis including psoriasis, eczema, seborrhea, dandruff, contact dermatitis or other skin conditions, that comprise administering (i) an opiate antagonist (e.g., naltrexone), partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor (e.g., caffeine), and (iii) an adenylate cyclase activator (e.g., forskolin), but the invention disclosed herein is not intended to be so limited and as described herein, contemplates a wide array of formulation components, and of conditions that may be treated therewith. According to non-limiting theory, the compounds that are specified herein for use in the formulations of the various embodiments have been at least partially characterized with respect to their biological mechanisms of action for altering (e.g., increasing or decreasing in a statistically significant manner relative to an appropriate control) a physiologically relevant process such as a biological signal transduction pathway, or a molecular, organellar, cellular, tissue, system (e.g., immunological, circulatory, gastrointestinal or neurological) or organismal biological response or process, or the like, but it has not been heretofore appreciated that the certain herein disclosed combinations of such compounds are capable of conferring beneficial effects, which effects could not be predicted prior to the present disclosure. Further according to non-limiting theory, it is believed that certain of the presently disclosed combinations advantageously provide unexpectedly beneficial (and in certain cases synergistic) effects even where two compounds in a formulation might previously have been regarded as inducing redundant biological events. For example, more than one class of compounds contemplated for use herein in combination according to certain embodiments may be capable of causing elevated levels of the well known intracellular "second messenger" molecule cyclic AMP (cAMP), but still further according to non-limiting theory, it is believed that the present disclosure of synergistic effects that result when two different cAMP- elevating compounds are administered in concert may suggest that additional presently uncharacterized cellular response mechanisms may be induced. Accordingly there are provided herein compositions and methods for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction, or hair color loss or restoration, as may relate to the administration of a formulation that comprises a combination of an effective amount of two, three or more compounds as described herein, and from which combinations previously unpredictable beneficial effects are manifest. In certain embodiments, combinations of compounds selected from two, three or more of the compound classes described herein may exhibit surprisingly synergistic effects (e.g., effects that are not merely additive, based on the activity of each compound when used alone, but instead unpredictably exceed the level of expected summed individual effects) for treating or reducing inflammatory and/or other conditions as described herein. Such synergy is not readily predictable based on profiles of any of the individual compounds' effects in a particular relevant context (e.g., as an anti-inflammatory agent, or as a cosmeceutical agent, or for treating any other clinically relevant condition such as those described herein), but surprisingly may result from selection of particular combinations (e.g., of two or more of an opiate antagonist, a PDE inhibitor and/or an adenylate cyclase activator as provided herein) in view of the specific condition being treated. The presently disclosed embodiments include compositions and methods for use in medical and veterinary contexts, preferably for treating human subjects such as patients in need of the presently described treatments, but also including non-human primates and other higher vertebrate species, which may include but are not limited to, non-human primates such as baboons, gorillas, chimpanzees, rhesus macaques and other non-human primates, and also include equine, bovine, sheep (ovine), goat (caprine), porcine, canine, feline, chicken, rat, hamster, guinea pig and mouse (murine) species. Certain embodiments contemplate treatment and/or prevention of any of the following non-limiting conditions: dermatitis, dandruff, poison oak exposure, poison ivy exposure, poison sumac exposure, exposure to an Anacardiaceae plant family member, gray hair, skin discoloration, vitiligo, an autoimmune disease, chronic inflammation, acute inflammation, cancer, amyotrophic lateral sclerosis (ALS), skin wrinkling, cardiovascular disease, organ transplant, hair transplant, diabetic coma, excessive appetite, obesity, depression, erectile dysfunction, glaucoma, inhibition of scar formation, balding, cosmetic skin peeling, ablation or abrasion, asthma, chronic obstructive pulmonary disease and pneumonia, psoriasis, irritant dermatitis, seborrheic dermatitis, atopic dermatitis (eczema), allergic contact dermatitis, thermal- induced dermatitis, drug-induced dermatitis, dyshidrotic dermatitis, urticaria, autoimmune dermatitis, and bullous dermatitis, dermatitis, including dermatitis in and around the ear and ear canal; eczema, seborrhea, dandruff, poison oak, poison ivy poison sumac and similar or related exposures such as exposure to {e.g., contact with) an Anacardiaceae plant family member or other plants that elicit similar inflammatory responses, hair loss or baldness, restoration of hair color in gray hair, darkening of natural hair color, restoration of skin color, vitiligo, various autoimmune diseases, other chronic or acute inflammation, or systemic or localized inflammation, cancer, aging including skin wrinkling, skin thinning or thickening, skin photodamage, and the like (e.g., Spry et al. 2009 Pigment Cell Melanoma Res. 22(2):2 19-29), cardiovascular disease, tissue damage associated with organ transplantation and diabetic coma, appetite suppression and weight loss, depression, erectile dysfunction, glaucoma, and/or scar formation. Criteria for assessing the signs and symptoms of these and other conditions, including for purposes of making differential diagnosis and also for monitoring treatments such as determining whether a therapeutically effective dose has been administered in the course of treatment, e.g., by determining improvement according to accepted clinical criteria, will be apparent to those skilled in the art and

are exemplified by the teachings of e.g., Berkow et al., eds., The Merck Manual, 16th edition, Merck and Co., Rahway, N.J., 1992; Goodman et al., eds., Goodman and

Gilman's The Pharmacological Basis of Therapeutics, 10th edition, Pergamon Press, Inc., Elmsford, N.Y., (2001); Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, Ltd., Williams and Wilkins, Baltimore, MD. (1987); Ebadi, Pharmacology, Little, Brown and Co.,

Boston, (1985); Osolci al., eds., Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, PA (1990); Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992). "Treat," "treatment," or "treating," as used herein refers to administering a formulation or pharmaceutical composition as provided herein for therapeutic, cosmeceutical and/or prophylactic purposes. The term "prophylactic treatment" refers to treating a patient who is not yet diseased, but who is susceptible to, or otherwise at risk for, a particular disease or condition. Therapeutic treatment thus may include administering treatment to a patient already suffering from a disease. In preferred embodiments, treating is the administration to a human subject, a non-human primate or a mammal (either for therapeutic or prophylactic purposes) of therapeutically effective amounts of the herein described formulations. According to certain embodiments, the present compositions and methods may relate to treating a subject having a condition that is characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype. According to certain other distinct embodiments, however, there are expressly contemplated compositions and methods that may relate to treating a subject having a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype. (e.g., Gudjonsson et al., 2009 J. Invest. Derm. 129:635) Criteria for determining whether a disease, disorder, condition or the like may or may not be characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, and/or a Smoothened gain-of-function phenotype, such as one or more indicators of any such phenotypes, are known to persons familiar with the relevant art, as disclosed, for example, in Zhou et al. (Physiol Genomics. 2003 Mar 18;13(l):69-78), and in Bowcock et al. (Human

Molecular Genetics, 2001, Vol. 10, No. 17 1793-1805). In these and related embodiments, it will be appreciated that based on the present disclosure, the skilled person can identify, readily and without undue experimentation, whether a subject may have a condition that is not characterized by a Hedgehog (Hh) gain-of-function phenotype, a Patched (Ptch) loss-of-function phenotype, or a Smoothened (Smo) gain- of-function phenotype according to art accepted criteria, such as determining one or more indicators of any such phenotypes. An altered (e.g., increased or decreased with statistical significance, relative to an appropriate control) Hh, Ptch, and/or Smo phenotypic indicator, which may in certain instances differ from that determined in a control known to be free of such a loss-of-function or gain-of-function by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20%, or more, may therefore in certain contemplated embodiments permit characterization of a sample from a subject for purposes of determining a suitable treatment method for the subject according to the invention embodiments that are disclosed herein. Accordingly, in certain of these and related embodiments there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator, wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype. In certain other related embodiments there is provided a method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising administering to the subject a formulation that comprises an effective amount of two or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor, wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype. In certain preferred further embodiments, the opiate antagonist is naltrexone (e.g., USP grade, available from Tyco/Mallinckrodt, St. Louis, MO), the PDE inhibitor is caffeine (e.g., available from Sigma-Aldrich, St. Louis, MO), and/or the adenylate cyclase activator is forskolin (e.g., available from Sabinsa Corp., Piscataway, NJ). Certain embodiments as disclosed herein relate to peptidomimetics, or "artificial" polypeptides. Such polypeptides may contain one or more amino acid insertions, deletions or substitutions, one or more altered or artificial peptide bond, one or more chemical moiety (such as polyethylene glycol, glycosylation, label, toxin, or other moiety), and/or one or more non-natural amino acid. Synthesis of peptidomimetics is well known in the art and may include altering naturally occurring proteins or polypeptides by chemical mutagenesis, single or multi- site-directed mutagenesis, PCR shuffling, use of altered aminoacyl tRNA or aminoacyl tRNA synthetase molecules, the use of "stop" codons such as amber suppressors, use of four or five base-pair codons, or other means. The practice of certain embodiments of the present invention will employ, unless indicated specifically to the contrary, conventional methods of virology, immunology, microbiology, molecular biology and recombinant DNA techniques within the skill of the art, many of which are described below for the purpose of illustration. Such techniques are explained fully in the literature. See, e.g., Sambrook, et al. Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Maniatis et al. Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A Practical Approach, vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., 1985);

Transcription and Translation (B. Hames & S. Higgins, eds., 1984); Animal Cell Culture (R. Freshney, ed., 1986); Perbal, A Practical Guide to Molecular Cloning (1984). Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is as "including, but not limited to". Reference throughout this specification to "one embodiment" or "an embodiment" or "an aspect" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. The following listing of terms refers without limitation to features that may pertain to certain embodiments of the present invention as disclosed herein: Ablation: The removal or destruction of tissue, a part of the body, or an abnormal growth by surgery, hormonal or other drugs, heat, or radiofrequency. Abrasion: A rubbed or scraped area on skin or mucous membrane. Activator: A chemical or substance that causes another substance to become reactive or that induces a chemical reaction, including a biochemical reaction. Acute: Characterizing a rapid onset of signs or symptoms of short duration. Adenylate Cyclase: An enzyme that initiates the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), a mediator of many physiologic activities. Agonist: A substance {e.g., a drug, hormone or neurotransmitter) that binds with a cell receptor to initiate a physiological response similar to that produced by the natural neurotransmitter or hormone. Allergic: Having an allergy to a substance. Allergy: A hypersensitive state acquired through exposure to a particular allergen. Allergen: An antigenic substance capable of producing immediate hypersensitivity. Amyotrophic Lateral Sclerosis (ALS): A disease of the motor neurons, those nerve cells reaching from the brain to the spinal cord (upper motor neurons) and the spinal cord to the peripheral nerves (lower motor neurons) that control muscle movement. In ALS, for unknown reasons, these neurons die, leading to a progressive loss of the ability to move virtually any of the muscles in the body. Alzheimer's Disease: The most common form of dementia, a neurological disease characterized by loss of mental ability severe enough to interfere with normal activities of daily living. Antagonist: a substance that tends to nullify the action of another, as a drug that binds to a cell receptor without eliciting a biological response, blocking binding of substances that could elicit such responses. Antioxidant: Any substance that reduces the damage caused by oxidation, such as the harm caused by free radicals. Apocynin: Also known as acetovanillone, is a natural organic compound structurally related to vanillin. Apocynin is an inhibitor of NAD(P)H oxidase activity and may have other activities as well, at least some of which may be influenced by interacting cofactors and/or by the oligomeric state of the inhibitor

(e.g., Heumuller et al., 2008 Hypertension 51:21 1; Touyz, 2008 Hypertension 51:172); See also, e.g., Stefanska et al, Apocynin: Molecular Aptitudes Mediators, Inflamm. v. 2008; 2008; Williams et al, NADPH oxidase inhibitors: new antihypertensive agents? J Cardiovasc Pharmacol. 2007 Jul;50(l):9-16. Asthma: A chronic inflammatory disease of the airways. In those susceptible to asthma, this inflammation causes the airways to narrow periodically. Autoimmune Dermatitis: Inflammation of the skin caused by, or associated with, an autoimmune disorder. Autoimmune Disease: An immune response by the body against one of its own tissues, cells, or molecules resulting in a disease state. Biocompatible: Compatible with living cells, tissues, organs, or systems, and posing no risk of injury, toxicity, or rejection by the immune system. Brain: The portion of the central nervous system that is enclosed within the cranium, continuous with the spinal cord, and composed of gray matter and white matter. Bulk Deposition: A relatively large quantity of substance that has been deposited within the body. Bullous Dermatitis: A circumscribed, fluid-containing, elevated lesion of the skin. cAMP: A cyclic nucleotide formed from adenosine triphosphate by the action of Adenylate Cyclase. This cyclic compound, known as the "second messenger," participates in the action of catecholamines, vasopressin, adrenocorticotropic hormone, and many other hormones. Cancer: A disease state in which these occurs an uncontrolled growth of cells in the human body and these have the ability to migrate from the original site and spread to distant sites. Cardiovascular: Relating to, or involving the heart and the blood vessels. Cellular Proliferation: An increase in the number of cells as a result of cell growth and cell division. Cerebrospinal fluid (CSF): The fluid that flows through and protects the four ventricles of the brain, the subarachnoid spaces, and the spinal canal. It is composed mainly of secretions of the choroid plexuses in the lateral ventricles and in the third and the fourth ventricles of the brain and is clear and colorless. Channel: An aqueous pathway through a protein molecule in a cell membrane that modulates the electrical potential across the membrane by controlling the passage of small inorganic ions into and out of the cell. Chronic: Referring to a disease or disorder persisting for a long period, often for the remainder of a person's lifetime.

COIQUS forskohlii: Coleusforskohlii is a tropical perennial plant in the mint family and related to the typical coleus species. Its roots are the only known natural source of the compound forskolin. This plant is also known as Plectranthus barbatus. Colonic: Pertaining to the colon. Conjunctiva: The mucous membrane that lines the inner eyelid and the exposed surface of the eyeball. Contact Dermatitis: The name for any skin inflammation that occurs when the skin's surface comes in contact with a substance originating outside the body. Chronic Obstructive Pulmonary Disease (COPD): Any disorder marked by persistent obstruction of bronchial air flow. Cosmetic: Serving to modify or improve the appearance of a physical feature, defect, or irregularity. Dandruff: An excessive amount of scaly material composed of dead, keratinized epithelium shed from the scalp that may be a mild form of seborrheic dermatitis or psoriasis. Dementia: Generally a progressive deterioration of intellectual functions such as memory. Depression: A mental state of altered mood characterized by feelings of sadness, despair, and discouragement. Dermatitis: Inflammation of the skin. Examples include but need not be limited to psoriasis, irritant dermatitis, seborrheic dermatitis, atopic dermatitis (eczema), allergic contact dermatitis, thermal-induced dermatitis, drug-induced dermatitis, dyshidrotic dermatitis, urticaria, autoimmune dermatitis, and bullous dermatitis. Dimer: A compound formed by combination of two molecules, which may be two identical molecules (e.g., a homodimer) or two non-identical molecules (e.g, a heterodimer). Drug Induced Dermatitis: Inflammation of the skin due to drug ingestion. Dyshidrotic Dermatitis: A type of eczema that occurs on the palms of the hands, sides of the fingers, and soles of the feet, and typically causes a burning or itching sensation and a blistering rash. Enzyme: A complex produced by living cells that catalyzes chemical reactions in organic matter. Formulation: A pharmacologic substance prepared according to a formula. Forskolin: A labdane diterpene that is produced by the Indian Coleus plant (Coleus forskohlii aka Plectranthus barbatus). Forskolin is commonly used to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology. A number of structural variants of forskolin are known in the art and may be referred to herein as forskolin derivatives, for example those described in Kokic, Curr Med Chem Cardiovasc Hematol Agents. 2005 Oct;3(4):333-9; Gao et al, Mini Rev Med Chem. 2005 Jun;5(6):545-53; Head, Altern Med Rev. 2001 Apr;6(2): 141-66; Zidek, Eur Cytokine Netw. 2001 Mar;12(l):22-32; Ong et al., Acta Pharmacol Sin. 2000 Feb;21(2):l 11-23; Chen et al., Lab Invest. 1998 Feb;78(2):165-74; Milligan et al., Receptors Channels. 1997; 5(3-4):209-13; Sulakhe et al.. MoI Cell Biochem. 1995 Aug-Sep; 149-150:103-26; Ehlert et al., Life Sci. 1995; 56(1 1-12):965-71; and Farah et al., Annu Rev Pharmacol Toxicol. 1984; 24:275-328. Preparation, including solubilization, and use of forskolin and related compounds including forskolin derivatives, are described in, e.g., U.S. 6,960,300 and in Chen et al., 2009 J. Nat. Prod. 72:769. Forskolin has been reported to act through incompletely understood pathways involving NF-kappaB and PBK/Akt {e.g., Sousa et al., 2009 Biochem Pharmacol. 78:396; Qi et al., 2009 MoI. Immunol. 46:1925), and forskolin has also been shown to inhibit several membrane transport and channel proteins through a mechanism independent of the production of cAMP. These and related criteria for identifying adenyl cyclase (also known as adenylate cyclase or adenylyl cyclase; e.g., Wats, 2007 Molec. Interven. 7:70; Uboldi et al., 2002 Cytokine 19:250; Tanaka, 2001 Prog. Neurobiol. (55:173; Dahle et al., 2005 Infect. Immun. 73:7290; Bernot et al., 2005 J. Cell Physiol. 202:434) activating activity will be recognized by those familiar with the art, such that such activity can be identified readily and without undue experimentation as a property of a forskolin derivative or a Coleus forskohlii extract for use as an adenylate cyclase activator as provided herein. Other non-limiting examples of well known adenylate cyclase activators include carbacyclin, isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I (prostacyclin). Adenylate cyclase activators may also include those disclosed in U.S. 6,333,354, certain teachings of which are expressly disclaimed as may relate to the present disclosure, including treatment of a subject having pulmonary hypertension, or of treating such a subject with an adenylate cyclase activator and a PDE inhibitor as disclosed therein. Topically applied forskolin caused no significant change in hair color in murine studies (D'Orazio et al., 2006 Nature 443:340); elsewhere forskolin has been implicated as an inducer of DOPAchrome tautomerase (TRP-2) or as a modulator of melanogenesis in publications {e.g., US 2005/0208086; US

2009/01 18203; Michelet et al., 2009 Dermatol. 18:414) that fail to contemplate co administration of forskolin with other agents according to the present disclosure. Accordingly, certain of the present embodiments expressly contemplate inclusion of forskolin as a component of a recited formulation, for instance, as an adenylate cyclase activator for use as described herein, while certain other of the present embodiments expressly contemplate exclusion of forskolin. See also, e.g., Adenylyl Cyclases, Volume 32 (Advances in Second Messenger & Phosphoprotein Research) by Dermot M.F. Cooper (Editor), Paul Greengard (Series Editor), Angus C. Nairn (Series Editor), Shirish Shenolikar (Series Editor) Academic Press; 1 edition (August 4, 1998) ISBN-10: 0120361329 ISBN-

13: 978-0120361328; Pinto C, et al, Activation and inhibition of adenylyl cyclase isoforms by forskolin analogs. J Pharmacol Exp Ther. 2008 Apr;325(l):27-36. Gain of Function: A genetic mutation that results in increased activity of its transcribed protein function. Genital: Of or relating to the genitalia. Hedgehog: Mammals have three Hedgehog homologues, of which Sonic hedgehog is the best studied. The pathway is equally important during vertebrate embryonic development. In knockout mice lacking components of the pathway, the brain, skeleton, musculature, gastrointestinal tract and lungs fail to develop correctly. Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Inflammation: The cellular and vascular response or reaction to injury. Inflammation is characterized by pain, redness, swelling, heat, and disturbance of function. It may be acute or chronic. Inhibition: Condition in which or the process by which a reaction is inhibited. Inhibitor: Any substance that interferes with a chemical reaction, growth, or other biologic activity. Intraperitoneal: Within the peritoneal cavity. Also refers to the administration of pharmaceutical substances within this cavity, usually by injection. Intravenous: Within or administered into a vein. Loss of Function: A genetic mutation that results in reduced or abolished protein function. Membrane: A thin layer of tissue that covers a surface, lines a cavity, or divides a space or organ. Metabolite: A substance produced by metabolic action or necessary for a metabolic process. Methylxanthine: Methylated derivatives of xanthine, including caffeine, paraxanthine, theobromine and theophylline, which may act as non-selective phosphodiesterase inhibitors and/or antagonists of adenosine receptors. Mucosa: A moist lining in the body passages of mammals that contains mucus-secreting cells and is open directly or indirectly to the external environment. Neuron: A nerve cell; any of the conducting cells of the nervous system, consisting of a cell body, containing the nucleus and its surrounding cytoplasm, and the axon and dendrites. Nicotinamide adenine dinucleotide (phosphate) oxidase (NAD(P)H oxidase): Generates superoxide by transferring electrons from NADPH and coupling these to molecular oxygen to produce superoxide, which is a free-radical. A number of NAD(P)H oxidase inhibitors are known to the art and are contemplated for inclusion in formulations for use according to certain herein disclosed embodiments; these may include, but need not be limited to, the antioxidant pro-drug apocynin and its active metabolites such as apocynin dimers (Touyz, Hypertension, 2008;5 1:172- 174), and the chimeric peptide gp9 Ids-tat (Rey et al., Circulation Research. 2001, 89:408-414). Opiate antagonist: An agent {e.g., naltrexone; 17-(cyclopropylmethyl)- 4, 5α-epoxy-3, 14-dihydroxymophinan-6-one hydrochloride) that binds to one or more of the body's opiate receptors thereby blocking the activity of administered opioid drugs and ligands or endogenous ligands. According to certain embodiments an opiate antagonist may be a peptide opiate antagonist as known in the art including those described, for example, in Kramer et al., J Pharmacol Exp Ther. 249:544-51, 1989; or other peptide antagonists as described, e.g., in Schiller et al., Life Sci. 73:691-698, 2003. Exemplary opiate antagonists, partial antagonists, or reverse agonists may thus be selected from amongst naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and peptide opiate antagonists (e.g., Schiller et al., 2003 Life Sci. 73:691) such as D-Phe-

CyS-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP) [SEQ ID NO:1] , D-Phe-Cys-Tyr-D-

Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP) [SEQ ID NO:2], D-Phe-Cys-Tyr-D-Trp-Arg-Thr-

Pen-Thr-NH 2 (CTAP) [SEQ ID NO:3], D-tetrahydroisoquinoline carboxylic acid (D-

Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (D-Tic-CTP) [SEQ ID NO:4], D-Tic-

CyS-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (D-Tic-CTOP) [SEQ ID NO:5] and D-Tic-

Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic-CTAP) [SEQ ID NO:6]. (Orn, ornithine; Pen, penicillamine; D-Tic, D-tetrahydroisoquinoline carboxylic acid). See also, Opiate Receptors and Antagonists: From Bench to Clinic (Contemporary Neuroscience) by Reginald Dean (Editor), Edward J. Bilsky (Editor), S. Stevens Negus (Editor) Humana Press; 1 edition (March 9, 2009) ISBN-10: 1588298817 ISBN-13: 978-1588298812. Opiate: A drug that contains opium, derivatives of opium, or any of several semisynthetic or synthetic drugs with opium-like activity. Oral: Designed for use in the mouth Organ: A somewhat independent body part that performs a specific function or functions and that is formed from tissues. Internal organs are typically wholly contained within a normal healthy body; examples include heart, lung, liver, pancreas, gall bladder, spleen, kidney, small intestine, large intestine, thyroid, adrenal gland, stomach, diaphragm and bladder. Oxidative Stress: Term used to describe the effect of oxidation in which an abnormal level of reactive oxygen species (ROS), such as the free radicals (e.g., hydroxyl, nitric acid, superoxide) or the non-radicals (e.g., hydrogen peroxide, lipid peroxide) lead to damage (called oxidative damage) to specific molecules with consequential injury to cells or tissue. See, e.g., Halliwell and Gutteridge, Free Radicals In Biology and Medicine (3rd. ed.) 1999, Oxford Univ. Press, Oxford, UK. Partial Antagonist: While antagonists display no efficacy to activate the receptors they bind, partial antagonists display little efficacy, which may manifest in a statistically significant manner relative to an appropriate control at a level that is

less than, e.g., 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 percent of the maximal level of receptor activation. Patched: The receptor of Hedgehog (Hh) is Patched (Ptc) and it is expressed in the cells close to the source of Hh. Ptc binds the ligand and transduces a signal which is modulated depending on the context and the concentration of Hh received. Peeling: The loss of all or part of the epidermis, as may occur after a sunburn or exposure to a chemical. Peptide: A compound of two or more amino acids in which the α- carboxyl group of one amino acid is united with the α-amino group of another, with the elimination of a molecule of water, creating a peptide bond —CO—NH— Phenotype: The complete observable characteristics of an organism or group, including anatomic, physiologic, biochemical, and behavioral traits, as determined by the interaction of genetic makeup and environmental factors. Phosphodiesterase (PDE) Inhibitor: A compound that blocks one or more of the five known subtypes of the enzyme phosphodiesterase (PDE), including, e.g., cAMP-PDEs, therefore preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), by the respective PDE subtype(s). Exemplary PDE inhibitors are known to the art, for example, those described in WO 92/19594 and WO 92/10190, and may also include a methylxanthine such as caffeine, theobromine, paraxanthine, 3-isobutyl-l-methylxanthine (IBMX) and theophylline; and also amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ 22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE selective inhibitor, a PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine. PDE inhibitors may also include those disclosed in U.S. 6,333,354, certain teachings of which are expressly disclaimed as may relate to the present disclosure, including treatment of a subject having pulmonary hypertension, or of treating such a subject with an adenylate cyclase activator and a PDE inhibitor as disclosed therein. See also, e.g., Methylxanthines and Phosphodiesterase Inhibitors in the Treatment of Airways Disease by J.F. Costello (Editor), P.J. Piper (Editor) Taylor & Francis; 1st edition

(October 15, 1994) ISBN-IO: 1850705976 ISBN-13: 978-1850705970; Phosphodiesterase Inhibitors (Handbook of Immunopharmacology) by Christian Schudt (Editor), Gordon Dent (Editor), Klaus F. Rabe (Editor), Clive Page (Series

Editor) Academic Press; 1st edition (September 10, 1996) ISBN-10: 0122107209 ISBN-13: 978-0122107207; Cyclic Nucleotide Phosphodiesterases: Structure, Regulation and Drug Action (Wiley Series on Molecular Pharmacology of Cell Regulation) (Paperback) by Joe Beavo (Author, Editor), Miles D. Houslay (Editor) John Wiley & Sons (November 1990) ISBN-10: 0471927074 ISBN-13: 978- 0471927075. Pneumonia: Acute or chronic disease marked by inflammation of the lungs. Pro-drug: A compound that, on administration, undergoes chemical conversion by metabolic processes before becoming an active pharmacological agent; a precursor of a drug. Proliferation: The growth and reproduction of similar cells, sometimes excessive. Psoriasis: A typically chronic, recurrent skin disease in humans marked by discrete macules, papules or patches covered with lamellated silvery scales resulting from an increased turnover of epidermal cells. The cause is multifactorial and poorly understood at this time. Reactive Oxygen Species (ROS): Molecules and ions of oxygen that have an unpaired electron, thus rendering them extremely reactive. Many cellular structures are susceptible to attack by ROS contributing to cancer, heart disease, and cerebrovascular disease, among others. See, e.g., Halliwell and Gutteridge, Free

Radicals In Biology and Medicine (3rd. ed.) 1999, Oxford Univ. Press, Oxford, UK. Receptor: A molecular structure in a cell or on the surface of a cell that allows binding of a specific substance that causes a specific physiologic response. Reverse Agonist: A drug which acts at the same receptor as that of an agonist, yet produces an opposite effect. Also called negative antagonists or inverse agonists. Scar: Fibrous tissue that replaces normal tissue destroyed by injury or disease. Seborrhea: A common inflammatory disease of the skin characterized by scaly lesions usually on the scalp, hairline, and face, also any of several common skin conditions in which an overproduction of sebum results in excessive oiliness or scaling. Skin: The tough, supple cutaneous membrane that covers the entire surface of the body; also described in greater detail above. Smoothened (SMO): A heptahelical membrane protein that functions as the transducer of Hedgehog signaling. Solvent: A substance in which another substance is dissolved, forming a solution. Typically a solvent will be a liquid under ambient conditions {e.g., room

temperature such as about 15-3O0C, preferably about 18-28 0C, about 20-26 0C, or about 22-24 0C, where "about" may be understood to reflect an approximate range of

the stated value that may vary by being higher or lower by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 percent. Certain preferred embodiments contemplate a solvent that is a biocompatible solvent, e.g., a solvent that does not damage, destroy, disrupt or otherwise harm an intact, viable cell, tissue, organ or organism such as a subject or a biological source. Exemplary solvents may comprise one or more of water, dimethylsulfoxide (DMSO), methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol and octanol or other solvents with which the skilled person will be familiar; when present at suitable concentrations and/or with suitable solutes dissolved therein such solvents may be present as biocompatible solvents. As non-limiting examples, certain formulations contemplated herein may comprise one or more of water, dimethylsulfoxide (DMSO), methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol and octanol or other solvents as colloidal mixes and suspensions, or bound to oatmeal, or emulsified or incorporated into cyclodextrins or other excipients or clathrates. Spinal Cord: Thick, whitish cord of nerve tissue that extends from the medulla oblongata down through the spinal column and from which the spinal nerves branch off to various parts of the body. Subcutaneous: Located, found, or placed just beneath the skin. Systemic: Used to describe an agent (e.g., a drug or other medication) that has effects throughout the body, as opposed, for instance, to an agent having effects that are only local to the site of administration, such as topical drugs that work on the skin. Thermal Dermatitis: Inflammation of the skin due to burns or thermal stress. Time Release: Relating to a preparation that gradually releases an active substance (especially a drug) over a period of time. Tissue: A collection of similar cells in a matrix acting together to perform a particular function. Topical: Used to describe medicine that has effects only in a specific area, not throughout the body, particularly medicine that is put directly on the skin. Transplant: An organ or tissue taken from the body for grafting into another area of the same body or into another individual. Transport: Movement of materials in biological systems, particularly into and out of cells and across epithelial layers. Uticaria: A skin condition characterized by welts that itch intensely, caused by an allergic reaction, an infection, or a nervous condition; often called "hives". Wrinkles: Creases in the skin, often associated with aging, drying or exposure to harsh conditions (e.g., extreme temperatures, excessive sunlight, chemicals, etc.). Xanthines: A family of chemicals that includes caffeine, theophylline, and theobromine, which stimulate the central nervous system, act on the kidneys to produce diuresis, stimulate cardiac muscle, and relax smooth muscle. A single report describes the clinical use of topically applied caffeine in treating dermatitis, and the results were neither statistically significant for most of the study (p>0.05) nor were they at all compelling when evaluated by the Psoriatic Area and Severity Index (PASI) (VaIi et al, 2005 J Dermatolog Treat. 16(4):234-7). Accordingly, little promise of arriving at an effective therapeutic approach is provided by such a report using an agent having well characterized pharmacological properties. Similarly, there is a dearth of publications relating seborrhea, eczema, dermatitis, or atopy with clinical forskolin treatment. A single clinical paper published nearly 25 years ago and attempting to relate forskolin to psoriasis contains data that are at best marginal and of unremarkable statistical relevance (Ammon et al., 1985 Planta Med. 51(6):473-7.), and has not resulted in sustained or successful follow-ups. Extremely potent anti-inflammatory properties have been observed in, and are disclosed here for the first time for, formulations that comprise therapeutically effective amounts of two or more of (and in some embodiments at least three of) (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP- phosphodiesterase (PDE) inhibitor, and (iii) an adenylate cyclase activator. Topical treatments with permutations of two or more of (and in some embodiments at least three of) naltrexone, caffeine and forskolin were tested on subjects having eczema, seborrhea and/or dandruff, as well as on normal skin of healthy control subjects. During multi-day courses of treatment, subjects' skin was regularly monitored according to standard clinical parameters as practiced in the dermatological arts, including, e.g., skin color, texture, smoothness, suppleness, and freedom from lesions, blemishes, wrinkles, dry spots, flaking, excessive oiliness or other signs of clinical distress. These topical treatment permutations included all of the possible combinations of two ingredients, as well as single compound trials. It was in these trials that it became evident that for inflammatory skin conditions specifically, single ingredient regimens were poor in efficacy. Mixtures containing two of the ingredients proved more effective than the sum of each single ingredient. This observation was especially noted for the two-component formulation comprising caffeine and forskolin, which yielded significantly healthier-appearing skin than did treatment with either agent alone. Some toxicity (e.g., extreme exercise-induced fatigue) was noted in formulations containing apocynin, although related tissue culture experiments (as well as published data from experimentally apocynin-treated tissue culture systems and observations in animals) demonstrated profound effects of apocynin on inflammation and the production of ROS. It is believed that the present disclosure describes the first use of apocynin in humans according to the methodologies presented herein. Formulations containing a non-specific PDE inhibitor typically used the methylxanthine caffeine because of its ubiquitous nature in foods (e.g., coffee, tea, chocolate, guarana) and accordingly its ready availability. The presently disclosed combination formulations, which comprise two, three, or all four of an opiate antagonist (or an opiate partial antagonist or reverse agonist), a PDE inhibitor, an adenylate cyclase activator and a NAD(P)H oxidase inhibitor, exhibit advantageously negligible side effect profiles and are contemplated as having uses over a wide range of subjects and indications, including but not limited to those expressly described herein. Highly positive results were observed using the compositions and methods described herein, and these data are summarized in the present application, based on studies of human subjects having clinically defined skin conditions (e.g., eczema, dandruff, etc.) and appropriately matched healthy (clinically normal) control subjects, and also based on trials conducted using normal healthy subjects in the following areas: inflammation as a result of cosmetic skin peeling using trichloroacetic acid (TCA); unidentified chronic skin scaling, including facial skin; as an oral rinse for gingivitis. Mode of Action: The primary biological activity according to certain preferred embodiments reflects the effects of a mixture of (i) an anti-opiate, (ii) an adenyl cyclase activator, forskolin, and in most formulations, (iii) the PDE inhibitor caffeine. The anti-opiate employed in certain such preferred embodiments was naltrexone, which may offer further advantages based on its stability, availability and cost. Apocynin: Originally obtained from the dogbane (Apocynum cannabinum), apocynin appears to be a pro-drug and an antioxidant, but through biological metabolic pathways forms one or more compounds exhibiting potent NAD(P)H oxidase inhibition activity thus preventing the production of the superoxide. Naltrexone: Initial clinical research work investigating the immunological effects of naltrexone (Tyco/Mallinckrodt, St Louis, Missouri 63147) on autoimmune diseases revealed the potential profoundly positive immunomodulatory effects of small doses of antiopiates. It had been observed in previous research that people suffering from systemic lupus erythematosus (SLE) had a disproportionate amount of autoantibodies formed against their "mu" opiate receptors which acted as agonists when compared to autoantibody agonists formed against the "delta" opiate receptor. In the healthy population, autoantibodies were also formed, but unlike SLE, the bulk of them acted as agonists against the "delta" opiate receptors. The present inventor theorized without limitation that it may not be the absolute stimulation of the "mu" receptor that was at least in part responsible for SLE and other autoimmune disease states, but rather the relative ratio of the two opiate receptor subtypes (mu and delta). To test this theory, a preliminary investigational clinical trial was set up in which small amounts of naltrexone were administered to patients with several autoimmune diseases. Naltrexone, a pure opiate antagonist, is known to have a great avidity for the "mu" opiate receptor, although it will bind to all the receptor subtypes to a lesser degree. At all accepted clinical dosages, naltrexone has an exceptional safety record and low side effect profile. Low dosages were used with the goal of preferentially targeting the "mu" receptor. In this study all patients responded in a clinically significant manner, some to a degree that would be considered full remission. This response may, according to non-limiting theory, be a result of an immunological shift from a predominantly Th2 to a ThI state, according to what may be recognized as an overly simplistic model. Because susceptibilities to autoimmune diseases are, in large part, dependent on variations within the major histocompatibility complex (MHC), as are most inflammatory skin diseases (including those as apparently benign as dandruff), a study was undertaken to evaluate the efficacy of the opiate antagonist naltrexone alone, applied topically. The results using topical naltrexone alone, though positive, were not overwhelmingly dramatic. It should also be noted that naltrexone, like anti- opiates in general, has been documented to increase the levels of intracellular adenylate cyclase, thus increasing the intracellular levels of cAMP, as well as decreasing intracellular ROS via NADH/NADPH oxidase (Koch T, et al, mu-Opioid receptor-stimulated synthesis of reactive oxygen species is mediated via phospholipase D2. J Neurochem. 2009 Jun 10). Forskolin: This diterpene is also a potent activator of adenylate cyclase and thus increases intracellular cAMP levels. Additionally forskolin has been shown to activate hedgehog signaling as well as the p53 gene, via this increase in intracellular cAMP levels (Zwain et al, Endocr Res. 2001 Feb-May;27(l-2):233-49.). Forskolin protects neurons from glutamate induced toxicity and cell death (Watts, Molecular Interventions 7:70-73, (2007)). Forskolin has also been shown to lower NF-kappaB as well as PI3K/Akt (Sousa et al., Biochem Pharmacol. 2009 May 4) and to inhibit several membrane transport and channel proteins through a mechanism independent of the production of cAMP. Without wishing to be bound by theory, forskolin-induced inhibition of NF-kappaB may represent a significant, although not necessarily the entire, mechanistic basis underlying the efficacies exhibited by the compositions and methods disclosed herein for the first time, which include administering formulations which comprise (i) an anti-opiate, (ii) an adenyl cylcases activator, forskolin, and in most formulations, (iii) a PDE inhibitor. A 98% pure forskolin extract, as well as other preparations containing lower forskolin concentrations, are available from Sabinsa Corporation (Piscataway, NJ 08854, USA). Caffeine: Among its many physiological effects, caffeine is a nonspecific inhibitor of cAMP-phosphodiesterase, which hinders the breakdown of cAMP, thus increasing intracellular cAMP levels by a pathway distinct from adenyl cyclase activation. Stimulation of the p53 pathway by caffeine has also been observed, and topical application of caffeine has been believed for several decades to inhibit skin cancer that arises due to excessive exposure to ultraviolet radiation, although the mechanism of action has only recently been proposed (Lu et al, Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-I mice. Carcinogenesis 2007 28(l):199-206; Kerzendorfer, et al, UVB and caffeine: inhibiting the DNA damage response to protect against the adverse effects of UVB. J

Invest Dermatol. 2009 JuI; 129(7): 161 1-3). Caffeine is a central nervous system stimulant believed to act through adenosine receptors and monoamine neurotransmitters. It is an adenosine receptor antagonist as well as an adenosine 3',5'- cyclic monophosphate (cAMP) phosphodiesterase inhibitor. It has been reported to affect intracellular calcium levels, releasing calcium from intracellular stores. The surprising disclosure is made here for the first time that naltrexone and forskolin, despite having seemingly redundant modes of action in view of evidence that both of these agents may be responsible for increasing intracellular cAMP by activating adenylate cyclase, may be combined into an unexpectedly effective treatment for, e.g., topical anti-inflammatory use, the synergistic activity of which may be further enhanced by adding a PDE inhibitor {e.g., caffeine) which similarly may be viewed as redundantly elevating intracellular cAMP, albeit by influencing a different biochemical process, namely, inhibiting the PDE-mediated degradation of cAMP. The present inventor's data indicate that, surprisingly, of the three agents ((i) the anti-opiate naltrexone, (ii) the adenyl cylcase activator, forskolin, and (iii) the PDE inhibitor caffeine) that were tested alone and in various permutations and combinations, the one ingredient that could be omitted from test formulations with the least deleterious effect on clinical outcome was the PDE inhibitor, caffeine. This observation was unexpected insofar as intracellular cAMP maintenance by blocking PDE-mediated cAMP degradation may be regarded as the mechanism most different from the potentiation of cAMP synthesis believed to be induced by the opiate antagonist and by the adenyl cyclase activator. Accordingly and further by way of non-limiting theory, it appears that the heretofore commonly accepted modes of action of opiate antagonists and adenyl cyclase activators in inflammation and proliferative tissue disorders fall far short of actually explaining the anti-inflammatory efficacy of the presently disclosed formulation mixtures. Still further by way of non- limiting theory, alterations in the immunological cytokine profile may reflect more relevant physiological effects of the active ingredients of the herein-described formulations, especially naltrexone and forskolin, Unexpectedly and unpredictably, despite such an apparent immunological shift in cytokine elaboration when the presently disclosed combination formulations were administered, no overt signs of immunosuppression were observed locally or systemically even with long term topical administration. Hence, it is believed that immunomodulatory rather than immunosuppressive effects may result from administration of the presently described combination formulations. Another unexpected advantage obtained by administering the presently described combination formulations is that, surprisingly, far better results were observed in subjects receiving combination therapy than would be expected as the sum of the effects of each ingredient if administered singly. These results were especially unpredicted given the redundancies of the biological signalling pathways (i.e., cAMP regulation) that were influenced by the classes of agents that were employed (i.e., opiate antagonists, PDE inhibitors and adenyl cyclase activators). In particular, despite such redundancies in the previously understood effect of elevating intracellular cAMP levels, by the presently described compositions and methods a 100% favorable clinical response rate has been obtained in human subjects treated for seborrhea and eczema, with combination therapies yielding far more than simply additive effects for each of the individual active ingredients (e.g., any two or more of naltrexone, forskolin, and caffeine), when clinical data were evaluated for efficacy. In this regard, the present compositions and methods may offer unprecedented and unexpected advantages over most if not all currently available treatments for seborrhea and eczema, which current treatments typically fail to confer sustained clinical benefit for a significant proportion of human patients to whom they are administered. Various topical formulations, as provided herein, have been prepared that contain any two or more of naltrexone, forskolin, and caffeine, and have been tested on human subjects including those having dermatitis and/or dandruff and/or other inflammatory skin conditions. The delivery systems have included shampoo bases and rinses, oil-in-water and water-in-oil emulsions, and various single phase suspensions, both hydrophilic and hydrophobic. Because forskolin is extremely insoluble in most acceptable topical vehicles, delivery systems have been developed that address this problem, including in certain embodiments colloidal suspensions, which may be effective, although settling of the forskolin in such suspensions may eventually occur unless adjuvant ingredients such as shear thinning gums are included. Alternatively or additionally, forskolin may be conjugated to colloidal oatmeal according to existing methodologies (e.g., Kurtz et al., 2007 J. Drugs Dermatol. 6:167) and/or formulated with cyclodextrins as carriers, excipients or clathrates. These amd related methods permit embodiments that allow for a single phase aqueous carrier of much lower viscosity, and with very good sensory and tactile acceptance by users. Solvents such as low molecular weight alcohols and dimethyl sulfoxide (DMSO) may be appropriate for some indications even if they are not completely biocompatible. These various formulations, containing any two or more of naltrexone, forskolin, and caffeine, were regularly topically administered to experimental human clinical subjects for over a year with no changes in reported side effects; no substantial tolerance has developed. Formulations, containing any two or more of naltrexone, forskolin, and caffeine, were tested on human subjects having mild to moderate seborrhea, eczema, dandruff and in some cases, certain other inflammatory skin conditions. Thirty-five official participants were recruited by local physicians in organized overseas studies,

with several separate smaller study cohorts, and a U.S. study cohort numbered 12 subjects. All volunteers were adults. Clinical responsiveness was readily apparent visually by noting the reduction of skin redness at afflicted sites, followed by the significant reduction, or elimination, of all signs of excessive skin growth visible as lesions or skin flaking. Tactilely, a smoothness of the skin at the lesion site was similar to that at areas of uninvolved (unaffected) skin. Treatment areas of test subjects' skin were generally

limited to no more than 16 square inches of pathological skin, and treated areas were compared to similarly pathological untreated skin areas existing on the same person as a control. This method of control was not used in the case of scalp rinses for dandruff. A number of women middle age or older in the U.S. cohort presented with seborrhea manifest as skin flaking and itching in their ear canals; the presently described formulations were effective in treating this condition. Excluded from the studies were weeping lesions or skin lesions that were bleeding or overly compromised as effective barriers to the external environment, in order to prevent the possibility of substantial absorption of any active or inactive ingredients systemically. Thus severe cases of dermatitis of any cause were not treated, and psoriasis of any type was not addressed in the studies described here, although based on the other clinical outcomes, it is believed that the formulations described herein would be an effective treatment for these conditions. The only reported side effects were itching and, in one case in which a subject was informed the formulation contained caffeine, "jitteriness", a likely placebo effect based on other data that were collected. Naltrexone, forskolin and caffeine are all poorly absorbed through the skin, making them ideal for topical use in adults. Formulations were designed to avoid the addition of any ingredients, such as detergents, that might facilitate transdermal absorption. The low toxicity of this mixture was also amenable to preliminary testing of oral administration in some of the subjects. Mild insomnia, stimulation, increased blood clotting time, and indigestion relieved by antacids were observed and were not unexpected side-effects in these oral formulations studies. It is contemplated according to certain embodiments that this formulation (naltrexone, forskolin and caffeine) may prove effective as a primary and/or adjunct treatment in some malignancies, due to the biological pathways affected by the various ingredients. Initially, formulations utilized a 20% forskolin extract (Sabinsa Corp., Piscataway, NJ). Some members of treatment groups that received formulations containing forskolin reported itching, consistent with known data indicating that forskolin can be a minor skin irritant. This itching generally was mild-to-moderate in severity, varied according to carriers or excipients used in the formulations, and seemed more likely to occur at the initiation of treatment, and was less prevalent later in a treatment regimen, when treatment was continued for maintenance of improved skin after remission of symptoms had occurred. Naltrexone is known to relieve itching, such that formulations which contain both forskolin and naltrexone may be less likely to elicit unpleasant itching as a side-effect. Naltrexone exerted beneficial effects in pathological skin conditions in humans at topically applied concentrations as low as 0.05%; typically formulations used in the present studies contained naltrexone concentrations between 0.2% and 1%, fully dissolved. A concentration of less than 1% of a 20% forskolin extract was generally used in the formulations, yielding less than a 0.2% final concentration of forskolin in the formulation, although up to 1% final concentration was tested with good results. Other components present in the standardized 20% forskolin powder as obtained from the supplier may have also contributed to the efficacy of the final formulation mixture (Chen et al, 2009 J. Nat. Prod. 72:769-771). Caffeine was typically used at less than a 1% final concentration in the formulations, to prevent precipitation if chilled. As described herein, certain embodiments contemplate the inclusion of apocynin in formulations for treating or reducing tissue inflammation, inflammation- associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject, or for treating or preventing gray hair. Apocynin appeared capable of being readily absorbed systemically via skin application in humans, contrary to published animal studies. Certain embodiments thus contemplate formulations designed to prevent or avoid systemic absorption of apocynin, in view of toxicology profiles for this agent. The observations made in the course of the human studies described herein using topical formulations containing naltrexone, forskolin and caffeine (and some of which included systemic effects when taken internally), in summary, indicated unparalleled efficacy in treating many inflammatory conditions with little or no observed toxicity or overt immunosuppression. The formulations were active both topically and systemically and no substantial onset of tolerance was noted Preferred embodiments contemplate compositions and methods for treating or reducing tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject, or for treating or preventing gray hair. Many of these and related diseases, disorders and conditions may involve inflammation as a component of the disease process, yet other beneficial results may be obtained independently of immune system modulation, nor is the end result dependent on treating or suppressing the symptoms of what would be thought of as a disease. The list of claimed ingredients includes a compound from two, three or all four of the following classes: (i) Naltrexone or any analog such as, but not limited to, Naloxone or any other anti-opiate, opiate antagonist, or reverse agonist as provided herein, or any compound exhibiting any anti-opiate or opiate "blocking" effect whether synthesized or existing as an herbal component; (ii) Caffeine or any analog, whether synthesized artificially or existing as an herbal component; (iii) Coleus forskohlii, or any extract of this plant including, but not limited to, forskolin or Coleus forskohlii extracts or analogs occurring naturally or synthesized; (iv) Apocynin (acetovanillone) or any herbal compound containing apocynin, or any analogs which exhibit NAD(P)H Oxidase inhibitory activity. Accordingly, any formulation comprising two, three or more of these compounds when used together or otherwise to be combined as a biologically active treatment in humans or animals, may be contemplated within certain embodiments of the present invention.

PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS As disclosed herein, certain embodiments relate to a method for treating or reducing tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and/or neuronal death or dysfunction in a subject that comprises administering to the subject a formulation comprising an effective amount {e.g., a therapeutically effective amount) of one or more of the compounds as expressly described herein for use in such method, for example, one, two, three or more of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP- phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor, all as provided herein. The step of administering may be performed by any means known to the art, for example, topically, intraperitoneally, orally, parenterally, intravenously, intraarterially, transdermally, sublingually, subcutaneously, intramuscularly, transbuccally, intranasally, via inhalation, intraoccularly, subcutaneously, intraadiposally, intraarticularly or intrathecally. In preferred embodiments administering may be performed topically, where pharmaceutical excipients or carriers for topical use are described herein and known in the art. Certain other embodiments contemplate administration of the formulations described herein as a bulk deposition, which may be, for example time-released or alternatively immediately available, for instance, after being introduced into the brain, spine, and/or cerebrospinal fluid, or generally administered to the central nervous system. In one embodiment, the present invention relates to a composition comprising one or more active compounds (e.g., opiate antagonist, PDE inhibitor, adenylate cyclase activator, etc.) in a pharmaceutically acceptable carrier, excipient or diluent and in a therapeutic amount, as disclosed herein, when administered to an animal, preferably a mammal, most preferably a human patient. Administration of the compounds, or their pharmaceutically acceptable salts, in pure form or in an appropriate formulation such as a pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The formulations or pharmaceutical compositions can be prepared by combining an active compound with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, intrathecal, intraspinal, intracranial, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. As noted above, certain invention embodiments described herein relate to topical formulations of the described compounds (e.g., an opiate antagonist including peptide antagonists and related peptidomimetics, a PDE inhibitor, an adenylate cyclase activator, and/or a NAD(P)H oxidase inhibitor), which formulations comprise the compounds in a pharmaceutically acceptable carrier, excipient or diluent and in a therapeutic amount, as disclosed herein, when administered topically to an animal, preferably a mammal, and most preferably a human. Topical administration of the compounds described herein, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of topical administration of agents for serving similar utilities. Topical application or administration of a composition means, in preferred embodiments, directly contacting the composition (e.g., a topical formulation) with skin of the subject undergoing treatment, which may be at one or more localized or widely distributed skin sites and which may generally refer to contacting the topical formulation with intact stratum corneum or epidermis but need not be so limited; for instance, certain embodiments contemplate as a topical application the administration of a topical formulation described herein to injured, abraded, wrinkled or damaged skin (including photodamaged skin), or skin of a subject undergoing surgery, such that contact of the topical formulation may take place not only with stratum corneum or epidermis but also with skin granular cell, spinous cell, and/or basal cell layers, and/or with dermal or underlying tissues, for example, as may accompany certain types of skin tissue remodeling. The topical formulations (e.g. , pharmaceutical compositions) may be prepared by combining the described compound (e.g., opiate antagonist, PDE inhibitor, adenylate cyclase activator, etc.) with an appropriate pharmaceutically acceptable carrier, diluent or excipient for use in a topical formulation preparation, and may be formulated into preparations in solid, semi-solid, gel, cream, colloid, suspension or liquid or other topically applied forms, such as powders, granules, ointments, solutions, washes, gels, pastes, plasters, paints, bioadhesives, microsphere suspensions, and aerosol sprays. Pharmaceutical compositions of these and related embodiments are formulated so as to allow the active ingredients contained therein to be bioavailable upon topical administration of the composition to skin of a subject, such as a mammal, including a human. Depending on the particular embodiments, which may vary as will be appreciated by the skilled artisan in part as a function of the condition to be treated in a given subject, the topical formulations described herein deliver a therapeutically effective amount of, e.g., the inflammation-reducing or other active compound(s) to skin cells such as epithelial cells, keratinocytes, cells of the scalp (including in certain embodiments cells involved in hair growth and coloration, such as follicular cells and/or melanocytes), and/or dermal fibroblasts. Preferred formulations may exhibit ready permeability into the skin, as can be determined according to any of a number of established methodologies known to the art for testing the skin permeability of a drug composition (see, e.g., Wagner et al., 2002 J. Invest. Dermatol. 118:540, and

references cited therein; Bronaugh et al., 1985 J. Pharm. Sci. 1A:6A; Bosman et al., 1998 J. Pharm. Biomed. Anal. 17:493-499; Bosman et al., 1996 J. Pharm Biomed Anal. 1996 14:1015-23; Bonferoni et al., 1999 Pharm Dev Technol. 4:45-53; Frantz, Instrumentation and methodology for in vitro skin diffusion cells in methodology for skin absorption. In: Methods for Skin Absorption (Kemppainen & Reifenrath, Eds), CRC Press, Florida, 1990, pp. 35-59; Tojo, Design and calibration of in vitro permeation apparatus. In: Transdermal Controlled Systemic Medications (Chien YW, Ed), Marcel Dekker, New York, 1987, 127-158; Barry, Methods for studying percutaneous absorption. In: Dermato logical Formulations: Percutaneous absorption, Marcel Dekker, New York, 1983, 234-295). Compositions that will be administered to the skin (including in certain embodiments the scalp) of a subject or patient may in certain embodiments take the form of one or more dosage units, where for example, a liquid-filled capsule or ampule may contain a single dosage unit, and a container of a topical formulation as described herein in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a skin tissue repair-promoting compound as provided herein {e.g., opiate antagonist, PDE inhibitor, adenylate cyclase activator, etc.) or a pharmaceutically acceptable salt thereof, in accordance with the present teachings. As noted above, the present topical formulations may take any of a wide variety of forms, and include, for example, creams, lotions, solutions, sprays, gels, ointments, pastes or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres. See, e.g., U.S. Patent No. 7,205,003. For instance, creams, as is well known in the arts of pharmaceutical and cosmeceutical formulation, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Lotions, which are preferred for delivery of cosmetic agents, are preparations to be applied to the skin surface without friction, and are typically liquid or semi-liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably comprise a liquid oily emulsion of the oil-in-water type. Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally preferred that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl- cellulose, or the like. Solutions are homogeneous mixtures prepared by dissolving one or more chemical substances (solutes) in a liquid such that the molecules of the dissolved substance are dispersed among those of the solvent. The solution may contain other pharmaceutically acceptable and/or cosmeceutically acceptable chemicals to buffer, stabilize or preserve the solute. Common examples of solvents used in preparing solutions are ethanol, water, propylene glycol or any other pharmaceutically acceptable and/or cosmeceutically acceptable vehicles. Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol, and, optionally, an oil. Preferred "organic macromolecules," i.e., gelling agents, may be chemically crosslinked polymers such as crosslinked acrylic acid polymers, for instance, the "carbomer" family of polymers, e.g., carboxypolyalkylenes, that may be obtained commercially under the Carbopol® trademark. Also preferred in certain embodiments may be hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof. Ointments, as also well known in the art, are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for a number of desirable characteristics, e.g., emolliency or the like. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating, and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), at pages 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifϊ able bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight (see, e.g., Remington, Id). Pastes are semisolid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels. The base in a fatty paste is generally petrolatum or hydrophilic petrolatum or the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Formulations may also be prepared with liposomes, micelles, and microspheres. Liposomes are microscopic vesicles having one (unilamellar) or a plurality (multilamellar) of lipid walls comprising a lipid bilayer, and, in the present context, may encapsulate and/or have adsorbed to their lipid membranous surfaces

one or more components of the topical formulations herein described, such as the anti inflammatory compounds (e.g., opiate antagonist, PDE inhibitor, adenylate cyclase activator, etc.) or certain carriers or excipients. Liposomal preparations herein include cationic (positively charged), anionic (negatively charged), and neutral preparations. Cationic liposomes are readily available. For example, N[l-2,3-dioleyloxy)propyl]- N,N,N-triethylammonium (DOTMA) liposomes are available under the tradename Lipofectin® (GIBCO BRL, Grand Island, N.Y.). Similarly, anionic and neutral liposomes are readily available as well, e.g., from Avanti Polar Lipids (Birmingham, AL), or can be easily prepared using readily available materials. Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with DOTMA in appropriate ratios. Methods for making liposomes using these materials are well known in the art. Micelles are known in the art as comprised of surfactant molecules arranged so that their polar headgroups form an outer spherical shell, while the hydrophobic, hydrocarbon chains are oriented towards the center of the sphere, forming a core. Micelles form in an aqueous solution containing surfactant at a high enough concentration so that micelles naturally result. Surfactants useful for forming micelles include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodium lauryl sulfate, docusate sodium, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride, polyoxyl-8 dodecyl ether, polyoxyl-12 dodecyl ether,

nonoxynol 10, and nonoxynol 30. Microspheres, similarly, may be incorporated into the presently described topical formulations. Like liposomes and micelles, microspheres essentially encapsulate one or more components of the present formulations. They are generally, but not necessarily, formed from lipids, preferably charged lipids such as phospholipids. Preparation of lipidic microspheres is well known in the art. Various additives, as known to those skilled in the art, may also be included in the topical formulations. For example, solvents, including relatively small amounts of alcohol, may be used to solubilize certain formulation components. It may be desirable, for certain topical formulations or in cases of particularly severe inflammatory conditions of the skin, to include in the topical formulation an added skin permeation enhancer in the formulation. Examples of suitable enhancers include, but are not limited to, ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer® (231, 182, 184), Tween® (20, 40, 60, 80), and lecithin (U.S. Pat. No. 4,783,450); alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; polyethylene glycol and esters thereof such as polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1 -methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes; alkanones; and organic acids, particularly citric acid and succinic acid. Azone® and sulfoxides such as DMSO and CioMSO may also be used, but are less preferred. Most preferred skin permeation enhancers are those lipophilic co- enhancers typically referred to as "plasticizing" enhancers, i.e., enhancers that have a molecular weight in the range of about 150 to 1000 daltons, an aqueous solubility of less than about 1 wt %, preferably less than about 0.5 wt %, and most preferably less than about 0.2 wt %. The Hildebrand solubility parameter of plasticizing enhancers is in the range of about 2.5 to about 10, preferably in the range of about 5 to about 10. Preferred lipophilic enhancers are fatty esters, fatty alcohols, and fatty ethers. Examples of specific and most preferred fatty acid esters include methyl laurate, ethyl oleate, propylene glycol monolaurate, propylene glycerol dilaurate, glycerol monolaurate, glycerol monooleate, isopropyl n-decanoate, and octyldodecyl myristate. Fatty alcohols include, for example, stearyl alcohol and oleyl alcohol, while fatty ethers include compounds wherein a diol or triol, preferably a C -C alkane diol or triol, are substituted with one or two fatty ether substituents. Additional skin permeation enhancers will be known to those of ordinary skill in the art of topical drug delivery, and/or are described in the relevant literature. See, e.g., Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995). Various other additives may be included in the topical formulations according to certain embodiments of the present invention, in addition to those identified above. These include, but are not limited to, antioxidants, astringents, perfumes, preservatives, emollients, pigments, dyes, humectants, propellants, and sunscreen agents, as well as other classes of materials whose presence may be cosmetically, medicinally or otherwise desirable. Typical examples of optional additives for inclusion in the formulations of the invention are as follows: preservatives such as sorbate; solvents such as isopropanol and propylene glycol; astringents such as menthol and ethanol; emollients such as polyalkylene methyl glucosides; humectants such as glycerine; emulsifϊ ers such as glycerol stearate, PEG- 100 stearate, polyglyceryl-3 hydroxylauryl ether, and polysorbate 60; sorbitol and other polyhydroxyalcohols such as polyethylene glycol; sunscreen agents such as octyl methoxyl cinnamate (available commercially as Parsol MCX) and butyl methoxy benzoylmethane (available under the tradename Parsol 1789); antioxidants such as ascorbic acid (vitamin C), α-tocopherol (Vitamin E), β-tocopherol , γ- δ ε ζ ζ η tocopherol, -tocopherol, -tocopherol , i-tocopherol, 2-tocopherol, -tocopherol , and retinol (vitamin A); essential oils, ceramides, essential fatty acids, mineral oils, vegetable oils {e.g., soy bean oil, palm oil, liquid fraction of shea butter, sunflower oil), animal oils {e.g., perhydrosqualene), synthetic oils, silicone oils or waxes {e.g., cyclomethicone and dimethicone), fluorinated oils (generally perfluoropolyethers), fatty alcohols {e.g., cetyl alcohol), and waxes {e.g., beeswax, carnauba wax, and paraffin wax); skin-feel modifiers; and thickeners and structurants such as swelling clays and cross-linked carboxypolyalkylenes that may be obtained commercially under the Carbopol® trademark. Other additives include beneficial agents such as those materials that condition the skin (particularly, the upper layers of the skin in the stratum comeum) and keep it soft by retarding the decrease of its water content and/or protect the skin. Such conditioners and moisturizing agents include, by way of example, pyrrolidine carboxylic acid and amino acids; organic antimicrobial agents such as 2,4,4'-trichloro- 2-hydroxy diphenyl ether (triclosan) and benzoic acid; anti-inflammatory agents such as acetylsalicylic acid and glycyrrhetinic acid; anti-seborrhoeic agents such as retinoic acid; vasodilators such as nicotinic acid; inhibitors of melanogenesis such as kojic acid; and mixtures thereof. Other advantageously included cosmeceutically active agents may be present, for example, α-hydroxyacids, α-ketoacids, polymeric hydroxyacids, moisturizers, collagen, marine extracts, and antioxidants such as ascorbic acid (vitamin C), α-tocopherol (Vitamin E) or other tocopherols such as those described above, and retinol (vitamin A), and/or cosmetically acceptable salts, esters, amides, or other derivatives thereof. Additional cosmetic agents include those that are capable of improving oxygen supply in skin tissue, as described, for example, in WO 94/00098 and WO 94/00109. Sunscreens may also be included. Other embodiments may include a variety of non-carcinogenic, non- irritating healing materials that facilitate treatment with the formulations of the invention. Such healing materials may include nutrients, minerals, vitamins, electrolytes, enzymes, herbs, plant extracts, glandular or animal extracts, or safe therapeutic agents that may be added to the formulation to facilitate dermal healing. The amounts of these various additives are those conventionally used in the cosmetics field, and range, for example, from about 0.01% to about 20% of the total weight of the topical formulation. The formulations of the invention may also include conventional additives such as opacifiers, fragrance, colorant, gelling agents, thickening agents, stabilizers, surfactants, and the like. Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and molds. Suitable antimicrobial agents are typically selected from methyl and propyl esters of/?-hydroxybenzoic acid (e.g., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and combinations thereof. The formulations may also contain irritation-mitigating additives to minimize or eliminate the possibility of skin irritation or skin damage resulting from the skin tissue repair-promoting compound to be administered, or from other components of the composition. Suitable irritation-mitigating additives include, for example: α- tocopherol ; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2- phenyl-1-ethanol; glycerin; salicylates; ascorbates; ionophores such as monensin; amphiphilic amines; animonium chloride; N-acetylcysteine; capsaicin; and chloroquine. The irritation-mitigating additive, if present, may be incorporated into the topical formulation at a concentration effective to mitigate irritation or skin damage, typically representing not more than about 20 wt %, more typically not more than about 5 wt %, of the formulation. Compounds for use in the present formulations, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, skin type and diet of the subject; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular inflammatory condition for which treatment is desired; and the subject undergoing therapy. Generally, a therapeutically effective daily dose is (for a 70 kg mammal) from about 0.001 mg/kg (i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 g); preferably a therapeutically effective dose is (for a 70 kg mammal) from about 0.01 mg/kg (i.e., 7 mg) to about 50 mg/kg (i.e., 3.5 g); more preferably a therapeutically effective dose is (for a 70 kg mammal) from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 g). The ranges of effective doses provided herein are not intended to be limiting and represent preferred dose ranges. However, the most preferred dosage will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant arts (see, e.g., Berkow et al., eds., The Merck Manual, 16th edition, Merck and Co., Rahway, N.J., 1992; Goodman et al., eds., Goodman and

Gilman's The Pharmacological Basis of Therapeutics, 10th edition, Pergamon Press, Inc., Elmsford, N.Y., (2001); Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, Ltd., Williams and Wilkins, Baltimore, MD. (1987); Ebadi, Pharmacology, Little, Brown and Co.,

Boston, (1985); Osolci al., eds., Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, PA (1990); Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)). The total dose required for each treatment can be administered by multiple doses or in a single dose over the course of the day, if desired. Certain preferred embodiments contemplate a single administration of the formulation per day. Generally, and in distinct embodiments, treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The recipients of the topical formulations described herein can be any vertebrate animal, such as mammals. Among mammals, the preferred recipients are mammals of the Orders Primate (including humans, apes and monkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs), Rodenta (including mice, rats, rabbits, and hamsters), and Carnivora (including cats, and dogs). Among birds, the preferred recipients are turkeys, chickens and other members of the same order. The most preferred recipients are humans. The compositions having anti-inflammatory activity (in certain preferred embodiments comprising two or more synergizing active compounds), or hair color-restoring or color-protecting activity, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770 and 4,326,525 and in P. J. Kuzma et al, Regional Anesthesia 22 (6): 543-551 (1997), all of which are incorporated herein by reference. The most suitable route will depend on the nature and severity of the condition being treated. Those skilled in the art are also familiar with determining topical administration methods (sprays, creams, open application, occlusive dressing, soaks, washes, etc.), dosage forms, suitable pharmaceutical excipients and other matters relevant to the delivery of the compounds to a subject in need thereof.

The following Examples are presented by way of illustration and not limitation. EXAMPLES

EXAMPLE 1

IN VITRO MODELS OF OXIDATIVESTRESS

Normal M059J glial cells or M059J cells harboring the G93A SODl mutation (cultured glial cell model of amyotrophic lateral sclerosis, ALS) were cultured, and reactive oxygen species (ROS) determinations were made, essentially as described by Harraz et al, 2008 J. Clin. Invest. 118(2):659-670. Compounds (naltrexone at indicated concentration) were added to cultures as indicated. Figure 1 shows levels of reactive oxygen species in a cultured glial cell model of amyotrophic lateral sclerosis. Left to right: First bar represents ROS levels in normal M059J cell line without added compounds; second bar shows ROS levels in G93A mutant glial cells without added compounds —these cells produced high levels of (ROS) and are regarded as a model for amyotrophic lateral sclerosis (ALS) with no additions. Third bar shows ROS levels in G93A mutant glial cells cultured in the presence of 50µM naltrexone. Fourth bar: G93A cells with 5µM naltrexone. Fifth bar: G93A cells with 0.5µM naltrexone. SH-SY (neuronal) or MO59J (glial) cells, cell culture conditions and assay methods were as described in Harraz et al, 2008 J. Clin. Invest. 118(2):659-670. Relative oxygen generation was assessed as indicated in Figure 2 in the presence or µ " absence of apocynin (100 M). Figure 2 shows the rate of NADPH-dependent O2 production in total endomembranes isolated from SH-SY (neuronal) or MO59J (glial) cells at 48 hours following infection with adenoviral vectors expressing LacZ, SOD1 WT, SOD1 L8Q, or SOD1 G93A . Values are mean ± SEM (n = 6 per group). EXAMPLE 2

IN VIVO STUDIES

Human volunteer subjects presenting for the clinical trails of the various formulations described herein already had a clinical diagnosis of their condition(s). Those that did not, or needed verification, were diagnosed using standard medical reference books such as Skin Disease: Diagnosis and Treatment (Mosby Publishing). For broadly encompassing descriptions of conditions, dandruff in particular, all that was noted was scalp flaking and no further diagnostics were required. Any additional clinical observations for dandruff, beyond mild inflammation and associated redness of the scalp, removed the candidate from participation in the clinical trial. There were a few participants that seemed to have mixed dermatitis issues and so long as they were not severe, covered an extensive portion of the body, and were not indicative of any well documented unrelated disease states or pathological infections, they were allowed to participate. Children, pregnant, or potentially pregnant women, as well as nursing women were excluded from this study. An inexpensive, non-medicated, off the shelf shampoo was used as a base to test the efficacy of two formulations of active ingredients on dandruff control. The first formulation (A) consisted of Suave™ brand shampoo (Unilever, London,

UK) with 0.25% of naltrexone (Tyco/Mallinckrodt, St. Louis, MO) dissolved completely. The second formulation (B) consisted of 0.25% naltrexone dissolved, 1% forskolin extract containing 20% forskolin (Sabinsa Corp., Piscataway, NJ) suspended, and 1% caffeine dissolved. Both shampoos were shaken well before use. Participants were instructed to apply and use the shampoo as they normally would, taking care to work the shampoo into all areas of the scalp and leave it in contact with the scalp and hair "for a few minutes" before rinsing well with water. Most participants did this while showering. No side effects were noted for either formula. For the dandruff formulations, self reporting by the users was the principal measure of efficacy. Results: Formula "A" displayed activity that was roughly comparable to commercially available dandruff shampoos. Formula "B" proved very efficacious by self reporting, with high user enthusiasm. Both itching and flaking seemed to be dramatically relieved after one application. Participants were generally free to use the shampoo as often as they would normally shampoo their hair, and after the first few reports, this project was also halted in favor of topical skin testing. There was a rinse, formula "C", which was created with the same formulation as formula "B" described above, but the shampoo base was replaced with distilled water containing a small amount of polysorbate 80 as a wetting agent. This formula was to be applied to the scalp after shampooing, following drying of the scalp and hair with a towel. This formula was highly efficacious, although the forskolin extract did cause minor scalp irritation in some subjects, which was not excessive, as well as some staining of clothes, pillow cases and other items which came in contact with the treated area. Formula "D" was designed for treating all types of proliferative skin diseases, especially eczema, seborrhea, and psoriasis. Original formulations were very concentrated and contained up to 1% naltrexone, 1% forskolin (as a 5% concentration of a 20% forskolin extract, or later in testing, as 1% of a 98%+ forskolin extract), and 1% caffeine dissolved as well as possible in a solution of 50% glycerin and 50% distilled water by volume. Naltrexone was dissolved first in the water, then the caffeine, though it was sometimes possible to see minor precipitation occur upon storage in the cold. Forskolin powder was added to the glycerin and suspended, not dissolved. These two components were then mixed to yield the formulation to be tested. If the 20% forskolin extract was used, the final product took on a dark brown opaque appearance, but the brown forskolin extract would eventually settle, revealing a clear solution in most of the upper portion of storage vials, and so the formulation would be mixed by shaking within an hour or so of use. This formula was kept refrigerated after formulating. Formula "E" contained 0.25% naltrexone and approximately 0.75% caffeine dissolved in distilled water as previously described, and approximately 0.2% forskolin, again suspended in the glycerin. Formula "E" was evaluated, and utilized on the bulk of the study participants, with approximately equal numbers using the oat-

containing formulation (Formula "Eoats") and non-oat containing formulation (Formula "E"). It is important to note that the concentrations given are not with respect to the solution components, but rather to the final mixed product. The proportion of glycerin was reduced to approximately 20% and distilled water was increased to 80% by volume. To this was added a small amount of ascorbic acid as an antioxidant and salts of EDTA as a chelating agent. Later modifications were made to this formulation; the most substantial was binding the forskolin extract to ground "colloidal" oatmeal. This was done by dissolving the forskolin extract in USP grade ethanol; though there was always some residue in the less pure extracts which was filtered out with standard lab filtration paper. This ethanol and forskolin extract mix was then added to the finely ground oatmeal and placed in a lab oven at 200 degrees F until the alcohol was evaporated and the oatmeal mix no longer had any residual smell of alcohol. This allowed for the forskolin bound to oatmeal to be treated as only oatmeal when compounding. Additionally, oatmeal has emulsification properties which allowed for the inclusion of various oils and lipophilic ingredients such as olive oil, Shea butter, mineral oil, ceresin and petrolatum, which have potential added benefits in the treatment of dermatitis, if for no other reason than their occlusive properties. Additionally oatmeal kept the forskolin in suspension much longer, and with the addition of shear thinning gums such as xanthan, the forskolin and all components could be kept in suspension for extended periods of time while increasing user acceptance because of increased tactile and sensory satisfaction. The oatmeal also potentially aided in symptomatic relief of various types of dermatitis (Pigatto et al, 1997 Am J Contact Dermat. 8(4):207-9.) (Vie et al., 2002 Skin Pharmacol Appl Skin Physiol. 15:120-124.) though no difference in efficacy was noted in the present work. Incorporation of oats into the formulation also allows for some pertinent FDA claims to be made on the packaging relating to dermatological problems and issues {Federal Register Vol. 68, No. 107/ Wednesday, June 4, 2003 / Rules and Regulations). To the oat containing formulation was added a small amount of ascorbic acid, as well as mixed tocopherols as antioxidants and salts of EDTA as a chelating agent. Vanilla extract was added as an identifiable scent. The bulk of the study utilized Formula "E" or Formula "Eoat" where

Formula "Eoat" did not incorporate any ingredients not included in Formula "E" described above with the exception of colloidal oats containing bound forskolin extract. All the active ingredients in all formulations were the same as described above, and contained the same concentrations given, the one potential variable being the effect of the colloidal oats on the bioavailability of the active ingredients, especially the forskolin extract which was physically bound to the oats as previously described. The formulations were prepared just prior to being distributed to study participants and were refrigerated while being stored. In this study only the effects of the formulations on eczema, seborrhea and psoriasis were investigated. Participants were told to treat one lesion topically and leave an equivalent lesion untreated as a control. For most participants, two lesions of approximately the same size and same severity were identified by examination and selected to be as remote from one another on the participant's body as possible. One lesion was actively treated with the test formulation and the other lesion was

monitored as an untreated control. The lesional areas were generally less than 16 square inches, and none of the ingredients were documented to be absorbed systemically to any significant degree (van de Sandt et al, 2004. Regul Toxicol Pharmacol. 39(3):271-81.) (Thakur et al, 2007 Drug development and industrial pharmacy. 33(5):5 13-21.) (D'Orazio et al, 2006 Nature. 443(7 109):340-4) (Wermeling et al, 2008 Proc Natl Acad Sci USA. 105(6):2058-63) although the lesions themselves offered the potential for greater penetration due to their compromised functioning as protective barriers from the external environment (Nielsen et al, Archives of Dermatological Research Vol. 299, Number 9/ November, 2007). Participants were instructed to shake the bottle well and apply a thin layer of the formula to their lesion twice a day (b.i.d.) with their fingers and smooth it into their skin gently for less than a minute. For subjects having mild or moderate eczema or seborrhea, a difference in the frank appearance of the skin lesions could often be readily observed the next day following initial treatment. Within a few days most study participants self reported that the lesion had vanished although the skin color may have been slightly different from that of unaffected skin, if this difference was historically part of their normal healing process. These differences in color between treated and healthy, unaffected skin disappeared over time. Since these cases were all classified as mild to moderate, scarring did not occur. It is very important to note that the forskolin did not activate pigmentation or cause tanning in any participants, as had been observed in mice treated topically with this agent (D'Orazio et al, Nature. 2006 Sep 21;443(7109):340-4). In fact this formulation was used on facial lesions without any discoloration whatsoever. One investigator tried the formula on a subject after the subject received a trichloroacetic acid (TCA) facial chemical skin peel (Dinner MI, Clin Plast Surg. 1998 Jan;25(l):53-62.) and noted significantly reduced pain and inflammation, but more importantly there was no change in skin pigmenting that could be attributable to forskolin, but only a change due to the intended purpose of reducing discrete areas skin discoloration due to years of overexposure to the sun.

At the start of the evaluation of Formula "E" and Formula "Eoat" for eczema, seborrhea, and psoriasis, it was intended to base scoring of clinical efficacy and objective success on the Dermatology Index of Disease Severity (DIDS) (Hahn HB, Using the Dermatology Index of Disease Severity (DIDS) to assess the responsiveness of dermatitis. Clin Exp Dermatol. 2006 Jan;31(l):19-22.) (Faust HB, Gonin R, et al. Reliability testing of the Dermatology Index of Disease Severity (DIDS). Arch Dermatol. 1997; 133: 1443-1448.) Additionally participants filled out a subjective evaluation of their perceived "success and their happiness" with the formulation based on past treatments they had used. Everyone that was included in this preliminary trial fell well within DIDS Stage II and most within stage I prior to treatment. Since only discrete areas of the skin were treated and evaluated, there arose a concern that the DIDS did not appropriately address this limitation. All participants with seborrhea and eczema (n=47) responded completely after a follow- up visit two weeks after beginning the start of the Formula "E" and Formula "Eoat" protocol. No signs of inflammation were observed, nor were any dermatological issues noted save for a few participants that had very minor skin discoloration which they reported as being typical. Control areas varied, some had worsened and some improved, but none at the rate or degree that the treated areas did. Among all study participants, self-reported overall satisfaction was 9.3 on a scale of 1-10, with 10 being complete satisfaction (which also included the feel and subjective evaluation of the final product). This formulation was tested on two cases of mild psoriasis and improvement was noted but not quantified. Several test subjects anecdotally reported smoother skin and reduced signs of skin wrinkles following treatment with the formulation, observations for which larger data sets are needed. Despite instructions to study participants not to share the formulation with others, or to use it for others' health issues, several did. An interesting anecdotal observation emerged from such middle aged and elderly participants, namely, their desire to treat skin flaking in the ear canal. Some had been using prescribed steroids or tar gel-based commercial products, although many developed tolerance or had negligible benefits from the start of such regimens. All of those who tried Formula "E" or "Eoat" in their ears, by introducing the formula well into the ear canal, achieved complete remission of itching and flaking with daily use in only a few days. This remission was maintained by a once- or twice- weekly maintenance application, with no side effects reported or noted. A caffeine and forskolin combination was also tried successfully on seborrhea and eczema on a very limited scale. It was very successful in treating skin flaking and itching in the ear canal of participants as described above for Formula "E" and Formula "Eoat", and appears, in this application, to be just as efficacious as the full formulation, Formula "E". The same concentrations of caffeine as forskolin were used in these studies as were used in Formula "E" Additionally, limited observations were made on the effects of an oral rinse for gingivitis and generalized inflammation in the mouth. Again, preliminarily, data recorded for this application indicate that the oral rinse is efficacious. Several male participants also reported an increased interest in sex, with more frequent desire, and an increased frequency of spontaneous erections, and morning erections. This observation was also consistently reported by men in the present inventor's previous research on the use of naltrexone in treating various autoimmune diseases. Unlike data generated in the course of testing currently FDA-approved cGMP-specific phosphodiesterase type 5 treatments for erectile dysfunction, in the naltrexone studies men reported an increase in desire for sex independent of erections. This increased frequency of erections was noted previously (Fabbri A, et al, Endorphins in male impotence: evidencefor naltrexone stimulation of erectile activity inpatient therapy. Psychoneuroendocrinology. 1989;14(l-2):103-l 1.), but not previously reported was an increased desire for sex independent of the erections, and not in men lacking a clinical diagnosis of impotence. Accordingly, certain embodiments are contemplated in which the presently described formulations may find uses in the treatment and/or management of these and related indications, disorders and conditions. Other contemplated embodiments according to the present disclosure relate to preventing the loss of hair color, commonly associated with aging, and or treating hair from which color has already been partially or completely lost {e.g., gray or white hair). In this regard, another unexpected observation made during the above described studies in human subjects was that in a small number of subjects for whom treatment regimens involved facial hair, long-term use of the full formulation (up to 2 years) resulted in hair in the treated areas of the face retaining its natural color when compared to facial hair on other, untreated areas of the test subjects. In the present studies, apocynin (Sigma Aldrich St. Louis, MO 63178) exhibited some toxicity both when administered orally and when applied topically. Specifically, over a period of days following initiation of treatment, there was an insidious and profound progression of exercise intolerance. At rest there were no noticeable side effects, but once exertion was required there was an inability to meet the physical demand, so much so that one person who had previously been readily able to run up five flights of stairs to his home, was unable to walk up even a half flight a stairs without resting for a few minutes. Loss of breath and heart pounding (palpitations) accompanied the inability to exert his muscles. No physiological data could be obtained, but this event ended that aspect of the study. (This phenomenon may have been a dosage issue, an as yet unknown theory and one for which no published references were identified.) It appears that this subject made a full recovery over the next few weeks. EXAMPLE 3

ADDITIONAL FORMULATIONS AND INDICATIONS

As described above in Example 1, apocynin (as a representative non- limiting example of a NAD(P)H oxidase inhibitor) and naltrexone (as a representative non-limiting example of an opiate antagonist, partial antagonist or reverse agonist), demonstrate the ability to reduce reactive oxygen species (ROS) levels in physiologically relevant model cells of the central nervous system (CNS) (see Figures 1 and 2). As also described above, a formulation comprising at least any three of the active classes of compounds discussed herein ((i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, and (iii) an adenylate cyclase activator), and most combinations of at least any two such agents as provided herein, exhibit potent anti-inflammatory abilities as described above. Recognizing the role of ROS in mechanisms of action of the immune system, including as a signaling element, certain embodiments of the present invention thus contemplate compositions and methods for the effective treatment of degenerative diseases that are characterized by unregulated or otherwise aberrant mechanisms involving inappropriate ROS generation, aging or aging-associated events, cellular proliferation, neuronal dysfunction, neuronal death (including apoptosis) and the like. A number of neurodegenerative diseases fall into this category such as amyotrophic lateral sclerosis (ALS) as well as many dementias and psychological diseases such as schizophrenia (M. Margarita Behrens, et al. Ketamine- Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH- Oxidase {Science 318, 1645 (2007);) and depression as well as other phenomena associated with the "normal" progression of aging; also contemplated are diseases and disorders that include heart disease, vascular disorders, chronic infections, arthritis, and many chronic illnesses that share mechanisms or are characterized by pathophysiological events such as those discussed above; see also, e.g., U.S. 7,005,274. . The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. CLAIMS

What is claimed is:

1. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising: administering to the subject a formulation that comprises an effective amount of (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, and (iii) an adenylate cyclase activator.

2. The method of claim 1 wherein: the opiate antagonist is selected from the group consisting of naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist that is selected from

the group consisting of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP) [SEQ ID

NO:1], D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP) [SEQ ID NO:2], D-

Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) [SEQ ID NO:3], D-

tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2

(D-Tic-CTP) [SEQ ID NO:4], D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (D-Tic-

CTOP) [SEQ ID NO:5] and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic- CTAP) [SEQ ID NO:6]; the PDE inhibitor is selected from the group consisting of a methylxanthine that is selected from caffeine, theobromine, paraxanthine, 3-isobutyl- 1-methylxanthine (IBMX) and theophylline; amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ

22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE2 selective inhibitor, a

PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine, and the adenylate cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin, isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I (prostacyclin).

3. The method of claim 1 wherein the opiate antagonist is naltrexone, the PDE inhibitor is caffeine and the adenylate cyclase activator is forskolin.

4. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising: administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator.

5. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising: administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator, wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype.

6. The method of either claim 4 or claim 5 wherein the PDE inhibitor is caffeine and the adenylate cyclase activator is forskolin.

7. The method of either claim 4 or claim 5 wherein the PDE inhibitor is selected from the group consisting of a methylxanthine that is selected from caffeine, theobromine, paraxanthine, 3-isobutyl- 1-methylxanthine (IBMX) and theophylline; amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ

22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE2 selective inhibitor, a

PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine, and the adenylate cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin,

isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I2 (prostacyclin).

8. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising: administering to the subject a formulation that comprises an effective amount of (i) an opiate antagonist, partial antagonist, or reverse agonist, and (ii) an adenylate cyclase activator.

9. The method of claim 8 wherein the opiate antagonist, partial antagonist, or reverse agonist is naltrexone, and the adenylate cyclase activator is forskolin.

10. The method of claim 8 wherein the opiate antagonist, partial antagonist, or reverse agonist is selected from the group consisting of naltrexone naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist that is selected from

the group consisting of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP) [SEQ ID

NO:1], D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP) [SEQ ID NO:2], D-

Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) [SEQ ID NO:3], D- tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2

(D-Tic-CTP) [SEQ ID NO:4], D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (D-Tic-

CTOP) [SEQ ID NO:5] and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic- CTAP) [SEQ ID NO:6]; and the adenylate cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin, isoproterenol, prostaglandin D2 , prostaglandin Ei and prostaglandin I2 (prostacyclin).

11. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, comprising: administering to the subject a formulation that comprises an effective amount of (i) an opiate antagonist, partial antagonist, or reverse agonist, and (ii) a cAMP-phosphodiesterase (PDE) inhibitor.

12. The method of claim 11 wherein the opiate antagonist, partial antagonist, or reverse agonist is naltrexone, and the cAMP-phosphodiesterase (PDE) inhibitor is caffeine.

13. The method of claim 11 wherein the opiate antagonist, partial antagonist, or reverse agonist is selected from the group consisting of naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist that is selected from the group consisting of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP), D-Phe-

Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-

Thr-NH2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-

Lys-Thr-Pen-Thr-NH 2 (D-Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2

(D-Tic-CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic-CTAP); and the cAMP-phosphodiesterase (PDE) inhibitor is selected from the group consisting of a methylxanthine that is selected from caffeine, theobromine, paraxanthine, 3-isobutyl-1-methylxanthine (IBMX) and theophylline; amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ 22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE selective inhibitor, a PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine.

14. A method of treating or preventing gray hair or restoring hair color, comprising administering to a subject a formulation that comprises an effective amount of an adenyl cyclase activator.

15. The method of claim 14 wherein the adenyl cylcase activator is forskolin.

16. The method of claim 14 wherein the adenyl cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin, isoproterenol, prostaglandin D , prostaglandin Ei and prostaglandin I2 (prostacyclin).

17. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising: administering to the subject a formulation that comprises an effective amount of two or more of: (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor. 18. The method of claim 17 wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss- of-function phenotype, or a Smoothened gain-of-function phenotype.

19. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising: administering to the subject a formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator, wherein the subject has a condition that is not characterized by a Hedgehog gain-of-function phenotype, a Patched loss-of-function phenotype, or a Smoothened gain-of-function phenotype.

20. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising: administering to the subject a formulation that comprises an effective amount of three or more of: (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, (iii) an adenylate cyclase activator, and (iv) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor.

21. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising: administering to the subject a formulation that comprises an effective amount of two or more of: (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) an adenylate cyclase activator, and (iii) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor.

22. A method for treating or reducing one or more of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress and neuronal death or dysfunction in a subject in need thereof, or for treating or preventing gray hair or restoring hair color, comprising: administering to the subject a formulation that comprises an effective amount of two or more of: (i) an opiate antagonist, partial antagonist, or reverse agonist, (ii) a cAMP-phosphodiesterase (PDE) inhibitor, and (iii) a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitor.

23. The method of any one of claims 17, 20 and 2 1 wherein the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist, and an adenylate cyclase activator.

24. The method of either claim 17 or claim 20 wherein the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist; a cAMP-PDE inhibitor; and an adenylate cyclase activator.

25. The method of any one of claims 17, 20 and 2 1 wherein the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist; an adenylate cyclase activator; and an NAD(P)H oxidase inhibitor. 26. The method of either claim 17 or claim 20 wherein the formulation comprises an opiate antagonist, partial antagonist, or reverse agonist; a c- AMP-PDE inhibitor; an adenylate cyclase activator; and an NAD(P)H oxidase inhibitor.

27. The method of any one of claims 1, 4, 5, 8, 11, 17, 19-21 or 22 wherein the step of administering comprises directly contacting a site of tissue inflammation, inflammation-associated cellular proliferation, oxidative stress, neuronal death or dysfunction with said formulation.

28. The method of any one of claims 1, 4, 5, 8, 11, 17, 19-21 or 22 wherein tissue inflammation, inflammation-associated cellular proliferation, oxidative stress or neuronal death or dysfunction is present at a site selected from the group consisting of skin, scalp, oral mucosa, genital mucosa, eye, conjunctiva, an internal organ and central nervous system.

29. The method of claim 28 wherein the site is (i) a central nervous system site that is selected from brain, spinal cord, meninges and cerebrospinal fluid, or (ii) an internal organ that is selected from heart, lung, liver, pancreas, gall bladder, spleen, kidney, small intestine, large intestine, thyroid, adrenal gland, stomach, diaphragm and bladder.

30. The method of any one of claims 1, 8, 11, 17, 20, 2 1 and 22 wherein the opiate antagonist is selected from the group consisting of naltrexone, naloxone, alvimopan, cyprodime, diprenorphine, 5'-guanidinonaltrindole, methylnaltrexone, nalmefene, nalorphine, naloxazone, naltriben, naltrindole, norbinaltorphimime, oxilorphan, and a peptide opiate antagonist.

31. The method of claim 30 wherein the peptide opiate antagonist is selected from the group consisting of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2

(CTP), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), D-Phe-Cys-Tyr-D-

Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D- Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (D-Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-

Thr-Pen-Thr-NH 2 (D-Tic-CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (D-Tic-CTAP).

32. The method of any one of claims 1, 4, 5, 11, 17, 19, 20 and 22 wherein the cAMP-PDE inhibitor is selected from the group consisting of a methylxanthine, amrinone, milrinone, a xanthine, anagrelide, cilostamide, medorinone, indolidan, rolipram, chelerythrine, cilostazol, a glucocorticoid, griseolic acid, etazolate, indomethacin, papaverine, MDL 12330A, SQ 22536, GDPssS, clonidine, a PDEi selective inhibitor, a PDE2 selective inhibitor, a PDE3 selective inhibitor, a PDE selective inhibitor, a PDE5 selective inhibitor, a pyrrolidinone, phenyl cycloalkane, a cycloalkene derivative, lisophylline and fenoxamine.

33. The method of claim 32 wherein the methylxanthine is selected from the group consisting of caffeine, paraxanthine, theophylline, 3-isobutyl-l- methylxanthine (IBMX) and theobromine.

34. The method of any one of claims 1, 4, 5, 8, 14, 17, 19, 20 and

2 1 wherein the adenylate cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin, isoproterenol, prostaglandin D2 , prostaglandin Ei and prostaglandin I2 (prostacyclin).

35. The method of claim 34 wherein the forskolin derivative has greater solubility than forskolin in a biocompatible solvent.

36. The method of claim 35 wherein the biocompatible solvent comprises a solvent selected from the group consisting of water, dimethylsulfoxide (DMSO), methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol and octanol. 37. The method of any one of claims 17, 20, 2 1 and 22 wherein the NAD(P)H oxidase inhibitor is selected from the group consisting of apocynin, an apocynin active metabolite dimer, and chimeric peptide gp9 Ids-tat.

38. The method of any one of claims 1, 4, 5, 8, 11, 17, 19, 20, 2 1 and 22 wherein the subject has a disease or condition selected from the group consisting of dermatitis, dandruff, poison oak exposure, poison ivy exposure, poison sumac exposure, exposure to an Anacardiaceae plant family member, gray hair, skin discoloration, vitiligo, an autoimmune disease, chronic inflammation, acute inflammation, cancer, skin wrinkling, cardiovascular disease, organ transplant, hair transplant, diabetic coma, excessive appetite, obesity, depression, erectile dysfunction, glaucoma, inhibition of scar formation, balding, cosmetic skin peeling, ablation or abrasion, asthma, chronic obstructive pulmonary disease and pneumonia.

39. The method of any one of claims 1, 4, 5, 8, 11, 17, 19, 20, 2 1 and 22 wherein the formulation is for at least one of topical administration, administration, colonic administration, intravenous administration, subcutaneous administration, intraperitoneal administration and central nervous system administration.

40. The method of claim 39 wherein central nervous system administration comprises administration to at least one of brain, spine and cerebrospinal fluid.

41. A method for treating or reducing dermatitis in a subject, comprising administering to the subject a topical formulation that comprises an effective amount of a cAMP-phosphodiesterase (PDE) inhibitor and an adenylate cyclase activator.

42. The method of claim 4 1 wherein the PDE inhibitor is caffeine and the adenylate cyclase activator is forskolin. 43. The method of claim 41 wherein the subject has psoriasis.

44. The method of claim 4 1 wherein the cAMP-PDE inhibitor is caffeine and the adenylate cyclase activator is selected from the group consisting of forskolin, a forskolin derivative, an extract of Coleus forskohlii, carbacyclin, isoproterenol, prostaglandin D2 , prostaglandin Ei and prostaglandin I2 (prostacyclin).

45. The method of claim 4 1 wherein the dermatitis is selected from the group consisting of psoriasis, irritant dermatitis, seborrheic dermatitis, atopic dermatitis (eczema), allergic contact dermatitis, thermal-induced dermatitis, drug- induced dermatitis, dyshidrotic dermatitis, urticaria, autoimmune dermatitis, and bullous dermatitis.

46. A method for treating or reducing psoriasis in a subject, comprising administering to the subject a topical formulation that comprises an effective amount of caffeine and forskolin.