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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • 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
  • A61K31/60—Salicylic acid; Derivatives thereof
  • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
  • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic 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
  • A61P25/04—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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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 a sodium ion channel blocker capable of binding to the outer receptor site of the SS1 or SS2 site of the ⁇ -subunit of a sodium ion channel, and aspirin.
• a sodium ion channel blocker capable of binding to the outer receptor site of the SS1 or SS2 site of the ⁇ -subunit of a sodium ion channel, and aspirin.
• the pharmaceutical composition according to the present invention can enhance the analgesic effect and reduce the amount of aspirin, thereby correspondingly reducing side effects and adverse reactions.
• aspirin drugs and steroid drugs belong to two major classes of anti-inflammatory drugs.
• Aspirin is a very widely used nonsteroidal analgesic and also used as an anti-inflammatory and analgesic.
• Salicylic acid-based aspirin mainly includes acetylsalicylic acid (ie, aspirin), salicylate (mainly sodium salt), and difluorosalicylic acid.
• Salicylic acid is the active ingredient of salicylate.
• the main mechanism of pharmacology, therapeutics and toxic side effects of aspirin drugs is the inhibition of prostaglandin (PG) biosynthesis in the body.
• the effects of aspirin include inhibiting the synthesis of prostaglandins and other nociceptive substances (such as bradykinin, histamine); inhibiting the vitality of white blood cells, and acting on the hypothalamic body temperature regulating center, thereby producing analgesic, anti-inflammatory and antipyretic effects; inhibiting platelets Prostaglandin cyclooxygenase, thereby preventing the production of thrombin (TXA T ) and inhibiting platelet aggregation (Chen Xiaozhi, Xiao Pingtian, Wang Zhongsen: New Practical Handbook of Drugs, 1994, SS10034400, Superstar Digital Library.). Aspirin has a significant analgesic effect, and can temporarily alleviate, for example, pain caused by a cold, headaches and fever caused by general nervous tension. Its main uses include:
• Aspirin may also cause the following side effects (Sun Qingwei, Hou Yi, New clinical uses and adverse reactions of aspirin drugs, 1998, SS10034347, Superstar Digital Library):
• Tetrodotoxin is a highly toxic non-protein neurotoxin with pharmacological effects such as analgesia, local anesthesia, and antispasmodic.
• TTX has a significant relief effect on a variety of dull and sharp pains, and has no dependence, but its clinical application value is limited due to the limitation of the dose.
• the chemical stimulation method that is, the mouse acetate torsion method (sensitivity to antipyretic analgesics), to observe whether there is synergistic analgesia between low-dose ⁇ and antipyretic analgesics. Effect to determine the clinical application of TTX as a synergistic analgesic.
• the object of the present invention is to provide a combination of a sodium ion channel blocker capable of binding to the outer receptor site of the SS1 or SS2 site of the ⁇ -subunit of a sodium ion channel and an aspirin in the preparation for use in mammals.
• a sodium ion channel blocker capable of binding to the outer receptor site of the SS1 or SS2 site of the ⁇ -subunit of a sodium ion channel and an aspirin in the preparation for use in mammals.
• synergistic analgesics According to the present invention, the sodium ion channel blocker and the aspirin-type analgesic are administered independently or mixed together and administered simultaneously to achieve a synergistic analgesic effect. Routes of administration include, but are not limited to, injection.
• the sodium ion channel blocker is tetrodotoxin and its analog
• the tetrodotoxin analog includes at least one of the following compounds: tetrodotoxin, dehydrated tetrodotoxin, amine tetrodotoxin, and alpha Tetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin, and tetrodoic acid. They are administered in a range of 0.01 ⁇ g to 20 ⁇ g per kg of body weight.
• the aspirin drug is salicylic acid or salicylate, and the dosage range is from 0.02 mg to 200 mg per kilogram of body weight.
• the sodium ion channel blocker also includes saxitoxin, which is a compound having a molecular formula of C 1Q H 17 N 7 0 4 and a derivative thereof.
• saxitoxin is a compound having a molecular formula of C 1Q H 17 N 7 0 4 and a derivative thereof.
• TTX analgesia The mechanism of TTX analgesia is mainly by blocking TTX-Sensitive (TTX-S) Na + channels, blocking Na + influx, and thus blocking the generation and conduction of nerve impulses.
• Aspirin a heat analgesic, reduces the pain and hyperalgesia caused by prostaglandin (PG) synthesis and prostaglandin PG (PGE 2 ) by inhibiting cyclooxygenase, and also reduces the pain caused by bradykinin. Effect and exert analgesic effect.
• PG prostaglandin
• PGE 2 prostaglandin PG
• the pain sensitivity caused by tissue damage is related to at least two mechanisms, namely bradykinin increase Thermal stimulation of sodium current and prostaglandin PGE 2 affects the voltage thresholds of several ion channels, including TTX-resistant (TTX-R) sodium channels.
• TTX-R TTX-resistant
• the analgesic effect of PGE 2 is closely related to TTX-R sodium channels (Khasar SG; Gold MS; Levine JD, A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat.
• TTX-RI Na TTX-resistant sodium current
• nociceptor sensitization is mediated by TTX-R sodium channels (Tanaka M; Cummins TR: Ishikawa K; Dib-Hajj SD; Black JA; Waxraan SG, SNS Na + channel expression increases in dorsal root ganglion neurons in the carrageenan in flammatory pain model.
• Tedoxine (tetrodotoxin, TTX) powder purity 95%, provided by Nanning Maple Leaf Pharmaceutical Co., Ltd., batch number: 0324C, diluted with citric acid buffer to the required concentration.
• Aspirin (ASP) powder purity 99%, produced by Shandong Xinhua Pharmaceutical Factory, batch number: 0005564, milled with 0.5% sodium carboxymethyl cellulose (CMO solution after use. Glacial acetic acid, analytical grade, Beijing May 2nd) Produced at the Nine-Five-Earth China Plant, batch number: 991117.
• mice Acetic acid writhing method in mice (Editor Xu Shuyun, Tong Ruyi, Chen Xiu, Pharmacological Experiment Methodology). A total of 380 mice were selected and fasted and water-free for 12 hours before the experiment. They were randomly divided into 19 groups, which were the control group (CMC solution) and the ASP group (25mg / kg, 50mg / kgs, 100mg / kgs, 150mg / kg, respectively). , 200 mg / kg in five dose groups), TTX alone (with LD 5 selected, 1/25 and 1/50 are 0.79 and 0.39 ⁇ g / kg, respectively), and the synergistic groups are: ⁇ (0.
• mice were injected intramuscularly (im) from mice, respectively
• the group was injected intramuscularly from both sides of the mouse at a volume of 0.1 ml / 10g. After 40 minutes, intraperitoneal injection of a painkiller 0.6% glacial acetic acid solution 0.1ml / 10g was observed and recorded within 15 minutes.
• mice showed repeated contraction of lumbar muscles, abdomen recession, extension of trunk and hind limbs, hip lifting, etc. as positive writhing response.
• the writhing body inhibition rate of each dose group was calculated according to the following formula ⁇
• Aspirin writhing half inhibition (ID 5 ) was calculated using the probability unit method.
• Carboxymethylcellulose sodium solution control 50 20 39.0 + 15.4

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• Health & Medical Sciences (AREA)
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• Chemical & Material Sciences (AREA)
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• Medicinal Chemistry (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Pain & Pain Management (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2001
  • 2001-06-22 CN CNB011159901A patent/CN1203860C/zh not_active Expired - Fee Related
• 2002
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  • 2002-06-18 ES ES02754135T patent/ES2296975T3/es not_active Expired - Lifetime
  • 2002-06-18 JP JP2003506913A patent/JP2004534821A/ja active Pending
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• 2008
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