WO2005000340A1 - Synergistic compositions comprising erythropoietin and succinic acid (salt) - Google Patents
Synergistic compositions comprising erythropoietin and succinic acid (salt) Download PDFInfo
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- WO2005000340A1 WO2005000340A1 PCT/RU2003/000281 RU0300281W WO2005000340A1 WO 2005000340 A1 WO2005000340 A1 WO 2005000340A1 RU 0300281 W RU0300281 W RU 0300281W WO 2005000340 A1 WO2005000340 A1 WO 2005000340A1
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- erythropoietin
- succinic acid
- mammal
- composition
- pharmaceutically acceptable
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
Definitions
- This invention relates to the compositions and methods for achieving a synergistic therapeutic effect in a mammal comprising co-administering erythropoietin and succinic acid or salts thereof.
- the combination is particularly suitable for treating patients suffering from anemia.
- Erythropoietin is a hormone essential for stimulation erythropoiesis in mammals. Erythropoietin is produced by fetal liver and adult kidney and released into the bloodstream in response to hypoxia. It binds to the erythropoetin receptor on the cell surface of erythroid progenitor cells and stimulates the proliferation and differentiation., of red blood cell precursors in the bone marrow and prolongs their survival by inhibiting apoptosis. This activity increases the blood hemoglobin concentration, correcting anemia.
- erythropoietin and erythropoietin analogs has been successfully used to treat anemia in many different conditions including chronic renal failure, cancer, HIV, rheumatoid arthritis, myelodysplasia, hemoglobinopathies, pregnancy, as well as the anemia of premature infants.
- erythropoietin manifests neurotrophic and neuroprotective function in different conditions of neuronal damage, such as hypoxia, cerebral ischemia, and subarachnoid hemorrhage, and, thus, could soon be used in clinical practice to limit neuronal damage induced by these diseases.
- Succinic acid is a mammalian metabolite playing the role in energy metabolism and heme biosynthesis.
- the present invention shows for the first time that co-administering of erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof is synergistically effective in achieving a therapeutic effect in mammals.
- the combination is particularly suitable for treating mammals suffering from anemia. It is an object of the present invention to provide methods and compositions for achieving a synergistic therapeutic effect in a mammal through co-administration of erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof.
- the present invention provides a composition for achieving a synergistic therapeutic effect in a mammal, comprising an amount of erythropoietin, an amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Further, the present invention provides a method for achieving a synergistic therapeutic effect in a mammal, comprising co-administering to a mammal in need thereof an amount of erythropoietin and an amount of succinic acid or a pharmaceutically acceptable salt thereof.
- Preferred therapeutic effects achieved according to this invention are stimulation of erythropoiesis, increasing hematocrit and blood hemoglobin levels.
- compositions and methods of the invention means that the therapeutic effect achieved with the compositions and methods of the invention is greater than the sum of the effects that result from compositions comprising erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof separately and in the amounts employed in the compositions and methods hereof. Accordingly to this invention, it is now possible to achieve a synergistic therapeutic effect in a mammal with amounts of erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof which, if administered in said amounts singly, are not capable of achieving said effect and which effect is greater than the sum of the effects achieved with erythropoietin and succmic acid or a pharmaceutically acceptable salt thereof administered separately.
- compositions hereof can comprise erythropoietin in amounts, which are less that those required for compositions containing erythropoietin without succinic acid or a pharmaceutically acceptable salt thereof. Therefore, in practicing this invention, it is possible to minimize potential adverse effects, which may be associated with larger, therapeutic doses of the erythropoietin and still achieve the therapeutic effect.
- erythropoietin as used herein means the naturally occurring human erythropoietin, recombinant human erythropoietin, or synthetic erythropoietin analogs which stimulate erythropoiesis by the same mechanism as natural erythropoietin.
- the present invention is not limited in any way to specific erythropoietin but is applicable to all such erythropoietin or erythropoietin analogs now known or subsequently discovered or developed. Nonetheless, a preferred erythropoietin for use in the methods and compositions of this invention is human recombinant erythropoietin.
- co-administering means that erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof can be administered together as a composition if the route of administration for each component is the same and the individual components can be administered separately but as part of the same therapeutic treatment program or regimen, and it is contemplated that separate administration of each compound, at different times and by different routes, will sometimes be recommended. Thus, the two compounds need not necessarily be administered at essentially the same time.
- the individual components are administered together as a composition.
- the pharmaceutically acceptable salt of succinic acid is prepared by known methods from organic and inorganic bases.
- Such bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, magnesium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, and triethanolamine base.
- the salt of succinic acid for use in the compositions and methods of the invention is monosodium succinate.
- the amount of erythropoietin to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein. Typically, erythropoietin will be present in methods and compositions of the invention in amounts within its normal or less dosage unit and daily regimen ranges as detailed in medical literature.
- the amount of erythropoietin for use in the compositions and methods of the invention is from 10 to 250 U/kg of erythropoietin per day.
- Succinic acid or a pharmaceutically acceptable salt thereof will be present in methods and compositions of the invention in amounts sufficient to achieve the desired therapeutic effect.
- the amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the compositions and methods of the invention is from 0.1 to 250 mg per day per kg of body weight of the mammal.
- erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof can be administered in a variety of routes such as subcutaneous, intravenous, or intramuscular injections; or oromucosally through buccal or sublingual mucosa.
- routes such as subcutaneous, intravenous, or intramuscular injections; or oromucosally through buccal or sublingual mucosa.
- Preferred route according to this invention is oromucosal route of administration.
- Compositions of the invention can be administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous solutions, elixirs, syrups and the like.
- suitable carriers and diluents include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystaUine cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl- and propylhydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil.
- the compositions of the invention can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
- the example shows that co-administration of erythropoietin and succinic acid results in synergistic stimulation of erythropoiesis in female mice.
- Recombinant human erythropoietin was from Institute of Highly Pure Biopreparation, St. Russia.
- Treatment C57B1 female mice 4 weeks aged and 17-20 g weight were treated for 3 days oromucosally with 100 U/kg erythropoietin (Epo), 2.5 mg kg succinic acid (SA), combination 100 U/kg Epo plus 2.5 mg/kg SA, or saline (control).
- the effect of the treatments on erythropoiesis was determined as elevation of blood hemoglobin and hematocrit levels at day 4 in comparison with the control.
- the therapeutic effect achieved with the combination of amounts Epo and SA is 7.1 g/dl increase in hemoglobin level from the control.
- EXAMPLE 2 The example shows that co-administration of erythropoietin and succinic acid results in synergistic enhancement of erythropoiesis in male mice.
- C57B1 male mice of 6 weeks aged and 20-25 g weight were treated for 3 days oromucosally with 100 U/kg Epo, 2.5 mg/kg succinic acid (SA), combination 100 U/kg Epo plus 2.5 mg/kg succinic acid, or saline (control).
- SA succinic acid
- control saline
- the co-administration of erythropoietin and succinic acid is synergistically effective for increasing hemoglobin and hematocrit levels in male mice.
- the therapeutic effects achieved with the combination of amounts Epo and SA at days 6, 10, and 15 and calculated by the method described in the example 1 is greater than the sum of effects of amounts Epo and SA administered individually.
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- Life Sciences & Earth Sciences (AREA)
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- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
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Abstract
The invention relates to the compositions and methods for achieving a synergistic therapeutic effect in a mammal comprising co-administering erythropoietin and succinic acid or salts thereof. The combination is particularly suitable for stimulation of erythropoiesis, increasing blood hematocrit and hemoglobin levels in mammal in need thereof. The oromucosal route (i.e. sublingual or buccal) is particularly suitable for administration of the combination.
Description
SYNERGISTIC COMPOSITIONS COMPRISING ERYTHROPOIETIN AND SUCCINIC ACID (SALT)
FIELD OF THE INVENTION This invention relates to the compositions and methods for achieving a synergistic therapeutic effect in a mammal comprising co-administering erythropoietin and succinic acid or salts thereof. The combination is particularly suitable for treating patients suffering from anemia.
BACKGROUND OF THE INVENTION Erythropoietin (Epo) is a hormone essential for stimulation erythropoiesis in mammals. Erythropoietin is produced by fetal liver and adult kidney and released into the bloodstream in response to hypoxia. It binds to the erythropoetin receptor on the cell surface of erythroid progenitor cells and stimulates the proliferation and differentiation., of red blood cell precursors in the bone marrow and prolongs their survival by inhibiting apoptosis. This activity increases the blood hemoglobin concentration, correcting anemia. Human recombinant erythropoietin and erythropoietin analogs has been successfully used to treat anemia in many different conditions including chronic renal failure, cancer, HIV, rheumatoid arthritis, myelodysplasia, hemoglobinopathies, pregnancy, as well as the anemia of premature infants. Besides of stimulation of erythropoiesis, erythropoietin manifests neurotrophic and neuroprotective function in different conditions of neuronal damage, such as hypoxia, cerebral ischemia, and subarachnoid hemorrhage, and, thus, could soon be used in clinical practice to limit neuronal damage induced by these diseases. Succinic acid is a mammalian metabolite playing the role in energy metabolism and heme biosynthesis. The present invention shows for the first time that co-administering of erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof is synergistically effective in achieving a therapeutic effect in mammals. The combination is particularly suitable for treating mammals suffering from anemia.
It is an object of the present invention to provide methods and compositions for achieving a synergistic therapeutic effect in a mammal through co-administration of erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a composition for achieving a synergistic therapeutic effect in a mammal, comprising an amount of erythropoietin, an amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Further, the present invention provides a method for achieving a synergistic therapeutic effect in a mammal, comprising co-administering to a mammal in need thereof an amount of erythropoietin and an amount of succinic acid or a pharmaceutically acceptable salt thereof. Preferred therapeutic effects achieved according to this invention are stimulation of erythropoiesis, increasing hematocrit and blood hemoglobin levels. The term "synergistic" as used herein means that the therapeutic effect achieved with the compositions and methods of the invention is greater than the sum of the effects that result from compositions comprising erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof separately and in the amounts employed in the compositions and methods hereof. Accordingly to this invention, it is now possible to achieve a synergistic therapeutic effect in a mammal with amounts of erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof which, if administered in said amounts singly, are not capable of achieving said effect and which effect is greater than the sum of the effects achieved with erythropoietin and succmic acid or a pharmaceutically acceptable salt thereof administered separately. Because of synergistic therapeutic effect, a particular advantage of the present invention is that the compositions hereof can comprise erythropoietin in amounts, which are less that those required for compositions containing erythropoietin without succinic acid or a pharmaceutically acceptable salt thereof. Therefore, in practicing this invention, it is possible to minimize potential adverse effects, which may be associated
with larger, therapeutic doses of the erythropoietin and still achieve the therapeutic effect. The term "erythropoietin" as used herein means the naturally occurring human erythropoietin, recombinant human erythropoietin, or synthetic erythropoietin analogs which stimulate erythropoiesis by the same mechanism as natural erythropoietin. The present invention is not limited in any way to specific erythropoietin but is applicable to all such erythropoietin or erythropoietin analogs now known or subsequently discovered or developed. Nonetheless, a preferred erythropoietin for use in the methods and compositions of this invention is human recombinant erythropoietin. The term " co-administering" as used herein means that erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof can be administered together as a composition if the route of administration for each component is the same and the individual components can be administered separately but as part of the same therapeutic treatment program or regimen, and it is contemplated that separate administration of each compound, at different times and by different routes, will sometimes be recommended. Thus, the two compounds need not necessarily be administered at essentially the same time. Preferably, the individual components are administered together as a composition. The pharmaceutically acceptable salt of succinic acid is prepared by known methods from organic and inorganic bases. Such bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, magnesium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, and triethanolamine base. Preferably, the salt of succinic acid for use in the compositions and methods of the invention is monosodium succinate. The amount of erythropoietin to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein. Typically, erythropoietin will be present in methods and compositions of the invention in amounts within its normal or less dosage unit and daily regimen ranges as detailed in medical literature. Preferably, the amount of erythropoietin for use in the compositions and methods of the invention is from 10 to 250 U/kg of erythropoietin per day.
Succinic acid or a pharmaceutically acceptable salt thereof will be present in methods and compositions of the invention in amounts sufficient to achieve the desired therapeutic effect. The amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the compositions and methods of the invention is from 0.1 to 250 mg per day per kg of body weight of the mammal. h practicing the compositions and methods of this invention, erythropoietin and succinic acid or a pharmaceutically acceptable salt thereof can be administered in a variety of routes such as subcutaneous, intravenous, or intramuscular injections; or oromucosally through buccal or sublingual mucosa. Preferred route according to this invention is oromucosal route of administration. Compositions of the invention can be administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous solutions, elixirs, syrups and the like. Some examples of suitable carriers and diluents include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystaUine cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl- and propylhydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil. The compositions of the invention can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
EXAMPLE 1.
The example shows that co-administration of erythropoietin and succinic acid results in synergistic stimulation of erythropoiesis in female mice.
Materials. Recombinant human erythropoietin (Epo) was from Institute of Highly Pure Biopreparation, St. Petersburg, Russia.
Treatment. C57B1 female mice 4 weeks aged and 17-20 g weight were treated for 3 days oromucosally with 100 U/kg erythropoietin (Epo), 2.5 mg kg succinic acid (SA), combination 100 U/kg Epo plus 2.5 mg/kg SA, or saline (control). The effect of the treatments on erythropoiesis was determined as elevation of blood hemoglobin and hematocrit levels at day 4 in comparison with the control. Δ Hemoglobin is difference between means of hemoglobin levels in treated and control mice calculated by equiation: Δ Hemoglobin = 15.5 - mean (g/dl). Δ Hematocrit is difference between means of hematocrit levels in treated and control mice calculated by equiation: Δ Hematocrit = 34 - mean (%). Data are presented in Table 1 and 2 as mean ±SD (n=5).
Table 1. Hemoglobin levels in female mice at day 4 from treatment beginning.
The therapeutic effect achieved with the combination of amounts Epo and SA is 7.1 g/dl increase in hemoglobin level from the control. The sum of effects of amounts Epo and SA administered individually is 4.6 (3.7+0.9=4.6) g/dl increases in hemoglobin level from the control. Since the therapeutic effect of the combination is greater than the sum of effects of Epo and SA administered individually, the combination is synergistically effective for increasing hemoglobin levels.
Table 2. Hematocrit levels in female mice at day 4 from treatment beginning.
EXAMPLE 2. The example shows that co-administration of erythropoietin and succinic acid results in synergistic enhancement of erythropoiesis in male mice.
Treatment. C57B1 male mice of 6 weeks aged and 20-25 g weight were treated for 3 days oromucosally with 100 U/kg Epo, 2.5 mg/kg succinic acid (SA), combination 100 U/kg Epo plus 2.5 mg/kg succinic acid, or saline (control). The effect of the treatments on erythropoiesis was determined as elevation of hemoglobin and hematocrit levels at days 6, 10, and 15 from the treatment beginning in comparison with the control. Data are presented in Table 3 and 4 as mean ±SD (n=5). Table 3. Hemoglobin levels in male mice.
*Differs significantly of control (pO.Ol). epoDiffers significantly of Epo (pO.Ol).
Table 4. Hematocrit levels in male mice.
*Differs significantly of control (pO.Ol). epoDiffers significantly of Epo (p<0.05).
The co-administration of erythropoietin and succinic acid is synergistically effective for increasing hemoglobin and hematocrit levels in male mice. The therapeutic effects achieved with the combination of amounts Epo and SA at days 6, 10, and 15 and calculated by the method described in the example 1 is greater than the sum of effects of amounts Epo and SA administered individually.
Claims
1. A composition for achieving a synergistic therapeutic effect in a mammal, comprising amounts of: (a) erythropoietin, (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone are each insufficient to achieve the effect, and wherein the effect of a composition comprising said amounts of (a) and (b) is greater than the sum of the therapeutic effects achievable with the individual amounts of (a) and (b); and (c) a pharmaceutically acceptable diluent or carrier.
2. The composition as claimed in Claim 1 wherein the effect comprises stimulation of erythropoiesis.
3. The composition as claimed in Claim 1 wherein the effect comprises increasing blood hemoglobin level.
4. The composition as claimed in Claim 1 wherein the effect comprises increasing blood hematocrit level.
5. The composition as claimed in Claim 1 wherein the amount of erythropoietin is 10 to 250 U per day per kilogram of body weight of the mammal.
6. The composition as claimed in Claim 1 wherein the amount of succinic acid or a pharmaceutically acceptable salt thereof is 0.1 to 250 mg per day per kilogram of body weight of the mammal.
7. The composition as claimed in Claim 1 wherein the composition is administered oromucosally.
8. A method for achieving a synergistic therapeutic effect in a mammal, comprising co- administering to a mammal in need thereof amounts of: (a) erythropoietin, and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect, and wherein the combined effect of the amounts of (a) and (b) is greater than the sum of the therapeutic effects achievable with the individual amounts of (a) and (b).
9. The method as claimed in Claim 8 wherein the effect comprises stimulation of erythropoiesis.
10. The method as claimed in Claim 8 wherein the effect comprises increasing blood hemoglobin level.
11. The method as claimed in Claim 8 wherein the effect comprises increasing blood hematocrit level.
12. The method as claimed in Claim 8 wherein the amount of erythropoietin is 10 to 250 U per day per kilogram of body weight of the mammal.
13. The method as claimed in Claim 8 wherein the amount of succinic acid or a pharmaceutically acceptable salt thereof is 0.1 to 250 mg per day per kilogram of body weight of the mammal.
14. The method as claimed in Claim 8 wherein erythropoietin is administered oromucosally.
15. The method as claimed in Claim 8 wherein succinic acid or a pharmaceutically acceptable salt thereof is administered oromucosally.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003291796A AU2003291796A1 (en) | 2003-06-27 | 2003-06-27 | Synergistic compositions comprising erythropoietin and succinic acid (salt) |
| PCT/RU2003/000281 WO2005000340A1 (en) | 2003-06-27 | 2003-06-27 | Synergistic compositions comprising erythropoietin and succinic acid (salt) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2003/000281 WO2005000340A1 (en) | 2003-06-27 | 2003-06-27 | Synergistic compositions comprising erythropoietin and succinic acid (salt) |
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| Publication Number | Publication Date |
|---|---|
| WO2005000340A1 true WO2005000340A1 (en) | 2005-01-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU2003/000281 WO2005000340A1 (en) | 2003-06-27 | 2003-06-27 | Synergistic compositions comprising erythropoietin and succinic acid (salt) |
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| AU (1) | AU2003291796A1 (en) |
| WO (1) | WO2005000340A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009025571A1 (en) * | 2007-08-15 | 2009-02-26 | Buddha Biopharma Oy Ltd | Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5661125A (en) * | 1992-08-06 | 1997-08-26 | Amgen, Inc. | Stable and preserved erythropoietin compositions |
| US20020094948A1 (en) * | 1997-03-18 | 2002-07-18 | Paul Lehmann | Method for treating disturbances in iron metabolism using a combination of erythropoietin and iron |
-
2003
- 2003-06-27 WO PCT/RU2003/000281 patent/WO2005000340A1/en active Application Filing
- 2003-06-27 AU AU2003291796A patent/AU2003291796A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5661125A (en) * | 1992-08-06 | 1997-08-26 | Amgen, Inc. | Stable and preserved erythropoietin compositions |
| US20020094948A1 (en) * | 1997-03-18 | 2002-07-18 | Paul Lehmann | Method for treating disturbances in iron metabolism using a combination of erythropoietin and iron |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009025571A1 (en) * | 2007-08-15 | 2009-02-26 | Buddha Biopharma Oy Ltd | Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease |
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| Publication number | Publication date |
|---|---|
| AU2003291796A1 (en) | 2005-01-13 |
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