WO2005018528A2

WO2005018528A2 - Method for the treatment prophylaxis and differential diagnosis of prostatitis

Info

Publication number: WO2005018528A2
Application number: PCT/EP2004/009005
Authority: WO
Inventors: Kuno Kirschfeld
Original assignee: Kuno Kirschfeld
Priority date: 2003-08-16
Filing date: 2004-08-12
Publication date: 2005-03-03
Also published as: WO2005018528A3; DE10337638A1

Abstract

The invention relates to the use of certain mucolytics and pharmaceutical compositions using said mucolytics, for the treatment, differential diagnosis and/or prophylaxis of prostatitis. The mucolytics applied are preferably characterised in containing at least one sulphydryl group and are preferably cysteine derivatives, for example acetylcysteine. The aim of the invention is to reduce the viscosity of the prostate secretions by application of said substances. The flow of said secretions can thus be improved. As a result the tension and the related tensional pain are reduced, the prostate swelling is reduced, blood supply increased and emptying of the bladder facilitated.

Description

Procedure for the treatment, prophylaxis and differential diagnosis of prostatitis

description

The present invention relates to the use of mucolytics for the treatment, differential diagnosis and prophylaxis of prostatitis.

25% of the outpatient male patients consult the general practitioner about prostatitis, 5 to 9% of the patients from specialists in urology appear there for this reason. In terms of the number of outpatient treatment cases with a urologist, prostatitis even comes first before the other two leading prostate diseases, benign prostatic hyperplasia (BHP, benign prostatic hyperplasia) and prostate cancer. Some urologists estimate that 35-50% of all men experience this condition at least once in their life. In the United States, approximately 2 million cases of prostatitis occur each year (J. Curtis Nickel: Prostatitis: The last frontier. World J. Surg. 24, 1197-1199, (2000); S. Lenk: Diagnostics of chronic prostatitis. Urologist (A ) 40, 9-11, (2001) Mc Nauphton Collins et al .: How common is prostatitis? A national survey of physician visits. Jnl. Urol. 159, 1224-1228 (1998)).

In contrast to BHP, which mainly affects older men, prostatitis occurs in all age groups. The cause and pathogenesis of their various forms are not yet known with the exception of the relatively rare acute (type I) or chronic (type II) bacterial prostatitis. The biggest problem is chronic abacterial prostatitis (type III) (chronic pelvic pain syndrome). It can be inflammatory (III a) or non-flammable (III b). Asymptomatic prostatitis (type IV), which can be discovered as a coincidence, plays no therapeutic role because of the absence of symptoms. While there are satisfactory treatment strategies for prostatitis types I and II, there is no satisfactory treatment management for prostatitis IM in either form.

The pattern of the various symptoms in prostatitis is called prostatitis syndrome. Patients with chronic forms of prostatitis suffer a significant decrease in quality of life. The most common complaints include pain and sensations in the genital and anorectal area, disorders of libido, erection and ejaculation, micturition disorders and myalgiform complaints. The complaints can be so serious that they can lead to suicidality themselves.

The known therapies of prostatitis syndrome are against inflammation, anatomical changes (enlargement), symptomatic e.g. directed against pain, or aim to improve the blood flow to the prostate and the emptying of the bladder. The preparations used in the treatment of prostatitis belong to the class of antibiotics, the alpha-receptor blockers, muscle relaxants, anti-inflammatory drugs or phytotherapeutics. Analgesics and anticholinergics are also used. Finally, psychosomatic or physical therapies, and ultimately also surgical procedures, are used (Wagenlehner and Naber: therapy of prostate syndrome. Urologist (A) 40: 24-28 (2001)). In many cases, however, these therapies do not provide satisfactory results, and the rate of successful treatments for the two most common forms (types III a and b) remains low (Special Report on Prostatitis Initiatives and Future Research. Rev. Urol. 2 (3): 158-166 (2000)).

The object of the present invention is to provide a possibility for the effective treatment, prophylaxis and differential diagnosis of prostatitis. For this purpose, a substance class is to be used, which according to prior art was not considered, and the mechanism of action for the treatment of prostatitis is novel.

To achieve this object, the invention primarily proposes a use with the features mentioned in claim 1. Further developments of this use and pharmacological compositions are the subject of the remaining dependent and independent claims 2 to 11, the wording of which is made by reference to the content of the description.

The above object is achieved according to the invention by a treatment approach in which mucolytically active substances are used. Mucolytically active substances, or mucolytics for short, are understood here and below to mean those active substances which change the physicochemical properties of mucous secretions, in particular secretions of the prostate, facilitate or accelerate their removal from the prostate or influence the secretion formation. According to the invention, the removal of the secretion from this gland is facilitated or accelerated by the therapy in the prostate.

The prostate is a composite gland that releases its secretion into the urethra when ejaculated and mixes it into the semen. Histologically, there are thickened, layered secretions in the lumen of the prostate glands (prostate stones, concretio prostaticä).

The use proposed here has the effect that the viscosity of the prostate secretion is reduced. This can improve the outflow of this secretion. In addition, it can be achieved in particular that prostate stones do not form or dissolve as far as possible. Both are beneficial in various ways. First, the tension and the associated tension pain decrease. Second, the prostate swells, which thirdly increases blood flow, and fourth, which Emptying the bladder is easier. Fifth, the improved blood flow leads to improved access of antibiotics to inflamed tissue.

According to the invention, all mucolytically active substances and combinations thereof can be used. Those mucolytic substances that additionally have anti-inflammatory properties can be used with particular advantage. Particularly preferred are substances containing thiol groups and / or cysteine derivatives (or substances belonging to the substance class of cysteine derivatives), especially those with free thiol groups. For example, many thiols (substances with thiol groups or sulfhydryl groups), which also include cysteine, are known to have mucolytic properties. Particularly suitable according to the invention are those cysteine derivatives which, in addition to the mucolytic, also have anti-inflammatory properties. Acetylcysteine is particularly preferred (N-acetyl-L-cysteine, ACC® is a registered trademark of Hexal AG Germany).

Acetylcysteine is already used in humans for expectorant therapy for acute and chronic diseases of the bronchi. Acetylcysteine also exerts its mucolytic effect on secretion accumulations in the sinuses and middle ear. The anti-inflammatory effect of acetylcysteine represents a further advantage for the use of this substance in urology.

The mechanism of action of acetylcysteine is essentially based on a reduction in the disulfide bonds between mucoproteins (glycoproteins) through its free sulfhydryl groups. As a result, mucoproteins are depolymerized and the viscosity of the mucus is reduced, for example in the sputum. Due to its antioxidant properties, acetylcysteine also has a local anti-inflammatory effect (DC Plumb: Veterinary Drug Handbook. PharmaVet Publishing, White Bear Lake, USA (1999)). Other advantages of acetylcysteine, which make its use in the treatment of prostatitis particularly advantageous, include minor side effects, which has been confirmed many years by years of use in other areas of indication.

Instead of the active ingredients described, in particular instead of acetylcysteine or in combination therewith, salts of the active ingredient, such as N-acetylcysteine-L-lysinate, can also be used with advantage. Furthermore, other derivatives, in particular thioethers and / or thioesters, can also be used. Other thiols, such as mercaptoethanesulfonic acid in particular, tiopronin and / or methylcysteine and / or derivatives thereof can also be used advantageously according to the invention. Salts, thioethers and / or thioesters are particularly suitable as derivatives.

In a particularly preferred embodiment, the mucolytically active substance promotes the formation of low-viscosity mucus. By promoting the formation of low-viscosity mucus, the secretion viscosity in the prostate is reduced. One active ingredient that is particularly suitable in this context is carbocysteine (S- (carboxymethyl) -L-cysteine). This substance does not have a thiol group and therefore does not react directly with slime molecules. However, it can be assumed that this substance intervenes intracellularly in the mucus synthesis and thereby promotes the formation of low-viscosity mucus. At the same time, the synthesis of highly viscous mucus is suppressed. This substance and / or comparable substances with similar mechanisms of action can thus be used with great advantage according to the invention. This takes place in a particularly advantageous manner in combination with other substances used according to the invention, as can be seen, for example, from the above description.

Derivatives of substances that promote the formation of low-viscosity mucus can also be used with advantage. From some of these Derivatives are already known to have mucolytic, analgesic, anti-inflammatory and / or antipyretic properties, so that they are of particular advantage for the treatment of prostatitis.

In a particularly preferred embodiment of the use according to the invention, the at least one mucolytically active substance is used in combination with at least one antibiotic. This combination can be administered to the patient, for example in the form of a single preparation or separately according to substances. When using antibiotics and mucolytically active substances, for example acetylcysteine, at the same time, it should be taken into account that some antibiotics should be administered separately and / or postponed due to possible interactions with the at least one mucolytically active substance. The antibiotics that have essentially no interactions with e.g. Have acetylcysteine and can thus advantageously be administered simultaneously with acetylcysteine include, for example, amoxicillin, erythrocycin and thiamphenicol.

The invention also includes a method for the treatment, prophylaxis and / or differential diagnosis of prostatitis, in which a therapeutically effective dose of at least one mucolytically active substance is administered. With regard to further details of this method according to the invention, reference is made to the above description or to the explanations below.

The invention further comprises a pharmaceutical composition for the treatment, prophylaxis and / or differential diagnosis of prostatitis, which comprises a therapeutically effective dose of at least one mucolytically active substance. In addition, this pharmaceutical composition comprises a pharmacologically acceptable carrier and / or auxiliary. In a particularly preferred manner, this pharmaceutical see composition intended for oral administration. With regard to the features of the mucolytically active substance in the pharmaceutical composition or further features of this pharmaceutical composition, reference is made to the above description or to the explanations below.

Mucolytics are preferably administered orally in a therapeutically effective dose and suitable formulation. For oral administration, acetylcysteine is particularly suitable, which has already been successfully used in other indication areas in the form of capsules, effervescent or lozenges or juices. However, other forms of administration are also encompassed by the invention.

As already mentioned, the preparations containing mucolytics can further comprise at least one pharmacologically acceptable carrier and / or auxiliary.

According to the previously common treatment regimen, different laboratory parameters for the detection of a possible prostate carcinoma are initially determined for prostate complaints. One of the most important parameters is the concentration of the so-called prostate-specific antigen (PSA). However, an increased value does not always have to mean the presence of prostate cancer, since inflammation of the prostate and its enlargement can also lead to increased PSA values (H.-J. Luboldt and H. Rübben: PSA - early detection of prostate cancer. Urologist (A ) 39: 22-26 (2000)). For this reason, antibiotic therapy is usually tried first, especially if it is possible to detect inflammatory pathogens. If the PSA values then drop, this indicates that inflammation was the cause of the increase, that is to say there is no prostate cancer. Often, however, the PSA value cannot be influenced or can not be influenced significantly by antibiotics. Then the next necessary diagnostic step is the (multiple) punch biopsy. In the removed tissue malignant tissue can be identified and the diagnosis can thus be specified. Despite consistently high PSA values, it is often not possible to histologically verify prostate carcinoma; cancer therapy, for example through surgery, is then not indicated. These therapy-resistant cases are a common problem in urological practice.

Taking into account the situation described, the following new treatment approaches are proposed according to the invention:

1) In the first embodiment, with increased PSA values, the first attempt is made, using antibiotics, to bring a possible bacterial inflammation to subside. If symptoms and PSA levels remain high, a punch biopsy is not initially carried out as previously to verify or rule out carcinomatous events. Rather, mucolytics that work very quickly (1-2 days) are used. If the PSA level normalized and the symptoms subsided, the treatment was successful and a punch biopsy was not necessary. In this case, the mucolytics used in accordance with the invention help, in particular, to have a favorable influence on, or even to eliminate, painful and inflammatory processes caused by backflow. If symptoms and the PSA value remain high despite the application of antibiotics and mucolytics, it is only now necessary to determine by means of a punch biopsy whether there is a prostate carcinoma. The use according to the invention of the mucolytically active substances can thus also be used with particular advantage for the differential diagnosis of prostatitis.

2) In the second embodiment, the mucolytics are administered at the same time or in a suitable manner, time-shifted with antibiotics. The advantage of this variant is that due to the expectorant effect of the mucolytics, the tissue tension of the prostate decreases and therefore the blood flow is increased, which improves the emptying of the bladder. WE Due to the improved blood circulation, antibiotics can reach the inflamed tissue better.

3) In the third version, the mucolytic preparation is initially used for prostatic complaints, i.e. also in the event that the PSA value is not increased or it has possibly not yet been determined. Because of the fast action of the mucolytics, a differential diagnosis or prophylaxis is possible within a few days. In the best case, the symptoms subside after the medication. If symptoms persist, antibiotics only need to be used in the next step. This treatment regimen may be preferred because of minor side effects compared to antibiotics.

4) For patients for whom mucolytic treatment has a positive effect, it may be advantageous to take mucolytics at regular, reasonable intervals (e.g. 2-4 times a month) when new symptoms begin or as a general prophylactic measure.

The proposed use of mucolytics thus includes the possibility of a gentle, efficient treatment of prostatitis, which after a short time can lead to significant improvement or even to the complete resolution of the symptoms. This treatment approach also results in a differential diagnosis.

Further features of the invention result from the following description of an exemplary embodiment in combination with the subclaims. The various features can be implemented individually or in combination with one another. embodiment

Comparative study: traditional therapy versus mucolytic treatment

The patient, 68 years old, had been suffering from prostatitis with significant symptoms as described above for years. As of autumn 2002, the PSA values were around 10 ng / dl. This PSA value could not be influenced by using different antibiotics (see Table 1). Since the so-called free PSA was also relatively low (another indicator for prostate cancer), multiple punch biopsies were first performed in the specialist's practice, after some time at a university clinic. The histological findings spoke against carcinoma.

In accordance with the previously known treatment regimen, the next recommended step in this patient, whose symptoms were significant, was a transurethral resection of the prostate. Instead, the therapeutic approach according to the invention was applied to this patient according to the scheme described in Table 1. After taking 2 x 600 mg acetylcysteine (ACC®), the patient described the occurrence of a feeling of warmth in the area of the prostate. The symptoms were significantly reduced after one day and disappeared after another day. Since then, the patient has been largely symptom-free. Occasional recurrence of symptoms (every 2-4 weeks) has always been managed by taking ACC®. Since then, the PSA value has dropped to a value corresponding to the size of the prostate (4.3 ng / ml, free PSA 19%) (see Table 1). Table 1

The present invention is not limited to the application examples described above. Rather, many modifications are possible that result from medical practice and are therefore covered by the scope of this invention.

Claims

claims

1. Use of at least one mucolytically active substance for the manufacture of a medicament for the treatment, prophylaxis and / or differential diagnosis of prostatitis.

2. Use according to claim 1, characterized in that the mucolytically active substance also has anti-inflammatory properties.

3. Use according to claim 1 or claim 2, characterized in that the mucolytically active substance is a thiol.

4. Use according to one of the preceding claims, characterized in that the mucolytically active substance is a cysteine derivative.

5. Use according to one of the preceding claims, characterized in that the mucolytically active substance is acetylcysteine (N-acetyl-L-cysteine, ACC®) and / or a derivative thereof, in particular a salt, thioether and / or thioester.

6. Use according to one of the preceding claims, characterized in that the mucolytically active substance is mercaptoethanesulfonic acid, tiopronin and / or methylcysteine and / or a derivative thereof.

7. Use according to one of the preceding claims, characterized in that the mucolytically active substance is a thioether and / or thioester.

8. Use according to one of the preceding claims, characterized in that the mucolytically active substance is S- (carboxymethyl) -L-cysteine and / or a derivative thereof.

9. Use according to one of the preceding claims, characterized in that the mucolytically active substance is used in combination with at least one antibiotic.

10. A pharmaceutical composition for the treatment, prophylaxis and / or differential diagnosis of prostatitis, comprising a therapeutically effective dose of at least one mucolytically active substance according to one of claims 1 to 9 and at least one pharmacologically acceptable carrier and / or auxiliary.

11. Pharmaceutical composition according to claim 10, characterized in that it is intended for oral administration.