DE3844798C2 - Medicaments contg. Urtica kiovensis extract - Google Patents

Abstract

Pharmaceutical compsns. contain an extract of the roots of the stinging nettle Urtica kiovensis. The extract is produced by extracting the roots with an aq. alcohol (esp. 20-40% aq. MeOH) at up to 50 (esp. 40-45) deg.C., evaporating the extract in vacuo at up to 70 (esp. 50-65) deg.C., and drying or spray-drying the residue. The extract contains aromatic carboxylic acids, phenols, lignans and phytosterols, esp. beta-sitosterol, campesterol, stigmasterol, 5,24(25)-stigmastadien-3-ol, 4-stigmasten-3-one and cholesterol. The compsns. are formulated for oral admin., with up to 15 wt.% of additives, esp. lactose, maltodextrin and/or silica

Description

The invention relates to the use of an extract the nettle roots of Urtica kioviensis (Rogowicz) in of human and / or veterinary medicine.

In the naturopathy one uses for a long time herbal extracts as well tolerated with moderate effect. These natural products often include a complex mixture of substances, with the actual Active substance is often unknown or is assumed that special combinations of ingredients which have pharmacological activity.

Medicinal interesting are extracts from the roots of Stinging nettle (Urtica radix), which is successful against Prostatic hyperplasia can be used. The extracts will be so far only from the underground parts the Urtica dioica, the Urtica urens and / or their Hybrids won (see Federal Gazette No. 173, p. 13 286). With the help of one on these plant extracts based drug can be the micturition volume and increase the maximum urine flow rate and at the same time reduce the Restharnmenge so that the Micturition complaints in prostate adenomas greatly alleviated  become. The active ingredients of nettle root extract are so far not exactly known, where it is assumed that regulated the function of the prostate via the hormone balance is that the drug behaves like a hormone. The Extract described above causes a swelling and Draining the prostate adenoma and thus alleviates the Prostatic hyperplasia symptoms appear. A Use of the root extract outside the indication Prostate hyperplasia is not yet available.

Although with the previous drugs based on Urtica dioica and Urtica urens good swelling or There is a need for other effective agents and agents used in the Therapy benign tumors are widely used. In particular, these should be in the therapy of Prostate can be used with advantage.

The object of the present invention is Indicate active substances based on plant products, which due to an inhibitory effect of cell growth to general treatment of benign tumors whose Cell growth regulated by sex hormones is used can be. The symptoms are not just alleviated but it should preferably also be a cure be achieved.

The object is achieved in that a Nettle Root Extract Urtica kioviensis (Rogowicz) for the treatment of benign tumors whose Cell growth is sex hormone dependent, in humans and animals is used. Optionally, pharmaceutically compatible additives in addition to the extract mentioned to be available.  

The Urtica kioviensis (Rogowicz) applies to newer conceptions the botanical classification as a separate species with distinct morphological and physiological differences towards Urtica dioica and Urtica urens. The Nettle root extract of Urtica kioviensis includes in particular aromatic carboxylic acids, phenols, lignans and phytosterols, in particular β-sitosterol, campesterol, Stigmasterol and its oxidation products.

In a preferred embodiment of the present invention Invention is an extract from the nettle roots of Urtica kioviensis (Rogowicz) used as active ingredients 5,24 (25) -stigmastadien-3-ol and stigmasta-4-en-3-one contains.

As aggregates, used together with the extract preferably lactose and / or Maltodextrin into consideration. Another advantageous Aggregate represents Kieselaerosil (silicon dioxide). The named additives facilitate the processing the hygroscopic extract that they stick to counteract this extract and the setting of the Enable effective content. One uses the aggregates preferably in an amount of at most 15 wt .-% with respect on the dry extract.

Extract of nettle root of Urtica kioviensis (Rogowicz) by making the raw material (Radix Urticae kioviensis (Rogowicz)) of an extraction with Alcohol / water mixtures at a maximum temperature 50 ° C, the resulting solution at a maximum Temperature of 70 ° C and evaporated under reduced pressure and optionally subsequently (spray) dries and the obtained dry extract with pharmaceutically acceptable Processed aggregates.  

Advantageously, for the extraction step the Percolation method used. As extraction medium have u. a. Water-alcohol mixtures are proven in which the alcohol, for example, methanol, ethanol, n- or i-propanol, butanol, amyl alcohol. For the Extraction has proven to be particularly favorable Methanol / water mixtures using 20-40% by volume Methanol, based on the mixture, particularly preferred are. The temperature for the extraction is preferably in the range of 40-50 ° C.

Evaporation of the solution obtained by extraction is preferably carried out at a temperature of 50-65 ° C and at a pressure of 150-250 mbar.

The extract from the roots of Urtica kioviensis (Rogowicz) is used to treat benign Tumors, such as adenomas, fibroids, fibroids, their Cell growth is controlled by sex hormones, at Humans and animals used. A special use The drug preparation takes place during the Treatment of prostate hyperplasia.

The invention will be apparent from the following Investigation results explained in more detail:

Trial 1 Inhibition of cell growth

The effectiveness of the use of the extract Nettle roots of Urtica kioviensis (Rogowicz) regarding the inhibition of cell growth of benign Tumors will be demonstrated by the following study. As a model system, explant cultures of human Hyperplasia tissue selected and the effect of  Extract of radix urticae kioviensis (Rogowicz) in vitro examined.

Tissue chips from transurethral resection material benign prostate hyperplasia were under sterile Conditions crushed and explant cultures in RPMI 1640 medium with addition of 10% FCS applied.

After 8 days, sufficient cells were trypsinized and increased for 6 weeks (medium: RPMI 1640 with addition of 10% FCS, bicarbonate (0.2%), amphotericin (250 μg / ml), Penicillin (100 U / ml), streptomycin (0.1 mg / ml), insulin (10 μg / ml), Na pyruvate (1 mM), non-essential Amino acids (0.1 mM), L-glutamine (2 mM); Culture conditions: 5% CO₂ at 37 ° C). Subsequently were the cells for 4 weeks each with 5 different Extracts of radicis urticae kioviensis (Rogowicz) cultivated (medium change twice a week). The single ones Extracts were mixed with methanol / water mixtures Extraction agent obtained, taking the Volume ratio of the two solvents varied. The following dosages were chosen:

Extract 1: 0.01 mg / 10 ml of medium (40% by volume of methanol)
Extract 2: 0.04 mg / 10 ml of medium (40% by volume of methanol)
Extract 3: 0.1 mg / 10 ml of medium (30% by volume of methanol)
Extract 4: 0.1 mg / 10 ml of medium (20% by volume of methanol)
Extract 5: 1.5 mg / 10 ml of medium (20% by volume of methanol)

After a 4-week application time of the cells with the single extracts were the growth behavior by Cell count examined. The cell numbers were until the 10. Quantified day after sowing. All 5 extracts have a significant inhibitory effect on growth the cells.  

This becomes clear in the figure, in the cell numbers of Explant cultures using resection material a benign prostatic hyperplasia applied and with extracts the radicis urticae kioviensis (Rogowicz) cultivated were shown. The characteristics 1-5 refer to Extracts 1-5, with varying Methanol / water fractions were recovered; the line 0 Characterizes cell growth in the untreated Explant culture (control).

Trial 2 In vivo studies of prostate volume

The following is about treatment attempts of a benign Prostate hyperplasia in the dog with the phytotherapeutic agent extractum radicis urticae kioviensis (Rogowicz) reports. Sonographic control of prostate volume of 10 treated dogs given the extract orally for 100 days was administered, resulted in an average decrease in the tumor to 70% of the initial value.

Trial 3 Inhibition of cell growth by Stigmasta-4-en-3-on compared to an im Commercially available nettle root extract

The following is the antiandrogenic effect of Stigmasta-4-en-3-on compared to the effect of an im Commercially available nettle root extract examined.

For the experimental procedure were full-grown male rats, CO breed (Sprague-Dawley, Charles River, Calco), weighing 280 to 300 g in Plastic boxes (26 × 42 × 16 cm) in air-conditioned Clear at constant temperature (22 ± 2 ° C) and at one relative humidity of 60 ± 10% as well as artificial  Light (10 h dark, 10 h light) held. Feed and Spring water was administered as desired.

The antiandrogenic effect of said active substance and of the known nettle root extract were at the adult rat in both absence and under Presence of increasing testosterone concentrations analyzed. For this purpose the animals became gonadectomized and received subcutaneous Silastic implants (Dow Corning, Cat No. 602-265, I.D.).

Implant manufacturing

The implants were increasing with Testosterone concentrations (T) filled to To achieve plasma testosterone levels between 0 and 2 ng / ml. The determination of plasma testosterone showed that the Implants that have different testosterone concentrations (0 to 100%) and cholesterol (0 to 100%), released proportionate amounts of testosterone that were over a certain period (4, 10 and 12 days) constant 1% implants were left for this trial chosen because they release testosterone levels which those similar to those in men with prostate cancer who have the Testicles were removed, were found. Likewise were 10%, 25% and 50% implants chosen since release these testosterone levels, some of them below, partly equal, partly above those who are at be found in healthy men; In addition, a should Get an overview of a dose-response relationship become. 48 hours before surgery were the implants in NaCl (0.9%) at a temperature of 37 ° C neutralized and the testosterone release was in in vitro every 3 hours over a period of 24 hours measured. The radioimmunoassay of testosterone in the medium  pointed out that the steroid in concentrations was released, which over a period of time were both proportional and constant.

Surgery and treatments

The animals were at least three days after their arrival and getting used to it. The gonadectomy was under performed light ether anesthesia and the implants were placed on the back after an incision was carried out.

For control were castrated, adult male Rats examined, on the one hand without Testosterone concentrations and on the other hand with the increasing testosterone concentrations 1%, 10%, 25% and 50%. These animals did not receive any of the test substances administered.

To check the effect of the active ingredient Stigmasta-4-en-3-on was added to the animals in addition to the above implants with increasing Testosterone concentrations the test substance with two administered at different concentrations. The Concentrations of the drug were 0.16 mg / kg Body weight or at 0.32 mg / kg body weight. Everyone Trial with the drug was given to 8 rats each carried out.

For comparison, a commercially available product, that represents a nettle root extract, examined, where also implants with increasing Testosterone concentrations were used. The Concentration of the commercial Nettle root extract was at one  Trial 10 mg / kg body weight, at one second trial 20 mg / kg body weight. Also with this test substance were used for each Experimental procedure 8 rats tested.

The administration of the test substance started on the day of Operation and continued for 10 consecutive days. The animals were killed on the 11th day of treatment, 12 hours after the last administration. The substances were all administered intraperitoneally.

The animals were killed by severing the head. The Blood was collected in heparin-containing test tubes, centrifuged and the plasma at -20 ° C for the determination of Stored plasma testosterone. The ventral prostate, seminal vesicles and adrenal glands were at 4 ° C collected, purified and stored at -20 ° C for further analysis kept.

Data were obtained using the Student's T-test analyzed.

The test substances were each in the form of a solution added. The commercial product of the Nettle root extract was in an amount of 15 g a 1% NaCl gelatin (0.9%) in solution chronic administered. Stigmasta-4-en-3-one was in a lot of 450 mg in a solution of ethanol and 1% NaCl gelatin (0.9%) administered chronically. The Concentrations of the active substances were as mentioned above.

Of the 8 rats examined, each was the Body weight as well as the weight of the ventral prostate (expressed in milligrams), both for the trial without additional testosterone concentration, as  also for the experiments with increasing Testosterone concentration. Of the 8 values obtained in each case the mean value was calculated. The thus obtained Values are given in the table below.  

table

Body weight (in grams) and weight of the ventral prostate (expressed in milligrams), in castrated, adult, male rats ± implants releasing increasing (% T) testosterone concentrations

In the control animals (without test substance) induced the Treatment with increasing testosterone doses one dose-dependent increase in prostate weight from 97.6 to 596.2 mg at doses from 0 to 50%.

Treatment with a commercial Nettle root extract at a dose of 20 mg / kg induced a reduction in prostate gland, starting at the testosterone concentration of 1% to one Concentration of 50% with values 145 to 403 mg after the implantation of increasing testosterone doses reached. An appropriate dosage of 10 mg / kg induced a lesser inhibitory effect on the Prostate weight, but in any case of significance Doses of 10%, 25% and 50% testosterone achieved.

Treatment with stigmasta-4-en-3-one reduces this Weight of the ventral prostate significant in both Doses, ie 0.16 mg / kg and 0.32 mg / kg. It was found that the effect at the higher Concentration is much bigger. In this case, a good significance already at one Testosterone concentration of 1% achieved.

A comparison of the experimental results thus obtained shows that when using stigmasta-4-en-3-one essential Lower quantities are required to be nearly the same Effect like the commercial product in a dose of 10 mg / kg.

Trial 4 Assessment of acute toxicity

There have been studies on the acute toxicity of the NMRI mouse performed when the nettle root extract the Urtica kioviensis (Rogowicz) is used. The animals  (18-22 g) were in artificially ventilated rooms (Sterile air) at 20-21 ° C and 50-61% more relative Humidity kept under artificial light. To the Experimental animals became an acute oral toxicity test carried out:

Test animals: NMRI mouse w./m. Test concentration: 17,5-50,0 g / kg body weight Application: p. O. Application volume: 111-91 ml / kg body weight Animal number per dose: n = 20 (10 m. + 10 w.) Observation period: 14 days

For the tested dry extract was among the given conditions an LD₅₀ of 33 g / kg body weight determined. This amount corresponds to 2.3 kg in humans.

The above test result shows that the extract used is to be called practically nontoxic.

By using a nettle root extract the Urtica kioviensis (Rogowicz) can with the due to a benign cell growth inhibitory effect Tumors whose cell growth is controlled by sex hormones is to be treated.

The following is an example of the recovery of a Extract of radicis urticae kioviensis (Rogowicz) described, which can be used according to the invention.

example Extraction of an extract from the roots of Urtica kioviensis (Rogowicz) and manufacture a pharmaceutical preparation containing this Contains extract

500 kg crushed radix urticae kioviensis (Rogowicz) are mixed with a methanol / water mixture (20 vol. Methanol) according to the percolation method. The Extraction takes place at a temperature of 40-45 ° C a period of 48 h. The solvent becomes then in vacuo (150-250 mbar) at a temperature subtracted from 50-65 ° C and the evaporated residue spray dried. This gives 100 kg of dry extract, which are then mixed with 15 kg of lactose. The This mixture can, optionally under Addition of other auxiliaries, in the usual way too Tablets are made up.

Claims (2)

1. Use of an extract from the nettle roots the Urtica kioviensis (Rogowicz), which as active ingredients in addition to aromatic carboxylic acids, phenols, lignans and phytosterols 5,24 (25) -stigmastadien-3-ol and Stigmasta-4-en-3-one contains, for the treatment of benign Tumors whose cell growth is sex hormone dependent is, in humans and animals. 2. Use of an extract according to claim 1 for the treatment of prostatic hyperplasia.