Compositions and methods for treating ocular diseases
阅读说明：本技术 用于治疗眼病的组合物和方法 (Compositions and methods for treating ocular diseases ) 是由 T·P·福斯特 C·D·尼克尔斯 于 2018-05-01 设计创作，主要内容包括：本发明提供了组合物、方法和试剂盒,其通过施用血清素受体激动剂来治疗与病理性眼部新血管形成相关的病状,减少眼睛中的瘢痕形成,治疗干眼症,治疗黄斑变性和治疗角膜炎。(The present invention provides compositions, methods, and kits for treating conditions associated with pathological ocular neovascularization, reducing scarring in the eye, treating dry eye, treating macular degeneration, and treating keratitis by administering a serotonin receptor agonist.)
1. A method of treating a condition associated with pathological ocular neovascularization, the method comprising administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist or a salt thereof in a pharmaceutically acceptable carrier.
2. The method of claim 1, wherein the pathological ocular neovascularization is corneal neovascularization or choroidal neovascularization.
3. The method of claim 1 or 2, wherein the pathogenic ocular neovascularization is associated with: macular degeneration, keratoconjunctivitis, conjunctivitis, diabetic retinitis, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, leber's disease, retinal detachment, retinal pigment epithelium detachment, iridocytosis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, cancer, or a combination thereof.
4. A method of reducing scarring of an eye comprising administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist or a salt thereof in a pharmaceutically acceptable carrier.
5. A method of treating dry eye comprising administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist or a salt thereof in a pharmaceutically acceptable carrier.
6. A method of treating macular degeneration, comprising administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist or a salt thereof in a pharmaceutically acceptable carrier.
7. The method of claim 6, wherein the macular degeneration is age-related macular degeneration.
8. A method of treating keratitis, comprising administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist or a salt thereof in a pharmaceutically acceptable carrier.
9. The method of claim 8, wherein the keratitis is viral keratitis.
10. The method of claim 9, wherein the viral keratitis is herpetic keratitis.
11. The method of any one of claims 1-10, wherein the serotonin receptor agonist is 5-HT2AA receptor agonist.
12. The method of claim 11, wherein the serotonin receptor agonist is the following compound
13. The method of claim 11, wherein the 5-HT2AThe receptor agonist is 2, 5-dimethoxy-4-iodoamphetamine (DOI).
14. The method of claim 12, wherein the 5-HT2AThe receptor agonist is R-2, 5-dimethoxy-4-iodoamphetamine (R-DOI).
15. The method of any one of claims 1-14, wherein the serotonin receptor agonist is administered in combination with one or more additional therapeutic agents.
16. The method of claim 15, wherein the one or more additional therapeutic agents comprise an antiviral agent, an antibacterial agent, an antibiotic agent, an anti-inflammatory agent, an anti-VEGF agent, a corticosteroid, or a combination thereof.
17. The method of claim 16, wherein the antiviral agent is trifluridine (TFT) or ganciclovir.
18. The method of any one of claims 15-17, wherein the serotonin receptor agonist and the additional therapeutic agent are administered at different times.
19. The method of any one of claims 15-17, wherein the serotonin receptor agonist is administered concurrently with the additional therapeutic agent.
20. The method of any one of claims 1-19, wherein the serotonin receptor agonist is administered ocularly.
21. The method of claim 20, wherein the ocular administration is topical administration, conjunctival intracapsular instillation, intravitreal administration, subconjunctival administration, retrobulbar administration, intracameral administration, or sub-tenon's capsule administration.
22. The method of claim 21, wherein the topical administration is by eye drops or gel.
23. The method of claims 1-19, wherein the serotonin receptor agonist is administered systemically.
24. The method of any one of claims 1 to 23, wherein the subject is a mammal.
25. The method of claim 24, wherein the mammal is a human.
26. A pharmaceutical composition comprising a serotonin receptor agonist and an antiviral agent.
27. The pharmaceutical composition of claim 26, wherein the serotonin receptor agonist is 5-HT2AA receptor agonist.
28. The pharmaceutical composition of claim 26 or 27, wherein the serotonin receptor agonist is the following compound
29. The pharmaceutical composition according to claim 27, wherein the 5-HT2AThe receptor agonist is 2, 5-dimethoxy-4-iodoamphetamine (DOI).
30. The pharmaceutical composition according to claim 29, wherein the 5-HT2AThe receptor agonist is R-2, 5-dimethoxy-4-iodoamphetamine (R-DOI)。
31. The pharmaceutical composition of any one of claims 26-30, wherein the antiviral agent is TFT, ganciclovir, acyclovir, penciclovir, famciclovir, cidofovir analog derivatives, ribavirin, interferon, phosphonoacetate, foscarnet, fomivirsen, or valganciclovir.
32. A kit comprising a pharmaceutical composition according to any one of claims 26 to 31.
Background
Physiological angiogenesis and neovascularization processes are important for embryonic development, tissue remodeling, and wound healing. However, in certain tissues and diseases such as the eye, dysregulation of these tightly controlled processes can lead to angiogenesis-mediated pathological conditions. Pathological ocular neovascularization and vascular dysfunction can result in and result from a variety of conditions, including stromal keratitis, proliferative retinopathy, and macular degeneration, which produce a number of health complications.
There is a need in the art to develop effective therapies for treating conditions associated with pathological ocular neovascularization.
Disclosure of Invention
The present invention provides compositions, methods, and kits for treating conditions associated with pathological ocular neovascularization, reducing scarring in the eye, treating dry eye, treating macular degeneration, and treating keratitis in a subject (e.g., a mammal, such as a human subject).
In one aspect, the invention provides a method of treating a condition associated with pathological ocular neovascularization (e.g., corneal neovascularization or choroidal neovascularization). Such methods comprise administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist (e.g., 5-HT) in a pharmaceutically acceptable carrier2AReceptor agonists such as DOI (±) -1- (2, 5-dimethoxyphenyl) -2-aminopropane hydrochloride; (R) -DOI ((R) -1- (2, 5-dimethoxy-4-iodophenyl) -2-aminopropane) (greater than 95% R enantiomer); LA-SS-Az (2'S,4' S) - (+) -9, 10-didehydro-6-methylergoline-8 β - (trans-2, 4-dimethylazetidine); 2C-BCB (4-bromo-3, 6-dimethoxybenzocyclobuten-1-yl) methylamine; or lysergic acid diethylamide (LSD)) or a salt thereof. In some embodiments, the condition associated with pathological ocular neovascularization includes, but is not limited to, macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis (adenoviral keratoconjunctivitis), conjunctivitis (adenoviral conjunctivitis), diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathies, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's disease, retinal detachment, retinal pigment epithelium detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, cancer (e.g., ocular cancer, such as retinoblastoma), or a combination thereof.
In another aspect, the invention provides a method of reducing scarring (e.g., corneal scarring or scarring associated with age-related macular degeneration (e.g., wet age-related macular degeneration)) in an eye by administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist (e.g., 5-HT) in a pharmaceutically acceptable carrier2AReceptor agonists such as DOI, R-DOI or LSD) or salts thereof.
In another aspect, the invention provides a method of treating dry eye (e.g., keratoconjunctivitis sicca) by administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist (e.g., 5-HT) in a pharmaceutically acceptable carrier2AReceptor agonists such as DOI, R-DOI or LSD) or salts thereof.
In another aspect, the invention provides a method of treating macular degeneration (e.g., age-related macular degeneration (AMD)) by administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist (e.g., 5-HT) in a pharmaceutically acceptable carrier2AReceptor agonists such as DOI, R-DOI or LSD) or salts thereof.
In another aspect, the invention provides a method of treating keratitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a serotonin receptor agonist (e.g., 5-HT) in a pharmaceutically acceptable carrier2AReceptor agonists such as DOI, R-DOI or LSD) or salts thereof. In some embodiments, the keratitis is viral keratitis (e.g., herpetic keratitis).
In some embodiments of any of the preceding aspects, the serotonin receptor agonist is 5-HT2AA receptor agonist (e.g., DOI, R-DOI, or LSD). In some embodiments, the serotonin receptor agonist is a compound of formula (I), formula (II), or formula (III).
In some embodiments, the 5-HT2AThe receptor agonist is 2, 5-dimethoxy-4-iodoamphetamine (DOI). In other embodiments, the 5-HT2AThe receptor agonist is R-2, 5-dimethoxy-4-iodoamphetamine (R-DOI).
In some embodiments of any of the foregoing methods, the serotonin receptor agonist is administered in combination with one or more additional therapeutic agents. For example, the one or more additional therapeutic agents may include an antibiotic agent, an antibacterial agent, an antiviral agent, an anti-inflammatory agent, an anti-VEGF agent, a corticosteroidSterols, or combinations thereof. In some embodiments, the antiviral agent is trifluridine (TFT) or ganciclovir. In some embodiments, serotonin receptor agonists (e.g., 5-HT)2AReceptor agonists such as DOI, R-DOI or LSD) are administered at a different time than the additional therapeutic agent. In other embodiments, serotonin receptor agonists (e.g., 5-HT)2AReceptor agonists such as DOI, R-DOI or LSD) are administered concurrently with the additional therapeutic agent. In some embodiments, the serotonin receptor agonist is administered to the eye (e.g., as an ophthalmic formulation). For example, the serotonin receptor agonist may be administered ocularly (e.g., by topical administration (e.g., by eye drop administration, gel administration, or ointment administration), conjunctival intracapsular instillation, intravitreal administration, subconjunctival administration, retrobulbar administration, intracameral administration, or sub-tenon's capsule administration). In some embodiments, the serotonin receptor agonist is administered systemically.
A subject of any of the foregoing aspects can be a mammal (e.g., a human, such as a human having a condition associated with pathogenic ocular neovascularization, such as a human having macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, leber's disease, retinal detachment, retinal pigment epithelium detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinochoroidal neovascularization, or a combination thereof).
In another aspect, the present invention provides a pharmaceutical composition comprising a serotonin receptor agonist and an antiviral agent. In some embodiments, the serotonin receptor agonist is a compound of formula (I), formula (II), or formula (III).
In some embodiments, the 5-HT2AThe receptor agonist is 2, 5-dimethoxy-4-iodoamphetamine (DOI). In other embodiments, the 5-HT2AThe receptor agonist is R-2, 5-dimethoxy-4-iodoamphetamine (R-DOI).
In some embodiments, the antiviral agent is TFT, acyclovir, ganciclovir, penciclovir, famciclovir, cidofovir analog derivatives, ribavirin, interferon, phosphonoacetate, foscarnet, fomivirsen, or valganciclovir.
In another aspect, the invention provides a kit comprising a pharmaceutical composition comprising a serotonin receptor agonist and an antiviral agent. In some embodiments, the serotonin receptor agonist is 5-HT2AA receptor agonist. In some embodiments, the serotonin receptor agonist is a compound of formula (I), formula (II), or formula (III).
In some embodiments, the 5-HT2AThe receptor agonist is 2, 5-dimethoxy-4-iodoamphetamine (DOI). In other embodiments, the 5-HT2AThe receptor agonist is R-2, 5-dimethoxy-4-iodoamphetamine (R-DOI). In some embodiments, the antiviral agent of the kit is TFT, acyclovir, ganciclovir, penciclovir, famciclovir, cidofovir analog derivatives, ribavirin, interferon, phosphonoacetate, foscarnet, fomivirsen, or valganciclovir.
Definition of
The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. In the claims and/or the description, the use of the words "a" or "an" when used in conjunction with the term "comprising" may mean "one" or "an", but is also consistent with the meaning of "one or more", "at least one", and "one" or "more than one".
Wherever any phrase "for example," "such as," "including," and the like is used herein, the phrase "without limitation" should be understood as being followed by the phrase "without limitation," unless expressly stated otherwise. Similarly, "examples," "illustrations," etc. should be construed as non-limiting.
The term "substantially" allows for variations from the descriptive information that do not adversely affect the intended purpose. Even if the word "substantially" is not explicitly recited, the descriptive term should be understood as being modified by the term "substantially".
The terms "comprising" and "including" and "having" and "involving" and the like are used interchangeably and have the same meaning. In particular, each term is consistent with the definition of "comprising" as is common in U.S. patent law, and should be understood to have the open meaning of "at least the following," and not to exclude additional features, limitations, aspects, and the like. Wherever the terms "a" or "an" are used, unless the context is meaningless, it is to be understood that "one or more" is used.
As used herein, "about" means about, approximately, left-right, or near. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Generally, the term "about" is used herein to modify numerical values above and below the stated values with a variance of greater than or less than 20% (higher or lower).
As used herein, "compounds of the invention" encompass, for example, compounds of formula (I), compounds of formula (II), compounds of formula (III), and any subgenus and/or species thereof. In embodiments, serotonin receptor agonists include agonists having at least one phenethylamine group, agonists having at least one tryptamine group, or agonists having at least one ergoline group.
Non-limiting examples of agonists comprising an phenethylamine group include 1- (4-iodo-2, 5-dimethoxyphenyl) propan-2-amine (DOI; also known as 2, 5-dimethoxy-4-iodoamphetamine), 1- (4-bromo-2, 5-dimethoxyphenyl) propan-2-amine (DOB), 1- (4-methyl-2, 5-dimethoxyphenyl) propan-2-amine (DOM), 1- (2, 5-dimethoxy-4-nitrophenyl) propan-2-amine (DON), 2- (4-iodo-2, 5-dimethoxyphenyl) ethan-1-amine (2CI), 4-bromo-2, 5-dimethoxyphenylethylamine (2CB), 1- (3,4, 5-trimethoxyphenyl) propan-2-amine (TMA), 2- (3,4, 5-trimethoxyphenyl) ethylamine (Mescaline), 1- [2, 5-dimethoxy-4- (trifluoromethyl) phenyl ] propan-2-amine (DOTFM), (8R) -1- [ (2S) -2-aminopropyl ] -8, 9-dihydro-7H-pyrano [2,3-g ] indazol-8-ol (Alcon #13), (2R) -1- [4- (trifluoromethyl) -2,3,6, 7-tetrahydrofuro [2,3-f ] [1] benzofuran-8-yl ] propan-2-amine (TFMFly) and 25 CINMOME. Non-limiting examples of agonists comprising a tryptamine group include DMT, [3- (2-dimethylaminoethyl) -1H-indol-4-yl ] dihydrogen phosphate (siloxybin), 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (silocin), and 5 MEO-DMT. In some embodiments, the serotonin receptor agonist is an indazole compound, such as (S) -2- (8, 9-dihydro-7H-pyrano [2,3-g ] indazol-1-yl) -1-methylethylamine (AL-38022A). Non-limiting examples of agonists comprising an ergoline group include (6aR,9R) -N, N-diethyl-7-methyl-4, 6,6a,7,8, 9-hexahydroindolo [4,3-fg ] quinoline-9-carboxamide (LSD), 1, 1-diethyl-3- (7-methyl-4, 6,6a,7,8, 9-hexahydro-indolo [4,3-fg ] quinolin-9-yl) -urea (lisuride) and (6aR,9R) -5-bromo-N, N-diethyl-7-methyl-4, 6,6a,7,8, 9-hexahydroindolo [4,3-fg ] quinoline-9-carboxamide (bromo-LSD; BOL). In some embodiments, the serotonin receptor agonist comprises 1- (4-iodo-2, 5-dimethoxyphenyl) propan-2-amine (DOI; also known as 2, 5-dimethoxy-4-iodoamphetamine).
An "effective amount," "sufficient amount," or "therapeutically effective amount" refers to an amount of a compound sufficient to achieve a beneficial or desired result, including a clinical result. Thus, an effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of a disorder or condition or one or more symptoms thereof, prevent the progression of a condition associated with a disorder or condition, prevent the recurrence, development, or onset of one or more symptoms associated with a disorder or condition, or enhance or otherwise improve the prophylactic or therapeutic effect of another therapy. An effective amount also includes an amount of the compound that avoids or substantially mitigates undesirable side effects.
As understood in the art, "treatment" refers to a method for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, prevention of spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "treatment" can also extend survival compared to expected survival without treatment. A therapeutic effect may include reversing, alleviating, reducing the severity of a disease or one or more symptoms or manifestations of a disease, curing it, inhibiting its development and/or reducing its likelihood of recurrence.
The term "in need thereof refers to a need for symptomatic or asymptomatic relief from a condition (e.g., a condition associated with pathological ocular neovascularization). A subject in need thereof may or may not be undergoing treatment for a condition associated therewith.
The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carrier may also be physiological saline, acacia, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants may be used. Other examples of suitable pharmaceutical carriers are described in remington: pharmaceutical sciences and practices (Remington: the science and Practice of Pharmacy), 21 st edition (edited by Philadelphia university of sciences, Lippincott Williams & Wilkins 2005); and "Handbook of Pharmaceutical Excipients" (Handbook of Pharmaceutical Excipients), 7 th edition (edited by Raymond Rowe et al, Pharmaceutical Press 2012); each of which is hereby incorporated by reference in its entirety.
The terms "animal," "subject," and "patient" refer to all members of the animal kingdom, including, but not limited to, mammals, animals (e.g., cats, dogs, cows, horses, pigs, etc.), and humans.
"ocular tissue" refers to tissue contained within the eye. Ocular tissue includes tissues comprising the following cells: the lens, cornea (e.g., endothelial, stromal, and/or epithelial corneal cells), iris, retina, choroid, sclera, ciliary body, vitreous body, ocular vasculature, schlemm's canal, ocular muscle cells, optic nerve, and other ocular sensory, motor, and autonomic nerves.
"ocular disease" refers to a disease or condition of the eye or eye tissue, including but not limited to macular degeneration (e.g., age-related macular degeneration; AMD), choroidal angiogenesis, diabetic retinopathy, viral retinopathy, glaucoma, corneal allograft rejection, ocular hypertension, corneal neovascularization, keratoconjunctivitis, viral conjunctivitis, keratoconjunctivitis, allergic conjunctivitis, uveitis, iritis, keratitis, infections, and cancer.
"symptoms" refer to biological and/or physiological sequelae including, but not limited to, hypersensitivity, burning, itching and light sensitivity, vision loss, redness, pain, irritation, and photophobia.
"agonist" refers to a compound that can combine with a receptor, such as a serotonin receptor, to generate a cellular response. An agonist may be a ligand that binds directly to a receptor. Alternatively, an agonist may be indirectly combined with a receptor, for example, by: (a) forming a complex with another molecule that directly binds to the receptor, or (b) otherwise causing modification of another compound such that the other compound directly binds to the receptor. Agonists may be referred to as agonists of specific serotonin receptors, e.g. 5-HT2AA serotonin receptor agonist.
Drawings
Figure 1 shows a comparison of acute and chronic disease scores in C57Black mice after treatment with BS, XTPFDOI or 0.5% TFT + XTPFDOI. Treatment: 4 μ l per
Figure 2 shows a comparison of acute and chronic disease scores in BALBc mice after treatment with BSS, 1% TFT and XTPFDOI; treatment: 4 μ l per
Figure 3 shows the ability of DOI to control the long-term chronic effects of HSV-mediated stromal keratitis studied: day 15 post infection. Three eyes in this group with disease that had not yet resolved clinically, had a pathologically relevant clinical score that was still low, as shown by the accompanying pathology.
Figure 4 shows ocular histology of BalBc-tested eyes, which investigated the ability of DOI to control the long-term chronic effects of HSV-mediated stromal keratitis: day 15 post infection. Uninfected normal eyes.
Figure 5 shows ocular histology of BalBc-tested eyes, which investigated the ability of DOI to control the long-term chronic effects of HSV-mediated stromal keratitis: day 15 post infection. HSV/RE infection; treatment drops against BSS; fig. 5A shows
Figure 6 shows ocular histology of BalBc-tested eyes, which investigated the ability of DOI to control the long-term chronic effects of HSV-mediated stromal keratitis: day 15 post infection. HSV/RE infection; control 1% TFT antiviral treatment drops: fig. 6A shows
Figure 7 shows comparative preclinical assessment of therapeutic efficacy of 5-HT receptor agonist (XTPFDOI, red) compared to gold standard ocular antiviral 1% TFT/virotic (blue) or control saline drops (black) in ocular chronic disease model of herpetic stromal keratitis. DOI drops were administered topically 7 days post infection and chronic disease was assessed until day 15. DOI inhibited the development of all clinical scoring parameters, and by
Fig. 8 shows a histopathological analysis of a representative eye from the clinical study shown in fig. 2. Top panel: the cornea of the uninfected mouse eye exhibits a regular and consistent uninterrupted outermost epithelial barrier, as well as an underlying tight corneal stroma layer of uniform thickness. There were no inflammatory cells or red blood cells at all, nor vascularization of the corneal tissue. Second row diagram: HSV infection and long-term inflammatory response induce epithelial destruction, matrix thickening and recognizable vascularization of corneal tissue (yellow arrows) with massive immune infiltration. Third row of diagrams: while treatment with antiviral TFT and complete inhibition of HSV replication, a disease course similar to control Tx predominated at 15 days. Fourth row and enlarged inset: in contrast, the ocular morphology of eyes treated with the 5-HT agonist DOI was normal with no clinical signs of ocular disease.
Figure 9 shows a series of experiments evaluating the effect of systemic and local treatment.
Figure 10 is a table listing various parameters that are clinically scored to quantitatively characterize the response to conditions associated with pathological neovascularization or herpetic keratitis.
Figure 11 shows an exemplary protocol for testing the effect of treatment on herpetic keratitis in a preclinical model. Day 0: corneal scratches and HSV infection. Day 3: initial clinical scores, divided into 6 clinically balanced groups, and treatment was initiated. 4 uninfected animals were sacrificed (8 eyes analyzed), and 4 infected animals were sacrificed (8 eyes analyzed). Animals were treated 4 times daily and a group of 4 animals was sacrificed on
FIG. 12 is a schedule of an exemplary study plan.
FIG. 13 is a series of photographs showing VEGF-mediated neovascularization from the aortic annulus in the presence of R-DOI, TCB2 and 4F4 PP.
FIG. 14 is a series of photographs showing VEGF-mediated human vascular endothelial tubule formation in the presence of R-DOI, TCB2, and 4F4 PP.
FIGS. 15A and 15B are graphs showing that R-DOI inhibits reactivation of HSV-1 from latent neurons in the Trigeminal Ganglion (TG). Reactivation of latent HSV-1 was induced by TG explants from mice previously infected with HSV-1. The ganglia were treated with either control (mock treatment; blue) or medium containing 500nM (R) -DOI (DOI 500 nM; red). The presence of infectious HSV-1 was assessed for 10 consecutive days.
Figure 16 is a series of fluorescence micrographs showing the effect of a 5HT2A receptor agonist on vascular tubule growth of tissue-like spheroids.
Fig. 17 is a series of graphs showing the effect of R-DOI doses on the cytotoxicity of healthy retinal pigment epithelial cells (APRE) and cancerous retinoblastoma cells (Y-79) at 24 hours (top), 48 hours (middle), and 72 hours (bottom).
Detailed Description
A detailed description of one or more preferred embodiments is provided herein. However, the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed manner.
The present invention provides means for treating or preventing ocular conditions (e.g., conditions associated with any region of the eye such as the cornea, retina, iris, uvea, conjunctiva, and macula). In particular, the methods and compositions of the present invention can treat conditions associated with pathological ocular neovascularization (e.g., conjunctivitis), reduce scarring in the eye, treat dry eye, treat macular degeneration (e.g., age-related macular degeneration), and/or treat keratitis (e.g., herpetic keratitis). The present invention is based, at least in part, on the discovery that serotonin receptors (e.g., 5-HT)2AReceptor) are useful (a) for treating a condition associated with pathological ocular neovascularization; (b) reducing scarring in the eye; (c) treating dry eye; (d) treating macular degeneration; and/or (e) treating keratitis (e.g., herpetic keratitis), for example, by inhibiting pathological neovascularization (e.g., angiogenesis and or lymphangiogenesis).
Serotonin and 5-HT2AReceptors
Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter and hormone whose action is mediated by interactions among seven distinct families of receptor proteins, which comprise 14 distinct subtypes, consisting of 13G protein-coupled receptors and a ligand-gated ion channel. Embodiments as described herein may comprise any of seven different receptor protein families.
Serotonin is known primarily for its function as a neurotransmitter in the CNS and is involved in many processes, including cognition and memory. Peripherally, however, serotonin also mediates processes such as vasoconstriction (e.g., through the serotonin receptor 5-HT)2A)。
In some embodiments of the invention described herein, the invention relates to 5-HT in the eye2AActivation of (2). In other embodiments, the serotonin receptor comprises other receptor proteins of the serotonin receptor family, such as 5-HT2BAnd 5-HT2CReceptors, or by serotonin 5-HT2AA receptor-activated downstream effector protein that delivers a therapeutic effect to a cell or tissue.
Ocular pathology
The term "ocular condition" may refer to a disease or condition of one or more tissues, portions or regions of the eye that impair the normal function of the eye. The anterior segment of the eye is the anterior third of the eyeball and includes structures located between the anterior surface of the cornea and the vitreous. The posterior segment of the eye refers to the posterior two-thirds of the eyeball (behind the lens) and includes the vitreous, retina, optic disc, choroid, and planar ciliary body.
The "eye" is the sensory organ of vision and includes the eyeball or sphere, which receives light and transmits visual information to the orbital sensory organ of the central nervous system. Broadly speaking, the eye includes the eyeball and the tissues and fluids that make up the eyeball, the periocular muscles (e.g., the oblique and rectus muscles), and the portion of the optic nerve within or near the eyeball.
Embryonic development, tissue remodeling and wound healing require physiological angiogenesis, neovascularization and a normal immune system. However, in certain tissues and diseases, these tightly controlled process disturbances can lead to pathological conditions, such as ocular conditions.
Pathologic angiogenesis, vascular dysfunction and hypersensitivity are key determinants of many ocular diseases and pathological outcomes. For example, pathological angiogenesis is a key component of blinding basal keratitis, proliferative retinopathy, and macular degeneration (e.g., age-related macular degeneration). Embodiments as described herein may treat conditions or symptoms of disease processes associated with ocular angiogenesis, for example in macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis, conjunctivitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, leber's disease, retinal detachment, retinal pigment epithelium detachment, rubeosis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, keratitis, or a combination thereof.
In ocular diseases, pathological angiogenesis is associated with the worsening of pathological processes within innervated tissues and reduces the prognosis for disease regression. The development of in vitro and in vivo angiogenesis-related disease model systems has expanded to other pathologic angiogenesis-related diseases and provides opportunities for the evaluation of additional therapeutic agents, including serotonin receptor agonists, such as the serotonin (5-HT)
Embodiments as described herein may be used to treat or ameliorate symptoms associated with ocular diseases. For example, dysregulation or hypersensitivity of the angiogenic process can lead to vision threatening ocular diseases or pathologies. In embodiments, the ocular disease or hypersensitivity associated with blood vessels may be associated with, caused by, or exacerbated by a vascular defect including, but not limited to, angiogenesis, lymphangiogenesis, neovascularization, vascular leakage, edema, increased oxygen, ischemia, vasoconstriction, vasodilation, bleeding, vascular occlusion, increased hypersensitivity and/or ocular hypertension. Non-limiting examples of ocular diseases, such as ocular diseases associated with angiogenesis, include macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis (e.g., adenoviral keratoconjunctivitis), conjunctivitis (e.g., adenoviral conjunctivitis), diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathies, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, leber's disease, retinal detachment, retinal pigment epithelium detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, keratitis.
In some embodiments, the present invention provides compositions, methods, and kits for treating dry eye, such as keratoconjunctivitis sicca.
The compositions, methods, and kits of the invention are also useful for reducing or ameliorating or preventing scarring of the eye (e.g., corneal scarring, or scarring caused by macular degeneration (e.g., age-related macular degeneration, such as wet age-related macular degeneration)).
Keratitis
The present invention provides compositions, methods and kits useful for reducing or ameliorating or preventing keratitis, non-limiting examples of which are described herein.
In some embodiments, keratitis may be associated with a fully resolvable infection. In other embodiments, the infection may never resolve, such as in the case of a herpes virus infection. For example, replication at the site of the initial infection may resolve, but the infection persists within latency with sporadic episodes of reinfection. It is important to control the recurrent nature of lifelong infections that reactivate from neurons, causing recurrent ocular diseases, as seen in chronic herpetic eye disease. Embodiments as described herein may control reactivation-mediated recurrent disease.
Embodiments as described herein can prevent reactivation of latent viruses, thereby preventing viral shedding, transmission, sporadic reinfection of tissues, and subsequent development of recurrent acute and chronic disease manifestations.
Viral retinopathy
"retinopathy" may refer to persistent or acute damage to the retina of an eye. In some cases, damage to the retina of an eye can result in loss of eye function. In some cases, hypersensitivity and vascular remodeling may occur over a long period of time, and subjects with lesions are not noticed.
Retinopathy may be caused by diabetes, arterial hypertension, retinopathy of prematurity, radiation retinopathy, solar retinopathy, sickle cell disease, retinal vascular diseases such as retinal vein or artery occlusions, trauma or infections such as viral infections (e.g. herpetic keratitis). In embodiments, the retinopathy is viral retinopathy and may be associated with Cytomegalovirus (CMV) or Varicella Zoster Virus (VZV).
Retinopathy tends to be proliferative and can result from neovascularization.
Viral retinopathies include CMV-related retinopathies, such as CMV retinitis, and VZV-related retinopathies.
Cytomegalovirus is a ubiquitous DNA virus that infects most of the adult population. In immunocompetent hosts, the infection may be asymptomatic or limited to only mononucleosis-like syndromes. Like many other herpesviruses, CMV remains latent in the host, where it may reactivate if the host immunity is compromised.
In immunocompromised individuals, primary infection or reactivation of latent viruses may lead to opportunistic infections of the multi-organ system. In the eye, CMV is most commonly manifested as viral necrotizing retinitis. CMV retinitis inevitably progresses to vision loss and blindness if left untreated.
Diabetic retinopathy
"diabetic retinopathy" may refer to retinal damage or retinal disorders caused by diabetes. For example, the damage may be to blood vessels in the retina of the eye, which is critical for bringing oxygen and nutrients into the retina.
Diabetic retinopathy is the third leading cause of blindness in adults (accounting for nearly 7% of blindness in the united states), and is associated with a wide range of angiogenic events. Non-proliferative retinopathy is accompanied by a selective loss of pericytes in the retina, and its loss leads to associated telangiectasia and the resulting increase in blood flow. In dilated capillaries, endothelial cells proliferate and form a bulge, which becomes a microaneurysm, and adjacent capillaries become occluded, thereby rendering the retinal area surrounding these microaneurysms non-perfusable. Eventually, shunted blood vessels appeared between adjacent regions of microaneurysms, and clinical manifestations of early stage diabetic retinopathy with microaneurysms and non-perfused retinal regions were seen. The microaneurysms leak and capillaries may bleed, leading to oozing and bleeding. Once the initial stage of background diabetic retinopathy is established, the condition progresses over the years to proliferative diabetic retinopathy and blindness in about 5% of cases. Proliferative diabetic retinopathy occurs when certain areas of the retina continue to lose their capillaries and become unperfused, resulting in new blood vessels appearing on the optic disc and elsewhere in the retina. These new blood vessels grow into the vitreous and bleed easily, resulting in preretinal hemorrhage. In advanced proliferative diabetic retinopathy, a large amount of vitreous hemorrhage may fill a large portion of the vitreous cavity. In addition, the new blood vessels are accompanied by fibrous tissue proliferation, which may lead to tractional retinal detachment.
Diabetic retinopathy is primarily associated with the duration of diabetes. Thus, the prevalence of diabetic retinopathy will increase as the population ages and the life of the diabetic patient increases. Laser therapy is currently used for non-proliferative and proliferative diabetic retinopathy. Focused laser treatment of microaneurysm leaks around the macular region can reduce vision loss by 50% in patients with clinically significant macular edema. In proliferative diabetic retinopathy, panretinal photocoagulation can result in thousands of tiny burns spreading across the retina (spreading the macular area); this treatment can reduce the rate of blindness by 60%. Early treatment of macular edema and proliferative diabetic retinopathy can prevent blindness in 5 years in 95% of patients, while late treatment can only prevent blindness in 50%. Therefore, early diagnosis and treatment are of great importance.
Age-related macular degeneration
"macular degeneration" may refer to the degeneration of the macula, a small yellow region of the back of the eye and located in the middle of the retina. The loss of vision resulting in macular degeneration is central vision due to the location of the macula (the center of the retina). In many cases, people with age-related macular degeneration have normal peripheral vision but produce blind spots in the middle of their lines of sight. Thus, macular degeneration affects a person's ability to read, drive, and recognize the face.
Age-related macular degeneration (AMD) is a disease affecting about one-tenth of the american population over the age of 65, characterized by a series of pathological changes in the macula in the central region of the retina, accompanied by a reduction in vision, particularly central vision. AMD involves a monolayer of cells called the retinal pigment epithelium that underlies the sensory retina. These cells nourish and support the portion of the retina that comes into contact with them, i.e., the photoreceptor cells that contain the visual pigment. The retinal pigment epithelium is located on the Bruch's membrane, a basement membrane complex that thickens and becomes hardened in AMD. New blood vessels may penetrate Bruch's membrane from the underlying choroid, which contains an abundant vascular bed. These blood vessels, in turn, may leak fluid or bleed under the retinal pigment epithelium and between the retinal pigment epithelium and the sensory retina. Subsequent fibrous scarring destroys the nutrition of the photoreceptor cells and causes them to die, resulting in central vision loss. This type of age-related macular degeneration is known as the "wet" type due to vascular leakage and subretinal edema or hemorrhage. The wet form accounts for only 10% of age-related macular degeneration cases, but leads to legal blindness in 90% of the elderly due to macular degeneration. The "dry" type of age-related macular degeneration involves the breakdown of the retinal pigment epithelium and the loss of upper photoreceptor cells. Dry types reduce vision, but generally only to levels of 20/50 to 20/100.
AMD is accompanied by distortion of central vision, with objects appearing larger or smaller or straight lines appearing distorted, curved or without a central segment. In wet AMD, small retinal detachments may be noticed in the macular region, but fluorescein angiography is required to definitively diagnose subretinal neovascular membranes. In the dry form, drusen may interfere with the pigmentation pattern of the macular area. Drusen are neoplasms of the basement membrane of the retinal pigment epithelium that protrude into the cells, causing them to bulge forward; their role as risk factors for age-related macular degeneration is unclear. There is currently no treatment for dry forms of age-related macular degeneration. Laser treatment is used for the wet form of age-related macular degeneration, initially eliminating neovascular membranes and preventing further vision loss in about 50% of patients at 18 months. However, by 60 months, only 20% of people still have substantial benefit.
Pathogenesis
Pathogenesis may refer to the mode of origin, biological mechanism, or development of a disease or condition. For example, pathogenesis may refer to hypersensitivity of, for example, blood or lymphatic vessels, angiogenesis; (ii) vascularization; occlusion of blood vessels; vascular leakage; vascular permeability; angiogenesis; lymphatic vessel generation; neovascularization; vasodilatation; vasoconstriction, such as constriction of lymphatic or blood vessels; occlusion of blood vessels; edema; a corneal epithelial defect; an elevated intraocular pressure; oxygen saturation is increased; ischemia; bleeding; necrotic inflammation; epithelial hyperproliferation; thickening of the epithelium; fiberizing; or a combination thereof.
The present invention provides methods and compositions for treating conditions associated with vasculopathy in the eye, including conditions associated with aberrant blood and lymphatic neovascularization (e.g., angiogenesis and lymphangiogenesis). Ocular conditions associated with pathological neovascularization include macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis (e.g., adenoviral keratoconjunctivitis), conjunctivitis (e.g., adenoviral conjunctivitis), diabetic retinitis, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, leber's disease, retinal detachment, retinal pigment epithelium detachment, rubeosis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, or a combination thereof.
Embodiments of the invention described herein may reduce, ameliorate or prevent a condition associated with the pathogenesis of an ocular disease. In some embodiments, the pathogenesis is chronic and persists after the resolution of the acute disease itself. Non-limiting examples of ocular pathogenesis include hypersensitivity, angiogenesis, neovascularization, vascular leakage, vascular permeability, or a combination thereof.
Pathological angiogenesis and vascular dysfunction are major factors in the process leading to all infectious diseases and many non-infectious diseases in ocular tissues. Embodiments as described herein may be used to reduce, ameliorate or inhibit angiogenesis, e.g., neovascularization, in ocular tissue of a subject.
Embodiments as described herein may reduce, ameliorate or prevent symptoms associated with angiogenesis in ocular tissue of a subject. Non-limiting examples of such symptoms include conjunctivitis, keratoconjunctivitis, ocular hypertension, glaucoma, macular degeneration, or edema.
In embodiments, the vascularized tissue may comprise tissue of the eye.
In embodiments, neovascularization may refer to any type of angiogenesis or neovascularization of a tissue. For example, angiogenesis may refer to angiogenesis of blood vessels, angiogenesis of lymphatic vessels, or a combination thereof.
Lymphangiogenesis plays a key role in the regulation of hypersensitivity reactions, tissue edema, intraocular pressure and hypersensitivity disease processes.
Non-limiting markers of angiogenesis and/or lymphangiogenesis include LYVE, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR-3, PROX1, CCL21, TNF, IL-6,
The embodiments as described herein may be used to reduce, prevent or ameliorate ocular hypersensitivity. Hypersensitivity refers to the local protective response of tissue to irritation, injury, infection, or disease, and is characterized by pain, redness, swelling, and potential loss of function.
Embodiments as described herein may be used to reduce, prevent, or ameliorate vascular leakage. Vascular leakage refers to the permeability of blood vessels and capillaries, which can lead to tissue hypersensitivity, the formation of edema, or the leakage of blood cells into the tissue. Vascular leakage may also be referred to as vascular permeability. Vascular leakage may be unidirectional flow of cells or fluid, or bidirectional flow of cells or fluid.
In embodiments, clinical diseases such as stromal disease, corneal haze, and ocular hypersensitivity are scored according to a graded scale. For example, the scale may be a three-point scale (0 to 3) and contain the following parameters in the literature: hill et al (Antiviral research, 2013, 10 months; 100(1):14-9) and Clement et al (ophthalmologic research and optomechanics, Invest Ophthalmol Vis Sci, 2011, 1 month, 21; 52(1):339-44), both of which are incorporated herein in their entirety.
In embodiments, the clinical score of a slit-lamp biomicroscope can be visualized using a fluorophore-enhanced slit-lamp biomicroscope. In embodiments, this may be scored according to a graded scale, such as a 4-point scale (0 to 4), as detailed in Hill et al (Antiviral research 2013 for 10 months; 100(1):14-9) and Clement et al (ophthalmologic research and optomechanics Sci) 2011 for 1 months, 21; 52(1):339-44), both of which are incorporated herein in their entirety.
Agonists
An "agonist" may refer to a compound that can combine and/or interact with a receptor, such as a serotonin receptor, to produce a cellular response. An agonist may be a ligand that binds directly to a receptor. Alternatively, an agonist may be indirectly combined with a receptor, for example, by: (a) forming a complex with another molecule that directly binds to the receptor, or (b) otherwise resulting in modification of another compound such that the compound directly binds to the receptor. Agonists may be referred to as agonists of specific serotonin receptors, e.g. 5-HT2ASerotonin receptor agonists (e.g., DOI or R-DOI).
The term "5-HT2AAgonist "may refer to any compound or ligand that increases the activity of the 5-hydroxytryptamine 2A receptor. Non-limiting examples of such agonists include, but are not limited to: DOI (±) -1- (2, 5-dimethoxyphenyl) -2-aminopropane hydrochloride; (R) -DOI ((R) -1- (2, 5-dimethoxy-4-iodophenyl) -2-aminopropane) (greater than 95% R enantiomer); LA-SS-Az (2'S,4' S) - (+) -9, 10-didehydro-6-methylergoline-8 β - (trans-2, 4-dimethylazetidine); 2C-BCB (4-bromo-3, 6-dimethoxybenzocyclobuten-1-yl) methylamine; andlysergic acid diethylamide (LSD).
Non-limiting examples of serotonin receptor agonists can be found in Nichols et al (WiREs Membr Transp Signal 2012), which is incorporated herein in its entirety.
In embodiments, the serotonin receptor agonist may be phenethylamine, tryptamine, ergoline, or a combination thereof. Non-limiting examples of phenethylamines include 1- (4-iodo-2, 5-dimethoxyphenyl) propan-2-amine (DOI), 1- (4-bromo-2, 5-dimethoxyphenyl) propan-2-amine (DOB), 1- (4-methyl-2, 5-dimethoxyphenyl) propan-2-amine (DOM), 1- (2, 5-dimethoxy-4-nitrophenyl) propan-2-amine (DON), 2- (4-iodo-2, 5-dimethoxyphenyl) ethan-1-amine (2CI), 4-bromo-2, 5-dimethoxyphenylethylamine (2CB), 1- (3,4, 5-trimethoxyphenyl) propan-2-amine (TMA), 2- (3,4, 5-trimethoxyphenyl) ethylamine (mescaline), 1- [2, 5-dimethoxy-4- (trifluoromethyl) phenyl ] propan-2-amine (DOTFM), (2R) -1- [4- (trifluoromethyl) -2,3,6, 7-tetrahydrofuro [2,3-f ] [1] benzofuran-8-yl ] propan-2-amine (TFMFly), and 25 CINMoMe.
Non-limiting examples of tryptamines include DMT, [3- (2-dimethylaminoethyl) -1H-indol-4-yl ] dihydrogen phosphate (siloxibin), 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (siloxin), and 5 MEO-DMT.
In embodiments, the serotonin receptor agonist is an indazole compound, such as (S) -2- (8, 9-dihydro-7H-pyrano [2,3-g ] indazol-1-yl) -1-methylethylamine (AL-38022A).
Non-limiting examples of ergoline include (6aR,9R) -N, N-diethyl-7-methyl-4, 6,6a,7,8, 9-hexahydroindolo [4,3-fg ] quinoline-9-carboxamide (LSD), 1, 1-diethyl-3- (7-methyl-4, 6,6a,7,8, 9-hexahydro-indolo [4,3-fg ] quinolin-9-yl) -urea (lisuride) and (6aR,9R) -5-bromo-N, N-diethyl-7-methyl-4, 6,6a,7,8, 9-hexahydroindolo [4,3-fg ] quinoline-9-carboxamide (bromo-LSD; BOL).
In embodiments, the composition comprises a compound having the following formula (II):
wherein non-limiting exemplary values for the R groups in the above-described substituted chemical structures are shown in table 1 below:
table 1 exemplary R groups for compounds of formula (II).
In some embodiments, R of formula (II)2Can be OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)5)2or-O- (C)2-C6Alkyl) -N (R)x)3 +Halogen element-(ii) a R of the formula (II)3Can be OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)x)2or-O- (C)2-C6Alkyl) -N (R)x)3 +Halogen element-(ii) a R of the formula (II)4May be halogen, C1-C2Haloalkyl, H, C1-C6Alkyl radical, C1-C6Alkyl sulfides, OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)x)2or-O- (C)2-C6Alkyl) -N (R)x)3 +Halogen element-(ii) a R of the formula (II)5May be halogen, C1-C2Haloalkyl, H, C1-C6Alkyl radical, C1-C6Alkyl sulfides, OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)x)2or-O- (C)2-C6Alkyl) -N (R)x)3 +Halogen element-(ii) a R of the formula (II)6May be halogen, C1-C2Haloalkyl, H, C1-C6Alkyl, -S- (C)1-C6Alkyl), OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)5)2or-O- (C)2-C6Alkyl) -N (R)5)3 +Halogen element-；RαIs H, halogen or C1-C6An alkyl group; r of the formula (II)βCan be OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)5)2or-O- (C)2-C6Alkyl) -N (R)x)3 +Halogen element-(ii) a R of the formula (II)NMay be halogen, C1-C2Haloalkyl, H, C1-C6Alkyl radical, C1-C6Alkyl sulfides, OH, O- (C)1-C6Alkyl), -O- (C)2-C6Alkyl) -N (R)x)2or-O- (C)2-C6Alkyl) -N (R)x)3 +Halogen element-(ii) a And R isxIndependently is H or C1-C4An alkyl group.
In embodiments, the composition comprises a compound having the following formula (I):
wherein non-limiting exemplary values for the R groups in the above-described substituted chemical structures are shown in Table 2 below:
table 2 exemplary R groups for compounds of formula (I).
Name (R)
R1
R2
R3
LSD
H
CH2CH3
CH2CH3
Ergot amides
H
H
H
R-2-butyl
H
H
CH(CH3)CH2CH3
R-2-pentylamine
H
H
CH(CH3)CH2CH2CH3
Analogs of ergotamine
H
C2H5
H
Analogs of ergotamine
H
H
C2H5
LSD
H
C2H5
C2H5
Analogs of ergotamine
H
C2H5
CH2CH2CH3
Analogs of ergotamine
H
C2H5
CH(CH3)2
Analogs of ergotamine
H
CH2CH2CH3
H
Analogs of ergotamine
H
H
CH2CH2CH3
Analogs of ergotamine
H
CH2CH2CH3
CH2CH2CH3
Analogs of ergotamine
H
CH2CH2CH3
C2H5
Analogs of ergotamine
H
CH2CH2CH3
CH(CH3)2
Analogs of ergotamine
H
CH(CH3)2
H
Analogs of ergotamine
H
H
CH(CH3)2
Analogs of ergotamine
H
CH(CH3)2
CH(CH3)2
Analogs of ergotamine
H
CH(CH3)2
C2H5
Analogs of ergotamine
H
CH(CH3)2
CH2CH2CH3
In some embodiments, R of formula (I)1May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; r of the formula (I)2May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; and R of formula (I)3May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group.
In embodiments, the composition comprises a compound having the following formula (III):
wherein non-limiting exemplary values for the R groups in the above-described substituted chemical structures are shown in Table 3 below:
table 3 exemplary R groups for compounds of formula (III).
Name (R)
RN 1
RN 2
Rα
R4
R5
R6
R7
6-fluoro-siloxan
C
C
H
OH
H
F
H
7-fluoro-siloxan
C
C
H
OH
H
H
F
4-fluoro-5-methoxy-DMT
C
C
H
F
OCH3
H
H
6-fluoro-5-methoxy-DMT
C
C
H
H
OCH3
F
H
D-methyl-tryptamine
H
H
CH3
H
H
H
H
Serotonin
H
H
H
H
OH
H
H
In some embodiments, R of formula (III)N1May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; r of the formula (III)N2May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; r of the formula (I)αMay be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; r of the formula (I)4May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; r of the formula (I)5May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group; r of the formula (I)6May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4Alkyl halidesA group; and R of formula (I)7May be H, C1-C6Alkyl, OH, O- (C)1-C6Alkyl), halogen or C1-C4A haloalkyl group.
In some embodiments, a compound of the invention (e.g., a compound of formula (I), (II), or (III)) binds to a serotonin receptor in a subject. Non-limiting examples of serotonin receptors include HTR2A (5-hydroxytryptamine receptor 2A isoform 1(GenBank accession No.: NM-000621.4 for nucleotide sequence and NP-000612.1 for amino acid sequence); 5-hydroxytryptamine receptor 2A isoform 2(GenBank accession No.: NM-001165947.2 for nucleotide sequence and NP-001159419.1 for amino acid sequence)); HTR2B (5-hydroxytryptamine receptor 2B isoform 1(GenBank accession No.: NM-000867.4 for nucleotide sequence and NP-000858.3 for amino acid sequence); 5-hydroxytryptamine receptor 2B isoform 2(GenBank accession No.: NM-001320758.1 for nucleotide sequence and NP-001307687.1 for amino acid sequence)); and HTR2C (5-hydroxytryptamine receptor 2C isoform a precursor (GenBank accession No.: NM-000868.3 for nucleotide sequence and NP-000859.1 for amino acid sequence)), 5-hydroxytryptamine receptor 2C isoform a precursor (GenBank accession No.: NM-001256760.2 for nucleotide sequence and GenBank accession No.: NP-001243689.1 for amino acid sequence), and 5-hydroxytryptamine receptor 2C isoform b precursor (GenBank accession No.: NM-001256761.2 for nucleotide sequence and GenBank accession No.: NP-001243690.1 for amino acid sequence)).
In some embodiments, the serotonin receptor comprises SEQ ID NO:1 (amino acids 1-481 of GenBank accession NP-000858.3):
MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALLILMVIIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAMWPLPLVLCPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVWLISIGIAIPVPIKGIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLTIHALQKKAYLVKNKPPQRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDETLMRRTSTIGKKSVQTISNEQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQMLLEIFVWIGYVSSGVNPLVYTLFNKTFRDAFGRYITCNYRATKSVKTLRKRSSKIYFRNPMAENSKFFKKHGIRNGINPAMYQSPMRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSYV
in some embodiments, the serotonin receptor comprises SEQ ID NO:2 (amino acids 1-471 of GenBank accession NP-000612.1):
MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGFLVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNSRTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCSMVALGKQHSEEASKDNSDGVNEKVSCV
in some embodiments, the serotonin receptor comprises SEQ ID NO 3 (amino acids 1-458 of GenBank accession NP-000859.1):
MVNLRNAVHSFLVHLIGLLVWQCDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSIVIIIIMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVWPLPRYLCPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHSRFNSRTKAIMKIAIVWAISIGVSVPIPVIGLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYVLRRQALMLLHGHTEEPPGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTMQAINNERKASKVLGIVFFVFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVCSGINPLVYTLFNKIYRRAFSNYLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTNEPVIEKASDNEPGIEMQVENLELPVNPSSVVSERISSV
in some embodiments, a compound of the invention may bind to an amino acid residue of a serotonin receptor comprising position 113, 114, 118, 131, 132, 133, 135, 136, 139, 140, 190, 203, 207, 209, 213, 214, 217, 218, 221, 222, 225, 242, 293, 308, 336, 337, 339, 340, 341, 343, 344, 362, 363, 366, 367, or a combination thereof of
In some embodiments, a compound of the invention may bind to amino acid residues T114, W131, L132, D135, V136, S139, T140, V190, L209, F214, F217, M218, G221, S222, a225, H242, W337, F340, F341, N344, L362, E363, V366 of SEQ ID No. 1, or a combination thereof.
In some embodiments, a compound of the invention may bind to amino acid residue M114, S131, L133, I135, L136, Y139, R140, T190, S203, S207, P209, F213, D217, D218, V221, F222, G225, S242, W336, F339, F340, N343, L362, N363, V366 of SEQ ID No. 2, or a combination thereof.
Embodiments as described herein may be administered to a subject as a prodrug. A prodrug is a drug or compound that is metabolized to a pharmaceutically active drug after administration. An inactive prodrug is a pharmacologically inactive drug or compound that is metabolized in vivo to an active form.
Specific 5-HT for use in the invention2AAgonists can be administered to a patient by any suitable means, including ophthalmic (e.g., topical ophthalmic (e.g., via eye drops or gels) or intraocular), oral, intravenous, parenteral, subcutaneous, intrapulmonary, topical, intravitreal, transdermal, transmucosal, rectal, and intranasal administration. Ocular administration includes eye drop administration, topical gel administration, conjunctival intracapsular instillation, intravitreal administration, subconjunctival administration or sub-tenon's capsule administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, or intraperitoneal administration. The compounds may also be administered transdermally, for example, in the form of a slow-release subcutaneous implant or as a transdermal patch. They may also be administered by inhalation. Although direct oral administration may cause some loss of anti-inflammatory activity, the agonist may be packaged by using an enteric coating, capsule, or other method known in the art to protect the active ingredient from digestion.
Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents such as water for injection, physiological saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting tonicity, such as sodium chloride or dextrose. The pH can be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide).
A compound of formula (I), (II), or (III), or a composition comprising a compound of formula (I), (II), or (III), may be administered to a subject once (e.g., as a single injection or deposition). Alternatively, one or two administrations per time can be administered to a subject in need thereof for about 2 days to about 28 days, or about 7 days to about 10 days, or about 7 days to about 15 days. The subject may also be administered once or twice daily for 1, 2,3, 4,5, 6,7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 times per year, or a combination thereof.
The dosage may vary according to known factors, such as the pharmacodynamic properties of the active ingredient and its mode and route of administration; the number of applications of the active ingredient; age, sex, health and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment, the frequency of treatment and the desired effect; and rate of excretion.
The therapeutically effective dose may depend on a number of factors known to those of ordinary skill in the art. The dosage may vary, for example, depending on the identity, size and condition of the subject or sample being treated, further depending on the route of administration of the composition (if applicable) and the effect desired by the practitioner. These amounts can be readily determined by one skilled in the art.
In some embodiments, a therapeutically effective amount of a compound of the invention (e.g., a serotonin receptor agonist and/or an additional therapeutic agent) administered to a subject is at least about 0.0001mg/kg body weight, 0.0005mg/kg body weight, 0.001mg/kg body weight, 0.005mg/kg body weight, 0.01mg/kg body weight, 0.05mg/kg body weight, 0.1mg/kg body weight, at least about 0.25mg/kg body weight, at least about 0.5mg/kg body weight, at least about 0.75mg/kg body weight, at least about 1mg/kg body weight, at least about 2mg/kg body weight, at least about 3mg/kg body weight, at least about 4mg/kg body weight, at least about 5mg/kg body weight, at least about 6mg/kg body weight, at least about 7mg/kg body weight, at least about 8mg/kg body weight, at least about 9mg/kg body weight, a, At least about 10mg/kg body weight, at least about 15mg/kg body weight, at least about 20mg/kg body weight, at least about 25mg/kg body weight, at least about 30mg/kg body weight, at least about 40mg/kg body weight, at least about 50mg/kg body weight, at least about 75mg/kg body weight, at least about 100mg/kg body weight, at least about 200mg/kg body weight, at least about 250mg/kg body weight, at least about 300mg/kg body weight, at least about 350mg/kg body weight, at least about 400mg/kg body weight, at least about 450mg/kg body weight, at least about 500mg/kg body weight, at least about 550mg/kg body weight, at least about 600mg/kg body weight, at least about 650mg/kg body weight, at least about 700mg/kg body weight, at least about 750mg/kg body weight, at least about 800mg/kg body weight, At least about 900mg/kg body weight or at least about 1000mg/kg body weight.
In some embodiments, a therapeutically effective amount of a compound of the invention (e.g., a serotonin receptor agonist and/or an additional therapeutic agent) administered to a subject is 0.0001 to 0.0005mg/kg body weight, 0.0005 to 0.001mg/kg body weight, 0.001 to 0.005mg/kg body weight, 0.01 to 0.05mg/kg body weight, 0.05 to 0.1mg/kg body weight, 0.1 to 0.5mg/kg body weight, 0.5 to 1.0mg/kg body weight, 1.0 to 2.0mg/kg body weight, 2.0 to 3.0mg/kg body weight, 3.0 to 4.0mg/kg body weight, 4.0 to 5.0mg/kg body weight, 5.0 to 7.5mg/kg body weight, 7.5mg/kg body weight to 10mg/kg body weight, 10mg/kg body weight to 25mg/kg body weight, 25mg/kg body weight to 50mg/kg body weight, 50mg/kg body weight to 100mg/kg body weight, 100mg/kg body weight to 250mg/kg body weight, 250mg/kg body weight to 500mg/kg body weight, or 500mg/kg body weight to 100mg/kg body weight.
In some embodiments, the serotonin receptor agonist is administered to the subject at a low dose (e.g., a sub-perceived dose, e.g., such that the behavior of the subject does not change). For example, the sub-perceived dose can be less than about 100 μ g/kg, less than about 75 μ g/kg, less than about 50 μ g/kg, less than about 25 μ g/kg, less than about 10 μ g/kg, less than about 7.5 μ g/kg, less than about 5.0 μ g/kg, less than about 2.0 μ g/kg, less than about 1.5 μ g/kg, less than about 1.0 μ g/kg, less than about 0.5 μ g/kg, less than about 0.1 μ g/kg, or less.
Any of the therapeutic applications described herein can be administered to any subject in need of such treatment, including, for example, a mammal, such as a human, mouse, rat, dog, cat, cow, horse, rabbit, monkey, pig, sheep, or goat. In some embodiments, the subject is a mouse, rat, pig, or human. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a pig. In some embodiments, the subject is a human.
In some embodiments, the therapeutic applications described herein can be administered in a veterinary setting. For example, the subject may be a cat or a dog.
The compounds of formula (I), (II) or (III) may be incorporated into pharmaceutical compositions suitable for administration. Such compositions may comprise a compound of formula (I), (II) or (III) and a pharmaceutically acceptable carrier. Thus, in some embodiments, the compounds of the present invention are present in a pharmaceutical composition.
In embodiments, the agonist is DOI. In other embodiments, the agonist is not DOI.
Composition comprising a metal oxide and a metal oxide
The term "composition" may refer to a single compound, or may refer to a combination of at least two compounds. For example, the composition may comprise a serotonin receptor agonist and a pharmaceutically acceptable carrier. In other embodiments, the composition may comprise more than two compounds. For example, the composition may comprise a serotonin receptor agonist (e.g., 5-HT)2AReceptor agonists, such as DOI), anti-pathogenic agents (e.g., antiviral agents, such as TFT or ganciclovir), and pharmaceutically acceptable carriers.
Pharmaceutically acceptable carrier formulations include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, carboxymethylcellulose, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including physiological saline and buffered media. Parenteral vehicles include sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, lactated ringer's solution or fixed oils. The active therapeutic ingredient may be mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients include water, physiological saline, dextrose, glycerol and ethanol, or combinations thereof. Intravenous vehicles include fluid and nutritional supplements, electrolyte supplements such as those based on ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
Embodiments such as those suitable for ophthalmic use incorporate additives to increase dispersion of the drug in the eye while also increasing retention in the eye. Non-limiting examples of such additives include carboxymethyl cellulose or polyethylene glycol.
The ophthalmic preparation of the present invention includes topical preparations such as eye drops, gels and ointments. The ophthalmic solution may contain one or more viscosity modifiers and have a viscosity of 1.0 to 100,000cP (e.g., 2.0 to 90,000cP or 2.5 to 75,000cP) which is acceptable because compositions in this viscosity range are comfortable to the eye and do not blur vision. Viscosity modifiers are useful in ophthalmic compositions and are substances that cause thickening (viscosity increase) of ophthalmic formulations. Viscous solutions are largely accepted by patients, primarily because of ease of administration. Viscosity modifiers include xanthan gum, edetate, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene glycol, propylene glycol alginate, chitosan, and tragacanth. Hydrogels are commonly used as viscosity-increasing excipients, especially in artificial tears and refer to colloids with high gelling power. Compatible viscosity modifiers may be used in all formulations mentioned herein if desired. The concentration of the selected viscosity modifier ranges from about 0.1% to about 10% by weight, and preferably 1% to 5%, when desired. Sorbitol can be used as a combined tonicity adjusting agent and viscosity adjusting excipient at a concentration ranging from about 0.1% to about 10%, preferably 2% to 5%.
The form may vary depending on the route of administration. For example, compositions for injection may be provided in the form of ampoules, each containing a unit dose, or in containers containing a plurality of doses. In some embodiments, parenteral formulations can be filled into ampoules, disposable syringes or multiple dose vials made of glass or plastic.
In some embodiments, suitable for injectionPharmaceutical compositions for use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EMTM(BASF, Parsippany, n.j.) or Phosphate Buffered Saline (PBS). In all cases, the compositions must be sterile and should flow to the extent that easy injection is possible. It must remain stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, pharmaceutically acceptable polyols such as glycerol, propylene glycol, liquid polyethylene glycols and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid and thimerosal. In many cases, it may be useful to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
In some embodiments, sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, examples of useful preparative methods are vacuum drying and freeze-drying which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
In some embodiments, the oral compositions generally include an inert diluent or an edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds may be combined with excipients and used in the form of tablets, dragees or capsules. Oral compositions may also be prepared for use as a mouthwash using a fluid carrier, wherein the compound in the fluid carrier is administered orally and expectorated or swallowed after rinsing.
The compounds according to the present invention may be formulated as pharmaceutically acceptable salts, such as hydrochloride salts (e.g., (R) -DOI used in the examples above) into therapeutic compositions. These salts include acid addition salts formed with inorganic acids such as hydrochloric or phosphoric acids, or organic acids such as acetic, oxalic or tartaric acids, and the like. Salts also include those formed from inorganic bases such as sodium, potassium, ammonium, calcium, or iron hydroxides, and organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like.
Methods for controlling duration of action include incorporating the active compound into particles of polymeric materials, such as polyesters, peptides, hydrogels, polylactide/glycolide copolymers, or ethylene vinyl acetate copolymers. Alternatively, the active compound may be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, by using hydroxymethylcellulose or gelatin microcapsules or poly (methylmethacylate) microcapsules, respectively, or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, beads and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles and liposomes.
Pharmaceutically compatible binding agents and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges and the like may comprise any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrating agents, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated as ointments, salves, gels, or creams as generally known in the art.
In embodiments, the serotonin receptor agonist may be administered to the subject in the form of a composition comprising at least one other biologically active agent. Non-limiting examples of bioactive agents include antimicrobial agents, antipathogenic agents, drugs, or combinations thereof. Non-limiting examples of antimicrobial agents include antiviral agents, antibacterial agents, antibiotic agents, antifungal agents, antiprotozoal agents, or combinations thereof.
Any suitable anti-infective agent (e.g., an antibiotic agent, such as an antiviral or antibacterial agent) may be administered in combination (e.g., simultaneously or at different times) with the serotonin receptor agonist. Anti-infective agents and formulations suitable for ophthalmic administration include, for example: levofloxacin, natamycin, tobramycin, polymyxin b/trimethoprim, ciprofloxacin, trifluridine, moxifloxacin, gatifloxacin, besifloxacin, moxifloxacin, ganciclovir, azithromycin, chloramphenicol, bacitracin/polymyxin b, tobramycin, povidone iodine, sodium sulfacetamide, idoxuridine, erythromycin, gentamicin, bacitracin/neomycin/polymyxin b, gramicidin/neomycin/polymyxin b, ofloxacin, oxytetracycline/polymyxin b, tobramycin, verarabitabine and gatifloxacin.
In embodiments, non-limiting examples of antiviral agents that may be used as part of the present invention include TFT, acyclovir, ganciclovir, penciclovir, famciclovir, cidofovir and analogue derivatives thereof; ribavirin, interferon, phosphonoacetate, foscarnet, and valacyclovir. For example, TFT and ganciclovir are associated with eye infections (e.g., herpes infections).
Reagent kit
The invention further provides kits that may have one or more containers (e.g., bottles, blister packs, vials, ampoules) containing a unit dosage form comprising the above-described composition, and optionally one or more additional pharmaceutical agents. Each agent (e.g., a serotonin receptor agonist or an antiviral agent) may be contained in a separate container or in the same container. Associated with such containers (e.g., packaged in a package with the container) may be a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals (e.g., the U.S. food and drug administration or the european medicines administration) which reflects approval by the agency of manufacture, use or sale for human administration for the treatment of acute or chronic pain. The notification may describe, for example, the dosage, route, and/or method of administration, approved indications, methods of monitoring therapeutically effective levels, and/or other usage information for the medical professional and/or patient.
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