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
  • A61K31/33—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
• • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the use of 5-(2-ethyl-2H-tetrazol-5-yl)-1 ,2,3,6-tetra- hydro-1 -methylpyridine for manufacturing a pharmaceutical preparation for the treatment of traumatic brain injury (TBI).
• TBI traumatic brain injury
• EP-A1 0 296 721 disclosed a class of piperidine or 1 ,2,3,6-terahydropyridine com ⁇ pounds substituted in the 5-position with a five-membered heterocyclic group includ ⁇ ing a subclass of optionally substituted 5-tetrazolyl-1 ,2,3,6-tetrahydro-pyridine com ⁇ pounds.
• the compounds were disclosed to have high affinity to central cholinergic receptors, in particular high affinity for central muscarinic Mi receptors, thus being useful in the treatment of Alzheimer's disease, senile dementia, and impaired learning and memory functions.
• TBI caused by physical or neurological conditions or various diseases is of in- creasing importance among the population and there is a great demand for effective and safe drugs for the treatment of such disorders and the sequelae thereof.
• the present invention relates to the use of 5-(2-ethyl-2H-tetrazol-5-yl)- 1 ,2,3,6-tetrahydro-1 -methylpyridine or an acid addition salt thereof
• traumatic brain injury is in this specification meant to include all conditions associated with trauma to the brain or spinal cord e.g. caused by physical forces acting on the scull or spinal column, ischaemia, stroke, arrested breathing, cardiac arrest, cerebral thrombosis or embolism, neurological problems caused by AIDS, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative events, cerebral infections, concussions or elevated intracranial pressure.
• the pharmaceutically acceptable acid addition salts of the compounds used in the invention are salts formed with non-toxic organic or inorganic acids.
• organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, suc ⁇ cinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propi- onic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sul ⁇ fonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline.
• Exemplary of such inorganic salts are those with hydrochlo ⁇ ric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
• the compound used according to the invention has now been found to be useful in the treatment of TBI. So, for example it improves cognitive performance following to moderate traumatic brain injury and it attenuates injury-reduced reductions of cholinergic neurones. Furthermore it has been found not to cause adverse cardiac 5 or other side effects in doses believed to be clinically relevant.
• the present invention provides a method for the prevention or treatment of TBI in man comprising the step of administering a therapeutically effective amount of 5-(2-ethyl-2H-tetrazol-5-yl)-1 ,2,3,6-tetrahydro-1 -methylpyridine io or acid addition salt thereof to a patient in need thereof.
• the compound used according to the invention and the pharmaceutically accep ⁇ table acid addition salts thereof may be administered in any suitable way, e.g. orally or parenterally, and the compounds may be presented in any suitable form for such 15 administration, eg. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
• An effective daily dose of the compound according to the invention or a pharmaceuti ⁇ cally acceptable salt thereof is from 10 ⁇ g/kg to 10 mg/kg body weight, preferably 20 25 ⁇ g/day/kg body weight to 1.0 mg/day/kg body weight. Accordingly, a suitable daily dose is 500 ⁇ g to 600 mg/day, preferably 1.0 mg to 100 mg.
• the compound used according to the invention may be obtained as described in EP-A1 0 296 721 and the acid addition salts thereof are easily prepared by methods 25 well known in the art.
• Rats were subjected to central fluid percussion traumatic brain injury as described by Dixon, C.E., et al., J. Neurosurgery, 67 (1987) 110- 119.
• the injured animals were treated s.c. daily on days 1 -15 postinjury beginning 24 hours after injury with either saline or 5-(2-ethyl-2H-tetrazol-5-yl)-1 , 2, 3, 6-tetrahydro-1 -methylpyridine, 3.6 ⁇ mol/kg or 15 ⁇ mol/kg.
• Body weight was recorded prior to injury and on Days 1 -5 postinjury and rotarod performance was determined on Days 1-5 post injury according to the method of Hamm, R.J., et al., J. Neurotrauma, 11 (1994) 187-196.
• the rotarod test was used to measure motor performance following TBI.
• Shaminjured animals (animals prepared for injury but not delivered a fluid pulse) were included for comparison.
• cortisol Following perfusion, brains were trimmed into two blocks and postfixed for 24 hours in the same solution at 10 °C. Coronal 40 ⁇ m sections were collected on a vibra- tome through the forebrain nuclei and every fifth section was processed for ChAT immunoreactivity. Parallel sections were stained for Nissi substance with cresyl violet for quantitative assesment of any possible cholinergic and non-cholinergic neuronal loss in the basal forebrain nuclei.
• Free floating forebrain sections were incubated in a final ChAT antibody concentra ⁇ tion (1 :50) of 1.0 ⁇ g/ml in a 0.01 M phosphate buffered saline (PBS) solution contain ⁇ ing 0.1% triton X-100.
• the forebrain sections were trimmed and incubated in the pri- mary antibody for 24 hours at room temperature in culture trays (4 sections/300 ⁇ LJwell).
• the ChAT immunoreactive neurones in the medial septal nucleus (MSN), the vertical limb nucleus of the diagonal band (VDB) and the nucleus basalis magnocel- lularis (NMB) were counted using a Microcomputer Imaging Device system (MCID) (Imaging Research Inc., Ontario, Canada).
• MSN medial septal nucleus
• VDB vertical limb nucleus of the diagonal band
• NMB nucleus basalis magnocel- lularis
• the boundary between MSN and VDB was defined as the anterior commisure.
• the NMB was defined as the imunolabelled neurons Iocated in the globulus pallidus and the adjoining part of the intemal capsule.
• Celle counts were made from each animal obtained at 0.2 mm intervals through the forebrain nuclei. Cell numbers are reported as group means per 10,000 ⁇ m2 for each forebrain nucleus.
• the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
• Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conven- tional tabletting machine.
• adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
• Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the vehicle, preferably sterile water, adjusting the solution to the desired volume, sterilization of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
• Typical examples of recipes for the formulations of the invention are as follows (amounts of active ingredient calculated as the free base):

Applications Claiming Priority (3)

Publications (1)

Family

ID=8102484

Family Applications (1)

Country Status (18)

Families Citing this family (9)

Family Cites Families (4)

• 1996
  • 1996-11-05 PL PL96326490A patent/PL326490A1/xx unknown
  • 1996-11-05 WO PCT/DK1996/000458 patent/WO1997017074A1/en not_active Application Discontinuation
  • 1996-11-05 HU HU9901051A patent/HUP9901051A2/hu unknown
  • 1996-11-05 AU AU74900/96A patent/AU706594B2/en not_active Ceased
  • 1996-11-05 KR KR1019980703360A patent/KR19990067353A/ko not_active Application Discontinuation
  • 1996-11-05 NZ NZ321546A patent/NZ321546A/xx unknown
  • 1996-11-05 CA CA002234824A patent/CA2234824A1/en not_active Abandoned
  • 1996-11-05 CZ CZ19981389A patent/CZ287441B6/cs not_active IP Right Cessation
  • 1996-11-05 SK SK581-98A patent/SK58198A3/sk unknown
  • 1996-11-05 EP EP96937193A patent/EP0866706A1/de not_active Ceased
  • 1996-11-05 TR TR1998/00801T patent/TR199800801T2/xx unknown
  • 1996-11-05 BR BR9611396A patent/BR9611396A/pt not_active Application Discontinuation
  • 1996-11-05 JP JP9517762A patent/JPH11514654A/ja active Pending
  • 1996-11-05 EA EA199800434A patent/EA000531B1/ru not_active IP Right Cessation
  • 1996-11-06 ZA ZA969320A patent/ZA969320B/xx unknown
• 1998
  • 1998-04-27 IS IS4726A patent/IS4726A/is unknown
  • 1998-05-05 NO NO982036A patent/NO982036L/no not_active Application Discontinuation
  • 1998-05-22 BG BG102480A patent/BG63150B1/bg unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events