WO2009031876A1 - Uso del aspartato de adenosina para la preparación de productos farmacéuticos para el tratamiento del cáncer hepático - Google Patents
Uso del aspartato de adenosina para la preparación de productos farmacéuticos para el tratamiento del cáncer hepático Download PDFInfo
- Publication number
- WO2009031876A1 WO2009031876A1 PCT/MX2008/000111 MX2008000111W WO2009031876A1 WO 2009031876 A1 WO2009031876 A1 WO 2009031876A1 MX 2008000111 W MX2008000111 W MX 2008000111W WO 2009031876 A1 WO2009031876 A1 WO 2009031876A1
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- WO
- WIPO (PCT)
- Prior art keywords
- adenosine
- cancer
- administered
- aspartate
- liver
- Prior art date
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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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to the use of pharmaceutical products to support the therapy against neoplastic diseases, more specifically it relates to a novel use of adenosine salts, such as aspartate and prolinate, to prepare medicaments to assist cancer therapy. and more specifically to a pharmaceutical formulation for use alone or in combination with the therapy used against cancer.
- adenosine salts such as aspartate and prolinate
- BACKGROUND The effect of adenosine aspartate to restore the proliferative capacity of liver tissue is well known, stopping the fibrogenesis that occurs in liver disorders that end in liver cirrhosis, regardless of the etiologic agent.
- the administration of adenosine in its aspartate salt form has yielded beneficial results in the control of liver cirrhosis, Mexican Patent 207422, by reducing collagen accumulation, notably improving the histological picture of the cryogenic process, an effect that is accompanied by an improvement in liver function tests and liver energy parameters.
- adenosine aspartate increases energy metabolism at the expense of mitochondrial metabolism by restoring the normal energy state diminished by toxic agents that damage hepatocytes thereby protecting the mitochondrial function and structure. Also its antioxidant effect prevents the spread of free radicals and the damage caused to proteins and DNA by hepatotoxic agents. On the other hand, it normalizes the regenerative response of the cirrhotic liver measured by the activity of thymidine kinase and by the mitotic index.
- the extracellular matrix is remodeled by modifying the effect of adhesion proteins such as integrins and adhesins and induces apoptosis of transformed cells, effects that could prevent the development of cancer and liver metastases.
- adhesion proteins such as integrins and adhesins
- the effect of a synthetic adenosine A3 receptor agonist has been demonstrated, which inhibits the carcinogenic growth of colon, melanoma, prostate, as well as liver and lung metastases demonstrating anticarcinogenic and chemoprotective effect.
- a synthetic adenosine A3 receptor agonist has been demonstrated, which inhibits the carcinogenic growth of colon, melanoma, prostate, as well as liver and lung metastases demonstrating anticarcinogenic and chemoprotective effect.
- adenosine salts in particular adenosine aspartate
- Hepatocellular carcinoma is responsible for 80 to 90% of all types of liver cancer. Its incidence is higher in men than in women and mostly attacks people between 50 and 60 years of age.
- Cirrhosis can be caused by viral hepatitis, especially hepatitis B and C, excessive consumption of alcohol, certain autoimmune diseases of the liver, hemochromatosis and countless other pathologies
- liver cancer such as the measurement of ⁇ -glutamyltranspeptidase levels called GGT. This test is used to detect diseases of the liver, bile ducts and kidneys; and also to differentiate disorders of the liver or bile ducts from bone disease.
- GGT ⁇ -glutamyltranspeptidase
- the GGT participates in the transfer of amino acids through the cell membrane and also in the metabolism of glutathione, and this enzyme is found in high concentrations in the liver, in the bile ducts and in the kidney.
- GGT is measured in combination with other tests.
- alkaline phosphatase is elevated in hepatobiliary and bone diseases and GGT is elevated in hepatobiliary diseases, but not in bone disease; hence, a patient with a high alkaline phosphatase level and a normal GGT level probably has bone disease and no hepatobiliary disease.
- the normal values of this marker are in the range of 0 to 51 Ul / L, and levels above normal may indicate congestive heart failure, cholestasis, cirrhosis, ischemia and liver necrosis, liver tumor and hepatitis.
- the present one developed invention using adenosine aspartate to formulate a medicament to prevent the development of cancer, mainly liver cancer due to its high relationship with cirrhosis. Also when pre-cancerous lesions have been established use adenosine aspartate to reverse the process.
- the present invention relates to the use of pharmaceutically acceptable adenosine salts to prepare medicaments to support therapy against neoplastic diseases, more specifically as an adjunct to cancer therapy and more specifically to prepare a medicament for administration alone or in combination with Ia therapy used against cancer in different mammalian tissues, preferably in human tissues.
- a particular feature of the invention is the use of adenosine salts as aspartate, without this being limiting to other salts of adenosine, to prepare medicaments to prevent and treat neoplastic diseases, or as an adjuvant, to colon cancer therapy, melanoma, prostate, liver lung metastases, without this being limiting to other types of tumors that respond to the adenosine A3 receptor block.
- the physiologically acceptable adenosine salts for preparing drugs that are used to prevent, treat cancer treatment are administered by any appropriate route of administration, for which the pharmaceutical composition is formulated in the appropriate pharmaceutical form to the chosen route of administration.
- a preferred embodiment is the administration of the medicament orally or any other regulated or sustained release route.
- compositions that include adenosine salts are those known to those skilled in the art and commonly used in the preparation of medicaments.
- the present invention demonstrates the beneficial effect of using adenosine aspartate on neoplastic lesions by performing various experiments that allowed evaluating its protective effect against preneoplastic lesions in the liver of the rat and reversal when the tumor had already developed, using the model of the resistant hepatocyte.
- preneoplastic lesions in the liver was induced, using the resistant hepatocyte model (Semple-Roberts E, Hayes MA, Armstrong D, Becker RA, Racz WJ and Farber E. (1987) Alternative methods of selecting rat hepatocellular nodules resistant to 2-acetylaminofluorence Int. J. Cancer. 40: 643-6451) modified by our research group (Carrasc-Legleu CE, Márquez-Rosado L, Fattel-Fazenda S, Arce-PopocaE, Pérez-Carreón Jl, Villa- Trevi ⁇ o S.
- IFC-I was administered to adenosine aspartate at a pharmacologically effective dose that for this case was 50 mg / kg of body weight dissolved in a saline solution Physiological pH 7.4 with 0.5% carboxymethyl cellulose, replacing the DEN starter carcinogen.
- adenosine aspartate was administered at a pharmacologically effective dose which for this case was 50 mg / kg of body weight dissolved in a physiological saline solution pH 7.4 with carboxymethyl cellulose at 0.5% replacing the 2-AAF promoter carcinogen.
- the fourth group identified as IFC-IP both the DEN initiating carcinogen and the 2AAF promoter carcinogen were replaced by adenosine aspartate in pharmacologically effective doses which in this case was 50 mg / kg body weight dissolved in a physiological saline solution pH 7.4 with 0.5% carboxymethyl cellulose.
- the fifth identified as C-2AAF only 2AAF was administered, being used as a control of the administration of adenosine aspartate at the start of the second IFC-I group.
- the sixth group identified as C-DEN which only received the DEN product, was used as a control of the administration of adenosine aspartate in the promotion of group 3 IFC-P.
- GGT is a marker widely used to detect preneoplastic lesions in rat liver, it is absent in hepatocytes of adult rats, while in altered hepatocytes the expression appears notably (Hanigan MH. (1988) ⁇ -Glutamyl transpeptidase, a grlutathionase : its expression and function in carcinogenesisi. Chemico-Biological interactions. 111-112: 333-342.).
- the quantification of preneoplastic lesions revealed that the positive CT control group that received the complete treatment reached an average of 30.06% foci / cm 2 and a percentage of the total positive GGT area of 2.41%. If we take these figures as 100%, in group two where adenosine aspartate was administered as an IFC-I initiator, the average of foci / cm 2 was 1.3% and the positive GGT area of 0.4% with respect to the control group With complete treatment. When adenosine aspartate was administered as a promoter in group three IFC-P, the average of foci / cm 2 was 7.1% and the positive GGT area was 4.6% with respect to the control group with complete treatment.
- adenosine aspartate was administered as an initiator and as a promoter group four IFC-IP the number of foci / cm 2 was 0.2% and the positive GGT area was 0.08% with respect to the control group with complete treatment with Io Previously, it is shown that adenosine aspartate has a protective effect on the development of preneoplastic lesions and by itself protects against the development of cancer and also presented a tumor reversal effect when the cancer had already developed.
- adenosine aspartate is preferably administered at doses of 750 mg per day in a single dose of 250 mg distributed in three oral doses, although this dose could be adjusted in order to achieve the pharmacological effect referred to herein with smaller amounts or in sustained release formulations without presenting the undesirable cardiovascular effects that could accompany the administration of this product.
- (A) schematically represents the model of the resistant hepatocyte where a cycle of 25 days of the experiment is represented indicating the days of administration of the diethylnitrosamine drugs referred to as DEN as a starting carcinogen at 0 days and 2-acetylaminofluorene, referred to as 2AAF as a promoter carcinogen at 7, 8 and 9 days, the HP partial hepatectomy at 10 days and the slaughter of the animals at 25 days.
- DEN diethylnitrosamine drugs
- 2AAF 2-acetylaminofluorene
- (B) schematically represents the model of the resistant hepatocyte indicating the administration of adenosine aspartate as a promoter and initiator referred to IFC at 0 days and from 8 months at a dose of 60 mg / Kg every 3 days until the time of sacrifice.
- Figure 2 is a schematic representation of the experimental design where 6 different experimental groups are shown with the treatments to which they were subjected, where group one is the CT control with 8 animals; group two IFC-I with 8 animals; group three IFC-P with 8 animals; group four IFC-IP with 7 animals; the fifth group C-2AAF with 6 animals and the sixth group C-DEN with 7 animals where the days of administration of each product are identified until the animals are slaughtered on day 25.
- Figure 3 shows the detection of preneoplastic lesions by means of the histochemical staining of the GGT enzyme in rat liver sections at 25 days post-initiation. Three representative sections of each group are shown where preneoplastic lesions are observed as dark spots.
- Figure 4 shows the quantification of the preneoplastic foci or lesions, the axis of the ordinates shows the area of GGT positive preneoplastic lesions, being able to observe that in the treated groups these foci decrease considerably or disappear.
- the results are presented as average values ⁇ standard error.
- Figure 5 shows in a schematic way a comparison of the TC group with the groups that received adenosine aspartate referred to as IFC, where the greatest amount of preneoplastic lesions as well as the highest percentage of the positive GGT area with respect to the total of the treated groups is given in the control group TC.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010523969A JP2010538061A (ja) | 2007-09-06 | 2008-08-21 | 肝癌治療用の医薬品の調製のためのアデノシンアスパラギン酸塩の使用方法 |
EP08829339A EP2186519A4 (en) | 2007-09-06 | 2008-08-21 | USE OF ADENOSINE ASPARTATE FOR THE PREPARATION OF PHARMACEUTICAL PRODUCTS FOR THE TREATMENT OF LIVER CANCER |
US12/676,953 US8507459B2 (en) | 2007-09-06 | 2008-08-21 | Use of adenosine aspartate for the preparation of pharmaceutical products for the treatment of liver cancer |
CA2698671A CA2698671C (en) | 2007-09-06 | 2008-08-21 | Use of adenosine aspartate for the preparation of pharmaceutical products for the treatment of liver cancer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2007010896A MX2007010896A (es) | 2007-09-06 | 2007-09-06 | Uso de sales de adenosina para la preparacion de productos farmaceuticos para el tratamiento del cancer. |
MXMX/A/2007/010896 | 2007-09-06 |
Publications (1)
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WO2009031876A1 true WO2009031876A1 (es) | 2009-03-12 |
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PCT/MX2008/000111 WO2009031876A1 (es) | 2007-09-06 | 2008-08-21 | Uso del aspartato de adenosina para la preparación de productos farmacéuticos para el tratamiento del cáncer hepático |
Country Status (6)
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US (1) | US8507459B2 (es) |
EP (1) | EP2186519A4 (es) |
JP (1) | JP2010538061A (es) |
CA (1) | CA2698671C (es) |
MX (1) | MX2007010896A (es) |
WO (1) | WO2009031876A1 (es) |
Families Citing this family (2)
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MX2013005735A (es) * | 2013-05-22 | 2014-11-24 | Univ Nac Autónoma De México | Uso de aspartato de adenosina en la activacion diferencial de los macrofagos en procesos inflamatorios-fibrogenicos y su reversion. |
CN112080503B (zh) * | 2020-09-23 | 2022-02-01 | 江南大学 | 一种优化启动子提高γ-谷氨酰胺转肽酶表达量的方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62289519A (ja) * | 1986-06-09 | 1987-12-16 | Dai Ichi Seiyaku Co Ltd | 抗肝細胞腫瘍薬 |
WO1991016056A1 (en) * | 1990-04-16 | 1991-10-31 | The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce | Use of purinergic receptor agonists as antineoplastic agents |
US20040116375A1 (en) * | 2002-10-15 | 2004-06-17 | Abraham Edward H. | Method of treating bone metastasis |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5182328A (en) | 1992-03-04 | 1993-01-26 | Air Products And Chemicals, Inc. | RF curable Type I wood adhesive composition comprising vinyl acetate/NMA copolymer emulsions containing tetramethylol glycoluril |
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2007
- 2007-09-06 MX MX2007010896A patent/MX2007010896A/es active IP Right Grant
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2008
- 2008-08-21 US US12/676,953 patent/US8507459B2/en active Active
- 2008-08-21 CA CA2698671A patent/CA2698671C/en active Active
- 2008-08-21 EP EP08829339A patent/EP2186519A4/en not_active Withdrawn
- 2008-08-21 WO PCT/MX2008/000111 patent/WO2009031876A1/es active Application Filing
- 2008-08-21 JP JP2010523969A patent/JP2010538061A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62289519A (ja) * | 1986-06-09 | 1987-12-16 | Dai Ichi Seiyaku Co Ltd | 抗肝細胞腫瘍薬 |
WO1991016056A1 (en) * | 1990-04-16 | 1991-10-31 | The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce | Use of purinergic receptor agonists as antineoplastic agents |
US20040116375A1 (en) * | 2002-10-15 | 2004-06-17 | Abraham Edward H. | Method of treating bone metastasis |
Non-Patent Citations (11)
Title |
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BAJAJ S. ET AL.: "Adenosine and adenosine analogues are more toxic to chronic lymphocytic leukemia than to normal lymphocytes", BLOOD, vol. 62, no. 1, 1983, pages 75 - 80, XP002102070 * |
CARRASC-LEGLEU CE; MARQUEZ-ROSADO L; FATTEL-FAZENDA S; ARCE-POPOCAE; PEREZ-CARREON JI; VILLA-TREVINO S: "Chemoprotective effect of caffeic acid phenethyl ester on promotion in amedium-term rat hepatocarcinogenesis assay", INT J. CANCER, vol. 108, 2004, pages 488 - 92 |
CHAGOYA DE SÁNCHEZ V.; HERNANDEZ-MUNOZ R.; YANEZ L.; VIDRIO S.; DIAZ-MUNOZ M: "Posible mechanism of adenosine protection in carbon tetrachloride acute hepatoxicity. Role of adenosine by-products and glutathione peroxidase", J., BIOCHEM. TOXICOLLOGY, vol. 10, 1995, pages 41 - 50 |
CHAGOYA DE SÁNCHEZ V; HERNÁNDEZ-MUÑOZ R; DIAZ-MUNOZ M; VILLALOBOS R; GLENDER W; VIDRIO S; SUAREZ J; YANEZ L: "Circadian variations of adenosine level in blood and liver and its possible physiological significance", LIFE SCIENCES, vol. 33, 1983, pages 1057 - 1064 |
FISHMAN P. ET AL.: "Adenosine acts as an inhibitor of lymphoma cell growth: a mojor role for the A3 adenosine receptor", EUROPEAN JOURNAL OF CANCER, vol. 36, 2000, pages 1452 - 1458, XP001035229 * |
FISHMAN P; BAR-YEHUDA S; BARER F; MADI L; MULTAN AS; PATHAK S: "The A3 adenosine receptor as a new target for cancer therapy and chemoprotection", EXP CELL RES, vol. 269, 2001, pages 230 - 236 |
HANIGAN MH.: "y-Glutamyl transpeptidase, a glutathionase: its expression and function in carcinogenesis", CHEMICO-BIOLOGICAL INTERACTIONS, vol. 111-112, 1988, pages 333 - 342 |
HERNANDEZ-MUNOZ R; DÍAZ-MUÑOZ M; SUÁREZ-CUENCA JA; TREJO-SOLIS C; LOPEZ V; SÁNCHEZ-SEVILLA L; YANEZ L; CHAGOYA DE SÁNCHEZ V: "Adenosine reverses a preestablished CC14 - induced micronodular cirrosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats", HEPATOLOGY, vol. 34, 2001, pages 677 - 687 |
OHANA G. ET AL.: "Differential effect of adenosine on tumor and normal cell growth:focus on the A3 adenosine receptor", JOURNAL OF CELLULAR PHYSIOLOGY, vol. 186, 2001, pages 19 - 23, XP009024527 * |
RUTENBURG AM; KIM H; FISCHBEIN JW; HANKER JS; WASSERKRUG HL; SELIGMAN AM: "Histochemical and ultrastructural demonstration of y-glutamiltranspeptidase activity", J. HISTOCHEM. CYTOCHEM., vol. 17, no. 8, 1969, pages 517 - 526 |
SEMPLE-ROBERTS E; HAYES MA; ARMSTRONG D; BECKER RA; RACZ WJ; FARBER E.: "Alternative methods of selecting rat hepatocellular nodules resistant to 2- acetylaminofluorence", INT. J. CANCER., vol. 40, 1987, pages 643 - 6451 |
Also Published As
Publication number | Publication date |
---|---|
US20110105425A1 (en) | 2011-05-05 |
US8507459B2 (en) | 2013-08-13 |
CA2698671A1 (en) | 2009-03-12 |
EP2186519A4 (en) | 2010-09-01 |
JP2010538061A (ja) | 2010-12-09 |
MX2007010896A (es) | 2009-03-06 |
CA2698671C (en) | 2015-04-21 |
EP2186519A1 (en) | 2010-05-19 |
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