WO2020160452A1 - Combining serms, sarms, and cannabinoids for improving safety and efficacy of endocrine therapies - Google Patents

Abstract

The present invention provides methods for the alleviation of symptoms of diseases or medical conditions impacted by dysfunction of the endocannabinoid system in a subject, the methods comprising administering an effective amount of a SERM, SARM, or other endocrine agent in combination with an effective amount of a cannabinoid or cannabimimetic agent or combination of such agents tailored to a subject's specific symptoms. In particular embodiments, the cannabinoid or cannabimimetic agent or combination of such agents alleviate chemotherapy-induced nausea and vomiting in a subject, while a prescription SERM treats the immuno-suppression associated with cannabinoid-based therapy. In some embodiments, the side effects associated with endocrine therapies in a subject are prevented or limited by administering cannabinoid or cannabimimetic agents or combinations of such agents to the subject. In other embodiments, the side effects associated with cannabinoid or cannabimimetic-based therapies in a subject are prevented or limited by administering a prescription endocrine therapy to the subject.

Description

COMBINING SERMS, SARMS, AND C ANNABIN OIDS FOR IMPROVING SAFETY AND EFFICACY OF ENDOCRINE THERAPIES

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/800,027, filed February 1, 2019, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Selective estrogen receptor modulators (SERMs; also known as estrogen receptor agonists antagonists) are a broad class of chemical compounds well known for their mixed estrogen agonist/antagonist effects in various estrogen-responsive tissues [Wurz G T. et ah, Current Topics in Pharmacology 9:61-85 (2005)]. Examples of SERMs that have been approved by the U.S. Food and Drug Administration (FDA) include tamoxifen, toremifene, clomiphene, and ospemifene (examples of triphenylethylenes), the benzothiophene raloxifene, and the indole bazedoxifene (used in combination with conjugated estrogens). While best known for their biologic effects mediated through estrogen receptors (ER), both a and b subtypes, SERMs such as tamoxifen have long been known to exert ER-independent effects [Radin D P. et ah, Eur J Pharmacol 781 : 173-180 (2016)]. Among the many ER-independent mechanisms of action that have been described as being potentially involved in tamoxifen’s anticancer effects, including induction of reactive oxygen species [Gundimeda U. et ah, JBiol Chem 271 : 13504-13514 (1996)], protein kinase C (PKC) inhibition [O’Brian C A. et ah, Biopolymers 29:97-104 (1990)], increasing cytosolic and mitochondrial Ca²⁺ levels [Kim J A. et al., Cancer Lett 147: 115-123 (1999); Nazarawicz R R. et al., Cancer Res 67: 1282-1290 (2007)], and the induction of transforming growth factor beta (TGF-b) [Perry R R. et al., Br J Cancer 72: 1441-1446 (1995)], more recent research has shown that tamoxifen and other SERMs, e.g., ospemifene, raloxifene, toremifene, and bazedoxifene, also act as inverse agonists of cannabinoid receptors type 1 (CBi) and type 2 (CB2) [Kumar P. et al., Biochem Biophys Res Commun 435:76-81 (2013); Ford B M. et al., PLoS ONE l l :e0167240 (2016); Franks L N. et al., Front Pharmacol 7:503 (2016)].

[0003] Analogous to SERMs, selective androgen receptor modulators (SARMs) are a diverse class of non-steroidal chemical compounds with selective androgen receptor agonist/antagonist effects in androgen-responsive tissues [Narayanan R. et al., Mol Cell Endocrinol 465: 134-142 (2018)]. Potential indications for this relatively new class of compounds include muscle wasting, muscular dystrophy, breast cancer, osteoporosis, and stress urinary incontinence [Narayanan R. et al., Mol Cell Endocrinol 465: 134-142 (2018)]. While there are currently no SARM class compounds that have received regulatory approval by the FDA, enobosarm [GTx-024; chemical name (2S)-3-(4-cyanophenoxy)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpro- panamide] appears to be the most advanced product in clinical development [Crawford J. et al., Curr Oncol Rep 18:37 (2016)], having completed phase II clinical trials for the treatment of stress urinary incontinence in postmenopausal women in late 2018. Examples of the different chemical classes of investigational SARMs include aryl propionamides [e.g., S-4; chemical name S-3-(4- acetylaminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)-propionamide), bicyclic hydantoins [e.g, BMS-564929; chemical name 4-[(7R,7aS)-7-hydroxy-l,3-dioxo- 5,6,7,7a-tetrahydropynOlo(l,2-c)-imidazol-2-yl]-2-chloro-3-methylbenzylnitrile], the quinolines [e.g, LGD-2226; chemical name 6-N,N-bis(2,2,2-trifluoroethyl)amino-4-trifluoromethyl- quinolin-2(lH)-one], and the tetrahydroquinolines [ e.g ., S-40503; chemical name 2-(4-dimethyl- amino-6-nitro-l,2,3,4-tetrahydroquinolin-2-yl)-2-methyl-propan-l-ol] [Wurz G T. et al., Ch 45 In: Development of Therapeutic Agents Handbook, Gad S C. (ed), Hoboken, NJ: John Wiley & Sons (2011)]. Fispemifene, a triphenylethylene closely related to ospemifene, was originally developed as a SERM, but it also displays characteristics of a SARM. Unlike other SARMs, fispemifene may function through the ER to increase testosterone levels in hypogonadal men by inhibiting estrogen feedback inhibition in the anterior pituitary [Wurz G T. et ah, Ch 45 In: Development of Therapeutic Agents Handbook , Gad S C. (ed), Hoboken, NJ: John Wiley & Sons (2011)]. Currently, there is no information available in the literature regarding interactions between SARMs and cannabinoid receptors, but androgens, like estrogens, are known to have multiple effects on the endocannabinoid system (ECS) and vice versa in the regulation of gonadal hormones and gonadotropins [Gorzalka B B. et ah, Endocrinology 153 : 1016-1024 (2012)].

[0004] Cannabinoid receptor CBi, located primarily in the central nervous system on the axon terminals of presynaptic neurons [Mechoulam R. et al., Annu Rev Psychol 64:21-47 (2013)], and CB2, found principally in peripheral tissue and cells of the immune system, with low-level expression in neurons and glial cells in the brain [Navarro G. et al., Front Neurosci 10:406 (2016)], are G protein-coupled receptors (GPCR) through which the endogenous cannabinoids (endocanna- binoids) anandamide ( -arachidonoyl -ethanol amine; AEA) and 2-AG (2-arachidonoylglycerol), and the phytocannabinoid A⁹ -tetrahydrocannabinol (A⁹-THC) exert their effects [Di Marzo V., Nat Rev Drug Discov 17:623-639 (2018)]. These two receptors, along with the major enzymes responsible for the biosynthesis and degradation of endocannabinoids [fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), sn-1 -specific diacyl-glycerol lipase-a (DGLa), and DGL ], form the principal components of the ECS. The degradation of anandamide occurs primarily through the action of FAAH [Cravatt B F. et al., Nature 384:83-87 (1996)], while MAGL is principally involved in the breakdown of 2-AG [Dinh T P. et al., Chem Phys Lipids 121 : 149-158 (2002)]. Other receptors thought to be involved in the ECS include peroxisome proliferator-activated receptor-a (PPARa), PPARy [Pistis M. et al., Adv Pharmacol 80:291-328 (2017)], G protein- coupled receptor 110 (GPR110) [Lee J W. et al., Nat Commun 7: 13123 (2016)], GPR55 [Ryberg E. et al., Br J Pharmacol 152: 1092-1101 (2007); Lauckner J E. et al., Proc Natl Acad Sci USA: 105:2699-2704 (2008)], GPR119 [Hansen H S. et al., Trends Pharmacol Sci 33:374-381 (2012)], GPR18 [McHugh D. et ak, Br J Pharmacol 165:2414-2424 (2012)], and transient receptor potential cation channel vanilloid 1 (TRPVl) [De Petrocellis L. et al., Adv Pharmacol 80:249-289 (2017)].

[0005] The ECS is involved in the regulation of numerous physiological functions including the immune system [Katchan V. et al., Autoimmun Rev 15:513-528 (2016)], male and female repro ductive systems and sexual behavior [Battista N. et al., Mol Cell Endocrinol 355: 1-14 (2012)], nervous and neuroendocrine systems [Katona I. et al., Annu Rev Neurosci 35:529-558 (2012)], stress [Morena M. et al., Neuropsychopharmacology 41 :80-102 (2016)], and appetite [Bermudez- Silva F J. et al., J Psychopharmacol 26: 114-124 (2012)]. Endocannabinoid signaling may also be involved in blood clotting, as studies conducted in rats showed that phytocannabinoids derived from cannabis exert anticoagulant effects [Coetzee C. et al., Phytomedicine 14:333-337 (2007)], and dietary hempseed was found to reduce platelet aggregation [Richard M N. et al., J Thromb Haemost 5:424-425 (2007)]. A number of different diseases and conditions potentially resulting from dysfunction or overactivation of the ECS, e.g. , type 2 diabetes [Gruden G. et al., Br J Pharmacol 173: 1116-1127 (2016)], schizophrenia [Ibarra-Lecue T et al., Biochem Pharmacol 157:97-107 (2018)], infertility, male and female sexual dysfunction [Gorzalka B B. et al., Endocrinology 153: 1016-1024 (2012)], autoimmune disorders such as systemic lupus erythematosus [Katchan V. et al., Autoimmun Rev 15:513-528 (2016)], Alzheimer’s disease and other neurodegenerative disorders [Fernandez -Ruiz J. et al., Handb Exp Pharmacol 231 :233-259 (2015)], and inflammation and neuropathic pain [Donvito G. et al., Neuropsychopharmacology 43 : 52-79 (2018)] are candidates for ECS modulating agents such as SERMs combined with natural or synthetic cannabinoids or cannabimimetics.

[0006] Chemical compounds that directly or indirectly affect the ECS, but which are not structurally related to cannabinoids, have come to be known as cannabimimetics for their ability to mimic the action of endocannabinoids or phytocannabinoids. This very broad class of compounds includes N-alkylamides derived from Echinacea spp., which exert immunomodulatory effects through the CB2 receptor [Gertsch J. et al., FEBS Lett 577:563-569 (2004); Raduner S. et al., J Biol Chem 281 : 14192-14206 (2006)], N-acylethanolamines ( e.g ., /V-oleoylethanolamine and A_'-linoleoyl -ethanol amine), found in multiple plant species such as Theobroma cacao , used to make chocolate [DiMarzo V. et al., Nature 396:636-637 (1998)], and act as inhibitors of FAAH [Gertsch J. et al., Br J Pharmacol 160:523-529 (2010)], and b-caryophyllene, which is a sesquiterpenoid now considered to be a phytocannabinoid [Gertsch J. et al., Proc Natl Acad Sci USA 105:9099-9104 (2008)]. b-Caryophyllene, natural, non-cannabis sources of which include Copaiba spp., black pepper ( Piper nigrum ), cloves ( Syzygium aromaticum ), and hops ( Humulus lupulus ), acts as a full agonist at CB2 receptors, and is well known for its anti-inflammatory properties [Gertsch J. et al., Proc Natl Acad Sci USA 105:9099-9104 (2008); Gertsch J., Commun Integr Biol 1 :26-28 (2008)]. Echinacea- derived N-alkylamides have also been shown to interact with PPARy nuclear receptors [Spelman K. et al., Int Immunopharmacol 9: 1260-1264 (2009)] and to exert partial/inverse agonist effects at the CBi receptor [Hohmann J. et al., Phytochemistry 72: 1848-1853 (2011)]. Many other natural compounds, e.g., salvinorin A from Salvia divinorum , falcarinol, also known as carotatoxin, from Daucus carota, yangonin from Piper methysticum , kaempferol from Kaemperia galanga, capsaicin from Capsicum annuum and many others, N- benzyloleamide, also known as macamide, from Lepidium meyenii , and perrottetinene and perrottetinenic acid from Radula marginata have demonstrated varying degrees of cannabimimetic activity [Gertsch J. et al., Br J Pharmacol 160:523-529 (2010); Russo E B., Trends Pharmacol Sci 37:594-605 (2016)].

[0007] Regarding the mechanism of action through which SERMs modulate CBi and CB2 receptor signaling, the compounds that have been studied to date act principally as inverse agonists, though with varying degrees of selectivity [Kumar P. et al., Biochem Biophys Res Commun 435:76-81 (2013); Ford B M. et al., PLoS ONE 11 :e0167240 (2016); Franks L N. et al., Front Pharmacol 7:503 (2016)]. The CBi and CB2 receptors are constitutively active GPCRs that modulate the activity of Gi_/0 proteins, resulting in downstream intracellular effects mediated through adenylyl cyclase inhibition, and the opening and closing, respectively, of inward rectifying K⁺ channels and voltage-gated Ca²⁺ channels [Dalton GD. et al., CNS Neurol Disord Drug Targets 8:422-431 (2009); Mackie K. et al., J Neurosci 15:6552-6561 (1995)]. When bound by endo- cannabinoids (anandamide or 2-AG) or other agonists such as A⁹-THC, the adenylyl cyclase enzyme is inhibited, resulting in a decrease in production of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Inverse agonists like the various SERMs have the opposite effect, increasing cAMP levels. As an example, ospemifene was shown to act as a full inverse agonist at both CBi and CB2 receptors, but has selective affinity for CBi receptors (Ki 753 nM) compared to CB2 receptors (Ki 3.7 mM) [Franks L N. et al., Front Pharmacol 7:503 (2016)]. This selectivity was reflected in ospemifene’s potency of G-protein activity inhibition, with IC50 values of 170 nM and 558 nM for CBi and CB2, respectively. Bazedoxifene was shown to be selective for CB2, while raloxifene showed no selectivity. Interestingly, when combined with a full agonist, ospemifene acted as a surmountable antagonist at both CBi and CB2 receptors, as did raloxifene and nafoxidine; bazedoxifene, however, demonstrated insurmountable antagonism at CB2 receptors [Franks L N. et al., Front Pharmacol 7:503 (2016)], which suggests potential interaction with an allosteric binding site. Experiments with the E- and Z-isomers of tamoxifen and its metabolites 4-hydroxytamoxifen and 4-hydroxy -N-desmethyl-tamoxifen (endoxifene) also showed inverse agonism at CBi and CB2 receptors, with isomer-specific activity [Ford B M. et al., PLoS ONE 11 : eO 167240 (2016)] .

[0008] With respect to the involvement of the ECS in regulation of male and female reproduction and sexual behavior, abundant scientific evidence has now been accumulated showing an intricate, bidirectional relationship between the ECS and gonadal hormones [Gorzalka B B. et al., Endocrinology 153 : 1016-1024 (2012)]. Testicular Leydig cells in male mice and rats have been shown to express CBi receptors [Cacciola G. et al., Biol Reprod 79:758-765 (2008); Gye M C. et al., Arch Androl 51 :247-255 (2005)], and significant quantities of the endocannabinoid anand- amide in the testes have been reported [Sugiura T. et al., Biochem Biophys Res Commun 218: 113- 117 (1996)]. In wild-type mice, A⁹-THC was shown to effectively decrease levels of testosterone, similar to anandamide. This effect was not observed in CBi receptor knockout mice [Wenger T. et al., Biochem Biophys Res Commun 284:363-368 (2001)]. The expression of CB2 receptors, the endocannabinoid 2-AG, and associated biosynthetic and degradative enzymes have been observed in Sertoli cells [Battista N. et al., Mol Cell Endocrinol 286:S17-S23 (2008); Maccarrone M. et al., Prostaglandins Leukot Essent Fatty Acids 66:09-317 (2002)], which are essential for spermato- genesis. In support of central regulation of androgens, expression of CBi and CB2 receptors has been found in the gonadotropin releasing hormone (GnRH)-producing neurons in the hypothalamus, along with 2-AG and FAAH [Gammon C M. et al., Endocrinology 146:4491-4499 (2005)]. Thus, endocannabinoid signaling appears to inhibit the production of androgens by Leydig cells, and the release of GnRH and luteinizing hormone (LH) from the hypothalamus and anterior pituitary, respectively. Low concentrations of testosterone result in decreased expression of CBi receptors in the hypothalamus and anterior pituitary, thereby reducing endocannabinoid signaling [Gorzalka B B. et al., Endocrinology 153: 1016-1024 (2012)].

[0009] An analogous relationship is seen the female endocrine system, where a large body of evidence exists supporting direct and indirect interactions between estrogens and the ECS. Just as the ECS is involved in the central regulation of androgens, the release of estrogens is modulated by the ECS by inhibition of the release of GnRH and LH from the hypothalamus and anterior pituitary [Gorzalka B B. et al., Endocrinology 153:1016-1024 (2012)]. Serum LH concentrations as well as LH pulsatility in oophorectomized female rats were decreased by A⁹-THC, the effects of which were reversed by administration of GnRH [Tyrey L., Endocrinology 102: 1808-1814 (1978); Tyrey L., J Pharmacol Exp Ther 213:306-308 (1980)]. Similar effects have been observed in oophorectomized female rhesus macaques [Smith C G. et al., Fertil Steril 31 :335-339 (1979)] and intact female mice [Dalterio S L. et al., Sub st Alcohol Actions Misuse 4:339-345 (1983)]. During the menstrual cycle in humans, CBi receptor expression in the brain fluctuates along with anandamide levels, which peak during ovulation and decrease during the luteal phase. The impact of gonadal hormones on CBi receptor expression in the anterior pituitary appears to be controlled by estrogen, as the administration of dihydrotestosterone to castrated male rats was unable to reverse the depressed levels of CBi mRNA, suggesting that aromatization of testosterone into estrogen is required [Gonzalez S. et al., Biochem Biophys Res Commun 270:260-266 (2000)]. Similar to its effects on fertility in males, the ECS appears to be integrally involved in female fertility, as evidenced by the presence of cannabinoid receptors and endocannabinoid biosynthetic and degradative enzymes in the uterus [Taylor A H. et al., Histochem Cell Biol 133 :557-565 (2010); Maia J. et al., J Steroid Biochem Mol Biol 174:40-47 (2017)]. There is also a relationship between anandamide levels and zygote implantation, pregnancy, and labor [Habayeb O M. et al., J Clin Endocrinol Metah 89:5482-5487 (2004); Lazzarin N. et al., Gynecol Endocrinol 18:212- 218 (2004)]. Lastly, FAAH, the enzyme primarily responsible for the inactivation of anandamide, appears to be a major point of interaction among the ECS, estrogen, and progesterone. These hormones down-regulate the expression of FAAH in the uterus and central nervous system [Maccarrone M. et al., Eur J Biochem 267:2991-2997 (2000); Waleh N S. et al., Gene 291 :203- 210 (2002)].

BRIEF SUMMARY OF THE INVENTION

[0010] The present invention provides a method for improving the safety and efficacy of treatments for endocrine-related and other medical diseases and conditions impacted by the ECS in a subject, the method comprising administering a combination therapy composed of an effective amount of a SERM, SARM, or other synthetic prescription therapeutic endocrine agent, and an effective amount of a natural or synthetic cannabinoid or cannabimimetic agent, or pharma ceutically acceptable salts thereof, to the subject.

[0011] In particular aspects, the present invention provides a method of preventing the unwanted side effects of cannabis or cannabinoid-based therapy in a subject, the method including administering an effective amount of a SERM, SARM, or other synthetic prescription endocrine agent, in combination with an effective amount of a natural or synthetic cannabinoid, cannabimimetic agent or mixture of such agents, or pharmaceutically acceptable salts thereof, to the subject.

[0012] In some embodiments, the subject is experiencing potentially detrimental immunosup pression as a result of cannabis or cannabinoid-based therapy for the alleviation of chemotherapy- induced nausea and vomiting (CINV) following treatment for cancer.

[0013] In particular embodiments, the synthetic prescription endocrine agent for a subject experiencing immunosuppression due to cannabis or cannabinoid-based therapy is selected from a group consisting of SERMs, SARMs, and other endocrine agents. In some instances, the SERM (see Fig. 1) is selected from a group consisting of ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, lasofoxifene, or metabolites, isomers, or derivatives thereof.

[0014] In some embodiments, the subject is experiencing an increased risk of blood clot formation, e.g ., deep vein thrombosis and pulmonary embolism, as a result of treatment with a prescribed SERM or other endocrine agent.

[0015] In particular embodiments, the natural or synthetic agent for a subject experiencing an increased risk of blood clot formation as a result of treatment with a SERM or other endocrine agent is selected from a group consisting of cannabinoids or cannabimimetic agents. In some instances, the natural or synthetic cannabinoid agent is selected from a group including, but not limited to, A⁹-THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabi- chromene (CBC), A⁹-tetrahydrocannabivarin (A⁹-THCV), including the carboxylic acid forms or derivatives of any of the foregoing, or any combination of these, especially THC (D⁸ or D⁹) and CBD (see Fig. 2). In other instances, the cannabimimetic agent is selected from a group including, but not limited to, N-alkylamides derived from Echinacea spp., N-acylethanolamines found in multiple plant species, b-caryophyllene found in multiple plant species, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyloleamide, and perrottetinene, among others, or any combination of these agents (see Fig. 3).

[0016] In some embodiments, the subject is experiencing vasomotor symptoms, e.g ., hot flashes, as a result of treatment with a prescribed SERM or other endocrine agent.

[0017] In particular embodiments, the natural or synthetic agent for a subject experiencing vasomotor symptoms due to treatment with a prescribed SERM or other endocrine agent is selected from a group consisting of cannabinoids or cannabimimetic agents. In some instances, the natural or synthetic cannabinoid agent is selected from a group including, but not limited to, A⁹-THC, CBD, CBG, CBN, CBC, A⁹-THCV, including the carboxylic acid forms or derivatives of any of the foregoing, or any combination of these, especially THC (D⁸ or D⁹) and CBD. In other instances, the cannabimimetic agent is selected from a group including, but not limited to, N-alkylamides derived from Echinacea spp., N-acylethanolamines found in multiple plant species, b-caryo- phyllene found in multiple plant species, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyloleamide, and perrottetinene, among others, or any combination of these agents.

[0018] In some embodiments, the subject is experiencing any other medical condition or disease potentially impacted by the ECS, including, but not limited to: autoimmune disorders, e.g. , systemic lupus erythematosus and multiple sclerosis; menopausal symptoms, both chemotherapy- induced and natural, e.g. , hot flashes and night sweats; male or female infertility and sexual dysfunction; neuropathic pain; inflammation and inflammatory pain; type 2 diabetes; obesity; neurode-generative disorders, e.g. , Alzheimer’s disease; schizophrenia; social anxiety disorders; or depression. [0019] In particular embodiments, the medication for a subject experiencing any other medical condition or disease potentially impacted by the ECS is selected from a group consisting of prescription SERMs, SARMs, and other endocrine agents, and natural or synthetic cannabinoids or cannabimimetic agents. In some instances, the SERM is selected from a group consisting of, but not limited to, ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, lasofoxifene, or metabolites, isomers, or derivatives thereof; the SARM (see Fig. 4) is selected from a group consisting of, but not limited to, fispemifene, enobosarm, S-l, S-4, BMS-564929, LGD-2226, S- 40503, or metabolites, isomers, or derivatives thereof; and other endocrine agents are selected from a group consisting of, but not limited to, estrogen replacement therapy and androgen replacement therapy. In other instances, the natural or synthetic cannabinoid is selected from a group consisting of, but not limited to A⁹-THC, CBD, CBG, CBN, CBC, A⁹-THCV, including the carboxylic acid forms or derivatives of any of the foregoing, or any combination of these, especially THC (A⁸ or A⁹) and CBD; and the natural or synthetic cannabimimetic agent is selected from a group consisting of, but not limited to, N-alkylamides derived from Echinacea spp., N-acylethanolamines found in multiple plant species, b-caryophyllene found in multiple plant species, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyloleamide, and perrottetinene, among others, or any combination of these agents.

[0020] In some embodiments, the prescription SERM, SARM, or other endocrine agent is administered in combination with one or more natural or synthetic cannabinoids or cannabimimetic agents.

[0021] In some embodiments, the effective amount of natural or synthetic cannabinoid or cannabimimetic agent or combination of such agents is an amount that, when used together with a SERM, SARM, or other endocrine medication prescribed by a physician, results in the satisfactory alleviation of a subject’s specific symptoms. That is, the amount of a particular cannabinoid or cannabimimetic used as a single agent or as a combination of agents is individually tailored to the treatment of symptoms in the subject.

[0022] In some embodiments, multiple dose levels of each cannabinoid, cannabimimetic agent, and various combinations are formulated to allow subjects to tailor their individual treatments to fit their specific symptoms. The cannabinoid component may consist of A⁹-THC, CBD, CBG, CBN, CBC, A⁹-THCV, including the carboxylic acid forms or derivatives of any of the foregoing, or any combination of these, especially THC (D⁸ or D⁹) and CBD; and the cannabimimetic component may consist of N-alkylamides derived from Echinacea spp., N-acylethanolamines found in multiple plant species, b-caryophyllene found in multiple plant species, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyloleamide, and perrottetinene, among others, or any combination of these agents with potentially beneficial effects against the subject’s specific symptoms.

[0023] In some embodiments, the ratios between the cannabinoid components can be equal ( e.g . , 1 : 1 A⁹-THC:CBD), or any other ratio designed to achieve a specific effect (e.g. , 3 : 1 A⁹-THC:CBD for the alleviation of hot flashes and night sweats, or 3 : 1 CBDA⁹-THC for symptoms of anxiety.

[0024] In some embodiments, the natural or synthetic cannabinoid or combination of cannabinoids is selected from a group consisting of, but not limited to, A⁹-THC, CBD, CBG, CBN, CBC, A⁹-THCV, including the carboxylic acid forms or derivatives of any of the foregoing, and the cannabimimetic agent is selected from a group consisting of, but not limited to, N-alkylamides derived from Echinacea spp., N-acylethanolamines found in multiple plant species, b-caryophyl- lene found in multiple plant species, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N- benzyloleamide, and perrottetinene, among others.

[0025] Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1. Chemical structures of representative SERMs: ospemifene; toremifene; tamoxifen; raloxifene; bazedoxifene; and lasofoxifene)

[0027] Figure 2. Chemical structures of common cannabinoids: A⁹-tetrahydrocannabinol (D⁹- THC); A⁹-tetrahydrocannabinolic acid (A⁹-THCA); cannabidiol (CBD); cannabidiolic acid (CBDA); cannabinol (CBN); cannabigerol (CBG); cannabigerolic acid (CBGA); cannabichro- mene (CBC); and A⁹-tetrahydrocannabivarin (A⁹-THCA).

[0028] Figure 3. Chemical structures of cannabimimetic agents: N-alkylamides (Al, A2, and A3 from Echinacea spp.); N-acylethanolamine; b-caryophyllene; salvinorin A; falcarinol; yangonin; kaempferol; capsaicin; N-benzyloleamide; and perrottetinene.

[0029] Figure 4. Chemical structures of representative SARMs: fispemifene; enobosarm; S-l; S-4; BMS-564929; LGD-2226; and S-40503.

DETAILED DESCRIPTION OF THE INVENTION

I. INTRODUCTION

[0030] This invention relates to the development of different combinations of selective estrogen receptor modulators (SERMs; e.g ., ospemifene) or selective androgen receptor modulators (SARMs; e.g, fispemifene) and cannabinoids or cannabimimetics for the treatment of endocrine- related and other medical diseases or conditions impacted by the endocannabinoid system (ECS). Cannabimimetics include chemical compounds that influence the ECS, either directly through cannabinoid receptors, or indirectly through enzymatic processing of endocannabinoids, but are not necessarily derived from the cannabis plant ( Cannabis spp.; marijuana, hemp). The intimate relationship between the ECS and gonadal hormones has major implications for SERMs and SARMs, the selective activity of which exerted through estrogen and androgen receptors, respectively, can be utilized to indirectly modulate endocannabinoid signaling, in addition to their direct, modulatory effects on CBi and CB2 receptors. Likewise, natural or synthetic cannabinoids or cannabimimetics can be used to modulate the effects of the SERMs and SARMs and other endocrine agents when used in combination. These novel combinations are designed to take advantage of the specific SERM/SARM and cannabinoid mechanisms of action as they pertain to the ECS and steroid hormone receptors to achieve efficacy and safety in treating the targeted indication, while minimizing side effects. Treatment combinations developed under this invention will be individually tailored such that the patient combines a dose of synthetic medication (SERM, SARM or other endocrine agent) as prescribed by their physician for a specific indication, e.g. , dyspareunia and/or vaginal dryness in postmenopausal women in the case of ospemifene (Osphena^®), with an amount of natural or synthetic cannabinoids and cannabimimetics, or combinations thereof, that results in the satisfactory treatment of the patient’s specific disease or condition with a level of safety and efficacy not achievable by these agents when administered individually.

[0031] The dosing regimens will be individually tailored for the treatment of targeted diseases or conditions in a subject by combining the synthetic SERM, SARM, or endocrine agents, e.g. , ospemifene, as prescribed with a low dose of natural or synthetic cannabinoid or cannabimimetic agent. If symptom relief is unsatisfactory, or if the side effect profile is not improved, the dosage of the cannabinoid or cannabimimetic agent will be gradually increased until maximum benefits are achieved. Different combinations of SERM, SARM or endocrine agent and natural or synthetic cannabinoids or cannabimimetics may be required to achieve maximum efficacy. These combinations include, but are not limited to: (1) a SERM ( e.g . , ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, lasofoxifene or metabolites, isomers or derivatives thereof) or SARM (e.g., fispemifene, enobosarm, S-l, S-4, BMS-564929, LGD-2226, S-40503 or metabolites, isomers or derivatives thereof) with a natural or synthetic cannabinoid or cannabimimetic; (2) an endocrine agent (e.g., estrogen replacement therapy, androgen replacement therapy) with a natural or synthetic cannabinoid or cannabimimetic; (3) a SERM, SARM, or endocrine agent in combination with multiple natural or synthetic cannabinoids or cannabimimetics. The cannabinoid component may consist of synthetic cannabinoids, or naturally-derived phytocannabinoids D⁹- THC, A⁸-THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), A⁹-tetrahydrocannabivarin (A⁹-THCV), including the carboxylic acid forms or derivatives of any of the foregoing, or any combination of these, especially THC (A⁸ or A⁹) and CBD. The cannabimimetic component may consist of N-alkylamides derived from Echinacea spp., N- acylethanolamines, found in multiple plant species, b-caryophyllene found in multiple plant species, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyloleamide, and perrottetinene, among others, or any combination of these agents. The ratios between cannabinoid and cannabimimetic components can be equal, e.g, 1 : 1 A⁹-THC:CBD, or any other ratio designed to achieve a specific effect, e.g, 3 : 1 A⁹-THC:CBD for hot flashes and night sweats, or 3 : l CBD:A⁹- THC for symptoms of anxiety. Multiple dose levels of each cannabinoid or cannabimimetic agent and various combinations can be formulated to allow patients to tailor their individual treatments to fit their specific condition or disease.

[0032] The natural or synthetic cannabinoids, cannabimimetic agents, and combinations of these agents are formulated as tinctures, gels, creams, lotions, patches for transdermal delivery, or other suitable formulation that most appeal to the individual subject.

II. DEFINITIONS

[0033] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined.

[0034] The terms“a,”“an,” or“the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“a SERM” includes a plurality of such compounds, and reference to“a SARM,”“a cannabinoid,”“a cannabimimetic,” or“an endocrine therapy” includes a plurality of such products or compounds known to those skilled in the art, and so forth.

[0035] The terms“subject,”“patient,” or“individual” are used herein interchangeably.

[0036] As used herein, the term“administering” includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration to a subject. Administration is by any route, including parenteral and transmucosal ( e.g ., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g, intravenous, intramuscular, intra arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. One skilled in the art will know of additional methods for administering an effective amount of the compounds described herein for the alleviation of menopausal symptoms in an individual.

[0037] The term“effective amount” includes an amount or quantity effective, at dosages and for periods of time necessary, to produce a desired (e.g, therapeutic or prophylactic) result with respect to the indicated disease, disorder, or condition. The desired result may comprise a subjective or objective improvement in the recipient of the effective amount. In one non-limiting example, an effective amount of the prescription medication ospemifene used in combination with cannabis includes an amount or dosage sufficient to prevent immunosuppression in a cancer patient using cannabis to relieve CINV. Also, for example, an effective amount of a cannabinoid or cannabimimetic agent, or a combination, is an amount or dosage sufficient to decrease the risk of blood clotting in a subject taking a prescription SERM for the treatment of menopausal symptoms. The effective amount will vary with the type of subject being treated and the compound or combination of compounds applied.

[0038] The term“SERM” or selective estrogen receptor modulator refers to any member of a broad class of structurally unrelated chemical compounds that have mixed estrogen receptor agonist and antagonist effects depending on the tissue, including, but not limited to ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, and lasofoxifene.

[0039] The term“SARM” or selective androgen receptor modulator refers to any member of a broad class of structurally unrelated chemical compounds that have mixed androgen receptor agonist and antagonist effects in different tissues, including, but not limited to fispemifene, enobosarm, S-l, S-4, BMS-564929, LGD-2226, and S-40503.

[0040] The term“endocrine agent” or“endocrine therapy” refers to any member of a broad class of therapeutic agents that affect the endocrine system, including, but not limited to SERMs, SARMs, estrogen replacement therapy and androgen replacement therapy.

[0041] The term“cannabinoid” refers to any member of the broad class of phytocannabinoid compounds derived from the cannabis plant ( Cannabis spp.), or their synthetic equivalents, including, but not limited to A⁸-THC, A⁹-THC, CBD, CBG, CBC, A⁸-THCV, A⁹-THCV, CBN and any of their associated carboxylic acid forms.

[0042] A⁸-THC and A⁹-THC refer to, respectively, A⁸-tetrahydrocannabinol and A⁹-tetrahydro- cannabinol.

[0043] CBD refers to cannabidiol.

[0044] CBDA refers to cannabidiolic acid.

[0045] CBG refers to cannabigerol.

[0046] CBGA refers to cannabigerolic acid.

[0047] CBC refers to cannabichromene.

[0048] CBN refers to cannabinol.

[0049] A⁸-THCV and A⁹-THCV refer to, respectively, A⁸-tetrahydrocannabivarin and A⁹-tetra- hydrocannabivarin.

[0050] The term “cannabimimetic” refers to any member of a broad class of chemical compounds that directly or indirectly affect the endocannabinoid system, but which are not structurally related to cannabinoids, including, but not limited to N-alkylamides (e.g., Al, A2, and A3 derived from Echinacea spp.), N-acylethanolamines (e.g, N-oleoylethanolamine and N-lino- leoylethanolamine), b-caryophyllene, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyloleamide, and perrottetinene.

[0051] The term“ECS” or endocannabinoid system collectively refers to cannabinoid receptors (CBi and CB2), their natural endocannabinoid ligands (e.g, AEA and 2-AG), and their synthetic and degradative enzymes.

[0052] The term“menopausal symptoms” refers to any unpleasant symptoms experienced due to natural or chemotherapy-induced menopause, including, but not limited to, vaginal dryness, dyspareunia, hot flashes, insomnia, and night sweats.

[0053] The term“CINV” refers to the symptoms of nausea and vomiting that commonly occur in cancer patients as a result of chemotherapy.

III. DESCRIPTION OF THE EMBODIMENTS

A. Selective Estrogen Receptor Modulators (SERMs)

[0054] SERMs can include any non-steroidal estrogen receptor agonist/antagonist medications prescribed for the treatment of various estrogen responsive diseases or conditions. Examples include, but are not limited to: ospemifene (Fig. 1), sold under the trade name Osphena^® and indicated for the treatment of moderate to severe dyspareunia and vaginal dryness associated with menopause; toremifene (Fig. 1) indicated for the treatment of metastatic breast cancer; tamoxifen (Fig. 1) indicated for the treatment of all stages of breast cancer as well as breast cancer prevention in patients at increased risk; raloxifene (Fig. 1) indicated for the treatment and prevention of postmenopausal osteoporosis and breast cancer prevention; bazedoxifene (Fig. 1), combined with conjugated estrogens and sold under the trade name Duavee^®, which is indicated for the treatment of moderate to severe hot flashes and the prevention of postmenopausal bone loss; and lasofoxifene (Fig. l), which has not received regulatory approval in the United States.

B. Selective Androgen Receptor Modulators (SARMs)

[0055] SARMs can include any non-steroidal androgen receptor agonist/antagonist medications that applications in the treatment of androgen responsive diseases or conditions. All SARM class compounds (Fig. 4) are currently investigational. Examples include, but are not limited to: fispemifene [IUPAC name 2-[2-[4-[(Z)-4-chloro-l,2-diphenylbut-l-enyl]phenoxy]ethoxy]- ethanol]; enobosarm [IUPAC name (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)- phenyl]-2-hydroxy-2-methylpropanamide)]; S-l [IUPAC name 3-(4-fluorophenoxy)-2-hydroxy- 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide]; S-4 [IUPAC name S-3-(4-acetyl- aminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)-propionamide; BMS- 564929 [IUPAC name (7R,7aS)-2-(3-chloro-4-cyano-2-methylphenyl)-7-hydroxytetrahydro-2H- pyrrolo[l,2-e]imidazole-l,3-dione]; LGD-2226 [IUPAC name 6-N,N-bis(2,2,2-trifluoroethyl)- amino-4-trifluoromethylquinolin-2(lH)-one]; and S-40503 [IUPAC name 2-(4-dimethylamino-6- nitro- 1 ,2,3 ,4-tetrahydroquinolin-2-yl)-2-methylpropan- 1 -ol] .

C. Cannabinoids

[0056] The medicinal qualities of cannabinoids, ( e.g ., A⁹-THC and CBD) are well known in the art, and have been studied for their potential utility in the management of numerous diseases and conditions, including CINV, appetite stimulation, neuropathic pain, inflammation, menopausal vasomotor symptoms, anxiety, cancer, among many others. Non-limiting examples of cannabinoids include CBD, CBDA, CBG, CBGA, CBC, CBN, A⁹-THCV, A⁹-THC, and A⁹-THCA derived from Cannabis spp. and their synthetic equivalents. [0057] In particular embodiments, a SERM, e.g, ospemifene, is given to prevent immuno suppression in a subject using cannabis or cannabinoids to alleviate their symptoms of CINV as a result cancer chemotherapy.

D. Cannabimimetics

[0058] Structurally unrelated to the cannabinoids (both plant-derived phytocannabinoids and endocannabinoids), cannabimimetics are chemical compounds that affect the ECS directly or indirectly by mimicking the action of cannabinoids. This class of compounds has been the subject of intense study regarding their effects on the ECS and their potential medicinal value. Non limiting examples include N-alkylamides (e.g, A-l, A-2, and A-3 derived from Echinacea spp.), N-acylethanolamines (e.g, N-oleoylethanolamine and N-linoleoylethanolamine derived from chocolate), b-caryophyllene, salvinorin A, falcarinol, yangonin, kaempferol, capsaicin, N-benzyl- oleamide, and perrottetinene.

[0059] In particular embodiments, one or more cannabimimetic compounds are combined with a prescription SERM (e.g, ospemifene) indicated for the treatment of moderate to severe vaginal dryness and dyspareunia in order to provide additional relief from menopausal vasomotor symptoms in subjects with menopausal symptoms.

E. Diseases and Conditions

1. Cannabinoid-Induced Immunosuppression

[0060] In certain aspects, immunosuppression occurring as a result of cannabis or cannabinoid use to control symptoms of CINV in cancer patients can be effectively treated by using a prescription medication to stimulate the immune system. Chemotherapy-induced nausea and vomiting can occur as a result of cancer treatment. Cannabis and cannabinoids can alleviate the symptoms of CINV, but they can also have potentially detrimental immunosuppressive effects, which are particularly troublesome for cancer patients who already have compromised immune systems as a result of their disease and chemotherapy. By combining an immunomodulator with natural or synthetic cannabinoids or cannabimimetics, cancer patients would benefit from the CINV-alleviating effects of the cannabinoid- or cannabimimetic-based treatment while being protected from its potentially detrimental immunosuppressive effects. The immunomodulator would also help stimulate the immune system so that cancer patients can better respond to chemotherapy and immunotherapy.

[0061] In particular embodiments, a subject experiencing immunosuppression as a result of cannabinoid-based treatment for CINV is treated with a prescription SERM, e.g, ospemifene, in combination to help stimulate the immune system.

2. Blood Clotting Disorders

[0062] One of the main side effects shared by SERMs and other hormonal therapies is the risk of blood clot formation, including deep vein thrombosis and pulmonary embolism. In certain aspects, a combination of natural or synthetic cannabinoids or cannabimimetic agents and SERMs could potentially reduce the risk of blood clot formation in subject being treated with a prescription SERM.

[0063] In particular embodiments, a subject experiencing a blood clotting disorder as a result of treatment with a prescription SERM, e.g. , raloxifene, is treated with a cannabinoid, cannabi mimetic agent, or a combination to manage their condition. 3. Vasomotor Symptoms

[0064] While prescription SERMs can be very effective in treating their targeted indications, vasomotor symptoms, e.g ., hot flashes, are a common side effect. In certain aspects, a cannabinoid, cannabimimetic agent, or a combination such agents can be used to alleviate the vasomotor symptoms being experienced by a subject undergoing treatment with a prescription SERM.

[0065] In particular embodiments, a subject being treated for menopausal symptoms of vaginal dryness and dyspareunia with a prescription SERM, e.g. , ospemifene, and who is experiencing hot flashes as a side effect, is treated with a cannabinoid, cannabimimetic, or a combination to alleviate these symptoms.

4. Other Diseases and Conditions

[0066] In certain aspects, a subject experiencing symptoms of any other medical condition or disease impacted by the ECS including, but not limited to, cancer, autoimmune disorders (e.g, systemic lupus erythematosus and multiple sclerosis), natural and chemotherapy-induced menopausal symptoms (e.g, hot flashes and night sweats), male or female infertility and sexual dysfunction, neuropathic pain, inflammation and inflammatory pain, type 2 diabetes, obesity, neurogenerative disorders (e.g, Alzheimer’s disease), schizophrenia, social anxiety disorders, and depression, can be treated using cannabinoids, cannabimimetic agents, SERMs, or SARMs, or combinations of these.

[0067] In particular embodiments, a subj ect experiencing male sexual dysfunction is treated with a cannabinoid or cannabimimetic agent in combination with a SARM, e.g, enobosarm, to manage their condition. F. Pharmaceutical Compositions

[0068] The natural and synthetic cannabinoids and cannabimimetic agents described herein are useful in the manufacture of a pharmaceutical composition or a medicament for alleviating diseases or medical conditions in a subject experiencing symptoms of such diseases or conditions as a result of ECS dysfunction or overactivation. In certain aspects, a pharmaceutical composition or medicament comprising one or more natural or synthetic cannabinoids or cannabimimetic agents can be administered to a subject for the treatment of symptoms in combination with a prescribed synthetic SERM, SARM, or other endocrine agent to enhance the safety and efficacy of the cannabinoid or cannabimimetic medication, i.e., to decrease unwanted side effects and impart an added clinical benefit. Similarly, the cannabinoid or cannabimimetic medication can be combined with a prescription SERM, SARM, or other endocrine agent to enhance the safety and efficacy of the SERM, SARM, or other endocrine agent.

[0069] Pharmaceutical compositions or medicaments for use in the present invention can be formulated by standard techniques or methods well-known in the art of pharmacy using one more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in, e.g ., Remington’s Pharmaceutical Sciences by E.W. Martin. Compounds and agents of the present invention and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including, but not limited to, orally, topically, nasally, rectally, pulmonary, parenterally (e.g, intravenously, subcutaneously, intramuscularly, etc.), and combinations thereof. In some embodiments, the cannabinoids and cannabimimetic agents are dissolved in a liquid, for example, water. The most suitable route of administration for a cannabinoid or cannabimimetic product or combination of such products in any given case will depend, in part, on the type of product or products being used as well as the nature and severity of the subject’s symptoms. In embodiments where the cannabinoid or cannabimimetic agents are administered in combination with a synthetic prescription medication, i.e ., a SERM, SARM, or other endocrine agent, the cannabinoid or cannabimimetic agents and prescription medication may be administered by the same or different route of administration. For example, the prescription medication may be administered orally, while the cannabinoid or cannabimimetic products may be administered transdermally or topically.

[0070] The pharmaceutical compositions or medicaments of the present invention can include one or more cannabinoid or cannabimimetic agents or any pharmaceutically acceptable salts thereof, as an active ingredient and a pharmaceutically acceptable carrier and/or excipient or diluent. In some embodiments, the pharmaceutical compositions comprising different cannabinoid or cannabimimetic agents are prepared as separate medicaments. In some embodiments, the pharmaceutical compositions comprising different cannabinoid or cannabimimetic agents are prepared as a single medicament.

[0071] In embodiments where more than one cannabinoid or cannabimimetic agent is used, these agents can be combined as an active ingredient in intimate admixture with a suitable pharma ceutical carrier and/or excipient according to conventional pharmaceutical compounding techniques. Any carrier and/or excipient suitable for the form or preparation desired for administration in contemplated for use with the compounds disclosed herein.

[0072] In certain embodiments, the pharmaceutical compositions or medicaments described herein are suitable for systemic administration, which includes enteral administration ( e.g ., absorption of the compound through the gastrointestinal tract) or parenteral administration (e.g., injection, infusion, or implantation). In some embodiments, the pharmaceutical compositions or medicaments may be administered via a syringe or intravenously. In preferred embodiments, the pharmaceutical compositions or medicaments are injected subcutaneously.

[0073] In some embodiments, the present invention provides a pharmaceutical composition including cannabinoids and cannabimimetic agents. In some embodiments, the cannabinoids and cannabimimetic agents are separately prepared pharmaceutical compositions. In some embodi ments, the pharmaceutically acceptable excipient includes a salt or a diluent.

[0074] In some embodiments, the present invention provides a pharmaceutical composition including a combination of one or more cannabinoids and cannabimimetic agents. In some embodiments, the cannabinoid or cannabimimetic agent or combination of combination of these agents are separately prepared pharmaceutical compositions. In some embodiments, the pharma ceutically acceptable excipient includes a salt or a diluent.

[0075] For oral administration, a pharmaceutical composition or a medicament can take the form of, e.g ., a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. Preferred are tablets and gelatin capsules comprising the active ingredient(s), together with (a) diluents or fillers, e.g. , lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g, ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g, silica, anhydrous colloidal silica, talcum, stearic acid, its magnesium or calcium salt (e.g, magnesium stearate or calcium stearate), metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, com starch, sodium benzoate, sodium acetate and/or polyethylene glycol; for tablets also (c) binders, e.g, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; if desired, (d) disintegrants, e.g, starches such as potato starch or sodium starch, glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, e.g, sodium lauryl, sulfate, and/or (f) absorbents, colorants, flavors and sweeteners. In some embodiments, the tablet contains a mixture of hydroxypropyl methyl cellulose, polyethylene glycol 6000 and titanium dioxide. Tablets may be either film coated or enteric coated according to methods known in the art.

[0076] Liquid preparations for oral administration can take the form of, e.g. , solutions, syrups, suspensions, and tinctures, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, e.g. , suspending agents such as sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents such as lecithin or acacia; non-aqueous vehicles, e.g. , almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, e.g. , methyl- or propyl-p-hydroxybenzenes or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated for any type of administration, e.g. , intradermal, subdermal, intravenous, intramuscular, or intranasal, with a syringe or other devices. Formulation for administration by inhalation (e.g, aerosol), or for oral, rectal, or vaginal administration is also contemplated.

[0077] Pharmaceutical compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound described herein, or a salt thereof, and the powder of a suitable carrier and/or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to a person skilled in the art. In certain instances, the compositions may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g, di chi orodifluorom ethane, tri chi orofluorom ethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g ., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound(s) and a suitable powder base such as lactose or starch.

[0078] The cannabinoid and cannabimimetic agents of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g. , containing conventional suppository bases such as cocoa butter or other glycerides.

[0079] The compositions set forth herein can be formulated for parenteral administration by injection, e.g. , by bolus injection. Formulations for injection can be presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Alternatively, the compound(s) can be in powder form for reconstitution with a suitable vehicle such as sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain approximately 0.1 to 75%, preferably about 1 to 50%, of the compound(s).

[0080] In some embodiments, the compounds are prepared with polysaccharide such as chitosan or derivatives thereof (e.g, chitosan succinate, chitosan phthalate, etc.), pectin and derivatives thereof (e.g, amidated pectin, calcium pectinate, etc.), chondroitin and derivatives thereof (e.g, chondroitin sulfate), and alginates. [0081] In some embodiments, the compositions further include a pharmaceutical surfactant. In other embodiments, the compositions further include a cryoprotectant. Non-limiting examples of cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl- 13 -cyclodextrin (HP 13 CD) glycerol, maltose, mannitol, saccharose, and mixtures thereof.

G. Methods of Administration

[0082] Pharmaceutical compositions or medicaments comprising a cannabinoid or cannabimimetic agent or agents can be administered to a subject at a therapeutically effective dose in combination with an effective amount of a SERM, SARM, or other endocrine agent, taken as prescribed by the subject’s physician, to more effectively alleviate the subject’s symptoms, as described herein, or to prevent or limit the side effects of the SERM, SARM, or other endocrine agent. In some embodiments, the pharmaceutical composition or medicament comprising a cannabinoid or cannabimimetic agent or agents is administered to a subject in an amount sufficient in combination with an effective amount of a SERM, SARM, or other endocrine medication to elicit an effective therapeutic response in the subject. In some embodiments, the pharmaceutical composition or medicament comprising a cannabinoid or cannabimimetic agent or agents can be administered to a subject at a therapeutically effective dose in combination with an effective amount of a SERM ( e.g ., ospemifene) to effectively alleviate menopausal vasomotor symptoms as a result of the SERM treatment. In some embodiments, the pharmaceutical composition or medicament comprising a cannabinoid or cannabimimetic agent or agents can be administered in combination with an effective amount of a SERM, SARM, or other endocrine medication (e.g., ospemifene) to effectively alleviate immunosuppression in a subject experiencing immuno suppression as a result of cannabinoid or cannabimimetic-based treatment for CINV. [0083] In some embodiments, one or more cannabinoids or cannabimimetic agents are admini stered to a subject in combination with a prescription SERM to alleviate vasomotor symptoms as a result of natural or chemotherapy-induced menopause.

[0084] In particular embodiments, one or more cannabinoids or cannabimimetic agents are administered to a subject in combination with ospemifene (Figure 1) to alleviate vasomotor symptoms as a result of natural or chemotherapy-induced menopause.

[0085] In some embodiments, a prescription SERM is administered to a subject in combination with a cannabinoid or cannabimimetic agent to alleviate symptoms of immunosuppression as a result of cannabinoid or cannabimimetic-based therapy for CINV.

[0086] In particular embodiments, ospemifene is administered to a subject in combination with a cannabinoid or cannabimimetic agent to alleviate symptoms of immunosuppression as a result of cannabinoid or cannabimimetic-based therapy for CINV.

[0087] In some embodiments, one or more cannabinoid or cannabimimetic agents is admini stered to a subject in combination with a prescription SERM to alleviate blood clotting disorders being experienced by a subject as a side effect of SERM treatment.

[0088] In particular embodiments, one or more cannabinoid or cannabimimetic agents is admini stered to a subject in combination with raloxifene to alleviate blood clotting disorders being experienced by a subject as a side effect of raloxifene treatment.

[0089] In some embodiments, a subject experiencing symptoms of any disease or medical condition related to dysfunction of the ECS, including, but not limited to, cancer, autoimmune disorders, male or female infertility and sexual dysfunction, neuropathic pain, inflammation and inflammatory pain, type 2 diabetes, obesity, neurodegenerative disorders, schizophrenia, social anxiety disorders, and depression, is administered a combination of a cannabinoid, cannabimimetic agent, SERM, SARM, or other endocrine agent to effectively alleviate symptoms of these diseases or medical conditions.

[0090] The formulations of the present invention are useful in the manufacture of a pharmaceutical composition or a medicament. A pharmaceutical composition or medicament can be administered to a subject in need thereof, e.g ., a subject experiencing blood clotting disorders as a result of SERM-based treatment for menopausal symptoms.

[0091] In certain methods of alleviating symptoms of diseases or medical conditions related to ECS dysfunction, set forth herein, the methods comprise administering a cannabinoid or cannabimimetic agent or combination of such agents together with a SERM, SARM, or other endocrine medication. The cannabinoids or cannabimimetic agents may be administered simultaneously with the SERM, SARM, or other endocrine agent or they may be administered according to a dosing schedule that best fits the subject’s symptoms.

H. Dosage

[0092] Pharmaceutical compositions or medicaments comprising a cannabinoid or cannabimimetic agent in combination with a synthetic SERM, SARM, or other endocrine prescription medication can be administered to a subject at a therapeutically effective dose to alleviate symptoms as a result of diseases or medical conditions related to ECS dysfunction as described herein. The pharmaceutical compositions or medicaments are administered to a subject in an amount sufficient to elicit an effective therapeutic response in the subject.

[0093] The dosage of compounds administered is dependent on the subject’s body weight, age, individual condition, and/or on the form of administration. The size of the dose will also be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound in a particular subject. Typically, a dosage of the active compounds is a dosage that is sufficient to achieve the desired effect. Optimal doses and dosing schedules of cannabinoid or cannabimimetic compositions can be determined on an individualized basis based on the needs of a particular subject. In general, dosage may be given once or more daily, weekly, or monthly. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies, and repetition rates.

[0094] The effective amount of a SERM, SARM, or other endocrine agent prescription medication administered in combination with a cannabinoid or cannabimimetic agent or combination of such agents may be provided at the dosages generally recommended for each prescription medication used.

[0095] In some embodiments, a unit dosage for oral administration of a cannabinoid or cannabimimetic agent or combination of such agents to a subject ( e.g ., a human) of about 50 to about 70 kg may contain about 1 and about 500 mg, about 5 and about 500 mg, about 5 and about 250 mg, about 25 to about 250 mg, about 100 and about 1000 mg, about 200 and about 2000 mg, about 500 and about 5000 mg, or about 1000 and about 2000 mg of the compound(s). In particular embodiments, a unit dosage for oral administration of a cannabinoid or cannabimimetic agent or combination of such agents to a subject (e.g., a human) of about 50 to about 70 kg may contain about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1250 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, or more of the compound(s).

[0096] In some embodiments, a unit dosage for topical administration of cannabinoid or cannabimimetic agent or combination of such agents to a subject (e.g, a human) of about 50 to about 70 kg may contain between 1 and about 100 mg, about 5 and about 100 mg, about 5 and about 50 mg, about 5 and about 25 mg, about 5 and about 10 mg, about 2.5 to about 50 mg, about 2.5 to about 25 mg, about 1 to about 50 mg, about 1 to about 25 mg, or about 1 to about 10 mg of the compound(s). In particular embodiments, a unit dosage for topical administration of a cannabinoid or cannabimimetic agent or combination of such agents to a subject ( e.g ., a human) of about 50 to about 70 kg may contain about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, or more of the compound(s).

[0097] When or more of the cannabinoid or cannabimimetic agent compositions of the invention is administered to a subject, a relatively low dose is recommended at first, with the subject subsequently increasing the dose until an appropriate response is achieved (i.e., satisfactory alleviation of the subject’s symptoms). In addition, it is understood that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific composition employed, the age, body weight, general health, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the nature and degree of severity of the symptoms to be treated.

[0098] In some embodiments, a pharmaceutical composition or medicament of the present invention is administered orally once per day or divided into sub-doses and administered in multiple doses, e.g., twice, three times, or four times per day. In particular embodiments, a pharmaceutical composition comprised of a cannabinoid or cannabimimetic agent or combination of such agents is administered twice per day, with or without a prescription SERM, SARM, or other endocrine agent (e.g, ospemifene), with each dose specifically formulated. As a non limiting example, the dose can be formulated to include a 3: 1 CBD:A⁹-THC cannabinoid ratio or a 3:1 A⁹-THC:CBD cannabinoid ratio.. However, as will be appreciated by a skilled artisan, oral compositions described herein may be administered in different amounts and at different times.

[0099] In some embodiments, a pharmaceutical composition or medicament of the present invention is administered topically once per day or divided into sub-doses and administered in multiple doses, e.g ., twice, three times, or four times per day. In particular embodiments, a pharmaceutical composition comprised of a cannabinoid or cannabimimetic agent or combination of such agents is administered twice per day, with or without a synthetic prescription SERM (e.g, ospemifene), with each dose specifically formulated. As a non-limiting example, the dose can be formulated to include a 3:1 CBDA⁹-THC cannabinoid ratio or a 3:1 A⁹-THC:CBD cannabinoid ratio. However, as will be appreciated by a skilled artisan, topical compositions described herein may be administered in different amounts and at different times.

[0100] In some embodiments, the cannabinoid or cannabimimetic agent or agents are admini stered for about 1 to about 31 days, e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the cannabinoid or cannabimimetic agent or agents are administered for at least 1 day. In other embodiments, the cannabinoid or cannabimimetic agent or agents are administered for one or more weeks, e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more weeks. In yet other embodiments, the cannabinoid or cannabimimetic agent or agents are administered for one or more months, e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.

[0101] To achieve the desired therapeutic effect, the cannabinoid or cannabimimetic agent or combination of such agents may be administered in combination with synthetic prescription SERM, SARM, or other endocrine medication for multiple days, weeks, months, or years at the therapeutically effective daily dose. Thus, therapeutically effective administration of the cannabinoid or cannabimimetic agent or combination of such agents to alleviate pertinent symptoms described herein in a subject requires periodic ( e.g ., daily or twice daily) administration that continues for a period ranging from a few days, to a few weeks, to few months or longer. While consecutive daily doses are a preferred route to achieve a therapeutically effective dose, a therapeutically beneficial effect can be achieved even if the agents are not administered daily, so long as the administration is repeated frequently enough to maintain a therapeutically effective concentration of the agents in a subject. For example, one can administer the agent every day, every other day, or if higher dose ranges are employed and tolerated by the subject, twice a week.

[0102] The dosage of a pharmaceutical composition or medicament of the present invention can be monitored and adjusted throughout treatment, depending on the severity of symptoms, frequency of recurrence, and/or the physiological response to the therapeutic regimen. Those of skill in the art commonly engage in such adjustments in therapeutic regimens. Single or multiple administrations of the pharmaceutical compositions or medicaments can be administered depending on the dosage and frequency as required and tolerated by the subject. In any event, the composition or medicament should provide a sufficient quantity of the compounds of the invention to effectively treat a subject. Generally, the dose is sufficient to alleviate menopausal symptoms without producing unacceptable toxicity or side effects in a subject.

IV. EXAMPLES

[0103] The following examples are offered to illustrate, but not to limit, the claimed invention.

Example 1: Treatment of Cannabinoid-Induced Immunosuppression

[0104] Chronic use of cannabis is known to have immunosuppressive effects, an unwanted side effect that could be prevented by administering a SERM, e.g. , ospemifene, in combination. The immunosuppressive effects of cannabis are particularly troublesome for cancer patients, who already have compromised immune systems as a result of their disease and chemotherapy. Cannabis use is common among cancer patients for the alleviation of CINV as well as appetite stimulation. By combining a SERM, e.g. , ospemifene, with natural or synthetic cannabinoids or cannabimimetic agents, cancer patients would benefit from the CINV-alleviating effects of the cannabinoid- or cannabimimetic-based treatment while being protected from its potentially detrimental immunosuppressive effects. The SERM treatment will also help stimulate the immune system so that cancer patients can better respond to chemotherapy and immunotherapy. The use of triphenylethylene SERMs as immunomodulators for the treatment of cancer and infectious diseases is already protected by a separate patent (US 10, 154,970).

Example 2: Treatment of Blood Clotting Disorders Associated with SERM Treatment

[0105] One of the main side effects shared by SERMs and other endocrine therapies is the risk of blood clot formation, including deep vein thrombosis and pulmonary embolism. Coadmini stration of natural or synthetic cannabinoids or cannabimimetic agents and SERMs could potentially reduce the risk of blood clot formation. The natural or synthetic cannabinoid or cannabimimetic agents and their various combinations can be formulated as tinctures, gels, creams, lotions, patches for transdermal delivery, or other suitable formulation that most appeals to the individual subject.

Example 3: Treatment of Vasomotor Symptoms Associated with SERM Treatment

[0106] While prescription SERMs can be very effective in treating their targeted indications, vasomotor symptoms, e.g., hot flashes, are a common side effect. A cannabinoid, cannabimimetic agent, or any combination such agents can be used to alleviate the vasomotor symptoms being experienced by a subject undergoing treatment with a prescription SERM. Specifically, a subject being treated for menopausal symptoms of vaginal dryness and dyspareunia with a prescription SERM, e.g. , ospemifene, and who is experiencing hot flashes as a side effect, is treated with a cannabinoid, cannabimimetic, or a combination to alleviate these symptoms.

[0107] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A method for preventing or limiting the side effects associated with the use of endocrine therapies in a subject, the method comprising administering an effective amount of a cannabinoid, cannabimimetic agent or combination of such agents, or pharmaceutically acceptable salts thereof, in combination with an effective amount of a prescription endocrine agent to the subject.

2. The method of claim 1, wherein the prescription endocrine agent is a SERM, SARM, or other endocrine therapy.

3. The method of claim 2, wherein the SERM is selected from a group consisting of ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, and lasofoxifene.

4. The method of claim 2, wherein the SARM is selected from a group consisting of fispemifene, enobosarm, S-l, S-4, BMS-564929, LGD-2226, and S-40503.

5. The method of claim 2, wherein the endocrine therapy is selected from a group consisting of estrogen replacement therapy, androgen replacement therapy or any other prescrip tion endocrine agent.

6. The method of any one of claims 1 to 5, wherein the subject is experiencing side effects of endocrine therapy, including, but not limited to, blood clotting disorders and vaso motor symptoms.

7. The method of claim 1, wherein the cannabinoid is selected from a group consisting of A⁸-THC, A⁹-THC, A⁸-THCA, A⁹-THCA, CBD, CBDA, CBC, CBN, CBG, CBGA, A⁸-THCV, A⁹-THCV, or their synthetic equivalents, and combinations thereof.

8. The method of claim 1, wherein the cannabimimetic agent is selected from a group consisting of N-alkylamides, N-acylethanolamines, b-caryophyllene, salvinorin A, falcarin- ol, yangonin, kaempferol, capsaicin, N-benzyloleamide, perrottetinene, or pharmaceutically acceptable salts thereof, or any other natural or synthetic compound with cannabimimetic activity, or their synthetic equivalents, and combinations thereof.

9. A method for preventing or limiting side effects associated with the use of cannabinoids or cannabimimetic agents in a subject, the method comprising administering an effective amount of a prescription endocrine therapy in combination with an effective amount of a cannabinoid, cannabimimetic agent, or combination of such agents, or pharmaceutically acceptable salts thereof, to the subject.

10. The method of claim 9, wherein the prescription endocrine therapy is selected from a group consisting of a SERM, SARM, or other endocrine therapy.

11. The method of claim 10, wherein the SERM is selected from a group consisting of ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, and lasofoxifene.

12. The method of claim 10, wherein the SARM is selected from a group consisting of fispemifene, enobosarm, S-l, S-4, BMS-564929, LGD-2226, and S-40503.

13. The method of claim 10, wherein the endocrine therapy is selected from a group consisting of estrogen replacement therapy, androgen replacement therapy or any other prescrip tion endocrine agent.

14. The method of any one of claims 9 to 13, wherein the subject is experiencing side effects of cannabinoid or cannabimimetic therapy, including, but not limited to, immuno suppression.

15. The method of claim 9, wherein the cannabinoid is selected from a group consisting of A⁸-THC, A⁹-THC, A⁸-THCA, A⁹-THCA, CBD, CBDA, CBC, CBN, CBG, CBGA, A⁸-THCV, A⁹-THCV, or their synthetic equivalents, and combinations thereof.

16. The method of claim 9, wherein the cannabimimetic agent is selected from a group consisting of N-alkylamides, N-acylethanolamines, b-caryophyllene, salvinorin A, falcarin- ol, yangonin, kaempferol, capsaicin, N-benzyloleamide, perrottetinene, or pharmaceutically acceptable salts thereof, or any other natural or synthetic compound with cannabimimetic activity, or their synthetic equivalents, and combinations thereof.

17. A method for treating or alleviating symptoms of diseases or medical conditions resulting from dysfunction of the endocannabinoid system in a subject, the method comprising administering an effective amount of a prescription endocrine therapy in combination with an effective amount of a cannabinoid, cannabimimetic agent, or combination of such agents, or phar maceutically acceptable salts thereof, to the subject.

18. The method of claim 17, wherein the prescription endocrine therapy is selected from a group consisting of a SERM, SARM, or other endocrine therapy.

19. The method of claim 18, wherein the SERM is selected from a group consisting of ospemifene, toremifene, tamoxifen, raloxifene, bazedoxifene, and lasofoxifene.

20. The method of claim 18, wherein the SARM is selected from a group consisting of fispemifene, enobosarm, S-l, S-4, BMS-564929, LGD-2226, and S-40503.

21. The method of claim 18, wherein the endocrine therapy is selected from a group consisting of estrogen replacement therapy, androgen replacement therapy or any other prescrip tion endocrine agent.

22. The method of any one of claims 17 to 21, wherein the subject is experiencing cancer, including chemotherapy-induced nausea and vomiting and treatment-related immuno suppression, autoimmune disorders, menopausal symptoms, male or female infertility and sexual dysfunction, neuropathic pain, inflammation and inflammatory pain, type 2 diabetes, obesity, neurodegenerative disorders, schizophrenia, social anxiety disorders, depression, or any other disease or condition associated with dysfunction of the endocannabinoid system.

23. The method of claim 17, wherein the cannabinoid is selected from a group consisting of A⁸-THC, A⁹-THC, A⁸-THCA, A⁹-THCA, CBD, CBDA, CBC, CBN, CBG, CBGA, A⁸-THCV, A⁹-THCV, or their synthetic equivalents, and combinations thereof.

24. The method of claim 17, wherein the cannabimimetic agent is selected from a group consisting of N-alkylamides, N-acylethanolamines, b-caryophyllene, salvinorin A, falcarin- ol, yangonin, kaempferol, capsaicin, N-benzyloleamide, perrottetinene, or pharmaceutically acceptable salts thereof, or any other natural or synthetic compound with cannabimimetic activity, or their synthetic equivalents, and combinations thereof.