WO2002069966A1 - Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction - Google Patents
Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction Download PDFInfo
- Publication number
- WO2002069966A1 WO2002069966A1 PCT/US2001/007111 US0107111W WO02069966A1 WO 2002069966 A1 WO2002069966 A1 WO 2002069966A1 US 0107111 W US0107111 W US 0107111W WO 02069966 A1 WO02069966 A1 WO 02069966A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- lomg
- patient
- injectable pharmaceutical
- erectile dysfunction
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Definitions
- the present invention relates to pharmaceutical compositions for treatment of erectile dysfunction.
- the invention also relates to methods of administering the compositions for treatment of erectile dysfunction, including by subcutaneous (sub-q), intramuscular (IM), mtracavernosal (IC), intravenous (IN), and intraartal injection.
- the invention further relates to methods for reversal of erectile dysfunction by administering the compositions disclosed herein to a patient in order to improve penile circulation, which has the long-term benefit of restoring erectile function well after administration of the compositions of the invention.
- Erectile dysfunction is a serious condition which afflicts a significant percentage of the male population worldwide. This condition often has significant psychological effects which can, in severe cases, significantly reduce the quality of life for the person affected. The effects are often most severe among elderly male patients, but this condition has become increasingly prevalent within the middle-aged, and even the youthful segments of the male population.
- a prostaglandin-El product (Muse, Vivus) is available for intra urethral administration.
- injectable products include products comprising prostaglandin-El for intramuscular/intracavernosal injection. None of these products interact with all of the important receptors or with the parasympathetic nerve. In fact, injectable products including only prostaglandin-El have been shown to have an efficacy of no greater than 50% . Moreover, none of these products have shown any efficacy for reversal of erectile dysfunction, and therefore injection or administration must be repeated each time an erection is desired.
- implants have also been used for treatment of erectile dysfunction. These include both permanently rigid implants (e.g. , Erectaid), as well as implants having pumping capabilities, and which therefore can be deflated after use.
- a product is needed for treatment of erectile dysfunction having an efficacy of greater than 50% .
- a product is needed for reversal of erectile dysfunction, a product for which one or a few administrations will restore to the patient normal erectile function.
- a pharmaceutical product is needed for treatment of impotence in male patients who have undergone prostatectomy, surgery (including lower back which affects the parasympathetic nerve), trauma, or who suffer from diabetes, psychological causes of impotence, obesity, smoking, or any other condition which constricts or restricts the arteries or reduces blood flow.
- the present invention relates to injectable pharmaceutical compositions as described below for treatment of erectile dysfunction.
- prostaglandin E-1 in combination with other agents disclosed herein, can be used successfully as a vasodilator for treatment of erectile dysfunction, and even for reversal to cause recovery from erectile dysfunction.
- the preparation includes prostaglandin E-1 in an amount effective to cause erection in a patient experiencing erectile dysfunction.
- the preparation will include additional vasodilators, such as antimuscarinics, e.g. , d,L-hyoscyamine and/or dicyclomine HCl.
- the preparation will include further vasodilators, such as calcium channel blockers, e.g. , verapamil and/or diltiazem HCl.
- the preparation will also include levsin and/or additional vasodilators, such as smooth muscle relaxants, e.g. , 6,7-dimethoxy-l-veratrylisoquinoline HCl.
- the preparation will also include chlorpromazine, a pharmaceutical having vasodilating action due to its effect on the autonomic nervous system and direct action on blood vessels.
- the invention also relates to preparations which include one or more agents to enhance the ability of the preparation to reverse erectile dysfunction by providing long- term improvement of penile circulation.
- the injectable pharmaceutical composition of the invention may include vitamin B-12, vitamin B-6, folic acid, and/or tissue plasminogen activator.
- the methods of the invention include methods for treatment of a patient having erectile dysfunction, and determination of reversal of erectile dysfunction.
- the physician provides a pharmaceutical composition having an effective amount of prostaglandin E-1, and optionally further having effective amounts of one or more of levsin, verapamil and 6,7-dimethoxy-l-veratrylisoquinoline HCL.
- the patient is injected with the pharmaceutical composition.
- the injection will typically occur in the penis, but may also occur elsewhere in the body. Injection may be subcutaneous, intracavernosal or intramuscular, and may also occur systemically (i.e., intravenous or intra-arterial).
- the patient Before, during, and after injection, the patient may be diagnostically monitored to determine the increase in penile hemodynamic function (circulation), in order to quantitatively or semi-quantitatively determine the effectiveness of treatment or reversal of erectile dysfunction.
- Any diagnostic technique useful to monitor or detect perfusion or blood circulation may be used.
- Useful techniques include ultrasound, MRI, CT, and X-ray (fluoroscopy), and any of these techniques may further include the use of contrast agents which are well known and commercially available.
- Techniques for measuring hemodynamic parameters include those disclosed in Place, U.S. Patent No. 5,482,039, incorporated herein by reference.
- the pharmaceutical composition will further include effective amounts of additional vasodilating agents, such as diltiazem HCl, d,L-hyoscyamine, dicyclomine HCl, chlorpromazine.
- additional vasodilating agents such as diltiazem HCl, d,L-hyoscyamine, dicyclomine HCl, chlorpromazine.
- the composition will include one or more agents which enhance the ability of the preparation to reverse erectile dysfunction by providing long-term improvement of penile circulation.
- the injectable pharmaceutical composition may include effective amounts of vitamin B-12, vitamin B-6, folic acid, and/or tissue plasminogen activator.
- the invention can also be used to treat tension headache and to treat Alzheimer's disease.
- the injectable pharmaceutical compositions for treatment of erectile dysfunction includes prostaglandin E-1 in an amount effective to cause an erection in a patient experiencing erectile dysfunction.
- the preparation will also include levsin and/or additional vasodilators, such as verapamil, and may optionally further include 6,7-dimethoxy-l-veratrylisoquinoline HCl.
- the effective amount of prostaglandin E-1 will typically be 0.0001-60 ⁇ g, more preferably 0.001-60 ⁇ g, more preferably 0.01-60 ⁇ g, more preferably 0.1-60 ⁇ g, more preferably 0.5-20 ⁇ g, more preferably 1.0-10 ⁇ g.
- the effective amount of verapamil will typically be 0.001-lOmg, more preferably 0.05-5mg, more preferably 0.1-lmg.
- the effective amount of 6,7-dimethoxy-l-veratrylisoquinoline HCl will typically be 0.0001- 60mg, more preferably 0.001-lOmg, more preferably 0.01-lmg, more preferably 0.1- 0.5mg. All of these pharmaceuticals are commercially available and the sources are known to those of skill in the art.
- the preparation will include any of the above compositions in combination with an effective amount of levsin, which will typically be 0.0001-lOmg, more preferably 0.0005-lmg, more preferably 0.001-0.5mg.
- Levsin hyoscyamine sulfate USP
- the empirical formula is (C17H23NO3)2.H2SO4.2H2O and the molecular weight is 712.85.
- Levsin inhibits specifically the actions of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of the smooth muscle, the cardiac muscle, the sinoatrial node, the atrioventricular node, and the exocrine glands.
- Levsin inhibits gastrointestinal propulsive motility and decreases gastric acid secretion. Levsin also controls excessive pharyngeal, tracheal and bronchial secretions.
- the preparation will include any of the above compositions in combination with one or more further vasodilating agents such as diltiazem HCl in an amount of 0.0001-50mg, more preferably 0.001-lmg, more preferably 0.01- 0.5mg; d,L-hyoscyamine in an amount of 0.0001-lOmg, more preferably 0.0005-lmg, more preferably 0.001-0.5mg; dicyclomine HCl in an amount of 0-40mg, more preferably 0.1- 20mg, more preferably 0.5-10mg, more preferably l-5mg; or chlorpromazine in an amount of 0.000 l-50mg, more preferably 0.001-lOmg, more preferably 0.01-8mg, more preferably l-5mg.
- further vasodilating agents such as diltiazem HCl in an amount of 0.0001-50mg, more preferably 0.001-lmg,
- the composition is a vasodilating amount (10- 80%) of prostaglandin-El.
- the composition further includes an effective amount (5-20%) of an antimuscarinic agent (such as dicyclomine HCl or d,L- hyoscyamine).
- an antimuscarinic agent such as dicyclomine HCl or d,L- hyoscyamine.
- the composition includes any of the above compositions (prostaglandin-El or prostaglandin-El and antimuscarinic) in combination with an effective amount (10-50%) of a calcium channel blocker (such as verapamil or diltiazem HCl, or other calcium blocker).
- the composition comprises any of the above compositions in combination with an effective amount (5-20%) of a smooth muscle relaxant (such as 6,7-dimethoxy-l-veratrylisoquinoline HCl).
- a smooth muscle relaxant such as 6,7-dimethoxy-l-veratrylisoquinoline HCl
- the composition comprises any of the above compositions in combination with an effective amount (5-20%) of an agent which acts on the autonomic nervous system, such as chlorpromazine.
- the composition includes all five different classes of compounds (vasodilator, antimuscarinic, calcium channel blocker, smooth muscle relaxant, and an agent which acts on the autonomic nervous system) in a pharmaceutical preparation.
- this pharmaceutical preparation When this pharmaceutical preparation is injected into the penile muscle body (corporal), it causes an increase in blood supply to the penis. Ten to fifteen minutes after injection, an erection results with the ability to penetrate during intercourse. This preparation also works to prevent premature ejaculation. In other embodiments the preparation will cure erectile dysfunction by repeated use over a period of time.
- administration of one injection per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more will cause long-term improvement in penile circulation and thus reversal of erectile dysfunction.
- administration will include two injections per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more.
- administration will include three injections per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more.
- administration will include four injections per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more.
- the preparation will include one or more agents which enhance the ability of the preparation to reverse erectile dysfunction by providing long-term improvement of penile circulation.
- the injectable pharmaceutical composition may include vitamin B-12 in an amount of 0-lOmg, more preferably 0.1-10mg, more preferably 0.5-8mg, more preferably l-5mg; vitamin B-6 in an amount of 0.0001-lOmg, more preferably 0.001-lmg, more preferably 0.01-0.8mg, more preferably 0.1-0.5mg; folic acid in an amount of 0.0001-lOmg, more preferably 0.001- 0.8mg, more preferably 0.01-0.6mg; and/or tissue plasminogen activator in an amount of 0-lmg, more preferably 0.1-0.8mg, more preferably 0.3-0.6mg.
- the pharmaceutical preparations may be formulated neat, or using any of a number of pharmaceutical carriers, diluents, or excipients well known in the art.
- a pharmaceutical carrier of benzyl alcohol, chlorobutanol, sodium chloride, Bacteriostatic water, and normal saline is used.
- the injectable composition will typically have a total volume of approximately 0.0005-lcc, more preferably 0.001-0.5cc, more preferably 0.01-0. Ice. A volume of O.Olcc will suffice to give a 50min erection.
- the pharmaceutical compositions will comprise oral tablets, such as for example capsules, caplets, gel caps, syrup, swallow tablets, chewable tablets, and the like.
- the methods disclosed herein are for treatment of a patient having erectile dysfunction.
- the methods include the steps of providing a pharmaceutical composition having an effective amount of prostaglandin E-1, and optionally further having effective amounts of one or both of verapamil and 6,7-dimethoxy-l-veratrylisoquinoline HCL.
- the patient is injected with the pharmaceutical composition.
- the injection will typically occur in the penis, but may also occur elsewhere in the body. Injection may be subcutaneous, intramuscular, or intracavernosal, and may also occur systemically (i.e., intravenous or intra-arterial). For intracavernosal injection a one-third inch needle penetration is sufficient.
- the pharmaceutical composition will further include effective amounts of additional vasodilating agents, such as diltiazem HCl, d,L- hyoscyamine, dicyclomine HCl, chlorpromazine.
- additional vasodilating agents such as diltiazem HCl, d,L- hyoscyamine, dicyclomine HCl, chlorpromazine.
- the composition will include one or more agents which enhance the ability of the preparation to reverse erectile dysfunction by providing long-term improvement of penile circulation. These compositions thus effect treatment which restores normal erectile function to the patient.
- the injectable pharmaceutical composition may include effective amounts of vitamin B-12, vitamin B-6, folic acid, and/or tissue plasminogen activator.
- compositions disclosed herein are characterized in that they are at least about 60% effective for treatment of erectile dysfunction, whereas existing pharmaceutical preparations are no more than 50% effective.
- Preferred compositions disclosed herein are at least about 70% effective for treatment of erectile dysfunction, more preferably at least about 80% effective, more preferably at least about 90% effective, more preferably at least about 95% effective.
- the compositions herein are characterized in that they stimulate the parasympathetic nerve for improvement of erectile function.
- the disclosed compositions moreover act on one or more receptor cites for vasodilation, more preferably two or more receptors, more preferably three or more receptors, more preferably four or more receptors, most preferably five or more receptors.
- compositions are also characterized in that they are effective for treatment of impotence associated with prostatectomy, surgery (including lower back which affects the parasympathetic nerve), trauma, diabetes, psychological causes of impotence, obesity, smoking, or any other condition which constricts or restricts the arteries or reduces blood flow.
- a first pharmaceutical composition suitable for either intramuscular, intracavernosal, or subcutaneous injection is prepared to include the following materials:
- a second pharmaceutical composition suitable for either intramuscular, intracavernosal, or subcutaneous injection is prepared to include the following materials:
- Example 1 A preparation made according to Example 1 was administered to a 43-year- old male patient LD with a history of premature ejaculation. A 0. lcc dose of formulated solution was injected intracavernosally into the penis. He experienced continuous sexual activity for 3 hours.
- Example 4 A preparation made according to Example 1 was administered to a 47-year- old male patient EH.
- the patient had experienced, over a period of 2-3 years, a gradual decline in his ability to maintain an erection for the entire duration of intercourse. He experienced a 6-hour erection (i.e., priapism) after injection of 0.23cc formulated solution intracavernosally into the penis.
- this treatment with the formulated solution actually restored his ability to maintain a strong erection for the entire duration of intercourse on subsequent occasions, even without having further injections.
- IC administration of the formulation disclosed herein demonstrated a reversal of erectile dysfunction.
- Example 5 A preparation made according to Example 1 was administered to a 48-year- old male patient WL. He experienced a 2-hour erection after injection of 0.27cc formulated solution intracavernosally into the penis.
- Example 6 A preparation made according to Example 1 was administered to a 47 -year- old obese male patient PP. He experienced a 1-hour erection after injection of 0.20cc formulated solution intracavernosally into the penis.
- Example 7 A preparation made according to Example 1 is administered to a 50-year-old male patient having a history of prostate inflammation and having undergone prostate removal. He experiences a 1-hour erection after injection of 0.20cc formulated solution intracavernosally into the penis.
- a preparation made according to Example 1 is administered to a 50-year-old male patient. He experiences a 1-hour erection after injection of 0.20cc formulated solution subcutaneously into the penis.
- Example 10 A preparation made according to Example 2 is administered to a male patient. He experiences a 1-hour erection after injection of O.Olcc formulated solution IC into the penis.
- Example 10 A preparation made according to Example 2 is administered to a male patient. He experiences a 1-hour erection after injection of O.Olcc formulated solution IC into the penis.
- a preparation made according to Example 2 is administered to a male patient. He experiences a 6-hour erection after injection of O.Olcc formulated solution IC into the penis.
- Two male patients, AA and BB, are selected, both suffering from impotence.
- Penile circulation is monitored by ultrasound to determine baseline circulation readings.
- a preparation made according to Example 1 is administered to A A by intracavernosal injection into the penis.
- Patient BB receives intracavernosal injection of placebo.
- Each week AA and BB are tested in this same manner, and pre- and post-injection circulation readings are recorded. The study is continued for 6-months. After 6-months, injections are discontinued, and only ultrasound recordings are continued for an additional 6-month period.
- the invention can also be used to treat tension headache and to treat Alzheimer's disease.
- a preparation made according to Example 1 is administered to TL and EH.
- the tension headache resolved in a short time.
Abstract
An injectable pharmaceutical composition for treatment of erectile dysfunction. The composition includes prostaglandin E-1, and optionally further includes levsin and/or additional vasodilators such as diltiazem HC1, veparamil, chlorpromazine, d,L-hyoscyamine, and 6,7-dimethoxy-1-veratrylisoquinoline HC1. The composition is effective for long-term restoration of normal erectile function to a patient having erectile dysfunction. The ability to reverse erectile dysfunction may be further enhanced by the inclusion of vitamin B-6, B-12, folic acid, and/or TPA. Also disclosed are methods for treatment and reversal of erectile dysfunction by injecting the pharmaceutical composition into the penis, either by subcutaneous or intracavernosal injection.
Description
INJECTABLE PHARMACEUTICAL COMPOSITION FOR TREATMENT AND REVERSAL OF ERECTILE DYSFUNCTION
This application is related to U.S. Application Serial No. 09/321,693, filed May 28, 1999, which is a continuation-in-part of U.S. Application Serial No. 09/110,814, filed July 6, 1998, which is a continuation-in-part of U.S. Application Serial No. 09/007, 166, filed January 14, 1998. This application is also related to U.S. Application Serial No. 09/007, 142, filed January 14, 1998. The contents of all of the above applications are incorporated herein by reference.
Field of the Invention
The present invention relates to pharmaceutical compositions for treatment of erectile dysfunction. The invention also relates to methods of administering the compositions for treatment of erectile dysfunction, including by subcutaneous (sub-q), intramuscular (IM), mtracavernosal (IC), intravenous (IN), and intraartenal injection. The invention further relates to methods for reversal of erectile dysfunction by administering the compositions disclosed herein to a patient in order to improve penile circulation, which has the long-term benefit of restoring erectile function well after administration of the compositions of the invention.
Background of the Invention
Erectile dysfunction is a serious condition which afflicts a significant percentage of the male population worldwide. This condition often has significant psychological effects which can, in severe cases, significantly reduce the quality of life for the person affected. The effects are often most severe among elderly male patients, but this condition has become increasingly prevalent within the middle-aged, and even the youthful segments of the male population.
It is believed that the parasympathetic nerve plays an important role in the regulation of erectile function. As noted above, impotence is most frequent in the elderly male population. Impotence is also a frequent affliction among male patients who have
undergone prostatectomy, either for treatment of prostate cancer or an enlarged prostate condition. In fact, although numerous patients are candidates for removal of enlarged prostate, many elect not to have the surgery, and to live with the effects of an enlarged prostate, because they fear loss of normal erectile function. In addition to prostatectomy, several other causes have been linked to erectile dysfunction, including diabetes, psychological causes, surgery (including lower back which affects the parasympathetic nerve), trauma, obesity, smoking, or any other condition which constricts or restricts the arteries or reduces blood flow.
There are currently five methods available for treatment of erectile dysfunction. First, a prostaglandin-El product (Muse, Vivus) is available for intra urethral administration. Injectable products include products comprising prostaglandin-El for intramuscular/intracavernosal injection. None of these products interact with all of the important receptors or with the parasympathetic nerve. In fact, injectable products including only prostaglandin-El have been shown to have an efficacy of no greater than 50% . Moreover, none of these products have shown any efficacy for reversal of erectile dysfunction, and therefore injection or administration must be repeated each time an erection is desired. Further drawbacks of these injectable preparations are that they produce pain and unnatural erection, in addition to the difficulties of injection. In addition to these pharmaceutical treatments for erectile dysfunction, implants have also been used for treatment of erectile dysfunction. These include both permanently rigid implants (e.g. , Erectaid), as well as implants having pumping capabilities, and which therefore can be deflated after use.
Thus, a product is needed for treatment of erectile dysfunction having an efficacy of greater than 50% . Moreover, a product is needed for reversal of erectile dysfunction, a product for which one or a few administrations will restore to the patient normal erectile function. Moreover, a pharmaceutical product is needed for treatment of impotence in male patients who have undergone prostatectomy, surgery (including lower back which affects the parasympathetic nerve), trauma, or who suffer from diabetes, psychological causes of impotence, obesity, smoking, or any other condition which constricts or restricts the arteries or reduces blood flow.
Summary of the Invention
The present invention relates to injectable pharmaceutical compositions as described below for treatment of erectile dysfunction. We have discovered that prostaglandin E-1, in combination with other agents disclosed herein, can be used successfully as a vasodilator for treatment of erectile dysfunction, and even for reversal to cause recovery from erectile dysfunction. Thus, in certain embodiments, the preparation includes prostaglandin E-1 in an amount effective to cause erection in a patient experiencing erectile dysfunction. In another embodiment the preparation will include additional vasodilators, such as antimuscarinics, e.g. , d,L-hyoscyamine and/or dicyclomine HCl. In other embodiments the preparation will include further vasodilators, such as calcium channel blockers, e.g. , verapamil and/or diltiazem HCl. In other embodiments the preparation will also include levsin and/or additional vasodilators, such as smooth muscle relaxants, e.g. , 6,7-dimethoxy-l-veratrylisoquinoline HCl. In other embodiments the preparation will also include chlorpromazine, a pharmaceutical having vasodilating action due to its effect on the autonomic nervous system and direct action on blood vessels.
The invention also relates to preparations which include one or more agents to enhance the ability of the preparation to reverse erectile dysfunction by providing long- term improvement of penile circulation. For example, the injectable pharmaceutical composition of the invention may include vitamin B-12, vitamin B-6, folic acid, and/or tissue plasminogen activator.
The methods of the invention include methods for treatment of a patient having erectile dysfunction, and determination of reversal of erectile dysfunction. The physician provides a pharmaceutical composition having an effective amount of prostaglandin E-1, and optionally further having effective amounts of one or more of levsin, verapamil and 6,7-dimethoxy-l-veratrylisoquinoline HCL. The patient is injected with the pharmaceutical composition. The injection will typically occur in the penis, but may also occur elsewhere in the body. Injection may be subcutaneous, intracavernosal or intramuscular, and may also occur systemically (i.e., intravenous or intra-arterial).
Before, during, and after injection, the patient may be diagnostically monitored to determine the increase in penile hemodynamic function (circulation), in order
to quantitatively or semi-quantitatively determine the effectiveness of treatment or reversal of erectile dysfunction. Any diagnostic technique useful to monitor or detect perfusion or blood circulation may be used. Useful techniques include ultrasound, MRI, CT, and X-ray (fluoroscopy), and any of these techniques may further include the use of contrast agents which are well known and commercially available. Techniques for measuring hemodynamic parameters include those disclosed in Place, U.S. Patent No. 5,482,039, incorporated herein by reference.
In other methods of the invention, the pharmaceutical composition will further include effective amounts of additional vasodilating agents, such as diltiazem HCl, d,L-hyoscyamine, dicyclomine HCl, chlorpromazine. In still other methods, the composition will include one or more agents which enhance the ability of the preparation to reverse erectile dysfunction by providing long-term improvement of penile circulation.
These compositions thus effect treatment which restores normal erectile function to the patient. For example, the injectable pharmaceutical composition may include effective amounts of vitamin B-12, vitamin B-6, folic acid, and/or tissue plasminogen activator. The invention can also be used to treat tension headache and to treat Alzheimer's disease.
Detailed Description
In a first embodiment the injectable pharmaceutical compositions for treatment of erectile dysfunction includes prostaglandin E-1 in an amount effective to cause an erection in a patient experiencing erectile dysfunction. In another embodiment the preparation will also include levsin and/or additional vasodilators, such as verapamil, and may optionally further include 6,7-dimethoxy-l-veratrylisoquinoline HCl. The effective amount of prostaglandin E-1 will typically be 0.0001-60μg, more preferably 0.001-60μg, more preferably 0.01-60μg, more preferably 0.1-60μg, more preferably 0.5-20μg, more preferably 1.0-10μg. When included, the effective amount of verapamil will typically be 0.001-lOmg, more preferably 0.05-5mg, more preferably 0.1-lmg. When included, the effective amount of 6,7-dimethoxy-l-veratrylisoquinoline HCl will typically be 0.0001- 60mg, more preferably 0.001-lOmg, more preferably 0.01-lmg, more preferably 0.1-
0.5mg. All of these pharmaceuticals are commercially available and the sources are known to those of skill in the art.
In other embodiments the preparation will include any of the above compositions in combination with an effective amount of levsin, which will typically be 0.0001-lOmg, more preferably 0.0005-lmg, more preferably 0.001-0.5mg. Levsin (hyoscyamine sulfate USP) is one of the principal anticholinergic/antispasmodic components of belladonna alkaloids. The empirical formula is (C17H23NO3)2.H2SO4.2H2O and the molecular weight is 712.85. Chemically, it is benzeneacetic acid, alpha-(hydroxymethyl)-,8- methyl-8- azabicyclo(3.2.1.)oct-3-yl ester, (3(S)- endo)-,sulfate(2: l),dihydrate. Levsin inhibits specifically the actions of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of the smooth muscle, the cardiac muscle, the sinoatrial node, the atrioventricular node, and the exocrine glands. At therapeutic doses, it is completely devoid of any action on autonomic ganglia. Levsin inhibits gastrointestinal propulsive motility and decreases gastric acid secretion. Levsin also controls excessive pharyngeal, tracheal and bronchial secretions.
In other embodiments the preparation will include any of the above compositions in combination with one or more further vasodilating agents such as diltiazem HCl in an amount of 0.0001-50mg, more preferably 0.001-lmg, more preferably 0.01- 0.5mg; d,L-hyoscyamine in an amount of 0.0001-lOmg, more preferably 0.0005-lmg, more preferably 0.001-0.5mg; dicyclomine HCl in an amount of 0-40mg, more preferably 0.1- 20mg, more preferably 0.5-10mg, more preferably l-5mg; or chlorpromazine in an amount of 0.000 l-50mg, more preferably 0.001-lOmg, more preferably 0.01-8mg, more preferably l-5mg.
Thus, in one embodiment, the composition is a vasodilating amount (10- 80%) of prostaglandin-El. In another embodiment, the composition further includes an effective amount (5-20%) of an antimuscarinic agent (such as dicyclomine HCl or d,L- hyoscyamine). In other embodiments, the composition includes any of the above compositions (prostaglandin-El or prostaglandin-El and antimuscarinic) in combination
with an effective amount (10-50%) of a calcium channel blocker (such as verapamil or diltiazem HCl, or other calcium blocker). In still other embodiments, the composition comprises any of the above compositions in combination with an effective amount (5-20%) of a smooth muscle relaxant (such as 6,7-dimethoxy-l-veratrylisoquinoline HCl). In still other embodiments, the composition comprises any of the above compositions in combination with an effective amount (5-20%) of an agent which acts on the autonomic nervous system, such as chlorpromazine.
In the most preferred embodiment, the composition includes all five different classes of compounds (vasodilator, antimuscarinic, calcium channel blocker, smooth muscle relaxant, and an agent which acts on the autonomic nervous system) in a pharmaceutical preparation. When this pharmaceutical preparation is injected into the penile muscle body (corporal), it causes an increase in blood supply to the penis. Ten to fifteen minutes after injection, an erection results with the ability to penetrate during intercourse. This preparation also works to prevent premature ejaculation. In other embodiments the preparation will cure erectile dysfunction by repeated use over a period of time. Thus, administration of one injection per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more, will cause long-term improvement in penile circulation and thus reversal of erectile dysfunction. More preferably, administration will include two injections per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more. More preferably, administration will include three injections per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more. More preferably, administration will include four injections per week for 2 months, more preferably 3 months, more preferably 4 months, more preferably 5 months, more preferably 6 months or more. In other embodiments the preparation will include one or more agents which enhance the ability of the preparation to reverse erectile dysfunction by providing long-term improvement of penile circulation. For example, the injectable pharmaceutical composition may include vitamin B-12 in an amount of 0-lOmg, more preferably 0.1-10mg, more preferably 0.5-8mg, more preferably l-5mg; vitamin B-6 in an
amount of 0.0001-lOmg, more preferably 0.001-lmg, more preferably 0.01-0.8mg, more preferably 0.1-0.5mg; folic acid in an amount of 0.0001-lOmg, more preferably 0.001- 0.8mg, more preferably 0.01-0.6mg; and/or tissue plasminogen activator in an amount of 0-lmg, more preferably 0.1-0.8mg, more preferably 0.3-0.6mg. The pharmaceutical preparations may be formulated neat, or using any of a number of pharmaceutical carriers, diluents, or excipients well known in the art. For details, the reader is referred to the Rernmington catalog, incorporated herein by reference. For example, in certain cases, a pharmaceutical carrier of benzyl alcohol, chlorobutanol, sodium chloride, Bacteriostatic water, and normal saline is used. The injectable composition will typically have a total volume of approximately 0.0005-lcc, more preferably 0.001-0.5cc, more preferably 0.01-0. Ice. A volume of O.Olcc will suffice to give a 50min erection. In certain other embodiments, the pharmaceutical compositions will comprise oral tablets, such as for example capsules, caplets, gel caps, syrup, swallow tablets, chewable tablets, and the like. The methods disclosed herein are for treatment of a patient having erectile dysfunction. The methods include the steps of providing a pharmaceutical composition having an effective amount of prostaglandin E-1, and optionally further having effective amounts of one or both of verapamil and 6,7-dimethoxy-l-veratrylisoquinoline HCL. The patient is injected with the pharmaceutical composition. The injection will typically occur in the penis, but may also occur elsewhere in the body. Injection may be subcutaneous, intramuscular, or intracavernosal, and may also occur systemically (i.e., intravenous or intra-arterial). For intracavernosal injection a one-third inch needle penetration is sufficient.
In other methods, the pharmaceutical composition will further include effective amounts of additional vasodilating agents, such as diltiazem HCl, d,L- hyoscyamine, dicyclomine HCl, chlorpromazine. In still other methods, the composition will include one or more agents which enhance the ability of the preparation to reverse erectile dysfunction by providing long-term improvement of penile circulation. These compositions thus effect treatment which restores normal erectile function to the patient. For example, the injectable pharmaceutical composition may include effective amounts of
vitamin B-12, vitamin B-6, folic acid, and/or tissue plasminogen activator. The compositions disclosed herein are characterized in that they are at least about 60% effective for treatment of erectile dysfunction, whereas existing pharmaceutical preparations are no more than 50% effective. Preferred compositions disclosed herein are at least about 70% effective for treatment of erectile dysfunction, more preferably at least about 80% effective, more preferably at least about 90% effective, more preferably at least about 95% effective. The compositions herein are characterized in that they stimulate the parasympathetic nerve for improvement of erectile function. The disclosed compositions moreover act on one or more receptor cites for vasodilation, more preferably two or more receptors, more preferably three or more receptors, more preferably four or more receptors, most preferably five or more receptors. The disclosed compositions are also characterized in that they are effective for treatment of impotence associated with prostatectomy, surgery (including lower back which affects the parasympathetic nerve), trauma, diabetes, psychological causes of impotence, obesity, smoking, or any other condition which constricts or restricts the arteries or reduces blood flow.
Example 1
A first pharmaceutical composition suitable for either intramuscular, intracavernosal, or subcutaneous injection is prepared to include the following materials:
A second pharmaceutical composition suitable for either intramuscular, intracavernosal, or subcutaneous injection is prepared to include the following materials:
According to this formula, 0.0 lcc will suffice to give a 50 minute erection. This preparation is also effective for treatment of premature ejaculation.
Example 3
A preparation made according to Example 1 was administered to a 43-year- old male patient LD with a history of premature ejaculation. A 0. lcc dose of formulated solution was injected intracavernosally into the penis. He experienced continuous sexual activity for 3 hours.
Example 4 A preparation made according to Example 1 was administered to a 47-year- old male patient EH. The patient had experienced, over a period of 2-3 years, a gradual decline in his ability to maintain an erection for the entire duration of intercourse. He experienced a 6-hour erection (i.e., priapism) after injection of 0.23cc formulated solution intracavernosally into the penis. Moreover, this treatment with the formulated solution actually restored his ability to maintain a strong erection for the entire duration of intercourse on subsequent occasions, even without having further injections. Thus, IC
administration of the formulation disclosed herein demonstrated a reversal of erectile dysfunction.
Example 5 A preparation made according to Example 1 was administered to a 48-year- old male patient WL. He experienced a 2-hour erection after injection of 0.27cc formulated solution intracavernosally into the penis.
Example 6 A preparation made according to Example 1 was administered to a 47 -year- old obese male patient PP. He experienced a 1-hour erection after injection of 0.20cc formulated solution intracavernosally into the penis.
Example 7 A preparation made according to Example 1 is administered to a 50-year-old male patient having a history of prostate inflammation and having undergone prostate removal. He experiences a 1-hour erection after injection of 0.20cc formulated solution intracavernosally into the penis.
Example 8
A preparation made according to Example 1 is administered to a 50-year-old male patient. He experiences a 1-hour erection after injection of 0.20cc formulated solution subcutaneously into the penis.
Example 9
A preparation made according to Example 2 is administered to a male patient. He experiences a 1-hour erection after injection of O.Olcc formulated solution IC into the penis.
Example 10
A preparation made according to Example 2 is administered to a male patient. He experiences a 6-hour erection after injection of O.Olcc formulated solution IC into the penis.
Example 11
Two male patients, AA and BB, are selected, both suffering from impotence.
Penile circulation is monitored by ultrasound to determine baseline circulation readings. A preparation made according to Example 1 is administered to A A by intracavernosal injection into the penis. Patient BB receives intracavernosal injection of placebo. Penile circulation is again monitored by ultrasound to determine enhanced circulation readings at t=0. Each week AA and BB are tested in this same manner, and pre- and post-injection circulation readings are recorded. The study is continued for 6-months. After 6-months, injections are discontinued, and only ultrasound recordings are continued for an additional 6-month period.
The results of this study are as follows. During the first 6-month period, pre-injection circulation readings are consistently higher for AA than for BB, with the exception of the readings at t=0. Moreover, the difference between circulation readings for AA and BB increases with each succeeding week. During the second 6-month period, circulation readings are consistently higher for A A than for BB. The difference between circulation readings for A A and BB remains approximately constant.
Example 12
The invention can also be used to treat tension headache and to treat Alzheimer's disease. Two patients, TL and EH, were selected, both suffering from tension headache. A preparation made according to Example 1 is administered to TL and EH. The tension headache resolved in a short time.
While particular compositions and methods have been described herein, once this description is known, it will be apparent to those of ordinary skill in the art that other embodiments and alternative steps are also possible without departing from the spirit and scope of the invention. Moreover, it will be apparent that certain features of each
embodiment as well as features disclosed in each reference incorporated herein can be used in combination with features illustrated in other embodiments. Accordingly, the above description should be construed as illustrative, and not in a limiting sense, the scope of the invention being defined by the following claims.
Claims
1. An injectable pharmaceutical composition for treatment of erectile dysfunction, comprising:
0.0001-60μg prostaglandin E-1; 0.0001-lOmg levsin;
0.0001-60mg 6,7-dimethoxy-l-veratrylisoquinoline HCl; 0.0001-50mg diltiazem HCl; and 0-20mg chlorpromazine.
2. The injectable pharmaceutical composition of claim 1, further comprising verapamil.
3. The injectable pharmaceutical composition of claim 1, further comprising 0.0001-30mg diltiazem HCl.
4. The injectable pharmaceutical composition of claim 1, further comprising 0- 40mg dicyclomine HCl.
5. The injectable pharmaceutical composition of claim 1 , further comprising 0- lOmg chlorpromazine.
6. The injectable pharmaceutical composition of claim 1, further comprising 0- lOmg vitamin B-12.
7. The injectable pharmaceutical composition of claim 1, further comprising 0- lOmg vitamin B-6.
8. The injectable pharmaceutical composition of claim 1, further comprising 0- lOmg folic acid.
9. The injectable pharmaceutical composition of claim 1, further comprising tissue plasminogen activator.
10. The injectable pharmaceutical composition of claim 1, further comprising a pharmaceutical carrier comprising benzyl alcohol and normal saline.
11. The injectable pharmaceutical composition of claim 10, wherein the composition is in the form of a solution having total volume of approximately 0.0005-lcc.
12. A method for treatment of a patient having erectile dysfunction, comprising the steps of: providing a pharmaceutical composition comprising 0.0001-60μg prostaglandin E-1 and 0.0001-lOmg levsin; and injecting the patient with the pharmaceutical composition.
13. The method of claim 12, wherein the treatment restores normal erectile function to the patient.
14. The method of claim 12, wherein the injection is subcutaneous.
15. The method of claim 12, wherein the injection is intracavernosal.
16. The method of claim 12, wherein the pharmaceutical composition further comprises 0-1 Omg vitamin B-12.
17. The method of claim 12, wherein the pharmaceutical composition further comprises 0-lOmg vitamin B-6.
18. The method of claim 12, wherein the pharmaceutical composition further comprises 0-1 mg folic acid.
19. A method for reversing erectile dysfunction in a patient, comprising the steps of: providing a pharmaceutical composition dose comprising a prostaglandin vasodilator, a calcium channel blocker, and a smooth muscle relaxant; and injecting the patient with approximately one dose of the pharmaceutical composition per week for approximately 2 months.
20. The injectable pharmaceutical composition of claim 1, further comprising 0.0001-60mg 6,7-dimethoxy-l-veratrylisoquinoline HCl.
21. An injectable pharmaceutical composition for treatment of erectile dysfunction, comprising:
0.0001-60μg prostaglandin E-1; 0.0001-lOmg levsin; 0.0001-60mg 6,7-dimethoxy-l-veratrylisoquinoline HCl;
0.0001-50mg diltiazem HCl; and 0.0001-50mg chlorpromazine.
22. The injectable pharmaceutical composition of claim 21 , wherein the diltiazem HCl is in an amount of 0.0001-30mg.
23. The injectable pharmaceutical composition of claim 21, further comprising 0.1-40mg dicyclomine HCl.
24. The injectable pharmaceutical composition of claim 21, wherein the chlorpromazine is in an amount of 0.0001-50mg.
25. The injectable pharmaceutical composition of claim 21, further comprising 0.1-lOmg vitamin B-12.
26. The injectable pharmaceutical composition of claim 1, further comprising 0.0001-lOmg vitamin B-6.
27. The injectable pharmaceutical composition of claim 1, further comprising 0.0001-lOmg folic acid.
28. The method of claim 12, wherein the pharmaceutical composition further comprises 0.1-10mg vitamin B-12.
29. The method of claim 12, wherein the pharmaceutical composition further comprises 0.0001-lOmg vitamin B-6.
30. The method of claim 12, wherein the pharmaceutical composition further comprises 0.0001-lOmg folic acid.
31. A method for reversing erectile dysfunction in a patient, comprising the steps of: providing a pharmaceutical composition comprising 0.0001-60μg prostaglandin E-1 and 0.0001-lOmg levsin; and injecting the patient with approximately one dose of the pharmaceutical composition per week for approximately 2 months.
32. A method for treatment of a patient having erectile dysfunction, comprising the steps of: providing a pharmaceutical composition comprising 0.0001-60μg prostaglandin E-1 and d,L-hyoscyamine; and injecting the patient with the pharmaceutical composition.
33. The method of claim 32, wherein the pharmaceutical composition further comprises a calcium channel blocker.
34. The method of claim 32, wherein the step of injecting the patient with the pharmaceutical composition includes the use of a needle.
35. The method of claim 32, wherein the treatment restores normal erectile function to the patient.
36. The method of claim 32, wherein the injection is subcutaneous.
37. The method of claim 32, wherein the injection is intracavernosal.
38. The method of claim 32, wherein the pharmaceutical composition further comprises 0-10mg vitamin B-12.
39. The method of claim 32, wherein the pharmaceutical composition further comprises 0-1 Omg vitamin B-6.
40. The method of claim 32, wherein the pharmaceutical composition further comprises 0-lmg folic acid.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/797,788 US20010014685A1 (en) | 1998-01-14 | 2001-03-02 | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction |
PCT/US2001/007111 WO2002069966A1 (en) | 2001-03-05 | 2001-03-05 | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction |
CN01822994A CN100581544C (en) | 2001-03-05 | 2001-03-05 | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2001/007111 WO2002069966A1 (en) | 2001-03-05 | 2001-03-05 | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002069966A1 true WO2002069966A1 (en) | 2002-09-12 |
Family
ID=34230989
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/007111 WO2002069966A1 (en) | 1998-01-14 | 2001-03-05 | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN100581544C (en) |
WO (1) | WO2002069966A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8716492B2 (en) | 2004-06-15 | 2014-05-06 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5773457A (en) * | 1995-02-15 | 1998-06-30 | Cesar Roberto Dias Nahoum | Compositions |
US5773592A (en) * | 1986-12-31 | 1998-06-30 | Mills; Randell Lee | Pro drugs for selective drug delivery |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5942545A (en) * | 1998-06-15 | 1999-08-24 | Macrochem Corporation | Composition and method for treating penile erectile dysfunction |
-
2001
- 2001-03-05 CN CN01822994A patent/CN100581544C/en not_active Expired - Fee Related
- 2001-03-05 WO PCT/US2001/007111 patent/WO2002069966A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5773592A (en) * | 1986-12-31 | 1998-06-30 | Mills; Randell Lee | Pro drugs for selective drug delivery |
US5773457A (en) * | 1995-02-15 | 1998-06-30 | Cesar Roberto Dias Nahoum | Compositions |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8716492B2 (en) | 2004-06-15 | 2014-05-06 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
Also Published As
Publication number | Publication date |
---|---|
CN1492761A (en) | 2004-04-28 |
CN100581544C (en) | 2010-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6197801B1 (en) | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction | |
EP0432199B2 (en) | Composition for the treatment of erectile dysfunction | |
Ishii et al. | Intracavernous injection of prostaglandin E1 for the treatment of erectile impotence | |
US9044452B2 (en) | Use of resiniferatoxin (RTX) for producing an agent for treating joint pains and method for applying said agent | |
CA2393437A1 (en) | Exo-s-mecamylamine formulation and use in treatment | |
US4877791A (en) | Method of treatment for interestitial cystitis | |
Brandsson et al. | Intraarticular morphine after arthroscopic ACL reconstruction: a double-blind placebo-controlled study of 40 patients | |
Goldberg et al. | Gangrene of the Upper Extremity Following Intra-arterial Injection of Drugs. | |
Wyndaele et al. | Intracavernous injection of vasoactive drugs, an alternative for treating impotence in spinal cord injury patients | |
Sutter et al. | Histamine liberation by codeine and polymyxin B in urticaria pigmentosa | |
US20120122919A1 (en) | Pharmaceutical composition combining tenatoprazole and a histamine h2-receptor antagonist | |
Martinez-Pineiro et al. | Preliminary results of a comparative study with intracavernous sodium nitroprusside and prostaglandin E1 in patients with erectile dysfunction | |
Schramek et al. | Intracavernous injection of prostaglandin E1 plus procaine in the treatment of erectile dysfunction | |
Watters et al. | Experience in the management of erectile dysfunction using the intracavernosal self-injection of vasoactive drugs | |
JPH07506333A (en) | Pyridylguanidine compounds for the treatment of erectile dysfunction | |
WO2002069966A1 (en) | Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction | |
US20040037896A1 (en) | Therapeutic treatment | |
Clarke | New drugs—boon or bane? Premedication and intravenous induction agents | |
US20010003120A1 (en) | Method for treating erectile dysfunction | |
Blendinger et al. | Comparison of intravenous acetylsalicylic acid and dipyrone in postoperative pain: an interim report. | |
WO2000050028A1 (en) | Compositions for the treatment of pain | |
Abdallah | Comparison of Alprostadil (Caverject) and a combination of vasoactive drugs as local injections for the treatment of erectile dysfunction | |
Parent | Acid reduction in peptic ulcer disease: Choosing therapy according to drug interactions, individual response, and cost | |
Pantridge et al. | Combined hydrallazine and reserpine in the therapy of hypertension | |
Anawalt et al. | Medical therapy for erectile dysfunction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CN JP MX SG US VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 018229948 Country of ref document: CN |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 69(1) EPC (EPO COMMUNICATION= 1205A DATED: 21.01.2004) |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: JP |