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EP1945238A2 - Extraits d'ecorce de varietes de corynanthe, utilisation de ceux-ci et medicaments, aliments dietetiques et preparations pharmaceutiques contenant ces extraits - Google Patents

Extraits d'ecorce de varietes de corynanthe, utilisation de ceux-ci et medicaments, aliments dietetiques et preparations pharmaceutiques contenant ces extraits

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Publication number
EP1945238A2
EP1945238A2 EP06818406A EP06818406A EP1945238A2 EP 1945238 A2 EP1945238 A2 EP 1945238A2 EP 06818406 A EP06818406 A EP 06818406A EP 06818406 A EP06818406 A EP 06818406A EP 1945238 A2 EP1945238 A2 EP 1945238A2
Authority
EP
European Patent Office
Prior art keywords
extract
disorders
extracts
corynanthe
bark
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06818406A
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German (de)
English (en)
Inventor
Egon Koch
Hermann Hauer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Willmar Schwabe GmbH and Co KG
Original Assignee
Dr Willmar Schwabe GmbH and Co KG
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Filing date
Publication date
Application filed by Dr Willmar Schwabe GmbH and Co KG filed Critical Dr Willmar Schwabe GmbH and Co KG
Publication of EP1945238A2 publication Critical patent/EP1945238A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to extracts of the bark of Corynanthe species, in particular of Corynanthe pachyceras, as well as their use for the therapy and prophylaxis of diseases of the urinary tract, sexual disorders, lipid metabolism disorders, cardiovascular diseases and acute and chronic pain conditions.
  • the invention further relates to these extracts containing drugs, dietetic foods and pharmaceutical preparations.
  • Benign prostatic hyperplasia BPH
  • concomitant Lower Urinary Tract Symptoms LUTS
  • BPH is considered to be an endocrinopathy of the aging male, which develops as a result of hormonal changes with advancing age.
  • BPH is a benign growth of epithelial and stromal parts of the prostate. The localization of the prostate at the urethra near the exit of the bladder leads to enlargement of the organ to urinary drainage disorders, which are accompanied by symptoms such as pollakisuria and nocturia as well as incomplete and delayed bladder emptying.
  • renal insufficiency and uremia may occur as a result of the backflow of urine. Due to secretion congestion and urinary retention also often develop an abacterial prostatitis, congestion and recurrent urinary tract infections, which are responsible for irritative micturition disorders in addition to the obstructive symptoms.
  • BPH is reserved for the histological or macroscopic diagnosis of prostate hyperplasia
  • the patients are presented with the associated LUTS such as: As urinary urgency, Pollakisurie and nocturia as well as incomplete and delayed bladder emptying in the foreground.
  • the range of treatment options of BPH ranges from a wait and see attitude
  • ccr antagonists are based on the view that the dynamic component of BPH / LUTS is caused by an increased tone of the smooth prostatic musculature, which is mediated by an increased release of norepinephrine from sympathetic neurons. It is generally accepted today that predominantly CCIA and CC I D adrenoceptors are expressed in the prostate. The results of clinical studies show that alpha-blockers produce a clinically significant improvement in symptoms and maximum urinary flow. A particular advantage of the alpha-blockers is their rapid onset of action. So far there are no convincing indications that they stop the further enlargement of the prostate.
  • alpha-blockers include dizziness, headache, weakness, orthostatic dysregulation, rhinitis and sexual dysfunction (retrograde ejaculation), which are mainly due to the effects on alpha receptors in the CNS and cardiovascular system.
  • subtype-specific alpha-blockers that primarily inhibit ⁇ -1 A and ⁇ -1 D receptors (eg, tamsulosin)
  • tamsulosin a subtype-specific alpha-blockers that primarily inhibit ⁇ -1 A and ⁇ -1 D receptors
  • the non-selective ⁇ r-antagonist alfuzosin has a similarly favorable side-effect profile as tamsulosin, which is commonly described as a uroselective ⁇ -i blocker.
  • BPH develops only in the presence of biologically active male sex hormones.
  • men who underwent castration before the age of 40, or who have no or only insufficient orogen formation in the gonads due to hypofunction of the hypophysis BPH is practically never observed.
  • a congenital defect or lack of androgen receptors eg, testicular feminization
  • normal prostate development and the development of BPH are suppressed.
  • the biologically most important androgen in the prostate is dihydrotestosterone (DHT), which is locally produced under the influence of 5- ⁇ -reductase from testosterone.
  • DHT dihydrotestosterone
  • DHT primarily stimulates the epithelial components of BPH
  • taking the 5- ⁇ -reductase inhibitor finasteride reduces prostate DHT levels by up to 85%, but the prostate size reduction is only about 20% on average and also takes up to 12 months , This effect is essentially clinically relevant only if the prostate volume at the beginning of the therapy is more than 40 ml.
  • Androgens are mediated in vivo via the local synthesis of growth factors, and that disorders of the paracrine and autocrine mechanisms of the
  • BPH epidermal growth factor
  • TGF-a transforming growth factor- ⁇
  • bFGF basic fibroblast growth factor
  • KGF keratinocyte growth factor
  • NGF nerve growth factor
  • IGF-1 insulin-like growth factor-1
  • Growth factors mediate their biological activity by binding to specific cell surface receptors that possess intrinsic tyrosine kinase activity. Upon binding of the ligand, phosphorylation of tyrosine residues on the intracellular receptor domain occurs which subsequently triggers a cascade of intracellular responses. These include the stimulation of protein and DNA synthesis as well as the activation of cell proliferation. Inhibitors of receptor tyrosine kinase are therefore considered to be promising agents for the development of new drugs for the treatment of diseases associated with increased cell proliferation (eg, cancer, atherosclerosis, psoriasis) (A. Levitzki and A. Gazit, Science 267, 1782 - 1788 (1995)). However, little attention has been paid to this mode of action in the treatment of BPH.
  • diseases associated with increased cell proliferation eg, cancer, atherosclerosis, psoriasis
  • Age between 50 and 80 is about 25%. This rate increases to over 80% in patients with severe symptoms.
  • the incidence of ED is also affected by other co-existing diseases, such as hypertension, diabetes,
  • Hypercholesterolemia, angina pectoris, and depression M. Shabbir et al., Curr. Med. Res. Opin. 20, 603, 2004.
  • the relaxation of the penis is maintained mainly by binding of noradrenaline to ⁇ - ⁇ A and Ot 1 B receptors in the corpus cavernosum. It is therefore not surprising that an improvement in sexual function has been observed in patients with ED on alpha-blocker therapy (eg, doxazosin and tamsulosin).
  • alpha-blocker therapy eg, doxazosin and tamsulosin
  • erections are mainly mediated by the vasodilator effect of nitric oxide (NO).
  • NO is released from nitrate neurons and is also synthesized by endothelial cells in the corpus cavernosum and corpus spongiosum.
  • NO causes smooth muscle cell relaxation.
  • a combination of ⁇ i and ⁇ .2-antagonistic action is considered to be particularly favorable for the treatment of ED, as it leads to blockade of ⁇ -i receptors directly to a muscle relaxation and the inhibition of presynaptic ct2 receptors with an increased Release of NO from nitrergic neurons is associated (http://www.bioportfolio.com/leadcliscovery/mdi002.htm).
  • sildenafil a PDE5 inhibitor that inhibits the breakdown of cGMP
  • sildenafil causes a number of side effects (eg headache, blurred vision, dyspepsia, haemodynamic effects), and there is evidence that efficacy decreases with increasing duration of treatment (Shabbir, M., et al., Curr 20, 603, 2004).
  • sildenafil can not be used in 30-50% of patients due to the severity of the disease and contraindications. More recent PDE5 inhibitors have limited clinical experience.
  • PGEi is also an effective substance for the treatment of ED, but must be injected or intraurethrally administered.
  • apomorphine acts as a dopamine agonist and has a central nervous system of action. It is more suitable for mild cases of ED. With a generally low rate of side effects (nausea, cardiovascular effects), the sublingual administration required to prevent first-pass hepatic metabolism is more likely RB Moreland et al., J. Pharmacol. Exp. Ther. 2004, 308, 797). Therefore, there is still a great need for effective and low-side-effect drugs for the treatment of ED.
  • This object is achieved according to the invention by the use of extracts of the bark of Corynanthe species, preferably of Corynanthe pachyceras, for the therapy and prophylaxis of diseases of the urinary tracts of man and woman (eg benign prostatic hyperplasia, LUTS, prostate carcinoma, bladder emptying disorders Urinary retention, stress urgency and urgency), male and female sexual disorders (eg impotence, erectile dysfunction, premature ejaculation, libido disorders, frigidity or anorgasmia), lipid metabolism disorders (eg hypercholesterolemia, hyperlipidemia and hypertriglycerinemia), cardiovascular diseases (eg endothelial dysfunction, hypertension, arteriosclerosis or restenosis following vascular dilation or by-pass surgery) and acute and chronic pain conditions such as migraine, neuropathic pain (eg diabetes), phantom pain , Allodynia, pain after tissue injury or inflammation n (eg postherpetic neuralgia).
  • Also part of the invention are extracts of the bark of Corynanthe species, preferably from the bark of Corynanthe pachyceras with a balanced ratio of efficacy components, as well as medicines and foods for the therapy and prophylaxis of diseases of the urinary tract, sexual disorders, disorders of lipid metabolism Cardiovascular diseases and of acute and chronic pain conditions, characterized by a content of an extract according to the invention, and a pharmaceutical preparation as oral, Parenteral or topical dosage form consisting of an extract according to the invention and suitable excipients as an oral, parenteral or topical administration form.
  • Foodstuffs include, in particular, dietetic foods, nutritional supplements as well as "medical food” and "dietary supplements”.
  • Corynanthe pachyceras is an approximately 15 - 2O m tall tree with a trunk diameter up to 60 cm, which grows in the evergreen tropical rain forest in West Africa (Sierra Leone to Zaire).
  • the wood is mainly used for building, but also for the production of mortars and combs.
  • the dried stem bark finds broad folk medicine application. For colds, it is chewed and used as a decoction for leprosy, stomach problems, diarrhea or heart and kidney problems. In the form of teas, the bark is used as an antipyretic agent in malaria, as well as an aphrodisiac and wax preservative.
  • the bark of Corynanthe pachyceras contains about 6% indole alkaloids, which belong to the group of corynanthine (eg Dihydrocorynanthein, Corynanthein, Corynantheidin) or yohimbine alkaloids (eg corynanthine, ⁇ -yohimbine).
  • corynanthine eg Dihydrocorynanthein, Corynanthein, Corynantheidin
  • yohimbine alkaloids eg corynanthine, ⁇ -yohimbine
  • alcoholic or ketonic, preferably ethanolic-aqueous extracts from the bark of Corynanthe species, in particular Corynanthe pachyceras have a number of other biological effects in addition to ⁇ r and ⁇ 2 -adrenoceptor antagonistic effects, such as B. cell proliferation inhibiting, endothelium-dependent vasorelaxierende, cholesterol-lowering, analgesic and antioxidant properties.
  • B. cell proliferation inhibiting, endothelium-dependent vasorelaxierende, cholesterol-lowering, analgesic and antioxidant properties suggest the therapeutic use of these extracts in various disease states. These disorders include BPH, LUTS, sexual dysfunction in men and women, bladder dysfunction, hypercholesterolemia, arteriosclerosis, endothelial dysfunction and pain.
  • the bark extracts of Corynanthe species containing polyphenols and alkaloids according to the invention can be obtained according to the following process: (a) extraction of dried and ground bark of Corynanthe species with an organic solvent or water or a mixture of one or more organic solvent and / or water at a temperature between 10 0 C and 100 0 C 1
  • step (c) if necessary, renewed extraction of the extracted plant material with a solvent according to step (a) and separation according to step (b),
  • step (e) evaporating and drying the combined solution from step (d) to the dry extract.
  • Preferred organic solvents in step (a) are alcohols or ketones, wherein the alcohol is preferably ethanol. Particularly preferred are mixtures of ethanol and water.
  • extraction method in step (a) preference is given to maceration or percolation.
  • Step (c) is usually carried out once, a waiver of step (c) or repeated implementation is also possible.
  • the drying in step (e) can be carried out by methods known per se, such as. B. freeze-drying or drying in vacuo at room temperature or elevated temperature.
  • Corynanthe pachyceras is used as a preferred Corynanthe species.
  • the extracts of the bark of Corynanthe species according to the invention contain both polyphenols and alkaloids, in a balanced ratio for the intended use.
  • the contents of polyphenols are preferably at least 15%, particularly preferably at least 24%, and at alkaloids at least 8%, particularly preferably at least 12%.
  • typical polyphenols we have isolated the compounds epicatechin, procyanidin B2 and procyanidin C1 from Corynanthe pachyceras.
  • the Corynanthe polyphenols are not limited to these three compounds.
  • the determination of the contents of polyphenols is carried out by a Botphenolbetician to Folin-Ciocalteu.
  • the levels of epicatechin, procyanidin B2 and procyanidin C1 can be determined.
  • alkaloid contents is the sum of Contents of the individual alkaloids corynanthine, ⁇ -yohimbine, Corynanthein, Dihydrocorynanthein and Corynantheidin to understand.
  • the extracts and extract fractions according to the invention can preferably be administered orally in the form of drops, powders, granules, tablets, dragées or capsules.
  • parenteral administration in the form of a solution for injection or topical application in the form of creams, ointments, suppositories, patches or similar preparations is also possible.
  • the extract For the preparation of tablets, the extract with suitable pharmaceutically acceptable excipients such as lactose, cellulose, silica, Croscarmellose and magnesium stearate and pressed into tablets, optionally with a suitable coating z.
  • suitable pharmaceutically acceptable excipients such as lactose, cellulose, silica, Croscarmellose and magnesium stearate and pressed into tablets, optionally with a suitable coating z.
  • suitable pharmaceutically acceptable excipients such as lactose, cellulose, silica, Croscarmellose and magnesium stearate and pressed into tablets, optionally with a suitable coating z.
  • suitable coating z for the preparation of tablets, the extract with suitable pharmaceutically acceptable excipients such as lactose, cellulose, silica, Croscarmellose and magnesium stearate and pressed into tablets, optionally with a suitable coating z.
  • the extracts of the invention may also, optionally with the addition of adjuvants such.
  • adjuvants such as stabilizers, fillers, etc., are filled into capsules.
  • the dosage is carried out so that 5 to 2000 mg, preferably 10 to 1000 mg, more preferably 50 to 500 mg extract per day are supplied.
  • the efficacy of the inventive bark extracts of Corynanthe species is demonstrated by the experiments described below.
  • Preparation of the cell membranes were male Sprague-Dawley rats (150- 250 g) were euthanized in CO 2 anesthesia and the brains (without the cerebellum) were removed. After removing adherent blood and meninges, the brains were immediately taken up in a 10-fold volume of ice-cold homogenization buffer (50 mM Tris-HCl, pH 7.4) and homogenized with an ice-cooled glass homogenizer. The cell homogenate was centrifuged for 10 min at 50,000 g (4 ° C.) and the pellet resuspended in ice-cold homogenization buffer.
  • ice-cold homogenization buffer 50 mM Tris-HCl, pH 7.4
  • the cell membranes were incubated in a 10-fold volume of binding buffer (50 mM Tris-HCl, 0.5 mM Na-EDTA, 0.01% ascorbic acid, 10 ⁇ M pargyline, pH 7, 4) was added, and stored in portions (1 ml) at -80 0 C.
  • binding buffer 50 mM Tris-HCl, 0.5 mM Na-EDTA, 0.01% ascorbic acid, 10 ⁇ M pargyline, pH 7, 4
  • the extract according to the invention or the alkaloid or polyphenol fractions were dissolved using DMSO in 150 ⁇ l of binding buffer and incubated together with 50 ⁇ l of brain cell membranes (2.5 mg / ml protein) and 50 ⁇ l of radiocidal ligand in binding buffer for 45 min at room temperature.
  • a radioligand for testing for interactions with ⁇ rAdrenozeptoren 3 H-prazosin (300 pM, specific activity 80 Ci / mmol) was used. Non-specific binding was measured in the presence of 2 ⁇ M phentolamine.
  • the radioligand used for the determination of ⁇ 2 -adrenoceptor binding was 3 H-clonidine (1 ⁇ M, specific activity 55.5 Ci / mmol).
  • Non-specific binding to ⁇ 2 -adrenoceptors was measured in the presence of 10 ⁇ M yohimbine.
  • the reaction mixtures were then filtered through glass fiber filters (GF / B type) pretreated overnight with polyethyleneimines (0.2% in distilled water). After washing twice with 3 ml of ice-cold binding buffer, the filters were dried at 60 ° C. for 24 h. The determination of the bound radioactivity was carried out after transfer of the filters in 4 ml scintillation fluid (filter safe, Zinsser analysis) in a beta counter.
  • NIH-3T3 mouse fibroblasts The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS), 2 mM glutamine and antibiotic / antimycotic solution. The change of the culture medium took place regularly twice a week. Four days after the last subculture, the adherent cells were detached with trypsin / EDTA from the bottom of the cell culture flask and resuspended at a density of 50,000 cells per ml in DMEM supplemented with 0.5% FCS.
  • DMEM Dulbecco's modified Eagle's medium
  • FCS fetal calf serum
  • FCS fetal calf serum
  • the cells were then transferred in a volume of 200 .mu.l per well in F-form microtiter plates and for further incubated for 96 h at 37 0 C. After changing the medium (DMEM without FCS) and adding the substances, the addition of 10 ng / ml of recombinant human Platelet-derived growth factor BB (PDGF-BB) was carried out 60 min later. Subsequently, the cells were cultured again for 24 h at 37 0 C in the incubator. Six hours prior to cell harvest was added per test, 0.5 uCi of 3 H-methyl thymidine. After the incubation period, the microtiter plates were centrifuged for 5 min at 400 g and the cell supernatants were carefully pipetted off.
  • DMEM without FCS fetal-derived growth factor BB
  • the cells were detached from the bottom with trypsin / EDTA and then harvested with a cell harvester (Inotech) on glass fiber filters (Type G-10, ICH-201).
  • a cell harvester Inotech
  • the measurement of the incorporation of 3 H-thymidine into newly synthesized DNA was carried out with the aid of a linear analyzer (LB 2842, Berthold).
  • the determination of the inhibition of cell proliferation in the presence of the extracts and extract fractions was in each case in comparison to simultaneously examined solvent controls.
  • the aortic rings were mounted on a steel cannula, slightly pressed and then the innermost vessel layer removed by rotation and simultaneous movement in the longitudinal direction.
  • the aortic rings were fixed by means of metal ticks in an organ bath (20 ml, Hugo Sachs, Hugstetten) filled with Tyrode's solution.
  • the nutrient solution 37 0 C was constantly gassed with carbogen (pH 7.4).
  • the test was for relaxant effect after induction of contraction with U-46619 (0.022 ⁇ g / ml, EC 0.063 ⁇ M) or KCl (3 mg / ml, EK 40 mM) in an identical manner.
  • the relaxing effect of the extracts on the agonists was determined as a percentage.
  • IC 5 o values were determined by non-linear regression analysis of concentration-effect curves using the software program Prism 3.0 (GraphPad Software Inc.).
  • mice Male NMRI mice (Janvier, Le Genest, France) with Triton WR1339-induced hypercholesterolemia.
  • the mice were kept under standardized environmental conditions (21 ° C, 60% relative humidity, 12 / 12h light / dark) and had free access to drinking water and pelleted feed (Altromin 1324).
  • Triton-WR1339 400 mg / kg, Sigma was dissolved in physiological NaCl solution and injected into the animals via the tail vein (10 ml / kg).
  • the extract was taken up in 0.2% agar suspension and administered to the animals 24 hours and 1 hour before and 6 hours after the Triton-WR1339 injection by gavage (450 mg / kg in 10 ml / kg). Animals in the control group were treated only with the carrier suspension (0.2% agar, 10 ml / kg).
  • a blood sample 32 ⁇ l was taken from the animals with a heparinized capillary and the cholesterol concentration determined immediately afterwards (Reflotron, Boehringer Mannheim).
  • Figure 1 shows the effect of oral treatment with the extract of the invention (450 mg / kg) on cholesterol levels in mice with Triton WR1339-induced hypercholesterolemia (# means P ⁇ 0.05 compared to the control (t-test)).
  • the results of the investigations demonstrate that treatment with the extract according to the invention according to example 1 results in a significant reduction of the elevated cholesterol levels.
  • mice formalin test was used for analgesic effects. Local injection of formalin into the hindfoot of mice results in increased sensitivity to pain, which occurs in two separate phases. The first phase is mediated by the direct stimulation of pain receptors due to the release of substance P, bradykinin and excitatory amino acids (eg glutamine). In the subsequent second phase, histamine, serotonin and prostaglandins are accumulated in the tissue, leading to a local inflammatory response and functional changes in the central nervous system.
  • male NMRI mice Jivier, Le Genest, France
  • the animals were treated orally with the extracts according to the invention or extract fractions.
  • the lipid-rich tissue used in the present studies was brain tissue of male mice (NMRI, 20-30 g, Center d'Elevage Janvier, Le Genest-Saint Isle, France). After removal, the brain was washed with ice cold phosphate buffered saline (PBS, pH 7.4) and freed from meninges and blood debris. The tissue samples were homogenized in a 4-fold volume (v / w) and PBS for 10 minutes at 1000 xg and centrifuged 4 0 C.
  • the determination of the total phenols is carried out in analogy to the pharmacopoeia method for tanning agents (DAB) photometrically after reaction with molybdate tungstate reagent.
  • DAB pharmacopoeia method for tanning agents
  • the extract is dissolved in aqueous ethanol, alkalized with sodium carbonate solution and mixed with molybdate tungstate reagent. After centrifugation, the absorbance of the supernatant solution is measured at 720 nm against water. The calculation is based on epicatechin.
  • the extract contains 14.62% alkaloids (4.75% corynanthine, 0.81% ⁇ -yohimbine, 3.86% corynanthein, 1.91% dihydrocorynanthein and 3.29% corynantheidine) and 26.8% total phenols (including 2.66% epicatechin, 3.05% procyanidin B2 and 1.25% procyanidin C1).
  • the extract does not contain any alkaloids (corynanthine, ⁇ -yohimbine, corynanthein, dihydrocorynanine and corynanthine respectively undetectable) and 28.4% total phenols (including 2.57% epicatechin, 2.24% procyanidin B2 and 0.76% procyanidin C1).
  • the ion exchange column from Comparative Example 1 was further eluted with a mixture of 50% by volume of ethanol and 5% NH 3 solution (25% strength). There were 16 L Run off and evaporated as in Example 2 and dried: 46.8 g (10.5%).
  • the extract contains 69.28% alkaloids (24.01% corynanthine, 2.25% ⁇ -yohimbine, 19.05% corynanthein, 9.56% dihydrocorynanthein and 14.41% corynantheidine) and 13.0% total phenols (epicatechin, procyanidin B2 and procyanidin C1 each undetectable).
  • the tablets are provided with a coating of hydroxypropyl methylcellulose (position 7-10).

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Abstract

L'invention concerne des extraits d'écorce de variétés de Corynanthe, notamment de Corynanthe pachyceras, et leur utilisation dans la thérapie et la prophylaxie de maladies des voies urinaires basses, de troubles sexuels, de troubles métaboliques, de troubles cardiovasculaires et d'états douloureux aigus et chroniques. L'invention concerne également des médicaments, des aliments diététiques et des préparations pharmaceutiques contenant ces extraits.
EP06818406A 2005-11-08 2006-11-07 Extraits d'ecorce de varietes de corynanthe, utilisation de ceux-ci et medicaments, aliments dietetiques et preparations pharmaceutiques contenant ces extraits Withdrawn EP1945238A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005053241A DE102005053241A1 (de) 2005-11-08 2005-11-08 Extrakte aus der Rinde von Corynanthe-Arten und deren Verwendung sowie diese Extrakte enthaltende Arzneimittel, diätetische Lebensmittel und pharmazeutische Zubereitungen
PCT/EP2006/010663 WO2007054269A2 (fr) 2005-11-08 2006-11-07 Extraits d'ecorce de varietes de corynanthe, utilisation de ceux-ci et medicaments, aliments dietetiques et preparations pharmaceutiques contenant ces extraits

Publications (1)

Publication Number Publication Date
EP1945238A2 true EP1945238A2 (fr) 2008-07-23

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EP06818406A Withdrawn EP1945238A2 (fr) 2005-11-08 2006-11-07 Extraits d'ecorce de varietes de corynanthe, utilisation de ceux-ci et medicaments, aliments dietetiques et preparations pharmaceutiques contenant ces extraits

Country Status (12)

Country Link
US (1) US20090142428A1 (fr)
EP (1) EP1945238A2 (fr)
JP (1) JP5435951B2 (fr)
KR (1) KR101306599B1 (fr)
CN (1) CN101291682A (fr)
AU (1) AU2006312678B2 (fr)
BR (1) BRPI0618634A2 (fr)
CA (1) CA2624703A1 (fr)
DE (1) DE102005053241A1 (fr)
RU (1) RU2399378C2 (fr)
UA (1) UA94434C2 (fr)
WO (1) WO2007054269A2 (fr)

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CN101683337B (zh) * 2008-09-27 2011-12-07 复旦大学 柯楠因在制备治疗心肌损伤性心脏病药物中的用途
JP2011125331A (ja) * 2009-11-17 2011-06-30 Taisho Pharmaceutical Co Ltd 魚鱗粉末含有コーティング錠剤
CN102002039B (zh) * 2010-11-12 2012-05-09 天医堂(厦门)生物工程有限公司 一种从育亨宾树皮中提取育亨宾的方法
CN102030747A (zh) * 2010-11-19 2011-04-27 陕西嘉禾植物化工有限责任公司 一种育亨宾碱的制备方法
EP3646871A1 (fr) * 2018-10-30 2020-05-06 SEROJAC PME Handels GmbH Traitement et prévention de l'éjaculation précoce (pe)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2112344A1 (en) * 1970-10-27 1972-06-16 Omnium Chimique Sa Hypotensive, sedative extract of pseudocni - chona africana
BE758049A (fr) * 1970-10-27 1971-04-01 Omnium Chimique Sa Produit pharmaceutique a proprietes hypotensives et sedatives et son procede d'obtention.
DE3204960A1 (de) * 1982-02-12 1983-08-25 Fa. Dr. Willmar Schwabe, 7500 Karlsruhe Corynanthein-derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US6323211B1 (en) * 1996-02-02 2001-11-27 Nitromed, Inc. Compositions and methods for treating sexual dysfunctions
FR2765483B1 (fr) * 1997-07-04 2000-02-04 Philippe Gorny Medicament destine a traiter les dysfonctions erectiles
IT1293539B1 (it) * 1997-07-16 1999-03-01 Sigma Tau Ind Farmaceuti Composizione nutritiva per soggetti in stato di debilitazione causato da stress
ITMI20011237A1 (it) * 2001-06-12 2002-12-12 Enzo Leone Uso della yohimbina per la preparazione di farmaci ad attivita' immunobiologica

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007054269A2 *

Also Published As

Publication number Publication date
KR20080071172A (ko) 2008-08-01
CA2624703A1 (fr) 2007-05-18
JP5435951B2 (ja) 2014-03-05
BRPI0618634A2 (pt) 2011-09-06
AU2006312678B2 (en) 2013-03-28
US20090142428A1 (en) 2009-06-04
KR101306599B1 (ko) 2013-09-10
CN101291682A (zh) 2008-10-22
WO2007054269A2 (fr) 2007-05-18
RU2399378C2 (ru) 2010-09-20
UA94434C2 (ru) 2011-05-10
AU2006312678A1 (en) 2007-05-18
WO2007054269A3 (fr) 2007-08-09
JP2009514916A (ja) 2009-04-09
RU2008119965A (ru) 2009-12-20
DE102005053241A1 (de) 2007-05-16

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