Armin J. Becker

Burnett

Bush

Carrier

Christian G. Stiff

Djamilian

Holmquist

Ignarro

Jünemann

Meyer

Michael C. Truss

Mohamad H. Djamilian

Rajfer

Stief

Udo Jonas

Wegner

Wetterauer

English

Truss, Michael C.

Becker, Armin J.

Djamilian, Mohamad H.

Stief, Christian Georg

Jonas, Udo

Universität München: Elektronischen Publikationen

Role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the diagnosis and treatment of erectile dysfunction

Crossref

Open Access LMU

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 i 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 re- sponders 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 ( otal 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 re- laxing effect than a combination of P/P. The absence of severe side effects, including pri- apisms, may be xplained 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 .s and vascular smooth muscle sed arterial inflow, and subse- ow restriction. Recent work sug- ~rn Deutsche Forschungsgemeinschcqt Stie!, 1994, accepted (with revisions): May gests that the initial step, cavernous and vascular smooth muscle relaxation, is mediated by the syn- thesis and release of nitric oxide from nerves in- nervating vascular and cavernous mooth mus- cles. >4 Therefore, the use of the L-arginine/nitric oxide pathway seems to be a possible approach in the treatment of erectile dysfunction. Linsidomine chlorhydrate (SIN-l ;  Corvasal Intracoronaire, Hoechst, France), the active hepatic metabolite of ~ t994 / VOLUME 44, NUMBER 4 553  mols idomine  (N-ethoxycarbomyl -3- -morpho-  l inosydninimine),  is believed to liberate nitric oxide nonenzymat ica l ly  (nitric oxide donor) .  Theoretically, a nitric oxide donor may be su- perior to other vasoactive drugs because it may resemble more closely the physiologic sequence of events in penile erection. Our pre l iminary results with the intracavernous appl icat ion of SIN-1 suggested a possible role in the treatment of patients with erectile dysfunction. 5 We now re- port our extended follow-up with SIN-1 in the diagnosis and treatment of patients with erectile dysfunction. MATERIAL AND METHODS All patients underwent  a comprehensive and standardized workup for erectile dysfunction, in- cluding a detailed case history, physical examina- tion, sexual case history (questionnaire), routine blood tests, pharmaco-Doppler ultrasound, corpus cavernosum electromyogram, 6 and pharmacotest- ing. When indicated, pharmacocavernosometry and pharmacocavernography were carried out (12 patients). All 113 patients (8 patients with primary and 105 patients with secondary impotence) and 10 normal control subjects received 1 mg SIN-1 intra- cavernously. Of 113 patients, 71 (62.8%) received additional, at least three, injections of a mixture of papaverine (15 mg/mL) and phentolamine (0.5 mg/mL) (P/P) pr ior to pharmacotest ing  with SIN-1. Increasing doses of 0.25 to 2.0 mL were given according to the erectile response. All injec- tions were given in a supine position. Responses to P/P and SIN-1 were evaluated by a urologist after 10, 20, and 30 minutes by inspection and palpation and graded as follows: E 0, no response; E 1, slight tumescence; E 2, medium tumescence; E 3, full tumescence but no rigidity; E 4, full tumescence with medium rigidity, sufficient for intercourse; E 5, full rigid erection. Forty-eight SIN-1 respon- ders entered an autoinjection program with SIN-1. All patients were seen as outpatients after the first 10 injections and thereafter following each series of 25 injections. At follow-up visits, a history and physical examination and routine blood tests were taken. All patients as well as the normal control subjects were extensively informed of the study and the possible side effects (prolonged erections, cav- ernous fibrosis, infection, cavernous necrosis, and systemic side effects uch as hyqootension). Written consent was obtained from all participants. The study was approved by the Ethics Committee of the Medizinische Hochschule Hannover. RESULTS The mean patient age was Erectile dysfunction was prew months. The mean age of the Subjects with normal erectile 8.4 years. The patients' past n cluded nicotine abuse (25 patie cular disease (21 patients), h 3 tients), diabetes (17 patients), patients), pelvic trauma (9 pa abuse (6 patients). In 27 parle: tory was not contributory. Fol lowing intracavernous SIN-l, all normal control suk erections (E 5) lasting 40 to spontaneously resolved. No cc effects such as penile pain, her or prolonged erections occun with erectile dysfunction, 40 lc 20 had E 3, 14 had E 2, and 1 intracavernous SIN-1 pharma~ side effects were noted. Electromyographic patterns ing with E 4 and E 5 erection mal, 40 pathologic) did not from patients responding with (18 normal, 23 pathologic). factors, no differences were sponders and nonresponders e: lowing pelvic trauma and pa erectile dysfunction. All 9 p trauma (mean age, 30.8 +_ 6.2 tients with primary erectile dys 35.6 _+ 9.6 years) responded t,E 5 erections. Nine of 12 patiq derwent pharmacocavernosorr cavernography for suspected not achieve erections ufficien! to E 3; mean age, 56.3 _+ 7.6 yt Of 113 patients, 71. (62.8' pharmacotesting with increas ture of papaverine (15 mg/mI_ (0.5 mg/mL). Of these 71 patie E 4 or E 5 erections, includi showed adequate response to patients (74.1%) who failed. I~ responders and onresponder~ 0.3 and 1.5 ± 0.5 mL, respectix dent's t test). Of 44 SIN-1 res and 1 of 27 SIN-1 nonrespo enced prolonged erections for utes with P/P. The 48 SIN-] responders 1160 self-injections (10 to 15 mean, 24.1). No complications 554. UROL.OGY ~ / OCTObeR 1994 s, infection, or prolonged erections were All pat ients  wi th  the except ion  of 3 ;'%) were satisfied with their response to Three patients withdrew from the study be- :he quality of the erectile responses to SIN-1 COMMENT i ~ntly~ nitric oxide has been identified as a me- io [  cavernous mooth muscle relaxation and te erection in vitro and in vivo 1-4 Nitric oxide iihesized from c-arginine by nitric oxide syn- i(NOS); it acts on guanylate cyclase activa- ~hich subsequently eads to an intracellular ise of cyclic guanosine 3',5' monophosphate !p).l The intracellular eceptor for cGMP is f dependent protein kinase G, which is be- [to phosphorylate ion channels, causing in- iular calcium depletion and smooth muscle ~i~ion. SIN-1 is a drug approved for the treat- !!of coronary spasms and for angiography of ilary arteries. It is believed to liberate nitric ~nonenzymatically. The recommended dosage ~giography '1 is 0.4 to 1 mg. Since our initial ;: e s~[low d a dose-dependent response to SIN-1 {more favorable results with 1 mg, all subse- ) patients received 1 mg.5 ~6ur present series 35 of 113 patients (31%) to respond with erections ufficient for in- ~rse. In our initial report 5 only 21% failed; our  present data are somewhat less favorable. may be attributed to the higher percentage of nts with assumed neurogenic erectile dys- !on in our first 63 patients, since patients with ~minantly neurogenic impotence, that is, dia- ii and patients after pelvic trauma, tend to re- J better to intracavernous pharmacotherapy, r fact that nonresponders to SIN-1 showed a incy toward multiple risk factors and 20 of 27 'sponders (74.1%) achieved erections uffi- for intercourse with P/P indicates that P/P ~e preferable to SIN-t in patients with a mul- 5rial origin of erectile dysfunction, that is, pa -  i with significant arterial vascular disease and tic neuropathy The higher smooth muscle re- ~, potential of P/P is also reflected by the fact ~IN-1 nonresponders needed a significantly ' dos{Ge of P/P than nonresponders to induce -~ction sufficient for intercourse (1.5 _+ 0.5 vs 0.3 mL; p <0.0001). Our observation that is not effective in the majority of patients Zenous leakage is in accordance with the find- ~f others, s If venous leakage is a symptom of lplete cavernous relaxation, further support en to the assumpt ion  that SIN-1 causes submaximum cavernous relaxation. 9 In contrast, SIN-1 gives excellent results in patients with (as- sumed) relatively intact cavernous tissue, that is, younger patients with primary erectile dysfunction 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 did not cause any prolonged erections, even in nor- mal subjects and in patients -who needed only min- imum amounts  of P/R Therefore, we consider SIN-1 the drug of choice in patients with proven or suspected increased sensitivity to other vasoactive agents. In addition, SIN-1 may prove to be the drug of choice in other subgroups of patients in the fu- ture (ie, impotence after pelvic surgery). If SIN-1 fails to induce a satisfactory erectile response, other agents, such as P/P or prostaglandin E> should be administered. Possible explanations for the absent priapismogenic potential of SIN-1 may be a more physiologic induction of erection and the rapid local metabolism of nitric oxide.l° After up to 150 injections/patient, o cavernous fibrosis was noted; with respect o local side ef- fects such as intrapenile discomfort or pain, SIN-1 compares favorably to prostaglandin E 1 and the combinat ion of papaverine and phentolamine.  With prostaglandin E 1 20% to 40% of patients ex- perience penile pain and with P/P, although less intense, most patients report a slight burning sen- sation during administration.ll With SIN-l, no pa- tients reported such a discomfort, which may indi- cate that the substance is well tolerated by the cavernous tissue. This is also supported by the fact that no inf lammatory or fibrous reactions were seen after multiple intracavernous injections in the rabbit model, ix Currently, all patients at our institution under- going intracavernous pharmacotesting receive 1 mg SIN-1. In case of a satisfactory erectile re- sponse, all patients are counseled to enter a self-in- jection program with SIN-1 tor a maximum reduc- t ion of poss ib le  s ide effects.  Pat ients  not  responding to SIN-1 are advised to undergo phar- macotesting with increasing doses of papaverine plus phentolamine. Responders continue with this regimen, whereas nonresponders are offered a trial with intracavernous calcitonin gene-related pep- tide plus prostaglandin El, since this combination was shown to be effective in the majority of P/P nonresponders, x3 In conclusion, our data suggest hat intracav- ernous SIN-1 is safe and efficacious in the majority of patients with erectile dysfunction; however, it has a lower smooth muscle relaxing potential than a combination of papaverine and phentolamine. t~J~¥ / OCTOBER t99~- / VOLUM~ 44, NVMSER 4 555 !, The fact that  no pro longed erect ions  were  se n even in pat ients  w i th  a past  h i s to ry  of  p r iap isms may be exp la ined  by  the more  phys io log ic  induc-  t ion of  erect ion  w i th  a n i t r i c  ox ide  donor  and  a rap id  in t racavernous  decompos i t ion  of  SIN-1. Michael C. Truss, M.D. Department of Urology Medizinische Hochschule Hantlover Konstanty-Gutschow-Str. 8 30623 Hannover, Germany ACKNOWLEDGMENT. To Nicola van Dornick for review of the linguistic style. REFERENCES 1. lgnarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, and Railer J: Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus caver- nosum smooth muscle. Biochem Biophys Res Commun 170: 843-850, 1990. 2. Holmquist E Stief CG,Jonas U, and Andersson KE: Ef- fect of the nitric oxide synthase inhibitor NG-nitro-k-arginine on the erectile response to cavernous nerve stimulation i  the rabbit. Acta Physiol Scand 143: 299-304, 1991. 3. Railer J, Aronsml WJ, Bush PA, Dorey FJ, and Ignarro LJ: Nitric oxide as a mediator of relaxation of the corpus cav- emosum in response to nonadrenergic, noncholinergic neu- rotransmission. N EnglJ Med 326: 90-94, 1992. 4. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, and Snyder SH: Nitric oxide: a physiologic mediator of penile erection. Science 257: 401-403, 1992. 5. Stief CG, Hohnquist F, Djamilia KE, and Jonas U: Preliminary resul donor linsidomine chloralhydrate in erectile dysfunction. JUrot 148: 1~3: 6. Stief CG, Djamilian M, Schaebs, RW, Abicht JH, Allhoff EP, and Jot analysis of cavernous electric activil of autonomic impotence? WorldJ Ut 7. Jflnemann KP: Pharmacotestin; in Jonas U, Thon WE and Stief CG tion, Berlin, Springer Verlag, 1991, Pl 8. Wegner HE, and Knispel HH donor, linsidomine chlorhydrate, in t tile dysfunction caused by venou: ~09-411, 1993. 9. Carrier S, Brock G, Kour NV~ physiology of erectile dysfunction. 1993. 10. Bush PA, Gonzalez NE, and of nitric oxide and citrulline from I_. nitric oxide synthase present in rak Biochem Biophys Res Commun 186: 11. Wetterauer U: lntracavernm erectile dysfunction, in Jonas U, (Eds): Erectile Dysfunction, Berlin, S 271-235. 12. Meyer ME Taher A, Krah H, Kirchner M, Mayer B, Jonas U, Forss Intracavernous application of SIN-1 tional and toxicological results. Ann 13. Djamilian M, Stief CG, Kucz, low up results of a combination ot peptide and prostaglandin E1 in the function. J Urol 149: 1296-1298, 1993. 556 UROLOGY ~ / Oc~oBe~ 19~4 / voLv,',4u 44, NU~i~ 

Allhoff EP, and Jot analysis of cavernous electric activil of autonomic impotence?

and of nitric oxide and citrulline from I_. nitric oxide synthase present in rak

donor, linsidomine chlorhydrate, in t tile dysfunction caused by venou:

Effect of the nitric oxide synthase inhibitor NG-nitro-k-arginine on the erectile response to cavernous nerve stimulation in the rabbit.

Forss Intracavernous application of SIN-1 tional and toxicological results.

Kour NV~ physiology of erectile dysfunction.

lntracavernm erectile dysfunction, in Jonas U, (Eds): Erectile Dysfunction,

low up results of a combination ot peptide and prostaglandin E1 in the function.

Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle.

Nitric oxide as a mediator of relaxation of the corpus cavemosum in response to nonadrenergic, noncholinergic neurotransmission.

Nitric oxide: a physiologic mediator of penile erection.

Preliminary resul donor linsidomine chloralhydrate in erectile dysfunction. JUrot 148: 1~3:

https://epub.ub.uni-muenchen.de/9825/1/stief_christian_9825.pdf

Role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the diagnosis and treatment of erectile dysfunction

Abstract

Similar works

Full text

Available Versions

Universität München: Elektronischen Publikationen

Crossref

Open Access LMU