The Journal of UROLOGY

Editor John T. Grayhack 1120 North Charles Street Baltimore, Maryland 21201

Associate Editor Associate Editor Terry D. Allen Jay Y. Gillenwater Dallas, Texas Charlottesville,Virginia

Section Editor Section Editor Stuart S. Howards Patrick C. Walsh Charlottesville, Virginia Baltimore, Maryland

EDITORIAL BOARD

Mid-Atlantic New England New York North Central A. Barry Belman Bernard Lytton Michael J. Droller Joseph W. Segura Washington, D. C. New Haven, Connecticut New York, New York Rochester, Minnesota

Northeastern South Central Southeastern Western Abraham Τ. K. Cockett Robert E. Donohue Floyd A. Fried Duncan E. Govan Rochester, New York Denver, Colorado Chapel Hill, North Carolina Stanford, California

BOARD OF CONSULTANTS

Jonathan Epstein Howard M. Pollack Baltimore, Maryland Cheltenham, Pennsylvania

Allyn W. Kimball William U. Shipley Baltimore, Maryland Boston, Massachusetts

William M. Murphy Ronald R. Townsend Memphis, Tennessee Denver, Colorado

Ryoichi Oyasu Colin White Chicago, Illinois New Haven, Connecticut

Charles Y. C. Pak Alan Yagoda Dallas, Texas New York, New York

FORMER EDITORS

Hugh H. Young J. A. Campbell Colston Hugh J. Jewett William W. Scott Herbert Brendler 1917-1945 1945-1966 1966-1977 1977-1983 1983-1985

The Journal of Urology (ISSN 0022-5347) is the Official Journal of the American Urologicai Association, Inc., and is published monthly by Williams & Wilkins, 428 East Preston Street, Baltimore, MD 21202. Second class postage paid at Baltimore, MD, and at additional mailing offices. Subscription rates individual $193.00 ($258.00 foreign); institutions $215.00 ($280.00 foreign); in-training $95.00 ($160.00 foreign); single copy $23.00 ($28.00 foreign). Subscription prices subject to change. The GST number for Canadian subscribers is 123394371. To order call 1-800-638-6423 from anywhere in the U.S.; in Maryland call 1-800-638-4007. POSTMASTER: Send address changes to The Journal of Urology, 428 East Preston Street, Baltimore, MD 21202. Indexed by Current Contents, Index Medicus, and Excerpta Medica. Copyright© 1992 by American Urologicai Association, Inc. A4 The Journal of UROLOGY

CLINICAL UROLOGY Review Article Use of Alloplastic Biomaterials in Bladder Substitution. M. J. Gleeson and D. P. Griffith 1377 Original Articles Renal Colic in Pregnancy. L. Stothers and L. M. Lee 1383 Therapeutic Use of Ganciclovir for Invasive Cytomegalovirus Infection in Cadaveric Renal Allograft Recipi­ ents. M. L. Jordan, R. L. Hrebinko, Jr., J. S. Dummer, D. P. Hickey, R. Shapiro, C. A. Vivas, R. L. Simmons, Τ. E. Starzl and T. R. Hakala 1388 Intraoperative Sonography of Renal Tumors. F. F. Marshall, S. S. Holdford and U. M. Hamper 1393 Clean Intermittent Catheterization and Urinary Diversion in Management of Renal Transplant Recipients With Lower Urinary Tract Dysfunction. /. S. Gill, J. M. Hayes, Ε. E. Hodge and A. C. Novick 1397 Complications of Radical Cystectomy and Urinary Diversion: Retrospective Review of 675 Cases in 2 Decades. H. A. Frazier, J. E. Robertson and D. F. Paulson 1401 Tamm-Horsfall Protein as Marker in Interstitial Cystitis. A. R. Stone, P. Vogelsang, C. H. Miller and J. P. MacDermott 1406 Idiopathic Reduced Bladder Storage Versus Interstitial Cystitis. S. A. Awad, S. MacDiarmid, J. B. Gajewski and R. Gupta 1409 Treated History of Noninvasive Grade 1 Transitional Cell Carcinoma. G. R. Ρ rout, Jr., B. A. Barton, P. P. Griffin and G. H. Friedell for National Bladder Cancer Group (Editorial Comment by Ε. M. Messing) . . 1413 Prognostic Significance of Mucosal Aneuploidy in Stage Ta/Tl, Grade 3 Carcinoma of Bladder. U. Norming, B. Tribukait, C. R. Nyman, B. Nilsson and N. Wang (Editorial Comments by Ε. M. Messing, R. W. deVere White and M. J. Droller) 1420 Value of Immediate or Early Catheterization of Traumatized Posterior Urethra. S. Herschorn, A. Thijssen and S. B. Radomski 1428 Penile Extensibility: To What is it Related? P. Moreira de Goes, E. Wespes and C. Schulman 1432 Vascular Impotence: Focal or Diffuse Penile Disease. E. Wespes, P. Moreira de Goes and C. Schulman .. . 1435 Preliminary Results With Nitric Oxide Donor Linsidomine Chlorhydrate in Treatment of Human Erectile Dysfunction. C. G. Stief, F. Holmquist, M. Djamilian, H. Krah, K.-E. Andersson and U. Jonas 1437 Volume-Dependent Intracavernous Hemodilution During Pharmacologically Induced Penile Erections. Q. H. Siraj, A. J. W. Hilson, J. Bomanji and M. Ahmed 1441 Early Experience With Controlled Girth and Length Expanding Cylinder of American Medical Systems Ultrex Penile Prosthesis. D. K. Montague and M. M. Lakin 1444 Varicocele Treatment: Prospective Randomized Trial of 3 Methods. J. Sayfan, Y. Soffer and R. Orda .... 1447 Test for Identification of Relevant Sympathetic Nerve Fibers During Nerve Sparing Retroperitoneal Lymph - adenectomy. K.-P. Dieckmann, Η. Huland and A. J. Gross (Editorial Comment by Κ. T. McVary) . . . 1450 Pilot Study to Evaluate Impact of Policy of Adjuvant Chemotherapy for High Risk Stage 1 Malignant Teratoma on Overall Relapse Rate of Stage 1 Cancer Patients. R. T. D. Oliver, M. A. Raja, J. Ong and C. J. Gallagher (Editorial Comments by J. P. Richie and J. P. Donohue) 1453 Quantitative Measurement of Prostatic Blood Flow and Blood Volume by Positron Emission Tomogra­ phy. T. Inaba 1457 Characterization of Nonbacterial Prostatitis: Search for Etiology. L. M. D. Shortliffe, R. G. Sellers and J. Schachter 1461 Randomized, Placebo-Controlled Multicenter Study of Efficacy and Safety of Terazosin in Treatment of Benign Prostatic Hyperplasia. H. Lepor, S. Auerbach, A. Puras-Baez, P. Narayan, M. Soloway, F. Lowe, T. Moon, G. Leifer and P. Madsen 1467 Transurethral Surgery Using Intravesical Bupivacaine and Intravenous Sedation. R. D. Matthews, J. F. Nolan, J. A. Libby-Straw and J. P. Sands, Jr 1475 Urologicai Neurology and Urodynamics Ambulatory Monitoring of Bladder Pressure in Low Compliance Neurogenic Bladder Dysfunction. R. J. Webb, C. J. Griffiths, P. D. Ramsden and D. E. Neal 1477 Pediatric Articles Quantitative Histological Analysis of Dilated Ureter of Childhood. B. R. Lee, A. W. Partin, J. I. Epstein, D. M. Quinlan, J. A. Gosling and J. P. Gearhart 1482 Prenatal Diagnosis of Megacystis-Megaureter Association. J. Mandell, R. L. Lebowitz, C. A. Peters, J. A. Estroff, A. B. Retik and B. R. Benacerraf 1487

Contents continued on page A10 A6 Contents continued from page A6

Endopyelotomy Associated Ureteral Necrosis: Complete Ureteral Replacement Using Boari Flap. R. S. Sutherland, R. R. Pfister and M. A. Koyle 1490 Influence of Preoperative Bladder Capacity and Compliance on Outcome of Artificial Sphincter Implantation in Patients With Neurogenic Sphincter Incompetence. F. I. P. de Badiola, D. Castro-Diaz, C. Hart- Austin and R. Gonzalez 1493 Adventitious Knots in Urethral Catheters: Report of 5 Cases. H. Foster, M. Ritchey and D. Bbom 1496 Radiographic and Serologic Correlates of Azotemia in Patients With Posterior Urethral Valves. P. A. Merguerian, G. A. McLorie, Β. M. Churchill, P. H. McKenna and A. E. Khoury 1499 Urethral Stricture in Children: Treatment by Urethroplasty With Bladder Mucosa Graft. G. Monfort, D. Bretheau, V. Di Benedetto and R. Bankole 1504 Onlay Island Flap Urethroplasty: Variation on Theme. J. P. Gearhart and R. N. Borland 1507 Penoscrotal Transposition With Hypospadias: 1-Stage Repair. S. Perovic and V. Vukadinovic 1510 Intraoperative Spermatic Venography During Varicocele Surgery in Adolescents. R. R. Hart, Η G. Rushton and A. B. Belman 1514 Case Reports Endocytosis of Calcium Oxalate Crystals and Proliferation of Renal Tubular Epithelial Cells in Patient With Type 1 Primary Hyperoxaluria. J. C. Lieske, Β. H. Spargo and F. G. Toback 1517 Arteriovenous Fistula Complicating Endopyelotomy. E. S. Maiden, D. Picus and R. V. dayman 1520 Control of Massive Hematuria in Idiopathic Hemorrhagic Cystitis After Administration of Conjugated Estrogen. J. M. Rodriguez Luna, J. L. Teruel, J. Vallejo, F. J. Burgos, F. Lovaco and T. Mayayo 1524 Leiomyoma of Female Urethra: Case Report and Review. C. Cheng, F. M.-M. Lai and P. S. F. Chan 1526 Management of Injuries to Urethra, Bladder or Vagina Encountered During Difficult Placement of Artificial Urinary Sphincter in Female Patient. J. A. Salisz and A. C. Diokno 1528 Use of Polytetrafluoroethylene Tube Graft as Circumferential Neotunica During Placement of Penile Prosthesis. A. D. Seftel, R. D. Oates and L Goldstein 1531 Epididymo-Orchitis Developing as Late Manifestation of Intravesical Bacillus Calmette-Guerin Therapy and Masquerading as Primary Testicular Malignancy: Report of 2 Cases. T. Truelson, Κ. I. Wishnow and D.E.Johnson 1534 Prostatic Abscess Due to Candida Tropicalis in Nonacquired Immunodeficiency Syndrome Patient. S. Yu andJ.Provet 1536 Idiopathic Resistance to Luteinizing Hormone-Releasing Hormone Analogue in Patient With Prostatic Carcinoma. J. L. Jorion 1539 Recurrent Prostate Cancer Despite Undetectable Prostate Specific Antigen. Τ. K. Takayama, J. N. Krieger, L. D. True and P. Η Lange 1541 Papillary Adenocarcinoma in Seminal Vesicle Cyst Associated With Ipsilateral Renal Agenesis. Y. Okada, H. Tanaka, H. Takeuchi and O. Yoshida 1543 Special Communications Hard Measures of Subjective Outcomes: Validating Symptom Indexes in Urology. M. P. O'Leary, M. J. Barry and F. J. Fowler, Jr 1546 American Urologicai Association Symptom Index for Benign Prostatic Hyperplasia. M. J. Barry, F. J. Fowler, Jr., M. P. O'Leary, R. C. Bruskewitz, Η L. Holtgrewe, W. K. Mebust, Α. Τ. Κ Cockett and Measurement Committee of American Urologicai Association 1549 Correlation of American Urologicai Association Symptom Index With Self-Administered Versions of Madsen- Iversen, Boyarsky and Maine Medical Assessment Program Symptom Indexes. M. J. Barry, F. J. Fowler, Jr., M. P. O'Leary, R. C. Bruskewitz, H. L. Holtgrewe, W. K. Mebust and Measurement Committee of American Urologicai Association 1558 Editorial. J. T. Grayhack 1564 Letters to the Editor Re: Balloon Ureteral Occlusion: New Reversible Technique in Management of Ureteral Fistulas, by D. R. Saltzstein, E. Orihuela and J. Reed. K. S. Fraser and M. Baga 1565 Re: Biopsy After External Beam Radiation Therapy for Adenocarcinoma of Prostate: Correlation With Original Histological Grade and Current Prostate Specific Antigen Levels, by T. C. Dugan, W. U. Shipley, R. H. Young, L. J. Verhey, A. F. Althausen, Ν. Μ. Heney, P. L. McManus and Ε. H. Abraham. J. N. Kabalin 1565

INVESTIGATIVE UROLOGY Gonadotropin-Releasing Hormone Specific Binding Sites in Normal and Malignant Renal Tissue. N. Sion- Vardi, J. Kaneti, T. Segal-Abramson, J. Giat, J. Levy and Y. Sharoni 1568 Effect of PSK and Its Subfractions on Peripheral Blood Lymphocytes Mediated Cytotoxicity Against Urinary Bladder Tumor Cells. Y. Mizutani, Y. Nio and O. Yoshida 1571 Impaired Immune Response by Isoniazid Treatment During Intravesical BCG Administration in Guinea Pig. L. C. De Boer, P. A. Steerenberg, A. P. M. Van Der Meijden, B. Van Klingeren, W. Η De Jong, A. Elgersma, F. M. J. Debruyne and E. J. Ruitenberg 1577 Expression of Adhesion Molecules by Bladder Cancer Cells: Modulation by Interferon-Gamma and Tumor Necrosis Factor-Alpha. A. M. Jackson, A. B. Alexandrov, S. Prescott, K. James and G. D. Chisholm .. 1583 Contents continued on page A16 A10 Contents continued from page A10

Diabetes Mellitus Impairs Neurogenic and Endothelium-Dependent Relaxation of Rabbit Corpus Cavernosum Smooth Muscle. Κ. M. Azadzoi and I. Saenz De Tejada 1587 Microbial Adhesion and Biofilm Formation on Ureteral Stents In Vitro and In Vivo. G. Reid, J. D. Denstedt, Y. S. Rang, D. Lam and C. Nause 1592 Allelic Loss of Chromosome 17P in Urothelial Cancer: Strong Association With Invasive Phenotype. T. Habuchi, 0. Ogawa, Y. Kakehi, K. Ogura, M. Koshiba, Τ. Sugiyama and O. Yoshida 1595 Establishment and Characterization of Human Primary Prostatic Adenocarcinoma Cell Line (ND-1). P. Narayan and R. Dahiya 1600 In Vitro Studies on Effect of Cofactors on 5a-Reductase and 3a- and 30-Hydroxy steroid Reductase Activities in Hyperplastic Human Prostate. Μ. E. Lombardo, S. I. Hakky, Μ. K. Hall and P. B. Hudson 1605 Urinary Bladder Function in Tight-Skin Mouse. P. A. Longhurst, B. Eika, R. E. Leggett and R. M. Levin 1611 Comparison of Urinary Bladder Function in 6 and 24 Month Male and Female Rats. P. A. Longhurst, B. Eika, R. E. Leggett and R. M. Levin 1615 UROLOGICAL SURVEY Principles of Oncology and Immunology, and Tumors of Bladder, Penis and Urethra 1622 Male Infertility 1626 Sexual Function and Dysfunction 1628 Renal Calculi 1630 Renal Tumors, Retroperitoneum, Ureter, and Urinary Diversion and Reconstruction 1633 Book Reviews 1635

News and Announcements 1637

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DISCLAIMER The statements and opinions contained in the articles of JOURNAL OF UROLOGY are solely those of the individual authors and contributors and not of the American Urologicai Association, Inc. or Williams & Wilkins. The appearance of the advertisements in the Journal is not a warranty, endorsement or approval of the products or services advertised or of thier effectiveness, quality or safety. The American Urologicai Association, Inc., and the Publisher disclaim responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements.

A16 0022-5347/92/1485-1437$03.00/0 THE JOURNAL OF UROLOGY Vol. 148, 1437-1440, November 1992 Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC. Printed in U.S.A.

PRELIMINARY RESULTS WITH THE NITRIC OXIDE DONOR LINSIDOMINE CHLORHYDRATE IN THE TREATMENT OF HUMAN ERECTILE DYSFUNCTION

CHRISTIAN G. STIEF, FREDRIK HOLMQUIST, MOHAMAD DJAMILIAN, HELMUT KRAH, KARL- ERIK ANDERSSON AND UDO JONAS

From the Department of Urology, Medical School, Hannover, Germany and Department of Clinical Pharmacology, University Hospital, Lund, Sweden

ABSTRACT Recent experimental studies showed an important role of endothelium derived relaxing factor for cavernous smooth muscle relaxation. Since nitric oxide seems to account for the biological actions of endothelium derived relaxing factor, a study was done to examine a possible role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the treatment of erectile dysfunction. To determine a therapeutically useful dose 0.1, 0.2, 0.5 and 1 mg. SIN-1 were injected intracav- ernously in patients with erectile dysfunction. Each dose was given to 2 patients. Then, 63 patients received 1 mg. SIN-1, including 7 who had prolonged erections to minimal doses of papaverine plus phentolamine and 4 who did not respond with a full erection to other pharmacological agents. Intracavernous injection of SIN-1 induced a dose-dependent erectile response by increasing the arterial inflow and relaxing cavernous smooth muscles. Of the patients 29 had a full, 21 an almost full and 13 a moderate erection to 1 mg. SIN-1. There were no systemic or local side effects. In the patients with prolonged erections to papaverine plus phentolamine the mean duration of a full erectile response to SIN-1 was 57 minutes. Compared to the responses to a papaverine (15 mg./ml.) and phentolamine (0.5 mg./ml.) mixture, the erection induced by SIN-1 was superior in 10, comparable in 47 and inferior in 6 patients. Our data suggest a possible role for SIN-1 in the treatment of erectile dysfunction. Possible advantages may be that erection is induced by a mechanism similar to that occurring physiologically, a decreased risk of inducing prolonged erections and low therapy costs.

KEY WORDS: penile erection, impotence, nitric oxide

Cavernous smooth muscles have a crucial role in penile PATIENTS AND METHODS erection. Relaxation of the arterial and sinusoidal cavernous SIN-1 was injected intracavernously in 63 patients from our smooth muscles induces an erection by decreasing peripheral impotence clinic. Before entering the study the patients under­ resistance, entrapping blood within the sinusoids and restrict­ went a comprehensive evaluation regarding the etiology of the ing cavernous outflow.1 In vascular smooth muscle endothelium erectile dysfunction, including case history, physical examina­ derived relaxing factor is an important physiological mecha­ tion, sexual case history (by a psychiatrist), blood laboratory nism for relaxation.2 The current view is that nitric oxide or a studies, pharmaco-Doppler ultrasound, single potential analy­ nitric oxide-containing compound, synthetized from L-argi- sis of cavernous electrical activity evaluation11 and pharmaco­ nine, accounts for the biological actions of endothelium derived logical testing.12 When indicated by case history or the afore­ relaxing factor.3 Recent in vitro studies on rabbit and human mentioned examinations,12 pharmaco-angiography or caverno- penile tissues have shown that nitric oxide or a nitric oxide- sometry was done. In case the standardized medication of 15 containing compound, probably released from nerves, has a role mg./ml. papaverine and 0.5 mg./ml. phentolamine, with a max­ in the regulation of cavernous smooth muscle tone.4"7 In vivo imal dose of 3 ml., did not induce a full erection (at least 3 studies in rabbits further support a role for the L-arginine/ intracavernous injections were done), prostaglandin El (maxi­ mal dose 40 μg.) was applied. In case of incomplete erection to nitric oxide pathway in penile erection.8 These experimental data suggest that in the treatment of prostaglandin El a combination of 10 ^g. prostaglandin El and 5 ßg. calcitonin gene-related peptide13 was tried. All injections erectile dysfunction use of the L-arginine/nitric oxide pathway were done with the patient in the supine position. Only 1 dose may be an interesting approach, since it would resemble the a day was injected. To enhance reproducibility the patients physiological sequence of events in erection. Linsidomine chlor­ were advised to restrain from psychogenic or reflexogenic stim• hydrate (SIN-1) is the active metabolite of the antianginal drug ulation. The erectile response was evaluated by a urologist 10, molsidomine9 (N-ethoxycarbonyl-3-morpholino-sydnonimine) 20 and 30 minutes after the injection. and it is believed to liberate nitric oxide nonenzymatically After the diagnostic evaluation all patients were injected (nitric oxide donor). Preliminary results showed that SIN-1 with SIN-1 intracavernously. Before the injection the patients produces an erection in patients with erectile dysfunction.10 We were extensively informed about the study and about possible examined the effects of intracavernous application of SIN-1 in side effects (prolonged erections, systemic side effects, such as 63 men with erectile dysfunction, and evaluated its possible decreased blood pressure with unconsciousness, cavernous fi• therapeutic potential in the treatment of erectile dysfunction. brosis and infection). After the explanation written consent was obtained from each patient. The study was approved by the Ethics Committee of the University of Hannover (approval Accepted for publication March 13, 1992. Supported by grants Sti 96/2-2 from the Deutsche Forschungs­ No. 532). gemeinschaft and the Swedish Medical Research Council (No. 6837). SIN-1 is officially approved for treatment of coronary spasms 1437 1438 STIEF AND ASSOCIATES

evaluated, patients receiving 2 mg. SIN-1 were advised to use additional reflexogenic and/or psychogenic stimulation to im­ prove the erectile response. The first 2 of these 9 patients were medical doctors. Before the injection ail patients receiving 2 mg. SIN-1 were informed about the unusually high dose with possible severe systemic side effects (hypotension and hypo­ volemic shock). The local response to SIN-1 was measured by inspection and palpation by a urologist; the erectile response was classified into 6 categories: E0—no response, El—mini­ mum tumescence, E2—medium tumescence, E3—full tumes­ cence without rigidity, E4—full tumescence with medium rigid­ ity and E5—full erection. Bidirectional Doppler sonography of the 4 penile arteries was done in the first 6 injections, 2 patients each receiving 0.1, 0.2 and 0.5 mg. SIN-1. Single potential analysis of cavernous electrical activity was done in 2 patients receiving 1 mg. SIN-1. Pulse and blood pressure were closely monitored in the first 8 patients. During the entire procedure the patient was in the supine position.

RESULTS At the dosages used intracavernous application of SIN-1 induced an erectile response in all patients. The erectile re­ sponse, measured by tumescence and rigidity, as well as by arterial flow velocity, was dose-dependent. Intracavernous in­ jection of 0.1 mg. SIN-1 (2 patients) induced a medium tumes­ cence without rigidity (E2) after a mean of 15 minutes and FIG. 1. Intracavernous injection of 0.5 mg. SIN-1 in 51-year-old lasting for 45 minutes. By Doppler sonography a significant patient with venogenic and arteriogenic erectile dysfunction induced significant increase in penile arterial blood flow velocity during 140 increase in cavernous arterial flow was observed for a mean of minutes (continuous wave Doppler ultrasound, 8 MHz. probe). 1, 85 minutes. Intracavernous injection of 0.2 mg. SIN-1 (2 pa­ Doppler signals before SIN-1. 2, 3 minutes after intracavernous injec­ tients) induced an almost full erection (E4 to E5) for 40 minutes tion of 0.5 mg. SIN-1 (El). 3, 10 minutes after SIN-1 (E2). 4, 35 minutes after SIN-1 (E4). and a significant increase in arterial flow was observed for 135 minutes. Intracavernous injection of 0.5 mg. SIN-1 (2 patients) induced a full erection (E5) in 1 patient for 40 minutes and full tumescence with medium rigidity (E4) in 1, and an increase in arterial inflow was observed for a mean of 150 minutes (fig. 1). Recording of cavernous electrical activity showed disappear­ ance of the potentials about 20 seconds after the intracavernous injection of 1 mg. SIN-1 in both patients (fig. 2). Intracavernous injection of 1 mg. SIN-1 was done in 63 patients and induced a full erection (E5) in 29, full tumescence with medium rigidity (E4) in 21 and full tumescence (E3) in 13. In 9 of the patients with an incomplete erectile response (E3) to 1 mg. SIN-1 pharmacocavernosometry showed venous leak­ age. These patients were injected with 2 mg. SIN-1. Among the 9 patients who received intracavernous injection of 2 mg. SIN-

FIG. 2. Recording of cavernous electric activity (frequency range 0.5 1 an almost full erection (E4 to E5) was observed in 4, while 5 to 500 Hz.) with 2 needle electrodes, 1 in each corpus, in 39-year-old achieved an erectile response (E4) comparable to that obtained patient with erectile dysfunction, negative organic findings and high with 1 mg. SIN-1. All 4 patients with an almost full erection probability of psychogenic etiology, a, upper recording shows normal after 2 mg. SIN-1 achieved a full erection (E5) with additional electric activity in flaccid state (recorded during 40 minutes), synchron­ ous in both cavernous bodies with upper tracing in right and lower in stimulation. Comparing the maximal erectile response to SIN- left cavernous body. 6, 20 seconds after intracavernous injection of 1 1 to that of the combination of papaverine and phentolamine, mg. SIN-1. Lower recording shows dramatically reduced cavernous SIN-1 was superior in 10 of the 63 patients, comparable in 47 electric activity in both cavernous bodies, with only short lasting and inferior in 6. potentials of low amplitude (arrows) in left corpus. This reduced cavernous electric activity lasted more than 60 minutes (end of regis­ In 2 of 4 patients with insufficient erectile response to tration). maximal doses of papaverine (45 mg.) plus phentolamine (1.5 mg.), prostaglandin El (40 Mg.) and the combination of pros­ and for angiography of the coronary arteries. The dosage rec­ taglandin El (10 Mg.) plus calcitonin gene-related peptide (5 ommended by the manufacturer is 0.4 to 1 mg. Therefore, we Mg.)14 intracavernous injection of 2 mg. SIN-1 induced an applied 0.1 mg. in 2 patients, 0.2 mg. in 2 and 0.5 mg. in 2. almost full erection (E4 to E5), which became a full erection Since a main purpose of this study was to evaluate a therapeu­ with additional stimulation. Both patients are currently on tically useful dose, considering effect versus possible side ef­ SIN-1 autoinjection therapy. fects, such as pain, prolonged erections and systemic reactions, A total of 4 patients did not respond to maximal doses of ail patients (including the aforementioned 6) received 1 mg. papaverine plus phentolamine or prostaglandin El with a full Nine patients were also given 2 mg. SIN-1, since 1 mg. induced erection. The combination of 10 μ%. prostaglandin El plus 5 only an insufficient (less than category E5) erectile response. Mg. calcitonin gene-related peptide induced a full erection (E5) In 6 of these 9 patients SIN-1 was considered the last thera­ for 60 minutes. In these patients intracavernous injection of 1 peutic alternative regarding available drugs for autoinjection mg. SIN-1 induced only an incomplete erectile response (E3 or therapy. Since a possible therapeutic use of SIN-1 was to be E4). In 2 other patients responding better to the papaverine- NITRIC OXIDE DONOR LINSIDOMINE CHLORHYDRATE IN ERECTILE DYSFUNCTION 1439 phentolamine combination the diagnostic evaluation was of prostaglandin El receptors is reduced in several diseases, highly suspicious for pure psychogenic impotence. such as diabetes mellitus,18 and that this may contribute to a A total of 7 patients showed a pure neurogenic etiology for lesser effect. In such cases SIN-1 may be an effective alterna• the erectile dysfunction on diagnostic evaluation. A dosage of tive. 1 mg. SIN-1 was injected into 6 patients with long lasting full A 1 mg. dose of SIN-1 was injected into 6 patients with long erections to relatively small doses of the combination of papav­ lasting full erections to small doses of the papaverine-phentol• erine and phentolamine. With a mean dose of 0.33 ml. (5 mg. amine combination. History revealed a spinal cord injury (com• papaverine and 0.16 mg. phentolamine) 4 of the 6 men had a plete below Til) in 1 patient and a vertebral nucleus prolapse mean full erectile duration of 230 minutes; 2 of them presented (L4/L5) in 1. In 4 patients abnormal single potential analysis with 2 episodes of prolonged erection. Another patient was of cavernous electrical activity findings was obtained, with the transferred to us because multiple prolonged erections devel­ other examinations being normal. With a mean dose of 0.33 oped of about 40 hours to doses of 20 mg. papaverine. In these ml. (5 mg. papaverine and 0.16 mg. phentolamine) 4 of 6 men 7 patients intracavernous injection of 1 mg. SIN-1 induced a had a mean duration of a full erection of 230 minutes (2 of full erection lasting for 40 to 90 minutes (mean 57 minutes). them presented with episodes of prolonged erections). One In all but 1 patient the injection of SIN-1 induced no objective patient was transferred to us because of multiple prolonged or subjective systemic side effects. One patient reported sweat­ erections about 40 hours in duration with doses of 20 mg. ing after intracavernous injection of 2 mg. SIN-1. No patient papaverine. The diagnostic constellation in these 7 patients is reported pain or burning during or after the intracavernous highly suggestive of pure neurogenic impotence. Although these injection of SIN-1. Of the patients who were on papaverine and patients are usually overreactive to intracavernous pharmaco• phentolamine autoinjections 4 noticed subjectively that intra­ therapy, intracavernous injection of 1 mg. SIN-1 induced a full cavernous application of SIN-1 was much more comfortable erection lasting 40 to 90 minutes (mean 57 minutes). This than injection of the papaverine-phentolamine mixture. finding may be explained by the local pharmacokinetics of SIN- 1 and the rapid decomposition of nitric oxide within the cav• ernous tissue, which should prevent the occurrence of prolonged DISCUSSION erections. Our study shows that the intracavernous injection of SIN-1 Most patients on autoinjection therapy with a papaverine- induces a dose-dependent erectile response. By Doppler sonog­ phentolamine mixture report a slight burning sensation at the raphy we could demonstrate that this erectile response is ac­ injection site during injection of the drug mixture. No patient companied by a dramatic increase in cavernous arterial blood who received SIN-1 intracavernously reported any pain or flow. In vitro studies showed cavernous smooth muscle relaxa­ burning sensation during or after the injection. This observa• tion to SIN-1.7 These findings are in agreement with our tion may further indicate the fact that SIN-1 is well tolerated recordings of cavernous electrical activity before and after by the cavernous tissue. intracavernous injection of SIN-1. We found an almost com­ In animal studies19 as well as at followup of patients on plete disappearance of cavernous electrical activity after SIN- autoinjection therapy,20 chronic intracavernous injection of pa• 1, which shows that the erectile response to intracavernous paverine has been shown to result in significant cavernous SIN-1 is due to cavernous smooth muscle relaxation.11 fibrosis. Chronic intracavernous injection of prostaglandin El Comparing the maximal erectile responses, the erection in­ seems to have less fibrotic potential on cavernous tissue, as duced by SIN-1 was superior to that produced by the combi­ shown in animal19 and human studies.20 Since SIN-1 is deliv• nation of papaverine and phentolamine in 10 of 63 patients, ered as lyophilized powder to be dissolved in physiological comparable in 47 patients and inferior in 6. The mechanisms (0.9%) saline solution, it should also have minor fibrotic effects behind the effects of the combination are complex, and prob­ on the cavernous tissue. Nevertheless, chronic animal studies ably not only include the phosphodiesterase inhibiting effects are urgently needed to elucidate this important issue. Since of papaverine and the α-adrenoreceptor blocking effect of phen­ therapy costs are of increasing importance in all countries, the tolamine but additional actions. SIN-1 is believed to liberate cost of SIN-1 therapy is of interest (the prices indicated are nitric oxide nonenzymatically, which, in turn, stimulates gua- those for Germany and France, respectively). The cost of 1 nylate cyclase leading to an increase in the intracellular con­ ampule of SIN-1 (1 mg. delivered lyophilized with 1 ampule centration of cyclic guanosine 3', 5' monophosphate. SIN-1 0.9% saline solution) equals approximately the cost of an am• also hyperpolarizes the cell membrane by influencing the so­ pule of papaverine (30 mg. in solution) and is approximately dium-potassium pump,14 thus rendering the smooth muscle cell one-fifth of the cost of prostaglandin El (20 fig. lyophilized, less responsive to adrenergically mediated contraction. The delivered without solution for dissolution). Thus, SIN-1 seems actions of the papaverine-phentolamine combination and of to be an affordable alternative in the treatment of erectile SIN-1 are not dependent on an intact endothelium, which dysfunction. should make both alternatives effective also in cases when the In conclusion, our preliminary results suggest that SIN-1 is erectile dysfunction may be due to endothelial malfunction, an attractive option in the autoinjection therapy for erectile such as in diabetes mellitus or hypercholesterolemia.15"17 Our dysfunction. The absence of prolonged erections, the high ef• series suggests SIN-1 to be comparable or even superior to the fectiveness to induce a sufficient erectile response and the low combination of papaverine and phentolamine. However, con­ cost indicate the potential of SIN-1 to become a standard drug trolled comparative studies are needed to strengthen these for intracavernous injections. Before widespread use can be assumptions. Furthermore, the reasons for possible differences advocated, long-term animal studies must examine the local in efficacy remain to be established. effect of this agent on the cavernous tissue. In 4 of 63 patients who received SIN-1 neither 45 mg. papaverine plus 1.5 mg. phentolamine, 40 μg. prostaglandin El nor 10 μg. prostaglandin El plus 5 ßg. calcitonin gene-related REFERENCES peptide induced an erectile response allowing intercourse (even 1. Lue, Τ. F. and Tanagho, Ε. Α.: Physiology of erection and phar­ with additional stimulation). In 2 of these 4 patients intracav• macological management of impotence. J. Urol., 137: 829,1987. ernous injection of SIN-1 combined with stimulation induced 2. Furchgott, R. F. and Zawadzki, J. V.: The obligatory role of endo­ thelial cells in the relaxation of arterial smooth muscle by a full erection, thus enabling the patients to have intercourse acetylcholine. 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