Role of the Nitric Oxide Donor Linsidomine Chlorhydrate (SIN-1) In

ADULT UROLOGY

ROLE OF THE NITRIC OXIDE DONOR LINSIDOMINE CHLORHYDRATE (SIN-l)IN THE DIAGNOSIS AND TREATMENT OF ERECTILE DYSFUNCTION*

MICHAEL C. TRUSS, M.D. ARMIN J. BECKER, M.D. MOHAMAD H. DJAMILIAN, M.D. CHRISTIAN G. STIEE M.D. UDO JONAS, M.D.

From the Department of Urology, Medizinische Hochschule Hannover, Hannover, Germany

ABSTRACT--Objectives. Recently, nitric oxide was shown to be a mediator of penile erection in men and the nitric oxide donor linsidomine chlorhydrate (StN-1) was intro- duced as a novel treatment option in patients with erectile dysfunction. We now present our follow-up results with the intracavernous application of SIN-1. Methods. One hundred thirteen patients with erectile dysfunction of various etiologies and 10 normal control subjects underwent intracavernous pharmacotesting with 1 mg SIN-1. Of the 113 patients, 71 (62.8%) underwent additional pharmacotesting with a mixture of papaverine (15 mg/mL) and phentolamine (0.5 mg/mL) (P/P). Forty-eight responders to SIN-1 were enrolled in an autoinjection program with this substance. Results. All normal control subjects had full rigid erections lasting 40 to 70 minutes. Of 113 patients, 78 (69%) had responses sufficient for intercourse with SIN-l, and the other 35 patients (31%) demonstrated inadequate responses. All 44 responders to SIN-1 who also received P/P had erections sufficient for intercourse with P/P in doses of 0.25 to 2 mL (mean, 0.6 + 0.3 mL). Six patients (13.6%) had prolonged erections with minimal to moderate doses of P/P. From the total of 27 patients who had erections insufficient for intercourse with SIN-I, 20 (74.1%) had good responses with 0.25 to 2.0 mL P/P (mean, 1.5 + 0.5 mL). One patient (4%) had a prolonged erection with 1.0 mL P/P. After 10 to 150 injections/patient (total of 1160 injections; mean, 24.1 injections), no significant side effects were noted with SIN-1. Conclusions. Our data suggest that intracavernous SIN-1 is safe and efficacious in the majority of patients with erectile dysfunction; however, it has a lower smooth muscle relaxing effect than a combination of P/P. The absence of severe side effects, including priapisms, may be explained by the use of a physiologic pathway for induction of the erectile response and the rapid intracavernous decomposition of SIN-1.

r'equires a series of events that gests that the initial step, cavernous and vascular .s and vascular smooth muscle smooth muscle relaxation, is mediated by the syn- sed arterial inflow, and subse- thesis and release of nitric oxide from nerves in- ow restriction. Recent work sug- nervating vascular and cavernous smooth mus- cles. >4 Therefore, the use of the L-arginine/nitric oxide pathway seems to be a possible approach in ~rn Deutsche Forschungsgemeinschcqt Stie the treatment of erectile dysfunction. Linsidomine !, 1994, accepted (with revisions): May chlorhydrate (SIN-l; Corvasal Intracoronaire, Hoechst, France), the active hepatic metabolite of

~ t994 / VOLUME44, NUMBER 4 553 molsidomine (N-ethoxycarbomyl-3--morpho- RESULTS linosydninimine), is believed to liberate nitric The mean patient age was oxide nonenzymatically (nitric oxide donor). Erectile dysfunction was prew Theoretically, a nitric oxide donor may be su- months. The mean age of the perior to other vasoactive drugs because it may Subjects with normal erectile resemble more closely the physiologic sequence 8.4 years. The patients' past n of events in penile erection. Our preliminary cluded nicotine abuse (25 patie results with the intracavernous application of cular disease (21 patients), h 3 SIN-1 suggested a possible role in the treatment tients), diabetes (17 patients), of patients with erectile dysfunction. 5 We now re- patients), pelvic trauma (9 pa port our extended follow-up with SIN-1 in the abuse (6 patients). In 27 parle: diagnosis and treatment of patients with erectile tory was not contributory. dysfunction. Following intracavernous SIN-l, all normal control suk MATERIAL AND METHODS erections (E 5) lasting 40 to All patients underwent a comprehensive and spontaneously resolved. No cc standardized workup for erectile dysfunction, in- effects such as penile pain, her cluding a detailed case history, physical examina- or prolonged erections occun tion, sexual case history (questionnaire), routine with erectile dysfunction, 40 lc blood tests, pharmaco-Doppler ultrasound, corpus 20 had E 3, 14 had E 2, and 1 cavernosum electromyogram, 6 and pharmacotest- intracavernous SIN-1 pharma~ ing. When indicated, pharmacocavernosometry side effects were noted. and pharmacocavernography were carried out (12 Electromyographic patterns patients). ing with E 4 and E 5 erection All 113 patients (8 patients with primary and mal, 40 pathologic) did not 105 patients with secondary impotence) and 10 from patients responding with normal control subjects received 1 mg SIN-1 intra- (18 normal, 23 pathologic). cavernously. Of 113 patients, 71 (62.8%) received factors, no differences were additional, at least three, injections of a mixture of sponders and nonresponders e: papaverine (15 mg/mL) and phentolamine (0.5 lowing pelvic trauma and pa mg/mL) (P/P) prior to pharmacotesting with erectile dysfunction. All 9 p SIN-1. Increasing doses of 0.25 to 2.0 mL were trauma (mean age, 30.8 +_ 6.2 given according to the erectile response. All injec- tients with primary erectile dys tions were given in a supine position. Responses to 35.6 _+ 9.6 years) responded t, P/P and SIN-1 were evaluated by a urologist after E 5 erections. Nine of 12 patiq 10, 20, and 30 minutes by inspection and palpation derwent pharmacocavernosorr and graded as follows: E 0, no response; E 1, slight cavernography for suspected tumescence; E 2, medium tumescence; E 3, full not achieve erections sufficien! tumescence but no rigidity; E 4, full tumescence to E 3; mean age, 56.3 _+ 7.6 yt with medium rigidity, sufficient for intercourse; Of 113 patients, 71. (62.8' E 5, full rigid erection. Forty-eight SIN-1 respon- pharmacotesting with increas ders entered an autoinjection program with SIN-1. ture of papaverine (15 mg/mI_ All patients were seen as outpatients after the first (0.5 mg/mL). Of these 71 patie 10 injections and thereafter following each series of E 4 or E 5 erections, includi 25 injections. At follow-up visits, a history and showed adequate response to physical examination and routine blood tests were patients (74.1%) who failed. I~ taken. responders and nonresponder~ All patients as well as the normal control subjects 0.3 and 1.5 ± 0.5 mL, respectix were extensively informed of the study and the dent's t test). Of 44 SIN-1 res possible side effects (prolonged erections, cav- and 1 of 27 SIN-1 nonrespo ernous fibrosis, infection, cavernous necrosis, and enced prolonged erections for systemic side effects such as hyqootension). Written utes with P/P. consent was obtained from all participants. The The 48 SIN-] responders study was approved by the Ethics Committee of 1160 self-injections (10 to 15 the Medizinische Hochschule Hannover. mean, 24.1). No complications

554. UROL.OGY ~ / OCTObeR 1994 s, infection, or prolonged erections were submaximum cavernous relaxation. 9 In contrast, All patients with the exception of 3 SIN-1 gives excellent results in patients with (as- ;'%) were satisfied with their response to sumed) relatively intact cavernous tissue, that is, Three patients withdrew from the study be- younger patients with primary erectile dysfunction :he quality of the erectile responses to SIN-1 and erectile dysfunction due to pelvic trauma. In 6 of 44 SIN-1 responders (13.6%) prolonged erections were seen with P/P. In contrast, SIN-1 COMMENT did not cause any prolonged erections, even in nor- i ~ntly~ nitric oxide has been identified as a me- mal subjects and in patients -who needed only min- io[ cavernous smooth muscle relaxation and imum amounts of P/R Therefore, we consider te erection in vitro and in vivo 1-4 Nitric oxide SIN-1 the drug of choice in patients with proven or iihesized from c-arginine by nitric oxide syn- suspected increased sensitivity to other vasoactive i(NOS); it acts on guanylate cyclase activa- agents. In addition, SIN-1 may prove to be the drug ~hich subsequently leads to an intracellular of choice in other subgroups of patients in the fu- ise of cyclic guanosine 3',5' monophosphate ture (ie, impotence after pelvic surgery). If SIN-1 !p).l The intracellular receptor for cGMP is fails to induce a satisfactory erectile response, other f dependent protein kinase G, which is be- agents, such as P/P or prostaglandin E> should be [to phosphorylate ion channels, causing in- administered. Possible explanations for the absent iular calcium depletion and smooth muscle priapismogenic potential of SIN-1 may be a more ~i~ion. SIN-1 is a drug approved for the treat- physiologic induction of erection and the rapid !!of coronary spasms and for angiography of local metabolism of nitric oxide.l° ilary arteries. It is believed to liberate nitric After up to 150 injections/patient, no cavernous ~nonenzymatically. The recommended dosage fibrosis was noted; with respect to local side ef- '1~giography is 0.4 to 1 mg. Since our initial fects such as intrapenile discomfort or pain, SIN-1 s~[low;: e d a dose-dependent response to SIN-1 compares favorably to prostaglandin E 1 and the {more favorable results with 1 mg, all subse- combination of papaverine and phentolamine. ) patients received 1 mg.5 With prostaglandin E 1 20% to 40% of patients ex- ~6ur present series 35 of 113 patients (31%) perience penile pain and with P/P, although less to respond with erections sufficient for in- intense, most patients report a slight burning sen- ~rse. In our initial report 5 only 21% failed; sation during administration.ll With SIN-l, no pa- our present data are somewhat less favorable. tients reported such a discomfort, which may indi- may be attributed to the higher percentage of cate that the substance is well tolerated by the nts with assumed neurogenic erectile dys- cavernous tissue. This is also supported by the fact !on in our first 63 patients, since patients with that no inflammatory or fibrous reactions were ~minantly neurogenic impotence, that is, dia- seen after multiple intracavernous injections in the ii and patients after pelvic trauma, tend to re- rabbit model, ix J better to intracavernous pharmacotherapy, r Currently, all patients at our institution under- fact that nonresponders to SIN-1 showed a going intracavernous pharmacotesting receive 1 incy toward multiple risk factors and 20 of 27 mg SIN-1. In case of a satisfactory erectile re- 'sponders (74.1%) achieved erections suffi- sponse, all patients are counseled to enter a self-in- for intercourse with P/P indicates that P/P jection program with SIN-1 tor a maximum reduc- ~e preferable to SIN-t in patients with a mul- tion of possible side effects. Patients not 5rial origin of erectile dysfunction, that is, pa- responding to SIN-1 are advised to undergo phar- i with significant arterial vascular disease and macotesting with increasing doses of papaverine tic neuropathy The higher smooth muscle re- plus phentolamine. Responders continue with this ~, potential of P/P is also reflected by the fact regimen, whereas nonresponders are offered a trial ~IN-1 nonresponders needed a significantly with intracavernous calcitonin gene-related pep- ' dos{Ge of P/P than nonresponders to induce tide plus prostaglandin El, since this combination -~ction sufficient for intercourse (1.5 _+ 0.5 vs was shown to be effective in the majority of P/P 0.3 mL; p <0.0001). Our observation that nonresponders, x3 is not effective in the majority of patients In conclusion, our data suggest that intracav- Zenous leakage is in accordance with the find- ernous SIN-1 is safe and efficacious in the majority ~f others, s If venous leakage is a symptom of of patients with erectile dysfunction; however, it lplete cavernous relaxation, further support has a lower smooth muscle relaxing potential than en to the assumption that SIN-1 causes a combination of papaverine and phentolamine.

t~J~¥ / OCTOBERt99~- / VOLUM~ 44, NVMSER 4 555 !, The fact that no prolonged erections were seen 5. Stief CG, Hohnquist F, Djamilia KE, and Jonas U: Preliminary resul even in patients with a past history of priapisms donor linsidomine chloralhydrate in may be explained by the more physiologic induc- erectile dysfunction. JUrot 148: 1~3: tion of erection with a nitric oxide donor and a 6. Stief CG, Djamilian M, Schaebs, rapid intracavernous decomposition of SIN-1. RW, Abicht JH, Allhoff EP, and Jot analysis of cavernous electric activil Michael C. Truss, M.D. of autonomic impotence? WorldJ Ut Department of Urology 7. Jflnemann KP: Pharmacotestin; Medizinische Hochschule Hantlover in Jonas U, Thon WE and Stief CG tion, Berlin, Springer Verlag, 1991, Pl Konstanty-Gutschow-Str. 8 8. Wegner HE, and Knispel HH 30623 Hannover, Germany donor, linsidomine chlorhydrate, in t tile dysfunction caused by venou: ACKNOWLEDGMENT.To Nicola van Dornick for review of the ~09-411, 1993. linguistic style. 9. Carrier S, Brock G, Kour NV~ physiology of erectile dysfunction. REFERENCES 1993. 1. lgnarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, 10. Bush PA, Gonzalez NE, and and Railer J: Nitric oxide and cyclic GMP formation upon of nitric oxide and citrulline from I_. electrical field stimulation cause relaxation of corpus caver- nitric oxide synthase present in rak nosum smooth muscle. Biochem Biophys Res Commun 170: Biochem Biophys Res Commun 186: 843-850, 1990. 11. Wetterauer U: lntracavernm 2. Holmquist E Stief CG,Jonas U, and Andersson KE: Ef- erectile dysfunction, in Jonas U, fect of the nitric oxide synthase inhibitor NG-nitro-k-arginine (Eds): Erectile Dysfunction, Berlin, S on the erectile response to cavernous nerve stimulation in the 271-235. rabbit. Acta Physiol Scand 143: 299-304, 1991. 12. Meyer ME Taher A, Krah H, 3. Railer J, Aronsml WJ, Bush PA, Dorey FJ, and Ignarro Kirchner M, Mayer B, Jonas U, Forss LJ: Nitric oxide as a mediator of relaxation of the corpus cav- Intracavernous application of SIN-1 emosum in response to nonadrenergic, noncholinergic neu- tional and toxicological results. Ann rotransmission. N EnglJ Med 326: 90-94, 1992. 13. Djamilian M, Stief CG, Kucz, 4. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, and low up results of a combination ot Snyder SH: Nitric oxide: a physiologic mediator of penile peptide and prostaglandin E1 in the erection. Science 257: 401-403, 1992. function. J Urol 149: 1296-1298, 1993.

556 UROLOGY ~ / Oc~oBe~ 19~4 / voLv,',4u44, NU~i~