Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-21
2002-06-11
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06403597
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to methods and pharmaceutical compositions for the treatment of premature ejaculation. More particularly, the invention relates to the use of phosphodiesterase inhibitors in such methods and compositions.
BACKGROUND
Premature ejaculation is a debilitating yet common sexual dysfunction, and has been estimated to affect at least 30 to 40 percent of men at some point in their lives (Derogatis (1980)
Med. Aspects Hum. Sexuality
14:1168-76; Frank et al. (1978)
New Engl. J Med.
299:111-115; Schein et al. (1988)
Fam. Pract. Res. J.
7(3):122-134). The condition can lead to an inability to enter into or sustain relationships, can cause psychological damage to sufferers, and can also impair reproductive success.
The Diagnostics and Statistical Manual of Mental Disorders (DSM-IV) (Washington, D.C.: American Psychiatric Association, 1994) delineates three criteria for a diagnosis of premature ejaculation: (1) “persistent or recurrent ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it,” which is (2) associated with “marked distress or interpersonal difficulty,” and (3) not due exclusively to the “direct” effects of a “substance” (with withdrawal from opioids cited as an example). The disorder is usually primary, but can also be secondary. “Primary” premature ejaculation refers to a lifelong, typically congenital condition, while “secondary” premature ejaculation refers to a late onset condition, acquired after a period of normal functioning. Sexual dysfunctions such as premature ejaculation may also be further characterized as being generalized or limited to certain situations, and with respect to degree or frequency of the disturbance.
Premature ejaculation has historically been treated by psychosexual counseling in combination with “behavioral” therapies such as the so-called “pause” and “pause-squeeze” techniques. See St. Lawrence et al. (1992), “Evaluation and Treatment of Premature Ejaculation: A Critical Review,”
Int. J. Psychiatry in Medicine
22(1):77-97; Semans, “Premature Ejaculation: A New Approach,”
Southern Medical Journal
49:353-357, regarding the “pause” technique; and Masters and Johnson,
Human Sexual Inadequacy,
Little, Brown & Company, Boston, Mass., 1970, regarding the “pause-squeeze” technique. Any improvement resulting from the aforementioned techniques is short-lived, however, and the cooperation of a man's sexual partner is required. Typically, psychosexual counseling also requires the cooperation of the partner. Furthermore, many men may demand a quicker solution to the problem or are unwilling to attend counseling sessions. In addition, psychosexual counseling requires specialized therapists who may not be available to all patients, particularly in remote locations. Finally, counseling benefits only a subset of patients, i.e., those for whom the condition is psychogenic. Psychological therapies cannot alleviate premature ejaculation resulting from non-psychological causes.
Topical anesthetic agents and intracavernosal injection of medicaments have also been employed to treat patients suffering from premature ejaculation. However, anesthetic agents are problematic insofar as they necessarily decrease tissue sensitivity and thereby diminish sexual pleasure. Also, topical anesthetics can be transferred to sexual partners and thereby decrease their sensitivity and pleasure as well. Intracavemosal injection is associated with pain and discomfort, and is not a preferred mode of drug administration. Various devices have also been proposed to delay ejaculation; however, such devices can be awkward, inconvenient and embarrassing to use.
Methods for treating premature ejaculation by systemic administration of several different antidepressant compounds have been described (U.S. Pat. Nos. 4,507,323, 4,940,731, 5,151,448, and 5,276,042; PCT Publication No. WO95/13072). However, these drugs may not be effective for all patients, and the side effects of these drugs can halt treatment or impair patient compliance. Disease states or adverse interactions with other drugs may contraindicate the use of these compounds or require lower dosages that may not be effective to delay the onset of ejaculation.
For example, administration of the antidepressant fluoxetine has been claimed to treat premature ejaculation; see U.S. Pat. No. 5,151,448. However, the administration of fluoxetine has many undesired aspects. Patients with hepatic or renal impairments may not be able to use fluoxetine due to its metabolism in the liver and excretion via the kidney. Systemic events during fluoxetine treatment involving the lungs, kidneys or liver have occurred, and death has occurred from overdoses. In addition, numerous side effects are associated with oral fluoxetine administration include hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia, drowsiness, fatigue, headache, tremor, dizziness, convulsions, sweating, pruritis, and skin rashes. Fluoxetine interacts with a range of drugs, often by impairing their metabolism by the liver.
U.S. Pat. No. 4,940,731 describes the oral or parenteral administration of sertraline for treating premature ejaculation. It has been recognized that sertraline shares many of the same problems as fluoxetine; see Martindale, The Extra Pharmacopoeia, 31st edition, at p. 333 (London: The Royal Pharmaceutical Society, 1996). Sertraline is metabolized in the liver, and is excreted in the urine and feces. Thus, patients with cirrhosis must take lower doses, and caution must be exercised when administering sertraline to patients with renal impairment. Individuals taking monoamine oxidase inhibitors cannot take sertraline due to the risk of toxicity. Side effects resulting from oral sertraline administration include nausea, diarrhea, dyspepsia, insomnia, somnolence, sweating, dry mouth, tremor and mania. Rare instances of coma, convulsions, fecal incontinence and gynecomastia have occurred in patients undergoing sertraline therapy.
U.S. Pat. No. 5,276,042 describes the administration of paroxetine for the treatment of premature ejaculation. Paroxetine is predominantly excreted in the urine, and decreased doses are recommended in patients with hepatic and renal impairments. Like sertraline, paroxetine cannot be given to patients undergoing treatment with a monoamine oxidase inhibitor. Side effects from oral administration of paroxetine include hyponatremia, asthenia, sweating, nausea, decreased appetite, oropharynx disorder, somnolence, dizziness, insomnia, tremor, anxiety, impaired micturition, weakness and paresthesia
All of the known methods to treat premature ejaculation are thus problematic in one or more respects. An ideal method would not require ongoing (“chronic”) drug therapy or use of active agents with numerous and/or serious side effects. An ideal method would be useful in the treatment of individuals with secondary, acquired premature ejaculation as well as those suffering from a primary, lifelong condition. The method would not involve application of anesthetic agents, intracavemosal drug administration, or use of devices, and would not require ongoing counseling sessions.
It has now been discovered by the present inventors that phosphodiesterase (PDE) inhibitors, as a class, are unexpectedly useful in treating premature ejaculation, and meet all of the aforementioned requirements. The discovery is indeed surprising insofar as PDE inhibitors—of which sildenafil citrate, commercially available as Viagra®, is a representative compound—are used to treat impotence and thus enhance sexual function, i.e., as opposed to modulating sexual function in a manner that allows delay of ejaculation.
Phosphodiesterases are a class of intracellular enzymes involved in the metabolism of the second messenger nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) (see, e.g., Doherty, “Oral, Transdermal and Transurethral Therapies for Erectile Dysfunction” in Male Infertility and Dys
Abdel-Hamid Abdou Ali Ibrahim AbouBakr
Doherty, Jr. Paul C.
Place Virgil A.
Smith William L.
Wilson Leland F.
Reamer James H.
Reed Dianne E.
Reed & Associates
Vivus Inc.
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