Method of preventing penile tissue degenerative change

The present invention is concerned with the use of TXA.sub.2 receptor antagonists for the preparation of pharmaceutical compositions for the prevention of degenerative changes in penile tissue.

The present invention is concerned with the preparation of pharmaceutical 
compositions for the prevention of degenerative changes in penile tissue. 
Eicosanoids, such as prostaglandins, thromboxanes and leukotrienes, are a 
group of compounds present in the body which participate in physiological 
regulatory mechanisms. In this connection, these compounds are of 
importance for local regulation. They thereby act not only directly upon 
the reacting organ but also indirectly via other hormones and transmitter 
substances. Their especial importance appears to be a membrane-standing 
protective mechanism which, in the case of disturbance of the cellular 
integrity, is activated and, together with other factors, adapts the 
tissue to the stress situation. On the other hand, increased local 
concentrations of these compounds, for example in the case of tissue 
damage or destruction, can additionally contribute to an aggravation of 
the state of the disease (see K. Schror, Prostaglandine, pub. 
Thieme-Verlag, Stuttgart, 1983; B. P. Curtis-Prior, Prostaglandins, pub. 
Churchill, Livingstone, Edinburgh, 1988). The particular pharmacological 
interest consists in that, by means of a selective intervention in these 
pathomechanisms, a damage of the organism in the widest sense or a disease 
can be prevented or treated. 
In the case of erectile insufficiency, ultrastructural changes of the 
penile tissue have been found. As a characteristic pathological sign, 
there has been described a loss of the contractile myofilaments actin and 
myosin (see Diabetologica, 25, 424/1983). An aggregation of mitochondria 
is, in particular, to be ascertained in the early stage of this change 
(see Ophthalmologica, 191, 172/1985). In the case of the progress of these 
degenerative processes, further intracellular changes result, such as an 
increase of the perinuclear organelles, and cell nucleus degeneration (see 
Seminars in Urology, VIII (2), 80-93/1990). These pathological processes 
finally end in an atrophy of the corpus cavernosum (see Proceedings of the 
Third Biennial World Meeting on Impotence, Boston, Mass., Oct. 6-9, 1988). 
The morphological changes correlate with the clinical picture of erectile 
disturbances. It is obvious that the described degenerative changes and 
not the penile arteries play an important part in the pathology of the 
organically caused erectile disturbances (see Seminars in Urology, VIII 
(2), 80-93/1990). In a further investigation, a connection was discussed 
between a disturbed lipid metabolism and the vascular erectile dysfunction 
(see Int. J. Impotence Res., Sep., 2, 1990, Suupl. 2, 34). 
Important changes in the case of the degeneration of the penile tissue, 
which cause an insufficiency of the erectile tissue of varying degree, are 
atrophy of the corpus cavernosum, cell nucleus degeneration and breakdown 
of the myofilaments. Active materials which prevent or greatly limit these 
processes are of therapeutic value in the case of a series of pathological 
conditions. 
It is an object of the present invention to provide appropriate 
pharmaceutical compositions which can be used for the treatment of 
degenerative changes of the penile tissue. 
In the scope of the present invention, we have now, surprisingly, found 
that TXA.sub.2 receptor antagonists reduce degenerative changes in the 
penis which lead to an insufficiency of the erectile tissue. 
Thus, the present invention is concerned with the use of TXA.sub.2 receptor 
antagonists for the preparation of pharmaceutical compositions for the 
prevention of degenerative changes in penile tissue, including the 
prevention of atrophy of the corpus cavernosum, the prevention of the 
degeneration of cell nuclei and the prevention of the breakdown of 
myofilaments. Such degenerative processes can be caused physically, 
chemically, surgically or pathologically and include those caused by 
nicotine abuse and alcoholism. 
Thromboxane (TX)-A.sub.2 receptor antagonists are able to reduce 
degenerative changes in the tissue of the penis which arise in rabbits due 
to special diets. Therefore, the compounds are appropriate for the 
treatment and prevention of degenerative processes in the penile tissue 
which are to be detected in the case of the presence of risk factors, for 
example the taking of medicaments, nicotine abuse and alcoholism. 
The TXA.sub.2 receptor antagonists prevent the degeneration of the penile 
tissue in doses which are of the same order of magnitude as those which 
are usual in the case of the therapeutic use of TXA.sub.2 receptor 
antagonists. It is to be expected that the suppression according to the 
present invention of degenerative processes in the penis and the 
prevention of insufficiency of the erectile tissue involved therewith by 
means of TXA.sub.2 receptor antagonists will be of therapeutic value in 
the case of a series of clinical situations. Besides the above-mentioned 
risk groups, to these belong the prevention of a penis prothesis, as well 
as the prevention and/or reduction of the intravenous injection of 
papaverine, papaverine/phentolamine, prostaglandins and/or yohimbine. 
TXA.sub.2 receptor antagonists appropriate for the purpose of the present 
invention include sulotroban (BM 13.177), daltroban (BM 13.505), 
L-640,035, L-641,953, L-655,240, OKY-046, PKY-1581, ONO-1078, ONO-1270, 
ONO-3708, ONO-11113, SQ 28668, SQ 29548, SQ 30741, AH 23848, SK&F 88046, 
EP 045, S-145, Sch 37224, KF 4939, EG-626, N-benzyl-trimethoquinol 
analogues, 9,11-epoxy-9-homo-14-thiaprost-5-enoic acid derivatives, 
13-azaprostanoic acid, 3-alkylaminopinane derivatives, pinane-TXA.sub.2 
derivatives, 9,11-azo-12-oxy-15-hydroxyprostanoic acid, 
9,11-epoxy-iminoprosta-5,11-dienoic acid and dandrolen, all of which are 
mentioned in the Cumulate Index Medicus 1978-1989, subject index under 
Thromboxanes or Thromboxane-A.sub.2 Antagonists and Inhibitors, as well as 
R 68070, AA 2414, SQ 33261, SQ 33552, FR 106881, BayU 3405, ICI 192695, L 
670596, L 657925, L 657926, GR 32191, all of which are mentioned in 
Thrombosis and Haemostasis, 62 (1), 1-647/1989, and W-4099, SCRIP No.1537, 
28/1990. As TXA.sub.2 receptor antagonists, those compounds are especially 
preferred which are described in published European Patent Specifications 
Nos.0,031,954; 0,221,344; 0,223,593; 0,239,907; 0,304,271; 0,322,692; 
0,325,245; 0,353,448; 0,356,989; 0,361,113 and 0,365,183, as well as in 
Federal Republic of Germany Patent Specification No. 40 06 640.1. 
The investigations which can be regarded as being representative for all 
TXA.sub.2 antagonists were carried out with daltroban 
(4-[2-(4-chlorophenyl) sulphonylaminoethyl]-phenylacetic acid). This 
compound is described in European Patent Specification No. 0,031,954. For 
the prevention of degenerative processes in the penile tissue, TXA.sub.2 
antagonists are administered systemically, preferably enterally and 
especially preferably orally but also parenterally (i.v.). The dosage 
varies according to the requirements of the individual patient and can be 
determined by the physician carrying out the treatment. For daltroban, in 
general, there should be administered a daily dosage of about 10 to 1000 
mg. and especially of 100 to 800 mg. The dosage range of 100 to 800 mg. 
per day corresponds to that which is preferably employed therapeutically 
in the case of thromboxane-caused diseases. The daily dosage can be 
administered by a single administration or several times daily by the 
administration of appropriate partial amounts. The other TXA.sub.2 
receptor antagonists can be administered in agreement with the particular 
dosage instructions determined individually by the physician carrying out 
the treatment. 
Because of the possibility of oral administration of the TXA.sub.2 receptor 
antagonists, the period of treatment is not chronologically limited, which 
is of importance for the use according to the present invention. 
As forms of administration for systemic administration, there can be used 
the conventional solid and liquid forms of administration, for example 
suppositories and solid oral forms of administration, such as capsules, 
tablets, lacquered tablets, dragees, pills, granulates and the like, or 
liquid forms of oral administration, such as solutions, syrups, 
suspensions, elixirs and the like, or parenteral forms of administration, 
such as infusion and injection solutions which can be injected 
intravenously or intramuscularly. 
It lies within the scope of the present invention to incorporate the 
TXA.sub.2 receptor antagonists into the enteral or oral forms of 
administration in any amount suitable for the administration. However, it 
is preferred to produce preparations which, per dosage unit, contain the 
active material in an amount of up to 800 mg. and preferably of about 100 
or 200 mg. The production of capsules, tablets and lacquered tablets as 
dosage units is especially preferred. These can be administered one or 
more times daily, according to the particular requirements ascertained by 
the physician. 
The production of the above-mentioned forms of use can take place in the 
conventional manner, for example as described in the following Example for 
daltroban.

EXAMPLE 1 
Preparation of a Tabletting or Capsule Filling Mass 
______________________________________ 
Tablets containing 200 mg. daltroban: 
component mg./capsule 
______________________________________ 
1. daltroban, fine 200.0 
2. lactose monohydrate 
50.0 
3. crospovidon 10.0 
4. povidon 25,000 10.5 
5. crospovidon 5.0 
6. colloidal silicon dioxide 
2.5 
7. microcrystalline cellulose 
20.0 
8. magnesium stearate 
5.0 
filling weight 303.0 
______________________________________ 
The components are mixed together in conventional manner and wet or dry 
granulated. The finished mass can be pressed to give cores and used 
directly as tablets or, coated with a film, can be used as film tablets. 
The mass can also be filled directly into capsules, for example into 
gelatine capsules of size 0. 
EXAMPLE 2 
Therapeutic Action 
The therapeutic action of daltroban in the case of degenerative changes of 
the penile tissue can be seen from the following experiment. 
a) General principle 
The administration of special diets to rabbits results in a cell nucleus 
degeneration, an intracellular loss of the myofilament and an atrophy of 
the corpus cavernosum in the penis corresponding to the processes in the 
case of humans (see Investigative Urology, 3, 53-59/1989; Seminars in 
Urology, VIII (2), 80-93/1990). These processes lead to an insufficiency 
of the erectile tissue of varying degree. The diet was administered over 
the course of 96 days. In addition, daltroban was administered in a dosage 
of 10 mg./kg./day from the 42nd day. The study gives conclusions as to 
whether daltroban possesses an action on the degenerative processes in 
penile tissue. The chosen experimental design represents test conditions 
possibly made difficult with regard to the daltroban administration during 
the whole period of treatment but, having regard to a therapeutic use, 
comes closest to the situation in humans. The extent of the degenerative 
changes is subsequently determined from transversal sections of the penis 
on the basis of light and electronic microscopic expert evaluation. 
b) Description of the experiment 
Male white New Zealand rabbits with a body weight of about 2.0 kg. at the 
commencement of the experiment received, over the course of 96 days, a 
semi-synthetic diet consisting of casein, glucose/starch, cellulose and 
0.5% cholesterol, as well as the conventional salt and vitamin mixtures. 
From the 42nd day, daltroban was additionally administered at a dosage of 
10 mg./kg./day. The administration took place via the drinking water and 
was monitored via the consumption of water. At the end of the experiment, 
segments were taken from the apical, medial and basal part of the penis. 
For the morphological expert evaluation, the penis segments were fixed, 
dehydrated and finally embedded. The extent of the degenerative changes 
were determined with the help of light and transmission electronic 
microscopic expert evaluation on transverse sections of the penis 
segments. The following characteristics were used for the evaluation: 
myofilament breakdown, cell nucleus degeneration and atrophy of the corpus 
cavernosum. 
c) Results 
The animals additionally treated with daltroban from the 42nd day show, in 
the investigated penis segments, a distinctly smaller manifestation of the 
myofilament breakdown, of the cell nucleus degeneration and of the atrophy 
of the corpus cavernosum in comparison with the diet control animals. 
Rabbits fed with a standard diet displayed no degenerative changes. 
The morphologically distinct reduction of the degenerative changes of the 
penile tissue due to daltroban, reproducibly ascertained in further 
investigations, show that this compound possesses an inhibiting action on 
the degenerative processes of the penile tissue. The results demonstrate a 
new activity quality of the compound. 
In this way, on the basis of daltroban, it is clearly shown that TXA.sub.2 
receptor antagonists reduce the increase of degenerative changes of the 
penis. 
The here-described new use of TXA.sub.2 receptor antagonists can be 
indicated not only in the case of metabolically healthy but also in the 
case of metabolically diseased subjects, for example dyslipidaemic and 
diabetic patients, in the case of normotonic subjects and also of 
hypertonic patients, when the above-described degenerative processes 
occur. In particular, an additional treatment with daltroban is indicated 
in the case of medication with the known appearance of potency 
disturbance. 
The documents identified above as describing especially preferred TXA.sub.2 
receptor antagonist compounds are hereby incorporated by reference for the 
teaching of such compounds therein. 
While it is preferred to administer a single TXA.sub.2 receptor antagonist 
to patients, it will be readily appreciated by those skilled in the art 
that mixtures of TXA.sub.2 receptor antagonists can be used if desired.