CA2348693C - Natural formulation for the treatment and prevention of depression, containing st john's wort and derivatives of dihydro- and tetrahydrofolic acid - Google Patents
Natural formulation for the treatment and prevention of depression, containing st john's wort and derivatives of dihydro- and tetrahydrofolic acid Download PDFInfo
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- A61P25/24—Antidepressants
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Abstract
The present invention relates to novel compositions containing a combination of the plant St. John's Wort (Hypericum perforatum L.), its extracts of active ingredients and derivatives of dihydro- and tetrahydrofolic acid. This natural formulation is useful for the treatment and prevention of depression with a better effect than the ingredient compounds alone.
Description
NATURAL FORMULATION FOR THE TREATMENT AND PREVENTION OF DEPRESSION, CONTAINING
ST JOHN'S
WORT AND DERIVATIVES OF DIHYDRO- AND TETRAHYDROFOLIC ACID
The present invention relates to novel compositions containing a combination of the plant St. John's Wort (Hypericum perforatum L.) and derivatives of folic acid. This natural formulation is useful for the treatment and prevention of depression with a better effect than the ingredient compounds alone.
Depression is an increasingly common psychiatric disorder, affecting a large part of the population, especially in developed countries. The etiology and precise mechanisms of depressive disorders are not completely understood, but are believed to involve the decrease of certain neutrotransmitters, par-ticularly serotonin (5-HT) and its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the central nervous system. High level of homocysteine and both folate and vitamin B12 deficiency are also linked to the etiology of depres-sion.
Modern standard pharmacological antidepression agents can be divided into several major groups: selective serotonin reuptake inhibitors, tricyclic and other heterocyclic antidepressants, monoamine oxidase (MAO) inhibitors, etc.
All of them provoke a wide range of adverse effects - from undesirable psy-chostimulation to hypertension and cardiotoxicity.
Despite some progress in this area and the availability of new antidepres-sants with fewer side effects, this direction of research has not granted a safe and efficient way to treat depression.
Therefore, there is a need for an innovative formulation based on the natural metabolites useful for the prevention and treatment of depression.
Now it has been found that the combination of natural compounds - St.
John's Wort or its extracts or active ingredients and folic acid derivatives -constitutes a unique safe multifaceted approach to the prevention and treat-ment of mild to moderate forms of depression.
St. John's Wort is a perennial flowering plant that has been traditionally used in foik medicine for thousands of years due to its anti-inflammatory, analgesic and sedative properties, particularly for wound healing and treatment of respi-ratory infections (see Miller, A.L., 1998, Altern. Med. Rev. 3,1,18-26).
ST JOHN'S
WORT AND DERIVATIVES OF DIHYDRO- AND TETRAHYDROFOLIC ACID
The present invention relates to novel compositions containing a combination of the plant St. John's Wort (Hypericum perforatum L.) and derivatives of folic acid. This natural formulation is useful for the treatment and prevention of depression with a better effect than the ingredient compounds alone.
Depression is an increasingly common psychiatric disorder, affecting a large part of the population, especially in developed countries. The etiology and precise mechanisms of depressive disorders are not completely understood, but are believed to involve the decrease of certain neutrotransmitters, par-ticularly serotonin (5-HT) and its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the central nervous system. High level of homocysteine and both folate and vitamin B12 deficiency are also linked to the etiology of depres-sion.
Modern standard pharmacological antidepression agents can be divided into several major groups: selective serotonin reuptake inhibitors, tricyclic and other heterocyclic antidepressants, monoamine oxidase (MAO) inhibitors, etc.
All of them provoke a wide range of adverse effects - from undesirable psy-chostimulation to hypertension and cardiotoxicity.
Despite some progress in this area and the availability of new antidepres-sants with fewer side effects, this direction of research has not granted a safe and efficient way to treat depression.
Therefore, there is a need for an innovative formulation based on the natural metabolites useful for the prevention and treatment of depression.
Now it has been found that the combination of natural compounds - St.
John's Wort or its extracts or active ingredients and folic acid derivatives -constitutes a unique safe multifaceted approach to the prevention and treat-ment of mild to moderate forms of depression.
St. John's Wort is a perennial flowering plant that has been traditionally used in foik medicine for thousands of years due to its anti-inflammatory, analgesic and sedative properties, particularly for wound healing and treatment of respi-ratory infections (see Miller, A.L., 1998, Altern. Med. Rev. 3,1,18-26).
Recently it attracted attention as an effective agent for the treatment of mild to moderate depression and also of the seasonal affective disorder. Other in-dications include psychovegetative dysfunctions, anxiety, nervous restless-ness and similar disorders. About 30 clinical studies confirmed that the effi-cacy of St. John's Wort (SJW) is compared to popular synthetic antidepres-sion agents (amitriptyline, imipramine, maprotiline, etc.) without any side ef-fects (see Lieberman, S., 1998, Altern. Complement. Therapies, June, 163-168). It did not lead to the impairment of attention, concentration or reaction.
The only side effect mentioned in the literature is the reversible increased photosensitivity to UV light after prolonged use of the St. John's Wort extract (see Golsch, S. et al., 1997, Hautarzt 48, 4, 249-252). No negative drug in-teraction associated with St. John's Wort is reported.
The mechanism of action of SJW is not completely defined. In its extract there could be identified eight secondary metabolites so far: amentoflavone, biapigenin, hyperforin, hypericin, hyperosid, pseudohypericin, quercetin and rutin (see Buter, B. et al., 1998, Planta Med. 64, 5, 431-437).
There are indications that hypericin, one active compound from SJW is a strong inhibitor of catechol-O-methyltransferase (see Mueller, W.E.G. et al., 1994, J. Geriatr. Psychiatr. Neurol. 7(Suppl. 1), 63-64; Mueller, W.E.G., 1995, Wissenschaftlicher Bericht, Lichtwer Pharma GmbH, Berlin) and monoamine oxidases (see Suzuki, O. et al., 1984, Planta Med. 50, 272-274). Monoamine oxidases participate in the breakdown of neurotransmitters serotonin and noradrenalin (see Perovic, S. et al., 1995, Arzn. Forsch/Drug Res. 45, 1145-2~ 1148).
Further effects include the modulation of the serotonin receptors or/and a general influence of hypericum extracts on central dopaminerge neurons (see Butterweck, V. et al., 1998, Planta Med. 64, 4, 291-294).
Other reports suggest that since pure hypericin shows no inhibiting effect on MAO (see Bladt, S. et al., 1994, J. Geriatr. Psychiatr. Neurol. 7, Suppl. 1, 59), the antidepressive effect of SJW cannot be explained in terms of MAO
inhibition. In a series of recent publications it has been demonstrated that hy-perforin, a major lipophilic non-nitrogenous constituent of SJW (and of Hy-perici Oleum), is also a potent inhibitor of uptake of serotonin, dopamine, noradrenaiine, GABA, and L-glutamate in vitro (see Chattarjee, S.S. et al., 1998, Life.Sci. 63, 6, 499-510).
Most of the known pharmacological properties of the SJW extract can also be demonstrated with pure hyperforin. Therefore it has been suggested that hy-perforin could be a major active principle of the plant (see Laakmann, G. et al., 1998, Pharmacopsychiatry 31, Suppl. 1, 54-59). Most researchers agree that the combination of low-grade monoamino oxidase inhibition and nora-drenaline and serotonin re-uptake blocade seems to be the most likely mechanism of action of SJW (see Nordfors, M. et al., 1997, Lakartidningen 94, 25, 2365-2367).
A close relationship between folate metabolism and depression is well docu-mented (see Alpert, J.E. et al., 1997, Nutrition Reviews 55, 5, 145-149). It is known that depressive symptoms are the most common indicator of folate deficiency. Depressed patients have been consistently found to have lower serum folate concentrations than control subjects (see Fava, M. et al., 1997, Am. J. Psychiatry 154, 426-428). Recently, low folate levels were linked to the poor response to selective serotonin uptake inhibitors.
The biochemical mechanisms by which folic acid derivatives affect the neuro-psychiatric status apparently involve transmethylation reactions with compo-nents (DNA, RNA, proteins, biomembranes) of the central nervous system.
The methyl group from folate (in the form of active metabolite 5-methyltetrahydrofolic acid, 5-MTHF, or 5-formyltetrahydrofolic acid, after be-ing reduced to 5-MTHF) is transferred to homocysteine to form methionine.
The de novo synthesis of methionine requires vitamin B12, since it involves a reaction catalyzed by vitamin B12-dependent methionine synthetase. Methio-nine then participates in the reaction producing S-adenosylmethionine which is an important intermediate in more than 35 transmethylation reactions in CNS (see Bottiglieri, T. et al., 1994, Drugs 48, 137-152). Among reactions relevant to the effect of folate level on depression is the synthesis of tetrahy-drobiopterin, a cofactor in the hydroxylation of phenylalanine and tryptophan playing a crucial role in the biosynthesis of the neurotransmitters dopamine, norepinephrine and serotonin.
The only side effect mentioned in the literature is the reversible increased photosensitivity to UV light after prolonged use of the St. John's Wort extract (see Golsch, S. et al., 1997, Hautarzt 48, 4, 249-252). No negative drug in-teraction associated with St. John's Wort is reported.
The mechanism of action of SJW is not completely defined. In its extract there could be identified eight secondary metabolites so far: amentoflavone, biapigenin, hyperforin, hypericin, hyperosid, pseudohypericin, quercetin and rutin (see Buter, B. et al., 1998, Planta Med. 64, 5, 431-437).
There are indications that hypericin, one active compound from SJW is a strong inhibitor of catechol-O-methyltransferase (see Mueller, W.E.G. et al., 1994, J. Geriatr. Psychiatr. Neurol. 7(Suppl. 1), 63-64; Mueller, W.E.G., 1995, Wissenschaftlicher Bericht, Lichtwer Pharma GmbH, Berlin) and monoamine oxidases (see Suzuki, O. et al., 1984, Planta Med. 50, 272-274). Monoamine oxidases participate in the breakdown of neurotransmitters serotonin and noradrenalin (see Perovic, S. et al., 1995, Arzn. Forsch/Drug Res. 45, 1145-2~ 1148).
Further effects include the modulation of the serotonin receptors or/and a general influence of hypericum extracts on central dopaminerge neurons (see Butterweck, V. et al., 1998, Planta Med. 64, 4, 291-294).
Other reports suggest that since pure hypericin shows no inhibiting effect on MAO (see Bladt, S. et al., 1994, J. Geriatr. Psychiatr. Neurol. 7, Suppl. 1, 59), the antidepressive effect of SJW cannot be explained in terms of MAO
inhibition. In a series of recent publications it has been demonstrated that hy-perforin, a major lipophilic non-nitrogenous constituent of SJW (and of Hy-perici Oleum), is also a potent inhibitor of uptake of serotonin, dopamine, noradrenaiine, GABA, and L-glutamate in vitro (see Chattarjee, S.S. et al., 1998, Life.Sci. 63, 6, 499-510).
Most of the known pharmacological properties of the SJW extract can also be demonstrated with pure hyperforin. Therefore it has been suggested that hy-perforin could be a major active principle of the plant (see Laakmann, G. et al., 1998, Pharmacopsychiatry 31, Suppl. 1, 54-59). Most researchers agree that the combination of low-grade monoamino oxidase inhibition and nora-drenaline and serotonin re-uptake blocade seems to be the most likely mechanism of action of SJW (see Nordfors, M. et al., 1997, Lakartidningen 94, 25, 2365-2367).
A close relationship between folate metabolism and depression is well docu-mented (see Alpert, J.E. et al., 1997, Nutrition Reviews 55, 5, 145-149). It is known that depressive symptoms are the most common indicator of folate deficiency. Depressed patients have been consistently found to have lower serum folate concentrations than control subjects (see Fava, M. et al., 1997, Am. J. Psychiatry 154, 426-428). Recently, low folate levels were linked to the poor response to selective serotonin uptake inhibitors.
The biochemical mechanisms by which folic acid derivatives affect the neuro-psychiatric status apparently involve transmethylation reactions with compo-nents (DNA, RNA, proteins, biomembranes) of the central nervous system.
The methyl group from folate (in the form of active metabolite 5-methyltetrahydrofolic acid, 5-MTHF, or 5-formyltetrahydrofolic acid, after be-ing reduced to 5-MTHF) is transferred to homocysteine to form methionine.
The de novo synthesis of methionine requires vitamin B12, since it involves a reaction catalyzed by vitamin B12-dependent methionine synthetase. Methio-nine then participates in the reaction producing S-adenosylmethionine which is an important intermediate in more than 35 transmethylation reactions in CNS (see Bottiglieri, T. et al., 1994, Drugs 48, 137-152). Among reactions relevant to the effect of folate level on depression is the synthesis of tetrahy-drobiopterin, a cofactor in the hydroxylation of phenylalanine and tryptophan playing a crucial role in the biosynthesis of the neurotransmitters dopamine, norepinephrine and serotonin.
The significant beneficial impact of the suggested composition on psychoneu-rological status is expected through a reduction of high levels of homocys-teine in the brain due to 5-methyl-tetrahydrofolic acid treatment. High levels of homocysteine have been recognized as a major risk factor for a wide range of diseases including neurological and cerebrovascular diseases. In particu-lar, increased plasma homocysteine level has been linked to depression, mental and severe psychomotoric retardation.
Among major causes of hyperhomocysteinemia are genetic deficiencies of methylenetetrahydrofolate reductase (MTHFR) or cystathionine f3-synthase (CS), key enzymes in the metabolism of folic acid. Methylenetetrahydrofolate reductase deficiency is a relatively common disorder, and about 15 % of the general population have abnormal MTHFR genotype. A successful treatment of hyperhomocysteinemia with folic acid and cofactors of folic acid metabo-lism (e.g. vitamin B6 and vitamin B12) has been documented in numerous studies (see Bottiglieri, T., 1996, Nutrition Reviews 54, 12, 382-390).
The active metabolite in the folic acid pathway is 5-methyltetrahydrofolic acid which, orally administered, should be more efficacious than folic acid. Folic acid given to the patients has to go through several reactions including a MTHFR catalyzed reaction to produce 5-methyltetrahydrofolic acid. All these steps can be by-passed with the direct introduction of 5-methyltetrahydrofolic acid. Of major importance is that 5-methyltetrahydrofolic acid is the only me-tabolite which is able to pass the blood-brain barrier. However, because of the possible conversion of other folic acid derivatives to 5-methyltetrahydrofolic acid, it is certainly possible to use for example 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylentetrahydrofolic acid, 5-methenyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid and folic acid itself.
Surprisingly it has been found that St. John's Wort, a traditional soft antide-pressant which improves the psychovegetative conditions by modulating the action of neurotransmitters, and 5-methyltetrahydrofolic acid which improves the psychiatric condition by a reduction of the homocysteine concentration in the brain augment their beneficial effect when used in combination. As the results of their synergistic effect, symptoms of depression are removed and also metabolic conditions of the central nervous system are improved. This leads to a decrease of intensity and frequency of attacks of depression.
Therefore, the object of the present invention is an orally applicable natural formulation comprising St. John's Wort (Hypericum perforatum) or its extracts or active ingredients in combination with folic acid derivatives or suitable salts thereof.
These natural formulations are highly useful for the prevention and the ther-apy of depression.
The St. John's Wort may be used as the whole plant, its water extract, etha-nol or any other extract. It is also possible to use just one or more of the plants ingredients. Especially preferred is the hypericin which is commercially available in different concentrations (e.g. 0.3% Hypericin St. John's Wort, Fa.
Lichtwer, Berlin).
As the second ingredient folic acid derivatives selected from the group con-sisting of 5-methyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid, 5-formyltetrahydrofolic acid, 1 0-formyltetrahydrofolic acid, 5,10-methylentetrahydrofolic acid and 5-methenyltetrahydrofolic acid or their suit-able salts are used.
5-methyltetrahydrofolic acid or 5-formyltetrahydrofolic acid are especially preferred.
The folic acid derivatives may also be in the form of their salts. Preferred are suitable salts like their sodium or calcium salts.
In the case of application of 5-formyltetrahydrofolic acid, additional ingredi-ents should be vitamin B12 and betaine anhydrous. Betaine is a donor for methyl groups which are transferred by vitamin B12 to homocysteine.
Useful compositions may contain in one serving 400 to 5 000 mcg of folic acid derivative and in case of 5-formyitetrahydrofolic acid 50 mg to 1 000 mg betaine and 0,5 to 10 mcg vitamin B12. The dose of St. John's Wort can be adjusted to the particular case in a wide range. Preferably a commercially available extract of 0.3 % Hypericin is applied in an amount of 100 mg to 1000 mg.
'26474-523 The formulations according to the present invention may be prepared in form of tabiets, gelcaps, capsules or syrups.
The compositions of the present invention preferably are useful as food sup-plements, but they may also be administered in a pharmaceutical treatment.
The present invention makes available:
a) a method of prevention of neurological and psychopathological dis-eases;
b) a method of supporting a pharmacological treatment of neuroiogical and psychopathological diseases;
c) a method leading to a decrease of intensity and frequency of attacks of depression;
d) a natural approach without any side effects for the prevention and treatment of depression;
by oral administration of a formulation described above andlor related and suggested above modifications of this composition.
Thus, this invention provides an innovative formulation based on natural in-gredients useful for the prevention and treatment of depression. The combi-nation of the natural compounds - St. John's Wort or its extracts or active in-15 gredients and derivatives of dihydro- and tetrahydrofolic acid, derivatives thereof or corresponding salts - constitutes a unique and safe approach to the prevention and treatment of mild to moderate forms of depression without any side effects.
From the foregoing description, one skilled in the art can easily ascertain the ;p essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the in-vention to adapt it to various usages and conditions.
Among major causes of hyperhomocysteinemia are genetic deficiencies of methylenetetrahydrofolate reductase (MTHFR) or cystathionine f3-synthase (CS), key enzymes in the metabolism of folic acid. Methylenetetrahydrofolate reductase deficiency is a relatively common disorder, and about 15 % of the general population have abnormal MTHFR genotype. A successful treatment of hyperhomocysteinemia with folic acid and cofactors of folic acid metabo-lism (e.g. vitamin B6 and vitamin B12) has been documented in numerous studies (see Bottiglieri, T., 1996, Nutrition Reviews 54, 12, 382-390).
The active metabolite in the folic acid pathway is 5-methyltetrahydrofolic acid which, orally administered, should be more efficacious than folic acid. Folic acid given to the patients has to go through several reactions including a MTHFR catalyzed reaction to produce 5-methyltetrahydrofolic acid. All these steps can be by-passed with the direct introduction of 5-methyltetrahydrofolic acid. Of major importance is that 5-methyltetrahydrofolic acid is the only me-tabolite which is able to pass the blood-brain barrier. However, because of the possible conversion of other folic acid derivatives to 5-methyltetrahydrofolic acid, it is certainly possible to use for example 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylentetrahydrofolic acid, 5-methenyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid and folic acid itself.
Surprisingly it has been found that St. John's Wort, a traditional soft antide-pressant which improves the psychovegetative conditions by modulating the action of neurotransmitters, and 5-methyltetrahydrofolic acid which improves the psychiatric condition by a reduction of the homocysteine concentration in the brain augment their beneficial effect when used in combination. As the results of their synergistic effect, symptoms of depression are removed and also metabolic conditions of the central nervous system are improved. This leads to a decrease of intensity and frequency of attacks of depression.
Therefore, the object of the present invention is an orally applicable natural formulation comprising St. John's Wort (Hypericum perforatum) or its extracts or active ingredients in combination with folic acid derivatives or suitable salts thereof.
These natural formulations are highly useful for the prevention and the ther-apy of depression.
The St. John's Wort may be used as the whole plant, its water extract, etha-nol or any other extract. It is also possible to use just one or more of the plants ingredients. Especially preferred is the hypericin which is commercially available in different concentrations (e.g. 0.3% Hypericin St. John's Wort, Fa.
Lichtwer, Berlin).
As the second ingredient folic acid derivatives selected from the group con-sisting of 5-methyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid, 5-formyltetrahydrofolic acid, 1 0-formyltetrahydrofolic acid, 5,10-methylentetrahydrofolic acid and 5-methenyltetrahydrofolic acid or their suit-able salts are used.
5-methyltetrahydrofolic acid or 5-formyltetrahydrofolic acid are especially preferred.
The folic acid derivatives may also be in the form of their salts. Preferred are suitable salts like their sodium or calcium salts.
In the case of application of 5-formyltetrahydrofolic acid, additional ingredi-ents should be vitamin B12 and betaine anhydrous. Betaine is a donor for methyl groups which are transferred by vitamin B12 to homocysteine.
Useful compositions may contain in one serving 400 to 5 000 mcg of folic acid derivative and in case of 5-formyitetrahydrofolic acid 50 mg to 1 000 mg betaine and 0,5 to 10 mcg vitamin B12. The dose of St. John's Wort can be adjusted to the particular case in a wide range. Preferably a commercially available extract of 0.3 % Hypericin is applied in an amount of 100 mg to 1000 mg.
'26474-523 The formulations according to the present invention may be prepared in form of tabiets, gelcaps, capsules or syrups.
The compositions of the present invention preferably are useful as food sup-plements, but they may also be administered in a pharmaceutical treatment.
The present invention makes available:
a) a method of prevention of neurological and psychopathological dis-eases;
b) a method of supporting a pharmacological treatment of neuroiogical and psychopathological diseases;
c) a method leading to a decrease of intensity and frequency of attacks of depression;
d) a natural approach without any side effects for the prevention and treatment of depression;
by oral administration of a formulation described above andlor related and suggested above modifications of this composition.
Thus, this invention provides an innovative formulation based on natural in-gredients useful for the prevention and treatment of depression. The combi-nation of the natural compounds - St. John's Wort or its extracts or active in-15 gredients and derivatives of dihydro- and tetrahydrofolic acid, derivatives thereof or corresponding salts - constitutes a unique and safe approach to the prevention and treatment of mild to moderate forms of depression without any side effects.
From the foregoing description, one skilled in the art can easily ascertain the ;p essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the in-vention to adapt it to various usages and conditions.
Examples Example 1 A lower dosed formulation according to the invention is obtained by mixing the following components:
300 mg of 0.3 % Hypericin St. John's Wort (Fa. Lichtwer, Berlin) and 400 mcg of 5-methyltetrahydrofolic acid calcium salt, formulated in gelcaps.
Example 2 A higher dosed formulation is obtained by mixing 600 mg of 0.3 % Hypericin St. John's Wort and 800 mcg of 5-methyltetrahydrofolic acid calcium salt, formulated in gelcaps.
Example 3 A formulation according to the invention is obtained by mixing 300 mg of 0,3 % Hypericin St. John's Wort, 400 mcg of 5-formyltetrahydrofolic acid calcium salt, 300 mg betaine anhydrous and 3 mcg vitamin B12 (cyanocobalamin), formulated in gelcaps.
Example 4 A higher dosed formulation is obtained by mixing 600 mg of 0,3 % Hypericin St. John's Wort, 800 mcg of 5-formyltetrahydrofolic acid calcium salt, 600 mg betaine anhydrous and 6 mcg vitamin B12 (cyanocobalamin), formulated in gelcaps.
300 mg of 0.3 % Hypericin St. John's Wort (Fa. Lichtwer, Berlin) and 400 mcg of 5-methyltetrahydrofolic acid calcium salt, formulated in gelcaps.
Example 2 A higher dosed formulation is obtained by mixing 600 mg of 0.3 % Hypericin St. John's Wort and 800 mcg of 5-methyltetrahydrofolic acid calcium salt, formulated in gelcaps.
Example 3 A formulation according to the invention is obtained by mixing 300 mg of 0,3 % Hypericin St. John's Wort, 400 mcg of 5-formyltetrahydrofolic acid calcium salt, 300 mg betaine anhydrous and 3 mcg vitamin B12 (cyanocobalamin), formulated in gelcaps.
Example 4 A higher dosed formulation is obtained by mixing 600 mg of 0,3 % Hypericin St. John's Wort, 800 mcg of 5-formyltetrahydrofolic acid calcium salt, 600 mg betaine anhydrous and 6 mcg vitamin B12 (cyanocobalamin), formulated in gelcaps.
Claims (16)
1. Orally applicable natural formulation comprising St. John's Wort (Hypericum perforatum) or its extracts or active ingredients in combination with derivatives of dihydro- and tetrahydrofolic acid or suitable salts thereof.
2. Formulation according to claim 1 comprising Hypericin St. John's Wort in form of its water or alcohol extract.
3. Formulation according to claim 1 or 2 comprising a derivative of folic acid selected from the group consisting of 5-methyltetrahydrofolic acid, tetrahydrofolic acid, dihydrofolic acid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylentetrahydrofolic acid and 5-methenyltetrahydrofolic acid or their suitable salts.
4. Formulation according to claim 3 comprising 5-formyltetrahydrofolic acid or its salts which comprises additionally vitamin B12 and betaine anhydrous.
5. Formulation according to any one of claims 1 to 4 in the form of a dosage unit, comprising 400 to 5000 mcg of dihydro- or tetrahydrofolic acid derivatives.
6. Formulation according to any one of claims 1 to 4 in the form of a dosage unit, comprising 400 to 5000 mcg of 5-formyltetrahydrofolic acid or its salts, 50 mg to 2000 mg of betaine anhydrous and 0.5 to 10 mcg of vitamin B12.
7. Use of the formulation according to any one of claims 1 to 6 as a food supplement.
8. Use of the formulation as defined in any one of claims 1 to 6 for the prevention of neurological and psychopathological diseases.
9. Use of the formulation as defined in any one of claims 1 to 6 for supporting a pharmacological treatment of neurological and psychopathological diseases.
10. Use of the formulation as defined in any one of claims 1 to 6 for treating depression.
11. Use of the formulation as defined in any one of claims 1 to 6 in the preparation of a medicament for preventing neurological and psychopathological diseases.
12. Use of the formulation as defined in any one of claims 1 to 6 in the preparation of a medicament for supporting a pharmacological treatment of neurological and psychopathological diseases.
13. Use of the formulation as defined in any one of claims 1 to 6 in the preparation of a medicament for treating depression.
14. The formulation according to any one of claims 1 to 6, which is for preventing neurological and psychopathological diseases.
15. The formulation according to any one of claims 1 to 6, which is for supporting a pharmacological treatment of neurological and psychopathological diseases.
16. The formulation according to any one of claims 1 to 6, which is for treating depression.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10471098P | 1998-10-19 | 1998-10-19 | |
| US60/104,710 | 1998-10-19 | ||
| PCT/EP1999/007556 WO2000023089A1 (en) | 1998-10-19 | 1999-10-08 | Natural formulation for the treatment and prevention of depression, containing st john's wort and derivatives of dihydro- and tetrahydrofolic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2348693A1 CA2348693A1 (en) | 2000-04-27 |
| CA2348693C true CA2348693C (en) | 2008-07-15 |
Family
ID=22301956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002348693A Expired - Fee Related CA2348693C (en) | 1998-10-19 | 1999-10-08 | Natural formulation for the treatment and prevention of depression, containing st john's wort and derivatives of dihydro- and tetrahydrofolic acid |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1121139A1 (en) |
| JP (2) | JP2002527484A (en) |
| CA (1) | CA2348693C (en) |
| WO (1) | WO2000023089A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003534373A (en) * | 2000-06-02 | 2003-11-18 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Composition for treating and / or preventing osteoporosis and / or inflammatory joint disease |
| DE10315022A1 (en) * | 2003-03-03 | 2004-09-23 | Bioplanta Arzneimittel Gmbh | Use of rutin or isorhamnetin, or plant parts or extracts containing them, to treat depression and related conditions, optionally incorporated into foods |
| UY29527A1 (en) | 2005-05-13 | 2006-12-29 | Schering Ag | PHARMACCUTIC COMPOSITION CONTAINING GESTRGENS AND / OR ESTRNGENS AND 5-METHYL - (6S) - TETRHYDROPHOLATE. |
| JP6333136B2 (en) * | 2014-09-10 | 2018-05-30 | サントリーホールディングス株式会社 | Beverages containing St. John's wort extract |
| CN105687169B (en) * | 2016-03-18 | 2018-06-12 | 西北工业大学 | Application of the hypericin as cystathionine beta-synthase inhibitor |
| WO2022040740A1 (en) * | 2020-08-25 | 2022-03-03 | State of Mind Australasia Pty Ltd | Method of treating depression and/or anxiety, and/or symptoms associated therewith |
| CN115177644A (en) * | 2021-04-07 | 2022-10-14 | 深圳芙莱特营养与健康有限公司 | Composition for relieving mood swings |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1229517B (en) * | 1989-01-31 | 1991-09-03 | Bioresearch Spa | USE OF 5-METHYLTETRAHYDROPHOLIC ACID, OF 5 FORMYLTHETRAHYDROPHOLIC ACID, AND OF THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS IN THE FORM OF CONTROLLED RELEASE SUITABLE FOR BEING EMPLOYED IN THE TREATMENT OF DISORDERS IN THE TREATMENT OF DISORDERS. |
| FR2643081B1 (en) * | 1989-02-14 | 1991-06-07 | Panmedica Sa | MAGNESIUM FOLATES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS |
| US5820867A (en) * | 1997-04-24 | 1998-10-13 | Bewicke; Calverly M. | General anti-depressant composition for dietary supplement |
| WO1999036080A1 (en) * | 1998-01-13 | 1999-07-22 | Rexall Sundown, Inc. | St. john's wort and methyl donor composition and uses thereof |
| WO1999037155A1 (en) * | 1998-01-27 | 1999-07-29 | Nutramax Laboratories, Inc. | Combinations of tyrosine, methylating agents, phospholipids, fatty acids, and st. john's wort for the treatment of mental disturbances |
-
1999
- 1999-10-08 CA CA002348693A patent/CA2348693C/en not_active Expired - Fee Related
- 1999-10-08 EP EP99950676A patent/EP1121139A1/en not_active Ceased
- 1999-10-08 WO PCT/EP1999/007556 patent/WO2000023089A1/en not_active Ceased
- 1999-10-08 JP JP2000576863A patent/JP2002527484A/en active Pending
-
2011
- 2011-02-14 JP JP2011029032A patent/JP2011132250A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002527484A (en) | 2002-08-27 |
| WO2000023089A1 (en) | 2000-04-27 |
| EP1121139A1 (en) | 2001-08-08 |
| CA2348693A1 (en) | 2000-04-27 |
| JP2011132250A (en) | 2011-07-07 |
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