DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the invention, a pharmaceutical vasodilator composition is administered to a male patient to cause a prolonged engorgement of the penis in order to cause expansion of the erectile tissue. The pharmaceutical composition comprises a pharmaceutically acceptable vasodilator for causing a prolonged suitable engorgement of the penis, together with a pharmaceutically acceptable diluent or carrier. The vasodilator may be a drug typically used to treat erectile dysfunction, but administered at a similar or higher dosage or sequentially as two or more lesser doses to achieve a prolonged period of engorgement followed by an additional period of lesser engorgement. Optionally, the agent may be administered at a slow rate with a micro infusion pump, time-release device or other self-injection technique or device. During a treatment, the penis should be engorged for a minimum of 3 hours and typically there is one treatment per day, and at least four treatments per week.
A very hard firm erection which is usually preferred for erectile dysfunction will have more veno-occlusive obstruction of the circulation and the reduced flow of fresh oxygenated blood into the erectile tissue will limit the maximum duration that the erection can be safely maintained. A softer less firm response can be safely and comfortably maintained for a greater length of time than a full erection.
The vasodilator drug may be one which either directly or indirectly causes vasodilation and may be classified, without limitation, in one of the following categories, namely, nitrovasodilators, ACE inhibitors, angiotensin receptor antagonists, phosphodiesterase inhibitors, direct vasodilators, adrenergic receptor antagonists, calcium channel blocking drugs, alpha blockers, beta blockers, lymphthomimetics, vitamins, organic nitrates, serotonin receptor-blocking agents, angina blocking agents, other hypertensive agents, cardiac stimulating agents, agents which improve renal, vascular function, sympathomimetic amine and mixtures thereof. For example, the drug may be any suitable vasodilator, such as papaverine, chlorpromazine, atropine, phentolamine, and prostaglandin E1, and salts, derivative, precursors, pharmaceutically active sequences or regions, peptidomimetics, mimetics, and mixtures thereof. Other drugs which may cause vasodilation include, without limitation, any of the following: niacin, nitroglycerine, nilatrin hydrochloride, pentoxyphylene, phenoxybenzamine, dichlophenac, hydralazine, hydrazaline, hydrochlorothiazide, sodium nitroprusside, isoxaprine hydrochloride, epoprostenol sodium, nylidrin hydrochloride, tolazoline hydrochloride, nicotinyl alcohol, phentolamine mesylate, phentolamine hydrochloride, yohimbine, thymoxamine imipramine, verapamil, isoxsuprine, naftidrofuryl, tolazoline, hydroisosorbide, dibenamine dinitrate, captopril, enalapril, enalaprilat, quinapril, lisinopril, ramipril, losartan, amrinone, milrinone, vesnarinone, nicorandil, prazosin, labetalol, celiprolol, carvedilol, bucindolol, nifedipine, dobutamine, minoxidil, nylidrin, and salts, derivatives, precursors, and mixtures thereof. Preferably, the vasodilator is prostaglandin E1, alone or with other vasodilators, administered as one or more doses that are typically lower than what would be used to treat erectile dysfunction. For example, the prostaglandin E1 may be administered by intracavernosal injection in a dosage range of 0.2 mcg to 500 mcg, more preferably in a dosage range of 0.5 mcg to 100 mcg. For example again, the prostaglandin E1 may be administered by an implantable sustained release drug or device in a dosage range of 0.5 mcg to 20,000 mcg, more preferably in a dosage range of 2 to 10,000 mcg (mcg=microgram).
Optionally, the patient may be treated with an additional, second pharmacological agent, to potentiate the effect of the composition which causes a prolonged, engorgement of the penis. Here, the second agent is called a "potentiator". The potentiator may be administered as part of the composition, separately from the composition, or a combination of both.
The potentiator may be a pharmacological agent or combination of agents that promote cellular processes that result in biological and/or mechanical creep and ultimately induce remodelling of the connective tissues that help define the size and shape of the penis. In addition, an agent which increases solubility of collagen may be used as a potentiator. Agents with very specific mechanisms of action may be used, or other agents with pleomorphic mechanisms of action, such as relaxin or growth hormone which trigger diverse mechanisms to induce growth in the penis may be used. For example, agents may be administered that facilitate the elongation of collagen fibres and accelerate the turnover remodelling rates of collagen through numerous mechanisms. For example, D-penicillamine and dimethyl sulfoxide (DMSO), which promote the elongation of collagen by inhibiting or interfering with inter- and intramolecular collagen cross-linkage may be used. Other agents include, but are not limited to, relaxin, insulin like growth factors, growth hormone, metalloproteinases or metalloproteinases agonists or promoters of collagenase activity, tissue inhibitors of matrix metalloprotenases (TIMPs) other agents that increase collagen solubility, prostaglandins, corticosteroids, or aminobenzoate potassium, a commercial brand being known as Potaba.TM.. Preferred prostaglandins are prostaglandin F2 alpha and prostaglandin E2. Also included are pharmaceutically active sequences, peptidomimetics, or mimetics above the above-listed molecules.
Relaxin directly and indirectly triggers a cascade of complex biochemical and cellular effects that can cause general morphological changes to genitalia. Prostaglandins such as prostaglandin F2 alpha and prostaglandin E2 have similar effects. This invention includes the mediators of these cascades as potentiators.
Collagen is a component of the extracellular matrix (ECM), which is a dynamic entity with many other components (e.g., proteoglycans, fibronectin, elastin, laminin, etc.) that functions as a storage reservoir for cytokines and enzymes and interacts intimately with surrounding cells to provide a structural scaffold and an efficient biochemical communication network within tissues. Enzymes primarily responsible for ECM remodeling are the Matrix MetalloProteinases (MMPs), which break down ECM components, and the Tissue Inhibitors of Matrix MetalloProteinases (TIMPs). Maintenance of a balance of ECM synthesis and MMP/TIMP activity in tissues is required for normal homeostasis; imbalances will generally lead to diseases or developmental problems such as scleroderma, periodontal disease, restenosis, osteoarthritis, liver cirrhosis, glomerulonephritis, and ulceration.
Relaxin is a 6 kDa peptide hormone that is structurally similar to insulin; the prohormone form consists of B-C-A chains (20 kDa), and the C chain is proteolytically excised in `mature` relaxin. However, unlike many other pro-hormones, pro-relaxin retains its biological activity. The profile of conserved amino acid sequences among various species such as pig, human, whale, porpoise, and shark suggests that relaxin is an ancient hormone with a unique molecular evolutionary history. The most recognized effect of relaxin on target cells is induction of MMP expression and inhibition of collagen synthesis.
Historically, relaxin has been classified as a "pregnancy hormone" that acts on reproductive tissues only during pregnancy, preparing the female for parturition by "relaxing" the pelvic ligaments and tendons. However, recent evidence suggests that relaxin may be classified as a "master hormone" that also induces biochemical, changes in a number of non-reproductive tissues. In addition to up-regulating MMP expression in reproductive tissues such as the cervix and placenta relaxin up-regulates expression of MMP-1 and MMP-3 in lung fibroblasts, skin fibroblasts, and fibrocartilaginous cells. Relaxin receptors are found in the brain heart, skin, nipples, small intestine, mammary gland, blood vessels, and testes. The bioactivity of relaxin is unique when compared with other cytokines that affect ECM remodeling.
The potentiator or potentiators may be administered as part of the composition, separately from the primary composition, or a combination of both. For example, the potentiator Potaba.TM. may be administered orally and the composition administered intracavernosally. Optionally, the potentiater may be administered locally into the cavernosal tissue, externally but adjacent the cavernosal tissue by injection into the surrounding connective tissue or the dorsal suspensory ligament of the penis, or a combination. The potentiator may be an agent which activates the androgen receptor, which is involved with male sexual development and function. For example, the potentiator may be an androgen hormone such as, but not limited to, the naturally occurring androgens and derivatives thereof, including androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate, androstenedione, dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone (DHT; also termed "stanolone"), 17.beta.-hydroxyandrost-4-en-3-one, 5.alpha.-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone; pharmaceutically acceptable esters of testosterone and 4-dihydrotestosterone, typically esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters; and pharmaceutically acceptable derivatives of testosterone such as methyl testosterone, testolactone, oxymetholone and fluoxymesterone. Testosterone and testosterone esters, such as testosterone enanthate, testosterone propionate and testosterone cypionate, may be used. The aforementioned testosterone esters are commercially available or may be readily prepared using techniques known to those skilled in the art or described in the pertinent literature.
The aforementioned androgenic agents are selected from the group consisting of naturally occurring androgens, synthetic androgens, and derivatives thereof, and any agent that will stimulate the androgen receptor directly or indirectly. The active agents may be incorporated into the present dosage units and thus administered in the form of a pharmaceutically acceptable derivative, analog, ester, salt, or amide, or the agents may be modified by appending one or more appropriate functionalities to enhance selected biological properties such as penetration through mucosal tissue. Preparation of esters, as noted in the preceding section, involves functionalization of hydroxyl and/or carboxyl groups that may be present, as will be appreciated by those skilled in the arts of pharmaceutical chemistry and drug delivery. For example, to prepare testosterone esters, the 17-hydroxyl group of the testosterone molecule is generally caused to react with a suitable organic acid under esterifying conditions, such conditions typically involving the use of a strong acid such as sulfuric acid, hydrochloric acid, or the like, and a temperature sufficient to allow the reaction to proceed at reflux. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
Testosterone is the principal steroid secreted by the testes and is the primary circulating androgen found in the plasma of males. Testosterone is converted to 4-dihydrotestosterone(DHT) by the enzyme 5 alpha-reductase in many peripheral tissues. DHT is thus thought to serve as the intracellular mediator for most androgen actions (Zhou, et al., Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone ("MENT'") and its acetate ester.
Optionally, a mechanical device such as a ring may be used at the base of the penis to prolong retention of the composition within the penis. The mechanical device may also be used to prolong retention of any pharmacological agent used to potentiate the effect of the composition, i.e., the potentiator.
The pharmaceutical composition is administered to the patient in a pharmaceutically acceptable dosage and schedule of administration to achieve engorgement which lasts for several hours. The treatment regimen typically begins with the physician determining a first dosage amount to try on a patient to determine that subject's erectile responsiveness to the composition. The amount of the first dosage given will be determined, among other things, by the route of intended administration, the age of the man, the recent history of erectile function of the man, and pre-existing health conditions of the man.
To achieve an erectile response, one or more doses may be administered which are typically of similar or a higher amount than that used to treat erectile dysfunction. This should produce a full erection. Alternatively, two or more lesser doses may be administered to achieve a prolonged engorgement of about 40-75% response. Optionally, a combination of similar, higher, and lesser doses may be administered.
It is the duration of a full erection and the subsequent period of engorgement that determines the starting dose. The penis may be visually inspected and palpated to determine the extent of the response to the composition.
A desirable first erectile response for the purposes of this invention is considered to be at least a 45-100% response for a period of at least two hours, but preferably 3-6 hours duration. For intracavernosal injections, first dosage amounts may range from about 0.5 mcg to about 30 mcg of prostaglandin E1, and more preferably from 1 mcg to 6 mcg. If a 70-100% erection is not achieved within 20 minutes of the first test dosage amount administered by intracavernosal injection, a second injection of less, the same or more of the composition as the initial test injection, depending on if there was any response with the first test dosage. For example, if there was a 55-70% response, a "booster" shot of a lesser amount than the first dosage amount may be administered. If there was no response, the same or more than the amount of the first dosage amount may be administered. Other administrative routes may take a longer or shorter time to achieve the initial response. The dosage is gradually increased by an amount that is usually within 50% to 200% the previously administered dosage until a satisfactory response is achieved. Using these general guidelines a maximum of two injections are administered per visit.
If an erection is not achieved with the first or second injection, one or more additional appointment/visits on another day may be required to establish the dose.
Once the correct response is achieved, it will be followed by one or more confirmatory doses on subsequent visits. Once a starting dosage amount of a single or a sequence of two or more injections is established that provides a response of suitable duration, the dosage may be titrated, for example, to provide the subject with an initial 70%-100% engorgement followed by a further period of reduced engorgement of at least 40% for at least 3-6 hours. The firmness of the penis generally decreases over this period, but will be at least 40% engorged for at least 3 and preferably up to 6 hours and less than 75% engorged for the majority of the time.
Depending on the subject's response to the treatment, higher dosages may be used as determined by the physician. However, it should be noted that higher dosages may increase the risk of a very firm erection that may cause ischemia. If the veno-occlusive mechanism closes to an extent that it reduces the inflow of fresh oxygenated blood for a sufficient period to cause pain and tissue damage it can cause a medical condition called a priapism. The risk of priapism can be reduced by using smaller multiple doses. The subject's condition should be monitored and the dosage adjusted to ensure that the patient experiences a prolonged period of engorgement, rather than a prolonged full erection, which may lead to priapism and associated health complications.
Subjects should have careful instruction in the signs and symptoms of priapism, and have access to 24 hour emergency medical treatment to allow prompt treatment and eliminate any risks of ischemia to the penis.
A physician should closely monitor the subject's response to medication, to determine signs of edema, tenderness, and other early signs that the dose is excessive and needs adjusting.
If lumps or unexpected thickening of the penis occurs during treatment, the patient may have to stop or suspend treatment for a period of time. Once the appropriate dosage for a given patient has been determined, the treatment may be self-administered under the close supervision of a properly trained physician or health professional.
The treatment is repeated over a period of time sufficient to cause a permanent increase in the length and girth of the patient's penis. The treatment may comprise administration with the composition alone, or in conjunction with potentiator. For example, the treatment may be repeated daily or at least two times a week over a period of several weeks or at least one month. More preferably, the treatment may be repeated at least 3-4 times a week for a period of at least 3 months. For treatment periods of between 12 and 18 months, an increase of at least 5% may be achieved in the length and girth of an erect penis, and increases of at least 30% or even at least 50% in the length and girth of an erect penis may be achieved. Active treatment for more extended periods, e.g. 24 months, may yield greater results.
