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Oral Sildenafil in the Treatment of Erectile Dysfunction
1944
SEXUAL FUNCTION AND DYSFUNCTION Reactive Oxygen Species: Potential Cause for DNA Fragmentation in Human Spermatozoa s. LOPES, A. JURISICOVA, J.-G. Sm AND R. F. CASPER,Division of Reproductive Sciences, Department of Obstetrics a n d Gynecology, University of Toronto a n d Toronto Center for Advanced Reproductive Technology, Toronto, Ontario, Canada Hum. Reprod., 13 896-900, 1998 Permission to Publish Abstract Not Granted Editorial Comment: These 2 intriguing studies indicate that unrecognized sperm deoxyribonucleic acid fragmentation may be responsible for fertilization failure following in vitro fertilization by intracytoplasmic sperm injection. To date the average fertilization rate with intracytoplasmic sperm injection is no greater than 65% of the oocytes injected. Lopes et al observed a correlation between fertilization failure and deoxyribonucleicacid fragmentation may be due to reactive oxygen species in the media. In addition, they demonstrate a protective effect of antioxidants of which hypotatwine, a naturally occurring seminal fluid antioxidant, was the most effective.' Jonathan P. Jarow, M.D. 1. Holmes, R P., Goodman, H. O., Shihabi, 2. K. and Jarow, J. P.: The taurine and hypotaurine content of human semen. J. Androl., 1 3 289,1992. Acute Testicular Ischemia Results in Germ Cell-SpecificApoptosis in the Rat T. T. TURNER, K. S. K, TUNG,H. TOMOMASA AND L. W. WILSON, Departments of Urology a n d Pathology, University of Virginia School of Medicine, Charlottesville, Virginia Biol. Reprod., 57: 1267-1274, 1997 Testis torsion-induced aspermatogenesis is not necessarily due t o permanent loss of blood flow nor to dysfunctional Leydig cells or Sertoli cells. This investigation was undertaken to gain further insight into the mechanism underlying torsion-induced germ cell loss. Male rats were subjected to 1-h or 2-h ischemiainducing torsion, and testes were examined at either 1,2,4,24, or 48 h after torsion, depending on the study. Testes were examined for evidence of 1)in situ apoptosis by the terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate (dUTP)-biotin nick-end labeling (TUNEL) technique, 2) apoptosis by the DNA "laddering" technique, 3)leukocyte margination and diapedesis in testicular vessels by immunocytochemical and histological techniques, and 4) testicular lipid peroxidation by the thiobarbituric acid reactive substances assay. The first TUNEL evidence for torsion-induced apoptosis was at 4 h after repair of 1-h torsion. Induction of apoptosis was confirmed by the electrophoretic laddering of DNA fragments. I t was hypothesized that apoptosis was induced by reactive oxygen species arising from reperfusing leukocytes. A significant increase in both leukocyte margination and diapedesis occurred 4 h after torsion repair as did a significant increase in intratesticular lipid peroxidation products. These events were contemporaneous with the first appearance of apoptosis and consistent with the hypothesis that post-torsion, germ cell-specific apoptosis is induced by reactive oxygen species.
Editorial Comment: Prolonged testicular ischemia destroys all interstitial and intratubular cell types through the process of necrosis. In contrast, transient testicular ischemia, as in 720-degree torsion for 1hour, results in selective depopulation of germ cells in the seminiferoustubules, while Leydig and Sertoli cells appear structurally and functionally intact. The authors demonstrate that the delayed germ cell loss observed following transient ischemia is due to apoptosis rather than necrosis. The mediator of apoptosis in this clinical scenario appears to be reactive oxygen species produced during testicular reperfusion (reperfusioninjury).The authors provide some insight into potential management strategies to prevent infertility following torsion. Jonathan P. Jarow, M.D.
SEXUAL FUNCTION AND DYSFUNCTION Oral Sildenafil in the Treatment of Erectile Dysfunction I. GOLDSTEIN, T. F. L m , H. PADMA-NATHAN, R. C. ROSEN,W. D. STEERS AND P. A. WICKER FOR THE SILDENAFIL STUDY GROUP,Departments of Urology, Boston University Medical Center, Boston, Massachusetts, University of Virginia, Charlottesville, Virginia, University of California, S a n Francisco, University of Southern California, Los Angeles, and Male Clinic, Santa Monica, California, Department of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey a n d Pfizer Center Research, Groton, Connecticut New Engl. J. Med., 338 1397-1404, 1998 BACKGROUND: Sildenafil is a potent inhibitor of cyclic guanosine monophosphate in the corpus cavernosum and therefore increases the penile response to sexual stimulation. We evaluated the efflcacy and
SEXUAL FUNCTION AND DYSFUNCTION safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. METHODS: In a 24-week dose-response study, 532 men were treated with oral sildenafil(25, 50, or 100 mg) or placebo. In a 12-week, flexible dose-escalation study, 329 different men were treated with sildenafil or placebo, with dose escalation to 100 mg based on efficacy and tolerance. After this dose-escalation study, 225 of the 329 men entered a 32-week, open-label extension study. We assessed efficacy according to the International Index of Erectile Function, a patient log, and a global-efficacy question. RESULTS: In the dose-response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). For the men receiving 100 mg of sildenafil, the mean score for the question about achieving erections was 100 percent higher after treatment than at base line (4.0 vs. 2.0 of a possible score of 5). In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P < 0.001). The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo (P < 0.001). Headache, flushing, and dyspepsia were the most common adverse effects i n the dose-escalation study, occurring in 6 percent to 18 percent of the men. Ninety-two percent of the men completed the 32-week extension study. CONCLUSIONS: Oral sildenafil is a n effective, well-tolerated treatment for men with erectile dysfunction.
Editorial Comment: Nitric oxide released by the nonadrenergic noncholinergic nerve terminals is believed to be the principal neurotransmitter for penile erection. After entering the penile smooth muscle cell, nitric oxide stimulates guanylate cyclase to produce cyclic guanosine monophosphate, which relaxes penile smooth muscle and produces penile erection. Type 5 phosphodiesterase is an enzyme that breaks down cyclic guanosine monophosphate to guanosine monophosphate. Sildenafil inhibits type 5 phosphodiesterase and, thus, increases penile response to sexual stimulation. Since the basal level of cyclic guanosine monophosphate in the penis is a minute amount, taking sildenafil without sexual stimulation does not produce an erection. However, with sexual stimulation, there is a substantial rise in cyclic guanosine monophosphate levels in the penis and the effects of sildenafil become apparent. In other words, sildenafil does not produce or enhance erections unless the patient is sexually stimulated and the production of cyclic guanosine monophosphate inside the penis is increased. Since its approval by the Food and Drug Administration in March 1998,more than 2.5 million prescriptions for sildenafil have been written. In the meantime, 30 deaths have been reported to the Food and Drug Administration, the majority of which were due to cardiopulmonary arrest, myocardial infarction or stroke. There are many misconceptions regarding sildenafil. Sildenafil is not an aphrodisiac. It does not enhance sexual drive nor will it make a normal erection harder or last longer. The effect of sildenafil on women has not been proved. Patients should not be given sildenafil unless they undergo a physical examination, and a detailed history and appropriate laboratory tests have been obtained. Patients with severe cardiovascular disease should not take sildenafil. Sildenafil and organic nitrides can be a deadly combination and should not be taken together. The long-term effects on the retina are unknown and, therefore, patients with severe retina disease should be warned about possible deterioration of vision. In addition, before sildenafil is given to the patient, the physician should discuss other treatment options in case it fails. Tom F. Lue, M.D.
Endogenous Neurotransmitters Mediating Penile Erection A. M. NAYLOR, Department of Discovery Biology, Pfizer Central Research, Sandwich, United Kingdom Brit. J. Urol., 81: 424-431, 1998
No Abstract Editorial Comment: The author discusses central and peripheral neurotransmitters as well as neuropeptides in penile erection and detumescence. For those who are interested in the mechanism of penile erection and neuropharmacology, this review is a useful and easily understandable reference. Tom F. Lue, M.D.
1945
SEXUAL FUNCTION AND DYSFUNCTION Reactive Oxygen Species: Potential Cause for DNA Fragmentation in Human Spermatozoa s. LOPES, A. JURISICOVA, J.-G. Sm AND R. F. CASPER,Division of Reproductive Sciences, Department of Obstetrics a n d Gynecology, University of Toronto a n d Toronto Center for Advanced Reproductive Technology, Toronto, Ontario, Canada Hum. Reprod., 13 896-900, 1998 Permission to Publish Abstract Not Granted Editorial Comment: These 2 intriguing studies indicate that unrecognized sperm deoxyribonucleic acid fragmentation may be responsible for fertilization failure following in vitro fertilization by intracytoplasmic sperm injection. To date the average fertilization rate with intracytoplasmic sperm injection is no greater than 65% of the oocytes injected. Lopes et al observed a correlation between fertilization failure and deoxyribonucleicacid fragmentation may be due to reactive oxygen species in the media. In addition, they demonstrate a protective effect of antioxidants of which hypotatwine, a naturally occurring seminal fluid antioxidant, was the most effective.' Jonathan P. Jarow, M.D. 1. Holmes, R P., Goodman, H. O., Shihabi, 2. K. and Jarow, J. P.: The taurine and hypotaurine content of human semen. J. Androl., 1 3 289,1992. Acute Testicular Ischemia Results in Germ Cell-SpecificApoptosis in the Rat T. T. TURNER, K. S. K, TUNG,H. TOMOMASA AND L. W. WILSON, Departments of Urology a n d Pathology, University of Virginia School of Medicine, Charlottesville, Virginia Biol. Reprod., 57: 1267-1274, 1997 Testis torsion-induced aspermatogenesis is not necessarily due t o permanent loss of blood flow nor to dysfunctional Leydig cells or Sertoli cells. This investigation was undertaken to gain further insight into the mechanism underlying torsion-induced germ cell loss. Male rats were subjected to 1-h or 2-h ischemiainducing torsion, and testes were examined at either 1,2,4,24, or 48 h after torsion, depending on the study. Testes were examined for evidence of 1)in situ apoptosis by the terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate (dUTP)-biotin nick-end labeling (TUNEL) technique, 2) apoptosis by the DNA "laddering" technique, 3)leukocyte margination and diapedesis in testicular vessels by immunocytochemical and histological techniques, and 4) testicular lipid peroxidation by the thiobarbituric acid reactive substances assay. The first TUNEL evidence for torsion-induced apoptosis was at 4 h after repair of 1-h torsion. Induction of apoptosis was confirmed by the electrophoretic laddering of DNA fragments. I t was hypothesized that apoptosis was induced by reactive oxygen species arising from reperfusing leukocytes. A significant increase in both leukocyte margination and diapedesis occurred 4 h after torsion repair as did a significant increase in intratesticular lipid peroxidation products. These events were contemporaneous with the first appearance of apoptosis and consistent with the hypothesis that post-torsion, germ cell-specific apoptosis is induced by reactive oxygen species.
Editorial Comment: Prolonged testicular ischemia destroys all interstitial and intratubular cell types through the process of necrosis. In contrast, transient testicular ischemia, as in 720-degree torsion for 1hour, results in selective depopulation of germ cells in the seminiferoustubules, while Leydig and Sertoli cells appear structurally and functionally intact. The authors demonstrate that the delayed germ cell loss observed following transient ischemia is due to apoptosis rather than necrosis. The mediator of apoptosis in this clinical scenario appears to be reactive oxygen species produced during testicular reperfusion (reperfusioninjury).The authors provide some insight into potential management strategies to prevent infertility following torsion. Jonathan P. Jarow, M.D.
SEXUAL FUNCTION AND DYSFUNCTION Oral Sildenafil in the Treatment of Erectile Dysfunction I. GOLDSTEIN, T. F. L m , H. PADMA-NATHAN, R. C. ROSEN,W. D. STEERS AND P. A. WICKER FOR THE SILDENAFIL STUDY GROUP,Departments of Urology, Boston University Medical Center, Boston, Massachusetts, University of Virginia, Charlottesville, Virginia, University of California, S a n Francisco, University of Southern California, Los Angeles, and Male Clinic, Santa Monica, California, Department of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey a n d Pfizer Center Research, Groton, Connecticut New Engl. J. Med., 338 1397-1404, 1998 BACKGROUND: Sildenafil is a potent inhibitor of cyclic guanosine monophosphate in the corpus cavernosum and therefore increases the penile response to sexual stimulation. We evaluated the efflcacy and
SEXUAL FUNCTION AND DYSFUNCTION safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. METHODS: In a 24-week dose-response study, 532 men were treated with oral sildenafil(25, 50, or 100 mg) or placebo. In a 12-week, flexible dose-escalation study, 329 different men were treated with sildenafil or placebo, with dose escalation to 100 mg based on efficacy and tolerance. After this dose-escalation study, 225 of the 329 men entered a 32-week, open-label extension study. We assessed efficacy according to the International Index of Erectile Function, a patient log, and a global-efficacy question. RESULTS: In the dose-response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). For the men receiving 100 mg of sildenafil, the mean score for the question about achieving erections was 100 percent higher after treatment than at base line (4.0 vs. 2.0 of a possible score of 5). In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P < 0.001). The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo (P < 0.001). Headache, flushing, and dyspepsia were the most common adverse effects i n the dose-escalation study, occurring in 6 percent to 18 percent of the men. Ninety-two percent of the men completed the 32-week extension study. CONCLUSIONS: Oral sildenafil is a n effective, well-tolerated treatment for men with erectile dysfunction.
Editorial Comment: Nitric oxide released by the nonadrenergic noncholinergic nerve terminals is believed to be the principal neurotransmitter for penile erection. After entering the penile smooth muscle cell, nitric oxide stimulates guanylate cyclase to produce cyclic guanosine monophosphate, which relaxes penile smooth muscle and produces penile erection. Type 5 phosphodiesterase is an enzyme that breaks down cyclic guanosine monophosphate to guanosine monophosphate. Sildenafil inhibits type 5 phosphodiesterase and, thus, increases penile response to sexual stimulation. Since the basal level of cyclic guanosine monophosphate in the penis is a minute amount, taking sildenafil without sexual stimulation does not produce an erection. However, with sexual stimulation, there is a substantial rise in cyclic guanosine monophosphate levels in the penis and the effects of sildenafil become apparent. In other words, sildenafil does not produce or enhance erections unless the patient is sexually stimulated and the production of cyclic guanosine monophosphate inside the penis is increased. Since its approval by the Food and Drug Administration in March 1998,more than 2.5 million prescriptions for sildenafil have been written. In the meantime, 30 deaths have been reported to the Food and Drug Administration, the majority of which were due to cardiopulmonary arrest, myocardial infarction or stroke. There are many misconceptions regarding sildenafil. Sildenafil is not an aphrodisiac. It does not enhance sexual drive nor will it make a normal erection harder or last longer. The effect of sildenafil on women has not been proved. Patients should not be given sildenafil unless they undergo a physical examination, and a detailed history and appropriate laboratory tests have been obtained. Patients with severe cardiovascular disease should not take sildenafil. Sildenafil and organic nitrides can be a deadly combination and should not be taken together. The long-term effects on the retina are unknown and, therefore, patients with severe retina disease should be warned about possible deterioration of vision. In addition, before sildenafil is given to the patient, the physician should discuss other treatment options in case it fails. Tom F. Lue, M.D.
Endogenous Neurotransmitters Mediating Penile Erection A. M. NAYLOR, Department of Discovery Biology, Pfizer Central Research, Sandwich, United Kingdom Brit. J. Urol., 81: 424-431, 1998
No Abstract Editorial Comment: The author discusses central and peripheral neurotransmitters as well as neuropeptides in penile erection and detumescence. For those who are interested in the mechanism of penile erection and neuropharmacology, this review is a useful and easily understandable reference. Tom F. Lue, M.D.
1945