20. Nisbet AP, Foster OJ, Kingsbury A, Eve DJ, Daniel SE, Marsden40. Berkowitz BA. The relationship of pharmokinetics to pharmaco-CD, Lees AJ. Preproenkephalin and preprotachykinin messengerlogical activity, morphine, methadone and naloxone. Clin Pharma-RNA expression in normal human basal ganglia and in Parkinson’sdisease. Neuroscience 1995;66:361–376. 41. Ngai SH, Berkowitz BA, Yang JC
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Pii: s0090-4295(97)00700-0ADULT UROLOGY
USE OF INTRALESIONAL VERAPAMIL TO DISSOLVE PEYRONIE’S DISEASE PLAQUE: A LONG-TERM SINGLE-BLIND STUDY JAMIL REHMAN, ALEXANDRU BENET, AND ARNOLD MELMAN ABSTRACT
Objectives. Multiple conservative therapies for the treatment of Peyronie’s disease have been offered with
variable and poor response rates. Calcium channel blockers have been shown in vitro and in vivo to inhibit
secretion and synthesis of extracellular matrix, including collagen, glycosaminoglycans, and fibronectin, as
well as causing increased collagenase and anti transforming growth factor-beta activity. Calcium antagonists,
including verapamil, are effective in stimulating the remodeling and degradation of extracellular matrix in
tissue by altering the metabolic pathways of fibroblasts. Recently, a pilot study (1994) showed preliminary
promising results in treating plaque caused by Peyronie’s disease. This randomized single-blind placebo-
based study (1994 to 1996) was undertaken to confirm the hypothesis.
Methods. In this randomized single-blind study, 14 patients completed the study and were divided into two
groups: the verapamil treatment group (n ϭ 7) or the control saline group (n ϭ 7). Verapamil or saline was
injected directly into the Peyronie’s plaque once a week for 6 months. Patients were evaluated before and
after treatment with duplex ultrasound to confirm the extent of the lesion and to measure volume of the
plaque, and by interview and mailed questionnaire 3 months after treatment. Patients being treated with
oral calcium antagonists were excluded from the study.
Results. A decreased plaque volume was measured in 57% of the verapamil-treated men versus 28% in the
control group (P Ͻ0.04). Penile curvature demonstrated an improvement trend of 37.71 Ϯ 9.3° to 29.57 Ϯ
7.3° in the verapamil-treated patients, but the difference was not significant (P Ͻ0.07). Plaque softening was noted in all patients treated with verapamil. There was significant objective improvement in plaque-associated penile narrowing in all patients in the verapamil group. Subjective plaque-associated erectiledysfunction (quality of erection) showed improvement in 42.87% of the verapamil group versus none in thecontrol group (P Ͻ0.02). There was no local or systemic toxicity except for an occasional ecchymosis/bruise at the injection site. After a positive clinical response, plaque size, penile angulation, and symptoms
continued to improve. Decrease in plaque size was noted in each of the responders in the first 3 months.
Conclusions. This randomized single-blind study suggests that intralesional injection of calcium channel
blocker may be a reasonable approach in some selected patients for the treatment of Peyronie’s disease with
noncalcified plaque and penile angulation of less than 30°. Patients whose plaque failed to respond to
intralesional verapamil therapy within 3 months or whose angulation was greater than 30° at presentation
were more likely to benefit from surgery. UROLOGY 51: 620–626, 1998. 1998, Elsevier Science Inc. All
first describing a disease that is characterized or dorsolateral surface of the penis under the neu- by a fibrous plaque formation involving the tunica rovascular bundle, but may involve any area of thecorpus cavernosum. Induration of the tunica albu-ginea results in focal loss of elasticity with im- This article was presented (podium session) at the American Uro- paired shaft elongation during penile erection. In logical Association annual meeting, 1996. From the Department of Urology, Albert Einstein College of the early stage of the disease, bending around the Medicine/Montefiore Medical Center, Bronx, New York plaque during penile erection may result in pain. In Reprint requests: Arnold Melman, M.D., Department of Urol- severe cases, the bend may interfere with vaginal ogy, Albert Einstein College of Medicine, Montefiore Medical penetration or may cause dyspareunia. In severe Center, 210th Street, Bronx, NY 10467 Submitted: July 14, 1997, accepted (with revisions): October Peyronie’s disease, the penis distal to plaque (hour- glass deformity) may be flaccid during erection.
620 ALL RIGHTS RESERVED
Although the exact etiology remains unknown,3,4 was 16 months (range 11 to 24). The patients were evaluated the following theories have been proposed: fre- by detailed history, physical examination, biothesiometry, and quent chronic irritation,1 vasculitis,5 genetic caus- penile plethysmography. Plaque length was measured by cal-ipers (Vmoeleov OP-270, Germany) and duplex ultrasound to es,6–10 delaminate injury,11 inherited predisposi- confirm the extent of the lesion and to measure volume of the tion and repeated trauma,12 autoimmune insult,13 plaque. The volume of the plaques averaged 1.4 cc (range 1.5 to 2.7) before therapy. Seven patients had been treated unsuc- Despite numerous options for treatment, none cessfully with oral vitamin E, and 1 patient had new plaque have been clearly successful and the disease re- formation after previous Nesbit plication. Twelve patientscompleted the treatment in 6 months and 2 patients com- mains a therapeutic dilemma for urologists.15 Var- pleted treatment in 4 months (total n ϭ 14). Of the 2 patients ious oral drugs including vitamin E,16,17 para-ami- who completed the study in 4 months, 1 left the state because nobenzoate (POTABA),18 procarbazine,19–22 col- of family emergency and the other dropped out because of chicine,23 tamoxifen,24 intralesional injection of personal reasons. Both of these patients were available for final steroids,24,25 alone or in combination with hyal- interview and examination. Patients being treated with oralcalcium antagonists were excluded from the study. The pa- uronidase, collagenase,26,27 orgotein,28–32 parathy- tients were divided into treatment group (n ϭ 7) and control roid hormone,33 dimethyl-sulfoxide (DMSO),29 in- group (n ϭ 7). The patients in the treatment group received terferon,34 a combination of para-aminobenzoate intralesional injections of verapamil in an isotonic saline ve- and vitamin E,35 ultrasound therapy along with hy- hicle, whereas the control group received injections of saline drocortisone therapy,36 and vitamin E combined alone. This study was approved by the institution reviewboard of the Albert Einstein College of Medicine/Montefiore with hydrocortisone14 have been attempted. With Medical Center, Bronx, NY. Inclusion criteria were as follows: POTABA and colchicine there is a significant inci- (1) age range 35 to 70 years with clinical evidence of Pey- dence of gastrointestinal toxicity. In addition, ronie’s disease, that is, pain and plaque along with deformity of there is the danger of bone marrow depression the penis of at least 1-year duration; (2) discontinuation of any with colchicine. A controlled trial of POTABA in previous oral or other medication for Peyronie’s disease for atleast 3 months. Exclusion criteria were any history of calcium comparison to vitamin E failed to show any thera- channel blocker therapy or therapy interfering with calcium peutic benefit.20 Parathyroid injections have had no long-term success.33 DMSO has been shown tocause cataract formation. Interferon-2␤ treated TECHNIQUE
cultures of fibroblast from Peyronie’s disease ex- After local penile blockage with 2% lidocaine, the verapamil hibit inhibited fibroblast proliferation and collagen or saline was injected into the plaque with a 10-mL syringe production but there are no in vivo study reports.
and a 25-gauge needle once a week (Figure 1). Approximately Calcium channel blockers have been shown in 4 to 8 plaque punctures were performed at each sitting in aneffort to distribute the drug uniformly through the plaque. The both in vitro and in vivo studies to inhibit synthe- verapamil was injected 1 mg/0.1 cc (10 mg/1 cc). The dosage sis/secretion of extracellular matrix molecules, in- ranged from 10 to 27 mg. This dosage was chosen after con- cluding collagen, glycosaminoglycans, fibronectin, sultation with a pharmacist, taking into consideration the re- as well as increasing collagenase and transforming sponse rate in the pilot study by Levine et al.37 The patient was growth factor-beta (TGF-␤) activity. Calcium asked to compress the injection site for 5 minutes to decreaseecchymosis. Blood pressure and heart rate were continuously channel blockers such as verapamil are effective in monitored throughout the procedure and after injection for stimulating the remodeling and degradation of ex- the first 3 months, and because no patient exhibited any drop tracellular matrix in tissue. Because the concentra- in blood pressure or any related cardiac effects, monitoring tion of verapamil required to induce the degrada- was discontinued for the remaining 3 months. No systemic, tive metabolic response in fibroblasts in the local, acute, or chronic toxicity was noted except for an occa-sional transient ecchymosis/bruise at the injection site. To laboratory exceeds the maximum safe serum level prevent the incidental injury to the dorsal nerve fibers or dor- by 100-fold, only intralesional therapy is possible.
sal arteries, the needle was inserted into the dorsolateral or At present, verapamil is the only calcium channel lateral side depending upon the location of plaque. Precaution blocker available in injectable form. A pilot study37 was taken not to instill the drug into the corpus cavernosum.
showed promising results with an intralesional in- Slight gentle pressure into the syringe was required for injec-tion into the tunica albuginea, whereas instillation into corpus jection of verapamil into plaques caused by Pey- cavernosum did not require pressure.
ronie’s disease. The purpose of the present studywas to test the effect of intralesional verapamil in asingle-blind, placebo-based study.
DATA ANALYSIS AND STATISTICS
Objective and subjective data were gathered at completion of the study. Objective assessment was done by direct inter- MATERIAL AND METHODS
view, physical examination, and measurement of plaquelength and width by two independent investigators with cali- PATIENT SAMPLE
pers, confirmed by penile ultrasound. Subjective data were A total of 18 men ranging in age from 37 to 67 years (mean gathered by questionnaire 3 months after completion of the 52) entered into this randomized single-blind study. Four study. The data are expressed as mean and standard error of men dropped out in the first month of the study, 1 preferring the mean (SEM). The groups were compared using the un- surgical intervention and 3 because of scheduling conflicts.
paired Student’s t test at a significance of P Ͻ0.05 by statistical The mean duration of the disease in these men prior to therapy software (STATVIEW 4.5, Abacus Concepts, Berkeley, Calif).
UROLOGY 51 (4), 1998
to 6.3 Ϯ 0.44 post-treatment in the control group(P Ͻ0.02).
Most urologists interested in sexual dysfunction in men agree that acute or repeated mechanicaltrauma (sexual or nonsexual) to the tunica albug-inea is delivered via the septal fibers, which areresponsible for maintaining the axial rigidity dur- Cross section of shaft of penis and dorsal ing erection. Trauma with an erect penis results in neurovascular bundle. Part of the figure has been en- tissue disruption and microvascular injury (focal larged to show the relationship of the neurovascular vasculitis) that leads to exudation of fibrin.5 Fibrin bundle to the plaque and the injection technique. First triggers fibroblast activation and proliferation that local block is obtained with 0.2% lidocaine. Then the results in excessive deposition of extracellular col- verapamil (1 mg/0.1 cc [or 10 mg/1 cc] of plaque vol- lagen matrix in the tunica albuginea.11,38,39 The ume as determined by ultrasound or calculated as pre- formation of excessive fibrous tissue may also be viously mentioned) is injected into the plaque with a10-mL syringe and 25-gauge needle. Injections are triggered in genetically predisposed individuals, given weekly. Approximately 4 to 6 plaque punctures either from abnormal fibroblastic activity or de- are needed per injection to distribute the drug uniformly creased fibrinolysis. Calcium channel blockers through the plaque. The injection site should be com- have been shown to inhibit synthesis/secretion of pressed for 5 minutes to decrease ecchymosis. To pre- extracellular matrix molecules, including collagen, vent the incidental injury to the dorsal nerve fibers or glycosaminoglycans, and fibronectin, as well as in- dorsal arteries, the needle is inserted into the dorsolat- creasing collagenase and TGF-␤ activity. During eral or lateral side depending upon the location of the last two decades, tremendous achievements plaque. Precaution is taken not to instill the drug deep have been made in calcium channel blockers and into corpus cavernosum. Slight gentle pressure into sy- their role in collagen synthesis by fibroblast, both ringe is always needed to inject into the tunica albug- at the structural and biochemical levels. Better un- inea as compared to easy instillation into the corpuscavernosum. derstanding ultimately led to their clinical studiesin humans for fibromatosis. Calcium channelblockers such as verapamil are effective in stimu- lating the remodeling and degradation of extracel- The results are described in Tables I and II. All lular matrix in tissue. Because the concentration of patients who responded to verapamil did so in the verapamil required to induce the degradative re- sponse in fibroblasts in the laboratory exceeds the (1) Plaque size and volume: plaque length de- safe serum level by 100-fold or more, only intrale- creased from 3.1 Ϯ 0.5 cm pretreatment to 1.8 Ϯ sional therapy is possible at present.
0.4 cm post-treatment in the verapamil group ver-sus 2.9 Ϯ 0.5 cm pretreatment to 3.0 Ϯ 0.2 cm FIBROBLAST, COLLAGEN METABOLISM, AND CALCIUM
post-treatment in the control group (P Ͻ0.03).
Plaque width decreased from 1.7 Ϯ 0.95 cm pre- Diegelmann and Peterkofsky40 provided evi- treatment to 0.8 Ϯ 0.1 cm post-treatment in the dence that calcium channel blockers alter cell verapamil group versus 1.59 Ϯ 0.31 cm pretreat- shape and tissue remodeling via epigenetic control ment to 1.81 Ϯ 0.57 cm post-treatment in the con- of the extracellular matrix. Ehrlich et al.41 de- trol group (P Ͻ0.05). Plaque volume decreased scribed experiments with antitubulin agents that from 1.421 Ϯ 0.23 cm3 pretreatment to 0.63 Ϯ resulted in inhibition of collagen synthesis and se- 0.19 cm3 post-treatment in the verapamil group cretion of osteoblasts and fibroblasts. Dietrich and versus 1.37 Ϯ 0.27 cm3 pretreatment to 1.39 Ϯ Duffield42 demonstrated that calcium antagonist 0.29 cm3 post-treatment (P Ͻ0.04).
verapamil can alter synthesis of collagen and non- (2) Penile curvature: penile curvature showed an collagen proteins. Aggeler et al.43 demonstrated improvement trend of 37.71 Ϯ 9.3° to 29.57 Ϯ 7.3° that calcium antagonists as well as a calmodulin in 28.57% of the verapamil-treated patients versus blocker change fibroblast shape. They induced de- no improvement in the control group, but the dif- tachment of rabbit synovia fibroblasts from their ference was not statistically significant (P Ͻ0.07).
substrate, resulting in altered morphology of the (3) Quality of erections (subjective): the quality fibroblast, decreased collagen synthesis, and a of erections improved from 5.69 Ϯ 6.5 pretreat- marked increase (20-fold) in the secretion of col- ment to 7.4 Ϯ 0.37 post-treatment in 42.86% of the lagenase. The altered cells were noted to alter the verapamil group versus 6.28 Ϯ 0.52 pretreatment secretion of extracellular matrix proteins on a con- UROLOGY 51 (4), 1998
TABLE I. Response to intralesional verapamil injection
(Mean ؎ SEM)
(Mean ؎ SEM)
(Mean ؎ SEM)
(Mean ؎ SEM)
KEY: SEM ϭ standard error of the mean.
* P Ͻ0.03 (plaque length post-treatment verapamil versus control group). † P Ͻ0.05 (plaque width post-treatment verapamil versus control group). ‡ P Ͻ0.04 (plaque volume post-treatment verapamil versus control group). § P Ͻ0.07 (penile curvature post-treatment verapamil versus control group). Ե Quality of erections scaled 1 to 10 (1 ϭ no erection; 10 ϭ very rigid erection).
** P Ͻ0.02 (quality of erections post-treatment verapamil versus control group). centration-related basis, which correlates posi- Kappas et al.49 found that rats with a surgically tively with the degree of cell shape change. Once created abdominal wound treated with verapamil triggered, the increased rate of collagenase synthe- (1 mg/kg administered intravenously) produced sis persists for up to 1 week, even after the agents significantly fewer peritoneal adhesions than con- are removed and the cells reanchored onto the sub- trols. Johnson et al.50 reported that nifedipine re- strate. Kelly44 demonstrated that the secretion of sulted in improved wound healing (skin and facial extracellular matrix is calcium dependent (regulat- wounds as well as enteric anastomoses) in animals IN VITRO CELLULAR STUDIES AND CALCIUM CHANNEL
CLINICAL HUMAN STUDIES, INCLUDING THE PRESENT
STUDY AND OTHER CALCIUM CHANNEL BLOCKER
In vitro experiments by Askey et al.45 found that STUDIES
verapamil specifically inhibits fibroblast secretion.
Lee et al.51 demonstrated that intralesional injec- Lee and Ping46 reported experiments with bovine tion of verapamil hydrochloride directly into a fibroblasts exposed to increasing concentrations of burn scar markedly reduced its size. In a pilot, sin- verapamil and nifedipine, and found decreased in- gle arm study, Levine et al.37 used verapamil to corporation of radiolabeled proline and sulfate into dissolve Peyronie’s plaque and reported promising extracellular matrix collagen and glycosaminogly- results. The findings of the present randomized cans, respectively. They demonstrated that treat- single-blind study suggest that verapamil injection ment of the fibroblast-populated collagen matrix results in a significant decrease in plaque size. A with calcium channel blockers (verapamil hydro- decreased plaque length of 30% or more was noted chloride [100 mol/L] and nifedipine [10 mol/L]) in 57.14% of patients treated with verapamil versus markedly reduced the incorporation of tritiated only a 28.57% decreased plaque length in the con- proline into the extracellular matrices of the fibro- trol group (P Ͻ0.04). There was no significant blast-populated collagen matrix. Therefore, it ap- change in penile angulation after treatment, al- pears necessary to deliver verapamil directly to the though a trend was noticed in one quarter fibrous tissue to avoid high blood level. Fitscha et (28.57%) of patients. The persistence of curvature al.47 demonstrated, in a vascular lesion induced in may mean that although plaque size is reduced, the an animal model, that treatment with calcium remaining collagen tissue is sufficient to cause channel blocker (isradipine) treated fibroblasts re- chordee. The more dramatic improvement in pe- sults in decreased incorporation of proline and sul- nile narrowing (bottleneck deformity) than curva- fate into collagen and glycosaminoglycans, respec- ture associated with plaque injection may be due to the relatively thinner lateral extension of theplaque compared to the thicker midline plaque IN VIVO ANIMAL STUDIES AND CALCIUM CHANNEL
with septal extension, as previously described.37 BLOCKERS
Penile pain improved in both groups though there Steinleitner et al.48 have shown that verapamil is a significantly more rapid improvement in penile markedly reduced adnexal adhesions in rabbits.
pain in the verapamil group (mean 4 weeks) than UROLOGY 51 (4), 1998
TABLE II. Response of patients to self-administered questionnaire
regarding intralesional therapy
Post-treatment (n ؍ 7)
Post-treatment (n ؍ 7)
* Pain improved in both groups but more quickly in the verapamil group (4 weeks) than in the control group (10 weeks).
† Excellent ϭ normal sexual function, residual deformity less than 15%. ‡ Moderate ϭ some improvement of erection or deformity 15°–30°, coitus possible. § Poor ϭ absent erections or deformity greater than 30°, coitus impossible. in the placebo group (mean 10 weeks). There was appears to induce rapid, beneficial results in some also no worsening of sexual dysfunction during the patients for reduction of plaque size (Figure 2).
study, which is significant because of the potential The beneficial effects of intralesional verapamil are injury to the dorsal neurovascular bundle of the apparent within the first 3 months. For patients penis. It seems calcium antagonists are best used who respond to treatment, the injections should be for immature plaque (plaque of less than 2-year continued for 6 months. The patient who fails to duration) with penile angulation of less than 30°.
respond to intralesional verapamil or whose angu- On the other hand, histologic evaluation of ad- lation is more than 30° at presentation should be vanced disease has revealed islands of active fibro- considered a candidate for surgery. Also, use of blasts randomly dispersed throughout plaques. In- calcium antagonists more potent than verapamil tralesional injection of verapamil at multiple sites should be considered as they become commer- into plaque appears to allow verapamil to inhibit cially available in injection form. The injection of the activity of these fibroblasts in older plaque, verapamil is clinically safe for patients with Pey- which may not be possible by other methods.
ronie’s disease if precautions are taken to preventinjury to the dorsal neurovascular bundle. When CONCLUSIONS AND FUTURE STUDY
compared with other methods of treatment, injec- The injection of verapamil appears to be clini- tion of verapamil appears to induce a rapid, bene- cally safe for treating patients with Peyronie’s dis- ficial effect in some patients (those with angulation ease if used judiciously. When compared with of less than 30°) for reduction of plaque size. Pa- other methods of treatment, injection of verapamil tients with localized plaque are the best candidates UROLOGY 51 (4), 1998
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UROLOGY 51 (4), 1998
Guideline No… pÉííáåÖ=ëí~åÇ~êÇë=íç=áãéêçîÉ=ïçãÉåÛë=ÜÉ~äíÜ DELIVERY AFTER PREVIOUS CAESAREAN BIRTH 1. Aim To provide evidence-based information on the management of women undergoing either trial of vaginal birth after previous caesarean section (trial of VBAC) or elective repeat caesarean section (ERCS). This guideline is primarily aimed at the