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Treatment of Impotence by Intrapenile Injections. A Comparison of Papaverine versus Papaverine and Phentolamine: A Double-Blind, Crossover Trial
0022-534 7 /89/1423-0726$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 142, September Printed in U.S.A.
TREATMENT OF IMPOTENCE BY INTRAPENILE INJECTIONS. A COMPARISON OF PAPAVERINE VERSUS PAPAVERINE AND PHENTOLAMINE: A DOUBLE-BLIND, CROSSOVER TRIAL EDWARD J. KEOGH, GREGORY R. WATTERS, CAROLYN M. EARLE, COLIN J. CARAT!,* Z. STAN WISNIEWSKI, ALASTAIR G. S. TULLOCH AND DAVID J. LORD From the Reproductive Medicine Research Institute, Nedlands, Western Australia, Australia
ABSTRACT
The efficacy of papaverine, and a combination of papaverine and phentolamine as a pharmacological treatment of impotence was compared in a double-blind, crossover trial. A total of 40 impotent men received intracavernous injections of papaverine (40 mg.) or a combination of papaverine (20 mg.) and phentolamine (0.5 mg.) at monthly intervals. Observations at 20 minutes after injection demonstrated that papaverine caused full erections in 27 per cent of the men and partial erections in 65 per cent. The combined injection resulted in full erections in 48 per cent of the men and 52 per cent had partial erections. The difference was significant (Z equals 2.29, p less than 0.05). (J. Ural., 142: 726-728, 1989) The option of a penile implant is daunting for impotent men who have partial erections. In fact, it is unacceptable to 44 per cent of our patients despite careful and positive discussion of the potential benefits of implantation. Therefore, we have been attracted to the notion of a pharmacological prosthesis as an interim measure or even as a long-term treatment. 1- 6 Zorgniotti and Lefleur reported on the efficacy of a combination of papaverine and phentolamine for long-term, self-injection use. 6 Therefore, we conducted a double-blind, crossover trial between papaverine, and a combination of papaverine and phentolamine to determine the most appropriate agent. METHODS
Patients were assessed clinically, by biochemical studies and with 2 consecutive nights of nocturnal penile tumescence monitoring. 7 A total of 45 men entered the trial, which had been approved by the Human Rights Committee of our hospital. Mean patient age was 58 years, with a range of 40 to 75 years. Duration of impotence varied from 1 to 23 years, with a mean of 5 years. The etiology was not always known: 3 patients had peripheral vascular disease, 6 had diabetes mellitus and 8 drank alcohol to excess (more than 420 gm. per week). Of the men 27 were taking prescribed medications; 12 were on hypotensive or cardioactive drugs. Seven patients were considered to have a psychogenic component to the impotence. Patients were allocated randomly by nonclinical staff to 1 of 2 groups to receive the drugs in a predetermined order. Each patient had 2 injections 1 month apart and then documented their sexual activity in a questionnaire for 4 weeks after each injection. Patients were placed in the supine position during and for 30 minutes after the injection. Systemic blood pressure was recorded. The right side (that is the lateral aspect) of the penis approximately 4 cm. from the glans was cleansed with an alcohol swab. A 40 mg. dose of papaverine or a combination of
Accepted for publication March 10, 1989. Supported by The NH&MRC of Australia, The Australian Associated Brewers Foundation, The Australian Kidney Foundation, The Kellion Foundation, The Australian Diabetes Research Foundation and The Royal Australasian College of Physicians. * Current address: Flinders Medical Centre, Adelaide, South Australia.
20 mg. papaverine and 0.5 mg. phentolamine had been made up previously to 5 ml. in volume by dilution in normal saline by the nursing staff who did not give the injections or assess the response. Patients were unaware of which medication was given. The syringe was fitted with a 26 gauge, 13 mm. needle, which was inserted by a quick jab up to the hilt of the needle such that the tip of the needle was in the center of the right corpus cavernosum. The injection was given during 1 to 2 minutes. If the patient complained of pain in the glans the injection rate was slowed. No local anesthetic was used and aseptic technique was adhered to throughout the procedure. Upon withdrawal of the needle the puncture site was compressed and the penis was massaged gently by squeezing intermittently for 3 minutes to distribute the drug throughout the shaft. A tourniquet at the base of the penis was not used. Responses were classified by 2 of us (E. J. K. and G. R. W.), who were unaware of which drug had been given, 20 minutes after injection as none, partial (if there was any increase in penile size relative to the initial size) and full (if the erection was sufficient for intromission). Patients were encouraged during the next month to have intercourse if desired and they were asked to fill out a simple questionnaire describing sexual function. They were warned about the possibility of prolonged erections, which were treated as recommended by Brindley, that is withdrawal of 20 ml. blood followed by injection of 1 mg. metaraminol into the corpus cavernosum. 1- 3
RESULTS
Five men withdrew from the trial after 1 injection and have been excluded from further evaluation. These patients found this mode of therapy unattractive. The injection of papaverine was followed by full erections in 11 men (27 per cent), compared to 19 (48 per cent) after the combination (table 1). All 11 men who achieved a full erection with papaverine also had a full erection after injection of the drug combination. Partial erections occurred in 65 per cent of the papaverine group and 52 per cent of the combination group. All patients had some degree of tumescence after injection of the drug combination but 8 per cent had no tumescence when papaverine alone was used. The difference between the drug regimens in producing full erections was statistically significant (Z = 2.29, p <0.05).
726
727
INTRAPENILE INJECTIONS FOR IMPOTENCE TABLE
1. Response to intrapenile injection of drugs
Response Drug Papaverine Combination
None No.(%)
Partial No.(%)
Full No.(%)
3 (8)
26 (65) 21 (52)
11 (27) 19 (48)
O
TABLE 2.
DISCUSSION
Penile erection involves arterial dilatation and increased blood flow into the corpora cavernosa. Increased corpus cavernosal pressure also occludes veins draining the erectile tissue. 8 • 9 Papaverine is a nonspecific smooth muscle relaxant of human and canine erectile tissue in vitro. 10• 11 It may induce erections by arteriolar relaxation, increased blood flow and volume due to relaxation of the sinusoidal wall of the corpora cavernosa, and subsequent compression of venous channels between the
Papaverine No. Pts.
Combination No. Pts.
5 12 23
15 18
10 18 12
12 13 15
Intercourse on day of injection: Successful Failed No attempt Subsequent intercourse:* Yes Failed No attempt
Response determined by direct observation. None-no change in penile size or rigidity. Partial-change in size of penis after injection but erection not sufficient for intromission. Full-erection sufficient for intromission.
Eleven men were observed to have a better quality erection in response to the combination than in response to papaverine but in none was the response to papaverine greater than the observed response to the drug combination. These results were based on direct observations and did not take into account the patient's own report of the erections. Subsequently, on the day of injection 15 men (38 per cent) had intercourse after injection of the drug combination compared to 5 (12 per cent) after papaverine (table 2). This result was significant (Z = 3.39, p <0.05). Erections and intercourse during sexual arousal within the ensuing 4 weeks occurred in 10 men after papaverine and 12 after the drug combination. Since patients with partial impotence had occasional erections this does not necessarily imply that the drugs were effective during this period. These results were not influenced by the order in which the drugs were given. To enable the 19 men who achieved full erections to use this mode of therapy on a long-term basis we offered to teach them a self-injection technique. Each patient was given the option of the preferred medication. Of the 12 patients who accepted this offer 11 continued to use this mode of therapy for at least 3 months after the trial: 6 used the drug combination and 5 used papaverine. Of the 7 men who chose not to use the self-injection technique 6 decided not to undergo further treatment and 1 received a penile prosthesis. We also offered to teach selfinjection to the 21 patients who achieved partial erections with 1 or other of the regimens. This was done in the hope that they would achieve a better result if the injection was given in a situation when coitus was possible. Four patients accepted this offer but only 1 has continued to use this mode of treatment. Discomfort during the procedure was reported by 11 men after papaverine and 7 men after the drug combination. It was related more to the injection phase rather than insertion of the needle. A burning pain in the glans occurred 30 seconds after the injection began and subsided 1 to 2 minutes after the injection was stopped. Several patients felt pain at the tip of the needle when the drug was injected. This was minimized by either withdrawing the needle a few mm. or by reinserting it through the same puncture site at a different angle. One patient had a prolonged erection after injection of the drug combina tion. He was treated with the method described by Brindley 1- 3 and he currently self-injects 10 mg. papaverine. Seven patients believed that sexual function was improved in the month after both injections. Additionally, 11 patients believed that this function was improved only in the month after injection with the drug combination, while 1 believed that erectile function was better only in the month after use of papaverine.
Sexual intercourse after intrapenile injection of drugs
7
* Any attempt at intercourse within 4 weeks after injection.
sinusoids and the tunica albuginea. It has been suggested that papaverine may cause relaxation of an elastic venous valve mechanism, which is maintained open by a-adrenergically mediated smooth muscle contraction. 2 • 3 • 12 • 13 Phentolamine blocks the a-adrenoceptor. 14 The penis usually remains flaccid, partly because of sympathetic nervous system activity via a-adrenoceptors. 15' 16 Blockade of the adrenoceptors with phentolamine in dogs resulted in increased arterial inflow and increases in cavernosal pressure, although there was little effect on venous outflow. 8 Our results show that more and better erections can be obtained when a combination ofpapaverine (20 mg.) and phentolamine (0.5 mg.) is injected intracavernously compared to papaverine (40 mg.) alone. In addition, more impotent men were able to have intercourse within the 24 hours after injection with the drug combination than after papaverine alone. However, when choosing the drug regimen for self-injection the patients were evenly divided between the 2 options. We believe that more patients did not choose to use the drug combination for self-injection because it is more difficult to draw up than papaverine alone. Nevertheless, the combination of phentolamine and papaverine remains a useful agent for self-injection particularly in patients who have unsatisfactory results with papaverine alone. This approach to the treatment of impotence represents a significant advance in a field that until recently was bereft of any practical therapeutic measures. Taken in conjunction with the advances in penile implants, the physician now has the opportunity to offer these men inexpensive and effective treatment. Drs. G. S. Brindley, G. Wagner, A. W. Zorgniotti and T. F. Lue provided invaluable advice. REFERENCES
1. Brindley, G. S.: Cavernosal alpha-blockade: a new technique for
2. 3. 4. 5. 6. 7.
8.
investigating and treating erectile impotence. Brit. J. Psychiat., 143: 332, 1983. Brindley, G. S.: New treatment for priapism. Lancet, 2: 220, 1984. Brindley, G. S.: Neurophysiology of erection. In: Proceedings of the First World Meeting on Impotence. Edited by R. Virag and H. Virag. Paris: Editions du Ceri, chapt. 3, p. 39, 1984. Virag, R.: Intracavernous injection of papaverine for erectile failure. Letter to the Editor. Lancet, 2: 938, 1982. Virag, R., Frydman, D., Legman, M. and Virag, H.: Intracavernous injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology, 35: 79, 1988. Zorgniotti, A. W. and Lefleur, R. S.: Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133: 39, 1985. Keogh, E. J., Carati, C. J., Earle, C. M., Wisniewski, Z. S., Lord, D. J., Glancy, J. J., Brayshaw, J. L., Csillag, E. R. and Tulloch, A.G. S.: Diagnosis and medical treatment of erectile dysfunction. In: Hormones and Behaviour. Edited by L. Dennerstein and I. Fraser. Amsterdam: Elsevier Science Publishers, p. 406, 1986. Juenemann, K.-P., Luo, J. A., Lue, T. F. and Tanagho, E. A.: Further evidence of venous outflow restriction during erection. Brit. J. Urol., 58: 320, 1986.
728
KEOGH AND ASSOCIATES
9. Creed, K. E., Carati, C. J. and Keogh, E. J.: Penile blood flow during erection. Proc. Aust. Physiol. Pharm. Soc. Perth., 17: 32P, 1986. 10. Aidakan, P. G.: Pharmacology of the human penis. Master of Science Thesis, University of Singapore, 1980. 11. Carati, C. J., Goldie, R. G., Warton, A., Henry, P. J. and Keogh, E. J.: Pharmacology of the erectile tissue of the canine penis. Pharm. Res. Comm., 17: 951, 1985. 12. Juenemann, K.-P., Lue, T. F., Fournier, G. R., Jr. and Tanagho, E. A.: Hemodynamics of papaverine- and phentolamine-induced penile erection. J. Urol., 136: 158, 1986.
13. Fournier, G. R., Jr., Juenemann, K.-P., Lue, T. F. and Tanagho, E. A.: Mechanisms of venous occlusion during penile erection: an anatomic demonstration. J. Urol., 137: 163, 1987. 14. Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 4th ed. New York: MacMillan Publishing Co., 1970. 15. Sjostrand, N. 0. and Klinge, E.: Principal mechanisms controlling penile retraction and protrusion in rabbits. Acta Physiol. Scand., 106: 199, 1979. 16. Carati, C. J., Creed, K. E. and Keogh, E. J.: Autonomic control of penile erection in the dog. J. Physiol., 384: 525, 1987.
Vol. 142, September Printed in U.S.A.
TREATMENT OF IMPOTENCE BY INTRAPENILE INJECTIONS. A COMPARISON OF PAPAVERINE VERSUS PAPAVERINE AND PHENTOLAMINE: A DOUBLE-BLIND, CROSSOVER TRIAL EDWARD J. KEOGH, GREGORY R. WATTERS, CAROLYN M. EARLE, COLIN J. CARAT!,* Z. STAN WISNIEWSKI, ALASTAIR G. S. TULLOCH AND DAVID J. LORD From the Reproductive Medicine Research Institute, Nedlands, Western Australia, Australia
ABSTRACT
The efficacy of papaverine, and a combination of papaverine and phentolamine as a pharmacological treatment of impotence was compared in a double-blind, crossover trial. A total of 40 impotent men received intracavernous injections of papaverine (40 mg.) or a combination of papaverine (20 mg.) and phentolamine (0.5 mg.) at monthly intervals. Observations at 20 minutes after injection demonstrated that papaverine caused full erections in 27 per cent of the men and partial erections in 65 per cent. The combined injection resulted in full erections in 48 per cent of the men and 52 per cent had partial erections. The difference was significant (Z equals 2.29, p less than 0.05). (J. Ural., 142: 726-728, 1989) The option of a penile implant is daunting for impotent men who have partial erections. In fact, it is unacceptable to 44 per cent of our patients despite careful and positive discussion of the potential benefits of implantation. Therefore, we have been attracted to the notion of a pharmacological prosthesis as an interim measure or even as a long-term treatment. 1- 6 Zorgniotti and Lefleur reported on the efficacy of a combination of papaverine and phentolamine for long-term, self-injection use. 6 Therefore, we conducted a double-blind, crossover trial between papaverine, and a combination of papaverine and phentolamine to determine the most appropriate agent. METHODS
Patients were assessed clinically, by biochemical studies and with 2 consecutive nights of nocturnal penile tumescence monitoring. 7 A total of 45 men entered the trial, which had been approved by the Human Rights Committee of our hospital. Mean patient age was 58 years, with a range of 40 to 75 years. Duration of impotence varied from 1 to 23 years, with a mean of 5 years. The etiology was not always known: 3 patients had peripheral vascular disease, 6 had diabetes mellitus and 8 drank alcohol to excess (more than 420 gm. per week). Of the men 27 were taking prescribed medications; 12 were on hypotensive or cardioactive drugs. Seven patients were considered to have a psychogenic component to the impotence. Patients were allocated randomly by nonclinical staff to 1 of 2 groups to receive the drugs in a predetermined order. Each patient had 2 injections 1 month apart and then documented their sexual activity in a questionnaire for 4 weeks after each injection. Patients were placed in the supine position during and for 30 minutes after the injection. Systemic blood pressure was recorded. The right side (that is the lateral aspect) of the penis approximately 4 cm. from the glans was cleansed with an alcohol swab. A 40 mg. dose of papaverine or a combination of
Accepted for publication March 10, 1989. Supported by The NH&MRC of Australia, The Australian Associated Brewers Foundation, The Australian Kidney Foundation, The Kellion Foundation, The Australian Diabetes Research Foundation and The Royal Australasian College of Physicians. * Current address: Flinders Medical Centre, Adelaide, South Australia.
20 mg. papaverine and 0.5 mg. phentolamine had been made up previously to 5 ml. in volume by dilution in normal saline by the nursing staff who did not give the injections or assess the response. Patients were unaware of which medication was given. The syringe was fitted with a 26 gauge, 13 mm. needle, which was inserted by a quick jab up to the hilt of the needle such that the tip of the needle was in the center of the right corpus cavernosum. The injection was given during 1 to 2 minutes. If the patient complained of pain in the glans the injection rate was slowed. No local anesthetic was used and aseptic technique was adhered to throughout the procedure. Upon withdrawal of the needle the puncture site was compressed and the penis was massaged gently by squeezing intermittently for 3 minutes to distribute the drug throughout the shaft. A tourniquet at the base of the penis was not used. Responses were classified by 2 of us (E. J. K. and G. R. W.), who were unaware of which drug had been given, 20 minutes after injection as none, partial (if there was any increase in penile size relative to the initial size) and full (if the erection was sufficient for intromission). Patients were encouraged during the next month to have intercourse if desired and they were asked to fill out a simple questionnaire describing sexual function. They were warned about the possibility of prolonged erections, which were treated as recommended by Brindley, that is withdrawal of 20 ml. blood followed by injection of 1 mg. metaraminol into the corpus cavernosum. 1- 3
RESULTS
Five men withdrew from the trial after 1 injection and have been excluded from further evaluation. These patients found this mode of therapy unattractive. The injection of papaverine was followed by full erections in 11 men (27 per cent), compared to 19 (48 per cent) after the combination (table 1). All 11 men who achieved a full erection with papaverine also had a full erection after injection of the drug combination. Partial erections occurred in 65 per cent of the papaverine group and 52 per cent of the combination group. All patients had some degree of tumescence after injection of the drug combination but 8 per cent had no tumescence when papaverine alone was used. The difference between the drug regimens in producing full erections was statistically significant (Z = 2.29, p <0.05).
726
727
INTRAPENILE INJECTIONS FOR IMPOTENCE TABLE
1. Response to intrapenile injection of drugs
Response Drug Papaverine Combination
None No.(%)
Partial No.(%)
Full No.(%)
3 (8)
26 (65) 21 (52)
11 (27) 19 (48)
O
TABLE 2.
DISCUSSION
Penile erection involves arterial dilatation and increased blood flow into the corpora cavernosa. Increased corpus cavernosal pressure also occludes veins draining the erectile tissue. 8 • 9 Papaverine is a nonspecific smooth muscle relaxant of human and canine erectile tissue in vitro. 10• 11 It may induce erections by arteriolar relaxation, increased blood flow and volume due to relaxation of the sinusoidal wall of the corpora cavernosa, and subsequent compression of venous channels between the
Papaverine No. Pts.
Combination No. Pts.
5 12 23
15 18
10 18 12
12 13 15
Intercourse on day of injection: Successful Failed No attempt Subsequent intercourse:* Yes Failed No attempt
Response determined by direct observation. None-no change in penile size or rigidity. Partial-change in size of penis after injection but erection not sufficient for intromission. Full-erection sufficient for intromission.
Eleven men were observed to have a better quality erection in response to the combination than in response to papaverine but in none was the response to papaverine greater than the observed response to the drug combination. These results were based on direct observations and did not take into account the patient's own report of the erections. Subsequently, on the day of injection 15 men (38 per cent) had intercourse after injection of the drug combination compared to 5 (12 per cent) after papaverine (table 2). This result was significant (Z = 3.39, p <0.05). Erections and intercourse during sexual arousal within the ensuing 4 weeks occurred in 10 men after papaverine and 12 after the drug combination. Since patients with partial impotence had occasional erections this does not necessarily imply that the drugs were effective during this period. These results were not influenced by the order in which the drugs were given. To enable the 19 men who achieved full erections to use this mode of therapy on a long-term basis we offered to teach them a self-injection technique. Each patient was given the option of the preferred medication. Of the 12 patients who accepted this offer 11 continued to use this mode of therapy for at least 3 months after the trial: 6 used the drug combination and 5 used papaverine. Of the 7 men who chose not to use the self-injection technique 6 decided not to undergo further treatment and 1 received a penile prosthesis. We also offered to teach selfinjection to the 21 patients who achieved partial erections with 1 or other of the regimens. This was done in the hope that they would achieve a better result if the injection was given in a situation when coitus was possible. Four patients accepted this offer but only 1 has continued to use this mode of treatment. Discomfort during the procedure was reported by 11 men after papaverine and 7 men after the drug combination. It was related more to the injection phase rather than insertion of the needle. A burning pain in the glans occurred 30 seconds after the injection began and subsided 1 to 2 minutes after the injection was stopped. Several patients felt pain at the tip of the needle when the drug was injected. This was minimized by either withdrawing the needle a few mm. or by reinserting it through the same puncture site at a different angle. One patient had a prolonged erection after injection of the drug combina tion. He was treated with the method described by Brindley 1- 3 and he currently self-injects 10 mg. papaverine. Seven patients believed that sexual function was improved in the month after both injections. Additionally, 11 patients believed that this function was improved only in the month after injection with the drug combination, while 1 believed that erectile function was better only in the month after use of papaverine.
Sexual intercourse after intrapenile injection of drugs
7
* Any attempt at intercourse within 4 weeks after injection.
sinusoids and the tunica albuginea. It has been suggested that papaverine may cause relaxation of an elastic venous valve mechanism, which is maintained open by a-adrenergically mediated smooth muscle contraction. 2 • 3 • 12 • 13 Phentolamine blocks the a-adrenoceptor. 14 The penis usually remains flaccid, partly because of sympathetic nervous system activity via a-adrenoceptors. 15' 16 Blockade of the adrenoceptors with phentolamine in dogs resulted in increased arterial inflow and increases in cavernosal pressure, although there was little effect on venous outflow. 8 Our results show that more and better erections can be obtained when a combination ofpapaverine (20 mg.) and phentolamine (0.5 mg.) is injected intracavernously compared to papaverine (40 mg.) alone. In addition, more impotent men were able to have intercourse within the 24 hours after injection with the drug combination than after papaverine alone. However, when choosing the drug regimen for self-injection the patients were evenly divided between the 2 options. We believe that more patients did not choose to use the drug combination for self-injection because it is more difficult to draw up than papaverine alone. Nevertheless, the combination of phentolamine and papaverine remains a useful agent for self-injection particularly in patients who have unsatisfactory results with papaverine alone. This approach to the treatment of impotence represents a significant advance in a field that until recently was bereft of any practical therapeutic measures. Taken in conjunction with the advances in penile implants, the physician now has the opportunity to offer these men inexpensive and effective treatment. Drs. G. S. Brindley, G. Wagner, A. W. Zorgniotti and T. F. Lue provided invaluable advice. REFERENCES
1. Brindley, G. S.: Cavernosal alpha-blockade: a new technique for
2. 3. 4. 5. 6. 7.
8.
investigating and treating erectile impotence. Brit. J. Psychiat., 143: 332, 1983. Brindley, G. S.: New treatment for priapism. Lancet, 2: 220, 1984. Brindley, G. S.: Neurophysiology of erection. In: Proceedings of the First World Meeting on Impotence. Edited by R. Virag and H. Virag. Paris: Editions du Ceri, chapt. 3, p. 39, 1984. Virag, R.: Intracavernous injection of papaverine for erectile failure. Letter to the Editor. Lancet, 2: 938, 1982. Virag, R., Frydman, D., Legman, M. and Virag, H.: Intracavernous injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology, 35: 79, 1988. Zorgniotti, A. W. and Lefleur, R. S.: Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133: 39, 1985. Keogh, E. J., Carati, C. J., Earle, C. M., Wisniewski, Z. S., Lord, D. J., Glancy, J. J., Brayshaw, J. L., Csillag, E. R. and Tulloch, A.G. S.: Diagnosis and medical treatment of erectile dysfunction. In: Hormones and Behaviour. Edited by L. Dennerstein and I. Fraser. Amsterdam: Elsevier Science Publishers, p. 406, 1986. Juenemann, K.-P., Luo, J. A., Lue, T. F. and Tanagho, E. A.: Further evidence of venous outflow restriction during erection. Brit. J. Urol., 58: 320, 1986.
728
KEOGH AND ASSOCIATES
9. Creed, K. E., Carati, C. J. and Keogh, E. J.: Penile blood flow during erection. Proc. Aust. Physiol. Pharm. Soc. Perth., 17: 32P, 1986. 10. Aidakan, P. G.: Pharmacology of the human penis. Master of Science Thesis, University of Singapore, 1980. 11. Carati, C. J., Goldie, R. G., Warton, A., Henry, P. J. and Keogh, E. J.: Pharmacology of the erectile tissue of the canine penis. Pharm. Res. Comm., 17: 951, 1985. 12. Juenemann, K.-P., Lue, T. F., Fournier, G. R., Jr. and Tanagho, E. A.: Hemodynamics of papaverine- and phentolamine-induced penile erection. J. Urol., 136: 158, 1986.
13. Fournier, G. R., Jr., Juenemann, K.-P., Lue, T. F. and Tanagho, E. A.: Mechanisms of venous occlusion during penile erection: an anatomic demonstration. J. Urol., 137: 163, 1987. 14. Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 4th ed. New York: MacMillan Publishing Co., 1970. 15. Sjostrand, N. 0. and Klinge, E.: Principal mechanisms controlling penile retraction and protrusion in rabbits. Acta Physiol. Scand., 106: 199, 1979. 16. Carati, C. J., Creed, K. E. and Keogh, E. J.: Autonomic control of penile erection in the dog. J. Physiol., 384: 525, 1987.