JP2011132250A - Natural formulation for treatment and prevention of depression, containing st. john's wort and derivative of dihydro and tetrahydrofolic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a natural formulation which is extremely useful for prevention and treatment of depression. <P>SOLUTION: A medical composition which is useful for the treatment and prevention of depression includes the combination of, as the active ingredients, the plant called St. John's Wort (Hypericum perforatum); an extract of the active ingredient thereof; and the derivative of dihydro and tetrahydrofolic acid. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel composition comprising a combination of a plant called St. John's wort (Hypericum perforatum L.) (hypericum perforatum) and a derivative of folic acid. This natural preparation is useful for treating and preventing depression with an effect superior to the component compounds alone.

  Depression is an increasingly common mental disorder, affecting most people, especially in developed countries. Although the etiology and exact mechanism of depressive disorders has not been fully elucidated, certain neurotransmitters, particularly serotonin (5-HT) and its metabolites in the central nervous system, 5-hydroxyindoleacetic acid (5 It is thought to occur with a decrease in -HIAA). High levels of homocysteine and folate and vitamin B12 deficiency have also been associated with the pathogenesis of depression.

  Current standard pharmacological antidepressants fall into several major groups such as selective serotonin reuptake inhibitors, tricyclic and other heterocyclic antidepressants, monoamine oxidase (MAO) inhibitors can do. All of these cause a wide range of side effects, from unwanted mental excitement to hypertension and cardiotoxicity.

  Despite some progress in this area and the availability of new antidepressants with fewer side effects, research in this area has not provided a safe and efficient way to treat depression.

  Thus, there is a need for innovative formulations based on natural metabolites useful for the prevention and treatment of depression.

  This time, the natural compound St. John's wort or its extract or active ingredient in combination with a folic acid derivative constitutes a unique and safe multifaceted method for the prevention and treatment of mild to moderate depression I understood.

  St. John's wort is a perennial flowering plant and has traditionally been used as a folk medicine for millennia for its healing properties, especially for wound healing and respiratory infections due to its anti-inflammatory, analgesic and sedative properties (Miller A. L., Alt. Med. Rev., 3 (1), 18-26, 1998).

  Recently, it has attracted attention as an effective drug for the treatment of mild to moderate depression and seasonal affective disorders. Other indications include psychegetative dysfunction, anxiety, neuropathic anxiety and similar disorders. Approximately 30 clinical trials confirmed the efficacy of St. John's wort (SJW) without side effects compared to popular synthetic antidepressants (amitriptyline, imipramine, maprotiline, etc.) (Lieberman, S., Altern. Complement). Therapies, June, pp. 163-168, 1998). This does not lead to failure of attention, concentration or responsiveness. The only side effect described in the literature is increased photosensitivity to reversible UV radiation after prolonged use of St. John's wort extract (Golsch, S. et al. Hautarzt, 48 (4), 249. ~ 252 pages, 1997). No negative drug interactions associated with St. John's wort have been reported.

  The mechanism of action of SJW has not been fully explained. The extract is thought to contain eight secondary metabolites identified to date, such as Amentoflavone, biapigenin, hyperforin, hypericin, hyperoside, pseudohypericin, quercetin and rutin ( Butter, B. et al., Plant Med., 64 (5), 431-437, 1998).

  Hypericin, one of the active compounds of SJW, is catechol-O-methyltransferase (Mueller, WE, et al., J. Geriatr. Psychiatr. Neurol., Vol. 7 (Appendix 1), pages 63-64. , 1994; Mueller, WE, Wissenschaffricher Bericht, Richter Pharma GmbH, see Berlin, 1995) and monoamine oxidase (Suzuki, O. et al., Plant Med., 50, 272-4. (See 1984)). Monoamine oxidase is involved in the degradation of the neurotransmitters serotonin and noradrenaline (see Perovic, S. et al., Arzn. Forsch / Drug Res., 45, 1145- 1148, 1995).

  Another effect includes the general effect of Hypericum extracts on the modulation of serotonin receptors or / and central dopaminergic neurons (Butterweck, V. et al., Plant Med., 64 (4), 291 ~ 294 pages, 1998).

  Other reports show that pure hypericin has no inhibitory effect on MAO (Bladt, S. et al., J. Geriatr. Psychiatr. Neurol., 7 (Appendix 1), pages 57-59, 1994. This suggests that the antidepressant action of SJW cannot be explained by MAO inhibition. In a recent series of publications, hyperforin, the major lipophilic nitrogen-free component of SJW (and Hypericium Oleum), is also a potent in vitro uptake of serotonin, dopamine, noradrenaline, GABA, and L-glutamic acid. It was found to be an inhibitor (see Chattarjee, SS et al., Life Sci. 63 (6), 499-510, 1998).

  Most of the known pharmacological properties of SJW extracts can also be demonstrated with pure hyperforin. Therefore, it is believed that hyperforin may be the main activator of this plant (see Laakmann, G. et al., Pharmacopsychiatry, 31 (Appendix 1), pages 54-59, 1998). Most investigators agree that a combination of low monoamino oxidase inhibition and noradrenaline and serotonin reuptake blockage must be the mechanism of action of SJW (Nordfors, M. et al., Lakatidningen, vol. 94). (25), pages 2365-2367, 1997).

  The close relationship between folate metabolism and depression is well documented (see Alpert, JE et al., Nutrition Reviews, 55 (5), 145-149, 1997). . Depressive symptoms are known to be the most common indicator of folate deficiency. Depressed patients were consistently found to have lower serum folate concentrations than control subjects (Fava, M. et al., Am. J. Psychiatry, 154, 426-428, 1997). See Recently, low folate levels have been associated with inadequate response to selective serotonin uptake inhibitors.

  The biochemical mechanism in which folic acid derivatives affect the neuropsychiatric state clearly includes methyl transfer reactions with components of the central nervous system (DNA, RNA, proteins, biological membranes). Methyl group of folate (form of 5-formyltetrahydrofolate after reduction to active metabolite 5-methyltetrahydrofolate, 5-MTHF, or 5-MTHF) is transferred to homocysteine to produce methionine To do. Vitamin B12 is required for de novo synthesis of methionine because it involves a reaction catalyzed by a vitamin B12-dependent methionine synthase. Methionine is then involved in the reaction to produce S-adenosylmethionine, an important intermediate of more than 35 methyl transfer reactions in the CNS (Bottiglieri, T. et al., Drugs, 48, 137-152, 1994). See year). Responses related to the effects of folate levels on depression include the synthesis of tetrahydrobiopterin, a cofactor for the hydroxylation of phenylalanine and tryptophan, which plays a crucial role in the biosynthesis of neurotransmitters dopamine, norepinephrine and serotonin There is.

  The highly beneficial effect of the proposed composition on the neuropsychiatric condition is thought to be due to the reduction of high levels of homocysteine in the brain with 5-methyl-tetrahydrofolic acid administration. High concentrations of homocysteine have been recognized as a major risk factor for a wide range of diseases, including neurological and cerebrovascular diseases. In particular, increased plasma homocysteine levels have been associated with depression, mental retardation and severe psychomotor retardation.

  A major cause of hyperhomocysteinemia is a gene deficiency of methylenetetrahydrofolate reductase (MTHFR) or cystathionine 竅 | synthase (CS), which are important enzymes in folate metabolism. Methylenetetrahydrofolate reductase deficiency is a relatively common disorder, with approximately 15% of the general population having an abnormal MTHFR genotype. Successful treatment of hyperhomocysteinemia with folic acid and cofactors of folate metabolism (eg, vitamin B6 and vitamin B12) has been demonstrated in many studies (Bottiglieri, T., Nutrition Reviews, Volume 54 ( 12), 382-390, 1996).

  The active metabolite in the folic acid pathway is 5-methyltetrahydrofolic acid, which appears to be more effective than folic acid when administered orally. Folic acid administered to a patient must undergo several reactions including MTHFR catalyzed to produce 5-methyltetrahydrofolic acid. All of these steps can be avoided by direct introduction of 5-methyltetrahydrofolic acid. Most importantly, 5-methyltetrahydrofolic acid is the only metabolite that can cross the blood brain barrier. However, since other folic acid derivatives can be converted to 5-methyltetrahydrofolic acid, for example, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 5-methenyltetrahydrofolic acid Tetrahydrofolic acid, dihydrofolic acid and folic acid itself can be used.

  Surprisingly, it is a traditional weak antidepressant, St. John's wort that improves the resting state by regulating the action of neurotransmitters, and mental state by reducing homocysteine levels in the brain It has been found that the combined use of improving 5-methyltetrahydrofolic acid increases the beneficial effects. As a result of their synergistic effects, the symptoms of depression are removed and the metabolic state of the central nervous system is improved. This leads to a decrease in the intensity and frequency of depression attacks.

Alpert, J. et al. E. Et al., Nutrition Reviews, 55 (5), 145-149, 1997 Fava, M .; Et al., Am. J. et al. Psychiatry, 154, 426-428, 1997 Bottiglieri, T .; , Nutrition Reviews, 54 (12), 382-390, 1996

  Accordingly, an object of the present invention is to provide an orally applicable natural formulation comprising St. John's wort (Hypericum perforatum) (hypericum perforatum) or an extract or active ingredient thereof in combination with a folic acid derivative or an appropriate salt thereof.

  Accordingly, the present invention is an orally applicable natural preparation comprising St. John's wort (Hypericum perforatum) (hypericum perforatum) or an extract or active ingredient thereof in combination with a folic acid derivative or an appropriate salt thereof.

  These natural preparations are extremely useful for the prevention and treatment of depression.

  St. John's wort can be used as a whole plant, its water extract, ethanol or any other extract. It is also possible to use only one or more plant components. Hypericin, commercially available in various concentrations (eg, 0.3% Hypericin St. John's Wort, Fa. Richter, Berlin) is particularly preferred.

  As a second component, 5-methyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid and 5-methenyltetrahydrofolic acid or their appropriate salts A folic acid derivative selected from the group consisting of: Particularly preferred are 5-methyltetrahydrofolic acid or 5-formyltetrahydrofolic acid. Folic acid derivatives may also be in the form of their salts. Suitable salts such as their sodium or calcium salts are preferred.

  When 5-formyltetrahydrofolic acid is applied, the additional ingredients are vitamin B12 and betaine anhydride. Betaine is a donor of the methyl group that is transferred to homocysteine by vitamin B12.

  Useful compositions contain 400 to 5000 mcg of folic acid derivative in a serving, and in the case of 5-formyltetrahydrofolic acid, contain 50 mg to 1000 mg of betaine and 0.5 to 10 mcg of vitamin B12. The dose of St. John's wort can be adjusted over a wide range for specific cases. It is preferred to apply a commercial extract of 0.3% hypericin in an amount of 100 mg to 1000 mg.

  The preparations according to the invention can be prepared in the form of tablets, gelcaps, capsules or syrups.

  The composition of the present invention is preferably useful as a supplement, but can also be administered by drug treatment.

The present invention
a) methods for preventing neurological and psychopathological disorders,
b) a method for supporting pharmacological treatment of neurological and psychopathological disorders;
c) a method that results in a decrease in the intensity and frequency of depression attacks;
d) Natural product research without any side effects for the prevention and treatment of depression,
It is made available by oral administration of the aforementioned formulations and / or related variations of this composition and suggested variations.

  Accordingly, the present invention provides innovative formulations based on natural ingredients useful for the prevention and treatment of depression. Prevention and treatment of mild to moderate depression in which the natural compound St. John's wort, an extract or active ingredient thereof, and dihydro and tetrahydrofolic acid derivatives, derivatives or corresponding salts thereof have no side effects Constitutes a unique and safe approach to.

  The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference.

  From the above description, those skilled in the art will readily recognize the essential features of the present invention, implement various modifications and partial changes to the present invention without departing from the spirit and scope thereof, and Can be adapted.

Example 1
The low dose formulation of the present invention is obtained by mixing the following ingredients.

  Formulated in 300 mg of 0.3% Hypericin St. John's Wort (Fa. Richter, Berlin) and 400 mcg of calcium methyl 5-methyltetrahydrofolate.

Example 2
The high dose formulation is obtained by mixing 600 mg of 0.3% hypericin / St. John's wort and 800 mcg of 5-methyltetrahydrofolate calcium salt and formulating into a gel cap.

Example 3
The preparation according to the present invention is obtained by mixing 300 mg of 0.3% hypericin / St. John's wort, 400 mcg of 5-formitetrahydrofolate calcium salt, 300 mg of anhydrous betaine and 3 mcg of vitamin B12 (cyanocobalamin) and formulating it into a gel cap.

Example 4
A high dose formulation is obtained by mixing 600 mg of 0.3% hypericin / St. John's wort, 800 mcg of 5-formitetrahydrofolate calcium salt, 600 mg of anhydrous betaine and 6 mcg of vitamin B12 (cyanocobalamin) and formulating into a gel cap.

  The natural preparation according to the present invention is extremely useful for the prevention and treatment of depression.

Claims (9)

  An orally applicable natural preparation comprising St. John's wort (hypericum perforatum) or an extract or active ingredient thereof in combination with a derivative of dihydro and tetrahydrofolic acid or an appropriate salt thereof.   The formulation of claim 1 comprising Hypericin St. John's wort in the form of water or alcoholic extract.   Selected from the group consisting of 5-methyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid and 5-methenyltetrahydrofolic acid or their appropriate salts The preparation according to claim 1 or 2, comprising a derivative of folic acid.   The formulation according to claim 3, comprising 5-formyltetrahydrofolic acid or a salt thereof, further comprising vitamin B12 and betaine anhydride.   5. A formulation according to claims 1 to 4 which is a unit dosage form comprising 400 to 5000 mcg of a dihydro or tetrahydrofolate derivative.   5. A formulation according to claims 1 to 4 in unit dosage form comprising 5-formyltetrahydrofolic acid or its salt 400 to 5000 mcg, betaine anhydride 50 mg to 2000 mg and vitamin B12 0.5 to 10 mcg.   The use method of the formulation of Claim 1 including using the formulation of Claim 1 as a supplementary food.   A method for preventing neurological and psychopathological diseases, comprising orally administering the preparation according to claim 1.   A method for supporting pharmacological treatment of neurological and psychopathological diseases comprising orally administering the formulation of claim 1.