WO1997045127A1 - Agent actif therapeutique comprenant de l'uridine pour le traitement de troubles neurodegeneratifs - Google Patents

Agent actif therapeutique comprenant de l'uridine pour le traitement de troubles neurodegeneratifs Download PDF

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Publication number
WO1997045127A1
WO1997045127A1 PCT/IT1997/000117 IT9700117W WO9745127A1 WO 1997045127 A1 WO1997045127 A1 WO 1997045127A1 IT 9700117 W IT9700117 W IT 9700117W WO 9745127 A1 WO9745127 A1 WO 9745127A1
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Prior art keywords
uridine
cells
nervous system
neurotrophins
ngf
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PCT/IT1997/000117
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English (en)
Inventor
Cinzia Piazza
Vincenzo Politi
Mario Materazzi
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Polifarma S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Polifarma S.P.A. filed Critical Polifarma S.P.A.
Priority to BR9709379-3A priority Critical patent/BR9709379A/pt
Priority to JP54197097A priority patent/JP3725172B2/ja
Priority to AU30468/97A priority patent/AU3046897A/en
Priority to CA002255748A priority patent/CA2255748C/fr
Priority to EP97925266A priority patent/EP0914131A1/fr
Publication of WO1997045127A1 publication Critical patent/WO1997045127A1/fr

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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
    • A61K31/70—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
    • A61K31/7068—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3

Definitions

  • the present invention relates to a new therapeutic use of uridine in neuron degenerative diseases resulting from pathological ageing or from functional losses due to various causes, for example peripheral neuropathies, lateral amyotrophic sclerosis and Alzheimer's disease.
  • This invention follows the evidence of the effects of uridine administering on various types of cells cultured.
  • uridine can act as a growth promoter when added to cell cultures, producing different effects due to the dose-levels (high or rather low) and the type of cells used as a target, and in particular when administered to neuronal and glial cell lines, has the same biological effects of Nerve Growth Factor.
  • Growth factors constitute a large family of proteins fundamentally devoted to reproduction, differentiation, maturation and survival of cells.
  • the tremendous developments in protein production through genetic engineering and biological techniques led to important discoveries on the physio-pathologic roles in mammalian bodies of several growth factors: as hyper- or hypo- production of growth factors by nearby or circulating cells has been linked to a large number of unrelated diseases, such as diabetes, angiogenesis, stroke, hypertensive arterial hypertrophy, atherosclerosis, restenosis, glomerular nephritis, cancer and so on.
  • NGF Nerve Growth Factor
  • NGF exerts its effects on defined cell populations of neurons within the CNS, where specific receptors have been identified, cloned and sequenced: its mechanism of activity appears related to increased expression of early response genes inside the cells, leading to changes in the genetic program.
  • uridine is a known compound that has been widely studied ever since it was found to be constituent element in ribonucleic acids.
  • the large variety of pharmacological effects of uridine lies in the fact that this py ⁇ midinic nucleoside, as well as going to form part of the ribonucleic acids, and thus stimulating biosynthesis of proteins inside the cells, also superintends a number of fundamental biochemical processes, such as the reconstitution of glycogen reserves from glucose, detoxification of cells from numerous exogenous components, and biosynthesis of important constituents that are of structural importance for the cell functions, such as glycolipids and glycoproteins .
  • uridine has been studied in various organs in experimental animals: for example, it has been seen in a number of studies that on the isolated heart uridine has positive effects on the use of energy reserves, and improves the myocardial functions.
  • cytidine another pyrimidinic nucleoside
  • Uridine is also one of the most important agents for the recovery of cell functions in mammals, and for this reason its concentration in the plasma is kept at more or less constant levels by means of enzymatic mechanisms, located above all in the liver.
  • the uridine can be formed ex novo using a complex enzymatic system, comprising a transfer of electrons inside the mitochondrions : however, if the mitochondrions are not functioning adequately, as is the case during ageing or as a result of cell intoxication, then the external supply of uridine through the blood stream becomes of fundamental importance, lack of supply resulting in degeneration and subsequent death of the cells involved.
  • the external uridine is quickly and easily taken up through the outside membrane of the cell.
  • anti-viral agents such as those currently in use to treat patients suffering from AIDS, are based on structures similar to uridine, in order to "intoxicate” the biosynthesis of viral proteins, or to inhibit the activity of particular enzymes (for example reverse transcriptase) .
  • uridine is capable of acting as a growth promoter stimulating various cell types to proliferate and differentiate in a sustained and extensive manner.
  • uridine shows biological effects quite similar to Nerve Growth Factor's, when administered on neuronal or glial cell lines. It has now been found, and this forms the basis of the present invention, that uridine is capable not only of reverting the harmful effects induced in cell cultures by important anti-tumour and anti-viral drugs, but, and this is by far more important, that it can act as a growth promoter. In fact it can stimulate various types of cell to proliferate in a sustained and extensive manner, when administered at fairly high doses.
  • tumour cell lines of CNS it can also promote cell differentiation and maturation when administered chronically at rather low doses, showing the same biological effects of NGF.
  • uridine can give the same results of the NGF when the growth factor is withdrawn from the medium.
  • NGF neurotrophins
  • pharmacological and clinical studies underway have been recently reported in a book (“Growth Factors as drugs for neurological and sensory disorders", John Wiley and sons, 1996) .
  • NGF is at present used extensively in clinical trials in patients with Alzheimer disease, with diabetes peripheral neuropathies, and with peripheral neuropathies due to antiviral (e.g. anti- AIDS) and antitumour therapies.
  • uridine can be considered as an advantageous substitute for NGF and other growth factors, because is well known that it is absorbed by oral route, maintains steady-state levels in blood, is absolutely safe, and crosses BBB(J.Natl. Cancer Inst . 83, 437-41, 1991; J. Neurochem. 45, 1411-18, 1985) .
  • an object of the present invention is the use of uridine for the manufacture of a medicament for the therapeutical treatment of disturbances of the nervous system due to degeneration of neuronal and glial cells in mammals, to counteract said degeneration.
  • object of the present invention is the use of uridine for the manufacture of a medicament for promoting differentiation, functioning and maturation of said cells, in the treatment of nervous system disturbances associated with cell degeneration, which conventionally can be treated in a per se known manner by administration of neurotrophins, for replacing said neurotrophins by uridine.
  • said medicament comprises a dose-levels of uridine, which is suitable to cause an effective concentration of 1 to 10 micrograms per milliliter of uridine in the tissues.
  • uridine is capable to act as a growth promoter, with the same biological effects of NGF. Therefore the present invention also comprises the use of uridine not only in substitution of these neurotrophins (like NGF, BDNF, NT-3, NT-4/5, CNTF FGF, IGF-I, TGF beta, GTNF) , but also in association with them, and in particular with NGF.
  • a further object of the present invention is a pharmaceutical composition
  • uridine at rather low doses, together with proteins defined neurotrophins or neuron growth factors, in a proportion ranging from 1:10 to 1:100, and with pharmaceutically compatible excipients, for the treatment of human diseases deriving from selective neuron degeneration, and in particular those mentioned above.
  • the cells were cultivated in DMEM medium (Dulbecco's Modified Eagle's Medium) , with the addition of 10% of FCS (Fetal Calf Serum) , 1000 U/ml of penicillin and 1000 U/ml of streptomycin, and grown in incubators at a temperature of 37°C, a C0 2 concentration of 7% and a humidity of 98%.
  • FCS Fetal Calf Serum
  • the cells underwent routine control three times a week, and were kept at a standard growth concentration of 0.3 x IO 6 per ml of medium.
  • the cells were measured at a concentration of 0.5 x 10 per ml in the normal culture medium, with the addition of various concentrations of AZT in the presence and in the absence of various doses of uridine.
  • the cultures were monitored in these conditions for two weeks. Every 48 hours the culture medium containing the drugs was renewed and simultaneously the cell growth was checked by microscope count in Neoubauer chambers. Before counting, the cells were coloured with Trypan blue so as to exclude the cells in necrosis from the growth curve. The time required to double the number of cells was then calculated, basing it on the increase in the number of cells observed every two days .
  • Table 1 shows the results obtained by treating the cells with different doses of AZT and uridine.
  • the AZT was used at doses of 0.1, 1 or 10 micro M.
  • uridine this was used in concentrations equivalent to 1, 2 or 5 times that of AZT.
  • AZT produces a dose-dependent reduction in cell growth, while uridine is capable of partially antagonising this effect, recovering most of the growth levels seen in the absence of the anti-viral drug.
  • This first test was carried out on two types of cell line, to evaluate the effect of high doses of uridine on proliferation, in the presence of AZT or of dideoxycytidine, the two anti-viral drugs currently in use for treatment of patients suffering from AIDS.
  • the cells used were Friend (murine erythroleukaemia) and CEM (human ly ⁇ nphoblast leukaemia) .
  • the cells were planted in 96-well plates at a concentration of 5000 cells in 200 microliters of medium per well (approximately 25000 cells per ml) .
  • UR dose 0 50 100 200 300 10 4000 32000 41000 68000 70000 25 3000 17000 65000 76000 77000 50 2000 11000 11000 28000 35000
  • the response of the medium in the ab ⁇ lence of additions is 5000 cpm.
  • uridine has clear stimulation effects on cell proliferation, which go well beyond recovery of the inhibitory action due to anti-viral drugs.
  • the effect of AZT is already completely reverted when the uridine is added at a dose of 50 microM, while at higher concentrations (100, 200, and 300 microM) a powerful dose-dependent stimulation of cell proliferation can be seen, reaching levels 6 or 7 times higher than the base level (that is to say the level observable in the absence of drugs) .
  • the effect is qualitatively the same, although a complete reversion of the inhibitory- effect due to dideoxycytidine can only be seen starting from a uridine dose equivalent to 100 microM. It is therefore possible to conclude that, at high doses, uridine has the effect of stimulating proliferation in both cell lines that goes well beyond recovery of the activity lost through administration of anti-viral drugs.
  • Cell proliferation test 2
  • the effect of uridine was tested on four different types of mammal cell (two mouse and two human) , to observe whether or not the potential cell proliferation stimulation effect is also evident in the absence of anti-viral drugs.
  • the cells used were the two described above (Friend and CEM) , plus the Jurkat (human T-lymphocyte leukaemia) and C2C12 (from the rat skeleton musculature) .
  • Table 4 The cells used were the two described above (Friend and CEM) , plus the Jurkat (human T-lymphocyte leukaemia) and C2C12 (from the rat skeleton musculature) .
  • uridine is capable of stimulating in a dose-dependent manner the proliferation of all the cell lines tested, even in the absence of anti-viral drugs. Moreover there is a difference in the extent of proliferation stimulation from one cell type to another (for further consideration see results below) .
  • CHP126 a lowly differentiated cell line with a rounded cell body, only weakly positive to markers for neurofilaments 200 Kda, derived from a neuroblastoma of the sympatethic nervous system
  • T67 a cell line selected from glial tumour, defined as an astrocytoma of III degree according to WHO classification, and cultured at Rome University lab of Prof. G.M. Lauro
  • Cells were cultured in the DMEM Dulbecco medium, with addition of 5% fetal bovine serum, 1% glutamine, 1% Hepes and 1% gentamycin. Cells were maintained in incubator at 37 °C and humidified atmosphere with 5% CO2.
  • uridine was used at two dose levels (1 and 10 micrograms per milliliter, equivalent to a dose level in vivo of 300-2000 mg/die in humans) , while beta-NGF at 100 nanograms per milliliter.
  • Cell proliferation was evaluated calculating cell numbers in wells (with a microscope) and using the MTT method: after addition of MTT (3- (4, 5-dimethylthiazole-2yl) 2,5- diphenyl bromide) and a lysing buffer, colour development was followed with a spectrophotometer (560 nm) . In order to avoid interferences due to the died bodies, cells were counted at the microscope after addition of the Trypan blue.
  • uridine is capable of stimulating in a dose-dependent manner the proliferation of all the non-neuronal cell lines tested, even in the absence of anti-viral drugs.
  • the effect usually starts to be seen at a dose of 50 microM of uridine, and becomes extraordinarily effective at a dose of from 100 microM up.
  • the effect is already very strong at the lowest concentration (219% increase at 50 microM) . This might mean that stimulation of cell proliferation by uridine on certain types of cell already occurs at doses in use in pharmacology (plasmatic levels of this size are obtained in humans by administration of approximately 1-2 grams of uridine) .
  • both uridine and beta- NGF when used alone, were unable to modify proliferation of the tumour cell lines measured after three days.
  • NGF was added with uridine (at both concentration) , the proliferation of cells after three days appeared reduced to roughly 45% of untreated samples.
  • uridine can be used in a number of pathological situations in which specific nervous cell populations have been damaged, and is necessary to reconstruct the integrity of the tissues by stimulating proliferation and differentiation of the remaining healthy cells.
  • uridine as a growth promoter capable of mimicking NGF's action, are those coming from pathological losses of neurons inside the CNS, e.g. Alzheimer disease, Parkinson disease, Stroke and any event producing destruction of functional neurons.
  • BDGF Brain-derived growth factor
  • NT-3 neurotrophin-3
  • NT-4/5 Neurotrophin 4/5
  • CNTF ciliary neurotrophic factor
  • FGF insulin-like growth factor
  • TGF beta transforming growth factor beta
  • GDGF glial-derived growth factor
  • the concentration of 4 micro M can be reached administering uridine at dose levels of 1 mcg/ml, and in the healthy people the blood-levels of uridine are between 3 and 5 micro M.
  • This physiological level of uridine can be increased till the value of 12 micro M or also 25 micro M, administering single oral doses of uridine respectively of 500 mg and 1800 mg, with a return to basal levels until 5 hours (J. Natl. Cancer Inst . 83, 437-41, 1991) .
  • the uridine concentration in the tissues are approximately ten times higher than the plasmatic one, owing to a mechanism of accumulation of the substance at the inner of the cells (Cancer Res. 46, 3490-4, 1986) .

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Abstract

L'uridine est un agent thérapeutique actif comme promoteur de la croissance pour le traitement de maladies neurodégénératives dérivant du vieillissement pathologique ou de la destruction sélective. En particulier, l'uridine présente les mêmes effets biologiques que le facteur de croissance nerveuse, lorsqu'il est ajouté à faibles doses au milieu de culture, de sorte qu'il peut remplacer ce facteur comme agent thérapeutique dans les maladies nerveuses et peut également être associé à d'autres facteurs de croissance permettant la différenciation des neurones, ou bien avec des médicaments anticancéreux ou antiviraux provoquant la lésion des neurones. En outre, l'uridine possède des propriétés trophiques importantes sur divers types de cellules mises en culture, stimulant la reproduction cellulaire lorsqu'elle est utilisée à des doses plutôt élevées.
PCT/IT1997/000117 1996-05-28 1997-05-23 Agent actif therapeutique comprenant de l'uridine pour le traitement de troubles neurodegeneratifs WO1997045127A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR9709379-3A BR9709379A (pt) 1996-05-28 1997-05-23 Uso de uridina, e, composição para o tratamento de distúrbios do sistema nervoso devido à degeneração seletiva de células neuroniais ou gliais em mamìferos.
JP54197097A JP3725172B2 (ja) 1996-05-28 1997-05-23 ウリジンからなる神経変性疾患の処置に活性な治療剤
AU30468/97A AU3046897A (en) 1996-05-28 1997-05-23 Uridine-comprising therapeutic active agent for treatment of neurodegenerative disorders
CA002255748A CA2255748C (fr) 1996-05-28 1997-05-23 Agent actif therapeutique comprenant de l'uridine pour le traitement de troubles neurodegeneratifs
EP97925266A EP0914131A1 (fr) 1996-05-28 1997-05-23 Agent actif therapeutique comprenant de l'uridine pour le traitement de troubles neurodegeneratifs

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IT96RM000364A IT1290781B1 (it) 1996-05-28 1996-05-28 Agente attivo terapeutico per il trattamento di malattie degenerative neuronali.
ITRM96A000364 1996-05-28
US1854396P 1996-05-29 1996-05-29

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006174A1 (fr) * 1998-07-31 2000-02-10 Massachusetts Institute Of Technology Methode permettant d'augmenter in vivo les niveaux de cytidine et traitement des maladies humaines dependant de la cytidine
EP1109453A1 (fr) * 1998-08-31 2001-06-27 Wellstat Therapeutics Corporation Compositions et procedes de traitement des maladies mitochondriales
US20050203053A1 (en) * 1999-07-30 2005-09-15 Wurtman Richard J. Uridine administration improves phosphatide synthesis, synaptic transmission and cogntive function
US6969479B2 (en) 2001-12-18 2005-11-29 3M Innovative Properties Company Tooling with helical coils for structured surface articles
EP1666092A2 (fr) * 2001-04-30 2006-06-07 Trommsdorff GmbH & Co.KG Arzneimittel Combinaison de médicaments comprenant un acide gras et une uridine.
US20060241077A1 (en) * 1998-07-31 2006-10-26 Richard Wurtman Methods and compositions for ameliorating or inhibiting decline in memory or intelligence or improving same
EP1750509A2 (fr) * 2004-05-13 2007-02-14 The Massachusetts Institute Of Technology Effets de l'uridine sur la liberation de la dopamine
EP1802314A2 (fr) * 2004-09-15 2007-07-04 The Massachusetts Institute Of Technology Compositions contenant une uridine et leurs procedes d'utilisation
US7807654B2 (en) 1998-08-31 2010-10-05 Wellstat Therapeutics Corporation Compositions and methods for treatment of mitochondrial diseases
US7915233B1 (en) 1998-08-31 2011-03-29 Wellstat Therapeutics Corporation Compositions and methods for treatment of mitochondrial diseases
US8143234B2 (en) 1998-07-31 2012-03-27 Massachusetts Institute Of Technology Uridine administration improves phosphatide synthesis, synaptic transmission and cognitive function
US8314064B2 (en) * 1998-07-31 2012-11-20 Massachusetts Institute Of Technology Uridine administration stimulates membrane production
US8318798B2 (en) 2005-11-24 2012-11-27 National University Corporation Hokkaldo University Therapeutic agent for neurodegenerative disease
US8551452B2 (en) 2007-11-02 2013-10-08 Massachusetts Institute Of Technology Uridine dietary supplementation compliance methods and use thereof

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Cited By (33)

* Cited by examiner, † Cited by third party
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EP2329829A3 (fr) * 1998-07-31 2011-07-20 Massachusetts Institute of Technology Utilisation de l'uridine en combinaison avec la choline pour le traitement des maladies de la mémoire
US6989376B2 (en) * 1998-07-31 2006-01-24 Massachusetts Institute Of Technology Methods for increasing blood cytidine and/or uridine levels and treating cytidine-dependent human diseases
EP1140104A1 (fr) * 1998-07-31 2001-10-10 Massachusetts Institute of Technology Methode permettant d'augmenter in vivo les niveaux de cytidine et traitement des maladies humaines dependant de la cytidine
EP2145627A1 (fr) * 1998-07-31 2010-01-20 Massachusetts Institute of Technology Utilisation de l'uridine en combinaison avec la choline pour le traitement des maladies de la mémoire
EP1140104A4 (fr) * 1998-07-31 2004-12-22 Massachusetts Inst Technology Methode permettant d'augmenter in vivo les niveaux de cytidine et traitement des maladies humaines dependant de la cytidine
US8518882B2 (en) 1998-07-31 2013-08-27 Massachusetts Institute Of Technology Methods and compositions for ameliorating or inhibiting decline in memory or intelligence or improving same
US8314064B2 (en) * 1998-07-31 2012-11-20 Massachusetts Institute Of Technology Uridine administration stimulates membrane production
US8143234B2 (en) 1998-07-31 2012-03-27 Massachusetts Institute Of Technology Uridine administration improves phosphatide synthesis, synaptic transmission and cognitive function
WO2000006174A1 (fr) * 1998-07-31 2000-02-10 Massachusetts Institute Of Technology Methode permettant d'augmenter in vivo les niveaux de cytidine et traitement des maladies humaines dependant de la cytidine
US20060241077A1 (en) * 1998-07-31 2006-10-26 Richard Wurtman Methods and compositions for ameliorating or inhibiting decline in memory or intelligence or improving same
EP2322187A3 (fr) * 1998-07-31 2011-07-20 Massachusetts Institute of Technology Utilisation de l'uridine en combinaison avec la choline pour le traitement des maladies de la mémoire
EP1870103A3 (fr) * 1998-07-31 2008-08-06 Massachusetts Institute of Technology Utilisation de l'uridine en combinaison avec la choline pour le traitement des maladies de la mémoire
JP2010195837A (ja) * 1998-08-31 2010-09-09 Wellstat Therapeutics Corp ミトコンドリア疾患の処置のための組成物および方法
EP2295063A3 (fr) * 1998-08-31 2011-09-14 Wellstat Therapeutics Corporation Compositions et leur utilisation pour le traitement de maladies mitochondriales
US7915233B1 (en) 1998-08-31 2011-03-29 Wellstat Therapeutics Corporation Compositions and methods for treatment of mitochondrial diseases
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EP1109453A1 (fr) * 1998-08-31 2001-06-27 Wellstat Therapeutics Corporation Compositions et procedes de traitement des maladies mitochondriales
EP1109453A4 (fr) * 1998-08-31 2006-11-02 Wellstat Therapeutics Corp Compositions et procedes de traitement des maladies mitochondriales
JP4717209B2 (ja) * 1998-08-31 2011-07-06 ウェルスタット セラピューティクス コーポレイション ミトコンドリア疾患の処置のための組成物および方法
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EP1666092A2 (fr) * 2001-04-30 2006-06-07 Trommsdorff GmbH & Co.KG Arzneimittel Combinaison de médicaments comprenant un acide gras et une uridine.
EP1666092A3 (fr) * 2001-04-30 2006-11-29 Trommsdorff GmbH & Co.KG Arzneimittel Combinaison de médicaments comprenant un acide gras et une uridine.
US6969479B2 (en) 2001-12-18 2005-11-29 3M Innovative Properties Company Tooling with helical coils for structured surface articles
US9572830B2 (en) 2004-05-13 2017-02-21 Massachusetts Institute Of Technology Uridine effects on dopamine release
EP1750509A4 (fr) * 2004-05-13 2010-03-24 Massachusetts Inst Technology Effets de l'uridine sur la liberation de la dopamine
EP1750509A2 (fr) * 2004-05-13 2007-02-14 The Massachusetts Institute Of Technology Effets de l'uridine sur la liberation de la dopamine
EP1802314A4 (fr) * 2004-09-15 2011-02-23 Massachusetts Inst Technology Compositions contenant une uridine et leurs procedes d'utilisation
EP1802314A2 (fr) * 2004-09-15 2007-07-04 The Massachusetts Institute Of Technology Compositions contenant une uridine et leurs procedes d'utilisation
US8318798B2 (en) 2005-11-24 2012-11-27 National University Corporation Hokkaldo University Therapeutic agent for neurodegenerative disease
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IT1290781B1 (it) 1998-12-10
AU3046897A (en) 1998-01-05
ITRM960364A1 (it) 1997-11-28
ITRM960364A0 (it) 1996-05-28
EP0914131A1 (fr) 1999-05-12

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