The Journal of

UROLOGY Editor

John T. Grayhack 1120 Nor th 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

E D I T O R I A L BOARD

Mid-Atlantic A. Barry Belman Washington, D. C.

Northeastern Abraham Τ. K. Cockett Rochester, New York

New England Bernard Lytton New Haven, Connecticut

South Central Robert E. Donohue Denver, Colorado

New York Michael J. Droller New York, New York

Southeastern Floyd A. Fried Chapel Hi l l , North Carolina

North Central Joseph W. Segura Rochester, Minnesota

Western Duncan E. Govan Stanford, California

BOARD OF Jonathan Epstein Baltimore, Maryland

Allyn W. Kimball Baltimore, Maryland

William M . Murphy Memphis, Tennessee

Ryoichi Oyasu Chicago, Illinois

Charles Y. C. Pak Dallas, Texas

C O N S U L T A N T S

Howard M. Pollack Cheltenham, Pennsylvania

William U. Shipley Boston, Massachusetts

Ronald R. Townsend Denver, Colorado

Colin White New Haven, Connecticut

Alan Yagoda New York, New York

F O R M E R E D I T O R S

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 ( I S S N 0022-5347) is the Official Journal of the American Urologicai Association, Inc., and is published monthly by Williams & Wilkins, 428 East Preston Street, Baltimore, M D 21202. Second class postage paid at Baltimore, M D , 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 G S T number for Canadian subscribers is 123394371. T o order call 1-800-638-6423 from anywhere in the U.S. ; in Maryland call 1-800-638-4007. P O S T M A S T E R : Send address changes to The Journal of Urology, 428 East Preston Street, Baltimore, M D 21202. Indexed by Current Contents, Index Medicus, and Excerpta Medica. Copyright© 1992 by American Urologicai Association, Inc.

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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 T a / T l , 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 Tomogra­phy. 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

P R O P R I E T A R Y NAMES Many of the words appearing in the JOURNAL OF UROLOGY are proprietary names even though

no reference to this fact is made in the text. The appearance of any name without designation as proprietary is, therefore, not to be regarded as a representation by the editorial committee or publisher that it is not the subject of proprietary rights.

G U I D E L I N E S FOR S U P P L E M E N T S The Editors of the Journal will consider requests for and

solicit sponsors of Supplements to The Journal of Urology. For those interested the following are the proposed steps for publication of a Supplement.

1) Proposal formulated by sponsors of the Supplement or solicited by the Journal Editorial Staff that would include an indication of the major topics with a limited outline of subtopics, the nature of the articles to be included (review, original papers with or without discussion), identification of a sponsoring group or individual, identification of the type of internal quality control group available for the Journal Editors to work with and an indication of the financial sup­port available.

2) Response by the Editorial Staff with identification of a specific individual to work with the Editorial Committee of the sponsors.

3) Agree to a deadline for submission of the papers, number of papers and so forth.

4) Formulation of and agreement on procedure for initial screening and editorial evaluation of manuscripts and discussions with active participation by the sponsoring group.

5) Submission to the Editorial Staff of the Journal for their evaluation.

6) Interaction between Journal and sponsoring editorial group. Final decision is retained by Journal Editorial Staff.

7) Redaction, page proofing and so forth by Editorial Staff. Articles in supplements would be indexed in the Journal.

8) Publication.

D I S C L A I M E R 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.

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0022-5347/92/1485-1437$03.00/0 T H E J O U R N A L O F U R O L O G Y Copyright© 1992 by A M E R I C A N U R O L O G I C A L A S S O C I A T I O N , I N C .

Vol. 148, 1437-1440, November 1992 Printed in U.S.A.

P R E L I M I N A R Y R E S U L T S W I T H T H E N I T R I C O X I D E DONOR L I N S I D O M I N E C H L O R H Y D R A T E I N T H E T R E A T M E N T OF

H U M A N E R E C T I L E D Y S F U N C T I O N

C H R I S T I A N G. S T I E F , F R E D R I K H O L M Q U I S T , M O H A M A D D J A M I L I A N , H E L M U T K R A H , K A R L -E R I K A N D E R S S O N A N D U D O JONAS

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

A B S T R A C T

Recent experimental studies showed an important role of endothelium derived relaxing factor for cavernous smooth muscle relaxation. Since nitr ic 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) i n the treatment of erectile dysfunction.

To determine a therapeutically useful dose 0.1, 0.2, 0.5 and 1 mg. S I N - 1 were injected intracav-ernously i n patients w i t h erectile dysfunction. Each dose was given to 2 patients. Then, 63 patients received 1 mg. S I N - 1 , including 7 who had prolonged erections to minimal doses of papaverine plus phentolamine and 4 who did not respond w i t h a fu l l erection to other pharmacological agents. Intracavernous injection of S I N - 1 induced a dose-dependent erectile response by increasing the arterial inflow and relaxing cavernous smooth muscles. Of the patients 29 had a fu l l , 21 an almost f u l l and 13 a moderate erection to 1 mg. S I N - 1 . There were no systemic or local side effects. I n the patients w i t h prolonged erections to papaverine plus phentolamine the mean duration of a ful l erectile response to S I N - 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 S I N - 1 was superior in 10, comparable i n 47 and inferior i n 6 patients.

Our data suggest a possible role for S I N - 1 i n 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.

K E Y W O R D S : peni le e r e c t i o n , i m p o t e n c e , n i t r i c oxide

Cavernous smooth muscles have a crucial role in penile erection. Relaxation of the arterial and sinusoidal cavernous smooth muscles induces an erection by decreasing peripheral resistance, entrapping blood within the sinusoids and restrict­ing cavernous outflow.1 In vascular smooth muscle endothelium derived relaxing factor is an important physiological mecha­nism for relaxation.2 The current view is that nitric oxide or a nitric oxide-containing compound, synthetized from L-argi-nine, accounts for the biological actions of endothelium derived relaxing factor.3 Recent in vitro studies on rabbit and human penile tissues have shown that nitric oxide or a nitric oxide-containing compound, probably released from nerves, has a role in the regulation of cavernous smooth muscle tone.4"7 In vivo studies in rabbits further support a role for the L-arginine/ nitric oxide pathway in penile erection.8

These experimental data suggest that in the treatment of erectile dysfunction use of the L-arginine/nitric oxide pathway may be an interesting approach, since i t would resemble the physiological sequence of events in erection. Linsidomine chlor­hydrate (SIN-1) is the active metabolite of the antianginal drug molsidomine9 (N-ethoxycarbonyl-3-morpholino-sydnonimine) and it is believed to liberate nitric oxide nonenzymatically (nitric oxide donor). Preliminary results showed that SIN-1 produces an erection in patients with erectile dysfunction.1 0 We examined the effects of intracavernous application of SIN-1 in 63 men with erectile dysfunction, and evaluated its possible therapeutic potential in the treatment of erectile dysfunction.

A c c e p t e d for p u b l i c a t i o n M a r c h 13, 1992. S u p p o r t e d by grants S t i 9 6 / 2 - 2 f r o m t h e D e u t s c h e F o r s c h u n g s ­

gemeinschaft a n d the S w e d i s h M e d i c a l R e s e a r c h C o u n c i l ( N o . 6837) .

P A T I E N T S A N D M E T H O D S

SIN-1 was injected intracavernously in 63 patients from our impotence clinic. Before entering the study the patients under­went a comprehensive evaluation regarding the etiology of the erectile dysfunction, including case history, physical examina­tion, sexual case history (by a psychiatrist), blood laboratory studies, pharmaco-Doppler ultrasound, single potential analy­sis of cavernous electrical activity evaluation11 and pharmaco­logical testing. 1 2 When indicated by case history or the afore­mentioned examinations,12 pharmaco-angiography or caverno-sometry was done. In case the standardized medication of 15 mg./ml. papaverine and 0.5 mg./ml. phentolamine, with a max­imal dose of 3 ml., did not induce a full erection (at least 3 intracavernous injections were done), prostaglandin E l (maxi­mal dose 40 μg.) was applied. In case of incomplete erection to prostaglandin E l a combination of 10 ^g. prostaglandin E l and 5 ßg. calcitonin gene-related peptide13 was tried. All injections were done with the patient in the supine position. Only 1 dose a day was injected. To enhance reproducibility the patients were advised to restrain from psychogenic or reflexogenic stim­ulation. The erectile response was evaluated by a urologist 10, 20 and 30 minutes after the injection.

After the diagnostic evaluation all patients were injected with SIN-1 intracavernously. Before the injection the patients were extensively informed about the study and about possible side effects (prolonged erections, systemic side effects, such as decreased blood pressure with unconsciousness, cavernous f i ­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 No. 532).

SIN-1 is officially approved for treatment of coronary spasms 1437

1438 S T I E F A N D A S S O C I A T E S

F I G . 1. I n t r a c a v e r n o u s i n j e c t i o n of 0.5 mg. S I N - 1 i n 51 -year -o ld p a t i e n t w i t h v e n o g e n i c a n d a r t e r i o g e n i c erect i le d y s f u n c t i o n induced s i g n i f i c a n t i n c r e a s e i n p e n i l e a r t e r i a l b lood flow ve loc i ty d u r i n g 140 m i n u t e s ( c o n t i n u o u s w a v e D o p p l e r u l t r a s o u n d , 8 M H z . probe) . 1, D o p p l e r s i g n a l s before S I N - 1 . 2, 3 m i n u t e s after i n t r a c a v e r n o u s in jec ­t i o n of 0.5 mg. S I N - 1 ( E l ) . 3, 10 m i n u t e s after S I N - 1 ( E 2 ) . 4, 35 m i n u t e s after S I N - 1 ( E 4 ) .

F I G . 2. R e c o r d i n g of c a v e r n o u s e lectr ic a c t i v i t y ( frequency range 0.5 to 500 H z . ) w i t h 2 needle e lectrodes , 1 i n e a c h c o r p u s , i n 39 -year -o ld p a t i e n t w i t h erect i le d y s f u n c t i o n , negat ive o r g a n i c f indings a n d high p r o b a b i l i t y of p s y c h o g e n i c etiology, a, u p p e r r e c o r d i n g shows n o r m a l e l e c t r i c a c t i v i t y i n f l a c c i d s tate ( r e c o r d e d d u r i n g 40 m i n u t e s ) , s y n c h r o n ­ous i n b o t h c a v e r n o u s bodies w i t h u p p e r t r a c i n g i n r i g h t a n d lower i n left c a v e r n o u s body. 6, 20 s e c o n d s after i n t r a c a v e r n o u s in ject ion of 1 mg . S I N - 1 . L o w e r r e c o r d i n g s h o w s d r a m a t i c a l l y r e d u c e d cavernous e l e c t r i c a c t i v i t y i n b o t h c a v e r n o u s bodies , w i t h o n l y short last ing p o t e n t i a l s of low a m p l i t u d e ( a r r o w s ) i n left c o r p u s . T h i s reduced c a v e r n o u s e lectr ic a c t i v i t y l a s t e d more t h a n 60 m i n u t e s (end of regis­t r a t i o n ) .

and for angiography of the coronary arteries. The dosage rec­ommended by the manufacturer is 0.4 to 1 mg. Therefore, we applied 0.1 mg. in 2 patients, 0.2 mg. in 2 and 0.5 mg. in 2. Since a main purpose of this study was to evaluate a therapeu­tically useful dose, considering effect versus possible side ef­fects, such as pain, prolonged erections and systemic reactions, ail patients (including the aforementioned 6) received 1 mg. Nine patients were also given 2 mg. SIN-1, since 1 mg. induced only an insufficient (less than category E5) erectile response. In 6 of these 9 patients SIN-1 was considered the last thera­peutic alternative regarding available drugs for autoinjection therapy. Since a possible therapeutic use of SIN-1 was to be

evaluated, patients receiving 2 mg. SIN-1 were advised to use additional reflexogenic and/or psychogenic stimulation to im­prove 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 hypo­volemic 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 tumes­cence without rigidity, E4—full tumescence with medium rigid­ity 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.

R E S U L T S

At the dosages used intracavernous application of SIN-1 induced an erectile response in all patients. The erectile re­sponse, measured by tumescence and rigidity, as well as by arterial flow velocity, was dose-dependent. Intracavernous in­jection of 0.1 mg. SIN-1 (2 patients) induced a medium tumes­cence without rigidity (E2) after a mean of 15 minutes and lasting for 45 minutes. By Doppler sonography a significant increase in cavernous arterial flow was observed for a mean of 85 minutes. Intracavernous injection of 0.2 mg. SIN-1 (2 pa­tients) induced an almost full erection (E4 to E5) for 40 minutes 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 disappear­ance 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 leak­age. These patients were injected with 2 mg. SIN-1. Among the 9 patients who received intracavernous injection of 2 mg. SIN-1 an almost full erection (E4 to E5) was observed in 4, while 5 achieved an erectile response (E4) comparable to that obtained with 1 mg. SIN-1. All 4 patients with an almost full erection after 2 mg. SIN-1 achieved a full erection (E5) with additional stimulation. Comparing the maximal erectile response to SIN-1 to that of the combination of papaverine and phentolamine, SIN-1 was superior in 10 of the 63 patients, comparable in 47 and inferior in 6.

In 2 of 4 patients with insufficient erectile response to maximal doses of papaverine (45 mg.) plus phentolamine (1.5 mg.), prostaglandin E l (40 Mg.) and the combination of pros­taglandin E l (10 Mg.) plus calcitonin gene-related peptide (5 M g . ) 1 4 intracavernous injection of 2 mg. SIN-1 induced an almost full erection (E4 to E5), which became a full erection with additional stimulation. Both patients are currently on SIN-1 autoinjection therapy.

A total of 4 patients did not respond to maximal doses of papaverine plus phentolamine or prostaglandin E l with a full erection. The combination of 10 μ%. prostaglandin E l plus 5 Mg. calcitonin gene-related peptide induced a full erection (E5) for 60 minutes. In these patients intracavernous injection of 1 mg. SIN-1 induced only an incomplete erectile response (E3 or E4). In 2 other patients responding better to the papaverine-

N I T R I C O X I D E D O N O R L I N S I D O M I N E C H L O R H Y D R A T E I N E R E C T I L E D Y S F U N C T I O N 1439

phentolamine combination the diagnostic evaluation was highly suspicious for pure psychogenic impotence.

A total of 7 patients showed a pure neurogenic etiology for the erectile dysfunction on diagnostic evaluation. A dosage of 1 mg. SIN-1 was injected into 6 patients with long lasting full erections to relatively small doses of the combination of papav­erine and phentolamine. With a mean dose of 0.33 ml. (5 mg. papaverine and 0.16 mg. phentolamine) 4 of the 6 men had a mean full erectile duration of 230 minutes; 2 of them presented with 2 episodes of prolonged erection. Another patient was transferred to us because multiple prolonged erections devel­oped of about 40 hours to doses of 20 mg. papaverine. In these 7 patients intracavernous injection of 1 mg. SIN-1 induced a full erection lasting for 40 to 90 minutes (mean 57 minutes).

I n all but 1 patient the injection of SIN-1 induced no objective or subjective systemic side effects. One patient reported sweat­ing after intracavernous injection of 2 mg. SIN-1. No patient reported pain or burning during or after the intracavernous injection of SIN-1. Of the patients who were on papaverine and phentolamine autoinjections 4 noticed subjectively that intra­cavernous application of SIN-1 was much more comfortable than injection of the papaverine-phentolamine mixture.

D I S C U S S I O N

Our study shows that the intracavernous injection of SIN-1 induces a dose-dependent erectile response. By Doppler sonog­raphy we could demonstrate that this erectile response is ac­companied by a dramatic increase in cavernous arterial blood flow. In vitro studies showed cavernous smooth muscle relaxa­tion to SIN-1. 7 These findings are in agreement with our recordings of cavernous electrical activity before and after intracavernous injection of SIN-1. We found an almost com­plete disappearance of cavernous electrical activity after SIN-1, which shows that the erectile response to intracavernous SIN-1 is due to cavernous smooth muscle relaxation.11

Comparing the maximal erectile responses, the erection in­duced by SIN-1 was superior to that produced by the combi­nation of papaverine and phentolamine in 10 of 63 patients, comparable in 47 patients and inferior in 6. The mechanisms behind the effects of the combination are complex, and prob­ably not only include the phosphodiesterase inhibiting effects of papaverine and the α-adrenoreceptor blocking effect of phen­tolamine but additional actions. SIN-1 is believed to liberate nitric oxide nonenzymatically, which, in turn, stimulates gua-nylate cyclase leading to an increase in the intracellular con­centration of cyclic guanosine 3', 5' monophosphate. SIN-1 also hyperpolarizes the cell membrane by influencing the so­dium-potassium pump,1 4 thus rendering the smooth muscle cell less responsive to adrenergically mediated contraction. The actions of the papaverine-phentolamine combination and of SIN-1 are not dependent on an intact endothelium, which should make both alternatives effective also in cases when the erectile dysfunction may be due to endothelial malfunction, such as in diabetes mellitus or hypercholesterolemia.15"17 Our series suggests SIN-1 to be comparable or even superior to the combination of papaverine and phentolamine. However, con­trolled comparative studies are needed to strengthen these assumptions. Furthermore, the reasons for possible differences in efficacy remain to be established.

In 4 of 63 patients who received SIN-1 neither 45 mg. papaverine plus 1.5 mg. phentolamine, 40 μg. prostaglandin E l nor 10 μg. prostaglandin E l plus 5 ßg. calcitonin gene-related peptide induced an erectile response allowing intercourse (even with additional stimulation). In 2 of these 4 patients intracav­ernous injection of SIN-1 combined with stimulation induced a full erection, thus enabling the patients to have intercourse without the insertion of a penile prosthesis or application of a vacuum device. We have no explanation for the apparent better efficacy of SIN-1 in these patients. It is known that the number

of prostaglandin E l receptors is reduced in several diseases, such as diabetes mellitus, 1 8 and that this may contribute to a lesser effect. In such cases SIN-1 may be an effective alterna­tive.

A 1 mg. dose of SIN-1 was injected into 6 patients with long lasting full erections to small doses of the papaverine-phentol­amine combination. History revealed a spinal cord injury (com­plete below T i l ) in 1 patient and a vertebral nucleus prolapse (L4/L5) in 1. In 4 patients abnormal single potential analysis of cavernous electrical activity findings was obtained, with the other examinations being normal. With a mean dose of 0.33 ml. (5 mg. papaverine and 0.16 mg. phentolamine) 4 of 6 men had a mean duration of a full erection of 230 minutes (2 of them presented with episodes of prolonged erections). One patient was transferred to us because of multiple prolonged erections about 40 hours in duration with doses of 20 mg. papaverine. The diagnostic constellation in these 7 patients is highly suggestive of pure neurogenic impotence. Although these patients are usually overreactive to intracavernous pharmaco­therapy, intracavernous injection of 1 mg. SIN-1 induced a full erection lasting 40 to 90 minutes (mean 57 minutes). This finding may be explained by the local pharmacokinetics of SIN-1 and the rapid decomposition of nitric oxide within the cav­ernous tissue, which should prevent the occurrence of prolonged erections.

Most patients on autoinjection therapy with a papaverine-phentolamine mixture report a slight burning sensation at the injection site during injection of the drug mixture. No patient who received SIN-1 intracavernously reported any pain or burning sensation during or after the injection. This observa­tion may further indicate the fact that SIN-1 is well tolerated by the cavernous tissue.

In animal studies19 as well as at followup of patients on autoinjection therapy,2 0 chronic intracavernous injection of pa­paverine has been shown to result in significant cavernous fibrosis. Chronic intracavernous injection of prostaglandin E l seems to have less fibrotic potential on cavernous tissue, as shown in animal 1 9 and human studies.20 Since SIN-1 is deliv­ered as lyophilized powder to be dissolved in physiological (0.9%) saline solution, i t should also have minor fibrotic effects on the cavernous tissue. Nevertheless, chronic animal studies are urgently needed to elucidate this important issue. Since therapy costs are of increasing importance in all countries, the cost of SIN-1 therapy is of interest (the prices indicated are those for Germany and France, respectively). The cost of 1 ampule of SIN-1 (1 mg. delivered lyophilized with 1 ampule 0.9% saline solution) equals approximately the cost of an am­pule of papaverine (30 mg. in solution) and is approximately one-fifth of the cost of prostaglandin E l (20 fig. lyophilized, delivered without solution for dissolution). Thus, SIN-1 seems to be an affordable alternative in the treatment of erectile dysfunction.

In conclusion, our preliminary results suggest that SIN-1 is an attractive option in the autoinjection therapy for erectile dysfunction. The absence of prolonged erections, the high ef­fectiveness to induce a sufficient erectile response and the low cost indicate the potential of SIN-1 to become a standard drug for intracavernous injections. Before widespread use can be advocated, long-term animal studies must examine the local effect of this agent on the cavernous tissue.

R E F E R E N C E S

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7. H o l m q u i s t , F . , H e d l u n d , H . a n d A n d e r s s o n , Κ. E . : C h a r a c t e r i s a t i o n of inhibi tory n e u r o t r a n s m i s s i o n i n the isolated corpus c a v e r ­n o s u m from rabbit a n d m a n . J . P h y s i o l . , i n press .

8. H o l m q u i s t , F . , Stief , C . G . , J o n a s , U . a n d A n d e r s s o n , K . - E . : E f f e c t s of the n i tr ic oxide s y n t h a s e i n h i b i t o r N G - n i t r o - L - a r g i n i n e on the erectile response to c a v e r n o u s nerve s t i m u l a t i o n i n the rabbit . A c t a P h y s i o l . S c a n d . , 1 4 3 : 299, 1991.

9. R e d e n , J . : M o l s i d o m i n e . B l o o d V e s s e l s , 2 7 : 282, 1990. 10. Stief , C . G . , H o l m q u i s t , F . , Allhoff , Ε. P . , A n d e r s s o n , Κ. Ε. a n d

J o n a s , U . : P r e l i m i n a r y report on the effect of the n i tr ic oxide donor S I N - 1 on h u m a n c a v e r n o u s t issue in vivo. W o r l d J . U r o l . , 9 : 237, 1991.

11. Stief , C . G . , D j a m i l i a n , M . , S c h a e b s d a u , F . , T r u s s , M . C , S c h l i c k , R . , A b i c h t , J . H , Allhoff , Ε. P . a n d J o n a s , U . : S ingle potent ia l a n a l y s i s of c a v e r n o u s electric a c t i v i t y — a possible diagnosis of autonomic impotence. W o r l d J . U r o l . , 8: 75, 1990.

12. Stief , C . G . , Bähren, W . , G a l l , H . a n d S c h e r b , W . : F u n c t i o n a l evaluat ion of penile h e m o d y n a m i c s . J . U r o l . , 1 3 9 : 734, 1988.

13. Stief , C . G . , W e t t e r a u e r , U . , S c h a e b s d a u , F . H . a n d J o n a s , U . : C a l c i t o n i n - g e n e - r e l a t e d peptide : a possible role i n h u m a n peni le erect ion a n d its t h e r a p e u t i c a l a p p l i c a t i o n i n impotent patients . J . U r o l . , 1 4 6 : 1010, 1991.

14. V a n h o u t t e , P . M . : V a s c u l a r physio logy : the end of the quest? N a t u r e , 3 2 7 : 459, 1987.

15. S a e n z de T e j a d a , I . , G o l d s t e i n , I . , A z a d z o i , K . , K r a n e , R . J . a n d C o h e n , R . Α.: I m p a i r e d n e u r o g e n i c a n d e n d o t h e l i u m - m e d i a t e d re laxat ion of penile s m o o t h m u s c l e f rom diabetic men w i t h impotence. N e w E n g l . J . M e d . , 3 2 0 : 1025, 1989.

16. Azadzoi , Κ. M . a n d S a e n z de T e j a d a , I . : I n h i b i t i o n of e n d o t h e l i u m -dependent re laxat ion by h y p e r c h o l e s t e r o l e m i a i n rabbit corpus c a v e r n o s u m smooth m u s c l e . J . U r o l . , p a r t 2, 1 4 5 : 230A, abstract 72, 1991.

17. Mersdorf , Α., G o l d s m i t h , P . C , D i e d e r i c h s , W . , P a d u l a , C . Α., L u e , Τ . F . , F i s h m a n , I . J . a n d T a n a g h o , Ε . Α. : U l t r a s t r u c t u r a l changes i n impotent peni le t i s sue : a c o m p a r i s o n of 65 p a t i e n t s . J . U r o l . , 1 4 5 : 749, 1991.

18. Aboseif , S . , R i e m e r , Κ. , S t a c k l , W . , L u e , Τ . a n d T a n a g h o , E . : Q u a n t i f i c a t i o n of p r o s t a g l a n d i n E l receptors i n t h e c a v e r n o u s t issue of h u m a n s , p r i m a t e s a n d c a n i n e s . J . U r o l . , p a r t 2, 1 4 5 : 230A, abstract 70, 1991.

19. Aboseif , S . R . , B r e z a , J . , D i e d e r i c h s , W . , B o s c h , R . , B e n a r d , F . , Stief , C . G . , L u e , Τ. F . a n d T a n a g h o , Ε . Α. : E f f e c t of c h r o n i c i n t r a c a v e r n o u s in ject ion of p a p a v e r i n e a n d p r o s t a g l a n d i n E l on erecti le t issue i n m o n k e y s . J . U r o l . , p a r t 2, 1 3 9 : 257A, abstract 377, 1988.

20. Jünemann, Κ . -Ρ . a n d A i k e n , P . : P h a r m a c o t h e r a p y of erecti le dys ­funct ion: a review. I n t . J . I m p o t e n c e R e s . , 1 : 71, 1989.