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WO2006110118A1 - Produit cytoprotecteur - Google Patents

Produit cytoprotecteur Download PDF

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Publication number
WO2006110118A1
WO2006110118A1 PCT/UA2006/000019 UA2006000019W WO2006110118A1 WO 2006110118 A1 WO2006110118 A1 WO 2006110118A1 UA 2006000019 W UA2006000019 W UA 2006000019W WO 2006110118 A1 WO2006110118 A1 WO 2006110118A1
Authority
WO
WIPO (PCT)
Prior art keywords
gluconate
magnesium
cytoprotective
hypoxia
preparation
Prior art date
Application number
PCT/UA2006/000019
Other languages
English (en)
Russian (ru)
Inventor
Victor Pavlovich Kutnyak
Vadym Alekseyevich Kozlovskiy
Yurii Iosifovich Kudryavets
Original Assignee
Victor Pavlovich Kutnyak
Vadym Alekseyevich Kozlovskiy
Yurii Iosifovich Kudryavets
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Victor Pavlovich Kutnyak, Vadym Alekseyevich Kozlovskiy, Yurii Iosifovich Kudryavets filed Critical Victor Pavlovich Kutnyak
Publication of WO2006110118A1 publication Critical patent/WO2006110118A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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 invention relates to the composition of cytoprotective preparations based on r-gluconic acid, and preferably based on its coordination compounds and double salts.
  • ischemia a decrease in blood flow (ischemia) is always accompanied by hypoxia and impaired activity of enzyme systems, which ensure the synthesis of the required amount of ATP from nutrients and oxygen coming from the blood.
  • cellular hypoxia can occur under the influence of other factors such as mechanical or asthmatic asphyxiation, poisoning (in particular, cyanides or fluorides, which block the enzymes responsible for the absorption of oxygen inside the cell) or the action of ionizing radiation, which inhibits the activity of any enzymes , etc.
  • poisoning in particular, cyanides or fluorides, which block the enzymes responsible for the absorption of oxygen inside the cell
  • ionizing radiation which inhibits the activity of any enzymes , etc.
  • hypoxia in the broad sense means a violation of the normal utilization of oxygen by the cell at the biochemical level. Therefore, in the treatment of this kind of condition, you can use tools that:
  • vasodilator drugs can have an antihypoxic effect (Chekman I.S., Gorchakova H.A., Frantsuzova SB., Mintser V.O. Cardioprotectors: aspects of pharmacodynamics / International Medical Journal. - 2002, Ns 1-2).
  • These drugs have long been nitro compounds (nitroglycerin, isosorbite dinitrate, etc.), papaverine and its synthetic analogue drotaverine, calcium channel blockers and, less commonly, class E prostaglandins (Mashkovsky MD. Medicines. In 2 volumes 14th edition, revised, amended and supplemented. - M .: New Publishing House LLC, 2002).
  • nitro compounds Unfortunately, the classic anti-ischemic drugs based on nitro compounds (Mosbu's, 2003) are quite toxic and effective only for ischemia of blood vessels that feed the myocardium. Indeed, the use of nitro compounds against the background of cerebrovascular accident reduces the rate of blood outflow from the cranial cavity, which can cause swelling, edema and, as a result, compression of the brain with impaired central nervous system functions.
  • papaverine and drotaverin are too slowly absorbed from the gastrointestinal tract and exhibit a weak vasodilating effect, while their intravenous administration can drastically lower blood pressure (up to collapse) and disrupt the heart rhythm (sometimes even to the point of stopping the heart). Therefore, these drugs are preferably administered intramuscularly. This reduces the duration of the manifestation of the therapeutic effect to 15-20 minutes and virtually eliminates these complications.
  • nitro compounds, papaverine and drotaverin do not exhibit a pronounced cytoprotective effect.
  • Calcium channel blockers (verapamil, diltiazem, nifedipine, cinnarizine, nimodipine, etc.) are less toxic than nitro compounds, are quite easily absorbed, and can exhibit a cytoprotective effect.
  • ⁇ -adrenoreceptor blockers, hypnotics and tranquilizers can also affect the functional activity of cells (and the corresponding tissues and organs). However, they are “highly specialized)). In particular, ⁇ -blockers primarily act on the heart, and tranquilizers and hypnotics on the brain. Therefore, to suppress pathological processes in several vital organs of their have to be used in combination, which significantly increases the risk of side effects.
  • ⁇ -blockers used in medicine disrupt the central nervous system, causing distraction, depression and weakness, the respiratory apparatus, causing bronchospasm (up to the development of asthma), and the cardiovascular system, inhibiting the cardiac conduction system and myocardial contractility and causing hypotension , bradycardia and Raynaud's syndrome.
  • ⁇ -blockers are undesirable in pregnancy and diabetes.
  • Side effects of the use of tranquilizers and sleeping pills include dysfunction of the central nervous system (up to coma) and suppression of the functions of the cardiovascular system, which limits their use in clinical practice.
  • the cytoprotective effect of these drugs was demonstrated mainly experimentally, and they are rarely used in clinical practice (Polishchuk H., Treshchinsky A. Intensive care for acute ischemic stroke Il Dostor. - 2003, Ns ⁇ , p. 21-23).
  • piracetam is effective as a cytoprotector only in large doses (6-12 g per dose), which is difficult to achieve even under clinical conditions.
  • magnesium compounds are now most used, because Mg 2+ ions participate in many enzymatic reactions and therefore play an important role in the regulation of metabolism, including ATP synthesis.
  • magnesium ions are able to modulate the activity of receptors and, thereby, regulate cellular activity.
  • magnesium preparations are almost the same in patients with its low and normal concentration in the blood. Their long-term use This improves the condition of patients with coronary heart disease and contributes to the regression of atherosclerosis, and in case of myocardial infarction it reduces the risk of sudden death (Shilov AM, Svyatov I. S, Kravchenko VV et al. Use of magnesium preparations for the prevention of cardiac arrhythmias in patients with acute myocardial infarction Il Russian Journal of Cardiology. - 2002, Ns1, p.16-19). And, finally, Mg 2+ ions are equally useful for regulating coronary and cerebral blood flow and mitigating the effects of ischemia (Chekman, I. S. Biochemical Pharmacodynamics. - Kiev: Zdorovya, 1991).
  • magnesium sulfate commonly used in therapy is practically not absorbed from the gastrointestinal tract and has laxative properties. Therefore, it is administered only parenterally. This leads to rapid dissociation of salt, a reduction in the duration of the therapeutic effect and saturation of the body’s liquid media with sulfate anions.
  • Magnesium asparaginate usually used in combination with potassium asparaginate in the form of the popular panangun drug (op. Chekman I.S.), has some cytoprotective effect against the background of ischemic and reperfusion injury to the myocardium. It is practically harmless to humans in typical therapeutic doses, because asparaginate anions can be included in metabolic processes and completely utilized in plastic exchanges. This preparation based on organic (aspartic) acid can be considered the closest in technical essence to the drug proposed further.
  • the basis of the invention is the task of changing the composition to create such a cytoprotective drug based on an organic acid that, when introduced into the human body, would exhibit a complex cytoprotective effect and thereby reduce the risk of complications in the prevention and treatment of hypoxia of various etiologies.
  • the cytoprotective agent based on organic 'acids according to the invention comprises at least gluconic acid and anions, respectively, in the simplest case represents the net-hand glyukono- acid (otherwise known as 2,3,4,5,6-pentagidpokcikapponovaya or 2,3,4,5,6- pentaoxyhexanoic acid).
  • gluconic acid provides a cytoprotective effect regardless of the causes of hypoxia and the resulting dysfunctions of the cell functions of such important organs as the brain and heart.
  • Gluconic acid is perfectly absorbed by the body, is practically non-toxic, has no side effects and is easily utilized in metabolic processes as a useful anabolite.
  • cytoprotective drug is pure magnesium gluconate, the intake of which is most effective in hypoxic conditions against the background of a deficiency of magnesium cations in the body.
  • the cytoprotective preparation is either a coordination compound duGAMK ⁇ Mg-gluconam based on magnesium gluconate and ⁇ -aminobutyric acid (hereinafter - GABA), or a double salt selected from the group consisting of succinate gluconate, ascorbate gluconate , magnesium glycinate gluconate and combinations thereof.
  • - GABA a coordination compound duGAMK ⁇ Mg-gluconam based on magnesium gluconate and ⁇ -aminobutyric acid
  • a double salt selected from the group consisting of succinate gluconate, ascorbate gluconate , magnesium glycinate gluconate and combinations thereof.
  • Gluconic acid empirical formula C 6 H 12 O 7
  • magnesium gluconate empirical formula dihydrate Ci 2 H 22 MgOi 4 * 2H 2 O
  • chemical reagents that must have a quality of at least “xh "(Chemically pure).
  • magnesium gluconate can be obtained by neutralizing gluconic acid (usually taken as an aqueous solution of easily hydrolyzable d-gluconolactone) with an almost equimolar amount of magnesium oxide or hydroxide.
  • Magnesium succinate gluconate (empirical formula Ci 0 Hi 6 MgOi i) and magnesium ascorbate-gluconate (empirical formula C 12 H 2b MgO 13 -2H 2 O) were obtained by dissolving in a 50% aqueous gluconic acid solution of equimolar amounts of succinic or ascorbic acid gradual introduction into the resulting solution with vigorous stirring of an equimolar (calculated as a cation) amount of magnesium oxide (or hydroxide). After complete assimilation of the magnesium source, the solution was cooled in an ice bath, the remaining water was separated on a Shot filter, and the precipitate was dried to constant weight.
  • Magnesium glycinate gluconate (empirical formula C 8 H 15 Mg NO 9 ) was prepared by dissolving equimolar amounts of magnesium glycinate and magnesium gluconate, which are available on the pharmaceutical market in water heated to 40-50 ° C with constant stirring. Then the water was evaporated, and the residue was dried to constant weight. Experimental dosage forms of these compounds were prepared by dissolving them in an isotonic aqueous solution of sodium chloride or glucose.
  • hypoxic cell damage brain hypoxia due to occlusion of both carotid arteries in rats (Spasov AA., Kosolapoe BA, Ostrovsky O.V. et al. (Anti-ischemic properties of the new antioxidant Enoxifol drugs Il Experimental and clinical pharmacology. - 2003, N ° 4, p.17); heart hypoxia due to perfusion of isolated rat hearts according to Lanrendorf; general hypoxia of the body due to hypercap ii) general hypoxia due to ionizing radiation of the whole organism. Manipulations (except ionizing radiation) were performed under sodium sodium anesthesia at a dose of 40 mg / kg.
  • Cytoprotective activity was evaluated by the number of surviving animals, biochemical indicators of the activity of tissue respiration enzymes and the amount of ATP, as the main energy substance, the preparations were administered in isotoxic doses (5% of LD 50 ), and piracetam was used as the reference drug. Numerical data were processed statistically. Table 1
  • the ionizing radiation of the rat organism was generally provided using an x-ray apparatus with an operating voltage of 190 kV, an operating current of 10 mA, and a field area of 40x40 cm 2 . Rats weighing 150-220 g were kept in the indicated field for a time sufficient to obtain an absorbed dose of 6 Gy.
  • Table 5 shows that, in contrast to piracetam, the preparations according to the invention showed a cytoprotective (in particular, radioprotective) effect on the bone marrow.
  • Example 1 In a rat weighing 150 g under ethanol-sodium anesthesia, bilateral occlusion of the carotid arteries was performed. After 8.2 hours, the animal died.
  • Example 2. A rat weighing 160 g was injected intraperitoneally with magnesium gluconate in a dose
  • Example 3 A rat weighing 160 g was injected intraperitoneally with diHAMK-Mg-muconate at a dose of 250 mg / kg. After 30 minutes, bilateral occlusion of the carotid arteries was performed under ethinal sodium anesthesia. The rat remained alive for 48 hours, after which it was euthanized.
  • Example 4 A rat weighing 135 g was placed in a sealed chamber with a volume of 600 cm 3 . After 12 minutes, the animal died from asphyxiation.
  • Example 5. A rat weighing 130 g was injected intraperitoneally with diHAMK-Mg-gluconate at a dose of 250 mg / kg. After 30 minutes, it was placed in a sealed chamber of 600 cm 3 . After 17 minutes, the rat developed cramps and she died.
  • the cytoprotective preparations according to the invention can be used as therapeutic and prophylactic in hypoxic conditions of arbitrary etiology.
  • intravenous administration is indicated for the treatment of tissue hypoxia in acute cerebrovascular accident, traumatic brain injuries, carbon monoxide poisoning or other tissue poisons, and for violations of pulmonary circulation.
  • Parenteral administration can be used to prevent hypoxia in firefighters, mountain rescuers and climbers.
  • the manniferous preparations according to the invention are expediently used in the complex treatment of electrolyte metabolic disturbances as a means of correcting the concentration of magnesium in body fluids.
  • cytoprotective preparations according to the invention can be easily manufactured industrially and used for the prevention and outpatient or clinical treatment of hypoxic conditions of arbitrary etiology. They have a wide spectrum of cytoprotective activity, are easily absorbed and in therapeutic doses are practically harmless to warm-blooded organisms.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le produit cytoprotecteur de l'invention à base d'un acide organique est destiné à la prévention et au traitement de l'hypoxie d'étiologies différentes. Il comprend au moins des anions d'acide gluconique, qui font notamment partie de l'acide gluconique pur ou du gluconate de magnésium pur, et se présente de préférence comme une composition coordonnée de diGABA-Mg-gluconate ou comme un sel double sélectionné dans un groupe constitué de succinate-gluconate de magnésium, d'ascorbate-gluconate de magnésium, de glycinate-gluconate de magnésium ou de leurs mélanges.
PCT/UA2006/000019 2005-04-15 2006-04-12 Produit cytoprotecteur WO2006110118A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
UA200503573 2005-04-15
UAA200503573 2005-04-15

Publications (1)

Publication Number Publication Date
WO2006110118A1 true WO2006110118A1 (fr) 2006-10-19

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Application Number Title Priority Date Filing Date
PCT/UA2006/000019 WO2006110118A1 (fr) 2005-04-15 2006-04-12 Produit cytoprotecteur

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WO (1) WO2006110118A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087265A2 (fr) * 2000-05-18 2001-11-22 Zentaris Ag Forme d'administration pharmaceutique pour des peptides, son procede de production et son utilisation
RU2223759C1 (ru) * 2002-09-18 2004-02-20 Виктор Павлович Кутняк Антиаритмический препарат
RU2002121640A (ru) * 2000-01-18 2004-03-27 Ф.Хоффманн-Ля Рош Аг (Ch) Лечение повреждений головного мозга, спинного мозга и нервов

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2002121640A (ru) * 2000-01-18 2004-03-27 Ф.Хоффманн-Ля Рош Аг (Ch) Лечение повреждений головного мозга, спинного мозга и нервов
WO2001087265A2 (fr) * 2000-05-18 2001-11-22 Zentaris Ag Forme d'administration pharmaceutique pour des peptides, son procede de production et son utilisation
RU2223759C1 (ru) * 2002-09-18 2004-02-20 Виктор Павлович Кутняк Антиаритмический препарат

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