CA1335346C - Method of treating erectile dysfunction - Google Patents
Method of treating erectile dysfunctionInfo
- Publication number
- CA1335346C CA1335346C CA000610172A CA610172A CA1335346C CA 1335346 C CA1335346 C CA 1335346C CA 000610172 A CA000610172 A CA 000610172A CA 610172 A CA610172 A CA 610172A CA 1335346 C CA1335346 C CA 1335346C
- Authority
- CA
- Canada
- Prior art keywords
- use according
- amount
- alpha
- phentolamine
- active substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- 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
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Lipophilic active substance composition and its use in a new method of treating erectile dysfunction by administration thereof, optionally together with a hydrophilic vehicle and optionally an antibacterial agent into the urethra.
Description
1 33S3~6 A NEW METHOD OF TREATING ERECTILE DYSFUNCTION
This invention relates to a lipophilic active substance compo-sition and its use in a new method of treating erectile dys-function by administration thereof, optionally together with a hydrophilic vehicle and optionally an antibacterial agent into the urethra.
Normal erection activity involves the coordination of a com-plex series of physiological and psychological factors. Any-thing that affects any one of these systems can cause impo-tence. Psychogenic impotence can be caused by e.g. anxiety, depression, tension and stress.
Physical impotence occurs when diseases or injury affects the nerves, blood vessels or hormones that control erectile abili-ty. The major causes of physical impotence in the United Sta-tes are diabetes mellitus, vascular diseases, impotence following radical surgery, spinal cord injury and other trau-mas, other endocrine problems and multiple sclerosis. Other causes include prostate infections, drug abuse, alcoholism and side effects of prescription medicines. Even smoking can interfere with normal erections.
-It is estimated that about 10 million men in the United Statessuffer from impotence. Above the age of 60 about one of three are no longer able to achieve a suitable erection.
There are several medical treatment alternatives currently available depending on the nature and cause of the impotence problem, such as therapy with Yohimbine, an Indian tree bark extract, thought to chemically stimulate the nerves in penis that control erections. Early reports indicate that normal erection is restored in 20-25 percent of the patients, but the effect is disputable. Side effects may include dizziness, nausea, nervousness and headaches.
For some men with low male hormone (testosterone) levels treatment with testosterone injections or pills may be bene-ficial. However, most patients do not have low testosterone levels and will not benefit from supplemental hormones. The side effects of testosterone treatment are several.
In recent years patients with erectile dysfunction of various origin have been treated by intracorporeal injection of various drugs. One such medicament is papaverin, which in small amounts dilates the arterial blood vessels and decreases the venous drainage (Virag R., Intracavernous injection of papaverin for erectile failure. Letter to the editor. Lancet 1982; 2:938). Brindley, G.S. describes in Brit. J. Psychiat.
(1983), 143, 332-337 a new technique for investigating and treating erectile impotence by intracavernous self-injection of small doses of phenoxybenzamine or phentolamine. The doses as used for intracorporeal injection are about 2-10 mg of phenoxybenzamine and about 0.5-1.5 mg of phentolamine.
The side effects of self-injection of medication are the risk of infection, bruises, fibrosis and scarring with permanent changes inside the penis. There is also a risk of painful longstanding erection (Priapism).
It is further known that intravenous or intramuscular injec-tion of phentolamine in moderate doses can cause an excessive fall in blood-pressure due to peripheral vasodilatation which puts the patient into a state of circulatory shock.
Experimentally it has been shown in some cases that cutaneous application of nitroglycerine paste to some extent can enhance the quality of erection.
Further, surgical implantation of penile prosthesi5. have been performed when simpler treatments are unsuccessful. However, all surglcal penile prosthetlc lmplants carry a high rlsk of lnfectlon. Other compllcatlons of surgery lnclude temporary urlnary retentlon, paln, bleedlng, scarrlng, mechanlcal fallure and extruslon of the lmplant.
Therefore, an ob~ect of the lnventlon was to provlde a method and a composltlon for the treatment of erectlle dysfunctlon, whlch should be non-lnvaslve, easy to use, have no slgnlflcant slde effects (short or longterm), be reasonably cheap, glve a penlle rlgldlty sufflclent for vaglnal penetratlon durlng a sultable tlme (20-30 mlnutes), be self-llmltlng, i.e. lt should not be posslble to overuse the drug(s) by taklng more than one dose at a tlme (to avold the rlsk of prlaplsm).
These ob~ects are achleved by a llpophlllc actlve substance composltlon and lts use ln a method of treatlng erectlle dysfunctlon by admlnistratlon thereof, optlonally together wlth a hydrophlllc vehlcle and optlonally an antlbacterlal agent lnto the urethra.
Hltherto lt has been commonly belleved that the urethral mucosal membrane does not allow transport of molecules across the same as waste products are transported vla the urlnary tract.
Surprlslngly and agalnst all theorles we have dlscovered that lt ls posslble to admlnlster pharmacologlcally active substances vla the urethral mucosa lnto the corpora cavernosa of the human penls.
Prevlously, drugs of different nature than those of the present lnvention have been administered to the urethra for purposes of local dlslnfectlon and prophylaxls agalnst venereal dlseases and to lnduce local anaesthesla. Admlnlstratlon of drugs 3a 1335346 63786-97 lnto the urethra to reach the corpora cavernosa and to achleve effect has not been performed prevlously slnce the fact that thls could be achleved was not known untll the present lnventlon.
Psychological erectile dysfunction is, at least partially, caused by an increased sympathetic tone that preven~ the activation of the erection mechanism in the corpora cavernosa.
Therefore, as mentioned above, one approach has been to inject an ~-receptor blocker, such as phentolamine and phenoxybenz-amine, intracorporeally. However, injection of phentolamine only gives a short lasting erection while phenoxybensamine has a long duration but is believed to have severe side effect and presents a number of risks.
By experimental results we have found that when phentolamine is administered in an amount of 10-200 mg, preferably 50-60 mg per urethra in a volume of 1-6 ml, in general 2-3 ml, a full and satisfactory erection occurs without any obvious systemic side effects. (The dose used for intracorporeal injection of phentolamine is 0.5-1,5 mg.) T'ne same desired results can also be achieved using phenoxybenzamine in high doses, 50-300 mg, preferably 100-150 mg per urethra, compared to the dose used for intracorporeal injection which is above about 2-10 mg.
Another well suited ~-receptor blocker candidate for this purpose is prazosine in an amount of about 20-200 mg, pre-ferably 30-70 mg. Other ~-receptor blockers might also be suitable.
According to our invention a large dose of the active substance is administered, preferably instilled, into the urethra and the slow uptake via the urethral mucosa to the corpora cavernosa gives a longer effect than the intracor-poreal injections according to prior art.
Moreover, the active substance administered according to the present invention can also comprise other ~1 and ~2-block-ing agents and vasoactive intestinal polypeptide, prostag-landins, preferably PGE , PGE2 and PGF2, and nitroglycerine.
The active substances must fulfil all the above listed objects of the present invention and also, which is very important, be fat soluble in order to pass through the mucosal membrane of the urethra.
- 13~346 When nitroglycerine is used as the active substance it should be administered in a dose not exceeding 5 mg per urethra because of the risk of blood-pressure fall. The dose range according to the invention is 0.5-5 mg, preferably 0.5-2,5 mg.
This dose, however, is very high compared to the dose of nitroglycerine normally given to Angina pectoris patients which is 0.25 mg to 0.5 mg.
The present invention also provides compositions containing two or more of the active substances, i.e. two or more of the ~-receptor blockers, vasoactive intestinal polypeptide, pro-staglandins and nitroglycerine, due to their different affi-nity for the ~ -receptor blockers ~1 and ~2. Such composi-tions are e.g. phentolamine and nitroglycerine, phenoxybenz-amine and nitroglycerine, prazosine and nitroglycerine, all in the dose stated above. Furthermore, for possible synergistic effects phentolamine + phenoxybenzamine and phentolamine +
prazosine and phenoxybenzamine and prazosine, respectively, can be administered together with nitroglycerine.
The purpose of the combination between ~-receptor(s) and nitroglycerine is that nitroglycerine gives a synergistic effect with ~-receptor blockers in that it obstructs sympa-thicus due to a local sympaticolytical effect and causes vasodilatation via a mecanism different from that of ~-recep-tor blockers. Nitroglycerine entails more rapid absorbation and therefore gives an earlier effect.
Moreover, the invention also comprises a composition which in addition to the fat soluble active substance(s) comprises a hydrophilic vehicle and optionally an antibacterial agent. The purpose of the hydrophilic vehicle, such as macrogols and/or fat-free cream or ointment bases, is not only to control the uptake via the urethral membrane into the corpora cavernosa and keep the active substance(s) in the urethra but also presumably to enhance the uptake or passage of the urethral mucosa by forcing the fat soluble substances into the corpora cavernosa due to the fact that the vehicle is hydrophilic and - 133s346 the fat soluble active substance(s) tend(s) to migrate to and through the membrane lipids rather than to stay in the hydrophilic environment. Thus, the purpose of the combina-tion of the lipophilic active substance(s) and the hydrophilic vehicle is keeping the receptors activated (blocked) in a controlled way and under a longer period of time.
The invention will now be described by way of an example with reference to the accompanying drawing.
Example Figure 1 is a graph showing the principles of the relation-ship between amount of phentolamine on the vertical axis and the duration of time on the horisontal axis. The patient was initially given 60 mg of the ~-receptor blocker phentolamine administered into the urethra and thereafter the penile rigidity was checked. During the peak of the curve, between 30 and 70 minutes from the administration of the active sub-stance, full erection was achieved. The level of phentolamine needed to achieve full erection is shown by the dotted line in Fig. 1. The peak area above the dotted line is divided into two sections showing the amount of phentolamine assumed to be metabolized in the corpora cavernosa and the amount of phentolamine assumed to leak to the systemic circulation, respectively. Thus, the erection achieved by administration of phentolamine according to the present invention is consider-ably longer than the time period achieved with injections according to prior art.
It is assumed that the transport capacity of the urethral mucosa only slightly exceeds the capability of the corpora cavernosa to metabolize phentolamine. The abundant phentol-amine, i.e. above the dotted line in Fig. 1 is mainly meta-bolized locally in the corpora cavernosa and only a minor part is assumed to leak to the systemic circulation. If a lower dose of phentolamine is used the rate of transportation over the urethral mucosa will be less than the rate of metaboli-7 133~346 zation in the corpora cavernosa and therefore a sufficientnumber of O~-receptors will not be activated to achieve a full erection~ A dose as high as 200 mg is possible, but the preferred range is between 50-60 mg, considering the risk of circulatory shock.
Thus, the present invention provides a new method, a composi-tion and use thereof for the treatment of erectile dysfunc-tion avoiding the prior art drawbacks and giving an opportuni-ty for millions of impotent men to have a sex life that is as close to normal as possible.
Table 1 shows the results of tests to treat impotence in cys-tectomized patients by the application of different substances per urethra.
~ 133~34 ~ ~ + + +
a ~~ I I I ! I
, ~ .
, o o 2 :~ o ~
a ~
+ ~ I + + + + + + + I + ` t + + + + + . ~
z ~ + ~ t + + 1- + + + + + + + + + + + + ~ + : + + + + + +, C, ~3 T . ' S ` ~ '` `
T, -C _ ~ ~3 ~ O
Q . ~ ~ o E C~ E ~ - Q S .~
E E ~, ~, E E ~ ~ ~ E " ~ E o E E s ~ t E U~ E U~ o o o o ~ 5 o,_ '~ o~
V~C~ C~ U~ ~ C~ C~ ~ U~ C~l ~ ~ + + ~ ~ U~
--o7 -H 2 c~ ~E~ ~ ~ s~
~ ~EEEEooEEEEE~EEEEEEEEEEEooEEEE s -s +~
~E_ oO~oo~O~OOOOO_OOOOOOOOOOOOOOOOO ~ ~,~, +~
~ c~ O O
C~ s c -- t~
a . ~ ~ ~ = r~ S E
~ 2 ~~~~~~~~~~'~~~'~~~~'~~~~~~~~~ ~ ~Ec~ ' os - ' ~ ~ s Z ~ ~~ '~~ ~' E~
Q ~ ~) ~ Q
C.) ~ r~
2 ~ r ~o ~ r~ ~ s ~s - +
a . C.eE ~ = = o ~ `' =-r ~ ~++++wwww Y~ e E e o~ ~ . .~ .~ .~ .--~ . .~ - ~ ~ ~ ~ s s s s - ~ s c~ cc cc c Sc'c4~ s s~
EE +++++++++EEEE++++ ~ ~ -E
~v w~~E- W~ a ~aS~ a~ , a 3~
This invention relates to a lipophilic active substance compo-sition and its use in a new method of treating erectile dys-function by administration thereof, optionally together with a hydrophilic vehicle and optionally an antibacterial agent into the urethra.
Normal erection activity involves the coordination of a com-plex series of physiological and psychological factors. Any-thing that affects any one of these systems can cause impo-tence. Psychogenic impotence can be caused by e.g. anxiety, depression, tension and stress.
Physical impotence occurs when diseases or injury affects the nerves, blood vessels or hormones that control erectile abili-ty. The major causes of physical impotence in the United Sta-tes are diabetes mellitus, vascular diseases, impotence following radical surgery, spinal cord injury and other trau-mas, other endocrine problems and multiple sclerosis. Other causes include prostate infections, drug abuse, alcoholism and side effects of prescription medicines. Even smoking can interfere with normal erections.
-It is estimated that about 10 million men in the United Statessuffer from impotence. Above the age of 60 about one of three are no longer able to achieve a suitable erection.
There are several medical treatment alternatives currently available depending on the nature and cause of the impotence problem, such as therapy with Yohimbine, an Indian tree bark extract, thought to chemically stimulate the nerves in penis that control erections. Early reports indicate that normal erection is restored in 20-25 percent of the patients, but the effect is disputable. Side effects may include dizziness, nausea, nervousness and headaches.
For some men with low male hormone (testosterone) levels treatment with testosterone injections or pills may be bene-ficial. However, most patients do not have low testosterone levels and will not benefit from supplemental hormones. The side effects of testosterone treatment are several.
In recent years patients with erectile dysfunction of various origin have been treated by intracorporeal injection of various drugs. One such medicament is papaverin, which in small amounts dilates the arterial blood vessels and decreases the venous drainage (Virag R., Intracavernous injection of papaverin for erectile failure. Letter to the editor. Lancet 1982; 2:938). Brindley, G.S. describes in Brit. J. Psychiat.
(1983), 143, 332-337 a new technique for investigating and treating erectile impotence by intracavernous self-injection of small doses of phenoxybenzamine or phentolamine. The doses as used for intracorporeal injection are about 2-10 mg of phenoxybenzamine and about 0.5-1.5 mg of phentolamine.
The side effects of self-injection of medication are the risk of infection, bruises, fibrosis and scarring with permanent changes inside the penis. There is also a risk of painful longstanding erection (Priapism).
It is further known that intravenous or intramuscular injec-tion of phentolamine in moderate doses can cause an excessive fall in blood-pressure due to peripheral vasodilatation which puts the patient into a state of circulatory shock.
Experimentally it has been shown in some cases that cutaneous application of nitroglycerine paste to some extent can enhance the quality of erection.
Further, surgical implantation of penile prosthesi5. have been performed when simpler treatments are unsuccessful. However, all surglcal penile prosthetlc lmplants carry a high rlsk of lnfectlon. Other compllcatlons of surgery lnclude temporary urlnary retentlon, paln, bleedlng, scarrlng, mechanlcal fallure and extruslon of the lmplant.
Therefore, an ob~ect of the lnventlon was to provlde a method and a composltlon for the treatment of erectlle dysfunctlon, whlch should be non-lnvaslve, easy to use, have no slgnlflcant slde effects (short or longterm), be reasonably cheap, glve a penlle rlgldlty sufflclent for vaglnal penetratlon durlng a sultable tlme (20-30 mlnutes), be self-llmltlng, i.e. lt should not be posslble to overuse the drug(s) by taklng more than one dose at a tlme (to avold the rlsk of prlaplsm).
These ob~ects are achleved by a llpophlllc actlve substance composltlon and lts use ln a method of treatlng erectlle dysfunctlon by admlnistratlon thereof, optlonally together wlth a hydrophlllc vehlcle and optlonally an antlbacterlal agent lnto the urethra.
Hltherto lt has been commonly belleved that the urethral mucosal membrane does not allow transport of molecules across the same as waste products are transported vla the urlnary tract.
Surprlslngly and agalnst all theorles we have dlscovered that lt ls posslble to admlnlster pharmacologlcally active substances vla the urethral mucosa lnto the corpora cavernosa of the human penls.
Prevlously, drugs of different nature than those of the present lnvention have been administered to the urethra for purposes of local dlslnfectlon and prophylaxls agalnst venereal dlseases and to lnduce local anaesthesla. Admlnlstratlon of drugs 3a 1335346 63786-97 lnto the urethra to reach the corpora cavernosa and to achleve effect has not been performed prevlously slnce the fact that thls could be achleved was not known untll the present lnventlon.
Psychological erectile dysfunction is, at least partially, caused by an increased sympathetic tone that preven~ the activation of the erection mechanism in the corpora cavernosa.
Therefore, as mentioned above, one approach has been to inject an ~-receptor blocker, such as phentolamine and phenoxybenz-amine, intracorporeally. However, injection of phentolamine only gives a short lasting erection while phenoxybensamine has a long duration but is believed to have severe side effect and presents a number of risks.
By experimental results we have found that when phentolamine is administered in an amount of 10-200 mg, preferably 50-60 mg per urethra in a volume of 1-6 ml, in general 2-3 ml, a full and satisfactory erection occurs without any obvious systemic side effects. (The dose used for intracorporeal injection of phentolamine is 0.5-1,5 mg.) T'ne same desired results can also be achieved using phenoxybenzamine in high doses, 50-300 mg, preferably 100-150 mg per urethra, compared to the dose used for intracorporeal injection which is above about 2-10 mg.
Another well suited ~-receptor blocker candidate for this purpose is prazosine in an amount of about 20-200 mg, pre-ferably 30-70 mg. Other ~-receptor blockers might also be suitable.
According to our invention a large dose of the active substance is administered, preferably instilled, into the urethra and the slow uptake via the urethral mucosa to the corpora cavernosa gives a longer effect than the intracor-poreal injections according to prior art.
Moreover, the active substance administered according to the present invention can also comprise other ~1 and ~2-block-ing agents and vasoactive intestinal polypeptide, prostag-landins, preferably PGE , PGE2 and PGF2, and nitroglycerine.
The active substances must fulfil all the above listed objects of the present invention and also, which is very important, be fat soluble in order to pass through the mucosal membrane of the urethra.
- 13~346 When nitroglycerine is used as the active substance it should be administered in a dose not exceeding 5 mg per urethra because of the risk of blood-pressure fall. The dose range according to the invention is 0.5-5 mg, preferably 0.5-2,5 mg.
This dose, however, is very high compared to the dose of nitroglycerine normally given to Angina pectoris patients which is 0.25 mg to 0.5 mg.
The present invention also provides compositions containing two or more of the active substances, i.e. two or more of the ~-receptor blockers, vasoactive intestinal polypeptide, pro-staglandins and nitroglycerine, due to their different affi-nity for the ~ -receptor blockers ~1 and ~2. Such composi-tions are e.g. phentolamine and nitroglycerine, phenoxybenz-amine and nitroglycerine, prazosine and nitroglycerine, all in the dose stated above. Furthermore, for possible synergistic effects phentolamine + phenoxybenzamine and phentolamine +
prazosine and phenoxybenzamine and prazosine, respectively, can be administered together with nitroglycerine.
The purpose of the combination between ~-receptor(s) and nitroglycerine is that nitroglycerine gives a synergistic effect with ~-receptor blockers in that it obstructs sympa-thicus due to a local sympaticolytical effect and causes vasodilatation via a mecanism different from that of ~-recep-tor blockers. Nitroglycerine entails more rapid absorbation and therefore gives an earlier effect.
Moreover, the invention also comprises a composition which in addition to the fat soluble active substance(s) comprises a hydrophilic vehicle and optionally an antibacterial agent. The purpose of the hydrophilic vehicle, such as macrogols and/or fat-free cream or ointment bases, is not only to control the uptake via the urethral membrane into the corpora cavernosa and keep the active substance(s) in the urethra but also presumably to enhance the uptake or passage of the urethral mucosa by forcing the fat soluble substances into the corpora cavernosa due to the fact that the vehicle is hydrophilic and - 133s346 the fat soluble active substance(s) tend(s) to migrate to and through the membrane lipids rather than to stay in the hydrophilic environment. Thus, the purpose of the combina-tion of the lipophilic active substance(s) and the hydrophilic vehicle is keeping the receptors activated (blocked) in a controlled way and under a longer period of time.
The invention will now be described by way of an example with reference to the accompanying drawing.
Example Figure 1 is a graph showing the principles of the relation-ship between amount of phentolamine on the vertical axis and the duration of time on the horisontal axis. The patient was initially given 60 mg of the ~-receptor blocker phentolamine administered into the urethra and thereafter the penile rigidity was checked. During the peak of the curve, between 30 and 70 minutes from the administration of the active sub-stance, full erection was achieved. The level of phentolamine needed to achieve full erection is shown by the dotted line in Fig. 1. The peak area above the dotted line is divided into two sections showing the amount of phentolamine assumed to be metabolized in the corpora cavernosa and the amount of phentolamine assumed to leak to the systemic circulation, respectively. Thus, the erection achieved by administration of phentolamine according to the present invention is consider-ably longer than the time period achieved with injections according to prior art.
It is assumed that the transport capacity of the urethral mucosa only slightly exceeds the capability of the corpora cavernosa to metabolize phentolamine. The abundant phentol-amine, i.e. above the dotted line in Fig. 1 is mainly meta-bolized locally in the corpora cavernosa and only a minor part is assumed to leak to the systemic circulation. If a lower dose of phentolamine is used the rate of transportation over the urethral mucosa will be less than the rate of metaboli-7 133~346 zation in the corpora cavernosa and therefore a sufficientnumber of O~-receptors will not be activated to achieve a full erection~ A dose as high as 200 mg is possible, but the preferred range is between 50-60 mg, considering the risk of circulatory shock.
Thus, the present invention provides a new method, a composi-tion and use thereof for the treatment of erectile dysfunc-tion avoiding the prior art drawbacks and giving an opportuni-ty for millions of impotent men to have a sex life that is as close to normal as possible.
Table 1 shows the results of tests to treat impotence in cys-tectomized patients by the application of different substances per urethra.
~ 133~34 ~ ~ + + +
a ~~ I I I ! I
, ~ .
, o o 2 :~ o ~
a ~
+ ~ I + + + + + + + I + ` t + + + + + . ~
z ~ + ~ t + + 1- + + + + + + + + + + + + ~ + : + + + + + +, C, ~3 T . ' S ` ~ '` `
T, -C _ ~ ~3 ~ O
Q . ~ ~ o E C~ E ~ - Q S .~
E E ~, ~, E E ~ ~ ~ E " ~ E o E E s ~ t E U~ E U~ o o o o ~ 5 o,_ '~ o~
V~C~ C~ U~ ~ C~ C~ ~ U~ C~l ~ ~ + + ~ ~ U~
--o7 -H 2 c~ ~E~ ~ ~ s~
~ ~EEEEooEEEEE~EEEEEEEEEEEooEEEE s -s +~
~E_ oO~oo~O~OOOOO_OOOOOOOOOOOOOOOOO ~ ~,~, +~
~ c~ O O
C~ s c -- t~
a . ~ ~ ~ = r~ S E
~ 2 ~~~~~~~~~~'~~~'~~~~'~~~~~~~~~ ~ ~Ec~ ' os - ' ~ ~ s Z ~ ~~ '~~ ~' E~
Q ~ ~) ~ Q
C.) ~ r~
2 ~ r ~o ~ r~ ~ s ~s - +
a . C.eE ~ = = o ~ `' =-r ~ ~++++wwww Y~ e E e o~ ~ . .~ .~ .~ .--~ . .~ - ~ ~ ~ ~ s s s s - ~ s c~ cc cc c Sc'c4~ s s~
EE +++++++++EEEE++++ ~ ~ -E
~v w~~E- W~ a ~aS~ a~ , a 3~
Claims (63)
1. Use of a lipophilic active substance, optionally together with a hydrophilic vehicle and optionally an antibacterial agent to treat erectile disfunction in a mammal.
2. A use according to claim 1, wherein the active substance is selected from the group consisting of .alpha.-receptor blockers, vasoactive intestinal polypeptide, prostaglandins and nitroglycerine.
3. A use according to claim 2, wherein the .alpha.-receptor blockers are selected from the group consisting of phentolamine, phenoxybenzamine and prazosine.
4. A use according to claim 1, wherein phentolamine is in a dose administrable in an amount of at least 10 mg.
5. A use according to claim 4, wherein phentolamine is in a dose administrable in an amount of 10-200 mg.
6. A use according to claim 4, wherein phentolamine is in a dose administrable in an amount of 50-60 mg.
7. A use according to claim 1, wherein phenoxybenzamine is in a dose administrable in an amount of at least 50 mg.
8. A use according to claim 6, wherein phenoxybenzamine is in a dose administrable in an amount of 50-300 mg.
9. A use according to claim 6, wherein phenoxybenzamine is in a dose administrable in an amount of 100-150 mg.
10. A use according to claim 2, wherein nitroglycerine is in a dose administrable in an amount of at most 5 mg.
11. A use according to claim 1, wherein nitroglycerine is in a dose administrable in an amount of 0.5-5 mg.
12. A use according to claim 1, wherein nitroglycerine is in a dose administrable in an amount of 0.5-1.5 mg.
13. A use according to claim 2, wherein the active substance and optionally the hydrophilic vehicle and optionally an antibacterial agent is in a dose administrable into the urethra in a volume of 1-6 ml.
14. A use according to claim 2, wherein the active substance andptionallyl the hydrophilic vehicle and optionally an antibacterial agent is in a dose administrable into the urethra in a volume of 2-3 ml.
15. A use according to claim 2, wherein the active substance is selected from at least 2 members of the group consisting of .alpha.-receptor blockers, vasoactive intestinal polypeptide, prostaglandins and nitroglycerine.
16. A use according to claim 2, wherein the active substance is selected from the group consisting of .alpha.-receptor blockers and nitroglycerine.
17. A use according to claim 16, wherein the .alpha.-receptor blocker is phentolamine.
18. A use according to claim 16, wherein the .alpha.-receptor blocker is phenoxybenzamine.
19. A use according to claim 16, wherein the .alpha.-receptor blocker is both phentolamine and phenoxybenzamine.
20. A use according to claim 11, wherein the active substances are in a dose administrable in an amount of at least 10 mg and in a volume of 1-6 ml.
21. A use according to claim 1, wherein the vehicle consists of macrogels or other fat-free cream or ointment bases.
22. A use according to claim 1, wherein the active substance is in a form administrable by instillation.
23. A composition for the treatment of erectile dysfunction via urethra, comprising a lipophilic active substance dispersed in a hydrophilic vehicle, and optionally an antibacterial agent.
24. A composition according to claim 23, wherein the active substance is selected from the group consisting of .alpha.-receptor blockers, vasoactive intestinal polypeptide, prostaglandins and nitroglycerine.
25. A composition according to claim 24, wherein the .alpha.-receptor blockers are selected from the group consisting of phentolamine, phenoxybenzamine and prazosine.
26. A composition according to claim 25, comprising phentolamine in an amount of at least 10 mg.
27. A composition according to claim 26, comprising phentolamine in an amount of 10-200 mg.
28. A composition according to claim 26, comprising phentolamine in an amount of 50-60 mg.
29. A composition according to claim 25, comprising phenoxybenzamine in an amount of at least 50 mg.
30. A composition according to claim 29, comprising phenoxybenzamine in an amount of 50-300 mg.
31. A composition according to claim 29, comprising phenoxybenzamine in an amount of 100-150 mg.
32. A composition according to claim 24, comprising nitroglycerine in an amount of at most 5 mg.
33. A composition according to claim 32, comprising nitroglycerine in an amount of 0.5-5 mg.
34. A composition according to claim 32, comprising nitroglycerine in an amount of 0.5-1.5 mg.
35. A composition according to claim 23, comprising the active substance dispersed in a hydrophilic vehicle and, if required, an antibacterial agent in a volume of 1-6 ml.
36. A composition according to claim 23, comprising the active substance dispersed in a hydrophilic vehicle and, if required, an antibacterial agent in a volume of 2-3 ml.
37. A composition according to claim 24, wherein the active substance is selected from at least 2 members of the group consisting of .alpha.-receptor blockers, vasoactive intestinal polypeptide, prostaglandins and nitroglycerine.
38. A composition according to claim 23, wherein the active substance is selected from the group consisting of .alpha.-receptor blockers and nitroglycerine.
39. A composition according to claim 37, wherein the .alpha.-receptor blocker is phentolamine.
40. A composition according to claim 37, wherein the .alpha.-receptor blocker is phenoxybenzamine.
41. A composition according to claim 37, wherein the .alpha.-receptor blocker is both phentolamine and phenoxybenzamine.
42. A composition according to claim 37, comprising the active substance in an amount of at least 10 mg and in a volume of 1-6 ml.
43. Use of a lipophilic active substance, optionally together with a hydrophilic vehicle and optionally an antibacterial agent for the preparation of a medicament for the treatment of erectile dysfunction by administration via urethra to corpora cavernosa.
44. Use according to claim 43, wherein the active substance is selected from the group consisting of .alpha.-receptor blockers, vasoactive intestinal polypeptide, prostaglandins and nitro-glycerine.
45. Use according to claim 44 of .alpha.-receptor blockers selected from the group consisting of phentolamine, phenoxybenzamine and prazosine.
46. Use according to claim 45 of phentolamine in an amount of at least 10 mg.
47. Use according to claim 46 of phentolamine in an amount of 10-200 mg.
48. Use according to claim 46 of phentolamine in an amount of 50-60 mg.
49. Use according to claim 45 of phenoxybenzamine in an amount of at least 50 mg.
50. Use according to claim 49 of phenoxybenzamine in an amount of 50-300 mg.
51. Use according to claim 49 of phenoxybenzamine in an amount of 100-150 mg.
52. Use according to claim 44 of nitroglycerine in an amount of at most 5 mg.
53. Use according to claim 52 of nitroglycerine in an amount of 0.5-5 mg.
54. Use according to claim 52 of nitroglycerine in an amount of 0.5-1.5 mg.
55. Use according to claim 43 of the active substance and optionally hydrophilic vehicle and optionally an antibacterial agent in a volume of 1-6 ml.
56. Use according to claim 43 of the active substance and optionally hydrophilic vehicle and optionally an antibacterial agent in a volume of 2-3 ml.
57. Use according to claim 44 of at least 2 members of the group consisting of .alpha.-receptor blockers, vasoactive intestinal polypeptide, prostaglandins and nitroglycerine.
58. Use according to claim 44 wherein the active substance is selected from the group consisting of .alpha.-receptor blockers and nitroglycerine.
59. Use according to claim 58, wherein the .alpha.-receptor blocker is phentolamine.
60. Use according to claim 58, wherein the .alpha.-receptor blocker is phenoxybenzamine.
61. Use according to claim 58, wherein the .alpha.-receptor blocker is both phentolamine and phenoxybenzamine.
62. Use according to claim 57 of the active substance in an amount of at least 10 mg and a volume of 1-6 ml.
63. Use according to claim 43, wherein the vehicle consists of macrogels or other fat-free cream or ointment bases.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8803087A SE463851B (en) | 1988-09-02 | 1988-09-02 | COMPOSITION FOR TREATMENT OF ERECT DYSFUNCTION THROUGH URETRA |
SE8803087-9 | 1988-09-02 |
Publications (1)
Publication Number | Publication Date |
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CA1335346C true CA1335346C (en) | 1995-04-25 |
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ID=20373202
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA000610172A Expired - Lifetime CA1335346C (en) | 1988-09-02 | 1989-09-01 | Method of treating erectile dysfunction |
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US (4) | US5843961A (en) |
EP (2) | EP0357581B2 (en) |
JP (1) | JPH0791199B2 (en) |
AU (1) | AU638414B2 (en) |
CA (1) | CA1335346C (en) |
DE (1) | DE68907909T3 (en) |
DK (1) | DK175560B1 (en) |
ES (1) | ES2055677T5 (en) |
FI (1) | FI102454B1 (en) |
GR (1) | GR900300093T1 (en) |
IE (1) | IE62587B1 (en) |
NO (1) | NO301046B1 (en) |
NZ (1) | NZ230400A (en) |
SE (1) | SE463851B (en) |
WO (1) | WO1990002545A1 (en) |
ZA (1) | ZA896681B (en) |
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1988
- 1988-09-02 SE SE8803087A patent/SE463851B/en not_active IP Right Cessation
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1989
- 1989-08-21 IE IE268089A patent/IE62587B1/en not_active IP Right Cessation
- 1989-08-22 NZ NZ230400A patent/NZ230400A/en unknown
- 1989-08-31 ES ES89850282T patent/ES2055677T5/en not_active Expired - Lifetime
- 1989-08-31 EP EP89850282A patent/EP0357581B2/en not_active Expired - Lifetime
- 1989-08-31 ZA ZA896681A patent/ZA896681B/en unknown
- 1989-09-01 AU AU41994/89A patent/AU638414B2/en not_active Expired
- 1989-09-01 WO PCT/SE1989/000462 patent/WO1990002545A1/en active IP Right Grant
- 1989-09-01 EP EP89909891A patent/EP0432199B2/en not_active Expired - Lifetime
- 1989-09-01 JP JP1509519A patent/JPH0791199B2/en not_active Expired - Lifetime
- 1989-09-01 CA CA000610172A patent/CA1335346C/en not_active Expired - Lifetime
- 1989-09-01 DE DE68907909T patent/DE68907909T3/en not_active Expired - Lifetime
-
1991
- 1991-02-27 FI FI910976A patent/FI102454B1/en active
- 1991-03-01 NO NO910828A patent/NO301046B1/en not_active IP Right Cessation
- 1991-03-01 DK DK199100364A patent/DK175560B1/en not_active IP Right Cessation
- 1991-09-27 GR GR90300093T patent/GR900300093T1/en unknown
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1995
- 1995-06-07 US US08/484,546 patent/US5843961A/en not_active Expired - Lifetime
- 1995-06-07 US US08/485,041 patent/US5886039A/en not_active Expired - Lifetime
- 1995-06-07 US US08/478,982 patent/US5849803A/en not_active Expired - Lifetime
- 1995-06-07 US US08/481,609 patent/US5942512A/en not_active Expired - Lifetime
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