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ATP-LONG - a representative of a new class of cardiotropic preparations

              During latest decades an interest to the study of body bioenergetic processes has significantly raised. This is proved by a collection of works on this subject, which where awarded by three Nobel prizes within last 20 years. In 1997 Nobel prize was awarded to Paul D. Boyer and John E. Walker for the ascertainment of fermentative mechanism, basing adenosine triphosphate (ATP) synthesis, and to Pense C. Skow for the discovery of the first ion-transport ferment Na+, K+ ATPase. Contemporary science attaches a great significance to the study of bioenergetic issues, as this is associated with the fact that vital activity of any body depends on its energetic status. Adenosine triphosphoric acid (ATP) plays a leading role in the basis of provision of human body vital activity. K. Lomann, German chemist, discovered this acid in 1929. In 1935 V. Enhelgardt (Russia) paid his attention on the fact that muscular contraction with no ATP is impossible During the period from 1939 to 1941 F. Lipmann, Nobel prize laureate, demonstrated that ATP is a main chemical energy carrier in the cell and proposed definition “energetically rich phosphate bonds”. In line with the study of biochemical mechanism of ATP action medicine at the end of 20th last century started the study of a pharmacological efficiency of this macroergic phosphate. However, within a long time the ATP action on human body was considered from the viewpoint of a substitution therapy for replenishment of human body energy loss. But such a concept of ATP role appeared erroneous, as in accordance with the latest data a large ATP quantity, equal to half body mass, and with a hard physical work almost a ton is processed within a day in adult human body. The study of ATP action had radically changed in the mid 70th last century, when existence of specific receptors over external surfaces of cell membranes, sensitive to ATP molecule, was discovered. Since that time triggering (regulatory) action of ATP on various body functions has being studied. During latest years an interest to the study of ATP raised again due to the fact that with hypoxia its earlier unknown properties such as endogenous intracell and intercell metabolism regulator, functioning as cell protector against damaging action of hypoxia, has raised. It was ascertained that ATP has an expressed anti-adrenergic action, play a significant role in vascular tonus regulation and affects cardiac muscle contractility and conduction system. ATP plays a significant role in energetic supply of cardiomyocytes, as cell energetic status is of a great significance for maintaining vital functions. First of all, the following vital functions are energy dependent: contractile, transport, metabolic, receptor, etc. Retention of cell receptor function is peculiarly significant for the treatment process, as with its damage major portion of medicinal preparations loose the base for implementation of their therapeutic effect and become ineffective. The majority of surveyors state, that any post-ischemia status is characterized by a drop of energy productivity in myocardium cells. Duration and depth of ischemia and reduction of the quantity of energetic resources in cardiomyocytes are interdependent. Deficiency of ATP in myocardium within the period of ischemia result in various functions damages at systematic, cellular, subcellular and molecular levels. These changes result in the fact that myocardium cells cannot maintain necessary metabolism for their vital activity and perform their inherent functions. As ATP re-synthesis with ischemia sharply drops while the use of pharmacological substances for cell energetic status increase also requires additional ATP energy, a hypothesis has originated that direct ATP administration will result in increase of cell energetic resources and correct damages arising with hypoxia. This approach was applied with early ischemia stages and resulted in certain improvement, however next studies had shown that in such case ATP has an insignificant effect and only with preventive administration or at earliest stages of microcirculation failure or ischemia. Further studies had demonstrated that low pharmacological efficiency of ATP application is due to the fact that the latter serves in human body as a complex-forming reagent showing its basic metabolic and hemodynamic effects in combination with magnesium, therefore the majority of metabolic reactions require not only ATP as a metabolic substrate, but also magnesium as a cofactor. In vitro and in vivo experiments have demonstrated that magnesium has a decisive affect on ATP biological activity, preventing its failure by inhibition of processes of ATP deaminization and dephosphorization by tissues. Therefore, reduction of ATP or magnesium concentration, arising during ischemia period, may result in reduction of metabolic processes in cells and of their energetic statuses. Thus, we may conclude that to successfully correct failures due to ischemia and cell damage, the use of ATP-magnesium complex is required. Data obtained by numerous surveyors had demonstrated that the use of ATP in combination with Mg++ has a multiple effect on physiological and biochemical processes in cells. This complex raises intracell ATP content, reduces lactic acid concentration in tissues, improves electrolytic exchange, normalizes membrane permeability, calcium and magnesium levels in mitochondria and reduces intracell acidosis when used during post-ischemia period. It is well known that chemical properties and biological activity of many substances depend on composition of their internal coordination sphere. As in chemical structure ATP in combination with magnesium is a uniform-ligand complex, a hypothesis originated that the change of coordination sphere may impact ATP biological activity. On the basis of the above data some new chemical substances containing ATP, magnesium, potassium and amino acids were synthesized. Further experimental studies on creatures had demonstrated that membrane-stabilizing and anti-ischemia action of these chemical substances are much higher than that of ATP combination with magnesium. Data of these studies were used for creating a new class of substances – heteroligand coordination compounds with macroergic phosphates. ATP-LONG is a first unique homemade preparation of this class of substances. Chemical structure of this preparation has no analogs throughout the world and is protected by Ukrainian and Russian patents. This preparation was derived by a topical synthesis with consideration of results of numerous works describing protective effects of ATP, amino acids and macroelements on organs and tissues during ischemia period. ATP-LONG has been so synthesized that its ingredients such as macroergic phosphate ATP, magnesium ion, amino acid histidine and potassium ions are coordinated so that the molecule is readily built in various links of metabolic processes and is relative to membrane cell receptors, which fact conditions its multiple pharmacological effect. Due to its unique structure this molecule has its own pharmacological action, which is not inherent to each of its chemical components: ATP, histidine, K+, Mg++. However, with coordination sphere change an action inherent to each of its chemical components (ATP, histidine, K+, Mg++) may develop, therefore the preparation can correct different structures and functions on systematic, cellular and subcellular levels. So, ions of magnesium, which is natural calcium ions antagonist, provides a negative inotropic effect on cardiac muscle, thus reducing its oxygen consumption and peripheral resistance due to reduction of tonuses of vascular smooth muscle structure. Magnesium inhibits deaminization and dephosphorization processes. Potassium ions maintain cell osmotic and acid-basic homeostasis, participates in provision of transmembrane potential difference and activates synthesis of ATP and creatine phosphate. Amino acid histidine is a natural trap of free radicals and inhibits lipids peroxidation processes, thus protecting structural membrane components against peroxidation and hydrolysis and preventing their degradation. Non-organic phosphorus, formed after hydrolysis, increases together with imidazole histidine ring cell buffer capacity, thus providing a more stable retention of cellular membrane structural elements under conditions of ischemia. Cellular membrane structures are retained due to the fact that with rise of cell pH imidazole and phosphate groups, forming microenvironment of membranes, release protons while with pH reduction they bond them and therefore local pH around membrane structures is maintained within physiological values despite change of intracellular pH, thus increasing the extent of cellular retention under conditions of ischemia (F.Z. Meerson, 1984; R.F. Burton, 1978; G.N. Somero, 1981). Due to the above factors medicinal preparation ATP-LONG is more effective by a number of indicators than well-known disodium salt ATP, which is nowadays used for treatment of some diseases of cardiovascular system. ATP-LONG is the first preparation in the form of tablets in Ukraine and in NIC containing in its structure macroergic phosphate ATP, which is released in the form of sublingual tablets containing 10 mg or 20 mg active substance. Sublingual use of ATP-LONG provides primary effect in 20 to 30 s, which is practically equal to the rate of effect onset with intravenous injection. In the process of pre- and pos-clinical tests it was demonstrated that preparation ATP-LONG has the following pharmacological effects: - under conditions of ischemia it protects myocardium cells against damage and death due to inhibition of activity of membrane-fixed phospholipases, reduces accumulation in membranes of products hydrolysis and peroxidation of phospholids – fatty acids, lysophospholipids having detergent properties and capability to damage cardiac contractility and rhythm under conditions of ischemia; - it enlarges energetic resources of myocardium cells due to increase of content of intracell ATP and glycogen, under conditions of coronary insufficiency and ischemia it gives an energy-saving effect by inhibiting activity of ferment 5’-nucleotidase, which is responsible for the rate of hydrolysis of energetic substrates; - under conditions of myocardium ischemia it raises activity of ion-transport systems of Na, K-ATPase and Ca-ATPase and calcium-fixing potential of membrane; - under conditions of ischemia it facilitates recovery of cell receptors function; - it improves indicators of central and peripheral hemodynamics and of coronary blood flow; - it raises myocardium contractility, improves functional status of left ventricle and cardiac ejaculation. Under conditions of ischemia the preparation reduces oxygen consumption by myocardium, number of stenocardia and dyspnea attacks in physical loads and raises physical workability indicators of both myocardium and the entire body; - it recovers normal sinus rhythm in patients with paroxysmal supraventricular tachycardia, supraventricular tachycardia, ventricle fibrillation and flutter and reduces active ectopic complexes (auricle and ventricle extrasystole); - it raises potassium and magnesium ion content in cells and tissues; - it reduces concentration of uric acid. Preparation ATP-LONG may be used for cupping acute statuses of cardiovascular insufficiency as well as in courses for improving myocardium functional activity. When cupping acute statuses, positive effect is noted in 30 to 40 s after tablet sublingual use. The preparation is indicated with the followings diseases and complex syndromes: - cardiac ischemia, unstable stenocardia, quietness and tension stenocardia; - post-infarction and myocardial cardiosclerosis; - cardiac insufficiency; - paroxysmal supraventricular tachycardia, supraventricular tachycardia and complex therapy of other rhythm disorders; - vegetative vascular dystonia; - myocardial dystrophy; - infective allergic myocarditis; - chronic fatigue syndrome; - hyperurikemia of various origin. With preparation us no side effects were ascertained. It is due to the fact that preparation ATP-LONG is composed of natural body metabolites such as ATP, histidine amino acids, and magnesium and potassium ions. Their advantage over other groups of pharmacological preparations consists in that preparations of metabolic action are natural products of the body itself. Therefore they are readily built in metabolic processes, related to cell receptors and correct damages arising in the body. As compared with other preparation their great advantage is nor toxicity nor side effects. ATP-LONG is just one of such metabolic drugs. Thus, the homemade preparation ATP-LONG is the first unique representative of a new class of drugs – heteroligand coordination compounds with macroergic phosphates, which has an expressed cardio-protecting, energy-saving membrane-stabilizing and metabolic effects with acute and chronic diseases of cardiovascular system.

Published: 06.09.1999