Pharmacological properties

Pharmacodynamics. arginine (α-amino-δ-guanidinovalerianovy acid) — amino acid which belongs to the class of conditionally irreplaceable amino acids and is the active and versatile cellular regulator of numerous vital functions of an organism renders important tire-tread effects in critical condition of an organism.

Arginine possesses anti-hypoxemic, membrane stabilizing, cytoprotective, antioxidant, disintoxication action, is shown as the active regulator of interstitial exchange and processes of power supply, plays a part in maintenance of hormonal balance in an organism. It is known that arginine increases the content in blood of insulin, a glucagon, STG and prolactin, participates in synthesis of proline, polyamines, an agmatina, joins in processes of a fibrinogenoliz, spermatogenesis, possesses membranodepolyariziruyushchy action.

Arginine is substrate for NO-SYNTHASE — enzyme which catalyzes synthesis of nitrogen oxide in endotheliocytes. Drug activates guanylate cyclase and increases the tsGMF level in an endothelium of vessels, reduces activation and adhesion of leukocytes and thrombocytes to an endothelium of vessels, synthesis of proteins of adhesion of VCAM-1 and MCP-1 oppresses, preventing thus education and development of atherosclerotic plaques, synthesis of endothelin-1 which is a powerful vasoconstrictor and a stimulator of proliferation and migration of smooth muscle cells of a vascular wall oppresses. Arginine oppresses also synthesis of asymmetric dimethylarginine — a powerful endogenous stimulator of an oxidative stress. Drug stimulates activity of a thymus which produces T-cells, regulates glucose content in blood during physical activity. Has acid-forming effect and promotes correction of acid-base equilibrium.

Arginine is one of the main substrates in a cycle of synthesis of urea in a liver. The Gipoammoniyemichesky effect is implemented by activation of transformation of ammonia into urea. Carries out hepatoprotective action thanks to antioxidant, anti-hypoxemic and membrane stabilizing activity, positively influences processes of power supply in hepatocytes.

Pharmacokinetics. At continuous C _{max in/in infusion} arginine in blood plasma it is observed in 20–30 min. from the beginning of introduction. Arginine gets through a placental barrier, is filtered in renal balls, however reabsorbirutsya almost completely in renal tubules.

solution Pharmacokinetics for oral administration was not investigated.

Indication

Atherosclerosis of vessels of heart and brain, atherosclerosis of peripheral vessels, including with manifestations of the alternating lameness, a diabetic angiopatiya, an ischemic heart disease, ag, states after the postponed acute myocardial infarction and an acute disorder of cerebral circulation, a myocardiopathy, chronic heart failure, a hypercholesterolemia, stenocardia, hobl, interstitial pneumonia, idiopathic pulmonary hypertensia, chronic post-embolic pulmonary hypertensia, acute and chronic hepatitis of various etiology, a giperammoniyemiya, hypoxemic states, asthenic states in the course of a convalescence, including after infectious diseases and surgeries, a metabolic alkalosis, depression of function of a thymus, an arrest of development of a fruit and a preeclampsia.

Use

Solution to oral administration are applied inside at meal time, by adults on 5 ml (1 measured spoon — 1 g of drug) 3–8 times a day; the maximum daily dose — 8 g

Duration of a course of treatment — 8–15 days; if necessary the course of treatment is repeated.

Solution for infusions is entered by

in/in by drop infusion with a speed of 10 thaws a minute the first 10–15 min., then it is possible to increase rate of administering to 30 drops a minute.

Daily dose of medicament — 100 ml of solution.

At heavy disturbances of blood circulation in the central and peripheral vessels, at the expressed phenomena of intoxication, a hypoxia, asthenic states the dose of medicament can be raised to 200 ml/days (100 ml 2 times a day).

Maximum rate of administering of infusional solution should not exceed 20 mmol/h

to Children aged to 12 years a dose of medicament is 5–10 ml/kg/days

For treatment of a metabolic alkalosis the dose can be calculated as follows:

Arginin's

hydrochloride (mmol) ‧ 0.3 ‧ weight kg body/excess of alkali (Ve) (mmol/l).

should begin Introduction with

with a half of the calculated dose. Additional correction has to be carried out after obtaining results of the restored acid-base balance.

Contraindication

Hypersensitivity, heavy renal failures, giperkhloremichesky acidosis, allergic reactions in the anamnesis, use of kaliysberegayushchy diuretics and also Spironolactonum.

Side effects

After use of oral solution seldom arise feeling of slight discomfort in a stomach and intestines, nausea which disappear independently.

Later in/in introductions are possible

: a headache, feeling of heat, phlebitis in the injection site, it is rare — allergic reactions.

Special instructions

Carefully should be applied at disturbances of exchange of electrolytes, diseases of kidneys. at use of medicament it is necessary to adhere to the balanced sleep pattern and rest, to refuse alcohol, nicotine and psychostimulants. if against the background of administration of medicament the expressiveness of symptoms of an asthenia increases, treatment needs to be cancelled.

At patients with a renal failure before infusion should check a diuresis and level of potassium in blood plasma as medicament can contribute to the development of a hyperpotassemia.

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With care at dysfunction of closed glands, medicament can stimulate secretion of insulin and growth hormone.

Children. Drug is used at children aged 3 years are more senior.

Use during pregnancy or feeding by a breast. Drug gets through a placenta therefore during pregnancy it can be applied only when the expected advantage for mother exceeds potential risk for a fruit.

uses of medicament Given relatively during feeding by a breast are absent.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Does not influence.

Interaction

Simultaneous use of Aminophyllinum with arginine can be followed by increase in content of insulin in blood.

Arginine can cause the expressed and resistant hyperpotassemia against the background of a liver failure in patients who accept or accepted Spironolactonum. The previous use of kaliysberegayushchy diuretics can also promote increase in potassium concentration in blood.

Arginine is incompatible

with thiopental.

Overdose

Symptoms: hypersensitivity reactions, hypoglycemic states.

At in in administration of solution the renal nedostatnost, a hypoglycemia, a metabolic acidosis are possible

.

Treatment. In the presence of the specified phenomena it is necessary to stop administration of drug.

to

At oral administration showed gastric lavage, reception of sorbents. For elimination of hypersensitivity reaction carry out the desensibilizing therapy.

At in in introduction should carry out by

monitoring of physiological reactions and maintenance of the vital functions of an organism. If necessary — introduction of alkalizing means and diuretics (saluretics), crystalloid solutions (0.9% NaCl solution, 5% dextrose solution).

Storage conditions

B the dry, protected from light place at a temperature of 15-25 °C.

Expiration date after disclosure of a bottle of Tivortin aspartate — 14 days. Not to freeze!

Relevant information

Tivortin according to ats-classification treats the medicaments influencing the system of blood and a hematopoiesis to amino acids and also to the medicines influencing a cardiovascular system. its active ingredient — arginine a hydrochloride (l-arginini hydrochloridum). medicament possesses a wide range of the effects caused by a physiological role of arginine in an organism, among which anti-hypoxemic, cytoprotective, membrane stabilizing, membranodepolyariziruyushchy and antioxidant. tivortin has anti-radical and disintoxication properties, regulatory influence concerning power and exchange processes. also this medicament influences a fibrinolysis, a spermatogenesis, hormonal exchange (increases the level of such hormones as insulin, somatotropic hormone and prolactin).

an arginine Role in a healthy organism and in diseases

Arginine (ARG; 2-amino-5-guanidovalerianovaya acid) are 1 of 6 conditionally irreplaceable amino acids. When the Swiss chemist Ernst E. Schulze for the first time emitted arginine from plant extract a lupine in 1886, he probably did not expect that arginine will have the potential for such broad use as medicine and nutritional supplement. Actually importance of arginine was not realized until G.A. Krebs and K. Henseleyt (H.A. Krebs, K. Henseleit) opened an urea cycle in 1932 (Patel J.J, 2016). Arginine has properties to improve healing of wounds, its positive effect is noted in a sickemia, premature births and a preeclampsia, during the postoperative period and in pulmonary hypertensia (Barbul A. et al., 1985) and also in therapy of mitochondrial diseases (Ganetzky R., Falk J.M., 2018), it explains a wide range of clinical effects of medicament Tivortin . Arginine is also offered as medicament for inclusion in complex therapy of bronchial asthma as its ability to reduce inflammation, hyperreactivity and remodeling of bronchial tubes (Morris C.R is proved. et al., 2013). Arginine is often included in the complex scheme of treatment of cardiovascular and metabolic diseases (Rodrigues-Krause J. et al., 2019). However in emergency conditions, at zhizneugrozhayushchy states the issue of inclusion of arginine in the therapeutic scheme of treatment remains controversial (Jayshil J. et al., 2016).

Arginine is an alpha amino acid which participates in a number of processes in a human body, supports a condition of the cardiovascular and immune system normal. Besides that arginine is a nitrogen source for the nitrogen oxide produced by endothelial and immune cells in vazodilatatorny and protective mechanisms, it is also used for synthesis of creatine for satisfaction of metabolic requirements of muscles and also for synthesis of urea for the purpose of maintenance of nitric balance in an organism. Besides, arginine stimulates broadcast of protein and synthesis of polyamines — anabolic and proliferative functions which become unregulated in cells after malignant transformation in this connection researches of opportunities of use of medicaments of arginine in oncology are conducted (Albaugh V.L. et al., 2019).

Arginine is a component for synthesis of protein in an organism. Moreover, arginine plays a key role in the metabolic ways catalyzed by various enzymatic systems (Wu G. et al., 1999).

Arginine is an intermediate link in an urea cycle in a liver. The cycle of urea represents a series from 5 consecutive reactions in which synthesis of urea is a final stage of a detoxication of ammonia. Besides, the cycle of urea is considered the main way of removal of metabolic generated bicarbonate. Other functions of arginine are connected with its derivatives. Creatine, ornithine and derivative polyamines (putrestsin, spermine and spermidine) which play an important role in growth and differentiation of cells concern them. Proline which is posttranslyatsionno hydroxylated to hydroxyproline also is derivative arginine and takes part in formation of collagen, restoration of fabrics and healing of wounds. Creatine takes part in energy balance in muscles and neurons (Wu G., Morris S.M., 1998).

L-arginine was identified by

In the 1980th years as the predecessor of nitrogen oxide (NO) (Palmer R.M. et al., 1988) which is formed in endothelial cells under the influence of activity of an isoenzyme of constitutive NO-SYNTHASE, this mechanism explains the majority of positive effects Tivortin in cardiovascular diseases. Though NO was for the first time revealed in endothelial cells, it represents everywhere the widespread molecule which is contained in various cells including cells of cardiovascular and nervous systems and also inflammatory cells. NO has a set of physiological functions that emphasizes the functional importance of arginine. NO is released from an endothelium, plays a vazodilatator role in vessels and inhibits aggregation of thrombocytes, adhesion of leukocytes and proliferation of cells of unstriated muscles of vessels. It was established that at an experimental hypercholesterolemia and atherosclerosis and also at patients with a hypercholesterolemia, NO - the mediated reactions are broken (Böger R.H. et al., 1996). NO in a brain works as a neurotransmitter and regulates many physiological processes affecting behavior and cognitive functions including synoptic plasticity. Besides, NO controls a brain blood stream, promotes angiogenesis and supports oxidation-reduction cellular reactions, cell-mediated immunity and survival of populations of neurons. NO performs immunoregulatory functions, such as control or destruction of infectious pathogenic organisms, modulation of products of cytokines and development T-helperov. Moreover, NO can work as the absorber of free radicals (Titheradge M.A., 1999). Arginine plays an indirect role in NO - the mediated functions, including immune modulation (Luiking C.Y. et al., 2012). Arginine — not only substrate for an ureagenez, but also the N-atsetilglutamat-sintetazy activator which is key ureagenny enzyme.

Metabolism of arginine changes at a condition of a disease — its synthesis of de novo decreases and use increases. The increased use of arginine for synthesis of protein connected with reaction to a stress such as proteins of a sharp phase, reduces availability of arginine in these conditions and can lead to changes of activity of NOS enzyme. There is a decrease in products NO (Kao C.C. et al., 1999). Besides, the increased oxidation of arginine is noted in sepsis at children (Luiking C.Y. et al., 2012).

Arginine in researches

to Studying effect of medicaments of arginine in therapy of various diseases devoted a set of researches.

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B one of them studied efficiency of administration of arginine for maintenance of functions of the immune system at seriously ill patients of patients. Administration of arginine led to improvement of immune function at patients. As a result of a research at premature children it was established that administration of L-arginine both parenterally, and it is enteral, reduces the frequency of development of a necrotic coloenteritis. In one research it was established that oral administration of arginine in combination with usual chemotherapy for an active form of tuberculosis by the HIV-positive patient increased the response to the main therapy (Wilmore D., 2004).

hydrochloride arginine Use in burns

In 2009 by group of scientists from China conducted clinical trial which purpose was a studying influence of arginine on the nutritive status and cell-mediated immunity of patients with heavy burns. 30 patients with heavy burns participated in a research, 14 received standard treatment, at 16 the scheme of treatment included arginine. Determined the level of serum protein, parameters of function of a liver, parameters of function of kidneys, glucose level in blood on an empty stomach and subpopulations of T lymphocytes in peripheral blood for the 7th and 14th days after a burn. By results of a research conclusions are drawn that inclusion in the scheme of treatment of enterally entered arginine considerably improved the nutritive status and functions of cell-mediated immunity at patients with burns.

35 patients with essential hypertensia who received or 6 g of L-arginine (18 patients), or placebo (17 patients) participated In the research devoted to studying influence of arginine on endothelial dysfunction at patients with arterial hypertension. By results of a research conclusions were drawn that administration of L-arginine considerably improves endoteliyzavisimy dilatation of a humeral artery at patients with essential hypertensia. Long-term effects of L-arginine demand further study from such patients (Lekakis J.P. et al., 2002).

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B other research conducted in Australia it was also estimated influence of L-arginine on function of an endothelium and adhesion of thrombocytes at healthy people.

Knows that L-arginine improves endoteliyzavisimy dilatation, inhibits aggregation of thrombocytes and reduces atherosclerotic plaques. At patients with a hypercholesterolemia in/in administration of L-arginine immediately improves endoteliyzavisimy dilatation. 12 healthy young people at the age of 27–37 years participated in a research. Defined the following indicators: arginine level in blood plasma, the speed of aggregation of thrombocytes, level of the cyclic guanozinmonofosfat, level of lipids on an empty stomach, the heart rate, arterial blood pressure, endoteliyzavisimy dilatation of a humeral artery. Scientists came to a conclusion that at healthy young adults L-arginine inhibited aggregation of thrombocytes (it is mediated NO). However it did not influence system hemodynamic indicators, levels of nitrozilirovanny protein in blood plasma or endoteliyzavisimy dilatation (Adams M.R. et al., 1995).

Scientific of Greece (Siasos G. et al., 2007) emphasize that L-arginine improves function of an endothelium at patients with a hypercholesterolemia, hypertensia and smokers. Oral administration of L-arginine leads to considerable improvement of an endoteliyzavisimy vazodilatation of a forearm at patients with a hypercholesterolemia while in/in injection of L-arginine improves function of an endothelium at healthy smokers. L-arginine has antihypertensive properties, patients can have a useful administration of L-arginine with early atherosclerosis.

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In the research conducted on rabbits it was established that prolonged oral administration of L-arginine has anti-atherosclerotic effect at giperkholesterinemichesky rabbits. In clinical trial it was shown what in/in administration of L-arginine causes NO - a dependent peripheral vazodilatation and inhibits aggregation of thrombocytes at healthy people and also at patients with heavy ischemia of extremities and generalized atherosclerosis (Böger R.H. et al., 1996).

Angiogenic properties of a growth factor of an endothelium of vessels and a growth factor-2 of fibroblasts are partially caused by release NO which availability decreases in endothelial dysfunction. The group of scientists from the USA studied influence of L-arginine on the endogenous angiogenic answer to ischemia in hypercholesterolemia model at pigs. The ameroidny constrictor on a peripheral artery (LCx) was established to pigs. In 7 weeks of an experiment the endoteliyzavisimy coronary microvascular answers to a growth factor of fibroblasts-2 and a vascular endothelial growth factor were estimated by means of video microscopy. Perfusion was estimated by means of radioactive microspheres. Angiogenesis was estimated by means of marking of molecules of adhesion of thrombocytes-endothelial cells-1 (CD31). Regional function of a myocardium was estimated by means of a sonomikrometriya. An expression of endothelial synthase of nitrogen oxide and indutsibelny synthase of nitrogen oxide measured a western-blotinga with the help. On the basis of results of a research conclusions were drawn that use of L-arginine leads to increase in perfusion, improvement of a condition of an endothelium of capillaries and level of endothelial synthase of nitrogen oxide in ischemic area. However despite this, improvements in regional function of a myocardium it is not revealed. Thus, use of L-arginine can partially restore endoteliyzavisimy vasorelaxation and improve perfusion of a myocardium in model of chronic ischemia of a myocardium at pigs with the endothelial dysfunction caused by a hypercholesterolemia (Nakai Y. et al., 2005).

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In clinical trial studied hydrochloride arginine use for treatment of a metabolic alkalosis and a hypochloraemia for children. The success of treatment was estimated by measurement of concentration of chloride and bicarbonate in blood serum after administration of arginine. At 50% of the patients receiving arginine the level of chlorides was normalized. At 83% of patients which administered this medicament the level of bicarbonates was normalized. Thus, arginine is effective for improvement of a metabolic alkalosis and a hypochloraemia (Sierra C.M. et al., 2018).

Metabolic alkalosis is the widespread acid-base disturbance arising at seriously ill patients of children. In clinical trial compared efficiency of treatment of a metabolic alkalosis at children of arginine a hydrochloride to therapy by acetazoleamide. Proceeding from the obtained data, the conclusion was drawn that acetazoleamide and arginine a hydrochloride are equally effective for correction of a metabolic alkalosis at children in critical condition (Heble D.E.Jr. et al., 2016).

Conclusion

Tivortin — medicament of a broad spectrum of activity, its effects are caused by a many-sided physiological role of arginine in a human body. The wide range of the states which are giving in to therapy by this medicament caused its broad use and popularity. Among indications there is Tivortina — an ischemic heart disease, the postponed myocardial infarction, atherosclerotic defeat of vessels, states after strokes, HOZL, defeats of vessels in diabetes, pulmonary hypertensia, interstitial pneumonia, hepatitis, a hypoxia. Drug can be also appointed pregnant at identification of a delay of pre-natal fetation and a preeclampsia. Tivortin is shown at some metabolic disturbances, an asthenia, during recovery after various diseases, including infectious.