SEARCH

SEARCH BY CITATION

Keywords:

  • captopril;
  • fibrosis;
  • urethra;
  • urethral stricture

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Objective:  The purpose of this study is to evaluate the effect of intraurethral captopril gel as an antifibrotic agent on patients with urethral stricture.

Materials and Methods:  In the first phase of clinical trial, 13 rabbits were included and local side-effects of captopril gel were evaluated. In the second phase, 56 patients were enrolled from April 2004 to January 2006. After internal urethrotomy the patients were classified into three patient groups: (i) received placebo gel (group I); (ii) received 0.1% captopril gel (group II); and (iii) instilled 0.5% captopril gel intraurethrally (group III).

Results:  In phase I, no significant local side-effects were seen in the urethra of rabbits. In phase II, the mean age of the patients was 39.5 and the mean follow-up duration was 16 months. The most common etiology of the urethral stricture in the patients was iatrogenic (35.7%), most of their strictures had a depth of 0.5 cm or less (67.8%), and the length of most strictures was between 1 and 2 cm (41.1%). The patients' maximum urine flow increased more in groups II and III, than in group I (P < 0.04, P < 0.05, respectively). The recurrence rate was less in groups II and III than in group I (P < 0.05). In terms of the maximal urine flow and recurrence rate, no significant difference was seen between group II and group III (P = 0.13, P = 0.21, respectively).

Conclusion:  Captopril gel is a safe, effective and non-toxic agent for decreasing the recurrence rate of the urethral stricture after internal urethrotomy. However, more studies, including more cases and a longer follow up, are needed to prove the effect of captopril gel on patients' urethra.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Urethral stricture (US) is a narrowing of lumen of the urethra due to spongiofibrosis and scars with variable depth and length.1 Trauma or inflammation lead to extravasation of urine beneath the urethral epithelium and then scar formation is induced. Some strictures, such as Cobb's collar in the congenital type of US, are a consequence of mucosal web rather than a fibrosis. This is an abnormal development and arrests in the perforation of cloacal membrane.2

Etiology of the US consisted of sexually transmitted disease, inflammatory, ischemic, traumatic, iatrogenic and unknown causes. Prevalence of each etiology is variable according to the setting and time of the study carried out.3

Urethral stricture is still a highly recurrent disease of the urethra with limited methods for prevention of recurrence after direct vision internal urethrotomy (DVIU), such as repeated urethral dilatation, self-intermittent catheterization, and intralesional injection of anti-inflammatory drugs like triamcinolone via cystoscopy port.4–6

Several antifibrotic agents have been used in other organs and have been suitable for some purposes.7 Captopril, an angiotensin-converting enzyme-inhibitor (ACE-I) with multiple mechanisms of antifibrosis, is one of the most commonly used drugs in other organs. This agent is a safe, non-toxic and available antifibrotic.8 DVIU is still a method of choice for some categories of US, but its recurrence rate is high (23–80%).9

Thus, the present study was conducted to ascertain the effect of captopril gel on reducing the recurrence of US after DVIU. Systemic side-effects of captopril are well known, but for an evaluation of possible short-term and long-term local side-effects of captopril gel, phase I of the clinical trial had to be done in an experimental model.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Phase I clinical trial

Captopril gel was formulated and constructed by SMS in various concentrations.

In this phase of the study, short-term and long-term side-effects of captopril gel were studied. Captopril gel 0.1% and 2.5% were made at the base of sodium carboxy methyl cellulose. Thirteen Dutch albino rabbits were included in this phase, and classified into four groups: group 1, rabbits taking lubricating gel (four rabbits); group 2, rabbits taking 0.1% captopril gel (four rabbits); group 3, rabbits receiving 2.5% captopril gel (four rabbits); and the control group, one rabbit for the inspection of the normal urothelium of the experimental model.

Two mL of variable types of gel were instilled via an intraurethral route via a 2-mL syringe for 3 consecutive days. Each rabbit's urethra was occluded with an elastic band for 20 min to prevent the exiting of gel. They were kept at a standard condition and at the end of the first week, seven rabbits (one of the control group and six rabbits from other groups) were killed. The urethra together with surrounding corpora spongiosa was excised till at the level of the bladder neck and sent to a pathology laboratory in 10% formalin solution for the evaluation of short-term side-effects. Another six rabbits (two of each group) were killed 3 months after instillation of gel for the evaluation of long-term side-effects.

Phase II clinical trial

According to the results of phase I of the clinical trial, the Medical Ethic Committee of Shiraz University of Medical Sciences permitted the use of captopril gel for the purpose of intraurethral instillation.

Seventy-one men, aged 18–79, entered this phase from April 2004 to January 2006. Eleven patients were lost to follow up and four patients were excluded due to significant side-effects. Overall, 56 patients were followed for analysis. Informed special consent was taken from all of them. The urine analysis, renal function test, serum electrolyte and cardiology consultation (if they were more than 50 years old) were parts of preoperative evaluations.

Exclusion criteria consisted of the following:

  • 1
    Renal failure or hyperkalemia.
  • 2
    A contraindication for captopril usage (noted by the cardiologist).
  • 3
    Multiple antihypertensive medications.
  • 4
    History of dry cough or sensitivity to ACE-I.
  • 5
    Active urethritis.
  • 6
    Obliterative US, on which DVIU was not possible.
  • 7
    Pediatric age group.
  • 8
    Significant side-effects during instillation of gels.

Then, retrograde urethrography (RUG) was requested for the patients who were suspected of having a history of US. In these cases, uroflowmetry was performed before DVIU, and voiding cystourethrography (VCUG) was performed where necessary (i.e. when it was impossible to see the urethra proximal to the stricture or to measure the length of the stricture in concomitant RUG and VCUG). The length, depth and site of the US as well as the number of previous surgical interventions for the management of US were matched in three groups.

Direct vision internal urethrotomy was performed under the local anesthesia of 2% lidocain gel using a cold knife of Sachse urethrotome by one surgeon (MS) at the 12 o'clock position or at the site of maximum fibrosis.

The patients were classified into three groups: group I, patients who received only lubricating gel as placebo (19 patients); group II, patients who had 0.1% captopril gel containing 10 mg of captopril (20 patients); and group III, patients who were instilled with 0.5% captopril gel containing 50 mg of captopril (17 patients).

Ten milliliters of different gels were instilled into the urethra in a double-blind, randomized, case-controlled study. Then, an indwelling catheter (16–20-Fr) was inserted for 2–5 days, according to the characteristics of the US. The urethral lumen was obstructed using sterile gauze for tying the penis.

The following protocol was used for gel instillation: week 1, once a day; weeks 2 and 3, every other day; and weeks 4–6, twice a week.

For the prevention and early detection of hyperkalemia, potassium was checked three times during the gel instillation (at the beginning, middle and end of the study). Every attempt was made to keep the urine sterile preoperatively and postoperatively using proper antibiotics such as fluoroquinolones. All the patients were treated as day cases and none had any need to stay in the hospital overnight.

For follow up, the maximal urine flow (MUF) was checked and the RUG was requested for all of the patients. Cystoscopy and VCUG were performed if needed. A good response without recurrence was defined as asymptomatic voiding without residual urine and normal RUG. If the result of RUG was doubtful, passage of greater than 19-Fr of cystoscope sheath was considered a good response. Data were analyzed using χ2 and Kruskal–Wallis tests.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Phase I clinical trial

Multiple sections of the anterior and posterior urethra were taken by the pathologist and stained with hematoxylin–eosin. Short-term side-effects consisted of small superficial ulceration and denudation of the urethral mucosa as well as aggregation of inflammatory cells beneath the epithelium and lamina propria in both the anterior and posterior urethra. These mild side-effects had a similar pattern in all six rabbits which were evaluated for short-term side-effects. These adverse effects happened even in rabbits of group I (Fig. 1).

image

Figure 1. Distal part of the urethra is lined with stratified squamous epithelium. Epithelium has been denuded in the lower half of the field. There is infiltration of inflammatory cells beneath the ulcerated region, 1 week after instillation of 2.5% captopril gel (HE stain, original magnification ×200).

Download figure to PowerPoint

In the long term, the mucosa, submucosa, muscle layers the surrounding corpora spongiosa (CS) were similar to those of the control group without any fibrosis, scar formation, ulceration or aggregation of inflammatory cells. According to the pathologist's report, normal urothelium were seen in rabbits of the three groups, all of which were evaluated for long-term side-effects (Fig. 2).

image

Figure 2. Normal urethral epithelium and adjacent corpora spongiosa of rabbits 3 months after instillation of intraurethral captopril gel 2.5% (HE stain, original magnification ×100).

Download figure to PowerPoint

Phase II clinical trial

Patients aged between 18 and 79 years (mean age was 39.5 ± 15.3) were followed for 6–30 months (mean, 16 months).

The most common etiology of US in the present study was iatrogenic (35.7%) and, in decreasing order, trauma (consisting of the straddle injury and pelvic fracture) in 17 patients (30.3%), infectious–inflammatory in nine of the patients (16.2%) and unknown in 10 (17.8%) (Table 1).

Table 1.  Etiology of the urethral stricture in three groups of intraurethral gel instillation
Type of gelNo. of patientsSTDTraumaIatrogenicUnknown
  1. STD, sexually transmitted disease. Values are shown as number (%).

Placebo gel192 (10.5)6 (31.6)7 (36.9)4 (21.1)
Captopril 0.1% gel203 (15)7 (35)7 (35)3 (15)
Captopril 0.5% gel174 (23.5)4 (23.5)6 (35.3)3 (17.6)
Overall569 (16.2)17 (30.3)20 (35.7)10 (17.8)

The stricture length, depth, site and recurrence times were matched in three groups and the P-value was greater than 0.05 in comparing of these parameters between three groups of intraurethral gel instillation (Table 2).

Table 2.  Length, depth, site of the urethral stricture and the number of previous surgical intervention in three groups before direct vision internal urethrotomy (DVIU) and intraurethral gel instillation
Character of urethral strictureIdentificationPlaceboCaptopril gel 0.1%Captopril gel 0.5%Overall
  1. All values are showed as number (%).

SiteAnterior16 (84.2)16 (80)12 (70.6)44 (78.5)
Posterior3 (15.8)4 (20)5 (29.4)12 (21.5)
Depth≤ 0.5 cm13 (68.4)15 (75)10 (58.8)38 (67.8)
> 0.5 cm6 (31.6)5 (25)7 (41.2)18 (32.2)
Length< 1 cm6 (31.6)8 (40)5 (29.4)19 (33.9)
1–2 cm10 (52.6)7 (35)6 (35.3)23 (41.1)
> 2 cm3 (15.8)5 (25)6 (35.3)14 (25)
Numbers of previous surgical interventions08 (42.1)11 (55)9 (52.9)28 (50)
14 (21.1)3 (15)3 (17.6)10 (17.9)
≥ 27 (36.8)6 (30)5 (29.4)18 (32.1)

The site of the US was in the anterior urethra in 44 patients (78.5%) and in the posterior urethra in 12 of them (21.5%). Of the latter group, 10 patients (83.3%) had stricture depths greater than 0.5 cm.

According to the length of stricture, the patients were classified into three groups, including the patients with US of less than 1 cm (19 patients), those with 1–2 cm of US length (23 patients), and patients with a length of greater than 2 cm (14 patients). Most of the patients were within the range 1–2 cm length of the stricture (41.1%). The depth of the US was 0.5 cm or less in 38 patients and greater than 0.5 cm in 18 patients.

The number of previous surgical interventions for the US was another important variable. Twenty-eight (50%) of the patients had no previous urethrotomy or other interventions for their US and 18 patients (32.1%) had undergone previous interventions more than twice. The rest had only one recurrence. As shown in Table 3, recurrence rate of stricture was more common in the patients with deeper, longer and posterior urethral strictures. Also, the recurrence rate in the group with more than two previous surgical interventions was higher.

Table 3.  Length, depth, site of the urethral stricture and the number of previous surgical intervention in three groups after DVIU and intraurethral gel instillation
Character of urethral strictureIdentificationPlaceboCaptopril gel 0.1%Captopril gel 0.5%Overall
  1. All values are showed as number (%).

SiteAnterior8 (80)3 (50)2 (33.3)13 (59)
Posterior2 (20)3 (50)4 (66.6)9 (41)
Depth≤ 0.5 cm6 (60)3 (50)3 (50)12 (54.5)
> 0.5 cm4 (40)3 (50)3 (50)10 (45.5)
Length< 1 cm2 (20)1 (16.7)2 (33.3)5 (22.7)
1–2 cm6 (60)3 (50)1 (16.7)10 (45.5)
> 2 cm2 (20)2 (33.3)3 (50)7 (31.8)
Numbers of previous surgical interventions03 (30)2 (33.3)2 (33.3)7 (31.8)
12 (20)1 (16.7)0 (0)3 (13.7)
≥ 25 (50)3 (50)4 (66.6)12 (54.5)

The MUF value before and after the trial is shown in Table 4. The increment of the urine flow was statistically different between groups II and I (P < 0.04), between groups III and I (P < 0.05) but it was not different between groups II and III (P = 0.13).

Table 4.  Preoperative and postoperative value of maximal urine flow in three groups of intraurethral gel instillation
Gel typeMUF (mL) before DVIUMUF (mL) after DVIU
  1. MUF, maximal urine flow.

Placebo gel8.5 ± 3.313.4 ± 5.3
Captopril 0.1% gel10.2 ± 2.721.6 ± 4.3
Captopril 0.5% gel9.3 ± 4.119.8 ± 3.8

Recurrence or poor response was 52.6% in group I, 30% in group II and 35.3% in group III (Fig. 3). It was not statistically different between groups II and III (P = 0.21), but was less in both groups II and III than in group I (P < 0.05).Table 3 shows the recurrence rate in the three groups.

image

Figure 3. Recurrence rate of urethral stricture in three groups of intraurethral gel instillation after internal urethrotomy.

Download figure to PowerPoint

The most common side-effect of the intraurethral gel was a mild burning sensation and pruritus of the penis (55%), which was not statistically different in three groups. This side-effect happened only at the start of gel instillation. It was improved simply by the use of antihistamines such as clemastine, diphenhydramin or hydroxyzine. Marked burning sensation and pruritis of the penis leading to discontinuation of medication was seen in two patients of the second group and one patient of the third group. One case of acute urethritis with urethral discharge happened in group III, which was due to the unsterile conditions at gel instillation. Dry cough and other systemic side-effects were not seen at all (Table 5).

Table 5.  Local side-effects of intraurethral instillation of different gels in 60 patients
Gel typeTotal numberMild burning sensation and pruritus of penisMarked burning sensation and pruritus of penisUrethritisDry cough
  1. Values are shown as number (%).

Placebo gel1911 (57.8)0 (0)0 (0)0 (0)
Captopril 0.1% gel2313 (56.5)2 (8.6)0 (0)0 (0)
Captopril 0.5% gel189 (50)1 (5.5)1 (5.5)0 (0)
Overall6033 (55)3 (5)1 (1.6)0 (0)

It should be noted that although the side-effects were evaluated in 60 patients, four patients were excluded from this study due to marked burning sensation or urethritis, so other parameters were evaluated in 56 patients.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

In the course of medical history, the treatment of urethral stricture ranged from catheterization and insertion of bogies to newer methods such as dilation, blind internal urethrotomy and open reconstruction of the urethra. With the rise of endoscopic equipment, the first report of DVIU was seen in 1865 and has been the gold standard of cold knife urethrotomy since 1971.10

The long-term and short-term results of DVIU have been evaluated and the success rate reported as 23–83% in several articles.9,11

For reducing the recurrence rate after DVIU, different methods have been used, such as self-intermittent catheterization. Although this method is simple, it should be continued for a long duration of time, possibly permanently. The short-term results of this method were not different to the observation group in the Bodker study.12,13

Geavlete et al. proved that the use of ultrasonography in the diagnosis and locating of the fibrosis area can reduce the recurrence rate of the urethral stricture.14

In the modern era, advanced techniques such as urethrotomy with neodymium:yttrium–aluminium–garnet (Nd:YAG), holmium and argon lasers have been introduced. These methods are safe with a low complication rate and good vision, but time consuming (range, 45–75 min). Vicente et al. compared laser urethrotomy with conventional cold knife urethrotomy and reported a 73% and 80% success rate in 1 year and 73% and 60% in 2 years, respectively. They concluded that laser urethrotomy is not better than cold knife in short-term results and more experience with longer follow up is needed.15,16

Urethral stenting after urethrotomy with a 22-Fr silicone catheter was used in 1982 by Fair.17 Then, covered, expandable, bioavailable and retrievable stents were used with acceptable results. Some limitations are seen in this method such as migration, erectile dysfunction, dense fibrosis and restricture around the stent and the high cost of the device.18,19

Today, with the failure of those methods (laser urethrotomy and urethral stent), several methods of open reconstruction of the urethra are used. Although results of open surgery are between 70 and 92% and are successful, the long duration of the operation, intraoperative bleeding, postoperative pain and hospital stay are limitations of its use.20,21

Homologous dermal acellular matrix and gene transfer have been mentioned in the published work. Although these methods are very attractive, they are found only as preliminary reports.22,23

Antifibrotic drugs (e.g. pirfenidone, d-penicillamine, L-Arginine, antioxidants) have been used in different organs, including the lung, kidney, liver and heart among others.24,25

Angiotensin II increases collagen type I synthesis, inflammatory and mast cell aggregation, fibroblast growth, proliferation and aggregation as well being able to decrease collagenase activity. The antifibrotic effect of ACE-I is mainly due to inhibition of transforming growth factor (TGF)-β1 and the subsequent mechanisms of action mentioned above.26,27

Huang et al. found a low level of collagenase and a high level of tissue inhibitor of metalloproteinase-1 and collagen type I in urethral scar tissue.28,29

Captopril, an ACE-I, can inhibit the formation of fibrosis in human organs by different mechanisms of action. Captopril gel from hydrophilic cellulose has a limited usage with a low incidence of side-effects. This usage has been reported for myocardial infarction and hypertension.30,31

In this study, captopril was chosen due to a high antifibrotic potential in the other organs and a low rate of systemic and local side-effects, without toxicity. Few studies have been carried out about the effect of antifibrotics on the recurrence of US after DVIU.

Jaidane et al. reported the use of halofuginone as an antifibrotic agent in reducing the scar tissue of US and of 73% efficacy compared with 27% of the control group.32

Ayyildiz et al. evaluated the effect of intraurethral mitomycin-C (MMC) on the urethral stricture of a rat model in Ankara. They infused 2 mg/L and 10 mg/L of MMC solution via the urethra for 5 min and reported good results in prevention of urethral fibrosis. They recommended low-dose intraurethral MMC following internal urethrotomy.33

Five years before the use of MMC as an antifibrotic agent, Yakubu et al. reported two interesting cases of extensive urethral necrosis, sloughing and then pan-urethral stricture formation after using MMC for superficial urethral tumors. Of course Ayyildiz et al. has not reported these serious complications.34

In the present study, satisfactory results were seen using intraurethral captopril gel instillation after DVIU. Significant side-effects were limited, and the mild burning sensation and itching of the penis was improved simply with the use of antihistamines. Many limitations of this study warrant mention. The number of cases was small and the duration of follow up was relatively short. To some extent, the high rate of recurrence which was seen in three groups may have been due to inclusion of all types of US in this study. Deep, long, posterior strictures, as well as recurrent strictures, were included. The posterior stricture has a high rate of recurrence and it needs 3–7 times of intervention for improvement.35 If many of the patients had undergone open urethroplasty, it would have been a better treatment for them.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Based on this study, the instillation of captopril gel after internal urethrotomy can reduce the risk of recurrence of US with few significant side-effects. However, more studies with various antifibrotic agents, longer follow up and more cases are needed.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

The authors would like to thank Alireza Rasti, MA, for editorial assistance, Alireza Tadayon for scientific assistance, and the Center for Development Clinical Studies of Nemazee Hospital for typing.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References
  • 1
    Andrich DE, Mundy AR. Urethral Strictures and their surgical treatment. BJU Int. 2000; 86: 5719.
  • 2
    Sugimoto M, Ueda N, Kakehi Y. Three cases of congenital urethral stricture in childhood. Hinyokika Kiyo 2003; 49: 1658.
  • 3
    Barbagli G, Palminteri E, Lazzeri M, Guazzoni G. Anterior urethral strictures. BJU Int. 2003; 92: 497502.
  • 4
    Natanhelia SS, Salaman R, Johns A, Matthews PN. A prospective randomized study of self-dilatation in the management of urethral strictures. J. R. Coll. Surg. Edinb. 1995; 40: 2957.
  • 5
    Hebert PW. The treatment of urethral stricture: transurethral injection of triamcinilone. J. Urol. 1972; 108: 7457.
  • 6
    Heyns CF, Steenkamp JW, De Kock ML, Whitaker P. Treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful? J. Urol. 1999; 101: 1583.
  • 7
    Davies HR, Recheldi L. Idiopathic pulmonary fibrosis: current and future treatment options. Am. J. Respir. Med. 2002; 1: 21124.
  • 8
    Jonsson JR, Clouston AD, Ando Y et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001; 121: 14855.
  • 9
    Holm-Neilsen A, Schultz A, Moller-Pedersen V. Direct vision internal urethrotomy. A critical review of 365 operations. BJU Int. 1984; 56: 30812.
  • 10
    Schultheiss D, Truss NC, Jonas U. History of direct vision internal urethrotomy. Urology 1999; 53: 546.
  • 11
    Prajsner A, Szkodny A, Salamon M, Bar K. Long-term results of treatment of male urethral strictures using direct vision internal urethratomy. Int. Urol. Nephrol. 1992; 24: 1716.
  • 12
    Ganaraj J, Devasia A, Gnanaraj L, Pondey AP. Intermittent self catheterization versus regular outpatient dilatation in urethral stricture: a comparison. Aust. NZ J. Surg. 1999; 69: 413.
  • 13
    Bodker A, Ostri P, Rye-Andersen J, Edvardsen L, Strackmann J. Treatment of recurrent urethral stricture by internal urethrotomy and intermittent self-cathetrization: a controlled study of a new therapy. J. Urol. 1992; 148: 30810.
  • 14
    Geavlete P, Cauni V, Georgescu D. Value of preoperative urethral ultrasound in optic internal urethrotomy. Eur. Urol. 2005; 47: 86571.
  • 15
    Dogra PN, Aron M, Rajeev TP. Core through urethrotomy with the neodymium: YAG laser for posttraumatic obliterative strictures of the bulbomembranous urethra. J. Urol. 1999; 161: 814.
  • 16
    Vicente J, Salvador J, Caffaratti J. Endoscopic urethrotomy versus urethrotomy plus Nd-YAG laser in the treatment of urethral stricture. Eur. Urol. 1990; 18: 1668.
  • 17
    Fair WR. Internal urethrotomy without a catheter: use of a urethral stent. J. Urol. 1982; 127: 6756.
  • 18
    Vcajanen A, Nuutinen JP, Isotalo T, Tormala P, Tammela TL, Talja M. Expansion and fixation properties of a new braided biodegradable urethral stent: and experimental study in the rabbit. J. Urol. 2003; 169: 11714.
  • 19
    Song HY, Park H, Suh TS et al. Recurrent traumatic urethral strictures near the external sphincter: treatment with a covered, retrievable, expandable nitinol stent – initial results. J. Urol. 2003; 170: 10567.
  • 20
    Martinez CL, Garimaldi PS, Cabezas CC, Fernandez GML, Zungri TE. Stenosis of the membranous bulbar urethra: our experience in termino-terminal urethroplasty. Actas Urol. Esp. 1998; 22: 3503.
  • 21
    Gorraiz OMA, Vicente PFJ, Tallade BM et al. Long-term results end-to-end urethroplasty. Actas Urol. Esp. 2005; 29: 499505.
  • 22
    Lin J, Hao JR, Jin J, Deng SM, Hu J, Na YQ. Homologous dermal acellular matrix graft for urethral reconstruction in man (report of 16 cases). Zhonghua Yi Xue Za Zhi 2005; 85: 10579.
  • 23
    Meria P, Anidjar M, Brouland JP, Teillac P, Berthon P, Gussenot O. Gene transfer to urethral strictures in rabbits: a preliminary report. BJU Int. 2000; 85: 11205.
  • 24
    Giri SN, Wang Q, Xie Y et al. Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration. Biopharm. Drug Dispos. 2002; 23: 20311.
  • 25
    Molteni A, Ward WF, Ts'ao CH, Solliday NH, Dunne M. Monocrotalline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. Proc. Soc. Exp. Biol. Med. 1985; 180: 11220.
  • 26
    Malsow JJ, Watson RW, Fitzpatrick JM, O'conell RP. Transforming growth factor-beta promotes pro-fibrotic behavior by serosal fibroblasts via PKC and ERK 1/2 mitogen activated protein kinase cell signaling. Ann. Surg. 2005; 242: 8807.
  • 27
    Pimental JL Jr, Sundell CL, Wang S, Kopp JB, Montero A, Martinez-Moldonado M. Role of angiotensin II in the expression and regulation of transforming growth factor-beta in obstructive nephropathy. Kidney Int. 1995; 48: 123346.
  • 28
    Huang X, Wei DP, Yang YR. Detections of collagenase activity and tissue inhibitor of metalloproteinase- 1 expression level in the urethral scar tissue. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2003; 17: 4335.
  • 29
    Baskin LS, Constantinescu SC, Howard PS et al. Biochemical characterization and quantitation of the collagenous components of urethral stricture tissue. J. Urol. 1993; 150: 6427.
  • 30
    Wu PC, Huang YB, Fang JY, Tsai YH. Percutaneous absorption of captopril from hydrophilic cellulose derivatives through excised rabbit skin and human skin. Drug Dev. Ind. Pharm. 1998; 24:17982.
  • 31
    Huang YB, Chang JS, Liu JC, Tsai MJ, Tsai YH, Wu PC. The influence of anti-irritants on captopril hydrophilic gel. Drug Dev. Ind. Pharm. 2004; 30: 1639.
  • 32
    Jaidane M, Ali-El-Dein B, Ounaies A, Hafez AT, Mohsen T, Bazeed M. The use of halofuginone in limiting urethral stricture formation and recurrence: an experimental study in rabbits. J. Urol. 2003; 170: 204952.
  • 33
    Ayyildiz A, Nohoglu B, Gulerkaya B et al. Effect of intraurethral mitomycin-C on healing and fibrosis in rats with experimentally induced urethral stricture. Int. J. Urol. 2004; 11: 11225.
  • 34
    Yakubu A, Salanki PM, Cade M, Barnes DG. Extensive urethral stricture after using mitomycin in local anaesthetic jelly for urethral tumors. BJU Int. 1999; 83: 8734.
  • 35
    Santacei RA, McAninch JW. Urethral reconstruction of strictures resulting from treatment of benign prostatic hypertrophy and prostate cancer. Urol. Clin. North Am. 2002; 29: 41727.