WO2013060715A1 - Use of filipendula extracts for the prophylaxis and treatment of extrapyramidal motor disorders - Google Patents

Abstract

The present invention relates to the prophylactic and therapeutic use of extracts from the filipendula species for treating extrapyramidal motor disorders.

Description

 Use of extracts from Filipendula for the prophylaxis and treatment of extrapyramidal motor disorders

The present invention relates to the prophylactic and therapeutic use of extracts of Filipendula species for the treatment of extrapyramidal motor disorders.

In extrapyramidal-motor disorders, a distinction is made between so-called early and late dyskinesias, which usually occur in a drug-induced manner and orofacial dykinesia (tics), whose pathophysiological causes are still largely unknown. In addition to degenerative changes in the root ganglia, however, certain drugs - especially older neuroleptics - can trigger such disorders. These motor disturbances manifest themselves through changes in automatic movement and in the regulation of muscle tone.

Currently available drugs for the treatment of extrapyramidal motor disorders, such as Parkinson's disease, include parasympatholytics, anticholinergics, spasmolytics, catechol O-methyltransferase inhibitors, and dopaminergics, such as levodopa and dopa decarboxylase inhibitors. However, the effectiveness of these funds is limited. Furthermore, they are also associated with significant side effects. These drugs may be contraindicated due to their psychological and neurological side effects, especially in the case of drug-induced Parkinson's syndrome, which occurs primarily in mentally ill or geriatric and demented patients.

Thus, it is an object of the present invention to provide an agent which can be effectively used to treat extrapyramidal motor disorders and is substantially free of side effects.

This object is achieved according to the invention by the use of extracts from Filipendula species, preferably from Filipendula ulmaria for the therapy and prophylaxis. xe of neuroleptics-induced dyskinesia or other extrapyramidal motor disorders selected from Parkinson's disease, Tourette's syndrome, chorea (eg, Huntington's chorea), ballism, tremor, athetosis, torticollis, blepharospasm, and extrapyramidal motor disorders resulting from spinal cord injury ,

Filipendula is classified in the family Rosaceae and according to the invention comprises the following species: F. ulmaria, F. angustiloba, F. digitata, F. formosa, F. glarabrima, F. kamchatat, F. kiraishiensis, F. multijuga, F. Occidentalis, F. palmata, F. purpurea, F. rufinervis, F. rubra, F. vestita and F. vulgaris (syn. F. hexapetala). A preferred Filipendula species is Filipendula ulmaria. Another preferred Filipendula species is Filipendula vulgaris. Another preferred Filipendula species is Filipendula purpurea. The distribution area of the preferred plant Filipendula ulmaria extends over the northern regions of Europe, America and Asia. The folk medicine applications can be found in the field of colds and rheumatoid diseases, as a drug both flowers, and the dried aerial parts of the flowering plant are used (herb).

Surprisingly, it has now been found that Filipendula extracts inhibit neuroleptic-induced catalepsy. Such an effect is not yet described for Filipendula extracts and was not expected due to the previously known for Filipendula pharmacological and clinical effects.

As a further unknown effect, inhibition of catechol-O-methyltranferase (COMT) was also found for Filipendula extracts. This is significantly involved in the degradation of the monoaminergic neurotransmitters dopamine, norepinephrine, and epinephrine (U. Trendelenburg, J. Neural., Transm. 1990 [Suppl.], 32, 3-18; Y. Hiorano et al., Biol. Pharm Bull., 2007, 30, 2178-2180). COMT inhibitors are used clinically as an adjunct to the treatment of Parkinson's disease (B. Konta, W. Frank, GMS Health Technology Assessment 2008, Vol 4, T. Muller, S. Muhlach, J. Neural, Transm. 2009, 16 , 1253-1256; P. Solla et al., Neuropsychiatric Disease and Treatment 2010, 6, 483-490). Filipendula extracts may thus be used for the therapy of neurological disorders associated with a disorder of extrapyramidal motor functions. In particular, extracts of Filipendula may be used to reduce dyskinesias induced by neuroleptics or similar drugs, or to support therapy for Parkinson's disease or other extrapyramidal motor disorders selected from Tourette's syndrome, chorea (eg, Huntington's chorea), ballism, tremor, Athetoses, torticollis, blepharospasm, as well as extra pyramidal motor disorders as a result of spinal cord injury, can be used.

Thus, according to the invention, a means is provided for the first time which, owing to its spectrum of action and lacking or at most minor side effects, can be used for the treatment and prophylaxis of extrapyramidal motor disorders, in particular of neuroleptics-induced dyskinesias. Advantageous in this case is the use of extracts of Filipendula as a supplement to other agents against extrapyramidal disorders such as tiapride or biperiden.

To prepare the extracts of Filipendula used in the present invention, the dried and ground plant material is extracted with an organic solvent or water or a mixture of one or more organic solvents and / or water at a temperature between 10 ° C and 100 ° C. The extracted plant material is removed from the extract solution, e.g. B. by filtration, and optionally extracted again with a solvent according to the first step and also separated from the extract solution. The extract solutions thus obtained are combined, evaporated and dried.

Preferred organic solvents for extraction are alcohols or ketones, preferably ethanol or acetone and mixtures thereof with water. Particularly preferred are mixtures of ethanol and water in a weight ratio of 20/80 to 80/20 (20 wt .-% to 80 wt .-%), preferably 50/50 to 70/30 (50 wt .-% to 70 wt. -%), as well as water. Suitable extraction methods are, for example, maceration or percolation (see European Pharmacopeia, Edition 6.0). The drying can by known per se methods such. B. freeze-drying or drying in a vacuum at room temperature or elevated temperature. For enrichment of selected ingredients further concentration steps can be performed such. B. liquid-liquid distribution with z. B. 1-butanol / water or ethyl acetate / water, adsorption-desorption on ion exchanger, Sephadex LH20, Diaion HP20 and other resins or chromatographic separations over RP18, silica gel, etc ..

In a preferred embodiment, one part ground herb (aerial parts) of the desired Filipendula species is mixed with five to ten parts of 50% to 70% by weight ethanol for 1/2 hour to 3 hours at 50 ° C to 60 ° C ° C stirred. The extracted plant material is separated from the extract solution by filtration and stirred again with 5 to 10 parts of 50 wt .-% to 70 wt .-% ethanol for 1/2 hr. To 3 hr. At 50 ° C to 60 ° C and filtered off. The combined filtrates from the two extraction steps are freed of ethanol in vacuo at 40 ° C to 60 ° C and freeze-dried and / or dried in a vacuum at 40 ° C to 60 ° C in a drying oven.

The extracts may preferably be administered orally in the form of drops, powders, granules, tablets, dragées or capsules. However, 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.

For the preparation of tablets, the extract with suitable pharmaceutically or food acceptable excipients such. As lactose, cellulose, silica, Croscarnnellose and magnesium stearate mixed and pressed into tablets, optionally with a suitable coating z. B. from Hydroxymethylpropylcellulo- se, polyethylene glycol, dyes (eg., Titanium dioxide, iron oxide) and talc are provided.

The extracts may also, optionally with the addition of pharmaceutically or food acceptable excipients 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, particularly preferably 60 to 600 mg extract are fed per day. The extracts and the products made therefrom can be used both as pharmaceuticals and as foodstuffs. Foodstuffs include, in particular, dietetic foods, nutritional supplements as well as "medical food" and "dietary supplements".

The efficacy of Filipendula extracts in the treatment of the above indications is demonstrated by the experiments described below.

Pharmacological investigations

1. Inhibition of catalepsy

The catalepsy inhibitory effect of Filipendula extracts was studied in rats. Catalepsy is generally understood to be a state of immobility in which the affected animals maintain postures that would change them immediately under normal conditions (W.R. Klemm, Experientia 1983, 39, 228-230). Catalepsy, experimentally induced in rats and mice, is a recognized animal model to detect so-called extrapyramidal motor effects of drugs (DC Hoffmann, H. Donovan, Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability, psychopharmacol. 1995, 120, 128-133). In addition to their desired neuroleptic activities, classical antipsychotics also frequently induce undesired extrapyramidal motor side effects such as As akathesis, Parkinson-like symptoms and acute Dsykinesien.

In order to check whether Filipendula extract also has the abovementioned effects in addition to the known effects on colds, the extract was tested in a rat catalepsy model in comparison to the antipsychotic (neuroleptic) haloperidol.

The animals were treated either with haloperidol alone (control) or with haloperidol and extract from Filipendula ulmaria according to example 1 (150, 300 and 450 mg / kg). For testing catalepsy, the animals were individually placed in a test cage and their forefeet laid on a wooden cube in such a way that the animals sat at an angle of about 45 ° to the horizontal. The animals were then observed for 3 minutes and the time the animals remained in this position was considered catalepsy time. The catalepsy time is over when the animal either leaves the wood cube with both paws or when the head is moved.

In all three doses tested, haloperidol-induced catalepsy time was dose-dependently reduced with haloperidol alone, with statistically significant increases at the two higher doses (error probability p <0.05) (Figure 1).

Fig. 1: Haloperidol (0.4 mg / kg) induced catalepsy in seconds. Animals: male SD rats. Groups: control (haloperidol only), haloperidol + Filipendula ulmaria extract according to example 1 (150mg / kg, 300mg / kg and 450mg / kg). Indicated is the average of 8 animals per group and the associated standard deviation.

Extracts of Filipendula species other than Filipendula ulmaria also show a significant reduction in haloperidol-induced catalepsy of the rat as demonstrated by the example of Filipendula vulgaris and Filipendula purpurea (error probability p <0.05) (Figure 2).

Fig. 2: Haloperidol (0.4 mg / kg) induced catalepsy in seconds. Animals: male SD rats. Groups: Control (Haloperidol only), Haloperidol + Filipendula vulgaris extract according to Example 2 (450 mg / kg) and Filipendula purpurea extract according to Example 3 (450 mg / kg). Indicated is the average of 8 animals per group and the associated standard deviation.

2. Inhibition of catechol O-methyltransferase

Catechol O-methyltransferase (COMT) inhibitory activity has been studied in vitro on COMT isolated from pig liver (Muller-Enoch et al., Z. Naturforsch., 1976, 31, 280-284). The substrate esculetin is converted by the enzymatic reaction into the product scopoletin, which is then detected fluorometrically. A reduced formation of the product at a constant amount of Enzyme mediated by the addition of the extract of Filipendula indicates the inhibition of the enzyme COMT.

Catechol O-methyltransferase was inhibited in all three doses tested (Figure 3).

Fig. 3: In vitro measurement of COMT activity. Groups: Extract from Filipendula ulmaria according to Example 1 (10, 3 and 1 μg / ml). Indicated is the mean of two experiments and the associated standard deviation.

Example 1: Extract from Filipendula ulmaria

600 g of finely ground herb (aerial parts) of Filipendula ulmaria are stirred twice each with 4200 g of 60 wt .-% ethanol for 1 hr. At 60 ° C, then the suspension sucked through a frit P4, the combined filtrates in vacuo Free from ethanol at 60 ° C, the remaining aqueous residue was frozen and lyophilized. The resulting solid is dried in vacuo at 40 ° C over P ₂ O ₅ and KOH: 146.2 g (24.4%) of dry extract.

Example 2: Extract from Filipendula vulgaris

200 g of finely ground herb (aerial parts) of Filipendula vulgaris are stirred twice each with 1400 g of 60 wt .-% ethanol for 1 hr. At 60 ° C, then the suspension sucked, the combined filtrates in vacuo at 60 ° C from Ethanol freed, the remaining aqueous residue is frozen and lyophilized. The resulting solid is dried in vacuo at 40 ° C over P2O5 and KOH: 59.7 g (29.9%) of dry extract.

Example 3: Extract from Filipendula purpurea

57 g of finely ground herb (aerial parts) of Filipendula purpurea are stirred twice each with 400 g of 60 wt .-% ethanol for 1 hr. At 60 ° C, then the suspension sucked, the combined filtrates in vacuo at 60 ° C from Ethanol freed, the remaining aqueous residue is frozen and lyophilized. Of the solid obtained is dried in vacuo at 40 ° C over P2O5 and KOH: 17.1 g (30.0%) of dry extract.

Example 4: Tablets

A dry extract from Filipendula ulmaria (extract according to Example 1) is mixed with excipients and pressed into tablets (tablet core = position 1 - 6). The tablets are provided with a coating of hydroxypropyl methylcellulose (position 7-10).

Claims

claims 1 . Use of extracts from Filipendula for the prophylaxis or treatment of extrapyramidal motor disorders. 2. Use according to claim 1, wherein the extrapyramidal motor disorders are neuroleptic-induced dyskinesias. Use according to claim 1, wherein the extrapyramidal motor disorder is selected from Parkinson's disease, Tourette's syndrome, chorea, ballism, tremor, athetosis, torticollis, blepharospasm, and extrapyramidal motor disorders resulting from spinal cord injury. Use according to claim 3, wherein the extrapyramidal motor disorder is Parkinson's disease. 5. Use according to one of claims 1 to 4, wherein the Filipendulaart for producing the extract is selected from the group F. ulmaria, F. angustiloba, F. digitata, F. formosa, F. glaberrima, F. Kamchatka, F. kiraishiensis F. multijuga, F. occidentalis, F. palmata, F. purpurea, F. rufinervis, F. rubra, F. vestita and F. vulgaris (syn. F. hexapetala). 6. Use according to one of claims 1 to 5, being used as Filipendulaart for the preparation of the extract Filipendula ulmaria. 7. Use according to any one of claims 1 to 6, wherein the aerial parts (cabbage) of Filipendula are used. 8. Use according to any one of claims 1 to 7, wherein an aqueous-ethanolic extract is used. 9. Use according to claim 8, wherein ethanol and water in a weight ratio of 20/80 to 80/20 are used. 10. Use according to claim 8, wherein ethanol and water in a weight ratio of 50/50 to 70/30 are used. 1 1. Use according to any one of claims 1 to 7, wherein an aqueous extract is used. 12. Use according to any one of claims 1 to 1 1, wherein the extract of Filipendula is used in addition to other agents against extrapyramidal disorders. Use according to claim 12, wherein the other anti-extrapyramidal agents are selected from tiapride or biperiden. 14. Medicament for use according to any one of claims 1 to 13, wherein the medicament contains pharmaceutically acceptable excipients in addition to the extract from Filipendula. 15. food for use according to any one of claims 1 to 13, wherein the food in addition to the extract from Filipendula food acceptable excipients. 16. Extract of Filipendula for use according to one of claims 1 to 13.