WO2014180238A1 - 一种抗缺氧的药物组合物及其应用 - Google Patents

一种抗缺氧的药物组合物及其应用 Download PDF

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WO2014180238A1
WO2014180238A1 PCT/CN2014/075770 CN2014075770W WO2014180238A1 WO 2014180238 A1 WO2014180238 A1 WO 2014180238A1 CN 2014075770 W CN2014075770 W CN 2014075770W WO 2014180238 A1 WO2014180238 A1 WO 2014180238A1
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Prior art keywords
carnitine
hypoxia
vinpocetine
acid
pharmaceutically acceptable
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PCT/CN2014/075770
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English (en)
French (fr)
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谢和兵
李庆宜
顾书华
吕伟红
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常州高新技术产业开发区三维工业技术研究所有限公司
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Priority to US14/889,594 priority Critical patent/US9421181B2/en
Priority to ES14794605.7T priority patent/ES2668525T3/es
Priority to EP14794605.7A priority patent/EP2995308B1/en
Priority to NO14794605A priority patent/NO2995308T3/no
Publication of WO2014180238A1 publication Critical patent/WO2014180238A1/zh

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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

Definitions

  • the present invention relates to the field of medicines, and in particular to an anti-hypoxia pharmaceutical composition and its use in the treatment of diseases and conditions caused by hypoxia.
  • Hypoxia refers to pathological processes that cause abnormal changes in the metabolism, function, and morphological structure of tissues due to insufficient oxygen supply or oxygen barriers in tissues, such as shock, respiratory insufficiency, cardiac insufficiency, anemia, etc., which can cause brain, Vital organs such as the heart can be damaged by hypoxia or even death. Hypoxia is also common in pathological processes caused by environmental influences, such as altitude, high-altitude flight, diving operations, closed cabins or operations in tunnels. The problem of hypoxia is more serious, directly affecting human activities and even life safety. Therefore, research and development of anti-hypoxia drugs have important social significance.
  • hypoxia can reduce aerobic metabolism in various tissues of the body.
  • Many studies have shown that mitochondrial damage may be the central link in cellular hypoxia energy metabolism disorders.
  • the body produces a large number of free radicals.
  • Mitochondria are the main site for the production of endogenous free radicals and are the target sites for free radical attack.
  • Oxygen free radicals produced after hypoxia have toxic reactions to biomacromolecules, mainly manifested by lipid peroxidation, resulting in abnormal membrane structure and dysfunction.
  • Membrane fluidity is reduced after mitochondria are damaged by free radicals, resulting in a decrease in mitochondrial function and intracellular enzyme activity.
  • hypoxia Mitochondrial membrane phospholipid degradation, damage to mitochondria, affecting the activity of cytochrome c oxidase and ATP synthase, can reduce ATP synthesis, directly lead to damage to tissues and cells, and energy metabolism disorders. Therefore, prevention and treatment of hypoxia is paramount. It is to ensure the body's oxygen supply, to ensure the normal operation of the body's energy metabolism, but also to prevent and treat tissue cell damage. Clinically common dizziness, headache, tinnitus, vertigo, weak limbs, decreased exercise capacity, slow thinking, decreased memory; or nausea, vomiting, palpitation, shortness of breath, shortness of breath, rapid heartbeat, and hypoxia are all related to hypoxia. General hypoxia, hypoxia can also lead to serious complications such as myocardial infarction, angina pectoris, heart failure, pulmonary edema, cerebral edema, respiratory disorder, optic nerve injury, cranial nerve injury, severe stroke and other diseases.
  • Hypoxia can be divided into four types: hypotonic hypoxia, anemia, hypoxia, circulatory hypoxia, and tissue hypoxia.
  • anemia and tissue hypoxia are oxygen disorders
  • hypotonic hypoxia and Circulating hypoxia is a deficiency of oxygen supply.
  • the common clinical hypoxia is mixed hypoxia, hypotonic hypoxia and cyclic hypoxia.
  • Hypotonic hypoxia refers to the most common hypoxic state in production and life due to the obvious decrease in oxygen partial pressure and the lack of tissue oxygen supply, such as hypoxia caused by external respiratory dysfunction, high altitude hypoxia, high altitude hypoxia, The lack of oxygen in the tunnel, the lack of oxygen in the diving, and the lack of oxygen in the sealed compartment are all hypotonic hypoxia. Among them, high altitude hypoxia is the most common, and it is also the focus of prevention and treatment of hypoxia.
  • the lack of oxygen in the tunnel means that in a certain depth of the tunnel or hole, due to the high specific gravity of carbon dioxide, the proportion of oxygen in the air at the bottom of the tunnel decreases, and the partial pressure of oxygen decreases, resulting in lack of oxygen.
  • the lack of oxygen in the diving and the lack of oxygen in the sealed compartment refer to the environment.
  • the proportion of oxygen in the lower part is lower, and the partial pressure of oxygen is lowered, resulting in lack of oxygen.
  • the most common method of prevention and treatment of hypoxia is to add fresh air, oxygen or evacuation. Oxygen zone, no application of drugs.
  • Plateau hypoxia and high altitude hypoxia refer to plateaus or altitudes above 3,000 meters above sea level. Due to low air pressure, the partial pressure of oxygen is also reduced. The difference between the partial pressure of oxygen in the atmosphere and alveoli decreases with the increase of the height. Affects the rate of alveolar gas exchange, blood oxygen transport, and oxygen release in tissues, resulting in hypoxia caused by insufficient oxygen supply in the body. If you enter the plateau above 3000m in a short period of time, or when you return to the plateau after living in the plains for a period of time, you can have acute altitude sickness. The light ones have headache, dizziness, palpitations, shortness of breath, etc.
  • hypoxia symptoms of high altitude hypoxia cannot disappear on their own, and eventually lead to necrosis and death of important organs such as heart, brain and lung.
  • Plateau The traditional non-pharmacological treatment of hypoxia is inhalation of hyperbaric oxygen and evacuation from high altitude areas. The treatment effect is good but subject to conditions and is not suitable for widespread use. Commonly used drugs for high altitude hypoxia for adjuvant therapy.
  • diuretics such as acetazolamide, adrenocortical hormone drugs such as dexamethasone, vasodilator nimodipine and various vitamins and aminophylline are used, but anti-hypoxia
  • acetazolamide is the most commonly used, but acetazolamide only has a certain effect on patients who stay in the plateau for a short time.
  • Adverse reactions such as dehydration are not suitable for long-term use.
  • Other drugs such as hormones should not be used for a long time.
  • Circulating hypoxia refers to the hypoxia caused by the decrease of tissue blood flow and the decrease of tissue oxygen supply. It is also called hypodynamic hypoxia. It is common in heart disease, angina pectoris, cardiac insufficiency, myocardial infarction, heart failure vascular occlusion disease, Patients with stroke, arteriovenous atherosclerosis, etc., are often treated with hemodynamic drugs, such as nitrates, beta blockers, calcium antagonists, and other cerebral vasodilators such as vinpocetine. Wait. These drugs have limited effects in preventing and treating damage to tissues and tissues due to hypoxia, and cannot meet the prevention and treatment cycle. The need for sexual hypoxia.
  • Trimetazidine a trimetazidine
  • Trimetazidine is commonly used in the treatment of coronary insufficiency, angina pectoris, and old myocardial infarction. It is a potent anti-angina drug that works slower than nitroglycerin. The effect lasts longer.
  • Normal myocardial energy (ATP) supply 60%-70% comes from free fatty acid ⁇ oxidation, 20%-25% is glucose oxidation, and 5%-10% is glycolysis.
  • Trimetazidine can promote glucose oxidation, although trimetazidine can inhibit fatty acid oxidation, promote glucose oxidation, and has certain anti-myocardial hypoxia, but glucose oxidation can only provide 20% of myocardial and skeletal muscle activity. Energy, far from meeting the energy required for myocardial and skeletal muscle activity, in addition, due to the oxidation of fatty acids under the inhibition of trimetazidine, a large number of fatty acids will accumulate, accumulated fatty acids will destroy cell membrane and mitochondrial structure, and destroy acetone The activity of acid dehydrogenase, in turn, inhibits glucose oxidation. Therefore, the use of trimetazidine alone for the prevention and treatment of hypoxia also has certain drawbacks.
  • the ideal anti-hypoxia drug should be under the condition of low air pressure or low oxygen supply, that is, under the condition of hypotonic hypoxia or circulating hypoxia, the oxygen supply of the body should be ensured first, and the energy metabolism of the body should be guaranteed to operate normally.
  • the protective effect of oxygen-damaged tissue cells, long-term application has no obvious adverse reactions, and the combination of prevention and treatment has dual characteristics. Obviously, there is currently no quality stable pharmaceutical preparation with the above characteristics.
  • One of the objects of the present invention is to provide an anti-hypoxia pharmaceutical composition.
  • Another object of the present invention is to provide a pharmaceutical preparation which is resistant to hypoxia and which prevents and treats diseases and conditions caused by hypoxia.
  • a third object of the present invention is to provide a method for preventing and treating diseases caused by hypoxia and hypoxia.
  • L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for promoting fatty acid oxidation are combined or combined into a composition, which has an anti- Hypoxia and the use of diseases and conditions caused by prevention and treatment of hypoxia, and it can not only ensure the body's oxygen supply, but also protect the body's energy metabolism, and protect the tissue cells damaged by hypoxia.
  • the combination of drugs or combinations into compositions has a significant synergistic effect compared to single-agent applications, exerts significant anti-hypoxia effects, and is suitable for the prevention and treatment of various diseases and conditions caused by hypoxia.
  • the present inventors have found that a drug for treating angina pectoris and a pharmaceutically acceptable salt thereof, particularly preferably trimetazidine hydrochloride, are combined or combined with vinpocetine and L-carnitine or a derivative thereof to form a composition.
  • the utility model has the advantages of anti-hypoxia and prevention and treatment of diseases and diseases caused by hypoxia, which can ensure the oxygen supply of the body, ensure the normal operation of the body's energy metabolism, and protect the tissue cells damaged by hypoxia, and the long-term application is not obvious.
  • the combination of adverse reactions, prevention and treatment combines synergistic effects with single agents to exert significant anti-hypoxia effects and is suitable for the treatment and prevention of various diseases and conditions caused by hypoxia.
  • hypotoxia can be understood as a pathological process which causes abnormal changes in the metabolism, function and morphological structure of tissues due to insufficient oxygen supply to the tissues or oxygen barriers.
  • the anti-hypoxia composition of the present invention is used for Prevention and treatment due to insufficient oxygen supply or oxygen barrier in the tissue, resulting in abnormal changes in the metabolism, function and morphological structure of the tissue, especially suitable for the prevention and treatment of tissue oxygen supply, resulting in abnormal metabolism, function and morphological structure of the tissue Variety.
  • hypotonic hypoxia and circulating hypoxia are insufficient oxygen supply to the tissue.
  • the anti-hypoxia composition of the present invention is preferably a composition resistant to hypotonic hypoxia and circulating hypoxia.
  • Hypetic hypoxia refers to the most common hypoxic state in production and life due to the obvious decrease in oxygen partial pressure and the lack of tissue oxygen supply, such as hypoxia caused by external respiratory dysfunction, high altitude hypoxia, high altitude hypoxia, tunnel Hypoxia, hypoxia in the diving, and hypoxia in the sealed compartment are all hypotonic hypoxia, and the most common in the plateau hypoxia. Circulating hypoxia is also a common type of hypoxia. Cyclic hypoxia refers to the hypoxia caused by the decrease of tissue blood flow and the decrease of tissue oxygen supply. It is also called hypodynamic hypoxia. It can be divided into vascular occlusion hypoxia.
  • Vascular stenosis hypoxia refers to occlusion of blood vessels due to the formation of blood clots, resulting in hypoxia due to insufficient tissue supply.
  • Vascular stenosis Hypoxia refers to an increase in blood flow resistance due to arteriovenous atherosclerosis, resulting in hypoxia due to insufficient tissue blood supply.
  • Cardiac insufficiency hypoxia refers to insufficient blood pumping capacity due to insufficient heart power, resulting in hypoxia due to insufficient tissue blood supply.
  • hypoxia The clinical manifestations of hypoxia include dizziness, headache, tinnitus, vertigo, weak limbs, decreased exercise capacity, slow thinking, memory loss, nausea, vomiting, palpitation, shortness of breath, shortness of breath, rapid heartbeat, and other general hypoxia.
  • serious diseases such as myocardial infarction, heart failure, angina pectoris, pulmonary edema, cerebral edema, shock, respiratory disorder, stroke, optic nerve injury, and cranial nerve injury.
  • the anti-hypoxia according to the present invention is a preventive and therapeutic effect on the clinical manifestations of diseases and diseases caused by hypoxia, especially for dizziness, headache, tinnitus, vertigo, weak limbs, decreased exercise ability, slow thinking, memory loss, General hypoxic clinical manifestations such as nausea, vomiting, palpitation, shortness of breath, shortness of breath, rapid heartbeat, and myocardial infarction, angina pectoris, pulmonary edema, cerebral edema, stroke, shock, respiratory disorder, optic nerve injury, cranial nerve injury, etc. The prevention and treatment of serious diseases.
  • the present invention inventively invents an anti-hypoxia pharmaceutical composition.
  • the pharmaceutical composition of the present invention comprises vinpocetine and L-carnitine or a derivative thereof and a pharmaceutically acceptable salt thereof, and the weight ratio between them is one of important technical features of the present pharmaceutical composition.
  • the weight ratio of vinpocetine and L-carnitine or a derivative thereof and a pharmaceutically acceptable salt thereof may be about 1:3 to 30,000, which is about 1:33 to 1800.
  • the weight ratio of vinpocetine and L-carnitine or a derivative thereof and a pharmaceutically acceptable salt thereof can be determined according to the selected compatible drug, the mode of administration, and the indication.
  • the pharmaceutical composition of the present invention comprises vinpocetine and L-carnitine, and the weight ratio between them is the weight of the pharmaceutical composition.
  • the weight ratio of vinpocetine to L-carnitine may be about 1:33-1800, about 1:300, and the vinpocetine and L-carnitine in the present invention.
  • the weight ratio can be determined according to the difference in the mode of administration and the indication.
  • the pharmaceutical composition of the present invention comprises but contains not only L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof and vinpocetine, and the pharmaceutical composition of the present invention may further comprise L-carnitine or a derivative thereof or a pharmaceutically acceptable drug thereof Salt, vinpocetine and trimetazidine or their medicinal ⁇
  • the pharmaceutical composition of the present invention comprises vinpocetine, L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof and trimetazidine or a pharmaceutically acceptable salt thereof, and the weight ratio between them is important for the pharmaceutical composition.
  • the weight ratio between vinpocetine and L-carnitine or a derivative thereof, and a pharmaceutically acceptable salt thereof and trimetazidine hydrochloride and a pharmaceutically acceptable salt thereof may be about It is 1:3-30000:0.03-60, which is about 1:33-1800:0.5-12.
  • the weight ratio of vinpocetine, L-carnitine or a derivative thereof, and a pharmaceutically acceptable salt thereof and trimetazidine hydrochloride and a pharmaceutically acceptable salt thereof may be selected according to the selected drug, the administration mode and the indication. The best weight ratio was studied differently.
  • the pharmaceutical composition of the present invention comprises vinpocetine, L-carnitine and trimetazidine hydrochloride, and the weight ratio between them is one of the important technical features of the present pharmaceutical composition.
  • the weight ratio between vinpocetine and L-carnitine and trimetazidine hydrochloride may be about 1:33-1800:0.5-12, about 1:300. :2.
  • the weight ratio of vinpocetine, L-carnitine or trimetazidine hydrochloride can be determined according to the difference in the mode of administration and the indication.
  • L-carnitine derivatives include, but are not limited to, L-carnitine, acetyl-L-carnitine, propionyl L-carnitine, and pharmaceutically acceptable salts thereof. Preference is given to L-carnitine, acetyl-L-carnitine and pharmaceutically acceptable salts thereof. Especially preferred is L-Carnitine.
  • the pharmaceutically acceptable salts of the present invention include salts of L-carnitine or a derivative thereof and trimetazidine with an inorganic or organic acid, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, Phosphate, acetic acid, maleic acid, fumaric acid, sulphuric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • the anti-hypoxia composition of the present invention may also be any combination of drugs capable of improving/promoting cardiac or cerebral hemodynamics, such as may be a nitrate ester such as isosorbide mononitrate, nitroglycerin, ⁇ A receptor blocker such as carvedilol, a calcium antagonist such as a combination of two or more of nifedipine, may also be a drug that improves/promotes cardiac or cerebral hemodynamics.
  • a pharmaceutical composition consisting of one or several drugs and a combination of L-carnitine or a derivative thereof, trimetazidine, a pharmaceutically acceptable salt thereof and vinpocetine, or a combination of two or three Things.
  • a pharmaceutical preparation comprising the active ingredient vinpocetine, an active ingredient L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical preparation of the present invention comprising vinpocetine and L-carnitine or a derivative thereof and a pharmaceutically acceptable salt thereof as an active ingredient and One or more pharmaceutically acceptable carriers.
  • the weight ratio of vinpocetine and L-carnitine or a derivative thereof and a pharmaceutically acceptable salt thereof may be from about 1:3 to about 1:30000, for example from about 1:33 to 1800.
  • the pharmaceutical preparation of the present invention contains vinpocetine and L-carnitine as active ingredients and one or more pharmaceutically acceptable carriers.
  • the weight ratio of vinpocetine to L-carnitine may be from about 1:33 to about 1:1800, for example about 1:300.
  • the pharmaceutical preparation of the present invention contains vinpocetine, L-carnitine or a derivative thereof, and a pharmaceutically acceptable salt thereof and trimetazidine and a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers.
  • the weight ratio of vinpocetine, L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof and trimetazidine or a pharmaceutically acceptable salt thereof may be about 1:3-30000:0.03-60, about 1: 33-1800: 0.5-33
  • the pharmaceutical preparation of the present invention contains vinpocetine, L-carnitine and trimetazidine hydrochloride as active ingredients and one or more pharmaceutically acceptable carriers.
  • the weight ratio of vinpocetine, L-carnitine and trimetazidine hydrochloride may be about 1:15-1500:0.1-25, which is about 1:300:2.
  • the pharmaceutical preparation of the present invention can be administered orally or parenterally.
  • Parenteral administration includes intravenous, intramuscular, peritoneal, subcutaneous, rectal, and topical routes of administration.
  • the pharmaceutical preparation of the present invention may be in a form suitable for oral use such as a tablet, a sustained release tablet, a troche, an aqueous solution or an oil suspension, a granule, an emulsion, a hard or soft capsule, or a syrup.
  • the pharmaceutical preparation of the present invention may be in the form of a combined package.
  • the combination packaged medicine may be the same as the oral preparation or the injection preparation.
  • compositions of the present invention for oral use can be prepared according to any of the known methods for preparing oral pharmaceutical compositions in the art, and such compositions may comprise one or more materials selected from the group consisting of: sweeteners, corrections Flavoring agents, colorants and preservatives to provide a pharmaceutically elegant and palatable preparation.
  • Tablets contain the active component in admixture with a pharmaceutically acceptable excipient suitable for the preparation of tablets.
  • excipients may be: inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, sodium carboxymethylcellulose, corn starch or alginic acid
  • Adhesives such as starch, gelatin, polyvinylpyrrolidone or gum arabic
  • lubricants such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or may be coated by techniques well known in the art to mask the unpleasant taste of the drug or delay its disintegration and absorption in the gastrointestinal tract, and thus over a longer period of time. Maintain a sustained role within.
  • a water-soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose or a time delay material such as ethylcellulose, cellulose acetate butyrate may be used.
  • the oral preparation of the present invention may also be provided in a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate and kaolin, or in a soft gelatin capsule, wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene Alcohol or oily media such as peanut oil, liquid paraffin or olive oil are mixed.
  • an inert solid diluent such as calcium carbonate, calcium phosphate and kaolin
  • a soft gelatin capsule wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene Alcohol or oily media such as peanut oil, liquid paraffin or olive oil are mixed.
  • aqueous suspensions of the present invention comprise the active substance and excipients or dispersing agents suitable for preparing the aqueous suspension in admixture therewith.
  • the excipients include: suspensions such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic.
  • the dispersing agent may be a natural phospholipid such as lecithin, or a condensation product of an alkylene oxide and a fatty acid, such as polyoxyethylene stearate, or a condensation product of an alkylene oxide with a long-chain aliphatic alcohol such as heptaethylene.
  • the injection of the present invention is a sterile injectable powder containing an active substance, which is obtained by dissolving crystals using water or an organic solvent such as alcohol, methanol, acetone, chloroform or the like, and drying or freeze-drying at room temperature to obtain a sterile injectable powder or crystal.
  • the injection of the present invention is a sterile injectable solution containing an active substance, and a sterile injectable solution can be formed using water, or Ringer's solution, sodium chloride solution and/or glucose solution as a carrier.
  • the injection of the present invention can be introduced into the bloodstream of a patient or other site where it can be administered by local rapid intramuscular injection, or introduced into the bloodstream of a patient by intravenous drip.
  • the preparation of the present invention may be a combined package preparation, and the marketed L-carnitine or a derivative thereof and a pharmaceutically acceptable salt preparation thereof and the trimetazidine and a pharmaceutically acceptable salt thereof are packaged according to a certain dose to prepare a combination.
  • Packaging preparation may be a combined package preparation, and the marketed L-carnitine or a derivative thereof and a pharmaceutically acceptable salt preparation thereof and the trimetazidine and a pharmaceutically acceptable salt thereof are packaged according to a certain dose to prepare a combination.
  • the preparation of the present invention may be a combined package preparation, and the marketed L-carnitine or a derivative thereof and a pharmaceutically acceptable salt thereof, and trimetazidine and a pharmaceutically acceptable salt thereof and a vinpocetine preparation are combined according to a certain dose.
  • Packaging is carried out to prepare a combined package preparation.
  • Another aspect of the invention provides a method of preparing a pharmaceutical formulation comprising admixing a pharmaceutical composition of the invention as described above with one or more pharmaceutically acceptable carriers or excipients.
  • a further aspect of the present invention provides a method for anti-hypoxia, which comprises a 3-keto acid-CoA thiolase inhibitor such as trimetazidine hydrochloride, a phosphodiesterase inhibitor such as vinpocetine,
  • a 3-keto acid-CoA thiolase inhibitor such as trimetazidine hydrochloride
  • a phosphodiesterase inhibitor such as vinpocetine
  • One of the drugs alone and L-carnitine or a derivative thereof and a pharmaceutically acceptable salt, or two drugs with L-carnitine or a derivative thereof and a pharmaceutically acceptable salt, will be introduced into the deficiency by sequential or simultaneous administration.
  • Oxygen environment or disease patients caused by hypoxia, or the pharmaceutical composition of the present invention or a pharmaceutical preparation prepared therefrom is administered to a patient who is going to enter an oxygen-deficient environment or a disease caused by hypoxia, and is used for anti-hypoxia treatment by hypoxia
  • the resulting disease can be used to prevent hypoxia.
  • a preferred example is a pharmaceutical preparation consisting of L-carnitine and Vinpocetine.
  • the daily dose for administration of 60 kg is: 10-500 mg/kg of L-carnitine or its derivative; and 0.05-0.5 mg/kg of Vinpocetine.
  • a preferred example is a pharmaceutical preparation consisting of L-carnitine and vinpocetine and trimetazidine hydrochloride.
  • the daily dose for administration to adults is: 10-500 mg/kg for L-carnitine or its derivatives; 0.05-0.5 mg/kg for vinpocetine and 0.1-1.5 mg for trimetazidine hydrochloride. /kg.
  • Example 1 Observing the effect of different doses of intravenous injection of vinpocetine and L-carnitine on hypoxia in mice
  • Vinpocetine 0.75, 2.25, 4.5 mg/kg, which is equivalent to a daily dose of 5, 15, 30 mg ;
  • L-carnitine 150, 450, 1350 mg/kg, which is equivalent to about 1, 3, and 9 g of daily dose for humans (the highest dose is about three to one-quarter of the maximum dose for clinical injection).
  • L-carnitine + vinpocetine According to the efficacy of two drugs, L-carnitine and vinpocetine, set 150+0.75, 150+2.25, 150+4.5, 450+0.75, 450+2.25, 450+4.5 1350+0.75, 1350+2.25, 1350+4.5mg/kg o 100 male mice were used, weighing 20 ⁇ 2g, randomly divided into 10 groups according to body weight, 10 mice in each group, 10ml/kg tail vein injection, The blank control group was given an equal volume of normal saline once a day for 7 days.
  • mice After the last administration for 1 hour, each group of mice was placed in a 160 ml jar with 5 g of sodium lime in advance, one bottle per bottle, then The cap was smeared with Vaseline, and the death was used as an indicator to record the survival time of the mice.
  • Common animal models of anti-hypoxia research and anti-hypoxia drugs Journal of PLA University of Pharmacy, 2010, 26 (2 ) : 170-173 The results are shown in Table 1.
  • Example 2 Observing the effect of different doses of L-carnitine + vinpocetine on hypoxia in mice under normal pressure and hypoxia
  • Vinpocetine 0.75, 1.5, 2.25mg/kg is equivalent to a daily dose of 5, 10, 15mg ;
  • L-carnitine 150, 300, 450mg/kg, which is equivalent to a daily dose of 1, 2, 3g;
  • L-carnitine + vinpocetine According to the efficacy of two drugs, L-carnitine and vinpocetine, 150+1.5, 300+0.75, 300+1.5, 300+2.25 450+1.5mg/kg.
  • mice Eighty male mice were used, weighing 20 ⁇ 2g, randomly divided into 8 groups according to body weight, 10 mice in each group, 20ml/kg The drug, the blank control group was given an equal volume of normal saline, once a day for 7 consecutive days. After the last administration for 1 hour, each group of mice was placed in a 160 ml jar with 5 g of sodium lime in advance, one bottle per bottle. Then, the cap was smeared with Vaseline and the death time was recorded using the death as an indicator.
  • Example 3 Comparison of L-carnitine 450mg/kg + vinpocetine 1.5mg/kg and unilateral intragastric administration on normal hypoxia in mice: 40 male mice, weighing 20 ⁇ 2g, were randomly divided into body weight according to body weight. 4 groups, 10 rats in each group, 20ml/kg were intragastrically administered, and the blank control group was given an equal volume of normal saline once a day for 7 days. After the last administration for 1 hour, each group of mice was pre-added. In a 160 ml jar of 5 g of sodium lime, one bottle per bottle, and then the cap was smeared with Vaseline, and the survival time was recorded using the death as an indicator. The results are shown in Table 3.
  • Example 4 The effects of different doses of vinpocetine, L-carnitine and trimetazidine hydrochloride on the hypoxia of mice under normal pressure and hypoxia
  • Trimetazidine Hydrochloride 1.12, 2.25, 4.5, 9 mg/kg is equivalent to a daily dose of 7.5, 15, 30, 60 mg.
  • Vinpocetine 0.75, 2.25, 4.5 mg/kg, which is equivalent to a daily dose of 5, 15, 30 mg ;
  • L-carnitine 150, 450, 1350mg / kg equivalent to human daily dose 1, 3, 9g; 370 male mice were used, weighing 20 ⁇ 2g, randomly divided into 37 groups according to body weight, 10 rats in each group, 10ml/kg for injection, and the blank control group was given an equal volume of normal saline, 1 time/day for 7 consecutive days. After the last administration for 1 h, each group of mice was placed in a 160 ml jar with 5 g of sodium lime in advance, one bottle per bottle, and then the cap was smeared with Vaseline, and the death was used as an indicator to record the survival of the mice. Time, the results are shown in Table 4.
  • Example 5 combination of L-carnitine and vinpocetine, combination of L-carnitine, vinpocetine and trimetazidine hydrochloride, intragastric administration, unilateral and compound effects on acute cerebral hypoxia model in mice
  • mice Seventy male Kunming mice were randomly divided into 7 groups: normal control group, L-carnitine 450 mg/kg, trimetazidine 9 mg/kg, Vinpocetine 1.5 mg/kg, L-Carnitine 450+ Qumei Hexazine 9 mg/kg group, trimetazidine 9+ vinpocetine 1.5 mg/kg, L-carnitine 450+ trimetazidine 9 + vinpocetine 1.5 groups, 10 rats in each group. 20 mg/kg was intragastrically administered, and the normal control group was given an equal volume of physiological saline once a day for 7 days. After the last administration for 1 h, the mice were quickly decapitated from behind the ear, and the stop time of the mice after the break of the head was recorded by the stopwatch. The results are shown in Table 5.
  • Trimetazidine 9 18.5 ⁇ 2.1
  • the brain tissue was made into a 10% brain tissue homogenate. The homogenate was centrifuged at 2000 r/min for 5 min at 4 ° C, and the supernatant was separated.
  • the amino acid analyzer was used to detect glutamic acid (Glu), aspartic acid (Asp), and Y-aminobutyric acid (GABA) in mouse brain tissue. , the content of glycine (Gly).
  • Excitatory amino acids (EAA) represented by Glu, Asp, GABA and Gly after brain injury are highly contained in the brain.
  • Glu N-methyl-D-aspartate
  • L-carnitine 450 + trimetazidine 9 mg / kg group and L-carnitine 450 + trimetazidine 9 + Vinpocetine 1.5 mg / kg group can significantly prolong the gasping time after decapitation in mice (P ⁇ 0.01), and synergistic effect, indicating significant anti-cerebral hypoxia, suggesting that the composition has hepatic ischemia and hypoxia in the treatment of stroke, sequelae of cerebral infarction, sequelae of cerebral hemorrhage and cerebral arteriosclerosis The role of the disease caused.
  • the compound can significantly reduce the EAA content in the brain tissue compared with the single side, thereby exerting a protective effect on hypoxic brain damage, suggesting that the composition has therapeutic nerve damage caused by ischemia and hypoxia, such as optic nerve damage, The efficacy of diseases such as cranial nerve injury.
  • Vinpocetine and L-carnitine were estimated according to the manufacturer's recommended dose.
  • the equivalent doses of the rats were: Vinpocetine: 0.75, 1.5, 2.25 mg/kg, equivalent to human daily dose 5, 10, 15mg
  • L-carnitine 150, 300, 450mg/kg, which is equivalent to the daily dose of human 1, 2, 3g
  • L-carnitine + vinpocetine According to the efficacy of L-carnitine and vinpocetine, the dose of L-carnitine + vinpocetine was 150+1.5, 300+1.5, 450+1.5, 300 +2.25, 300+0.75mg/kg.
  • mice 70 Wister rats, weighing 150g ⁇ 190g, were randomly divided into 7 groups: normoxia control group: plain words, materials; acute hypoxia group: animals were placed in hypobaric oxygen chamber, the oxygen partial pressure in the chamber was Ll.OlKpa (about equivalent to an oxygen partial pressure of 5000m above sea level) After continuous decompression and oxygen deprivation for 3d, it is placed in a low-pressure oxygen chamber with a partial pressure of oxygen of 13.25Kpa (about the equivalent of 4000m of oxygen). Specimens, Qi Yang. Common animal models and anti-hypoxia drugs for anti-hypoxia research. Chinese Journal of Pharmacy, 2010, 26 (2): 170-173]; Administration group: 10ml/kg intragastric administration.
  • Blood gas analysis blood sampling of aorta lml, heparin anticoagulation, determination of blood oxygen partial pressure Pa0 2 , oxygen saturation Sa0 2 and other blood gas indicators, the results are shown in Table 8.
  • Morphological changes of myocardial tissue After the rats were sacrificed, the hearts were embedded in paraffin, 4 ⁇ sections, HE staining, and the myocardial changes of myocardial tissue were observed by light microscopy. Under the light microscope, the myocardial fibers in the normoxic control group were arranged neatly, and the cells were full.
  • the administration group can significantly increase the hemodynamic index, indicating that the composition has anti-hypoxia effect, and can be used for prevention of diseases characterized by low hemodynamic indexes such as cardiac insufficiency, heart failure, shock and the like. And treatment.
  • each of the drug-administered groups significantly increased the arterial oxygen partial pressure and oxygen saturation (P ⁇ 0.01).
  • the patented composition has anti-hypoxia for preventing and treating high altitude disease and external respiratory dysfunction. Effect.
  • Example 7 Observation of the protective effect of vinpocetine 1.5+ L-carnitine 450 + trimetazidine hydrochloride 9 mg/kg on the acute myocardial hypoxia in rats
  • Rats were anesthetized with pentobarbital sodium 45 mg/kg intraperitoneally, placed supine on the rat table, shaved in the surgical area, iodophor disinfected, the trachea was incision and intubated, and the thoracic rib was opened along the left sternal border.
  • the laser Doppler flowmeter probe was placed in the hypoxic zone at 2 min, 30 min, and 180 min after ligation of the anterior descending coronary artery (the blood flow in other regions was above the upper limit of the instrument detection), and the instrument was adjusted to be relatively stable when the blood flow was relatively stable.
  • the myocardial blood flow was recorded for 1 min, and the mean value was taken.
  • the animals were sacrificed at the end of the recording, and the myocardial tissue homogenate was taken from the infarcted area, the hypoxic area and the non-anoxic area.
  • the myocardial blood flow and myocardial muscle were measured at 2 min, 30 min and 3 h after myocardial ischemia.
  • the content of glucose, adenosine triphosphate, 6-phosphate fructokinase, pyruvate dehydrogenase and free fatty acid in the tissue was centrifuged at 4000 rpm for 10 min, and the supernatant was tested for glucose by semi-automatic biochemical analyzer; Elisa kit was used. Detection of 6-phosphokinase (6-PFK), pyruvate dehydrogenase (PDH); detection of free fatty acids and ATP by spectrophotometry. The results are shown in Tables 10 ⁇ 12.
  • Glucose In the three-time observation window after acute hypoxia in the myocardium, the glucose content in the myocardial tissue in the non-anoxic area does not change much; in the hypoxic and infarcted myocardium, the glucose content should be increased due to dysfunction and glycolysis. Significantly lower, but The content of glucose in myocardial tissue at 30 min and 3 h after hypoxia was not significantly decreased, and there was no statistically significant difference compared with saline control group (P ⁇ 0.05).
  • ATP Compared with the saline group at 2 min, 30 min and 3 h after myocardial hypoxia, the results showed that the myocardial tissue in the infarcted area of the treatment group increased significantly after myocardial hypoxia for 2 min (P ⁇ 0.01).
  • the increase of glucose was consistent in a short time after hypoxia; the non-anoxic area was significantly decreased after 30 min (P ⁇ 0.001); the ATP in the non-hypoxic area of the normal saline control group was significantly decreased after 3 h of hypoxia and the treatment group was significantly increased.
  • 6-phosphofrutokinase (6-PFK) is an enzyme that catalyzes the conversion of fructose 6-phosphate fructose to fructose 1,6-diphosphate in a glycolysis reaction. It is a non-equilibrium reaction and is an important rate-limiting enzyme in glycolysis. An increase in the amount means that the glycolytic pathway is active.
  • the results of this experiment showed that compared with the corresponding saline control group, the 6-PFK content in the drug-administered group was decreased in a short period of time after administration, but it increased significantly from 30 minutes after administration to 3 hours (P ⁇ 0.05), suggesting that the drug was used for 2 minutes. Post-glycolysis is very active.
  • PDH Pyruvate dehydrogenase
  • the role of PDH is an important enzyme for the aerobic oxidation of pyruvate to acetyl-CoA; an increase in its activity means an increase in aerobic oxidation.
  • the experimental results show that the drug-administered group is coronaryly ligated.
  • the amount of PDH in the non-anoxic area, hypoxic area and infarct area of the myocardium was significantly lower than that of the control group within 2 min, but the amount of PDH increased gradually after 2 min; 3 h after the connection in the non-anoxic area, anoxic area
  • the PDH content in the infarcted area has increased significantly, which is significantly different from the corresponding saline group.
  • Free fatty acid After 2 minutes of treatment, the amount of free fatty acids increased in non-anoxic, hypoxic, and infarcted areas compared with the saline group, but the increase did not reach statistical significance.
  • Blood flow in myocardial infarction blood flow, physiological and myocardial tissue in infarcted area were measured at different time after injection of trimetazidine hydrochloride 9 + vinpocetine 1.5 + L-carnitine 450 mg/kg in acute myocardial hypoxia rat model.
  • the saline group had an increase in blood flow, but the increase did not reach statistical significance.
  • composition can optimize the energy supply of hypoxic myocardial tissue, suggesting the use of prevention and treatment of myocardial infarction, and other severe ischemic cardiomyopathy.
  • Non-anoxic area hypoxic area infarct area saline group treatment group saline group treatment group saline group treatment group
  • Example 8 L-carnitine: combination drug formulation of different doses of vinpocetine
  • the present invention is exemplified by a combination of L-carnitine and Vinpocetine, and various combination preparations containing different dose ratios of L-carnitine and Vinpocetine can be prepared according to the following data:
  • L-carnitine 100mg-30000mg / day; vinpocetine lmg-30mg / day
  • Vinpocetine L-carnitine Vinpocetine (heavy): L-carnitine (heavy)
  • L-carnitine and vinpocetine are sieved through 80 mesh, mixed with starch and lactose, and added with starch slurry to make soft material. After granulating with 14 mesh sieve, set it at 70 ° C ⁇ 8 (after TC drying) The 12-mesh sieve is granulated, and after adding dry starch and magnesium stearate, it is compressed and obtained.
  • Cod liver oil or refined edible vegetable oil Cod liver oil or refined edible vegetable oil
  • Example 9 Combination pharmaceutical preparation containing L-carnitine, vinpocetine and trimetazidine hydrochloride
  • L-carnitine Vinpocetine: Trimetazidine Hydrochloride (300mg: lmg: 2mg)
  • the drug is passed through a 80 mesh sieve, mixed with starch lactose, and added with starch slurry to make a soft material. After granulating with a 14 mesh sieve, set it at 70 ° C ⁇ 8 (TC dry after 12 mesh sieve, add dry After the starch and magnesium stearate are mixed, the tablet is obtained.
  • Example 10 Combination pharmaceutical preparation containing L-carnitine and Vinpocetine
  • L-carnitine Vinpocetine, suppository size 300mg: 0.25mg.
  • Example 11 Combination pharmaceutical preparation containing vinpocetine, L-carnitine and trimetazidine hydrochloride
  • L-Carnitine Trimetazidine Hydrochloride: Vinpocetine, Tablet Size 500mg: 20mg: 10mg.
  • L-carnitine, vinpocetine and trimetazidine hydrochloride are passed through an 80 mesh sieve, mixed with starch and lactose, and starch slurry is added.
  • Made of soft material granulated with 14 mesh sieve, placed at 70 ° C ⁇ 8 (TC dried and then sieved on a 12 mesh sieve, add dry starch and magnesium stearate to mix, then tablet, that is.
  • Example 13 Combination packaging of L-carnitine preparation, trimetazidine hydrochloride preparation and vinpocetine preparation
  • the L-carnitine formulation and the trimetazidine hydrochloride formulation and the vinpocetine formulation were separately prepared or purchased as shown in Table 13. Table 13 Different specifications of L-carnitine preparation and trimetazidine hydrochloride preparation

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Abstract

本发明公开了一种抗缺氧的药物组合物及其应用。该药物组合物包含长春西汀和左卡尼汀或其衍生物及其可药用盐，还可以包含曲美他嗪或其可药用盐。

Description

一种抗缺氧的药物组合物及其应用
技术领域
本发明涉及药物领域， 具体地说， 涉及一种抗缺氧的药物组合物及其在缺氧导致疾病和 病症中的应用。
技术背景
缺氧是指因组织的氧气供应不足或用氧障碍， 而导致组织的代谢、 功能和形态结构发生 异常变化的病理过程， 例如休克、 呼吸功能不全、 心功能不全、 贫血等， 可以引起脑、 心脏 等生命重要器官会因缺氧受损甚至导致死亡。 缺氧还常见于环境影响而造成的病理过程， 比 如高原、 高空飞行、 潜水作业、 密闭舱或坑道内作业等环境下缺氧问题较为严重， 直接影响 人类活动甚至生命安全。 因此研究开发抗缺氧药物具有重要的社会意义。
缺氧可以使全身各组织有氧代谢降低。 许多研究表明线粒体损伤可能是细胞缺氧能量代 谢障碍的中心环节。 缺氧环境下机体产生大量自由基， 线粒体是产生内源性自由基的主要场 所， 是自由基攻击的靶部位。 缺氧后产生的氧自由基对生物大分子具有毒性反应， 主要表现 为脂质过氧化作用， 导致膜结构异常， 功能障碍。 线粒体受到自由基损伤后膜流动性降低， 从而导致线粒体功能和膜内酶活性的下降。 线粒体膜磷脂降解， 线粒体受损， 影响细胞色素 C氧化酶及 ATP合成酶的活性， 可使 ATP合成减少， 直接导致机体组织细胞受损以及能量 代谢障碍， 因此， 缺氧的预防和治疗首要的是保证机体供氧， 保障机体能量代谢正常运转， 还要预防和治疗组织细胞受损。 临床上常见的头晕、 头痛、 耳鸣、 眼花、 四肢软弱无力、 运 动能力下降、 思维迟钝、 记忆力下降； 或者产生恶心、 呕吐、 心慌、 气短、 呼吸急促、 心跳 快速无力均与缺氧有关，都是一般性的缺氧表现，缺氧也可以导致严重的并发症如心肌梗死、 心绞痛、 心力衰竭、 肺水肿、 脑水肿、 呼吸障碍、 视神经损伤、 脑神经损伤、 脑卒中等严重 疾病。
缺氧可分为低张性缺氧、 贫血性缺氧、 循环性缺氧、 组织性缺氧四种类型， 其中贫血性 缺氧和组织性缺氧属于用氧障碍， 低张性缺氧和循环性缺氧属于氧气供应不足， 临床上常见 的缺氧多为混合型缺氧、 低张性缺氧和循环性缺氧共同存在。
低张性缺氧是指由于氧分压明显降低并导致组织供氧不足， 是生产、 生活中最为常见的 缺氧状态， 比如外呼吸功能障碍导致的缺氧， 高原缺氧， 高空缺氧、 坑道缺氧、 潜水缺氧、 密封舱缺氧均属于低张性缺氧， 其中以高原缺氧最为常见， 也是缺氧预防和治疗的重点。
坑道缺氧是指在一定深度的坑道或洞中， 由于二氧化碳的比重较高， 造成坑道底部空气 中氧气比例下降， 氧分压降低， 造成缺氧； 潜水缺氧、 密封舱缺氧是指环境中的氧的比例较 低， 氧分压降低， 造成缺氧。 上述缺氧最常见的防治方法是补充新鲜的空气， 吸氧或撤离缺 氧区域， 无应用的药物手段。
高原缺氧和高空缺氧是指在海拔 3000米以上的高原地区或高空， 由于气压低， 氧分压也 相应降低， 大气与肺泡中氧分压之差随着登高度的增加而缩小， 直接影响肺泡气体交换、 血 液携氧和结合氧在组织中释放的速度，致使机体供氧不足而产生的缺氧。短时间内进入 3000m 以上高原， 或在高原地区居民在平原生活一段时间后重返高原时， 均可产生急性高原反应， 轻者有头痛、 头昏、 心悸、 气短等表现； 重者有食欲减退、 恶心、 呕吐、 失眠、 疲乏、 排尿 减少、 腹胀和胸闷等表现， 临床检查常见口唇发绀及面部、 手、 踝浮肿等现象； 更严重的急 性高原缺氧可引起肺小静脉血管收缩， 阻力增加， 导致肺动脉高压， 又可使肺毛细血管通透 性增高， 加上缺氧引起的淋巴循环障碍， 最终促发肺水肿， 并可引起脑部小血管痉挛和通透 性增加， 产生脑水肿等一系列急性高原病。 高原反应持续 3个月不消退者可演变为慢性高原 反应， 如高原缺氧症状不能自行消失， 最终会导致心、 脑、 肺等重要脏器坏死而死亡。 高原 缺氧的传统非药物治疗手段是吸入高压氧、 撤离高海拔地区， 治疗效果好但受条件限制， 不 适宜广泛使用。 高原缺氧常用药物进行辅助治疗， 临床上常用利尿剂如乙酰唑胺、 肾上腺皮 质激素类药物如地塞米松、 血管扩张药尼莫地平和各种维生素及氨茶碱等药物， 但抗缺氧的 效果有限， 其中乙酰唑胺最为常用， 但乙酰唑胺仅对于在高原地区短暂停留的患者有一定的 作用， 而对于长期处在高原地区的患者， 由于其易造成机体电解质紊乱、 尿量多和脱水等不 良反应而不宜长期使用。 其他药物如激素也不宜长期使用。 此外， 高原缺氧常用含红景天的 中药制剂进行预防和治疗， 这类中药制剂能够辅助提高机体对缺氧的适应性， 但起效缓慢， 抗缺氧的效果也有限。 据文献报道 （中国发明专利， 专利申请号 200310104871.X) ， 补充左 卡尼汀可预防和治疗高原病，通过常压缺氧小鼠生存时间试验和低气压下小鼠游泳试验表明， 左卡尼汀具有一定的抗低压缺氧作用。 使用左卡尼汀可以促进脂肪酸代谢， 减少酸性代谢产 物如乳酸等的累积， 通过增加脂肪酸氧化不但能够增加供能， 而且能够降低游离脂肪酸和酰 基脂肪酸含量， 从而减少对细胞膜的损害， 增加细胞膜稳定性， 尤其增加重要组织细胞如心 肌细胞和脑组织细胞的膜稳定性， 起到一定的抗缺氧作用。 但由于脂肪酸氧化需要消耗大量 的氧， 机体在缺氧情况下， 氧供受到限制， 因此， 使用左卡尼汀促进脂肪酸氧化可能会因消 耗大量氧而加重机体组织缺氧。
循环性缺氧在临床上较为常见。 循环性缺氧指组织血流量减少使组织氧供应减少所引起 的缺氧， 又称为低动力性缺氧， 常见于心脏病、 心绞痛、 心功能不全、 心肌梗死、 心力衰竭 血管堵塞性疾病、 脑卒中、 动静脉粥样硬化等患者， 临床上常用改变血流动力学药物进行治 疗， 如硝酸酯、 β受体阻滞剂、 钙拮抗剂等药物， 也使用脑血管扩张药如长春西汀等。 上述 药物在预防和治疗由于缺氧导致的机体组织细胞受损的作用有限， 不能满足预防和治疗循环 性缺氧的需要。 此外， 临床上也常用不改变血流动力学的药物曲美他嗪治疗心脑等组织的循 环性缺氧。 曲美他嗪的学名为三甲氧苄嗪 (Trimetazidine), 临床常用于冠脉功能不全、 心绞 痛、 陈旧性心肌梗死等治疗， 是一种强抗心绞痛药物， 其起效较硝酸甘油慢， 但作用持 续时间较长。 正常心肌的能量 (ATP)供给 60%-70%来自游离脂肪酸 β氧化， 20%-25%为葡萄 糖氧化， 5%-10%为糖酵解。曲美他嗪能够促进葡萄糖氧化，虽然曲美他嗪可抑制脂肪酸氧化， 促进葡萄糖氧化， 具有一定的抗心肌缺氧的作用， 但是由于葡萄糖氧化只能提供心肌和骨骼 肌活动需要的 20%的能量， 远远不能满足心肌和骨骼肌活动需要的能量， 此外， 由于脂肪酸 的氧化在曲美他嗪的抑制下， 大量脂肪酸会发生累积， 累积的脂肪酸会破坏细胞膜和线粒体 结构， 并破坏降低丙酮酸脱氢酶的活性， 使反过来抑制葡萄糖氧化， 因此， 单纯使用曲美他 嗪用于预防和治疗缺氧也存在一定的缺陷。
综上所述， 目前还缺乏理想的抗缺氧药物。 理想的抗缺氧的药物应具备在低气压或低供 氧的条件下，即在低张性缺氧或循环缺氧下首先保证机体供氧，保障机体能量代谢正常运转， 还要具有对缺氧受损的组织细胞的保护作用， 长期应用无明显不良反应， 预防和治疗相结合 的双重特点。 显然， 目前市场上缺乏具备上述特点的质量稳定的药物制剂。
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本发明的目的之一是提供一种抗缺氧的药物组合物。
本发明的目的之二是提供一种抗缺氧以及预防和治疗缺氧导致的疾病和病症的药物制剂。 本发明的目的之三是提供一种抗缺氧以及缺氧导致的疾病的预防和治疗方法。
本发明人通过研究发现， 将促进脂肪酸氧化的左卡尼汀或其衍生物或其可药用盐， 特别 优选左卡尼汀与脑血管扩张药长春西汀联合或组合成组合物， 具有抗缺氧以及预防和治疗缺 氧导致的疾病和病症的用途， 而且具有既能够保证机体供氧， 保障机体能量代谢正常运转， 又对缺氧受损的组织细胞有保护作用， 长期应用无明显不良反应， 预防和治疗相结合的双重 特点。 药物联合应用或组合成组合物应用与单方药物应用相比， 具有明显的协同作用， 发挥 显著的抗缺氧作用， 适合预防和治疗缺氧导致的各种疾病和病症。
本发明人研究发现， 将治疗心绞痛的药物曲美他嗪及其可药用盐， 特别优选盐酸曲美他 嗪， 与长春西汀和左卡尼汀或其衍生物联合或组合成组合物， 具有抗缺氧以及预防和治疗缺 氧导致的疾病和病症的用途， 既能够保证机体供氧， 保障机体能量代谢正常运转， 又具有对 缺氧受损的组织细胞的保护作用，长期应用无明显不良反应，预防和治疗相结合的双重特点， 与单一用药相比， 具有协同作用， 发挥显著的抗缺氧作用， 适合用于治疗和预防缺氧导致的 各种疾病和病症。 "缺氧 "一词可以理解为因组织的氧气供应不足或用氧障碍， 而导致组织的代谢、 功能和 形态结构发生异常变化的病理过程， 本发明所述的抗缺氧组合物是用于预防和治疗因组织的 氧气供应不足或用氧障碍， 而导致组织的代谢、 功能和形态结构发生异常变化， 尤其适合预 防和治疗组织的氧气供应不足而导致组织的代谢、功能和形态结构发生异常变化。显而易见， 低张性缺氧和循环性缺氧属于组织的氧气供应不足。 本发明所述的抗缺氧组合物， 优选抗低 张性缺氧和循环性缺氧的组合物。 低张性缺氧指由于氧分压明显降低并导致组织供氧不足， 是生产、 生活中最为常见的缺氧状态， 比如外呼吸功能障碍导致的缺氧， 高原缺氧， 高空缺 氧， 坑道缺氧， 潜水缺氧、 密封舱缺氧均属于低张性缺氧， 其中又以高原缺氧最为常见。 循 环性缺氧也是一种常见的缺氧类型， 循环性缺氧指组织血流量减少使组织氧供应减少所引起 的缺氧， 又称为低动力性缺氧， 可分为血管堵塞性缺氧、 血管狭窄性缺氧、 心功能不全性缺 氧， 常见于心脑血管以及神经系统疾病， 如休克， 心功能不全， 心绞痛， 心肌梗死， 血管堵 塞性疾病， 血管粥样硬化， 脑梗塞， 头痛， 偏头痛， 视神经损伤， 脑神经损伤等患者。 血管 堵塞性缺氧是指由于血栓的形成堵塞血管， 使得组织供血不足导致缺氧。 血管狭窄性缺氧是 指由于动静脉粥样硬化， 使得血液流动阻力增加， 使得组织供血不足导致缺氧。 心功能不全 性缺氧是指由于心脏动力不足， 泵血能力不足， 使得组织供血不足导致缺氧。
缺氧的临床表现有头晕、头痛、耳鸣、 眼花、 四肢软弱无力、运动能力下降、 思维迟钝、 记忆力下降、 恶心、 呕吐、 心慌、 气短、 呼吸急促、 心跳快速无力等一般性的缺氧表现， 以 及心肌梗死、 心力衰竭、 心绞痛、 肺水肿、脑水肿、休克、 呼吸障碍、 脑卒中、 视神经损伤、 脑神经损伤等严重型疾病。
本发明所述的抗缺氧是对缺氧临床表现的病症和疾病的预防和治疗作用， 尤其是指对头 晕、 头痛、 耳鸣、 眼花、 四肢软弱无力、 运动能力下降、 思维迟钝、 记忆力下降、 恶心、 呕 吐、 心慌、 气短、 呼吸急促、 心跳快速无力等一般性的缺氧临床表现， 以及心肌梗死、 心绞 痛、 肺水肿、 脑水肿、 脑卒中、 休克、 呼吸障碍、 视神经损伤、 脑神经损伤等严重型疾病的 预防和治疗作用。
综上研究发现， 因此， 本发明创造性发明了一种抗缺氧的药物组合物。
本发明的药物组合物包含长春西汀和左卡尼汀或其衍生物及其可药用盐， 它们之间的重 量比是本药物组合物的重要技术特征之一。 一般而言， 在本发明的药物组合物中， 长春西汀 和左卡尼汀或其衍生物及其可药用盐的重量比可以约为 1:3-30000， 约为 1:33-1800， 本发明 中长春西汀和左卡尼汀或其衍生物及其可药用盐的重量比可以根据所选配伍药物、 给药方式 和适应症的不同而研究出最佳重量比。
本发明的药物组合物包含长春西汀和左卡尼汀， 它们之间的重量比是本药物组合物的重 要技术特征之一。 一般而言， 在本发明的药物组合物中， 长春西汀和左卡尼汀的重量比可以 约为 1:33-1800， 约为 1:300， 本发明中长春西汀和左卡尼汀的重量比可以根据给药方式和适 应症的不同而研究出最佳重量比。
本发明的药物组合物包含但不仅含左卡尼汀或其衍生物或其可药用盐和长春西汀， 本发 明药物组合物还可以包含左卡尼汀或其衍生物或其可药用盐、 长春西汀和曲美他嗪或其可药 用 έ&
本发明的药物组合物包含长春西汀， 左卡尼汀或其衍生物或其可药用盐和曲美他嗪或其 可药用盐， 它们之间的重量比是本药物组合物的重要技术特征之一。 一般而言， 在本发明的 药物组合物中， 长春西汀与左卡尼汀或其衍生物及其可药用盐和盐酸曲美他嗪及其可药用盐 之间的重量比可以约为 1:3-30000:0.03-60, 约为 1:33-1800:0.5-12。 本发明中长春西汀， 左卡 尼汀或其衍生物及其可药用盐和盐酸曲美他嗪及其可药用盐的重量比可以根据所选配伍药物、 给药方式和适应症的不同而研究出最佳重量比。
本发明的药物组合物包含长春西汀， 左卡尼汀和盐酸曲美他嗪， 它们之间的重量比是本 药物组合物的重要技术特征之一。 一般而言， 在本发明的药物组合物中， 长春西汀与左卡尼 汀和盐酸曲美他嗪之间的重量比可以约为 1:33-1800:0.5-12，约为 1:300:2。本发明中长春西汀， 左卡尼汀或和盐酸曲美他嗪的重量比可以根据给药方式和适应症的不同而研究出最佳重量比。
本发明的药物组合物中， 左卡尼汀衍生物包括但不局限于： 左卡尼汀、 乙酰左卡尼汀、 丙酰左卡尼汀和它们可药用的盐。 优选左卡尼汀、 乙酰左卡尼汀和它们可药用的盐。 特别优 选左卡尼汀。
本发明所述的可药用的盐包括左卡尼汀或其衍生物和曲美他嗪与无机酸或有机酸形成的 盐， 例如与盐酸、 溴氢酸、 碘氢酸、 硫酸、 硝酸、 磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁桃酸、 三氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸 形成的盐。
本发明所述的抗缺氧组合物还可以是任何能改善 /促进心脏或脑血流动力学的药物组合 成的组合物， 如可以是由硝酸酯如单硝酸异山梨酯、 硝酸甘油， β受体阻滞剂如卡维地洛， 钙拮抗剂如硝苯地平中的二种或二种以上组成的组合物， 也可以是这类改善 /促进心脏或脑血 流动力学的药物中的其中一种或几种药物组成的药物组合物与左左卡尼汀或其衍生物、 曲美 他嗪及其可药用盐和长春西汀中的一种或者二种或者三种组成的组合物。
本发明的另一方面， 提供了一种药物制剂， 该药物制剂包括活性成分长春西汀、 活性成 分左卡尼汀或其衍生物或其可药用盐， 和药学上可接受的辅料。
本发明的药物制剂， 含有长春西汀和左卡尼汀或其衍生物及其可药用盐作为活性成分和 一种或多种可药用载体。 其中长春西汀和左卡尼汀或其衍生物及其可药用盐的重量比可以约 为 1:3至约为 1:30000， 例如约为 1:33-1800。
本发明的药物制剂， 含有长春西汀和左卡尼汀作为活性成分和一种或多种可药用载体。 其中长春西汀和左卡尼汀的重量比可以约为 1:33至约为 1:1800， 例如约为 1:300。
本发明的药物制剂， 含有长春西汀， 左卡尼汀或其衍生物及其可药用盐和曲美他嗪及其 可药用盐作为活性成分和一种或多种可药用载体。 其中长春西汀， 左卡尼汀或其衍生物或其 可药用盐和曲美他嗪或其可药用盐的重量比可以约为 1:3-30000:0.03-60， 约为 1:33-1800:0.5-33
本发明的药物制剂， 含有长春西汀， 左卡尼汀和盐酸曲美他嗪作为活性成分和一种或多 种可药用载体。其中长春西汀，左卡尼汀和盐酸曲美他嗪的重量比可以约为 1:15-1500:0.1-25， 约为 1:300:2。
本发明的药物制剂可口服给药或肠胃外给药。肠胃外给药包括静脉、肌内、腹膜、皮下、 直肠和局部给药途径。
本发明的药物制剂可以呈适于口服使用的形式， 例如片剂、 缓释片、 锭剂、 水溶液或油 混悬液、 颗粒剂、 乳液、 硬或软胶囊、 或糖浆剂。
本发明的药物制剂可以以组合包装的形式。 组合包装的药品可以同是口服制剂， 也可以 同是注射制剂。
用于口服使用的本发明制剂可依据本领域用于制备口服药物组合物的任何已知方法制得， 并且这样的组合物可包含一种或多种选自下列的物质： 甜味剂、 矫味剂、 着色剂和防腐剂， 以提供药学美观和适口的制剂。
片剂含有活性组分以及与其混合的适于制备片剂的药学上可接受的赋形剂。 这些赋形剂 可以是： 惰性稀释剂如碳酸钙、 碳酸钠、 乳糖、 磷酸钙或磷酸钠； 制粒剂和崩解剂例如微晶 纤维素、 羧甲基纤维素钠、 玉米淀粉或藻酸； 粘合剂例如淀粉、 明胶、 聚乙烯吡咯垸酮或阿 拉伯树胶； 和润滑剂例如硬脂酸镁、 硬脂酸或滑石粉。
片剂可以是未包衣的或者可通过本领域公知的技术将其包衣以掩蔽药物的令人不愉快的 味道或者延迟其在胃肠道的崩解和吸收， 以及由此在更长的时间内维持持续的作用。 例如， 可使用水溶性味道掩蔽材料例如羟丙基甲基纤维素或羟丙基纤维素或者时间延迟材料例如乙 基纤维素、 乙酸丁酸纤维素。
本发明的口服制剂还可以以硬明胶胶囊提供， 其中活性组分与惰性固体稀释剂例如碳酸 钙、 磷酸钙和高岭土混合， 或以软明胶胶囊提供， 其中活性成分与水溶性载体例如聚乙二醇 或油性介质例如花生油、 液体石蜡或橄榄油混合。 本发明的水混悬液含有活性物质以及与其混合的适于制备水混悬液的赋形剂或分散剂。 所述的赋形剂包括： 混悬剂例如羧甲基纤维素钠、 甲基纤维素、羟丙基甲基纤维素、藻酸钠、 聚乙烯吡咯垸酮、 黄蓍树胶和阿拉伯树胶。 所述的分散剂可以是天然磷脂例如卵磷脂、 或烯 化氧与脂肪酸的缩合产物， 例如聚氧乙烯硬脂酸酯， 或烯化氧与长链脂族醇的缩合产物例如 十七乙稀氧基鲸蜡醇， 或者烯化氧与衍生自脂肪和己糖醇的偏酯的缩合产物， 例如聚氧乙垸 山梨糖醇单油酸酯。
本发明的注射剂是含有活性物质的无菌注射粉末，通过使用水或有机溶剂如酒精、甲醇、 丙酮、 氯仿等溶解结晶， 通过常温干燥或冷冻干燥得到无菌注射的粉末或结晶。
本发明的注射剂是含有活性物质的无菌注射液， 可使用水、 或林格溶液、 氯化钠溶液和 / 或葡萄糖溶液做载体， 形成无菌注射溶液。
本发明的注射剂可通过局部快速肌注引入到患者血流中或者其他可以给药的部位， 或者 通过静脉滴注的形式引入到患者血流中。
本发明的制剂可以是组合包装制剂， 将上市的左卡尼汀或其衍生物及其可药用盐制剂和 曲美他嗪及其可药用盐制剂按照一定的剂量组合进行包装， 制备组合包装制剂。
本发明的制剂可以是组合包装制剂， 将上市的左卡尼汀或其衍生物及其可药用盐制剂和 曲美他嗪及其可药用盐制剂和长春西汀制剂按照一定的剂量组合进行包装， 制备组合包装制 剂。
本发明的另一方面是提供了一种制备药物制剂的方法， 包括将上述的本发明的药物组合 物与一种或多种可药用的载体或赋形剂混合。
本发明的再一方面是提供了一种抗缺氧的方法， 该方法将 3-酮酸辅酶 A硫解酶抑制剂如 盐酸曲美他嗪， 磷酸二酯酶抑制剂如长春西汀， 上述其中的一种药物单独与左卡尼汀或其衍 生物以及可药用的盐， 或二种药物与左卡尼汀或其衍生物以及可药用的盐， 通过先后或同时 给予将要进入缺氧环境或因缺氧导致的疾病患者， 或者将本发明的药物组合物或由其制备的 药物制剂给予将要进入缺氧环境或因缺氧导致的疾病患者， 用于抗缺氧治疗由缺氧导致的疾 病， 并可用于预防缺氧。
在本发明药物制剂中，一个优选的实例是左卡尼汀与长春西汀组成的药物制剂。成人（按
60公斤算）给药的日剂量为：左卡尼汀或其衍生物为 10-500mg/kg;长春西汀为 0.05-0.5mg/kg。
在本发明药物制剂中， 一个优选的实例是左卡尼汀与长春西汀与盐酸曲美他嗪组成的药 物制剂。 成人 （按 60公斤算） 给药的日剂量为： 左卡尼汀或其衍生物为 10-500mg/kg; 长春 西汀为 0.05-0.5mg/kg， 盐酸曲美他嗪为 0.1-1.5mg/kg。
具体实 式 下面的实施例仅仅用于进一步解释本发明， 而不是对本发明范围的限制。
实施例一： 观察长春西汀和左卡尼汀组合不同剂量配比静脉注射对小鼠常压缺氧的影响
长春西汀： 0.75、 2.25、 4.5mg/kg, 约相当于人用日剂量 5、 15、 30mg;
左卡尼汀： 150、 450、 1350mg/kg, 约相当于人用日剂量 1、 3、 9g, (其中最高剂量约 相当于临床注射最高用量的三到四分之一） 。
左卡尼汀 +长春西汀： 根据左卡尼汀、 长春西汀两个药的药效情况， 设置 150+0.75、 150+2.25、 150+4.5、 450+0.75、 450+2.25、 450+4.5、 1350+0.75、 1350+2.25、 1350+4.5mg/kg o 选用雄性小鼠 100只， 体重 20 ± 2g， 按体重随机分为 10组， 每组 10只， 10ml/kg尾静 脉注射给药， 空白对照组给予等体积生理盐水， 1次 /天， 连续 7天， 末次给药 lh后， 将各组 小鼠放入预先加有 5g钠石灰的 160ml广口瓶中， 每瓶 1只， 然后将瓶盖用凡士林涂抹封紧， 以死亡为指标， 记录小鼠存活时间 嵇扬.抗缺氧研究常用动物模型及抗缺氧药物.解放 军药学学报， 2010， 26 (2 ) ： 170-173] , 结果见表 1。
表 1 常压耐缺氧存活时间比较 （n=10， ± S)
组别 /剂量 （mg/kg) 存活时间 (min) 延长存活时间 (％)
正常对照组 22.1 ±4.4 - 左卡尼汀 150+长春西汀 0.75 27.6± 3.2* 24.9
左卡尼汀 150+长春西汀 2.25 29.4±4.6** 33.0
左卡尼汀 150+长春西汀 4.5 31.7 ±5.1** 43.4
左卡尼汀 450+长春西汀 0.75 31.2±2.4** 41.1
左卡尼汀 450+长春西汀 2.25 33.8 ±2.8** 53.8
左卡尼汀 450+长春西汀 4.5 36.9 ± 1.9** 66.6
左卡尼汀 1350+长春西汀 0.75 33.8 ± 3.7** 52.9
左卡尼汀 1350+长春西汀 2.25 36.6± 6.1** 65.6
左卡尼汀 1350+长春西汀 4.5 39.1 ±5.6** 76.9
注： 与正常对照组比较， *P<0.05， **P<0.01。
结果表明： 各给药组均能显著延长小鼠耐缺氧存活时间， 说明左卡尼汀与长春西汀组合 成的组合物具有抗缺氧以及预防和治疗缺氧导致的疾病和病症的用途， 存活时间的延长受左 卡尼汀用量影响较大， 且与左卡尼汀的剂量呈正相关， 以长春西汀和左卡尼汀重量比 1 :300 效果最佳。
实施例二： 观察左卡尼汀 +长春西汀不同剂量配比灌胃对小鼠常压缺氧的影响
长春西汀： 0.75、 1.5、 2.25mg/kg相当于人用日剂量 5、 10、 15mg;
左卡尼汀： 150、 300、 450mg/kg, 约相当于人用日剂量 1、 2、 3g;
左卡尼汀 +长春西汀：根据左卡尼汀、长春西汀两个药的药效情况，设置 150+1.5、 300+0.75、 300+1.5、 300+2.25 450+1.5mg/kg。
选用雄性小鼠 80只， 体重 20 ± 2g， 按体重随机分为 8组， 每组 10只， 20ml/kg灌胃给 药， 空白对照组给予等体积生理盐水， 1次 /天， 连续 7天， 末次给药 lh后， 将各组小鼠放入 预先加有 5g钠石灰的 160ml广口瓶中， 每瓶 1只， 然后将瓶盖用凡士林涂抹封紧， 以死亡为 指标， 记录小鼠存活时间。 结果显示当长春西汀用量为 1.5mg/kg， 左卡尼汀与长春不同重量 比均能显著延长常压下小鼠耐缺氧时间， 且伴随左卡尼汀用量增加耐缺氧时间延长有上升趋 势； 当左卡尼汀用量 300mg/kg， 左卡尼汀与长春西汀不同重量比均能显著延长常压下小鼠耐 缺氧时间， 且伴随长春西汀用量增加缺氧时间延长有上升趋势， 结果见表 2。
表 2 常压耐缺氧存活时间比较 （n=10， ±S)
组别 /剂量 （mg/kg) 存活时间 (min) 延长存活时间 (％)
正常对照组 22.6 ±3.4 - 左卡尼汀 150+长春西汀 1.5 28.5 ±3.2** 26.1
左卡尼汀 300+长春西汀 0.75 29.1 ±4.5** 28.8
左卡尼汀 300+长春西汀 1.5 31.6±5.4** 44.2
左卡尼汀 300+长春西汀 2.25 32.8±5.7** 45.1
左卡尼汀 450+长春西汀 1.5 33.9±4.9** 5O0
注： 与正常对照组比较， **P<0.01。
结果表明： 左卡尼汀与长春西汀组合成的组合物具有显著的抗缺氧以及预防和治疗缺氧 导致疾病和病症的用途， 以长春西汀和左卡尼汀重量比 1:300效果最佳。
实施例三： 左卡尼汀 450mg/kg+长春西汀 1.5mg/kg与单方灌胃给药对小鼠常压缺氧的比较 选用雄性小鼠 40只， 体重 20±2g， 按体重随机分为 4组， 每组 10只， 20ml/kg灌胃给 药， 空白对照组给予等体积生理盐水， 1次 /天， 连续 7天， 末次给药 lh后， 将各组小鼠放入 预先加有 5g钠石灰的 160ml广口瓶中， 每瓶 1只， 然后将瓶盖用凡士林涂抹封紧， 以死亡为 指标， 记录小鼠存活时间。 结果见表 3。
表 3 常压耐缺氧存活时间比较 （n=10， x ±S)
组别 /剂量 （mg/kg) 存活时间 (min) 延长存活时间 (％)
正常对照组 22.5 ±5.6 - 长春西汀 1.5 25.1 ±4.8* 13.6
左卡尼汀 450 29.6±3.6** 31.6
长春西汀 1.5+左卡尼汀 450 35.2±5.1** 56.4
注： 与正常对照组比较， *P<0.05， **P<0.01。
结果表明： 长春西汀 1.5mg/kg+左卡尼汀 450mg/kg， 与单用左卡尼汀或长春西汀相比， 能显著延长小鼠耐缺氧时间， 且两药合用有协同作用， 复方优于单方。
实施例四： 考察不同长春西汀、 左卡尼汀和盐酸曲美他嗪的重量比下， 注射给药对小鼠常压 缺氧的影响
盐酸曲美他嗪： 1.12、 2.25、 4.5、 9mg/kg相当于人日用剂量 7.5、 15、 30、 60mg。 长春西汀： 0.75、 2.25、 4.5mg/kg, 约相当于人用日剂量 5、 15、 30mg;
左卡尼汀： 150、 450、 1350mg/kg相当于人用日剂量 1、 3、 9g; 选用雄性小鼠 370只， 体重 20±2g， 按体重随机分为 37组， 每组 10只， 10ml/kg注射 给药， 空白对照组给予等体积生理盐水， 1次 /天， 连续 7天， 末次给药 lh后， 将各组小鼠放 入预先加有 5g钠石灰的 160ml广口瓶中， 每瓶 1只， 然后将瓶盖用凡士林涂抹封紧， 以死亡 为指标， 记录小鼠存活时间， 结果见表 4。
表 4 常压耐缺氧存活时间比较 （n=10，
组别 /剂量 ： (mg/kg) 存活时间 (min) 延长存活时间 (％) 正常对照:组 22.4 ± 3.2 - 左卡尼汀 150+长春西汀 0.75+盐酸曲美他嗪 9 33.1 ±4.6** 47.1
左卡尼汀 150+长春西汀 0.75+盐酸曲美他嗪 4.5 31.5 ±4.5** 40.0
左卡尼汀 150+长春西汀 0.75+盐酸曲美他嗪 2.25 30.8 ±5.1** 36.9
左卡尼汀 150+长春西汀 0.75+盐酸曲美他嗪 1.12 29.9 ±5.1** 32.9
左卡尼汀 450+长春西汀 0.75+盐酸曲美他嗪 9 35.6±4.2** 58.2
左卡尼汀 450+长春西汀 0.75+盐酸曲美他嗪 4.5 34.4±4.1** 52.9
左卡尼汀 450+长春西汀 0.75+盐酸曲美他嗪 2.25 32.5 ±5.1** 44.4
左卡尼汀 450+长春西汀 0.75+盐酸曲美他嗪 1.12 31.2±4.6** 38.7
左卡尼汀 1350+长春西汀 0.75+盐酸曲美他嗪 9 36.1 ±4.9** 60.4
左卡尼汀 1350+长春西汀 0.75+盐酸曲美他嗪 4.5 34.7 ±5.7** 54.2
左卡尼汀 1350+长春西汀 0.75+盐酸曲美他嗪 2.25 33.2±5.4** 47.6
左卡尼汀 1350+长春西汀 0.75+盐酸曲美他嗪 1.12 32.4±5.2** 44.0
左卡尼汀 150+长春西汀 2.25+盐酸曲美他嗪 9 35.1 ±4.2** 56.0
左卡尼汀 150+长春西汀 2.25+盐酸曲美他嗪 4.5 34.2±4.5** 52.0
左卡尼汀 150+长春西汀 2.25+盐酸曲美他嗪 2.25 32.6±4.6** 44.9
左卡尼汀 150+长春西汀 2.25+盐酸曲美他嗪 1.12 31.4±5.0** 39.6
左卡尼汀 450+长春西汀 2.25+盐酸曲美他嗪 9 35.9 ±4.4** 59.6
左卡尼汀 450+长春西汀 2.25+盐酸曲美他嗪 4.5 34.9 ±4.7** 55.1
左卡尼汀 450+长春西汀 2.25+盐酸曲美他嗪 2.25 33.6±4.4** 49.3
左卡尼汀 450+长春西汀 2.25+盐酸曲美他嗪 1.12 32.8 ±4.4** 45.8
左卡尼汀 1350+长春西汀 2.25+盐酸曲美他嗪 9 37.4±4.7** 66.2
左卡尼汀 1350+长春西汀 2.25+盐酸曲美他嗪 4.5 36.4±4.6** 61.8
左卡尼汀 1350+长春西汀 2.25+盐酸曲美他嗪 2.25 35.7 ±4.6** 58.7
左卡尼汀 1350+长春西汀 2.25+盐酸曲美他嗪 1.12 33.9 ±4.8** 50.7
左卡尼汀 150+长春西汀 4.5+盐酸曲美他嗪 9 37.3 ±4.6** 65.8
左卡尼汀 150+长春西汀 4.5+盐酸曲美他嗪 4.5 36.5 ±4.5** 62.2
左卡尼汀 150+长春西汀 4.5+盐酸曲美他嗪 2.25 35.3 ±5.1** 56.9
左卡尼汀 150+长春西汀 4.5+盐酸曲美他嗪 1.12 34.4±5.4** 52.9
左卡尼汀 450+长春西汀 4.5+盐酸曲美他嗪 9 39.3 ±5.2** 74.7
左卡尼汀 450+长春西汀 4.5+盐酸曲美他嗪 4.5 37.5 ±5.1** 66.7
左卡尼汀 450+长春西汀 4.5+盐酸曲美他嗪 2.25 36.6±4.8** 62.7
左卡尼汀 450+长春西汀 4.5+盐酸曲美他嗪 1.12 35.1 ±4.6** 56.0
左卡尼汀 1350+长春西汀 4.5+盐酸曲美他嗪 9 40.2 ±4.9** 78.7
左卡尼汀 1350+长春西汀 4.5+盐酸曲美他嗪 4.5 38.9 ±5.7** 72.9
左卡尼汀 1350+长春西汀 4.5+盐酸曲美他嗪 2.25 37.8 ±5.4** 68.0
左卡尼汀 1350+长春西汀 4.5+盐酸曲美他嗪 1.12 36.1 ±5.2** 60.4
注： 与正常对照组比较， **P<0.01。 结果表明： 长春西汀、 左卡尼汀和盐酸曲美他嗪不同重量比均能显著延长小鼠常压耐缺 氧时间 （P<0.01 )， 组合物具有抗缺氧以及预防和治疗缺氧导致的疾病的用途， 以长春西汀： 左卡尼汀:盐酸曲美他嗪重量比 （1 :300:2) 效果最优。
实施例五：左卡尼汀和长春西汀组合，左卡尼汀、长春西汀和盐酸曲美他嗪组合，灌胃给药， 单方和复方对小鼠急性脑缺氧模型的作用
将 70只雄性昆明小鼠随机分为 7组：正常对照组、左卡尼汀 450mg/kg、曲美他嗪 9 mg/kg、 长春西汀 1.5 mg/kg, 左卡尼汀 450+曲美他嗪 9 mg/kg组、 曲美他嗪 9+长春西汀 1.5mg/kg、 左卡尼汀 450+曲美他嗪 9+长春西汀 1.5组， 每组 10只。 20mg/kg灌胃给药， 正常对照组给 予等体积的生理盐水， 1次 /天， 连续给药 7天。 末次给药 lh后， 将小鼠从耳后迅速断头， 立 即按秒表记录小鼠断头后至张口喘气停止时间。 结果见表 5。
表 5 单、 复方对小鼠急性脑缺氧模型的作用 （n=10， ± S)
组别 /剂量 （mg/kg) 断头后喘气时间（s )
正常对照组 17.4 ± 1.8
左卡尼汀 450 18.6± 1.2
曲美他嗪 9 18.5 ±2.1
长春西汀 1.5 19.5 ± 1.5
左卡尼汀 450+曲美他嗪 9 23.8 ± 1.3**
曲美他嗪 9+长春西汀 1.5 20.1 ± 1.6*
左卡尼汀 450+曲美他嗪 9+长春西汀 1.5 25.4±2.5**
注： 与正常对照组比较， *P<0.05， **P<0.01。
脑组织生化指标测定： 小鼠死亡后， 立即冰浴条件下取脑组织， 以冰生理盐水冲洗， 除 去残血， 按 1 :9比例加入冰冷的无水乙醇， 冰浴条件下用高速匀浆机 （10s/次， 间隔 15s， 共
4次）将脑组织制成 10%脑组织匀浆。 将匀浆液于 4°C以 2000r/min离心 5min， 分离上清， 采 用氨基酸分析仪检测小鼠脑组织中谷氨酸（Glu)、天冬氨酸（Asp)、 Y -氨基丁酸（GABA)、 甘氨酸（Gly)的含量。脑损伤后以 Glu、 Asp, GABA和 Gly等为代表的兴奋性氨基酸（EAA) 在脑内含量较高。 尤其是 Glu的过度释放是导致继发性脑损伤神经元死亡的重要机制之一， 特别是 Glu激活 N-甲基 -D-天门冬氨酸 （NMDA) 受体引起神经元内钙超载而激发的级联损 伤效应是导致迟发性神经元死亡的重要原因。 线粒体功能的损伤程度决定了神经元的死亡方
^[Clemens J A , Stephenson D T， Smalsting E B. Global ischemia activate nuclear. Storke , 1997 ,
28:1073-1076.] , 结果见表 6。 组别 /剂量 （mg/kg) Glu Asp GABA Gly
( μ mol/L) ( μ mol/L) ( μ mol/L) ( μ mol/L) 正常对照组 21.15 ± 1.06 16.03 ±2.11 4.11 ±0.78 4.96±2.25 左卡尼汀 450 18.45 ± 1.22 15.68 ±4.23 3.71 ± 1.11 3.54± 1.29 曲美他嗪 9 17.02±0.99 15.21 ±2.06 3.44± 1.12 3.49 ± 1.12 长春西汀 1.5 19.12 + 2.01 15.46 + 2.21 3.15 + 1.05 3.82 + 1.84 左卡尼汀 450+曲美他嗪 9 12.54± 1.31** 15.20± 1.05 3.15 ±0.68* 3.25 ±2.11 曲美他嗪 9+长春西汀 1.5 13.45 ± 1.91* 15.02± 3.76 3.26± 1.55 3.65 ±2.01 左卡尼汀 450+曲美他嗪 9+长春西 11.45 ± 1.43** 14.98 ± 1.48* 2.64 ± 1.74** 3.22 ± 1.48* 汀 1.5
注： 与正常对照组比较， *P<0.05， **P<0.01。
结果表明：
由表 5，左卡尼汀 450+曲美他嗪 9mg/kg组及左卡尼汀 450+曲美他嗪 9+长春西汀 1.5mg/kg 组均能显著延长小鼠断头后喘气时间 （P<0.01 )， 并具有协同作用， 说明具有显著的抗脑缺氧 的作用， 提示本组合物具有治疗脑卒中、 脑梗塞后遗症、 脑出血后遗症和脑动脉硬化等脑部 组织缺血缺氧引起的疾病的作用。
由表 6， 复方与单方相比， 可显著降低脑组织中 EAA含量， 从而发挥对缺氧脑损伤的保 护作用， 提示本组合物具有治疗因为缺血缺氧导致的神经损伤， 如视神经损伤、 脑神经损伤 等疾病的药效。
实施例六： 观察左卡尼汀 +长春西汀不同配比灌胃给药对大鼠低压缺氧的影响
长春西汀、 左卡尼汀， 两种药物根据厂家推荐人用剂量推算出大鼠等效剂量分别为： 长春西汀： 0.75、 1.5、 2.25mg/kg相当于人用日剂量 5、 10、 15mg
左卡尼汀： 150、 300、 450mg/kg, 约相当于人用日剂量 1、 2、 3g
左卡尼汀 +长春西汀： 根据左卡尼汀、 长春西汀两个药的药效情况， 设置左卡尼汀 +长春 西汀剂量为 150+1.5、 300+1.5、 450+1.5、 300+2.25、 300+0.75mg/kg。
选用 Wister大鼠 70只， 体重 150g〜190g， 随机分为 7组： 常氧对照组： 平原地区词养、 取材； 急性缺氧组： 将动物置于低压氧舱内， 仓内氧分压为 l l .OlKpa (约相当于海拔 5000m 的氧分压） 连续减压缺氧 3d后， 再置于仓内氧分压为 13.25Kpa (约相当于海拔 4000m的氧 分压） 的低压氧舱内采取标本 ， 嵇扬.抗缺氧研究常用动物模型及抗缺氧药物.解放军药 学学报， 2010, 26 (2 ) ： 170-173]； 给药组： 10ml/kg灌胃给药。 于进低压氧舱前 4d开始， 持续 7d， 在仓内氧分压为 13.25Kpa (约相当于海拔 4000m的氧分压） 的低压氧舱内采取数 据及标本。 所有动物自由进食及饮水。
血液动力学测定： 各组动物在相应时间点内分别经右颈外静脉插至心导管、 肺动脉、 经 左颈总动脉插入心导管至主动脉、 左心室； 用四道生理记录仪检测记录心率 （HR)、 肺动脉 压 （PAP)、 主动脉收缩压 （SAP)、 主动脉舒张压 （DAP)、 左室收缩压 （LVSP)、 左室舒张 压 （LVEDP)、 左心室压力最大上升速率 （+dp/dtmax)。 结果见表 7。
表 7 左卡尼汀 +长春西汀不同配比对模拟高原缺氧条件下大鼠血液学指标的影响 （n=10， X 组别 /剂量 PAP SAP DAP LVSP +dp/dt HR
(mg/kg) (kPa) (kPa) (kPa) (kPa) (kPa) (heat/min) 常氧对照组 3.5±0.6 15.8±1.6 10.5 ±2.8 16.9±1.6 664 ±83 360 ±40 急性缺氧组 5.3±0.7 22.9 ±3.7 15.6±3.2 25.5 ±3.0 695 ±72 377 ±50 左卡尼汀 150+长 4.8±0.7* 20.1 ±2.1* 13.5±3.2* 22.0±2.8* 630 ±75* 375 ±50 春西汀 1.5
左卡尼汀 300+长 4.0±0.5** 17.2±1.8** 11.5±2.4** 18.5±1.9** 515±60** 370 ±45 春西汀 1.5
左卡尼汀 450+长 3.9±0.7** 7.6士 2.2** 11.2±2.1** 18.3±2.4** 520 ±45** 370 ±45 春西汀 1.5
左卡尼汀 300+长 3.5±0.8** 16.2±3.4** 10.6±2.7** 17.4±1.2** 495 ±55** 365 ±50 春西汀 2.25
左卡尼汀 300+长 4.9±0.5* 20.1 ±2.9* 14.0±2.8* 22.1 ±3.6* 660 ±75* 375 ±50 春西汀 0.75
注： 与急性缺氧组比较， *P<0.05, **P<0.01
血气分析：主动脉采血 lml，肝素抗凝，测定血氧分压 Pa02、氧饱和度 Sa02等血气指标， 结果见表 8
表 8 左卡尼汀 +长春西汀不同配比对模拟高原缺氧条件下大鼠血气分析的影响 （n=10 士 组别 Pa02(kPa) Sa02(%)
常氧对照组 12.2±2.4 91.4±6.3
急性缺氧组 5.5±1.5 63.7±13.8
左卡尼汀 150+长春西汀 1.5 6.8±1.6** 73.5 ±12.5**
左卡尼汀 300+长春西汀 1.5 7.8±1.6** 77.2±14.8**
左卡尼汀 450+长春西汀 1.5 8.3 ±2.2** 85.1 ±9.8**
左卡尼汀 300+长春西汀 2.25 10.2±1.9** 91.2±16.1**
左卡尼汀 300+长春西汀 0.75 6.5 ±1.2** 71.2±12.3**
注： 与急性缺氧组比较， * *P<0.01
心肌损伤标志物测定：主动脉采血 2ml，测定乳酸脱氢酶（LDH)活性及血浆内皮素（ET-1)、 心钠素 （ANP) 含量， 结果见表 9
表 9 左卡尼汀 +盐酸曲美他嗪不同配比对模拟高原缺氧条件下大鼠心肌损伤的保护（n=10
±S)
组别 LDH (U/L) ET-1 (pg/ml) ANP (pg/ml) 常氧对照组 3469.17±236.15 188.52± 30.05 172.13±52.17 急性缺氧组 4575.25 ±391.05 861.25±58.13 431.21 ±74.24 左卡尼汀 150+长春西汀 1.5 4011.05 ±257.48** 352.57±55.04** 206.82±58.19** 左卡尼汀 300+长春西汀 1.5 3826.25 ±352.67** 336.54±32.51** 278.45 ±51.23** 左卡尼汀 450+长春西汀 1.5 3769.32± 194.25** 306.22±56.67** 254.11 ±60.15** 左卡尼汀 300+长春西汀 2.25 3652.01 ±225.36** 247.14±42.15** 295.16±51.14** 左卡尼汀 300+长春西汀 0.75 4215.01 ±321.05* 355.03±48.12** 312.03±65.14** 注： 与急性缺氧组比较， *P<0.05, **P<0.01
心肌组织形态学变化： 大鼠处死后， 取心脏石蜡包埋， 4μηι切片， HE常规染色， 光学 显微镜观察心肌组织心态学变化。 光镜下可见常氧对照组心肌纤维排列整齐， 细胞饱满， 胞 核清晰； 急性缺氧组心肌纤维排列紊乱， 心肌细胞异形， 损伤成波浪状， 局部出现嗜酸性染 色；给药组心肌组织形态学变化均有不同程度的改善，左卡尼汀 300+长春西汀 1.5mg/kg组肌 纤维排列基本整齐， 偶见嗜酸性染色。
结果表明：
由表 7， 给药组均能显著增加血液动力学指标， 说明本组合物具有抗缺氧的作用， 可用 于心功能不全， 心力衰竭， 休克等以低血液动力学指标为特征的疾病的预防和治疗。
由表 8， 各给药组均能显著提高大鼠动脉血氧分压和氧饱和度 （P<0.01 )， 本专利组合物 具有抗缺氧用于预防和治疗高原病、 外呼吸功能障碍的作用效果。
由表 9， 与常氧对照组相比， 急性缺氧组大鼠血浆 LDH活性明显升高 （P<0.01 )， ET-1 和 ANP含量明显增加 （P<0.01 )。 与急性缺氧组比较， 各给药组 LDH活性明显降低， ET-1 和 ANP含量均显著下降 （P<0.01 )。 可见本专利组合物可明显减轻低压缺氧下的心肌组织损 伤程度， 对心肌组织具有一定的保护作用。
心肌组织形态学观察结果表明本专利组合物对心肌细胞膜的稳定作用， 保护心肌细胞。 实施例七 ： 观察长春西汀 1.5+左卡尼汀 450+盐酸曲美他嗪 9 mg/kg配比注射给药对大鼠急 性心肌缺氧的保护作用
大鼠用戊巴比妥钠 45mg/kg腹腔注射麻醉，仰卧固定于鼠台，手术区域剃毛，碘伏消毒， 切开气管并插管， 沿胸骨左缘第 3-4肋开胸， 行机械通气， 钝性分离心包膜， 暴露心脏， 手 术操作完毕稳定 15分钟， 静脉注射受试药物， 给药结束后在肺动脉圆锥与左心耳交界处下方 2mm处结扎冠状动脉前降支， 冠状动脉前降支被结扎后， 结扎线以下心肌组织呈灰白色， 非 缺氧区的正常心肌呈暗红色， 呈灰白变色区域中心为梗死区， 灰白色与暗红色交界的边缘为 缺氧区。 在冠状动脉前降支结扎后 2min、 30min和 180min将激光多普勒血流仪探头放置在 缺氧区（其他区域血流量高于仪器检测上限处于饱和状态）， 调节仪器在血流相对稳定时记录 心肌组织血流量 lmin， 取平均值； 记录结束处死动物， 取梗死区、 缺氧区和非缺氧区心肌组 织匀浆， 测定心肌缺血后 2min、 30min和 3h时心肌组织血流量和心肌组织中葡萄糖、三磷酸 腺苷、 6-磷酸果糖激酶、 丙酮酸脱氢酶及游离脂肪酸的含量， 按检测试剂盒说明书要求离心 4000rpm, lOmin, 用半自动生化分析仪检测上清液中葡萄糖； 用 Elisa试剂盒检测 6-磷酸果 糖激酶 （6-PFK)、 丙酮酸脱氢酶 （PDH); 用分光光度仪检测游离脂肪酸和 ATP。 结果见表 10~12。
长春西汀 1.5+左卡尼汀 450+盐酸曲美他嗪 9 mg/kg对心肌组织能量代谢的影响
葡萄糖： 在心肌急性缺氧后的三个时间观察窗， 非缺氧区心肌组织中葡萄糖含量变化不 大； 在缺氧区和梗死区的心肌组织， 葡萄糖含量本应因运转障碍和酵解增加而显著降低， 但 实际检测缺氧后 30min和 3h心肌组织中葡萄糖的含量降低并不明显，与生理盐水对照组比较 无统计学意义 （P<0.05)。
ATP: 与心肌缺氧后 2min、 30min和 3h的生理盐水组相比， 结果显示， 治疗组在心肌缺 氧 2min后的梗死区心肌组织中的含量增加显著 （P<0.01 )， 这一点与心肌缺氧后短时间内葡 萄糖的升高相一致； 30min后非缺氧区显著降低 （P<0.001 ); 缺氧 3h后非缺氧区生理盐水对 照组 ATP降低明显而治疗组显著升高。纵观心肌三个区域治疗组 ATP的水平可以发现， 非缺 氧区随着时间延长而升高（2min为 563， 30min为 406， 3h为 807)，缺氧区无明显降低（741， 698， 607)， 缺氧区治疗组虽然随着时间延长有降低趋势（683， 477， 461 )， 但降低未达到统 计学显著意义。
6-磷酸果糖激酶 (6-PFK)是糖酵解反应中催化 6-磷酸果糖转变为 1， 6-二磷酸果糖的酶， 属非平衡反应， 是糖酵解反应的重要限速酶， 其含量的增加意味着糖酵解途径的活跃。 本实 验结果显示， 与相应的生理盐水对照组比较， 用药后短时间内给药组的 6-PFK含量处于减少 状态， 但从用药 30min以后到 3h却显著上升 （P<0.05)， 提示用药 2min后糖酵解十分活跃。
丙酮酸脱氢酶 （PDH): PDH的作用是使丙酮酸经有氧氧化生成乙酰辅酶 A的重要酶； 其活性增加意味着有氧氧化的增加， 实验结果显示，给药组在冠脉结扎后 2min内心肌非缺氧 区、缺氧区和梗死区 PDH的量均显著低于对照组， 但 2min后 PDH的量均逐渐升高； 到接扎 后 3h在非缺氧区、 缺氧区和梗死区的 PDH含量已显著增加， 与相应的生理盐水组比较相差 显著。
游离脂肪酸 （FFA): 用药 2min后， 游离脂肪酸的量在非缺氧区、 缺氧区和梗死区与生 理盐水组比较均有升高， 但升高没有达到统计学显著意义。
心肌梗死区血流量：给急性心肌缺氧大鼠模型注射盐酸曲美他嗪 9+长春西汀 1.5+左卡尼 汀 450mg/kg后不同时间， 在梗死区心肌组织中测量血流， 与生理盐水组比较血流有增加， 但 增加没有达到统计学显著意义。
结果表明：本组合物能够优化缺氧心肌组织的能量供给，提示具有预防和治疗心肌梗死， 等严重缺血心肌病的用途。
表 10 复方左卡尼汀对心肌缺血 2min后心肌能量代谢和血流量的影响
非缺氧区 缺氧区
生理盐水组 治疗组 生理盐水组 治疗组 生理盐水组 治疗组
G.S 0.44 ±0.15 0.45 ±0.14 0.37 ±0.03 0.31 ±0.07 0.34±0.16 0.41 ±0.29
ATP 747 ± 345 563 ±260 879 ±210 741 ±211 351 ± 117 683 ±273**
6-PFK 4.06 ±0.99 3.01 ±0.21* 4.47 ± 1.54 2.79 ±0.21** 4.54±0.51 3.31 ±0.51**
PDH 1.76±0.71 1.00 ±0.09** 1.78 ±0.61 1.14±0.14* 1.88 ±0.39 1.36±0.24**
FFA 226 ± 14.0 237 ± 16.2 312± 30.9 347 ± 32.3 260 ± 65.9 256 ±28.9 血流量 836± 19.3 852±21.6 与生理盐水组比较 *P<0.05 **P<0.01
表 11 复方左卡尼汀对心肌缺血 30min后心肌能量代谢和血流量的影响
非缺氧区 缺氧区 梗死区
生理盐水组 治疗组 生理盐水组 治疗组 生理盐水组 治疗组
G.S 0.45 ±0.12 0.48±0.13 0.62 ±0.24 0.53±0.12 0.43±0.12 0.36 ±0.07
ATP 966±313 406±65.7*** 579 ±197 698 ±146 580 ±207 477 ±245
6-PFK 3.07 ±0.09 2.73 ±0.32* 3.66±0.66 3.10±0.41 3.89±0.64 4.03 ±0.70
PDH 1.06 ±0.09 1.16±0.15 1.17±0.28 1.08±0.17 1.56 ±0.23 1.64 ±0.28
FFA 256±17.9 275 ±39.1 246 ±39.4 250 ±26.4 261 ±90.1 246 ±80.8 血流量 818±36.9 832±38.6 与生理盐水组比较 *P<0.05 **P<0.01 ***P<0.001
表 12 复方左卡尼汀对心肌缺血 3h后心肌能量代谢和血流量的影响
非缺氧区 缺氧区 梗死区 生理盐水组 治疗组 生理盐水组 治疗组 生理盐水组 治疗组
G.S 0.42 ±0.10 0.44 ±0.10 0.83 ±0.21 0.93±0.14 0.85±0.15 0.63 ±0.22*
ATP 237 ±125 807 + 469** 917 ±320 607 ±228 385 ±196 461 ±286
6-PFK 2.88 ±0.44 3.91 ±0.66*** 3.42±0.89 4.29+0.90* 3.99±0.81 5.21 ±1.28*
PDH 1.10 + 0.32 1.50 ±0.26** 1.15±0.18 1.47±0.39* 1.65±0.33 2.02 ±0.43
FFA 270 ±32.9 315±45.7 258±18.4 274 ±21.5 198±28.5 211±41.2 血流量 859 ±17.7 870 ±21.7 与生理盐水组比较 *P<0.05 **P<0.01 ***P<0.001。
实施例八： 左卡尼汀:长春西汀不同剂量配比的组合药物制剂
本发明以由左卡尼汀和长春西汀的组合药物为例， 可以按如下数据配制各种含不同左卡 汀和长春西汀剂量配比的组合药物制剂：
左卡尼汀 100mg-30000mg/日； 长春西汀 lmg-30mg/日
确定比例范围为 30g:lmg至 O.lg: 30mg
长春西汀： 左卡尼汀 长春西汀 （重） ：左卡尼汀 （重）
1:30000 33.3mg:1000g
1:10000 100mg:1000g
1:1800 lg:1800g
1:1000 lg:1000g
1:500 lg:500g
1:300 lg:300g
1:100 lg:100g
1:66 lg:66g
1:10 lg:10g 1:3 lg:3g
1:30000 333mg: 1000g
实施例： 复方 （长春西汀 +左卡尼汀） 口服溶液
处方： 左卡尼汀 1000g
长春西汀 0.0333g
蒸熘水 加至 10000ml
工艺： 取左卡尼汀、 长春西汀， 加蒸熘水 3000ml溶解后， 加蒸熘水至 10000ml即得。
1: 10000 100mg: 1000g
实施例： 复方 （左卡尼汀 +长春西汀） 口服溶液
处方： 左卡尼汀 1000g
长春西汀 O.lg
蒸熘水 加至 10000ml
工艺： 取左卡尼汀、 长春西汀， 加蒸熘水 3000ml溶解后， 加蒸熘水至 10000ml即得。
1: 1800 lg: 1800g
实施例： 复方 （左卡尼汀 +长春西汀） 糖浆
处方： 左卡尼汀 1800g
长春西汀 lg
蒸熘水 150ml
单糖浆 加至 10000ml
工艺： 取左卡尼汀、 长春西汀溶于蒸熘水后， 加单糖浆至全量， 即得。
1: 1000 lg: 1000g
实施例： 复方 （左卡尼汀 +长春西汀） 乳剂
处方： 左卡尼汀 1000g
长春西汀 ig
阿拉伯胶细粉 125g
西黄耆胶细粉 Vg
糖精钠 O. lg
挥发杏仁油 1ml
尼泊金乙酯 0.5g
蒸熘水 加至 1000ml
工艺： 将阿拉伯胶与左卡尼汀、 长春西汀研匀， 一次加入 250ml蒸熘水， 用力沿 向研磨成初乳，加糖精钠水溶液，挥发杏仁油，尼泊金乙酯醇液， 再缓缓加入西黄耆胶胶浆， 加蒸熘水至全量， 搅匀， 即得。
1:500 lg:500g
实施例： 复方 （左卡尼汀 +长春西汀） 注射液
处方： 左卡尼汀 500g
长春西汀 lg
依地酸二钠 0.5g
盐酸 20g
注射用水 加至 1000ml
工艺： 在制备容器中， 加处方量 80%的注射用水， 加左卡尼汀、 长春西汀溶解后， 加入 预备配置好的依地酸二钠和盐酸溶液， 搅拌均匀， 调节药液 PH6.0~6.2， 注射用水至全量， 再 加入 0.1%活性炭脱色， 用垂熔玻璃滤器与膜滤器过滤， 并在氮气气流下灌封， 最后于 10CTC 流通蒸汽 15min灭菌。
1:300 lg:300g
实施例： 复方 （左卡尼汀 +长春西汀） 输液
处方： 左卡尼汀 300g
长春西汀 lg
依地酸二钠 5g
盐酸 200g
注射用水 加至 10000ml
工艺： 取约 8000ml热注射用水， 按处方量投入左卡尼汀、 长春西汀， 搅拌使全溶， 加 抗氧剂， 并用 10%盐酸调 PH至 6.0左右， 加注射用水适量， 在加入 0.15%活性炭脱色， 过滤 至澄明， 灌封于 100ml输液瓶内， 充氮气， 加塞， 轧盖， 于 10CTC灭菌 30min即可。
1:66 lg:66g
实施例： 复方 （左卡尼汀 +长春西汀） 输液
处方： 左卡尼汀 660g
长春西汀 10g
依地酸二钠 5g
盐酸 200g
注射用水 加至 10000ml
工艺： 取约 8000ml热注射用水， 按处方量投入左卡尼汀、长春西汀， 搅拌， 加抗氧剂， 并用 10%盐酸调 PH至 6.0左右， 加注射用水适量， 在加入 0.15%活性炭脱色， 过滤至澄明， 灌封于 100ml输液瓶内， 充氮气， 加塞， 轧盖， 于 10CTC灭菌 30min即可。
1:10 lg:10g
实施例： 复方 （左卡尼汀 +长春西汀） 片
处方： 左卡尼汀 1000g
长春西汀 100g
乳糖 1500g
淀粉 500g
10%淀粉浆 200g
干淀粉 20g
硬脂酸镁 15g
制成 10000片
工艺： 将左卡尼汀、 长春西汀过 80 目筛， 与淀粉、 乳糖混匀， 加淀粉浆制成软材， 用 14目筛制粒后， 置 70°C~8(TC干燥后于 12目筛整粒， 加入干淀粉及硬脂酸镁混匀后， 压片， 即得。
1:10 lg:10g
实施例： 复方 （左卡尼汀 +长春西汀） 缓释片
处方： 左卡尼汀 2000g
长春西汀 200g
枸橼酸 10g
HPMC (K4M) 160g
乳糖 180g
硬脂酸镁 2mg
制成 10000片
工艺：将左卡尼汀、长春西汀与 HPMC乳糖混匀，枸橼酸溶于乙醇中作润湿剂制成软材， 制粒， 干燥， 整粒， 加硬脂酸镁混匀后， 压片， 即得。
1:3 lg= 3g
实施例： 复方 （左卡尼汀 +长春西汀） 胶丸
处方： 左卡尼汀 3000份
长春西汀 1000份
明胶 1000份 甘油 55~66份
水 1200份
鱼肝油或精炼食用植物油 适量
工艺:取左卡尼汀和长春西汀，加鱼肝油或精炼食用植物油（在 0°C左右脱去固体脂肪）， 溶解， 并调整浓度至每丸含维生素左卡尼汀应为标示量的 90%~120%， 含维生素 D应为标示 量的 85%以上， 作为药液待用； 另取甘油与水加热至 70°C~8(TC， 加入明胶， 搅拌溶化， 保 温 1~2小时， 除去上浮的泡沫， 过滤， 加入滴丸机滴制， 以液体石蜡为冷却液， 收集冷凝的 胶丸， 用纱布拭去黏附的冷却液， 在室温下吹冷风 4小时， 放于 25~35°C下烘 4小时， 再经 石油醚洗涤两次 （每次 3~5min)， 除去胶丸外层液体石蜡， 再用 95%乙醇洗涤乙醇， 最后在 30~35°C烘干约 2小时， 筛选， 质检， 包装， 即得。
1:3 lg:3g
实施例： 复方 （左卡尼汀 +长春西汀） 栓
处方： 左卡尼汀 300g
长春西汀 100g
羟苯乙酯 0.5g
50%乙醇 100ml
聚山梨酯 80 100ml
甘油明胶加至 3000g
共制 2000枚
工艺： 取左卡尼汀、 长春西汀加乙醇煮沸溶解， 加入羟苯乙酯搅拌溶解， 再加适量甘油 搅匀， 缓缓加入明胶甘油基质中， 保温待用。 加入聚山梨酯， 搅拌均匀后， 缓缓搅拌下加至 上述保温基质中， 充分搅拌， 保温 55°C， 灌膜冷却即得。
实施例九： 含左卡尼汀、 长春西汀和盐酸曲美他嗪的组合药物制剂
左卡尼汀： 长春西汀： 盐酸曲美他嗪 （300mg: lmg:2mg)
实施例： 复方左卡尼汀片
处方： 左卡尼汀 300g
长春西汀 lg
盐酸曲美他嗪 2g
乳糖 150g
淀粉 50g
10%淀粉浆 100g 干淀粉 10g
硬脂酸镁 5g
制成 1000片
工艺： 将原料药过 80目筛， 与淀粉乳糖混匀， 加淀粉浆制成软材， 用 14目筛制粒后， 置 70°C~8(TC干燥后 12目筛整粒， 加入干淀粉及硬脂酸镁混匀后， 压片， 即得。
实施例十： 含左卡尼汀和长春西汀的组合药物制剂
左卡尼汀： 长春西汀， 栓剂规格 300mg:0.25mg。
实施例： 复方 （左卡尼汀 +长春西汀） 栓
处方： 左卡尼汀 300g
长春西汀 0.25g
羟苯乙酯 0.5g
50%乙醇 100ml
聚山梨酯 80 100ml
甘油明胶加至 3000g
共制 1000枚
工艺： 取左卡尼汀、 长春西汀加乙醇煮沸溶解， 加入羟苯乙酯搅拌溶解， 再加适量甘油 搅匀， 缓缓加入明胶甘油基质中， 保温待用。 加入聚山梨酯， 搅拌均匀后， 缓缓搅拌下加至 上述保温基质中， 充分搅拌， 保温 55°C， 灌膜冷却即得。
实施例十一： 含长春西汀、 左卡尼汀和盐酸曲美他嗪的组合药物制剂
左卡尼汀： 盐酸曲美他嗪： 长春西汀， 片剂规格 500mg:20mg: 10mg。
实施例： 复方 （左卡尼汀 +盐酸曲美他嗪 +长春西汀） 片
处方: 左卡尼汀 500g
盐酸曲美他嗪 20g
长春西汀 10g
乳糖 150g
淀粉 50g
10%淀粉浆 100g
干淀粉 10g
硬脂酸镁 5g
制成 1000片
工艺： 将左卡尼汀、 长春西汀和盐酸曲美他嗪过 80目筛， 与淀粉、 乳糖混匀， 加淀粉浆 制成软材， 用 14 目筛制粒后， 置 70°C~8(TC干燥后于 12 目筛整粒， 加入干淀粉及硬脂酸镁 混匀后， 压片， 即得。
实施例十二： 复方 （左卡尼汀 +盐酸曲美他嗪 +长春西汀） 片
处方： 左卡尼汀 1000g
盐酸曲美他嗪 5g
长春西汀 5g
乳糖 200g
淀粉 100g
10%淀粉浆 100g
干淀粉 20g
硬脂酸镁 15g
制成 2000片
工艺： 将左卡尼汀、 盐酸曲美他嗪、 长春西汀过 80 目筛， 与淀粉、 乳糖混匀， 加淀粉 浆制成软材， 用 14 目筛制粒后， 置 70°C~8(TC干燥后于 12 目筛整粒， 加入干淀粉及硬脂酸 镁混匀后， 压片， 即得。
实施例十三： 左卡尼汀制剂、 盐酸曲美他嗪制剂和长春西汀制剂的组合包装
分别制备或购买左卡尼汀制剂和盐酸曲美他嗪制剂和长春西汀制剂， 如表 13所示。 表 13 不同规格的左卡尼汀制剂和盐酸曲美他嗪制剂
左卡尼汀制剂 盐酸曲美他嗪制剂 长春西汀制剂
注射液 0.5g 盐酸曲美他嗪片 2mg 注射液 5 mg
注射液 lg 盐酸曲美他嗪片 3mg 注射液 10 mg
注射液 2g 盐酸曲美他嗪片 5mg 注射液 20 mg
口服片 0.25g 盐酸曲美他嗪片 10mg 注射液 30 mg
口服片 0.333g 盐酸曲美他嗪片 15mg 口服片 5 mg
口服片 0.5g 盐酸曲美他嗪包衣片 20mg 口服片 10 mg
口服片 lg 盐酸曲美他嗪缓释片 35mg 口服片 15 mg
□服液 2.5ml:0.25g 盐酸曲美他嗪注射液 2ml:5mg 缓释片 10 mg
口服液 5ml:0.5g 盐酸曲美他嗪注射液 5ml: 10mg 缓释片 15 mg
口服液 10ml: lg
口服液 50ml:5g 口服液 100ml: lOg
口服液 500ml:50g
将上述 3种制剂任意两两组合， 或三个共同组合分别进行组合包装， 每种组合制剂的 以按照临床需要进行确定。

Claims

1、 一种抗缺氧的药物组合物， 其特征在于该药物组合物包含长春西汀和左卡尼 汀或其衍生物或其可药用盐；其中长春西汀与左卡尼汀或其衍生物或其可药用盐 的重量比 1:3-30000。
2、 权利要求 1的药物组合物， 其特征在于所述的左卡尼汀或其衍生物或其可药 用盐选自左卡尼汀、 乙酰左卡尼汀、 丙酰左卡尼汀及其可药用盐。
3、 权利要求 1的药物组合物， 其中所述的左卡尼汀或其衍生物的可药用的盐包 括它们与盐酸、 溴氢酸、 碘氢酸、 硫酸、 硝酸、 磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁桃酸、 三氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸形成的盐。
4、 权利要求 1-3所述的药物组合物， 其特征在于长春西汀与左卡尼汀或其衍生 物或其可药用盐的重量比为 1:33-1800。
5、 权利要求 4的药物组合物， 其特征在于所述组合物中包含长春西汀和左卡尼 汀， 其中长春西汀与左卡尼汀重量比为 1:33-1800。
6、 权利要求 5的药物组合物， 其特征在于所述组合物中包含长春西汀和左卡尼 汀， 其中长春西汀与左卡尼汀重量比为 1:66-600。
7、 权利要求 6的药物组合物， 其特征在于所述组合物中长春西汀与左卡尼汀的 重量比为 1:300。
8、 权利要求 1的药物组合物， 其特征在于所述组合物中还包含曲美他嗪或其可 药用盐，其中长春西汀与左卡尼汀或其衍生物或其可药用盐与曲美他嗪或其可药 用盐的的重量比为 1:3-30000:0.03-60。
9、 权利要求 8的药物组合物， 其特征在于所述组合物中还包含曲美他嗪及其可 药用盐，其中长春西汀与左卡尼汀或其衍生物及其可药用盐与曲美他嗪及其可药 用盐的重量比为 1:33-1800:0.5-12。
10、权利要求 9的药物组合物， 其特征在于所述药物组合物包含长春西汀、左卡 尼汀和盐酸曲美他嗪， 其中长春西汀与左卡尼汀与盐酸曲美他嗪的重量比为 1:300:2。
11、 一种药物制剂，其特征在于所述制剂由权利要求 1一 10中任一项的药物组合 物的成分一起或者分别作为活性成分和一种或多种可药用的载体辅料制备而成。
12、权利要求 11的药物制剂，其特征在于其中所述的药物制剂是口服给药形式、 注射给药形式或局部给药形式。
13、 权利要求 12的药物制剂， 其特征在于其中所述口服给药形式包括普通片、 缓释片、 颗粒剂、 硬或软胶囊、 糖浆剂、 溶液剂、 乳剂。
14、 权利要求 12的药物制剂， 其特征在于其中所述注射给药形式是无菌注射的 水溶液或无菌注射的水包油微乳液或注射用无菌粉末。
15、权利要求 12的药物制剂，其特征在于其中所述局部给药形式是贴剂、栓剂、 霜剂、 膏剂、 凝胶剂、 溶液或混悬液。
16、 权利要求 11的药物制剂， 其特征在于所述的药物制剂是组合包装。
17、 权利要求 1-10中任一项的药物组合物在制备用于抗缺氧以及预防和治疗由 缺氧导致的各种疾病和病症的药物中的用途。
18、权利要求 17所述的用途，其特征为所述的缺氧是低张性缺氧和循环性缺氧。
19、 权利要求 18所述的用途， 其特征在于所述低张性缺氧包括高原缺氧、 坑道 缺氧、 高空缺氧、 潜水缺氧， 密闭舱缺氧， 所述的循环性缺氧包括血管堵塞性缺 氧、 血管狭窄性缺氧、 心功能不全性缺氧。
20、权利要求 17所述的用途，其特征为所述的缺氧导致的疾病和病症包括头晕、 头痛、 耳鸣、 眼花、 四肢软弱无力、 运动能力下降、 思维迟钝、 记忆力下降、 恶 心、 呕吐、 心慌、 气短、 呼吸急促、 心跳快速无力等临床表现以及高原病、 心肌 梗死、 心绞痛、 心功能不全、 心力衰竭、 休克、 外呼吸功能障碍、 视神经损伤、 脑神经损伤、 脑卒中、 脑梗塞后遗症、 脑出血后遗症和脑动脉硬化症。
21、 权利要求 17-20所述的用途， 其特征在于其中所述的药物以口服给药形式、 注射给药形式或局部给药形式给药。
22、 权利要求 17-20所述的用途， 其特征在于成人给药的日剂量为： 左卡尼汀或 其衍生物或其可药用盐 10-500mg/kg， 长春西汀 0.05-0.5mg/kg， 曲美他嗪及其可 药用盐 0.1-1.5mg/kg。
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