DE102010027595A1 - Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks - Google Patents

Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks Download PDF

Info

Publication number
DE102010027595A1
DE102010027595A1 DE102010027595A DE102010027595A DE102010027595A1 DE 102010027595 A1 DE102010027595 A1 DE 102010027595A1 DE 102010027595 A DE102010027595 A DE 102010027595A DE 102010027595 A DE102010027595 A DE 102010027595A DE 102010027595 A1 DE102010027595 A1 DE 102010027595A1
Authority
DE
Germany
Prior art keywords
body temperature
ethyl
dihydroxyphenyl
purin
oxolane
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
DE102010027595A
Other languages
German (de)
Inventor
Anmelder Gleich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to DE102010027595A priority Critical patent/DE102010027595A1/en
Publication of DE102010027595A1 publication Critical patent/DE102010027595A1/en
Withdrawn legal-status Critical Current

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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Clinical application of adenosine derivative (II), preferably (5R)-2-(6-{[2-(3,4-dihydroxyphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks and strokes after accidents, preferably drowning accidents and during prolonged surgical interventions, preferably cardiac operations, is claimed. Clinical application of adenosine derivative of formula (II), preferably (5R)-2-(6-{[2-(3,4-dihydroxyphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks and strokes after accidents, preferably drowning accidents and during prolonged surgical interventions, preferably cardiac operations, is claimed. R1 : H, NH 2or OH; and R2 : CH 2OH, CH 2OR 3, CH 2PO(OH) 2, CH 2OPO(OH)OX, CH 2POO(OH)O ->HNR 3+>; X : Na, K, Li, N(R3)4 or lysine; R3 : Me, Et, (CH 2) 2OH or O(CH 2) 2O(CH 2) 2OH, and R4 : H, acetyl, OCOEt or COC 17H 35. [Image] ACTIVITY : Antipyretic. No biological data given. MECHANISM OF ACTION : None given.

Description

Wie sich seit einiger Zeit abzeichnet, können insbesondere chirurgische Operationen am offenen Herzen besonders effektiv durchgeführt werden, wenn der Organismus des Patienten durch ein Kühlbad auf eine Körpertemperatur von ca. 28°C herunter gekühlt wird. Bei dieser herabgesetzten Körpertemperatur minimalisiert man effektiv die Folgeschäden, die auf Grund von Sauerstoffmangel (Ischämie) im Gehirn auftreten können. Gleichermaßen können solche Spätschäden im Gehirn auch nach Herzinfarkten oder Schlaganfällen durch eine solche Abkühlung des Körpers dramatisch vermindert werden. (Vergl. „Der Spiegel” 2010, 27, 114–116 ). Als Ergänzung oder Alternative zu den Kühlbädern wäre aber eine relativ schnell wirkende pharmakologisch induzierte Senkung der Körpertemperatur von Patienten von großem Interesse.As has emerged for some time, especially open heart surgery can be carried out particularly effectively when the patient's body is cooled by a cooling bath to a body temperature of about 28 ° C. With this lowered body temperature, one minimizes effectively the consequential damages that can occur due to lack of oxygen (ischemia) in the brain. Similarly, such late damage in the brain can be dramatically reduced even after heart attacks or strokes due to such cooling of the body. (Comp. "Der Spiegel" 2010, 27, 114-116 ). As a supplement or alternative to the cooling baths, however, a relatively fast-acting pharmacologically induced lowering of the body temperature of patients would be of great interest.

Gegenstand dieser Patentanmeldung ist also die pharmakologische Anwendung der Adenosin-Derivate der allgemeinen Formel 2 insbesondere aber des Adenosin-Derivats 1 bei länger andauernden chirurgischen Eingriffen wie in der Herz-Chirurgie, bei Kreislauf-Problemen wie Herzinfarkten oder Schlaganfällen sowie bei Parkinson-Patienten. Diese Pharmaka wie 1 oder 2 können oral gegeben oder als isotonische oder Kochsalz-Lösung intravenös infundiert oder intraperitonal bzw. intramuskulär injiziert werden.The subject of this patent application is therefore the pharmacological application of the adenosine derivatives of the general formula 2 but especially of the adenosine derivative 1 in prolonged surgical interventions such as in cardiac surgery, in circulatory problems such as heart attacks or strokes and Parkinson's patients. These drugs, such as 1 or 2, may be given orally, infused intravenously as an isotonic or saline solution, or injected intraperitoneally or intramuscularly.

Da insbesondere das kristalline N6-[2-(3,4-Dihydroxyphenyl)ethyl]adenosin 1 bei Verabreichung an Versuchstieren wie Mäusen die Körpertemperatur der Versuchstiere um bis zu 20°C senkt, sind 1 bzw. die in der allgemeinen Formel 2 aufgeführten Adenosin-Analoga 2, hervorragend geeignet, nach Herzinfarkten oder Schlaganfällen wie auch bei längeren chirurgischen Eingriffen wie z. B. bei der Herzchirurgie die Körpertemperatur von Patienten zu senken und dadurch häufig auftretende schwerwiegende neurologische Spätschäden zu vermeiden oder gänzlich zu verhindern.In particular, since the crystalline N 6 - [2- (3,4-dihydroxyphenyl) ethyl] adenosine 1, when administered to experimental animals such as mice, lowers the body temperature of the experimental animals by up to 20 ° C, 1 or those listed in general formula 2 Adenosine analogues 2, excellent after heart attacks or strokes as well as during prolonged surgical procedures such. B. in cardiac surgery to lower the body temperature of patients and thereby avoid frequently occurring serious neurological late damage or prevent it altogether.

Da das Adenosin-Derivat 1 die Blutgehirn-Barriere mühelos passiert und aus 1 im Gehirn anscheinend Dopamin freigesetzt wird, ist 1 auch für den Dopamin-Transport ins Gehirn d. h. für die Therapie von Parkinson-Patienten geeignet.Since the adenosine derivative 1 passes the blood-brain barrier effortlessly and 1 apparently releases dopamine in the brain, 1 is also responsible for the transport of dopamine to the brain d. H. suitable for the treatment of Parkinson's patients.

Die aufgeführten Substanzen wie 1 oder 2 mit R1 = H, R2 = OH bzw. R1 = H; R2 = OPO(OH)ONa oder R1 = NH2; R2 = OH oder OPO(OH)ONa lassen sich durch Silylierung-Aminierung von Inosin oder Inosin-5'-O-phosphat, Guanosin oder Guanosin-5'-O-phosphat bzw. Xanthosin oder Xanthosin-5'-O-phosphat mit Dopamin-Hydrochlorid, 3,4-Dimethoxyphenäthylamin-Hydrochlorid, Histamin-Hydrochlorid oder Tryptamin-Hydrochlorid in Gegenwart von überschüssigen Hexamethyldisilazan (HMDS) und Erhitzen auf ca. 140–160° und anschließender Transsilylierung der aliphatischen wie aromatischen O-SiMe3-Gruppen mit kochendem überschüssigen Methanol sehr einfach herstellen. ( H. Vorbrüggen und K. Krolikiewicz, Liebigs Annalen 1976, 745–761 ; Nucleic Acid Chemistry, Part TWO, Edited by L. B. Townsend and R. S. Tipson, J. Wiley N. Y. Page 533–535 ) The listed substances such as 1 or 2 with R 1 = H, R 2 = OH or R 1 = H; R 2 = OPO (OH) ONa or R 1 = NH 2 ; R 2 = OH or OPO (OH) ONa can be obtained by silylation-amination of inosine or inosine 5'-O-phosphate, guanosine or guanosine 5'-O-phosphate or xanthosine or xanthosine 5'-O-phosphate with dopamine hydrochloride, 3,4-dimethoxyphenethylamine hydrochloride, histamine hydrochloride or tryptamine hydrochloride in the presence of excess hexamethyldisilazane (HMDS) and heating to about 140-160 ° and subsequent transsilylation of the aliphatic and aromatic O-SiMe 3 groups very easy to make with boiling excess methanol. ( H. Vorbrüggen and K. Krolikiewicz, Liebigs Annalen 1976, 745-761 ; Nucleic Acid Chemistry, Part TWO, Edited by LB Townsend and RS Tipson, J. Wiley NY Page 533-535 )

Die Adenosin-5'-Nukleotid-Analoga mit freien 5'-O-Phosphaten werden anschließend mit verdünnter NaOH in ihre entsprechenden Mono-Natrium Salze überführt. An Stelle der Natrium Salze lassen sich durch Zugabe anderer Alkali- oder Erdalkali-Basen wie auch von Ammoniak, primären, sekundären wie tert. Aminen, Amidinen oder Guanidinen oder freien, insbesondere basischen, Aminosäuren wie Lysin zu freien 5'-O-Phosphaten die entsprechenden alternativen Salze der 5'-O-Phosphate herstellen, die ebenfalls Gegenstand dieser Patentanmeldung sind. Durch Acylierung z. B. mit Acetanhydrid oder aktivierten Derivaten z. B. der Palmetinsäure, Stearinsäure oder ungesättigten C4-C20 Karbonsäuren wie Elaidinsäure können die freien aliphatischen und phenolischen Hydroxylgruppen in 1 oder 2 in die entsprechenden lipophilen Derivate z. B. mit R4 = COCH3, R4 = COC15H33,. R4 = COC17H35 bzw. R4 = COC17H33 überführt werden.The adenosine 5'-nucleotide analogs with free 5'-O-phosphates are then converted into their corresponding mono-sodium salts with dilute NaOH. In place of the sodium salts can be by adding other alkali or alkaline earth bases as well as ammonia, primary, secondary, such as tert. Amines, amidines or guanidines or free, especially basic, amino acids such as lysine to produce free 5'-O-phosphates, the corresponding alternative salts of 5'-O-phosphates, which are also the subject of this patent application. By acylation z. B. with acetic anhydride or activated derivatives z. As the palmetic acid, stearic acid or unsaturated C4-C20 carboxylic acids such as elaidic acid, the free aliphatic and phenolic hydroxyl groups in 1 or 2 in the corresponding lipophilic derivatives z. B. with R 4 = COCH 3 , R 4 = COC 15 H 33 ,. R 4 = COC 17 H 35 or R 4 = COC 17 H 33 are transferred.

Figure 00020001
Figure 00020001

Pharmakologische Resultate:Pharmacological results:

Das N6-[2-(3,4-Dihydroxyphenyl)ethyl]adenosin 1 ist gut löslich in heißem Wasser (5 mg/ml H2O bei 100°) und bewirkt bei Mäusen bei i. p. Applikation eine 30fach stärkere Senkung der Körpertemperatur im Vergleich mit Chlorpromazin-Hydrochlorid als Standard, während z. B. das N6-[2-(3,4-Dimethoxyphenyl)ethyl]adenosin oder das N6-[2-(4-imidazolyl)ethyl]adenosin nur eine ca. 10fach stärkere Senkung der Körpertemperatur im Vergleich mit Chlorpromazin-Hydrochlorid erzeugen. Während diese Adenosin-Analoga 2 auch bei Katzen wirksam sind, haben sie bei Ratten keinen Einfluss auf die Körpertemperatur. Bei Katzen wurde neben dem hypothermischen Effekt noch eine sedative und analgetische Wirkung von 1 beobachtet.The N 6 - [2- (3,4-dihydroxyphenyl) ethyl] adenosine 1 is readily soluble in hot water (5 mg / ml H 2 O at 100 °) and causes a 30-fold greater reduction in body temperature in mice in ip administration Comparison with chlorpromazine hydrochloride as standard, while z. B. N 6 - [2- (3,4-dimethoxyphenyl) ethyl] adenosine or N 6 - [2- (4-imidazolyl) ethyl] adenosine only an approximately 10-fold greater reduction in body temperature in comparison with chlorpromazine hydrochloride produce. While these adenosine analogues 2 are also effective in cats, they have no effect on body temperature in rats. In cats, in addition to the hypothermic effect, a sedative and analgesic effect of 1 was observed.

ZITATE ENTHALTEN IN DER BESCHREIBUNG QUOTES INCLUDE IN THE DESCRIPTION

Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Zitierte Nicht-PatentliteraturCited non-patent literature

  • „Der Spiegel” 2010, 27, 114–116 [0001] "Der Spiegel" 2010, 27, 114-116 [0001]
  • H. Vorbrüggen und K. Krolikiewicz, Liebigs Annalen 1976, 745–761 [0005] H. Vorbrüggen and K. Krolikiewicz, Liebigs Annalen 1976, 745-761 [0005]
  • Nucleic Acid Chemistry, Part TWO, Edited by L. B. Townsend and R. S. Tipson, J. Wiley N. Y. Page 533–535 [0005] Nucleic Acid Chemistry, Part TWO, Edited by LB Townsend and RS Tipson, J. Wiley NY Page 533-535 [0005]

Claims (2)

Die klinische Applikation von Adenosin-Derivaten der allgemeinen Formel 2 insbesondere aber von 1 zur Senkung der Körpertemperatur bei drohender Ischämie der Gehirngefäße, wie sie bei Herzanfällen und Schlaganfällen, nach Unfällen (Badeunfällen) und auch bei länger andauernden chirurgischen Eingriffen wie bei Herzoperationen auftreten kann.The clinical application of adenosine derivatives of the general formula 2 but in particular of 1 for lowering the body temperature in the case of imminent ischemia of the cerebral vessels, as may occur in heart attacks and strokes, after accidents (swimming accidents) and also in prolonged surgical procedures such as cardiac surgery. Die Anwendung von Adenosin-Derivaten 2 insbesondere aber von 1 bei der Therapie von Parkinson-Patienten.The use of adenosine derivatives 2 but especially of 1 in the treatment of Parkinson's patients.
DE102010027595A 2010-07-23 2010-07-23 Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks Withdrawn DE102010027595A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE102010027595A DE102010027595A1 (en) 2010-07-23 2010-07-23 Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE102010027595A DE102010027595A1 (en) 2010-07-23 2010-07-23 Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks

Publications (1)

Publication Number Publication Date
DE102010027595A1 true DE102010027595A1 (en) 2012-01-26

Family

ID=45443298

Family Applications (1)

Application Number Title Priority Date Filing Date
DE102010027595A Withdrawn DE102010027595A1 (en) 2010-07-23 2010-07-23 Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks

Country Status (1)

Country Link
DE (1) DE102010027595A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2144038A (en) * 1980-04-22 1985-02-27 Bioresearch Spa Adenosine derivatives of antiinflammatory and analgesic activity and therapeutic compositions containing them
EP0821964A2 (en) * 1990-05-10 1998-02-04 FUKUNAGA, Atsuo F. Use of adenosine and adenosine derivatives for analgesia and attenuation of stress or stress responses
WO2010015260A2 (en) * 2008-08-07 2010-02-11 Neurokey A/S Administration by infusion for the treatment of ischemic effects

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2144038A (en) * 1980-04-22 1985-02-27 Bioresearch Spa Adenosine derivatives of antiinflammatory and analgesic activity and therapeutic compositions containing them
EP0821964A2 (en) * 1990-05-10 1998-02-04 FUKUNAGA, Atsuo F. Use of adenosine and adenosine derivatives for analgesia and attenuation of stress or stress responses
WO2010015260A2 (en) * 2008-08-07 2010-02-11 Neurokey A/S Administration by infusion for the treatment of ischemic effects

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Der Spiegel" 2010, 27, 114-116
DALY J W [et al.]: Structure-activity relationships for N6-substituted adenosines at a brain A1-adenosine receptor with a comparison to an A2-adenosine receptor regulating coronary blood flow. In: Biochemical Pharmacology Vol. 35(15), 1986, S. 2467-2481. ISSN 0006-2952. *
DALY J W [et al.]: Structure-activity relationships for N6-substituted adenosines at a brain A1-adenosine receptor with a comparison to an A2-adenosine receptor regulating coronary blood flow. In: Biochemical Pharmacology Vol. 35(15), 1986, S. 2467–2481. ISSN 0006-2952.
H. Vorbrüggen und K. Krolikiewicz, Liebigs Annalen 1976, 745-761
H. W. HAMILTON [et al.]: Correlation of adenosine receptor affinities and cardiovascular activity. In: Life Sciences, Vol. 41(20), 1987, S. 2295-2302. ISSN 0024-3205. *
Kinga K. BOROWICZ, Zdzislaw KLEINROK, Stanislaw J. CZUCZWAR: N6-2-(4-Aminophenyl) ethyl-adenosine enhances the anticonvulsive activity of antiepileptic drugs. In: European Journal of Pharmacology. Vol. 327(2-3), 1997, S. 125-133. *
Kinga K. BOROWICZ, Zdzisław KLEINROK, Stanisław J. CZUCZWAR: N6-2-(4-Aminophenyl) ethyl-adenosine enhances the anticonvulsive activity of antiepileptic drugs. In: European Journal of Pharmacology. Vol. 327(2-3), 1997, S. 125-133.
Matinder MALHOTRA, Yogendra K. GUPTA: Effect of adenosine receptor modulation on pentylenetetrazole-induced seizures in rats. In: Br. J. Pharmacol. Vol. 120(2), 1997, S. 282-288. *
Nucleic Acid Chemistry, Part TWO, Edited by L. B. Townsend and R. S. Tipson, J. Wiley N. Y. Page 533-535
Rainer LENHARDT [et al.]: Suppression of shivering during hypothermia using a novel drug combination in healthy volunteers. In: Anesthesiology, Vol. 111(1), 2009, S. 110-115. *
Shozo KUSACHI [et al.]: Dog Coronary Artery Adenosine Receptor: Structure of the N6-Alkyl Subregion. In: J. Med. Chem. Vol. 29(6), 1986, S. 989-996. ISSN 0022-2623. *

Similar Documents

Publication Publication Date Title
JP2018076328A5 (en)
US9744186B2 (en) Substituted gemcitabine aryl amide analogs
CN103251579A (en) Substituted acylanilides and methods of use thereof
JP2006515859A5 (en)
BR0011823A (en) Benzimidazole derivative, compound, pharmaceutical composition, use of a benzimidazole derivative, and, method for treating, preventing or relieving a disease or disorder or condition of a living animal body
RU2019121667A (en) AMINOPYRAZOLES AS SELECTIVE INHIBITORS OF JANUS KINASE
CA2552855A1 (en) Azabicyclooctan-3-one derivatives and use thereof
DE60301878T2 (en) PHARMACEUTICAL COMPOSITION CONTAINING ALPHA-KETOALKANIC ESTER OR AMID AND MILKY ACID OR MILKIC ACID SALT
EP3006022B1 (en) Osmolytes for the treatment of viral respiratory diseases
CN110167595A (en) The prevention of non-alcohol fatty liver and medicine
JP2016513707A (en) How to give optic nerve protection
Harstrick et al. A phase I dose escalation trial of intravenous treosulfan in refractory cancer
DE102010027595A1 (en) Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks
CN1872067A (en) Non-sedating barbiturate compounds as neuroprotective agents
DE3875016T2 (en) THERAPEUTIC FOR TREATING AIDS.
DE2708826A1 (en) SUBSTITUTED 8-AZAPURINE AND METHOD FOR PRODUCING IT
JP5570429B2 (en) Method for administering an antitumor agent containing a deoxycytidine derivative
EP0028660A1 (en) Xanthinoxydase inhibitors and utilization of benzotriazine derivatives
CN113350358A (en) Application of polygala tenuifolia sapogenin single or combined with hydroxysafflor yellow A in preparation of medicine for improving cognitive impairment after ischemic stroke
US9192602B2 (en) Indication of anthra[2,1,c][1,2,5]thiadiazole-6,11-dione compound in alleviating pain
JPH07126162A (en) Intracerebral administration agent of ascorbic acids
JP2007186477A (en) Therapeutic agent for neurogenic pain
Klapetek An early stage of a brain abscess discovered and correctly located by electroencephalographic examination
Venkatarathnamma et al. Jagadish basavaih (2013) Phenytoin Induced Cerebellar Ataxia and Orofacial Dyskinesia in a Case of Disseminated Cysticercosis: A Case Report
van Gorkom et al. Gadolinium deposition in tissue after long-term IP GBCA injection in rats–in vitro studies

Legal Events

Date Code Title Description
R016 Response to examination communication
R119 Application deemed withdrawn, or ip right lapsed, due to non-payment of renewal fee

Effective date: 20130201