Zebra 365, Here is the recent article in UROLOGY.( took a long time to scan and edit; lousy HP scanner, IMHO!! waiting for fat VIVUS
profits to get me a new machine !! ).
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MUSE THERAPY: PRELIMINARY CLINICAL OBSERVATIONS
PHILIP WERTHMAN AND JACOB RAJFER UROLOGY 50 (5), Page 809
ABSTRACT
Objectives. lntracavernosal injection of vasodilating agents has been a mainstay in the treatment of erectile dysfunction. Recently, a transurethral delivery system (MUSE) for alprostadil (prostaglandin El) was introduced as an alternative form of pharmacotherapy.
Methods. One hundred consecutive patients with erectile dysfunction were treated with MUSE in doses ranging from 1 25 to I 000 ug and their erections were observed in the clinical setting. All patients had previous intracavernosal injections of combination pharmacotherapy (papavarine, Regitine, and/or prostaglandin El).
Results. Of these I 00 patients that used MUSE, only 7% had well-sustained, rigid erections while 30% had full erections but with partial rigidity. The remaining 63 % of patients did not achieve erections that they thought were adequate for penetration. Penile and/or perineal pain occurred in 24% of patients, 3% had a syncopal episode, and 3% experienced urethral bleeding. One patient had priapism that required drainage. Using intracavernosal injections, 49% had sustained rigid erections, 40% had full erections with partial rigidity, and I I % did not have a response satisfactory for penetration.
Conclusions. These data suggest that intracavernosal injections appear to be more effective than MUSE in achieving a rigid erection in men with erectile dysfunction. UROLOGY 50: 809-811, 1 997. Science Inc.
[ From the Dept of Urololgy, University of Calif @ Los Angeles School of Medicine
Reprint requests: Philip Werthman, M.D.. Dept of Urolgy, UCLA School of Medicine, 10833 Le Conte Ave, Box 951738, Los Angeles, CA 90095-1738; Submitted May 5, 1997, accepted with revisions: June 27,1997]
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Erectile dysfunction is a condition that affects an estimated 10% of adult men.' Current therapeutic modalities for this disorder include medical, mechanical, and/or surgical methods. intracavernosal pharmacotherapy, which was introduced clinically in 1983, is considered the mainstay of treatment for impotence. However, studies havee shown a significant attrition rate from these intracavernosal programs mainly because of patient aversion to injections, penile pain from the injections, and the simple inconvenience of maintaining, a supply of medicines that require refrigeration.( 3 - 5 )
In an attempt to develop a more acceptable method of administering, pharmacoactive compounds to induce penile erection. a transurethrat svstem for delivering alprostadil (MUSE, Vivus, Menlo Park, Calif) was developed and recently approved by the Food and Drug Administration for use in the management of erectile dvsflinction. (6-8) We evaluated the response of this MUSE system in a university clinical setting and compared its response in the same men who were on intricavernosal injection therapy for their erectile dysfunction.
MATERIAL AND METHODS
One hundred consecutive men with erectile dysfunction agcd 25 to 86 years were treated with MUSE in doses ranging from 125 to I 000 mcg and their erections were observed in the clinic. All patients had a previous diagnostic intracavernosil injection of prostaglandin E l or combination pharinacotherapy (papaverine, Regitine, and prostigIandin El) and came in requesting a trial of MUSE.
In all patients, transurethral alprostadil was administered by a physician according to the package insert protocol. The patients were asked to void prior to instillation of medication intraurethrally),. The MUSE system was then gentIy. inserted 3 cm into the urethral meatus and the medicated pellet was dispensed. Patients were asked to pinch their glans penis for I minute to prevent the pellet from escaping the meatus- Five minutes after administration, patients were asked to stand and 10 minutes later they were asked to manually self-stiniulate to augment their erectile responses
The erectile response was then graded according to the following objective criteria: GO = no responses G I= elongation of shaft only; G2 = moderate tumescence: G3 full tumescence but easily bendable: G4 = full erection with partial rigidity, adequate for penetration. and G5 = well sustained rigidity for 20 minutes. For purposes of this report, only the response of the highest dose of MUSE will be considered. This was compared to the response of these same patients to their .current or last intracavernosal injection.
RESULTS
Initially patients were started at the 125 mcg dose of alprostadil, but no patient responded with full tumescence at this dose level. The patients were asked to return for the 250-pg dose, but onlv 15% (n = 6) of the next 39 responded with fulf erections and partial rigidity (G4) and only I patient achieved a full, sustained erection (G5). Based on the experience with these initial 39 patients, all subsequent patients were given an initial 500 mcg dose. Of the next 61 patients, 17 achieved G4 erections and 2 had a G5 response. At the 1000 mcg dose, 29% (n = 10) and 9% (n = 3) of patients had a G4 and G5 response, respectively.
Overall, onlv 7% of the total group of 100 patients had well sustained, rigid erections (G5) while 30% had full erections but partial rigidity (G4). The remaining 63 % of patients did not achieve erections that they thought were adequate for penetration. Regardless of the dose and response in clinic, 29 % of patients wished to try MUSE at home.
The complication rate with MUSE was 29% of the 100 patients ( not exclusive). Pain occurred in 24%, 3% had a syncopal episode, and 31 % experienced urethral bleeding. One patient had priapism at the 500-Ag dose that required cavernosal drainage. Complications did not appear to be dose related.
All 100 patients had received prior intracavernosal injections with various medications but primarily with a standard triple therapy mixture used at our institution-, of these 100, 49% had sustained rigid erections (G5), 40% had full erections with partial rigiditv (G4), and 11% did not have a response satisfactory for penetration (grades 0 to 3). Only 1 patient had a G4-5 response with the MUSE who did not have a G4-5 response with the intracavernosal injections.
COMMENT
Vasoactive agents such as papavarine. phentolamine, and prostaglandin El have been shown to be extremely effective in inducing an erection when given bv intracavernous injection ( 1,9,10). Patients have had difficulty, both psychologic and otherwise, accepting this method of drug self-administration to induce an erection notwithstanding the complications indigenous to these injections such as pain, priapism, corporal fibrosis, and syncope.( 11, 12 ) As a result, any less invasive method than a self injection would certainly be more appealing
to those men who shy, away from intracavernous therapy to treat their dysfunction.
Intraurethral delivery of medication to the penis to induce an erection was initially described in 1993,( 6 )and a commercial delivery system using alprostadil was recentlv approved for treatment of men with erectile dvsftinction. (7,8) The initial studies on this product indicated a high efficacy and low complication rate. We therefore evaluated this system of intraurethral alprostadil and compared it to intracavernous therapy in the first 100 patients wishing to try the MUSE system at our institution.
Intraurethral alprostidil via MUSE produced a rigid sustained erection (G5) in only, 7% of our 100 patients as compared to 43% of the patients using intracavernosal therapy. About 63% of the patients did not obtain an erection that was satisfactory for intercourse using the intraurethral MUSE system. Overall injections provided a usable erection in 89% of the impotent men versus 37 %, with intraurethral alprostadil. Our results are in contradistinction to the recently published studies using intraurethral alprostadil that report a 49.2% G4 or G5 erectile response using the maximum 1000 mcg dose.(8). One possible explanation for this discrepancy is that patients may, experience a better erection with MUSE in the home setting. On the other hand, these preliminary studies using MUSE only studied men in the home setting once they demonstrated a response to MUSE in the clinic. At doses below 500 mcg, our data show that MUSE is very ineffective in most men.(8).
Penile pain was the most common complication of transurethral alprostadil administration and occurred in 24% of our patients, similar to that reported in the original clinical trials. We did not attempt to add any anesthetic agents to the alprostadil compound in an attempt to control penile pain as has been reported previously with the intraurethral administration of prostaglaiidin E2.(6). One of our patients developed priapism at the 500,ug dose which required drainage (and alpha-antagonist instillation) to resolve. Another previously unreported complication is urethral breeding, which occurred in 3% of our patients. Presumably trauma from insertion of the MUSE device could account for this side effect. Syncope within 10 minutes of receiving the MUSE occurred in 3 % of our patients as opposed to the 0.4 % reported in the original triaI (7 ), however, a majority of our patients were started with higher doses of MUSE than previoulsv reported.
As a result of these observations in our first 100 patients at Universitv of California at Los Anccles School of Medicine, we have developed a clinical protocol for the treatment of erectile dysfunction with transurethral alprostadil. Because onIy. I patient who did not respond well to intracorporeal injections did respond well (G4) to MUSE, we have institituted a protocol that requires that any new patient requesting MUSE first receive a diag nostic intracavernosal injection of triple therapy, the standard form of intracavernosal medication used in our clinic. if the patient obtains a grade 5 response to the injection, they are then offered MUSE starting at 500 pg and are then titrated up from there if necessary. if the patient has a moderate response (grade 4) to the injection, they are initially started on 1000 pg of alprostadil. Those patients who do not respond well to injection therapy are not encouraged to try the MUSE svstem. Because of the possibility of a syncopal episode from the medication, we require all first-time instillations of MUSE to be performed in the clinic under our observation. First-time prescriptions are never written for self-administration at home for this reason.
The less than optimum response with the MUSE svstem in most of our patients highlights the need for pursuing other more amenable avenues of therapy for men with erectile dysfunction. Whether the addition of a restrictive ring or combination medications will augment the response of the intraurethral alprostadil remains to be determined. Patients with erectile dysfunction eagerly await the results of ongoing clinical trials utilizing oral medications to induce an erection. (13 ).
CONCLUSIONS
Transurethral administration of alprostadil appears clinically to be not as effective as intracavernosal injection therapy in producing a rigid, sustained erection suitable for intercourse in the majority of patients with erectile dysfunction. Despite this difference in efficacy, MUSE can still produce the complications of syncope and priapism similar to that seen in men with intracorporeal injections. As a result of our initial experience with the drug, we have developed a practical clinical algorithm for the selection of patients for MUSE therapy that requires all men who present with erectile dysfunction to undergo an initial diagnostic injection of intracavernosal medication.
REFERENCES
1. NIH Consensus Developement Panel on impotence: NIH Consensus Conference: impotence. JAMA 270: 83-90, 1993.
-). Brindley GS: Cavernosal alpha-blockade: a new technique for investigating and treating erectile impotence. Brj Psychiatry 143: 332-337, 1983.
3. Irwin MK, and Kata EJ: High attrition rate With intracavernous injection of prostagiandin El for impotency. Urology 43: 84-87, 1994.
4. WeissjN, Badiani GH, Ravelli R, and Brettschneider N: Reason for hiah drop out rate with self injection therapy for impotence. Intj Impotence Res 6: 171-174, 1994.
5. Gupta R, Kirschenj, Barrow 11 RC, and EidjF: PredicLors of success and risk factors for attrition in the use of intracavernous injection. j Urol 157: 1681 - 1686, 1997.
6. Wolfson B, Pickett S, Scott NE. DeKernion JB, and
lntraurethral prostaglandin E-2 creani: a possible alternative treatment for erectile dysfunction. Urolog@, 42: 7375, 1993.
7. P-,idma-N-,iLhaii H, Hellstrom NA"J, Kaiser FE, LabaskN RF, Luc TF, LNOILcn WE, Nor%vood PC. Peterson CA, Sliabsig@ R, Tam P@', ct til: Treatment of men With erectile dysfunction with transurethral alprostadil. N Enalj Med 336: 1-7, 1997. 8. Hellstroni 'vN'J, Bennett AH, Gesundheit N, Kaiser FE, Luc TF, Padmi-Nathan H, Peterson CA, Tam PY, Tocid LK, Var,id,@. JC, ct til: A double-blind, placebo-controlled evaluation of the erectile response to transurethral alprostadil. Llrolog@, 48: 851-856, 1997.
9. Ishii N, Watanabe H, Irisawa C, et al: Intraca,,,ernoLis injection of prostagiandin El for the treatment of erectile iiiipotence. J Urot 141: 323-325, 1989.
10. Bechara A. Casabe A, Cheli@- G, Romano S, Rev Y, and Fredotovich N: Prostaglandin El versus mixture o( prostialandin El, papa%-arine and phentolamine in nonresponders to high papavarine plus phentolamine doses.j Urol 155: 913914, 1996.
11. Waldhatiser NI, and Schramek P: Efficiencv and side effects of prostagiandin El in the treatment of erectile dN,sfi.inction.j Urot 140: 525-527, 1988.
12. Le@,-ine SB, Althof SE, Turner L-k, Risen CB, Bodner DR, Kursh ED, and Resnick N,11: Side effects of self administration of iiitr-,ic-,ivernous pap-,ivarine and phentolamine for the treatiiienl of impotence. J Urol 141: 54-57, 1989.
13. Bootell M, Allen NIJ, Ballard SA, Gepi-Attee S, Muirhead Gj, NaN,Ior Aivl. Osterloh IH, and Gingell C: SildenaEl: an oralln@ active type 5 c\-clic GIYIP-specific phosphodiesterase inhibitor For the treatment of penile erectile dvsftiiiction. Int J Impotence Res 8: 47-52, 1996.
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COMMENTS ( mine ).:
-NOTE that 39% of men using MUSE achieved a G4 , G5 erection adequate for intercourse.
-If it had been used at home it might havre been higher.
-MUSE was compared with the GOLDEN STANDARD in ED therapy, intracavernosal injection.The triple mixture used IS R O C K E T F U E L !!! and thus at 37% efficacy I think discharged itself very well.
-WITH Viagra it may do even better.
-ALL these 100 men were VERY SICK since they had ALL PREVIOUSLY been on injection therapy ( very FEW psychogenic men go for the needle!! )..
-for investment purposes the mathematical thinking is as follows: 37% men with ED X 200,000,000men with ED worldwide
== 37, 000,000 men who could benefit from MUSE; X average $ 300 per year expenditure on MUSE ( at greatly discounted price to allow for lower price in not so rich countries) == $ 11 Billion/year sales for MUSE.
In the USA, 37% X 20 mill ED men = 7.4 mill men, X $1000/year on MUSE = $ 7,400,000,000/year in sales !! ( check it out, < GG>. )
TA
(PS the reference for the 20 mill men with ED is reference No 1 in the above article, the NIH consensus conference.).
TA |
