Secure Connection FailedBenign prostatic hyperplasia BPH is a benign enlargement of the glandular epithelium, of the connective tissue and of the nichtsteroidale antiandrogen muscles in the transitional zone of the prostate. Thus, BPH is responsible for the most frequent form of bladder dysfunction in men. The symptoms nichtsteroidale antiandrogen BPH comprise obstructive and irritative complaints. The obstructive symptoms include diminished urinary stream, prolonged micturation time, dribbling and residual urine, while the irritative symptoms are manifested in increased micturation frequency, painful micturation, and urge incontinence. Regarding the etiology of BPH, there are various hypotheses currently being discussed. Prostate carcinoma is the most common cancer affecting men in the Western countries and nichtsteroidale antiandrogen the second most common cause of cancer death after lung cancer. Although, in its etiology, statistics of college athletes using steroids prostate carcinoma is not nichtsteroidale antiandrogen connected to BPH, patients suffering from a severe form of BPH show gene anomalies that are very similar to those of prostate cancer patients.
ein nichtsteroidales Anti-Androgen translation English | German dictionary | Reverso
Benign prostatic hyperplasia BPH is a benign enlargement of the glandular epithelium, of the connective tissue and of the smooth muscles in the transitional zone of the prostate. Thus, BPH is responsible for the most frequent form of bladder dysfunction in men. The symptoms of BPH comprise obstructive and irritative complaints.
The obstructive symptoms include diminished urinary stream, prolonged micturation time, dribbling and residual urine, while the irritative symptoms are manifested in increased micturation frequency, painful micturation, and urge incontinence. Regarding the etiology of BPH, there are various hypotheses currently being discussed. Prostate carcinoma is the most common cancer affecting men in the Western countries and represents the second most common cause of cancer death after lung cancer.
Although, in its etiology, the prostate carcinoma is not directly connected to BPH, patients suffering from a severe form of BPH show gene anomalies that are very similar to those of prostate cancer patients. While BPH affects above all the transitional zone of the prostate, a carcinoma occurs preferably in the peripheral zone. The reasons for the development of a prostate carcinoma are various gene defects, which may be due to a predisposition in the family.
Thus, various mutations of the androgen receptor occur in the persons suffering from prostate carcinoma. Furthermore, different tumour suppressor genes, such as Rb gene on chromosome 13 q, can be affected by mutations and can thus become inactivated.
On the other hand, a hyperfunction of oncogenes contributes to tumour formation. In addition, a significant role is played by methylations of important growth-regulating and detoxifying genes, the genes thereby becoming unable to function and clearing the way for cancer. According to the most recent state of science, a big contribution is made by inflammation processes from which emanate preneoplastic or neoplastic lesions.
The initial therapy for treating prostate carcinoma usually consists in removing the prostate by radical prostatectomy, or in irradiation to remove the degenerated cells. An advanced, metastasising prostate carcinoma can be treated by a palliative hormone therapy.
The total androgen blockade, which is applied nowadays, includes the combination of operative and chemical castration. However, hormone therapy cannot heal advanced prostate cancer. The treatment initially causes an antiandrogen-dependent inhibition of tumour growth. However, after two years, on average, resistance to the therapy occurs. First, a hyperexpression of various coactivators enables the activation of the androgen receptor through non-androgenic steroids. Later on, even antiandrogens, such as the active flutamide metabolite, 2-hydroxyflutamide, are able to activate the androgen receptor, and the tumour becomes independent of androgens.
Spinobulbar muscular atrophy SBMA is a neurodegenerative disease or a hereditary neurogenic muscle disorder which is connected with muscular atrophy and which afflicts only men.
The death of the peripheral motoneurons spinal anterior horn cells , which are located in the spinal cord and whose processes extend to the muscles, leads to muscular atrophy, muscular asthenia pareses , involuntary muscle twitching fasciculations , as well as trembling tremor. Muscular asthenia initially affects the proximal regions upper arms, thighs.
If the motoneurons which are located in the brain stem bulbus , that is, the nerve cells in the cerebral cortex and their connections to the spinal cord, are affected, the speech muscles, masticatory muscles and swallowing muscles are weakened, too.
In addition, the disorder of the central motor system leads to an increase in muscle tone spastic paralysis. The genetic cause of spinobulbar muscular atrophy is thought to be an increase in the number of CAG base triplets in exon 1 of the androgen receptor gene which is located on the sex-determining X chromosome.
This leads to an expansion of the polyglutamine region in the androgen receptor. The thus pathologically altered androgen receptors accumulate over a prolonged period of time, form inclusions in the cell nucleus, and are likely to lead to the death of the neurons.
The ligand-dependent accumulation of pathologically altered androgen receptors in the cell nucleus is made responsible for the pathogenesis of spinobulbar muscular atrophy.
Transgenic mice that had a human androgen receptor gene with an increased number of CAG base triplets, revealed neuromotor impairments that were particularly distinct in male experimental animals. The impairments of these rats that were similar to SBMA could be alleviated by castration or aggravated by administration of testosterone.
These experimental results lead to the assumption that inactivation of the androgen receptor in SBMA patients can alleviate the progress of the disease.
The significance of their ligand bond for the aggregation of androgen receptors was also examined with the aid of androgens and androgen antagonists. Stimulation with testosterone of cells that expressed a pathologically altered androgen receptor led to characteristic inclusions in the cytoplasm. By contrast, only a small number of inclusions were observed when treating these cells with the partial androgen antagonist cyproterone, and no inclusions when they were treated with flutamide.
These observations support the hypothesis that androgen antagonists are able to prevent the formation of androgen receptor aggregates. However, to date, there is no proof that the formation of androgen receptor aggregates is responsible for the progress of spinobulbar muscular atrophy.
Another object of the present invention was thus to find new active substances for the treatment of spinobulbar muscular atrophy. The objects of the present invention were achieved by isolating substances having antiandrogenic activity from the bark of the African plum tree P. Surprisingly, the substance atraric acid was isolated from the bark of P.
Atraric acid is even able to inhibit the growth of prostate cancer cells that do not respond to a treatment with hydroxyflutamide. It has already been approved in France for the treatment of benign prostatic hyperplasia since and has meanwhile become wide-spread in Italy and the USA as well. In Germany, however, this chloroform extract has not been approved. The Prunoideae include woody plants with stone fruits. The genus of Prunus is the most comprehensive genus in this subfamily. It includes, for example, the cherry Prunus avium L.
The African plum tree, Prunus africana Hook. The object of the present study was to isolate the antiandrogenically active natural substances from the bark of Prunus africana since an extract containing a large number of components can be standardised only when all the active substances, including their exact strength of action, are known, and because such an extract causes greater stress to the organism.
A further object was to produce new antiandrogenic active substances on the basis of the antiandrogenically active substances isolated from P. First, the antiandrogenic efficacy of different Pygeum extracts was compared.
The active compounds were then isolated by activity-guided fractionation. For selective fractionation of the bark material of P. Generally, the components of plant drugs are characterized by a high degree of biodiversity which is reflected in a large number of the most varied compounds.
To nevertheless obtain extracts having a manageable number of components, it has proven useful to perform a prefractionation according to solubility in solvents of increasing polarity. Because of the restriction in the range of polarity and the enrichment of substances of lower concentrations, the resulting selective extracts are easier to handle chromatographically and thus, following further fractionation, ultimately enable the isolation of active components.
In the present study, the procedure of selective extraction was performed twice. This extraction was in each case performed to exhaustion, and the extracts obtained were then, under reduced pressure, narrowed down to dryness.
This extraction method is extremely mild, so that temperature, stress and direct action of oxygen and light on the drug are prevented. What is essential, however, is that the components are thereby presorted in extracts ordered according to polarity, and can thus be chromatographed more easily.
Considering the mass proportions of the selective extracts in the total amount of extract, it is clear that the plant material predominantly contains methanol-soluble components. The amounts of the lipophile extracts from n-hexane and dichloromethane were less significant. Generally, there are resins, oils, fats or fat-like substances contained in the hexane extract.
The long-chain alcohols and fatty acids from P. The phytosterols and pentacyclic triterpenes can be assumed to be contained in the dichloromethane extract. Apart from the selective extracts, an ethanolic complete extract from the bark of P. Then, the extract was filtered and finally narrowed down to dryness under reduced pressure. The potentially antiandrogenic efficacy of the extracts obtained was examined with the androgen receptor-dependent MMTV-luc reporter gene assay, in the following designated as luciferase assay.
In that assay, the enzyme luciferase serves as a reporter gene. The energy emitted in the process is emitted as light. The plasmid pMMTV-luc is transfected, together with the androgen receptor expression vector, into fibroblasts of the monkey kidney. If an androgen is added thereto, this androgen will bind, in a complex with the androgen receptor, to the androgen-responsive element.
This process then initiates the transcription of the following gene, namely that of the luciferase reporter gene. If apart from the androgen there is also an antiandrogenic substance or an antiandrogenic extract, the transactivation of the luciferase reporter gene by the androgen-responsive element is inhibited and later, when the substrate is added, a correspondingly smaller amount of light energy is released.
Since the decrease in the amount of light is directly proportional to the inhibitory effect of the antiandrogen, this assay is excellently suitable for the search for new antiandrogenic lead structures.
For evaluation, the antiandrogenic effect was calculated as the percent inhibition against a control wherein only pure solvent had been added. The most effective extract was then to be subjected to a further activity-guided fractionation. The selective dichloromethane extract from P. This extract was therefore selected for the further activity-guided fractionation.
With increasing hydrophilicity of the selective Pygeum extracts, the antiandrogenic activity decreases significantly. The ethanolic complete extract from P. This suggests that with ethanol the same antiandrogenic substances were extracted as in the selective dichloromethane extract.
The latter is even more potent since in this extract an enrichment with active substances was successfully accomplished. In the search for active compounds in a complex mixture of numerous substances, the method of activity-guided fractionation has proved to be useful.
To this end, the plant extract is first tested for its bioactivity. When an effect occurs, the sample is separated by chromatography, and all of the fractions are again tested for their activity. As a rule, the activity is not distributed over all fractions, but is found in a small number of clearly defined fractions since in those fractions an accumulation of active substances has taken place. These active fractions are then selected and are further fractionated with another separation method.
This procedure is repeated with increasingly specific separation methods until the active substances have finally been isolated. The combination of different separation methods selective extraction, extraction by shaking out, normal phase chromatography and reversed phase chromatography, etc. The isolated substances are then identified and quantified using various analytical methods, and finally tested for their efficacy, as individual substance and in mixtures of all active compounds.
If there is correspondence between a reference substance and the compound isolated from the extract, the identified substances are considered to be confirmed. This method was also applied in the present study. First, the extract showing the highest efficacy was selected. This was the selective dichloromethane extract from P. The further fractionation of the extract was performed by gradient extrography—a chromatography on normal phase.
The process of extrography was developed for the fractionation of crude oil distillation residues. It serves to separate complex mixtures, the components of which encompass a wide range of polarities.