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WO1997015323A1 - Perfusions de neuroprotecteurs et d'agents thrombolytiques - Google Patents

Perfusions de neuroprotecteurs et d'agents thrombolytiques Download PDF

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Publication number
WO1997015323A1
WO1997015323A1 PCT/EP1996/004609 EP9604609W WO9715323A1 WO 1997015323 A1 WO1997015323 A1 WO 1997015323A1 EP 9604609 W EP9604609 W EP 9604609W WO 9715323 A1 WO9715323 A1 WO 9715323A1
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WIPO (PCT)
Prior art keywords
neuroprotectant
product according
lubeluzole
solution
thrombolytic
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Ceased
Application number
PCT/EP1996/004609
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English (en)
Inventor
Ludwig Norbert Michel Hantson
Marc Roger De Ryck
Luc Remi Mathilde Tritsmans
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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 Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to JP9516280A priority Critical patent/JPH11515010A/ja
Priority to AU74913/96A priority patent/AU7491396A/en
Priority to EP96937215A priority patent/EP0862457A1/fr
Publication of WO1997015323A1 publication Critical patent/WO1997015323A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21068—Tissue plasminogen activator (3.4.21.68), i.e. tPA

Definitions

  • the present invention is concerned with products comprising a neuroprotectant and a thrombolytic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of acute ischaemic stroke; with the use of such products for the preparation of a medicament for the tieatment of acute ischaemic stroke and with the use of a neuroprotectant for the preparation of a medicament for preventing or delaying the process of infarction accompanying acute ischaemic stroke from being completed, thus enlarging the inclusion period during which the above combined preparation can be administered safely.
  • the treatment of acute ischaemic stroke currently consists mainly of neuroprotective and of haematologic therapeutic strategies. As described in Cerebrovasc. Dis. 1995 ; 5
  • thrombolytic agents such as pro-urokinase and tissue plasminogen activator (t-PA) are currently in the final stages of clinical developments with a view to the approved therapeutic use of these thrombolytic agents in acute ischaemic stroke (The New England Journal of Medicine, 333 (24), 1581-1587, December 14, 1995).
  • the therapeutic utility of thrombolytic agents in the treatment of acute ischaemic stroke is severely limited by the fact that their administration must be effected within a short, limited period of time following the ischaemic event. This limited period of time is known in the art as the so-called 'inclusion period' during which stroke agent patient can be included in the group of patients who can be treated safely with a thrombolytic agent.
  • CT computer tomographic
  • thrombolytic agent Those patients who are diagnosed as positive in the screening will be excluded from receiving thrombolytic treatment.
  • the underlying reason for this exclusion is that treatment with a thrombolytic agent will almost certainly be detrimental to the health of the patient, as the thrombolytic agent will cause thrombolytic recanalisation of the blood flow and subsequently cerebral haemorrhage (intracranial bleeding).
  • neuroprotectants such as lubeluzole do not suffer from the limitations characterizing thrombolytic agents in the treatment of ischaemic events involving cerebral hypoxia. Thus, there is no need to screen patients beforehand (although such may well be advisable), before initiating treatment of a stroke victim with a neuroprotectant.
  • neuroprotectants act by preventing or delaying the occurence and completion of neurological damage in occluded arterial blood vessels. In the event of sudden revascularisation or recanalisation of an occluded blood vessel, the neuroprotectant will actually prevent, attenuate or delay the catastrophic event which is known as reperfusion damage.
  • Reperfusion damage is the detrimental effect which follows the removal of, for example, a blood clot by a number of biochemical agents released by damaged (e.g. hypoxic) tissue at the site of infarction.
  • neuroprotectant treatment therefore is a first-line treatment for patients suffering from acute ischaemic stroke.
  • the present invention is concemed with a product containing (a) a composition suitable for intravenous administration comprising a pharmaceutically effective amount of a neuroprotectant and a pharmaceutically acceptable carrier ; and (b) a composition suitable for intravenous or intra-arterial administration, optionally after reconstitution with sterile water for injection, comprising a pharmaceutically effective amount of a thrombolytic agent and a pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate or sequential use in the treatment of acute ischaemic stroke.
  • Neuroprotectants in particular are 2-aminobenzothiazole derivatives of formula (I)
  • R 1 represents hydrogen or C ⁇ _ 4 alkyl
  • R 2 represents hydrogen, hydroxy or trifluoromethoxy
  • L represents hydrogen or a radical of formula (TJ)
  • R ⁇ represents hydrogen or fluoro
  • Particular neuroprotectants are lubeluzole (R 1 is methyl; R 2 is hydrogen, L is a radical of formula (II) wherein R 3 is fluoro and the atom marked * has the (S) configuration), lubeluzole N-oxide hemihydrate (oxidized piperidine nitrogen atom, preferably cis- oriented), 6-hydroxylubeluzole (R 2 is hydroxy) or riluzole (R 1 and L are both hydrogen, R 2 is trifluoromethoxy).
  • the most preferred neuroprotectant is lubeluzole.
  • Lubeluzole is generic to (S)-4-[(2-benzothiazolyl) methylamino]- ⁇ -[(3,4-difluorophenoxy)methyl]-l- piperidineethanol. Its preparation and properties are described in WO-92/14731.
  • Neuroprotectants may also be NMDA receptor antagonists such as aptiganel, eliprodil, selfotel, tirilazad or remacemide or combinations of the abovementioned 2-aminobenzo- thiazole derivatives of formula (I) therewith.
  • NMDA receptor antagonists such as aptiganel, eliprodil, selfotel, tirilazad or remacemide or combinations of the abovementioned 2-aminobenzo- thiazole derivatives of formula (I) therewith.
  • Pharmaceutically acceptable acid addition salts comprise the therapeutically active, non ⁇ toxic salt forms obtained by treating a base form with an acid such as, for example, an inorganic acid, e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid ; or an organic acid, e.g. acetic, propanoic, hydroxyacetic, lactic, pyruvic, malonic, succinic, maleic, fumaric, tartaric, citric, methanesulfonic, ethanesulfonic, benzene-sulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic acid.
  • an acid such as, for example, an inorganic acid, e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid ; or an organic acid, e.g. acetic, propanoic, hydroxyacetic, lactic
  • N-oxide forms of the compounds of formula (I) are meant to comprise those compounds wherein one or more of the nitrogen atoms are oxidized, in particular those wherein the piperidine nitrogen is oxidized.
  • the oxygen atom on the piperidine nitrogen is cis-oriented, i.e. to the same side of the plane defined by the piperidine ring as the 4-substituent.
  • physically stability refers to a solution for which less than 10% by weight of active ingredient is adsorbed after passing through an infusion device. Preferably less than 5% by weight of active ingredient is adsorbed.
  • the pharmaceutically acceptable carrier for the neuroprotectant lubeluzole is an aqueous solution (a) comprising water ; an isotonizing agent ; and acid, base or buffer substances sufficient to adjust the pH of the solution in the range of from 2.5 to 3.6.
  • the concentration of lubeluzole in the present solutions (a) may range from 0.005% to 5%, preferably from 0.01% to 1%, more preferably from 0.02% to 0.2% and in particular is about 0.05%.
  • the present solutions (a) conveniently comprise from 1 to 10% isotonizing agent.
  • the use of glucose as isotonizing agent has the advantage that very clear solutions are obtained.
  • glucose is used in a concentration from 2 to 10%, most preferably of about 5%.
  • the solutions (a) further comprise acid and base substances to maintain the pH of the solution in the range from 2.5 to 3.6, preferably in the range from 3.0 to 3.4, most preferably at about 3.2.
  • the pH of the solutions (a) is adjusted by appropriate amounts of hydrochloric acid and sodium hydroxide.
  • the pH may also be adjusted by buffer systems comprising mixtures of appropriate amounts of an acid such as phosphoric, tartaric or citric acid, and a base, in particular sodium hydroxide.
  • a solubilizer may be used.
  • a cyclodextrin (CD) or a derivative thereof may be used.
  • Appropriate cyclodextrin derivatives are ⁇ -, ⁇ -, ⁇ cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with Cj.galkyl, particularly methyl, ethyl or isopropyl, e.g.
  • ⁇ -cyclodextrin randomly methylated ⁇ -cyclodextrin; hydroxyC galkyl, particularly hydroxyethyl, hydroxypropyl or hydroxy-butyl ; carboxy C ⁇ _6alkyl, particularly carboxymethyl or carboxyethyl; Ci-6alkyl-carbonyl, particularly acetyl; Ci-6aJ_ yloxycarbonylC ⁇ _6al_-yl or carboxyCi- ⁇ alkyl-oxyCi.galkyl, particularly carboxymethoxypropyl or carboxyethoxy- propyl; Ci ⁇ aJJ ylcarbonyloxyCi- ⁇ alkyl, particularly 2-acetyloxypropyl.
  • solubilizers are ⁇ -CD, 2,6-dimethyl- ⁇ -CD, randomly methylated ⁇ -cyclo- dextrin, 2-hydroxyethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD.
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
  • the average molar substitution is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose.
  • the M.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative.
  • the M.S. as determined by mass spectrometry is in the range of 0.125 to 10, in particular of 0.3 to 3, or from 0.3 to 1.5.
  • the M.S. ranges from about 0.3 to about 0.8, in particular from about 0.35 to about 0.5 and most particularly is about 0.4.
  • M.S. values determined by NMR or IR preferably range from 0.3 to 1, in panicular from 0.55 to 0.75.
  • the average substitution degree refers to the average number of substituted hydroxyls per anhydroglucose unit.
  • the D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative.
  • the D.S. as determined by MS is in the range of 0.125 to 3, in particular of 0.2 to 2 or from 0.2 to 1.5.
  • the D.S. ranges from about 0.2 to about 0.7, in particular from about 0.35 to about 0.5 and most particularly is about 0.4.
  • D.S. values determined by NMR or IR preferably range from 0.3 to 1, in particular from 0.55 to 0.75.
  • More particular ⁇ - and ⁇ -cyclodextrin hydroxyalkyl derivatives for use in the compositions according to the present invention are partially substituted cyclodextrin derivatives wherein the average degree of alkyiation at hydroxyl groups of different positions of the anhydroglucose units is about 0% to 20% for the 3 position, 2% to 70% for the 2 position and about 5% to 90% for the 6 position.
  • the amount of unsubstituted ⁇ - or ⁇ -cyclodextrin is less than 5% of the total cyclodextrin content and in particular is less than 1.5%.
  • Another particularly interesting cyclodextrin derivative is randomly methylated ⁇ -cyclodextrin.
  • Most preferred cyclodextrin derivatives for use in the present invention are those partially substituted ⁇ -cyclodextrin ethers or mixed ethers having hydroxypropyl, hydroxyethyl and in particular 2- hydroxypropyl and/or 2- (1 -hydroxypropyl) substituents.
  • the most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl- ⁇ -cyclodextrin having a M.S. in the range of from 0.35 to 0.50 and containing less than 1.5% unsubstituted ⁇ -cyclodextrin.
  • M.S. values determined by NMR or IR preferably range from 0.55 to 0.75.
  • an intravenous formulation preferably contains as few ingredients as possible. Therefore, a formulation without a solubilizer such as a cyclodextrin is preferred. It was found that the solubility of lubeluzole in formulations without a solubilizer ranges between about 9.2 mg/ml (pH 2.5) and about 2 mg/1 (pH 3.6). Formulations of pH 3.2 without a solubilizer comprise at maximum about 3 mg/ml dissolved lubeluzole. Further, the neuroprotectant solution (a) preferably does not contain a preservative.
  • the present invention relates to neuroprotectant solutions (a) comprising: (i) 0.005 to 5% lubeluzole or a pharmaceutically acceptable addition salt thereof; (ii) 1 to 10% isotonizing agent;
  • the invention relates to neuroprotectant solutions (a) comprising: (i) 0.01 to 1% lubeluzole or a pharmaceutically acceptable addition salt thereof; (ii) 2 to 10% glucose;
  • the invention relates to neuroprotectant solutions (a) containing approximately : (i) 0.05% lubeluzole or a pharmaceutically acceptable addition salt thereof; (ii) 5% glucose;
  • the solutions (a) are sterilized using art-known techniques.
  • the neuroprotectant solution (a) of the present product is conveniently used in the treatment of patients suffering from acute ischaemic stroke.
  • an effective treatment for acute ischaemic stroke involves administering to the patient first an amount of a neuroprotectant solution (a 1 ), in particular lubeluzole, in the range of 10 to 30 ml of solution (a') or from 5 to 15 mg of lubeluzole during the first hour of therapy following the attendance by a physician.
  • a neuroprotectant solution (a 1 ) in particular lubeluzole
  • a' ml of solution
  • 5 to 15 mg of lubeluzole during the first hour of therapy following the attendance by a physician.
  • about 4/3 or 133 % of that amount in the form of solution (a) may be administered. That is, one starts with a relatively high initial flow which is then lowered considerably.
  • the maintenance dose may be administered for several consecutive days.
  • lubeluzole Preferably about 15 ml of solution (a') or about 7.5 mg of lubeluzole is administered by infusion during the first hour of therapy, followed by about 20 ml of solution (a) or about 10 mg of lubeluzole during the next 24 hours.
  • said effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the effective amount ranges mentioned hereinabove are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent.
  • the subject solutions may conveniently be co-administered with a physiological salt solution according to art-known procedures.
  • Thrombolytic agents in the products according to the present invention in particular are proteolytic enzyme plasmins selected from the group consisting of streptokinase, urokinase, pro-urokinase, tissue plasminogen activator (t-PA), fibrinolysin, staphylokinase and the like agents; most preferably tissue plasminogen activator (t-PA).
  • proteolytic enzyme plasmins selected from the group consisting of streptokinase, urokinase, pro-urokinase, tissue plasminogen activator (t-PA), fibrinolysin, staphylokinase and the like agents; most preferably tissue plasminogen activator (t-PA).
  • the thrombolytic agent composition (b) as used in clinical practice comprises water as the carrier and pharmaceutical adjuvants as known in the art, i.e. isotonizing agents; acid, base or buffer substances to adjust the pH of the solution; and stabilizing agents for the thrombolytic agent.
  • Said thrombolytic agent composition (b) as stored before use is preferably a lyophilized product which can be reconstituted with Sterile Water for Injection (USP).
  • USP Sterile Water for Injection
  • the concentration of the thrombolytic agent in the lyophilized product depends on the nature of the thrombolytic agent.
  • tissue plasminogen activator t-PA
  • Tissue plasminogen activator may be present in an amount of from 20 mg to 100 mg per dosage form (i.e. 11.6 million IU to 58 million IU).
  • concentration of tissue plasminogen activator (t-PA) in the lyophilized product is usually in the range of from 20 mg to 100 mg per dosage form (i.e. 11.6 million IU to 58 million IU).
  • phosphoric acid and optionally sodium hydroxide may be used, so that upon reconstitution with sterile water for injection, a pH of about 7.3 is reached; in particular the lyophilized product comprises from 15 to 25% (w/w) of phosphoric acid.
  • stabilizing agent for the thrombolytic agent it is convenient to use an amino acid, for example, L-arginine in the case of tissue plasminogen activator (t-PA).
  • the stabilizing agent makes up the bulk of the lyophylized thrombolytic agent, typically from about 70% to about 80% (w/w).
  • tissue plasminogen activator t-PA compositions (b) comprising in the lyophilized state :
  • compositions (b) are, for example, wetting agents, e.g. polysorbate, in particular polysorbate 80 which may be used in a concentration up to 1%, more in particular up to 0.85%.
  • wetting agents e.g. polysorbate, in particular polysorbate 80 which may be used in a concentration up to 1%, more in particular up to 0.85%.
  • the thrombolytic agent according to the present invention is conveniently used in stroke patients in the following manner.
  • the lyophilized product comprising 20, 50 or 100 mg t-PA per dosage form (vial) is reconstituted with sterile water for injection, in the case of tissue plasminogen activator (t-PA), for example, to a solution having a concentration of 1 mg/ml.
  • the total dose of thrombolytic agent, in particular of t-PA will be at most 0.95 mg/kg bodyweight, preferably about 0.90 mg/kg bodyweight, with an absolute upper limit of 100 mg; preferably an upper limit of 90 mg.
  • Tissue plasminogen activator is administered to the stroke patient in the following dose regimen : up to 10% of total dose is administered as a bolus, the remaining 90% then being administered as a constant infusion during the next hour.
  • the administration of the thrombolytic agent will occur simultaneously with the administration of the neuroprotectant solution (a), which -it should be noted- will be continued after the administration of the thrombolytic agent has been completed.
  • the neuroprotectant and thrombolytic solutions may conveniently be co-administered with a physiological salt solution following to art-known infusion procedures.
  • Preferred products according to the present invention are those wherein the neuroprotectant solution (a) and the thrombolytic preparation (b) are miscible and - when mixed - form a stable formulation for up to eight hours at room temperature.
  • the two formulations can then be stored together, but in separate containers such as vials, pre ⁇ filled syringes and the like, and mixed immediately before use.
  • a preferred container comprises the neuroprotectant solution (a) and thrombolytic preparation (b) separately in a two-chamber container including means to mix both Uquids.
  • the two-chamber container ideally is a pre-filled, two-chamber syringe with bypass or similar means (e.g. a breakable seal) allowing mixing of the two separate solutions prior to administration, and which is further adapted for use with infusor devices.
  • a specific product is adapted for administering a neuroprotectant solution (a) and a thrombolytic preparation (b) following an hour of neuroprotectant therapy by an attending physician, and within three to six hours of the occurence of the ischaemic event. If the neuroprotectant is the preferred active ingredient lubeluzole, then the product comprises about 20 ml of solution or about 10 mg of lubeluzole.
  • the present invention evidently also concerns the use of a product as described hereinbefore for the preparation of a medicament for acute ischaemic stroke treatment.
  • the present invention relates to a method of treating patients suffering from acute ischaemic stroke, comprising administering simultaneously, separately or sequentially to said patients the components of a product as described hereinbefore.
  • the present invention also concerns the use of a neuroprotectant for the preparation of a medicament for preventing or delaying the process of infarction accompanying acute ischaemic stroke from being completed, thus enlarging the inclusion period during which the combined preparation of neuroprotectant/thrombolytic agent can be administered safely.
  • Example 1 Preparation of (-)-[cis] lubeluzole N-oxide hemihydrate.
  • Example 2 Preparation of 6-hydroxylubeluzole. a) Ethyl 4-(methylamino)-l-piperidinecarboxylate (59 mmol), 2-chloro-6-methoxy- benzothiazole (49 mmol) and sodium carbonate (50 mmol) were stirred at 180°C under N2 flow on an oil bath overnight. The mixture was cooled to room temperature. CHCI3 was added. The mixture was stirred on in ultrasonic bath for 10 minutes and then washed twice with water and once with a NaCl 50% solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated.
  • Ethyl 4-(methylamino)-l-piperidinecarboxylate 59 mmol
  • 2-chloro-6-methoxy- benzothiazole 49 mmol
  • sodium carbonate 50 mmol
  • Example 3 Post-Treatment in a Rat Photochemical Stroke Model.
  • mice Male Wistar rats, weighing 260-280 g, are anesthetized with halothane in a N2O/O2 mixture.
  • the animals are placed in a stereotactic apparatus, the scalp is incised for exposure of the skull surface, and a catheter is inserted into a lateral tail vein.
  • Rose Bengal (30mg/kg; 15 mg/ml in 0.9% NaCl) is infused intravenously for 2 minutes in animals with normal hemodynamics and blood gases.
  • the skull is focally illuminated with cold white light for 5 minutes by means of a fiber-optic bundle inside a 1-mm diameter objective. The light is aimed at the hindlimb area of the right parietal sensorimotor neocortex. Five minutes after infarct induction (i.e. 5 min after light offset), the rats are injected with the product.
  • Neurologic tests involving limb placing reactions, are conducted on the first two days after infarction at 24-hour intervals after its induction.Tactile forward and sideways placing are tested by lightly contacting the table edge with the dorsal or lateral aspect of a paw (2 tests). Proprioceptive forward and sideways placing involves pushing the paw against the table edge in order to stimulate Umb muscles and joints (2 tests). Rats are also put along the edge of an elevated platform in order to assess proprioceptive adduction : a paw is gently pulled down and away from the platform edge, and, upon sudden release, it is checked for retrieval and placing (1 test). For each of the 5 tests, placing scores are : 0, no placing; 1, incomplete and/or delayed placing; or 2, immediate, complete placing. For each limb, the summed tactile/proprioceptive placing score, including the platform test, is maximally 10. Results are reported from the deficient hindlimb contralateral to the neocortical infarct. Six rats are used for each dose.

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Abstract

Ces perfusions comprennent un neuroprotecteur et un agent thrombolytique sous forme d'une préparation combinée destinée à une utilisation simultanée, séparée ou séquentielle, dans le traitement de l'accident ischémique cérébral aigu. On a également prévu l'utilisation d'un neuroprotecteur dans la préparation d'un médicament destiné, d'une part, à traiter l'accident ischémique cérébral aigu et, d'autre part, à prévenir ou retarder l'accomplissement du processus de l'infarctus accompagnant l'accident ischémique cérébral aigu, augmentant ainsi la phase d'inclusion pendant laquelle on peut administrer sans danger la préparation combinée ci-dessus.
PCT/EP1996/004609 1995-10-25 1996-10-21 Perfusions de neuroprotecteurs et d'agents thrombolytiques Ceased WO1997015323A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9516280A JPH11515010A (ja) 1995-10-25 1996-10-21 神経保護物質および血栓溶解剤の注射剤
AU74913/96A AU7491396A (en) 1995-10-25 1996-10-21 Infusions of neuroprotectants and thrombolytic agents
EP96937215A EP0862457A1 (fr) 1995-10-25 1996-10-21 Perfusions de neuroprotecteurs et d'agents thrombolytiques

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EP95202887 1995-10-25
EP95202887.6 1995-10-25
EP96201642.4 1996-06-12
EP96201642 1996-06-12

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WO1997015323A1 true WO1997015323A1 (fr) 1997-05-01

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WO2005046615A3 (fr) * 2003-11-12 2006-06-22 Pharmacia & Upjohn Co Llc Compositions d'un inhibiteur selectif de la cyclo-oxygenase 2 et d'un agent modulateur de facteur neurotrophique pour le traitement de troubles lies au systeme nerveux central
US8652476B2 (en) 2009-07-27 2014-02-18 Niigata University Pharmaceutical composition for treating ischemic events
US12109265B2 (en) 2017-01-05 2024-10-08 Shimojani, LLC Drug regimen for treatment of cerebral ischemia

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WO2011013668A1 (fr) * 2009-07-27 2011-02-03 国立大学法人新潟大学 Composition pharmaceutique utilisable dans le cadre du traitement d'événements ischémiques

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Publication number Priority date Publication date Assignee Title
WO2005046615A3 (fr) * 2003-11-12 2006-06-22 Pharmacia & Upjohn Co Llc Compositions d'un inhibiteur selectif de la cyclo-oxygenase 2 et d'un agent modulateur de facteur neurotrophique pour le traitement de troubles lies au systeme nerveux central
US8652476B2 (en) 2009-07-27 2014-02-18 Niigata University Pharmaceutical composition for treating ischemic events
US9439961B2 (en) 2009-07-27 2016-09-13 Niigata University Pharmaceutical composition for treating ischemic events
US12109265B2 (en) 2017-01-05 2024-10-08 Shimojani, LLC Drug regimen for treatment of cerebral ischemia

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EP0862457A1 (fr) 1998-09-09
AU7491396A (en) 1997-05-15

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