WO2000056404A1 - Formulations for treatment of pain comprising vitamin b12 and phenylanine - Google Patents
Formulations for treatment of pain comprising vitamin b12 and phenylanine Download PDFInfo
- Publication number
- WO2000056404A1 WO2000056404A1 PCT/GB2000/001092 GB0001092W WO0056404A1 WO 2000056404 A1 WO2000056404 A1 WO 2000056404A1 GB 0001092 W GB0001092 W GB 0001092W WO 0056404 A1 WO0056404 A1 WO 0056404A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenylalanine
- pain
- vitamin
- formulation
- component
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/24—Antidepressants
Definitions
- Chronic long-term pain is often associated with nerve damage of one type or another.
- the nerve damage may result from a medical illness such as diabetes or alcoholism, or from damage to nerves resulting from local physical pressure or injury such as many forms of back pain and lower limb pain, or pain resulting from severance of a nerve with partial regrowth, or pain with no very obvious, cause such as fibrositis or fibromyalgia.
- opiates such as morphine, heroin, pethidine, codeine and related compounds
- the steroids which work by reducing inflammation
- the non-steroidal anti-inflammatory drugs which inhibit the enzymes cyclo-oxygenase 1, cyclo-oxygenase 2 or both
- a group of miscellaneous compounds which sometimes work in the pain associated with nerve damage (neuropathic pain) and whose most important members are the tricyclic antidepressants
- anti-migraine agents which often interact with the serotonin system
- a group of compounds which are antagonists of various peptides which are believed to be involved in the production of pain.
- vitamin B 12 and phenylalanine are unexpectedly effective when presented orally in particular ratios and when the vitamin B 12 is given in a high absolute dose and in a relatively high ratio to phenylalanine as compared to normal therapeutic doses of vitamin B 12 .
- this oral combination is effective not just in the pain of diabetic neuropathy but in all forms of chronic neuropathy, in pain associated with the spinal column, including low back pain and sciatica, in pain of unknown origin such as trige inal neuralgia, and in headaches of many different types, including tension headaches and migraines.
- this oral combination is effective not just in the pain of diabetic neuropathy but in all forms of chronic neuropathy, in pain associated with the spinal column, including low back pain and sciatica, in pain of unknown origin such as trige inal neuralgia, and in headaches of many different types, including tension headaches and migraines.
- it beneficial in chronic fatigue syndromes we have also found it beneficial in chronic fatigue syndromes.
- an orally administrable formulation containing a vitamin B 12 component and phenylalanine, in a weight ratio of 1/100 to 1/1000, and wherein the concentrations of each are such as to provide, in a daily specified dosage of the formulation, from 50.0 mg to 5000.0 mg phenylalanine and from 0.2 mg to 50.0 mg vitamin B 12 component.
- the total daily dose of the phenylalanine component may be anything from 50mg to 5000mg, but is preferably from 200mg to 2000mg.
- the phenylalanine should usually be in the L- or DL-forms.
- recent findings of racemase enzymes in humans which can interconvert D and L a ino acids mean that the D-form can also be effective.
- the total daily dose of the vitamin B 12 component may be from 0.2mg to 50mg but is preferably from 0.5mg to 5mg. These doses are much higher than oral doses normally used in treating vitamin B 12 deficiency states .
- the vitamin B 12 may be in the form of hydroxocobalamin or cyanocobalamin: however, hydroxocobalamin is the preferred form.
- hydroxocobalamin is a cyanide antagonist whereas cyanocobalamin is not. Since some forms of nerve damage may be related to cyanide accumulation either because of exposure to toxic cyanide-generating materials or to nutritional deficiency states when cyanide may accumulate, or to errors of metabolism which may lead to elevated cyanide levels, it is preferable to use hydroxocobalamin as the source of vitamin B 12 . Surprisingly, no oral pharmaceutical products containing hydroxocobalamin are presently available. All currently contain cyanocobalamin. The materials may be formulated together in any appropriate dosage form known to those skilled in the art.
- Appropriate dosage forms include tablets, hard or soft gelatin capsules, powders, micro-encapsulated products, solutions, syrups, emulsions, mousses, gels, or other oral forms known to those skilled in the art.
- the daily dose may be taken at one time, or divided, for example into two, three or four portions.
- the formulations may also contain other drugs or nutrients provided that the ratios of vitamin B 12 component to phenylalanine, and the total doses of vitamin B 12 component and phenylalanine are as claimed.
- An additional ingredient of particular value is glucosamine or glucosamine derivatives when the formulation is used to relieve the pain of arthritis.
- the vitamin B 12 and phenylalanine act rapidly to relieve the pain whereas the glucosamine helps to provide long term repair of the damaged joints.
- Folic acid is another ingredient of particular value since it acts synergistically with vitamin B 12 in several metabolic pathways. When folic acid is included, the ratio of vitamin B 12 to folic acid should be between 1:4 and 4:1. Since chronic pain is often a feature of depression, an antidepressant drug of any appropriate type may also be added to the formulation in an appropriate dose.
- L-phenylalanine is replaced by DL-phenyalanine or D-phenylalanine .
Abstract
Orally administrable formulations containing a vitamin B12 component, preferably hydroxocobalamin, and phenylalanine are described. They may be taken at a specified daily dosage to provide 50 to 5000 mg phenylalanine per day and 0.2 to 50 mg of vitamin B12 component. They are used to treat pain or chronic fatigue syndrome. Other drugs or essentiel nutrients may be added such as folic acid, glucosamine or an anti-depressant drug as appropriate.
Description
FORMULATIONS FOR TREATMENT OF PAIN COMPRISING VITAMIN B12 AND PHENYLANINE
Pain is a major human problem. It comes in many different forms, such as the pain of an acute injury or surgical procedure, the pain associated with chronic inflammation, for example of the joints, the pain of headaches, including migraine attacks, the pain associated with muscle spasms, and many types of long term, chronic, ill-defined pain. Chronic long-term pain is often associated with nerve damage of one type or another. The nerve damage may result from a medical illness such as diabetes or alcoholism, or from damage to nerves resulting from local physical pressure or injury such as many forms of back pain and lower limb pain, or pain resulting from severance of a nerve with partial regrowth, or pain with no very obvious, cause such as fibrositis or fibromyalgia.
Many types of drugs may relieve pain. Currently they fall into six major categories although, as pain mechanisms become better understood, more categories are likely to be discovered. These major categories are the opiates such as morphine, heroin, pethidine, codeine and related compounds; the steroids which work by reducing inflammation; the
non-steroidal anti-inflammatory drugs which inhibit the enzymes cyclo-oxygenase 1, cyclo-oxygenase 2 or both; a group of miscellaneous compounds which sometimes work in the pain associated with nerve damage (neuropathic pain) and whose most important members are the tricyclic antidepressants; anti-migraine agents which often interact with the serotonin system; and a group of compounds which are antagonists of various peptides which are believed to be involved in the production of pain. International publication WO 98/01157 discloses that, in the pain associated with diabetes, the antidepressant lofepramine may be particularly effective, especially when combined with the co-administration of neurotransmitter precursors such as L-phenylalanine and tryptophan and with vitamin B12. Under certain circumstances it was stated that the combination of vitamin B12 with one of the neurotransmitter precursors might be beneficial but there is no disclosure of any particular treatment regimes.
We have now surprisingly found that two of the compounds described in the previous application, vitamin B12 and phenylalanine, are unexpectedly effective when presented orally in particular ratios and when the vitamin B12 is given in a high absolute dose and in a relatively high ratio to phenylalanine as compared to normal therapeutic doses of vitamin B12. We have also found that this oral combination is effective not just in the pain of diabetic neuropathy but in all forms of chronic neuropathy, in pain associated with the spinal column, including low back pain and sciatica, in pain of unknown origin such as trige inal neuralgia, and in headaches of many different types, including tension headaches and migraines. In addition to pain we have also found it beneficial in chronic fatigue syndromes. Over 80 patients with these various types of pain have been treated with good to
excellent relief in about three quarters. The relief usually begins within 24 to 72 hours of the first dose, sometimes within 6 hours, and then may show further improvement over one to two weeks. The improvement is then maintained indefinitely. Chronic fatigue usually takes about one week to improve initially and then shows f rther improvement over several weeks or months . In contrast to all other approaches to relieving pain, administration of formulations according to the present invention does not appear to be associated with any significant adverse effects.
Thus in accordance with a first feature of the present invention there is provided an orally administrable formulation containing a vitamin B12 component and phenylalanine, in a weight ratio of 1/100 to 1/1000, and wherein the concentrations of each are such as to provide, in a daily specified dosage of the formulation, from 50.0 mg to 5000.0 mg phenylalanine and from 0.2 mg to 50.0 mg vitamin B12 component.
The total daily dose of the phenylalanine component may be anything from 50mg to 5000mg, but is preferably from 200mg to 2000mg. The phenylalanine should usually be in the L- or DL-forms. However, recent findings of racemase enzymes in humans which can interconvert D and L a ino acids mean that the D-form can also be effective. The total daily dose of the vitamin B12 component may be from 0.2mg to 50mg but is preferably from 0.5mg to 5mg. These doses are much higher than oral doses normally used in treating vitamin B12 deficiency states . The vitamin B12 may be in the form of hydroxocobalamin or cyanocobalamin: however, hydroxocobalamin is the preferred form. This is because hydroxocobalamin is a cyanide antagonist whereas cyanocobalamin is not. Since some forms of nerve damage may be related to cyanide accumulation either because of exposure to toxic cyanide-generating materials or to
nutritional deficiency states when cyanide may accumulate, or to errors of metabolism which may lead to elevated cyanide levels, it is preferable to use hydroxocobalamin as the source of vitamin B12. Surprisingly, no oral pharmaceutical products containing hydroxocobalamin are presently available. All currently contain cyanocobalamin. The materials may be formulated together in any appropriate dosage form known to those skilled in the art. Appropriate dosage forms include tablets, hard or soft gelatin capsules, powders, micro-encapsulated products, solutions, syrups, emulsions, mousses, gels, or other oral forms known to those skilled in the art. The daily dose may be taken at one time, or divided, for example into two, three or four portions.
The formulations may also contain other drugs or nutrients provided that the ratios of vitamin B12 component to phenylalanine, and the total doses of vitamin B12 component and phenylalanine are as claimed. An additional ingredient of particular value is glucosamine or glucosamine derivatives when the formulation is used to relieve the pain of arthritis. The vitamin B12 and phenylalanine act rapidly to relieve the pain whereas the glucosamine helps to provide long term repair of the damaged joints. Folic acid is another ingredient of particular value since it acts synergistically with vitamin B12 in several metabolic pathways. When folic acid is included, the ratio of vitamin B12 to folic acid should be between 1:4 and 4:1. Since chronic pain is often a feature of depression, an antidepressant drug of any appropriate type may also be added to the formulation in an appropriate dose.
EXAMPLES
1. Tablets containing 200mg L-phenylalanine with
between 2mg and 0.2mg of vitamin B12, either as cyanocobalamin or hydroxocobalamin.
2. Tablets as in 1 but containing 500mg or lOOOmg of L-phenylalanine in a ratio to the vitamin B12 component of 1/100 to 1/1000.
3-4. Formulations as in 1 and 2 but using hard or soft gelatin capsules
5. A syrup containing 500mg L-phenylalanine and between 5 and 0.5mg of vitamin B12 component in 10ml, together with appropriate flavouring.
6-10. Formulations as in 1-4 but in which the
L-phenylalanine is replaced by DL-phenyalanine or D-phenylalanine .
11-15. Formulations as in 1-4 in which in addition there is included 100-500mg of glucosamine in an appropriate form as an anti-arthritic agent.
16-20. Formulations as in 1-4 in which other essential nutrients are included, particularly folic acid in a 1:1 ratio with vitamin B12.
21-24. Formulations as in 1-4 in which an antidepressant drug of any type is added in an appropriate dose.
Claims
1. An orally administrable formulation containing a vitamin B12 component and phenylalanine, in a weight ratio of 1/100 to 1/1000, and wherein the concentrations of each are such as to provide, in a daily specified dosage of the formulation, from 50.0 mg to 5000.0 mg phenylalanine and from 0.2 mg to 50.0 mg vitamin B12 component
2. A formulation according to Claim 1 wherein the vitamin B12 component is hydroxocobalamin.
3. A formulation according to Claim 1 wherein the phenylalanine is L-phenylalanine.
4. A formulation according to Claims 1, 2 or 3 wherein the phenylalanine is DL-phenylalanine, or D- phenylalanine .
5. A formulation according to any one of Claims 1 to 4 wherein the daily specified dosage of the formulation contains 200.0 mg to 2000.0 mg phenylalanine.
6. A formulation according to any one of Claims 1 to 5 wherein the daily specified dosage of the formulation contains 0.5 mg to 5.0 mg of the vitamin B12 component.
7. A formulation according to any one of the preceding Claims and additionally containing one or more essential nutrients or drugs.
8. A formulation according to any one of the preceding Claims and additionally containing glucosamine or one or more glucosamine derivatives.
9. A formulation according to any one of the preceding Claims and additionally containing folic acid or related bioactive derivative.
10. A formulation according to any one of the preceding Claims and additionally containing an anti-depressant drug.
11. A method of treatment of pain or chronic fatigue syndrome which comprises the oral administration of a formulation in accordance of any one of the preceding Claims_
12. A method according to Claim 11 wherein the pain is diabetic pain due to peripheral nerve damage.
13. A method according to Claim 11 wherein the pain is a chest, abdominal, limb, pelvic, back or other pain originating from the spinal column.
14. A method according to Claim 11 wherein the pain is a headache or migraine headache.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU33129/00A AU3312900A (en) | 1999-03-24 | 2000-03-23 | Formulations for treatment of pain comprising vitamin b12 and phenylanine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9906808.2 | 1999-03-24 | ||
GBGB9906808.2A GB9906808D0 (en) | 1999-03-24 | 1999-03-24 | Formulation for treatment of pain |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000056404A1 true WO2000056404A1 (en) | 2000-09-28 |
WO2000056404B1 WO2000056404B1 (en) | 2000-12-21 |
Family
ID=10850289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2000/001092 WO2000056404A1 (en) | 1999-03-24 | 2000-03-23 | Formulations for treatment of pain comprising vitamin b12 and phenylanine |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU3312900A (en) |
GB (1) | GB9906808D0 (en) |
WO (1) | WO2000056404A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7232805B2 (en) | 2003-09-10 | 2007-06-19 | Inflabloc Pharmaceuticals, Inc. | Cobalamin conjugates for anti-tumor therapy |
WO2008120766A1 (en) * | 2007-03-30 | 2008-10-09 | Kobayashi Pharmaceutical Co., Ltd. | Analgesic composition |
WO2008120765A1 (en) * | 2007-03-30 | 2008-10-09 | Kobayashi Pharmaceutical Co., Ltd. | Analgesic composition |
EP2561879A1 (en) * | 2011-08-23 | 2013-02-27 | Protea Biopharma N.V. | Macrophage activating factor for use in the treatment of chronic fatigue syndrome (CFS) and CFS-related diseases and disorders |
JP2020172548A (en) * | 2020-07-28 | 2020-10-22 | 株式会社東洋新薬 | Joint function improvement agent |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4331145A (en) * | 1981-01-28 | 1982-05-25 | Arthur Winter | Multiple sclerosis treatment |
GB2286528A (en) * | 1994-02-17 | 1995-08-23 | Robert John Woodward | Dietary supplement |
WO1996011009A1 (en) * | 1994-10-05 | 1996-04-18 | Cari Loder | Treatment of multiple sclerosis (ms) and other demyelinating conditions using lofepramine in combination with l-phenylalanine, tyrosine or tryptophan and possibly a vitamin b12 compound |
WO1998001157A1 (en) * | 1996-07-05 | 1998-01-15 | The Wwk Trust | Compositions for the treatment of peripheral neuropathies containing antidepressants and/or monoamine oxidase inhibitors and/or vitamin b12 and/or precursors or inducers of a neurotransmitter |
WO1998008520A1 (en) * | 1996-08-29 | 1998-03-05 | Worsley, Andrew, Peter | Treatment of pain |
EP0835660A1 (en) * | 1996-10-14 | 1998-04-15 | Gaston Edmond Filomena Merckx | Products containing methylcobalamin for the treatment of multiple sclerosis or other demyelinating conditions |
DE19720818A1 (en) * | 1996-11-15 | 1998-05-20 | Sportmedizin Team Muenchen Arz | Composition enhancing sports performance |
-
1999
- 1999-03-24 GB GBGB9906808.2A patent/GB9906808D0/en active Pending
-
2000
- 2000-03-23 AU AU33129/00A patent/AU3312900A/en not_active Withdrawn
- 2000-03-23 WO PCT/GB2000/001092 patent/WO2000056404A1/en not_active Application Discontinuation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4331145A (en) * | 1981-01-28 | 1982-05-25 | Arthur Winter | Multiple sclerosis treatment |
GB2286528A (en) * | 1994-02-17 | 1995-08-23 | Robert John Woodward | Dietary supplement |
WO1996011009A1 (en) * | 1994-10-05 | 1996-04-18 | Cari Loder | Treatment of multiple sclerosis (ms) and other demyelinating conditions using lofepramine in combination with l-phenylalanine, tyrosine or tryptophan and possibly a vitamin b12 compound |
WO1998001157A1 (en) * | 1996-07-05 | 1998-01-15 | The Wwk Trust | Compositions for the treatment of peripheral neuropathies containing antidepressants and/or monoamine oxidase inhibitors and/or vitamin b12 and/or precursors or inducers of a neurotransmitter |
WO1998008520A1 (en) * | 1996-08-29 | 1998-03-05 | Worsley, Andrew, Peter | Treatment of pain |
EP0835660A1 (en) * | 1996-10-14 | 1998-04-15 | Gaston Edmond Filomena Merckx | Products containing methylcobalamin for the treatment of multiple sclerosis or other demyelinating conditions |
DE19720818A1 (en) * | 1996-11-15 | 1998-05-20 | Sportmedizin Team Muenchen Arz | Composition enhancing sports performance |
Non-Patent Citations (3)
Title |
---|
SIMON K H: "ZUR BEHANDLUNG THERAPIERESISTENTER SCHMERZZUSTAENDE MIT HYDROXOCOBALAMIN", MEDIZINISCHE MONATSSCHRIFT,DE,WISSENSCHAFTLICHE VERLAGSGESELLSCHAFT MBH,, vol. 28, no. 10, 1 October 1974 (1974-10-01), pages 466 - 468, XP002047638, ISSN: 0025-8474 * |
WORSLEY A P ET AL: "COMBINED TREATMENT FOR SEVERE DIABETIC NEUROPATHY SYMPTOMS", DIABETIC MEDICINE,GB,JOHN WILEY & SONS, LTD, vol. 15, no. 8, 1998, pages 797 - 798, XP000886764, ISSN: 0742-3071 * |
YARYURA: "Phenylethylamine and Glucose in True Depression", JOURNAL OF ORTHOMOLECULAR PSYCHIATRY, vol. 5, no. 3, 1976, pages 199-202, XP000925212 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7232805B2 (en) | 2003-09-10 | 2007-06-19 | Inflabloc Pharmaceuticals, Inc. | Cobalamin conjugates for anti-tumor therapy |
WO2008120766A1 (en) * | 2007-03-30 | 2008-10-09 | Kobayashi Pharmaceutical Co., Ltd. | Analgesic composition |
WO2008120765A1 (en) * | 2007-03-30 | 2008-10-09 | Kobayashi Pharmaceutical Co., Ltd. | Analgesic composition |
JP2008247823A (en) * | 2007-03-30 | 2008-10-16 | Kobayashi Pharmaceut Co Ltd | Analgesic composition |
JP2008247822A (en) * | 2007-03-30 | 2008-10-16 | Kobayashi Pharmaceut Co Ltd | Analgesic composition |
EP2561879A1 (en) * | 2011-08-23 | 2013-02-27 | Protea Biopharma N.V. | Macrophage activating factor for use in the treatment of chronic fatigue syndrome (CFS) and CFS-related diseases and disorders |
JP2020172548A (en) * | 2020-07-28 | 2020-10-22 | 株式会社東洋新薬 | Joint function improvement agent |
Also Published As
Publication number | Publication date |
---|---|
AU3312900A (en) | 2000-10-09 |
GB9906808D0 (en) | 1999-05-19 |
WO2000056404B1 (en) | 2000-12-21 |
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