By a News Reporter-Staff News Editor at Pharma Business Week According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors THOMPSON, RONALD J. (Cincinnati, OH); Thompson, James M. (Cincinnati, OH), filed on February 19, 2016, was made available online on August 31, 2017 (see also Pharmaceutical Companies).
The assignee for this patent application is FSD Pharma Co, LLC.
Reporters obtained the following quote from the background information supplied by the inventors: "Female sexual arousal disorder is defined by a complete lack of, or significant reduction in, sexual interest or sexual arousal. The problem may be lifelong or acquired, it can be the result of environmental and/or cultural factors, and its severity may fall on a continuum of mild to moderate to severe. The problem may be situational, occurring only in some instances and not others, or generalized with no apparent limitations. Personal and relationship distress can also be an important cause, making it difficult to identify clinical trial end points in the development of drugs While maintaining safety and efficacy.
"Tadalafil (Cialis.RTM.), vardenafil (Levitra.RTM., Staxin.RTM.), sildenafil (Viagra.RTM.), avanafil (Stendra.RTM./Spedra.RTM.), udenafil (Zydena.RTM.), mirodenafil (Mvix.RTM.) and lodenafil (Helleva.RTM.) are all inhibitors of the phosphodiesterase-5 enzyme (ME-5) which destroys cyclic guanosine monophosphate (cGMP). The primary mechanism of action of PDE-5 inhibitors involves a temporary disabling of the phosphodiesterase-5 enzyme, allowing cGMP to persist. All of these drugs are able to treat male impotence caused by compromised blood flow to the penis. The Nitric Oxide Synthase biochemical pathway converts tissue 1-arginine into nitric oxide (NO) and cGMP, both potent vasodilators. The physiologic action of NO is very transient, measured in seconds, but it stimulates the production of cGMP Cyclic GMP in turn signals the smooth muscles lining the blood vessels of the penis to dilate and allow stronger blood flow. Therefore, cGMP is a key player in the erectile process.
"Cyclic GMP is normally degraded by the PDE-5 enzyme. The PDE-5 enzyme inhibitors slow down the normal degradation of cGMP, and cGMP accumulates for an extended period of time, measured in hours. By holding PDE-5 at bay for 4 to 36 hours, these drugs allow cGMP to facilitate the erectile process without interference. The PDE-5 inhibitors sildenafil and vardenafil, for example, provide 4-5 hours duration of action, while tadalafil (approved for daily use) provides up to 36 hours duration.
"The sildenafil/Viagra.RTM. story is one of pharmaceutical legend, Sildenafil was initially developed as an oral anti-angina medication, but in the clinical studies 80% of men reported sustained penile erections. The scientists at Pfizer, headed by Dr. John Lamattina, decided to use sildenafil as an oral therapy for impotence. The definition of 'impotence' is the inability to establish and maintain a penile erection adequate for intercourse. In the 1990's there were no oral therapies for impotence. Viagra was the first. Pfizer marketers rebranded impotence as Erectile Dysfunction, and further as ED. In 1998, Viagra was introduced into the U.S. Also in 1998, the FDA first allowed direct-to-consumer advertising of prescription drugs. The combination of the first oral therapy for impotence, marketed as ED, and print and television advertising, propelled Viagra.RTM. to a multibillion dollar per year product.
"U.S. Pat. No. 5,250,534 to Bell et al. (and assigned to Pfizer) titled 'Pyrazolopyrimidione antianginal agents' is the original sildenafil 'composition of matter' patent. This patent addresses only an antianginal use for sildenafil. U.S. Pat. No. 6,469,012 to Ellis et al. titled 'Pyrazolopyrimidiones for the treatment of impotence' was filed alter the discovery of sildenafil's action as an effective impotence therapy. Both of these patents are incorporated by reference herein in their entirety. Impotence is a male-only dysfunction, and the 'method of use' for the '012 patent only applies to males being treated with sildenafil.
"Female Sexual Interest/Arousal Disorder (FSIAD) and the FDA: Female sexual arousal is a neurophysiologic process and is characterized by increased clitoral and vaginal blood perfusion, leading to enhanced sensation, genital swelling and vaginal lubrication. Female sexual interest/arousal disorder (FSIAD) has been reported to be quite severe for women who suffer from atherosclerosis or diabetes mellitus. FSIAD has also been called Female Sexual Dysfunction (FSD), Female Sexual Arousal Disorder (BAD), and Hypoactive Sexual Desire Disorder (HSDD), and is generally characterized by a lack or absence of sexual fantasies and desire for sexual activity FSIAD has been classified as having four separate components: (1) desire: libido disorders (decreased or absence of sexual desire/libido); (2) arousal disorders (decreased or absence of sexual arousal); (3) orgasmic disorders (difficulty achieving orgasm, and/or anorgasmia (complete lack of orgasm); and (4) sexual pain disorders (dyspareunia, painful intercourse).
"In the 16 years following the FDA's publication of the 2000 Guidance for Industry on the clinical development of drug products for treatment of FSIAD, numerous pharmaceutical companies have expended hundreds of millions of dollars in search for an. FDA-approvable drug to treat FSIAD. Only recently (in 2015) was flibanserin, an oral selective serotonin reuptake inhibitor sold under the trade name Addyi.RTM., approved for the treatment of pre-menopausal women with FSIAD. Flibanserin is a systemically absorbed serotonin uptake modulator medication (not a testosterone) initially developed as an antidepressant; however, because of flibanserin's dangers, the FDA requires a very stringent Risk Evaluation and Mitigation Strategy (REMS) that requires all prescribing physicians and dispensing pharmacists to be credentialed for flibanserin. Further, flibanserin only achieved FDA approval after two separate FDA denials. Flibanserin labeling also contains a 'Black Box' warning not to take the drug with anti-fungal medications or alcohol.
"Prior to Flibanserin, only two New Drug Applications for Female Sexual Dysfunction had been submitted to, accepted by, and evaluated by the FDA. Both drugs were denied approval because of safety concerns. Initially the FDA evaluated a transdermal testosterone patch, Intrinsa.RTM., which is worn on the abdomen and delivers systemic testosterone to a woman. Since the efficacy of Intrinsa.RTM. was marginal (with one more sexually satisfying event per month than placebo) and because of safety concerns (exogenous testosterone is converted into estrogen in the female body, and excess exogenous estrogen is a risk factor for breast cancer), the FDA overwhelmingly voted against approval of Intrinsa. In December 2011, BioSante Pharmaceuticals announced the failure of phase three clinical trials of LibiGel.RTM., a topical testosterone gel applied daily to the skin of the upper arm. The gel, which delivers a lower testosterone dose than Intrinsa.RTM., failed to work better than placebo in boosting desire,
"The demanding FDA efficacy tests for drugs for FSIAD has halted other developmental drug programs. For example, Vivus Pharmaceuticals discontinued the development of Alista.RTM., a topical alprostadil cream applied directly to the clitoris for vasodilation, because the phase IIb clinical trials could not establish efficacy. Femprox.RTM.), owned by Apricus Biosciences, is also a topical alprostadil clitoral cream but formulated with a specific topical drug delivery vehicle. Femprox.RTM. is in development with positive clinical efficacy in 400 women. The FDA New Drug Application for Femprox.RTM. is several years away.
"Why are there so few drugs FDA-approved for FSIAD after multiple drug development programs? In short, because human female sexual responses are complex. Dr. Elizabeth Kavaler, a urologist at Lenox Hill Hospital in New York City was quoted in the Associated Press after the initial flibanserin denial of FDA-approval, 'It's a fairly complicated area. Unlike in men's sexual dysfunction where there is a major mechanical concern, in women there's no mechanical concern, so if she's not having a successful sex life, where is the problem?' A woman's sexual responsiveness has multiple variables, such as, age, estrogen status, testosterone status, and medications commonly used by women such as oral contraceptives and antidepressants. Antidepressants, especially serotonin reuptake inhibitors, are well known to decrease libido and sexual desire in the hypothalamus of the brain. Oral contraceptives decrease effective levels of normal free testosterone by increasing the production of sex binding globulins by the liver. Age itself does not impact a woman's sexual responsiveness, hut the normal decrease in estrogen in a woman's mid-thirties and beyond compromises sexual responses. Age also is associated with a decrease in a woman's effective testosterone level. When it comes to female androgen insufficiency and treatment of women with low sexual desire, it is important for clinicians to recognize that in normal women androgen levels decline by 50% from the early 20's to the mid 40's, and therefore age-related androgen insufficiency may occur in women's late 30's and 40's, as well as in postmenopausal women.
"Testosterone and a Woman's Genital Sexual Responsiveness: Clitoral erection is a physiological phenomenon where the clitoris becomes enlarged and firm. Clitoral erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually associated with sexual arousal.
"The female clitoris is the homologue of the male penis. The corpora cavernosa clitoridis is an adjoining, expandable pair of sponge-like regions of erectile tissue which contain most of the blood in the clitoris during clitoral erection. This is homologous to the corpus cavernosum penis in the male, with a recognizably similar structure. The part of the clitoris visible on the outside varies in size from a few millimeters to one centimeter and is located hidden in the upper labial fold. Any type of motion can increase blood flow to this organ, resulting in increased secretions which lubricate the vagina. During sexual arousal, for example, arterial blood flow to the clitoris is increased and trabecular smooth muscle within the clitoris relaxes, allowing blood to engorge the erectile tissues. The ischiocavernous and bulbocavernous muscles contract to compress the dorsal vein of the clitoris to stop drainage of the clitoris, trapping the blood, The corpora cavernosa form a main body that connects to the glans clitoridis. There is also a strip of erectile tissue (similar to the placement of the corpus spongiosum in males) running along the ventral surface of the corpora cavernosa main body. These female genital tissues make up the shaft, which is connected to the glans clitoridis. The tunica albuginea, a fibrous-elastic sheath, surrounds the shaft and glans clitoridis.
"There are many ways to stimulate the clitoris, which ultimately leads to clitoral erection. In females, clitoral stimulation results in vasodilation and filling of the corporal shaft and glans clitoridis with blood, increased clitoral length and diameter, and increased blood flow and tumescence of associated structures such as the labia folds. There is also increased vaginal secretion and lubrication, engorgement of the vaginal wall, and increased diameter of the vaginal lumen. Thus, an agent that causes sexual arousal will also relieve conditions of a contracted vagina, such as vaginismus, vaginal dryness, and dyspareunia (difficult or painful coitus). Ultimately, appropriate integration of the sensory inputs from the nerve endings of the clitoris together with other stimuli culminates in orgasm, satisfaction, and termination of coitus. A woman typically achieves orgasm from an erect clitoris just as a man typically achieves an orgasm from an erect penis.
"Female genital tissue vasodilation is afforded by cGMP from the nitric oxide synthase pathway, which has been reviewed above. In females the speed of the conversion of 1-arginine into nitric oxide and cGMP, and the efficiency of the conversion in the nitric, oxide pathway, are both dictated by testosterone levels. Testosterone is important for the female libido, sexual desire, and genital sexual responsiveness. A high testosterone titer causes the rapid conversion of 1-arginine into nitric oxide and cGMP, and a prompt clitoral erection. Research has shown that testosterone rapidly induces nitric oxide (NO) production via the androgen receptor-dependent activation of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells. it is thus apparent why pharmaceutical developmental programs have focused on exogenous testosterone as a treatment for FSIAD. Exogenous testosterone for women can improve libido and improve genital sexual responsiveness.
"Phosphodiesterase-5 enzyme (PDE-5) inhibitors for Female Sexual Dysfunction: The use of sildenafil alone for treating sexual dysfunction in women has not been satisfactorily demonstrated in 2004, Pfizer issued a statement that it was abandoning research testing of sildenafil/Viagra.RTM. as a treatment for female sexual arousal disorder and would not file the drug with regulators for this indication, Pfizer stated, 'Clinical studies, which began in 1996, tested sildenafil citrate on about 3000 women, and failed to show any benefit of sildenafil for women.' Further, Pfizer stated 'Female Sexual Arousal Disorder is an emerging area of research and is far more complex than male erectile dysfunction.'
"A recent study by H. G. Nurnberg et al, showed a complete or very significant reversal of a female's sexual dysfunction upon taking oral sildenafil one hour prior to sexual activity. In this study, eight out of the nine women required 50 mg of sildenafil by mouth, white the 9th woman required 100 mg of sildenafil. Another option for women who have serotonin reuptake inhibitor-induced anorgasmia is the use of vardenafil. As noted above, PDE-5 inhibitors such as vardenafil facilitate muscle relaxation and improve penile erection in men. However, there is much controversy about the efficiency of the drug used in the reversal of female sexual dysfunction. Vardenafil is similar to sildenafil, but is less expensive and may be covered under some insurance plans. A study by A. K. Ashton M.D. has shown that in the case of one particular woman, the effects of vardenafil as opposed to sildenafil have not only been comparable in the effectiveness, but that vardenafil is cheaper and requires a smaller dose. So far, vardenafil has been approved by the FDA only for use in men.
"In light of the above, it would be advantageous to provide a new medication for treatment of Female Sexual Interest/Arousal Disorder (FSIAD), including difficulty achieving orgasm and anorgasmia. It would also be advantageous to provide a new medication for treatment of FSIAD which induces and prolongs sustained clitoral vasodilation and erection, without the administration of exogenous testosterone. It would also be useful to provide a topical clitoral formulation/composition that has minimal systemic absorption, a favorable risk/benefit ratio, and efficacy to establish significance over placebo, in order to allow FDA-approval of either a prescription or an over-the-counter drug indicated for the treatment of FSIAD."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "A first aspect of the invention relates to a composition comprising tadalafil, menthol, and 1-arginine for treatment of orgasmic disorders in a female subject, wherein the composition is topically applied to the clitoris and genital tissues of the subject, and wherein the composition compensates for low testosterone levels in the subject by inducing and prolonging sustained clitoral vasodilation and erection. The inventive composition typically further comprises an extended release mucoadhesive polymer, prepared as a topical film, cream or gel.
"A second aspect of the invention is a composition comprising tadalafil at a concentration of between 0.1% and 4.0%, menthol at a concentration of between 0.1% and 2.0%, and 1-arginine at a concentration of between 0.1% and 5.0%, for treatment of orgasmic disorders in a female subject, wherein the composition is topically applied to the clitoris and genital tissues of the subject, and wherein the composition compensates for low testosterone levels in the subject by inducing and prolonging sustained clitoral vasodilation and erection.
"A third aspect of the invention is a method for treating orgasmic disorder in a female subject, comprising topically administering a composition comprising tadalafil, menthol, and 1-arginine to the clitoris and genital tissues of the subject, wherein the topical application of the composition induces and prolongs sustained clitoral vasodilation and erection.
"While the nature and advantages of the. present invention will be more fully appreciated, from the following detailed description, and more particularly defined by the appended claims."
For more information, see this patent application: THOMPSON, RONALD J.; Thompson, James M. Topical Anorgasmia Therapy. Filed February 19, 2016 and posted August 31, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170239175%22.PGNR.&OS=DN/20170239175&RS=DN/20170239175
Keywords for this news article include: Antiimpotence, Antipruritic, Pharmaceutical Companies, Pfizer, Arginine, Synthase, Androgens, Autacoids, Serotonin, Gynecology, Advertising, Alprostadil, Eicosanoids, FDA Actions, Tryptamines, Nitric Oxide, Contraception, Viagra Therapy, Women's Health, Biogenic Amines, Menthol Therapy, Nitrogen Oxides, Impotence Agents.
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