COMPOUNDS FOR METHODS FOR PROMOTING FEMALE REPRODUCTIVE HEALTH THROUGH MEDIATION OF RENIN ANGIOTENSIN FUNCTION

Abstract

The invention provides safe and efficacious treatments for the improvement of sexual function such as Genitopelvic Pain/Penetration Disorders; vulvovaginal atrophy, vestibulodynia, dyspareunia, Sexual Interest/Arousal Disorder, low female libido and Female Orgasmic Disorder.

Claims

1. A composition for treating a female sexual disorder (FSD), the composition comprising an angiotensin modulator for oral administration, wherein said FSD is at least one selected from the group consisting of genitopelvic pain disorder (GPPD), vulvovaginal atrophy (VVA), vestibulodynia, dyspareunia, sexual interest arousal disorder (SIAD), and female orgasmic disorder (FOD).

2. The composition of claim 1, wherein the angiotensin modulator is selected from the group comprising Angiotensin-converting enzyme inhibitors (ACE inhibitors), Angiotensin II receptor blockers (ARB), or include renin inhibitors (RI).

3. The composition of claim 2, wherein the Angiotensin-converting enzyme inhibitors includes Benazepril (Lotensin), Captopril (Capoten), Enalapril/Enalaprilat (Vasotec oral and injectable), Fosinopril (Monopril), Lisinopril (Zestril and Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik), the renin inhibitor includes Tekturna (Aliskiren) and the Angiotensin II receptor blockers include Azilsartan (Edarbi), Candesartan (Atacand) Eprosartan, Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), Telmisartan (Micardis), Valsartan (Diovan).

4. The composition of claim 3, wherein said composition further comprises a selective estrogen receptor modulator (SERM).

5. The composition of claim 4, wherein said SERM is ospemifene.

6. The composition of claim 2, wherein said composition further comprises estrogen.

7. The composition of claim 3, wherein said composition further comprises a cannabinoid such as THC or CBD based compounds

8. The composition of claim 2, wherein said composition further comprises a melatonin or bremelanotide or hyaluronic acid.

9. A method for treating a female sexual disorder (FSD), comprising orally administering an angiotensin modulator, wherein said FSD is selected from at least one of the the group consisting of genitopelvic pain disorder (GPPD), vulvovaginal atrophy (VVA), vestibulodynia, dyspareunia, sexual interest arousal disorder (SIAD), and female orgasmic disorder (FOD).

10. The method of claim 9, wherein the angiotensin modulator is selected from the group comprising an Angiotensin-converting enzyme inhibitors (ACE inhibitors), Angiotensin II receptor blockers (ARB), or renin inhibitors (RI).

11. The method of claim 10, wherein the Angiotensin-converting enzyme inhibitors includes Benazepril (Lotensin), Captopril (Capoten), Enalapril/Enalaprilat (Vasotec oral and injectable), Fosinopril (Monopril), Lisinopril (Zestril and Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik), the renin inhibitor includes Tekturna (Aliskiren) and the Angiotensin II receptor blockers include Azilsartan (Edarbi), Candesartan (Atacand) Eprosartan, Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), Telmisartan (Micardis), Valsartan (Diovan).

12. The method of claim 9, wherein said composition further comprises a selective estrogen receptor modulator (SERM).

13. The method of claim 12, wherein said SERM is ospemifene.

14. The method of claim 10, wherein said composition further comprises estrogen.

15. The method of claim 10, wherein said composition further comprises a cannabinoid such as THC or CBD based compounds

16. The method of claim 10, wherein said composition further comprises a melatonin or bremelanotide.

17. The method of claim 10 wherein a dosage for the angiotensin modulator for non-hypertensive patients is less than the minimum therapeutic dose for treatment of hypertensive patients.

18. The method of claim 10 wherein the angiotensin modulator dosage is increased until a desired outcome is achieved without a substantially hypotensive result.

19. An article of manufacture for treating a Female Sexual Disorder (FSD) comprising (i) one or more dosages of a therapeutic composition including an angiotensin modulator component or a derivative thereof suitable for treating the FSD, and (ii) a label containing instructions for oral use in treating the FSD.

20. The article of manufacture of claim 19 wherein said angiotensin modulator component comprises one or more of the following: an Angiotensin-converting enzyme inhibitors (ACE inhibitors), Angiotensin II receptor blockers (ARB), or renin inhibitors (RI).

21. The article of manufacture of claim 20, wherein the Angiotensin-converting enzyme inhibitors includes Benazepril (Lotensin), Captopril (Capoten), Enalapril/Enalaprilat (Vasotec oral and injectable), Fosinopril (Monopril), Lisinopril (Zestril and Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik), the renin inhibitor includes Tekturna (Aliskiren) and the Angiotensin II receptor blockers include Azilsartan (Edarbi), Candesartan (Atacand) Eprosartan, Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), Telmisartan (Micardis), Valsartan (Diovan).

Description

DETAILED DESCRIPTION OF THE INVENTIONS

[0091] Aspects of the invention provide methods and compounds for treating female sexual disorders by modulating and/or regulating the renin-angiotensin cycle in afflicted individuals thereby improving both blood flow and restoring circulatory function in the reproductive organs, improving organ function and thereby minimizing or reducing pain and improving functional ability thus increasing neurological and physiological response to sexual stimuli.

[0092] Hypertension may generally be treated with numerous known classes of medications including, Diuretics, Beta-blockers, ACE inhibitors, Angiotensin II receptor blockers, Calcium channel blockers, Alpha blockers, Alpha-2 Receptor Agonists, Combined alpha and beta-blockers, Central agonists, Peripheral adrenergic inhibitors and vasodilators.

[0093] Diuretics help the body get rid of excess sodium (salt) and water and help control blood pressure. They are often used in combination with additional prescription therapies.

[0094] Beta-blockers reduce the heart rate, the heart's workload and the heart's output of blood, which lowers blood pressure.

[0095] ACE inhibitors. Angiotensin is a chemical that causes the arteries to become narrow (vasoconstrictor), especially in the kidneys but also throughout the body. ACE stands for Angiotensin-converting enzyme. ACE inhibitors help the body produce less angiotensin, which helps the blood vessels relax and open up (vasodilator), which, in turn, lowers blood pressure.

[0096] Angiotensin II receptor blockers. These compounds block the effects of angiotensin, a chemical that causes the arteries to become narrow. Angiotensin needs a receptor-like a chemical “slot” to fit into or bind with-in order to constrict the blood vessel. ARBs block the receptors, so the angiotensin fails to constrict the blood vessel. This means blood vessels stay open and blood flow is increased.

[0097] Calcium channel blockers. This drug prevents calcium from entering the smooth muscle cells of the heart and arteries. When calcium enters these cells, it causes a stronger and harder contraction, so by decreasing the calcium, the hearts' contraction is not as forceful. Calcium channel blockers relax and open up narrowed blood vessels, reduce heart rate and lower blood pressure.

[0098] Alpha blockers. These drugs reduce the arteries' resistance, relaxing the muscle tone of the vascular walls.

[0099] Alpha-2 Receptor Agonists. These drugs reduce blood pressure by decreasing the activity of the sympathetic (adrenaline-producing) portion of the involuntary nervous system. Methyldopa is considered a first line antihypertensive during pregnancy because adverse effects are infrequent for the pregnant woman or the developing fetus.

[0100] Central agonists. Central agonists also help decrease the blood vessels' ability to tense up or contract. The central agonists follow a different nerve pathway than the alpha and beta-blockers, but accomplish the same goal of blood pressure reduction.

[0101] Peripheral adrenergic inhibitors. These medications reduce blood pressure by blocking neurotransmitters in the brain. This blocks the smooth muscles from getting the “message” to constrict. These drugs are rarely used unless other medications don't help.

[0102] Blood vessel dilators (vasodilators). Blood vessel dilators, or vasodilators, can cause the muscle in the walls of the blood vessels (especially the arterioles) to relax, allowing the vessel to dilate (widen). This allows blood to flow through better.

[0103] Generally speaking, systemic blood pressure medications and vasodilators described above are known to have minimal if any effect on female sexual performance or health. Doses of Viagra and Levitra have been administered to women without improvement to sexual health, performance or libido and accordingly are not marketed as such. Similarly, other vasodilators or blood pressure medications such as diuretics, beta-blockers, calcium channel blockers, alpha blockers, alpha-2 receptor agonists, central agonists and Peripheral adrenergic inhibitors are also not known to if any material effect on female sexual performance or health and thus operate through a mechanism of action which as no direct effect on female sexual performance or health.

[0104] On the other hand, the renin-angiotensin (RA) cycle is one known metabolic system for controlling blood pressure and blood volume in humans, primarily through vasoconstriction, which has an impact female sexual health and wellbeing. One key component of that system is the angiotensin-converting enzyme (ACE) 2 which modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, and exerts its physiological functions by modulating the levels of angiotensin II (Ang

[0105] II) and Ang-(1-7) in affected areas. The distribution and function of ACE2 in the female reproductive system shows that ACE2 is widely expressed in female reproductive organs including ovary, uterus, vagina, and vulvar regions. See for example, Potential influence of COVID-19/ACE2 on the female reproductive system by Yan Jin et al. Mol Hum Reprod. 2020 Jun. 1;26(6): 367-373.doi: 10.1093/molehr/gaaa030. PMID: 32365180. Therefore, such reproductive organs and tissues are significantly affected by angiotensin 2 which acts as vasoconstrictor restricts blood flow.

[0106] Regulating the RA cycle (e.g., through inhibition of the ACE2) affects blood flow in the female reproductive system including as well as modulating luteal angiogenesis and degeneration, which also influence changes in endometrial tissue. Generally speaking, improving blood flow by limiting the vasoconstriction caused by the RA cycle improves neurological function and facilitates production of a mucus membrane in the female reproductive organs and limits, minimizes or reduces endometriosis, a common cause of dyspareunia, as well as promoting normal lubrication and improved response to sexual stimuli. This is preferable and more efficacious to general systemic blood pressure reducers described herein which have no such targeted effect on female reproductive systems.

[0107] For example, during sexual arousal, improved genital engorgement occurs as a result of increased blood flow, which may have become have been reduced through certain AT-based vasoconstriction. With adequate local blood flow, the vaginal canal is lubricated by secretions from uterine glands and from a transudate that originates from the subepithelial vascular bed, passively transported through the intraepithelial spaces, sometimes referred to as intercellular channels. Engorgement of the vaginal wall raises pressure inside the capillaries and creates an increase in transudation of plasma through the vaginal epithelium. This vaginal lubricative plasma flows through the epithelium onto the surface of the vagina, initially forming droplets that coalesce to form a lubricative film that covers the vaginal wall. Additional moistening during intercourse comes from secretions of the paired greater vestibular or Bartholin's glands. In addition to lubricating, the vagina lengthens and dilates during sexual arousal as a result of relaxation of the vaginal wall smooth muscle. In human and animal models, sexual stimulation results in increased vaginal blood flow and decreased vaginal luminal pressure.

[0108] Moreover, physiologic changes occur in the clitoris and vestibular bulbs during sexual arousal. With sexual stimulation, increased blood flow to the clitoral cavernosal and labial arteries resulting in increased clitoral intracavernous pressure, tumescence, and protrusion of the glans clitoris, and eversion and engorgement of the labia minora. Studies show that, unlike the penis, the clitoris and vestibular bulbs lack a subalbugineal layer between the erectile tissue and the tunica albuginea layer. In the male, this layer possesses a rich venous plexus that, during sexual excitement, expands against the tunica albuginea, reducing venous outflow and making the penis rigid. The absence of this venous plexus in the clitoris and vestibular bulbs illustrates that this organ achieves tumescence, but not rigidity during sexual arousal, making increased blow and key aspect in sexual wellness and performance.

[0109] Accordingly, the present invention provides for the use of known AT cycle regulation compounds for vasodilation of affected erogenous and sexual reproductive zones in both male and females. Such compounds may include Angiotensin-converting enzyme inhibitors (ACE inhibitors) such as, but not limited to, Benazepril (Lotensin), Captopril (Capoten), Enalapril/Enalaprilat (Vasotec oral and injectable), Fosinopril (Monopril), Lisinopril (Zestril and Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik). In some embodiments, this may also include renin inhibitors such as Tekturna (Aliskiren) and/or may include Angiotensin II receptor blockers such as Azilsartan (Edarbi), Candesartan (Atacand) Eprosartan, Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), Telmisartan (Micardis), Valsartan (Diovan). The foregoing list is intended to be exemplary and other compounds with ACE inhibitor and/or ARB properties may be used if desired. Typically, only one of these compounds would be used. but multiple could be used for patients that demonstrate adequate response and tolerance to such combinations.

[0110] In accordance with aspects of the present invention, persons with known hypertension and female sexual dysfunction may be prescribed one of an ACE inhibitors, an Angiotensin II receptor blocker or renin inhibitor as described above to treat both indications. Dosages may begin a lowest therapeutic amount and increased accordingly as needed to effectively treat presenting symptoms, which may include sexual dysfunction, hypertension or both. In some embodiments, ACE inhibitor, an Angiotensin II receptor blockers may be preferred over renin inhibitors. Some embodiments may include hyaluronic acid to promote nerve regeneration and function and may include systemic vasodilators such as nitric oxide for fast acting kick off and well as other known vasodilators such as sildenafil, vardenafil etc. and the like.

[0111] In the case of non-hypertensive women with sexual dysfunction, such persons may be initially provided with treatment amounts below the minimum therapeutic dose recommended for hypertension treatment and then may be provided with increasing amounts to until undesirable low blood pressure results. For example, if one such AT cycle regulation compound has a minimum therapeutic dose of 200 mg-600 mg per day, an initial starting dosage for non-hypertensive could be half of the minimum hypertension amount, (e.g.,100 mg) may be provided and results monitored, and the dosage changed (increased or decreased) as treatment goals require. The therapeutic goal being to achieve treatment objectives with materially altering blood pressure. Prescribed doses may be increased or decreased accordingly to achieve treatment objectives. Furthermore, may not be necessary for such treatment to necessarily occur daily, but rather periodically (e.g., once, twice or three times a week) after an initialization stage where medication is provided daily until a steady state response is achieve and then tapering off as to an effective point for long term maintenance and treatment. The specific type of AT modulator and specific treatment regimen will be determined by a medical practitioner based on the patients physiological condition, response on other known factors influencing such as decision. As, above, some such embodiments may include hyaluronic acid to promote nerve regeneration and function and may include systemic vasodilators such as nitric oxide for fast acting kick off and well as other known vasodilators such as sildenafil, vardenafil etc. and the like.

[0112] As is known in the art, the therapeutic effects of pharmaceuticals on target tissues are frequently dose dependent. For virtually all drugs treatment protocols there are dosage parameters where the therapeutic benefit of the drug is manifest but where exceeding that therapeutic dosage range causes adverse, unwanted side effects, and in some cases, toxicity or exacerbation or worsening of condition for which the drug was supposed to benefit, which is generally undesirable and is therefore clinically avoided.

[0113] Sexual response includes desire, arousal, lubrication and orgasm. It is known that, if perceived as unpleasant or toxic, sensations of pain can interfere with a woman's sexual response. Genital pelvic pain disorder in VVA and vulvodynia, vestibulodynia is characterized by genital hypersensitivity and sensory hyperinnervation with unmyelinated sensory nociceptor neurons. Although direct effects of estrogen withdrawal on vaginal cells is implicated in VVA, (e.g., thinning of the vaginal epithelium) estrogen withdrawal also causes both autonomic and somatic sensory nerves to proliferate, suggesting that indirect effects mediated by changes in vulvar vaginal innervation may be a major contributor to pain associated with VVA. This has been shown by histopathological analysis of relevant tissues. Topical application of estradiol is a well-documented and effective therapeutic for pain associated with VVA.

[0114] Exogenous progesterone use, in contraceptives, in premenopausal women, may be one etiology of vulvar hyperinnervation in vestibulodynia and or vulvodynia. Progesterone can induce both autonomic and somatic sensory nerves to proliferate. Oral progesterones can increase the risk of developing vestibulodynia by four to ninefold. Topical estradiol has been shown to reduce the sensory hyperinnervation and vulvar pain associated with vestibulodynia and vulvodynia.

[0115] Symptoms of VVA and GPPD (vulvodynia, vestibulodynia and dyspareunia) can be caused by proliferation of autonomic and sensory nerve vulvar vaginal innervation density. Reduction or normalization of nociceptive (or pain afferent) pathways that are localized in the area of the vulva, vestibule, vaginal introitus, and posterior fourchette, in VVA, vulvodynia and vestibulodynia is the most likely mechanism for the therapeutic efficacy of the application of topical estrogens. Increased blood flow through the use of AT modulators increases vulvar mucosa and vaginal introitus and is effective in alleviating vulvar pain and dyspareunia in both VVA and vulvodynia/vestibulodynia.

[0116] Another mode of action of the present invention is on the improvement in mucous membranes which may help reduce inflammation and irritation that can be a factor in VVA, vulvodynia, and vestibulodynia. Increased sympathetic innervation may augment vasoconstriction and promote vaginal dryness.

[0117] The normal female sexual response depends on the function of the peripheral autonomic nervous system and intact signaling pathways controlling the tone of genital vascular and nonvascular smooth muscle.

[0118] The first measurable sign of sexual arousal is an increase in vaginal blood flow. This creates the engorged condition, that saturates the fluid resabsorptive capacity of the vaginal epithelium. This results in increase in vaginal fluid, i.e. lubrication which enables less friction during coitus.

[0119] Genital motor responses to sexual stimulation including vaginal lubrication is mediated by autonomic vasoactive neurotransmitters including, vasoactive intestinal peptide (VIP) and Nitric oxide synthetases.

[0120] The mechanisms underlying vaginal lubrication appear to be mediated by several vasoactive neurotransmitters especially Vasoactive Intestinal Peptide (VIP). VIP injection into or topical application to the vaginal wall increases vaginal blood flow and induces vaginal fluid production which may be mediated by AT modulators.

[0121] Nitric Oxide cyclic guanosine monophosphate pathway is involved in the physiological mechanism of female genital arousal. Endothelial Nitric Oxide Synthases (NOS) and VIP vasoactive intestinal peptides are co-localized in the human vagina. Nitric Oxide synthases are located on the vaginal vessels in close proximity to vasoactive intestinal peptides (VIP) on the vaginal nerve fibers. They are both directly involved in effecting vaginal blood flow and thus lubrication. Disturbances in these pathways are thought to contribute to the pathophysiology of sexual dysfunction. Nitric oxide relaxes genital vascular and nonvascular smooth muscle which plays a pivotal role in mediating the normal sexual response to visual and/or tactile erotic stimulation. Insufficient bioavailability of Nitric Oxide (NO) and/or vasoactive peptides decreases vasodilation which decreases vaginal lubrication. Proper use of AT modulators affects the level of NO in endothelial cells to increase lubrication.

[0122] An “effective amount” refers to an amount of therapeutic compound that is effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A “therapeutically effective amount” of a therapeutic compound may vary according to factors such as the disease state, age, sex, and weight of the individual. A therapeutically effective amount may be measured, for example, by improved survival rate, more rapid recovery, or amelioration, improvement or elimination of symptoms, or other acceptable biomarkers or surrogate markers. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount of therapeutic compound that is effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0123] An “individual,” “subject” or “patient” is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, primates (including human and non-human primates) and rodents (e.g., mice, hamsters, guinea pigs, and rats). In certain embodiments, a mammal is a human. A “control subject” refers to a healthy subject who has not been diagnosed as having a disease, dysfunction, or condition that has been identified in an individual, subject, or patient. A control subject does not suffer from any sign or symptom associated with the disease, dysfunction, or condition.

[0124] A “medicament” is an active drug that has been manufactured for the treatment of a disease, disorder, or condition.

[0125] “Patient response” or “response” can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including stabilization, slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) inhibition (i.e., reduction, slowing down or complete stopping) of a disease cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e. reduction, slowing down or complete stopping) of disease spread; (5) decrease of an autoimmune condition; (6) favorable change in the expression of a biomarker associated with the disorder; (7) relief, to some extent, of one or more symptoms associated with a disorder; (8) increase in the length of disease-free presentation following treatment; or (9) decreased mortality at a given point of time following treatment.

[0126] As used herein, a “pharmaceutically acceptable carrier” or “therapeutic effective carrier” is aqueous or nonaqueous (solid), for example alcoholic or oleaginous, or a mixture thereof, and can contain a film-forming agent, adhesion agent, surfactant, emollient, lubricant, stabilizer, dye, perfume, preservative, acid or base for adjustment of pH, a solvent, emulsifier, gelling agent, moisturizer, stabilizer, wetting agent, time release agent, humectant, or other component commonly included in a particular form of pharmaceutical composition. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, and oils such as olive oil or injectable organic esters. A pharmaceutically acceptable carrier can contain physiologically acceptable compounds that act, for example, to stabilize or to increase the absorption of specific inhibitor, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.

[0127] As used herein, “treatment” refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated and can be performed before or during the course of clinical pathology. Desirable effects of treatment include preventing the occurrence or recurrence of a disease or a condition or symptom thereof, alleviating a condition or symptom of the disease, diminishing any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, ameliorating or palliating the disease state, and achieving remission or improved prognosis. In some embodiments, methods and compositions of the invention are useful in attempts to delay development of a disease or disorder.

[0128] Cannabis and cannabinoid preparations have been linked to improvements of subjective indices of sexual function in women. These include self-reported increases in sexual desire, orgasmic function, sexual satisfaction, enjoyment, and pleasure. (Osborne & Fogfel, Substance Use & Misuse 43:539-572 (2008); Palamar et al., Arch Sex Behay. doi:10.1007/s10508-016-0782-7 (2016).) Furthermore, cannabinoids have been used to alleviate pain disorders. (Hill, Kevin, J. Am. Med. Assoc. 313(24):2474-2483 (2015).) AT-modulators can be combined with cannabinoids such as known THC or CBD based compounds treat Male and/or Female Sexual Disorders. The foregoing citations are incorporated by reference in their entirety.

Other Observations

[0129] All publications and patent documents disclosed or referred to herein are incorporated by reference in their entirety. The foregoing description has been presented only for purposes of illustration and description. This description is not intended to limit the invention to the precise form disclosed. It is intended that the scope of the invention be defined by the claims appended hereto.