EP2240180A2

EP2240180A2 - Prevention of recurrence of urethral stricture after a conventional treatment

Info

Publication number: EP2240180A2
Application number: EP08841527A
Authority: EP
Inventors: Mehdi Jaidane
Original assignee: WINDGAN TRADING Ltd
Current assignee: LEBET, ALAIN
Priority date: 2007-10-23
Filing date: 2008-10-23
Publication date: 2010-10-20
Also published as: CN101917998A; US20100305144A1; RU2010120687A; RU2014105453A; AU2008315685A1; WO2009053842A2; FR2922451A1; WO2009053842A3; US20140288102A1

Abstract

Prevention of recurrence of urethral stricture after a conventional treatment. Composition applicable to the prevention of recurrence of urethral stricture after a conventional treatment, including a pharmaceutically effective amount of halofuginone. Urethral stricture, a common disease, appears secondary to urethritis, urethral infection, urethral inflammation, urethral instrumentation, urethral catheterization, urethral trauma, urethral surgery and all types of urethral lesions. Conventional treatments by internal urethrotomy, urethral dilation or surgical urethroplasty are available and can cure urethral stricture, but with a relatively high rate of recurrence of the stricture. Halofuginone can prevent the recurrence of urethral stricture after a conventional treatment via internal urethrotomy, urethral dilation or surgical urethroplasty.

Description

Prevention of recurrence of narrowing of the urethra after conventional treatment

Domain and technological background of the invention:

The present invention relates to a composition for the prevention of recurrence of urethral stricture after any other type of conventional treatment such as endoscopic internal urethrotomy, urethral dilatation or chirurchical urethroplasty.

Narrowing of the urethra is a common pathology characterized by stenosis of the urethral lumen due to the appearance of sclerous tissue, usually following healing of a lesion of the urethra. The most common causes are urethral instrumentation and catheterization, external trauma and urethral infections. The most common treatments for urethral stricture, namely endoscopic internal urethrotomy and urethral dilatation, are effective for the treatment of urethral stricture in the short term. They can rapidly treat a large number of first-line patients, but the recurrence rate of urethral stricture is high (Stormont TJ et al, Journal of Urology, Volume 150 (5 Pt 2), p 1725-8 November 1993 Holm-Nielsen A et al, British Journal of Urology, Vol 56, p 308, 1984). In addition, the recurrence rate of urethral stricture increases with the time of evolution and the repetition of the interventions (Heyns CF et al, Journal of Urology, volume 160 (2), p 356-358, August 1998).

Surgical urethroplasty techniques also have a good success rate, reaching 85 to 90% in some series (Barbagli G et al, Journal of Urology, volume 165, p 1918-1919, June 2001, Webster GD et al, Journal of Urology, Vol. 134, p. 892, 1985), but these techniques are often complex and require specific training. There is also a significant rate of recurrence of narrowing of the urethra after this first surgical treatment.

To reduce the rate of recurrence after internal urethrotomy, several techniques have been employed: prolonged urethral catheterization, urethral stenting (Jordan GH et al., P 3346-3347, in Walsh et al: Campbell's Urology, 7 ^th edition, Philadelphia, WB Saunders, 1998, Milroy E, Journal of Urology, Volume 150, p 1729- 1733, 1993), or intermittent self-probing (Harriss DR et al, British Journal of Urology, Volume 74, p 790, 1994, Kjaergaard B et al, British Journal of Urology, Volume 73, p 692, 1994; Kjaergaard B et al, Journal of Urology, volume 148, p 308, 1992) with varying results. All these techniques are invasive and are not widely used.

In comparison with the normal urethra, the quantification of the different collagen subtypes in the fibrous tissue of urethral stricture found a change in the ratio of collagen to the relative proportion of collagen type I and type III. The proportion collagen type I and collagen type III. The proportion of type I collagen is increased in the tissue of the urethral stricture with a correlated decrease in the proportion of collagen type III. These two subtypes of collagen have different mechanical properties and it has been shown that the change in collagen type III / collagen type I ratio results in a change in tissue compliance (Baskin LS et al, British Journal of Urology, volume 150, p 642, 1993). Drugs modulating the synthesis of different collagen subtypes may be useful in preventing the onset or recurrence of urethral strictures. More particularly, a specific inhibitor of collagen subtype synthesis may be useful in inhibiting the process leading to stenosis of the urethra.

This specific inhibitor is a composition containing a pharmaceutically effective amount of a pharmaceutically active compound having the formula:

In which :

R1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; R2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and R3 is a member of the group consisting of hydrogen and lower alkenoxy carbonyl; n being either 1 or 2; and pharmaceutically acceptable salts thereof.

Among this group of compounds, Halofuginone is the compound that has been found to be particularly effective for this type of treatment.

In 2003, one of the present inventors published an article reporting the effect of Halofuginone on an experimental model of urethral stricture. This work demonstrates the effect of halofuginone in preventing the appearance of new urethral strictures. In addition, this work demonstrates for the first time the effect of Halofuginone in preventing recurrence of urethral stricture after endoscopic internal urethrotomy (Jaidane et al, Journal of Urology, Vol. 170, p-2049-2052). -November 2003). This effect of preventing recurrence of urethral stricture after successful treatment with endoscopic internal urethrotomy was never demonstrated before this work. Thus, halofuginone can prevent recurrence of urethral stricture after endoscopic internal urethrotomy or similar treatment such as urethral dilatation.

There is a recognized medical need for an urethral stricture recurrence inhibitor after conventional treatment.

Summary of the invention

In accordance with the present invention, there is provided a composition for preventing recurrence of urethral stricture after conventional primary treatment such as internal urethrotomy, urethral dilatation or surgical urethroplasty, including an effective amount from a point of view pharmaceutical composition of a compound in association with a pharmaceutically acceptable carrier, the compound being a member of a group having a formula:

In which :

R1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy;

R2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and

R3 is a member of the group consisting of hydrogen and lower alkenoxycarbonyl; n being either 1 or 2; and pharmaceutically acceptable salts thereof.

Of this group of compounds, the preferred compound is halofuginone.

According to another embodiment of the present invention, there is provided a composition for preventing recurrence of urethral stricture after conventional first treatment such as internal urethrotomy, urethral dilatation or surgical urethroplasty, including a step of administering to the patient a pharmaceutically effective amount of a compound having a formula:

In which :

R2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and R3 is a member of the group consisting of hydrogen and lower alkenoxy carbonyl; n being either 1 or 2; and pharmaceutically acceptable salts thereof.

For all of these embodiments, the preferred compound is halofuginone. In the context hereinafter, the term "Halofuginone" is defined as a compound having a formula:

and pharmaceutically acceptable salts thereof. The composition preferably includes a pharmaceutically acceptable carrier for the compound.

Preferably, all of the compounds referred to above may be either the compound itself as described by the formula, and / or pharmaceutically acceptable salts thereof.

Description of the preferred modes of application:

Unexpectedly, Halofuginone has been shown to be an effective inhibitor of urethral stricture recurrence after internal urethrotomy. Such an effect was not provided by the prior art. Indeed, no other substance was previously described as preventing the recurrence of urethral strictures after internal urethrotomy or urethral dilatation. In addition, the prior art did not teach that recurrence of urethral stricture could be prevented by Halofuginone. Therefore, and as detailed below, Halofuginone can be used as a treatment to prevent recurrence of urethral strictures after first treatment with internal urethrotomy, urethral dilatation or surgical uretroplasty.

The present invention may be more readily understood by reference to the following examples. It should be noted that although reference is made exclusively to Halofuginone, it is considered that the other quinazoline derivatives have similar properties.

Example 1

Halofuginone to prevent the appearance of new strictures of the urethra:

20 male rabbits from New Zealand underwent near circumferential endoscopic electrocoagulation of the bulbar urethra over a length of 15 mm using a pediatric resector and a ball coagulation electrode. Rabbits were randomized into two groups of 10. The first group received a diet containing 10 mg / kg Halofuginone started 4 days before electrocoagulation and continued for 3 weeks. The second group received a normal diet free of Halofuginone.

Three weeks after electrocoagulation, the rabbits underwent video urethrocystoscopy and retrograde urethrocystography and were subsequently sacrificed for histological examination. The urethra was removed en bloc and fixed in 10% buffered formaldehyde. Histological examination was performed after paraffin embedding and Masson trichrome stain, hematoxylin eosin, and Sirius Red (IMEB, Inc., Chicago Illinois) to evaluate fibrosis. With this last coloration, the collagen is colored red.

All rabbits in the control group had significant urethral stricture. There was a reduction in urethral light of 70% to 95% (with a average of 87.5%). The length of the contractions ranged from 9 to 18 mm (with an average of 12 mm). In these rabbits, the histological study revealed a regenerated urothelium covering the lumen of the urethra and a thick hyaline fibrosis affecting the submucosa and muscularis and sometimes reaching the adventitious. The fibrosis was severe in all rabbits.

Only 2 of the 10 rabbits in the Halofuginone group had significant urethral stricture. In these two strictures, there was a decrease in urethral light of 70 and 90%, respectively. Both narrows had a length of 10 and 8 mm, respectively. Two other rabbits had a decrease in urethral light of less than 30%. With this level a rigid urethra and white to yellow. The urethra was normal in the remaining 6 rabbits. The histological appearance in the two rabbits with narrowing was comparable to that found in the rabbits of the control group.

In the other rabbits in the Halofuginone group, the histological study found only focal alterations with limited areas of fibrosis alternating with a normal or sub-normal urethral wall. The difference between the two groups looking at the number of rabbits with urethral stricture was statistically significant (p <0.001).

Table 1 shows this effect of Halofuginone in preventing the occurrence of narrowing of the urethra after this lesion of the urethra.

Table 1: Effect of Halofuginone in preventing the occurrence of narrowing of the urethra after urethral injury.

Example 2

Halofuginone to prevent recurrence of urethral strictures after internal urethrotomy:

48 male rabbits from New Zealand underwent endoscopic quasi-circumferential electrocoagulation of the bulbar urethra over a length of 15 mm using a pediatric resector and a ball coagulation electrode. Three weeks after electrocoagulation, an evaluation of the urethral strictures obtained was performed using video-urethrocystoscopy and retrograde urethrocystography. All live rabbits had significant narrowing of the urethra. There was a decrease in urethral light at the narrowing level from

70 to 95% (with an average of 88.5%). The length of the contractions obtained ranged from 7 to 19 mm (with an average of 11.7 mm). All live rabbits underwent endoscopic internal urethrotomy under visual control using a cold slide and a 0.028 inch endoscopic guide. A single deep incision at 12 hours was performed in all rabbits.

The rabbits were subsequently randomized into two groups: a study group receiving Malofuginone and a control group without Halofuginone for 10 weeks from the date of urethrotomy. The study group received a diet containing 10 mg / kg Halofuginone while the control group received a normal diet without Halofuginone.

The rabbits were subsequently monitored and an evaluation for narrowing of the urethra was performed if certain signs appeared: decrease in diuresis by 24 h, anorexia, deterioration of the general state with a bladder eyeball on palpation. In the absence of these signs, the evaluation for a narrowing of the urethra was performed systematically 10 weeks after urethrotomy. This evaluation was performed using video-urethrocystoscopy and retrograde urethrocystography. The rabbits were subsequently sacrificed for histological study. The urethra was removed en bloc and fixed in 10% buffered formaldehyde. Histological examination was performed after paraffin embedding and Masson trichrome stain, hematoxylin eosin, and Sirius Red (IMEB, Inc., Chicago, Illinois) to evaluate fibrosis. With this last staining, the collagen is colored red.

Table 2 presents the results. During the first week after electrocoagulation, 3 of the 48 rabbits died; The number of rabbits in the study group and in the control group was 22 and 23 rabbits, respectively. The two groups were comparable for shrinkage obtained after electrocoagulation in terms of urethral lumen reduction and stenosis length. Two rabbits died immediately after endoscopic internal urethrotomy by urethral perforation. 3 rabbits per group died from unrelated causes at follow-up. As a result, in the study and control groups, 18 and 19 evaluable rabbits remained respectively at the end of the experiment.

In the control group, there was a higher rate of urethral stricture recurrence than in the study group in a statistically significant manner (see Table 2). In the control group, recurrence of urethral stricture was suspected by clinical signs and confirmed by retrograde urethrocystography and video urethrocystoscopy in 6 rabbits on average 19.6 days after urethrotomy (with from 11 to 36 days). In all other rabbits, the diagnosis of narrowing was made at 10 weeks. Figure 1 shows the histological appearance of severe urethral stricture in a rabbit in the control group.

In the study group, 13 rabbits showed no recurrence of urethral stricture (Figure 2). 3 other rabbits had recurrence of suspected narrowing due to clinical signs and confirmed by radiology and endoscopy

12 to 43 days after urethrotomy. In the remaining two rabbits, recurrence of narrowing was diagnosed at the 10-week assessment. In rabbits free from recurrence of narrowing, the histological study of the site of prior internal rural thorotomy revealed the absence of fibrosis or a minimal degree of fibrosis (Figure 3).

Table 2: Effect of Halofuginone on the recurrence of urethral stricture after endoscopic internal urethrotomy:

In the accompanying drawings:

Figure 1 shows a photomicrograph of a section of the urethra at the site of the urethral stricture in a control rabbit receiving a diet without Halofuginone showing severe fibrosis. (A) Hematoxylin and Eosin. (B) Collagen type 1 fibers stained red with Sirius Red staining.

Figure 2 shows retrograde urethrocystography in a rabbit from the study group receiving Halofuginone. (A) Prior to internal urethrotomy, there was significant narrowing of the bulbar urethra. (B ₁ ) At 10 weeks, the bulbar urethra is of normal caliber and there has been no recurrence of narrowing. Figure 3 shows a photomicrograph of a section of the urethra at the site of prior internal urethrotomy in a rabbit from the study group receiving Halofuginone showing minimal fibrosis (A) Hematoxylin and Eosin. (B) Collagen type 1 fibers stained red with Sirius Red staining.

Example 3

Appropriate formulas for the administration of Halofuginone:

Halofuginone can be administered to a subject in a variety of ways, which are well known in the art. In what follows, the term "subject" refers to a human or a lower animal to which Halofuginone has been administered. For example, administration may be topical (including the trans-urethral route), orally or parenterally.

Topical administration formulas may include, but are not limited to, lotions, gels, creams, suppositories, drops, liquids, powders or sprays.

Conventional pharmaceutical carriers, aqueous, oily, or powder bases, thickeners and the like may be necessary or desirable.

Compositions for oral administration include powders or granules, aqueous suspensions or solutions or in non-aqueous media, sachets, capsules or tablets. Thickeners, diluents, flavoring agents, dispersants, emulsifiers or binders may be desirable.

Parenteral formulations may include, but are not limited to, sterile aqueous solutions which may also contain buffers, diluents and other suitable additives.

The dosage depends on the severity of the symptoms and the subject's response to Halofuginone. Those of ordinary skill in the art can easily determine optimal dosages, dosing methodologies, and repeat rates. Example 4

Applications for the prevention of recurrence of urethral stricture.

As noted previously, Halofuginone has been shown to be effective in preventing recurrence of urethral stricture after initial treatment with internal urethrotomy.

The following example is only an illustration of the applications for the prevention of recurrence of urethral strictures and is not intended to be restrictive. The application includes the step of administering Halofuginone, in a pharmaceutically acceptable carrier as described in Example 3 above, to a subject to be treated. Halofuginone is administered according to an effective assay methodology in a subject immediately after the first treatment of urethral stricture by internal urethrotomy, urethral dilation or surgical urethroplasty for a period of time sufficient to be most effective and to prevent recurrence of narrowing of the urethra.

Example 5

Method of making a medicament containing Halofuginone

The following is an example of a process for producing halofuginone. First, Halofuginone is synthesized according to good manufacturing practice. Examples of the methods for synthesizing halofuginone and related derivatives of quinazolinones are given in US Pat. No. 3,338,909. Thereafter, Halofuginone is placed in a suitable pharmaceutical carrier, as described in Example 3 below. above, again in accordance with good pharmaceutical manufacturing practice. While the invention is described with respect to a limited number of embodiments, it should be noted that several variations, modifications, and other applications of the present invention may be made.

Claims

1- Composition for the prevention of recurrence of urethral stricture in a subject after initial treatment with internal urethrotomy, urethral dilatation or urethral surgery, the application comprising the step of administration of an effective amount from a pharmaceutical point of view a compound having the formula:

In which :

R1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; R2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and R3 is a member of the group consisting of hydrogen and lower alkenoxy carbonyl; not being either 1 or 2; and pharmaceutically acceptable salts thereof.

2- Composition according to claim 1, characterized in that it is Halofuginone.

3. Composition according to claim 1, characterized in that it is administered to the subject by a route selected from the group consisting of the oral route, the parenteral route and the topical route.

4. Composition according to claim 3, characterized in that it is administered to the subject by topical intraurethral application.

5. Composition according to claim 4, characterized in that it is contained in a pharmaceutical carrier selected from the group consisting of a gel, a liquid, a lotion, a cream, an ointment and a spray.

6. The composition of claim 5, characterized in that it is administered to the subject until the prevention of recurrence of a narrowing of the urethra.