RU2295340C2 - Method for treating chronic pancreatitis cases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves excluding provoking factors influence, administering diet, carrying out substitution therapy with enzymes, inhibiting pain syndrome, applying infusion therapy, introducing anabolic steroids, phosphodiesterase inhibitors, anti-diarrhea drugs and antioxidants like Freedox and Emoxipin. Perfluorane is introduced daily at a dose of 2 ml/kg, Freedox at a dose of 3-9 mg/kg and Emoxipin at a dose of 3 mg/kg once a day not less than 3 days long but not longer than 7 days.

EFFECT: provided combined oxygenation normalization, metabolic cell control and phospholipid composition of cell membranes; accelerated pain syndrome alleviation.

Description

The invention relates to medicine, namely to gastroenterology and surgery, and for the conservative treatment of chronic pancreatitis (CP).

A known method of treating chronic pancreatitis, including the use of analgesics, pancreatic enzymes, fractional nutrition with a restriction of fats, the exclusion of alcohol (V.T. Ivashkin, G.A. Minasyan. Treatment of chronic pancreatitis. // Ros. Zhur. Gastroenterol., Hepatol., Coloproctol. - 1996. - No. 4. - S.10-17).

The disadvantage of this method of treatment is the lack of funds in it that restore antioxidant activity and the elimination of hypoxia in the pancreas (pancreas).

There is a known method of treating CP, including the relief of pain by taking analgesics, suppressing inflammation of pancreatic tissue, stopping alcohol intake, affecting innervation, the use of antioxidants, allopurinol, reducing intrapancreatic pressure, treating exocrine pancreatic insufficiency, in case of severe steatorrhea, fat-soluble, D, E, K), as well as group B (A.V. Okhlobystin. Diseases of the pancreas. / Consilium medicum. Dyspepsia / Appendix // 2002. - P.26-31).

The disadvantage of this method of treatment is the lack of funds in it that restore the elimination of hypoxia in the pancreas.

A known method of treatment of CP, including relief of pain, reduction and removal of intoxication, relief of progression of the edematous-interstitial stage of pancreatitis by creating functional rest of the pancreas with a gradual release of the pancreas to functional loads, treatment of complications: acute period - insolvency of external and intracretory pancreatic insufficiency, treatment of surgical complications and prevention of relapse with a continuing causative factor, rehabilitation of patients with CP (O. Minushkin. Chronic pancreatitis: some aspects of pa ogeneza, diagnosis and treatment // Consilium medicum / Appendix // 2002. -. Issue №1 -. S.23-26).

The disadvantage of this method of treatment is the lack of funds in it that restore antioxidant activity and the elimination of hypoxia in the pancreas.

There is a known method of treating CP, including bed rest, diet, aspiration of gastric contents, relief of pain, suppression of pancreatic secretion, infusion therapy, blockers of H ₂ histamine receptors, antacid and boning agents (Yu.G. Bozhenkov, A.N. Scherbyuk , S.A.Shalin. Practical pancreatology // M .: Medical book. - 2003. - S.94-95).

The disadvantage of this method of treatment is the lack of funds in it that restore antioxidant activity and the elimination of hypoxia in the pancreas.

The closest in technical essence and the achieved effect is a method of treating CP, according to which provoking factors are first excluded, then a diet, enzyme replacement therapy are prescribed, pain is suppressed, anabolic steroids, phosphodiesterase inhibitors are administered, infusion therapy is administered, antioxidants and antidiarrheal drugs are administered (PM Evtikhov et al. Mechanical jaundice. Chronic pancreatitis. // 1999. - Moscow-Ivanovo-Kirov. - S.220-221). This method is adopted as a prototype.

The disadvantage of this method of treatment is the lack of funds in it that effectively restore antioxidant activity and eliminate hypoxia in the pancreas.

The objective of the present invention is to reduce complications and mortality in chronic pancreatitis by increasing antioxidant activity and suppressing pancreatic hypoxia.

These objectives are achieved by the fact that in the method of treating chronic pancreatitis, which consists in eliminating provoking factors, prescribing a diet, conducting enzyme replacement therapy, suppressing pain, administering anabolic steroids, phosphodiesterase inhibitors, administering infusion therapy, administering antioxidants and antidiarrheal drugs as antioxidants use fridox and emoxipin, and also use perfluorane, while drugs are administered intravenously once a day, in a dose of perfluoran - 2 ml / kg, fridox - 3-9 mg / kg, emoxipin - 3 mg / kg and the introduction is carried out daily for at least 3, but not more than 7 days.

The method is as follows.

A patient with a diagnosis of exacerbation of primary chronic recurrent pancreatitis, the pain form from the first day is prescribed: the exclusion of provoking factors, the appointment of a diet, enzyme replacement therapy, pain suppression, the introduction of anabolic steroids, phosphodiesterase inhibitors, the implementation of infusion therapy, the introduction of antioxidants and antidiarrheal drugs, moreover, fridox and emoxipin are used as antioxidants, and perfluorane is also used, while drugs administered intravenously once a day at a dose perfluorane - 2 ml / kg, fridoks - 3-9 mg / kg, emoksipin - 3 mg / kg, and the administration is daily for at least 3 but no more than 7 days.

A specific example of the method.

Patient V., 32 years old (medical history No. 5418) was hospitalized in the department of hepatic surgery of the Kemerovo City Clinical Hospital No. 3 named after M.A. Podgorbunsky on the second day after the onset of the disease with complaints of sharp paroxysmal pain of herpes zoster in the epigastric region, right and left hypochondrium. Diagnosis: exacerbation of primary chronic recurrent pancreatitis, pain form, acute accumulation of fluid in the stuffing bag. The patient was treated for one day: antispasmodics, infusion and vitamin therapy. The patient's condition did not improve, the pain syndrome intensified and did not decrease after the use of antispasmodics. On the second day, the exclusion of provoking factors, the appointment of a diet, enzyme replacement therapy, pain suppression, the administration of anabolic steroids, phosphodiesterase inhibitors, the implementation of infusion therapy, the administration of antioxidants and antidiarrheal drugs were prescribed, and fridox and emoxipine were used as antioxidants, as well as perftoran while the drugs were administered intravenously once a day, at a dose of perftoran - 2 ml / kg, fridox - 3-9 mg / kg, emoxipin - 3 mg / kg and the introduction was carried out daily for 5 days. After applying the method on the 3rd day, the patient's condition improved, the pain syndrome decreased. On the 5th day after the started treatment, the indicators of blood and urine amylase, as well as lipid peroxidation (POL) (a significant decrease in the level of amylase, malondialdehyde and diene conjugates, an increase in the antioxidant activity of blood serum and a decrease in the activity of catalase, ceruloplasmin and an increase in superoxide dismutase in red blood cells) came to a conditional norm with a completely stopped pain syndrome. The patient was discharged after 10 days with recovery.

The significance of the differences of the proposed method is as follows.

In the last decade, there has been a significant increase in the frequency of pancreatic (pancreas) diseases, which affects an average of 1 person per 10,000 of the world's population (A.I. Khazanov. Chronic pancreatitis. New in etiology, pathogenesis, diagnosis. Modern classification. // Ros. Zh. Gastroenterol., Hepatol., Coloproctol. - 1997. - No. 1. - P.56-62). Over the past 30 years, the world has seen a twofold increase in the number of patients with acute and chronic pancreatitis (A.I. Khazanov, A.P. Vasiliev, V.N. Spesivtsev et al. / Chronic pancreatitis, its course and outcomes. // Ros. gastroenter., hepatol., coloproctol. - 1999. - No. 4. - P.24-30). The incidence of CP is 4-8 cases per 100,000 population per year, and the prevalence of the disease in Europe is 25 cases per 100,000 population. In Germany, there are more than 20 thousand, and in Russia more than 60 thousand patients with chronic pancreatitis (Lohr J.M. Medication and endoscopic methods of treating chronic pancreatitis. // Creon: Satelitis. Symposium. "Exocrine pancreatic insufficiency. Optimal correction path." - M., 1998. - C.3-6).

Primary chronic pancreatitis (PCP) is one of the most serious diseases of the hepatopancreatoduodenal organs with numerous problems, with poorly understood and unclear pathogenesis and treatment (P. Zhao, J. Tu, JJ. Van den Oord et al. Damage to duct epithelium is necessary to develop progressing lesions of chronic pancreatitis in the cat // Hepatogastroenterology. - 1996. - Vol. 43. - No. 12. - P. - 1620-1626; NTPedersen, H.Worning / Chronic pancreatitis // Scand. J. Gastroenterol. Suppl. - 1996. - Vol. - 216. - P - 52-58). The incidence of primary chronic pancreatitis inevitably leads to progressive pancreatic insufficiency, as well as to other complications and remains worthy of close attention of surgeons - pancreatologists.

From the available literature it becomes clear that primary CP occupies 8-9% in the structure of diseases of the digestive system (Guide to gastroenterology. / Under the general editorship of F.I. Komarov, A.L. Grebneva. - M., 1996. - T.3), including those who consume alcohol (38-95% of cases of chronic pancreatitis). In industrialized countries, alcohol intoxication in 70-80% of cases is the cause of CP in adults (Y. Iimuro, BUBradford, W. Gao et al. Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat / / Mol. Pharmacol. - 1996. - Vol. - 50. - No. 3. P.656-661), but the results of treatment of these patients remain disappointing. In recent years, the number of surgical interventions on the pancreas with primary chronic pancreatitis has been naturally increasing (V.I. Sokolov. Surgical diseases of the pancreas. // M .: Medicine. - 1998. - 192 p .; Yu.A. Nesterenko, V.P. Glabay, S.G. Shapovalyants / Chronic pancreatitis: a monograph. - M.: Publisher Mokeev, 2000. - 182 p.).

The urgency of the problem of modern gastroenterology and surgery is chronic pancreatic disease, in the diagnosis of which there are still no clear criteria, and treatment is not effective enough. Affecting people of the most working age, CP with a recurring or persistent pain syndrome characteristic of this disease, psychophysiological and emotional discomfort causes a significant limitation of labor and social activity. The great economic damage caused by this disease gives the problem not only medical and biological, but also social significance (T.N. Postnikova. The condition and relationship of humoral regulatory systems and cellular defense factors in the clinic and the pathogenesis of chronic pancreatitis. // Dis ... Doctor of Medical Sciences - Sverdlovsk. - 1984. - 375 p.).

Chronic pancreatitis is characterized by the presence of inflammatory infiltrate, progressive destruction of acinar cells and fibrosis leading to destruction of pancreatic tissue (Kakugawa, Y. Alterations in pancreatic microcirculation and expression of endothelin-1 in a model of chronic pancreatitis / Kakugawa Y; Paraskevas S; Metrakosas S; Metrakosas S; Metrakosas S; Metrakosas S; Metrakosas;; al. // Pancreas. - 1996. - Vol. - 13. No. 1. - P.89-95; Y. Iimuro, BUBradford, W. Gao et al. Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat // Mol. Pharmacol. - 1996. - Vol. - 50. - No. 3. - P.656-661). There is fragmentary evidence that free radicals form in the early stages of chronic inflammation with alcohol consumption even before the development of the pathology itself (DJ Bowrey. Selenium deficiency and chronic pancreatitis: disease mechanism and potential for therapy // DJBowrey, GJMorris-Stiff, MCPuntis et al. // HPB Surg. - 1999. - Vol. - 11. - No. 4. P.207-215).

Lipid peroxidation processes play one of the leading roles in the onset and development of this disease: chronic pancreatitis (A. Van Gossum. Deficiency in antioxidant factors in patients with alcohol-related chronic pancreatitis / A. Van Gossum, P. Closset, E. Noel et al // Dig. Dis. Sci. - 1996. - Vol. - 41. - No. 6. - P.1225-1231).

At a number of CP stages, the deficiency of antioxidant factors is more secondary against the background of CP. External factors - alcohol consumption, smoking are supposedly involved in the depletion of the antioxidant system. The study of antioxidant support in patients with early stages of CP is intended to determine the theory of free radical damage in the pathogenesis of this disease. The noticeable role of antioxidant factors in the origin of this disease seems acceptable for recommending antioxidant support for patients with CP. Getting some of them with food (selenium, vitamin E) is adequate and necessary. This deficiency is secondary in pancreatic insufficiency and is presumably associated with increased stress oxidation (Deficiency in antioxidant factors in patients with alcohol-related chronic pancreatitis / A. Van Gossum, P. Closset, E. Noel et al. // Dig. Dis . Sci. - 1996. - Vol. - 41. - No. 6. - P.1225 - 1231). To solve the tasks in animal experiments, we evaluated the effect of antioxidants fridox, emoxipin, a drug with a gas transport function of perfluorocarbon compounds (PFOS) - perfluorane on the course of model CP, studied the morphological picture of the pancreas, liver, duodenum, spleen, and also the state of free radical oxidation in animals in the development, chronicity and outcomes of pancreatitis. Based on the obtained data, a scheme was developed for pre- and postoperative treatment of patients with antioxidants, perfluorane with laboratory control of lipid peroxidation processes.

Perftoran is known to increase tissue viability directly by improving their oxygenation and indirectly through normalization of microcirculation and metabolic support of cells (G.A.Sofronov et al., 2001, A.A. Orazmuradov et al., S.-P., 2001 ) Perfluorocarbon emulsions dissolve in lipids of cell membranes, transfer oxygen and carbon dioxide in themselves, and become part of the oxygen transport system in cells and tissues of the body. Integrating into the structure of cell membranes, these emulsions are able to stabilize the structure of the endothelium of blood vessels and cell membranes (V. I. Shumakov et al. In the book: “Organofluorine compounds in biology and medicine.” Pushchino, 1999, pp. 144-145). Perftoran eliminates peripheral vascular spasm, restores microcirculation, reduces vascular endothelial edema, restores tissue gas exchange and metabolism (V.V. Moroz, N.L. Krylov, 1999, ibid., Pp. 26-30). Perftoran increases the saturation of hemoglobin with oxygen and facilitates the release of oxygen to tissues due to its own oxygen capacity, low viscosity, small particle size, large total surface area and mobility in the bloodstream (G.R. Ivanitsky, 1999, ibid., P. 242). Perftoran reduces the intensity of lipid peroxidation in tissues, resolving vasospasm, weakening microcirculatory disorders and tissue ischemia (H.A. Musalatov et al., 1999, ibid., Pp. 62-69). The introduction of perftoran reduces the severity of toxemia and favorably affects the rheological properties of blood (G.A.Safronov et al., 1999, ibid., P.21). The ability of perfluorocarbons to stabilize the cell membrane leads to a decrease in edema, diuretic effect and improvement of gas exchange conditions. Perftoran reduces the viscosity of whole blood. It is effective in violation of microcirculation and tissue gas exchange, cellular metabolism to eliminate circulatory and tissue hypoxia, detoxification, as well as to protect organs and tissues from hypoxia and reperfusion complications. Thus, the beneficial effect of perftoran on the tissue in the claimed method is mainly due to its oxygen transport, membrane-protective, antiexudative, anti-alterative and detoxifying effects. According to the instructions, perftoran is administered intravenously at a dose of 5-30 ml / kg.

A modified model of dibutylindindichloride pancreatitis was performed in 64 animals. All animals were divided into three groups: the first group - control animals; the second group - animals with experimental CP, which were not used drugs; the third group - animals with experimental CP, which were administered drugs. The dry substance dibutyltindichloride was diluted in a 70% solution of ethyl alcohol. Given the content of the active substance in an amount of 6 mg in one milliliter (ml), the animal was injected with 0.3 ml of a 0.6% solution into the tail vein at a rate of 0.1 ml per second.

To correct changes in LPO processes in model chronic pancreatitis, one of the most powerful new generation antioxidants fridox (tirilazade mesylate, Upiohn s.a. Puurs Belgium) and the antioxidant emoxipin widely used in clinical practice were used. Fridox at a dose of 3-9 mg / kg and emoxipin at a dose of 3 mg / kg were administered intravenously. In similar doses, the preparations were added to incubated liver homogenates. Previously, in vitro experiments showed that with an increase in the dose of Fridox to 9 mg / kg, its inhibitory effect on lipid peroxidation in incubated homogenates does not significantly increase.

Fridox, of the antioxidants known at the time of the study and to date, is one of the most powerful inhibitors of lipid peroxidation processes (Saniova B. Tirilazad mesylate (Freedox) - an effective inhibitor of lipid membrane peroxidation / B. Saniova // Bratisl. Lek. Listy. - 1998. - Vol. 98. - No. 6. - P.339-342). The advantage of this drug over other, the most widely studied and traditionally used fat-soluble antioxidants α-tocopherol and ionol, is associated with the ability to inject fridox directly into the bloodstream. Accumulating in the lipid layer of membranes, where the processes of lipid peroxidation and other free radical reactions proceed most intensively, it exhibits a fairly wide spectrum of action:

- reduces the formation of the most aggressive hydroxyl radicals;

- contributes to the preservation of endogenous α-tocopherol in cell membranes;

- promotes the utilization of peroxide radicals with a membrane-destructive effect;

- integrates into the lipid biolayer of membranes, changes their physicochemical properties, reduces the distribution of lipid peroxidation reactions in membranes.

Fridox compatible with other drugs used in intensive care is well tolerated. The most studied is considered its use in acute cerebrovascular accidents (Smith SL Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury / SLSmith, HMScherch, EDHall // J. Neurosurg. - 1996. - Vol. 84. - No. 2. - P.229-233; Smith SL Tirilazad widens the therapeutic window for riluzole-induced attenuation of progressive cortical degeneration in an infant rat model of the shaken baby syndrome / SLSmith , EDHall // J.Neurotrauma. - 1998. - Vol.15. - No. 9 - P.707-719).

The initial results of his clinical trials for cerebral ischemia and subarachnoid hemorrhages were encouraging, but later in the information sources there were discussions about the effectiveness and feasibility of using this drug (Information from the manufacturer; Sloan TB Success in solving the problem of brain protection. / TB. Sloan // Vestnik Intensive Therapy. - 1993. - No. 1. - P.14-18.) In addition, with the exception of certain brain structures (Razumov A.S. General patterns of early postresuscitative changes in lipo processes peroxidation in the brain: the role of reperfusion, pathogenetic significance, principles of correction: Dis .... Dr. med.Sci. / A.S. Razumov. - M., 2001. - 258 p.), there is practically no information about the effect fridox on the processes of lipid peroxidation in other organs and tissues.

The antioxidant effect of emoxipin is based on its ability to inhibit the stage of initiation of LPO processes by binding to catalytically active ferrous ions and to interact with water-soluble radicals (Antioxidant properties of 3 derivatives of oxypyridine: mexidol, emoxipin and proxypine. / G.I. Klebanov, O.B. .Lyubitsky, O.V. Vasilieva and others // Issues of medical chemistry. - 2001. - T. 47. - No. 3. - S. 288-300). With a wide spectrum of action, emoxipin also exhibits antihypoxic, angioprotective, antiaggregatory ability. The literature contains information on the use of emoxipin to protect against ischemic and reperfusion injuries of the renal transplant, as well as on the positive effects of its use in ophthalmic and cardiological practice. In particular, the cardioprotective properties of emoxipin allow it to be used for the prevention of myocardial insufficiency as a result of reperfusion injuries after acute blood loss (A. Golikov, Effect of emoxipin on the formation of a necrosis focus, reparative process and lipid peroxidation in myocardial infarction. / A.P. Golikov, V.L. Ovchinnikov, B.V. Davydov // Man and medicine: Thesis of the 1st Russian National Congress.- M., 1992. - P.155).

With the development of experimental chronic pancreatitis, changes in lipid peroxidation status - activation of prooxidant systems with subsequent development of deficiency of LPO substrates and depletion of antioxidant activity systems - are more pronounced in the liver, which is secondarily involved in the pathological process, compared with the pancreas, in which the structural and functional disorders are primary.

Analysis of changes in the static (lipid peroxidation and lipid peroxidase (SOD) activity in tissues in vivo) and dynamic (lipid peroxidation (lipid peroxidation) products in vitro changes in vitro incubation of homogenates) lipoperoxidation data showed that 30 days after modeling of chronic pancreatitis in the liver and pancreas deficiency of lipid peroxidation substrates and deficiency of antioxidant defense due to increased prooxidant activity develops in the gland. Based on this, the possibility of correcting changes in the lipid peroxidation status of the liver and pancreas with the help of antioxidant drugs (fridox and emoxipin) was studied. Taking into account the inevitable involvement of the microvasculature in the inflammatory process with the subsequent development of hypoxia and insufficient metabolic support of tissues, the possibility of correction of lipid peroxidation status using an artificial oxygen carrier, perftoran, intravenously from the rate of 2 ml / kg 30 days after the reproduction of the chronic pancreatitis model, was also studied.

It was found that under the influence of perfluorane, the content of lipid peroxidation (TBA-ap) products in the liver in vivo increased on average by 25% compared with animals without treatment and exceeded that in control animals by 60%. During subsequent incubation, in contrast to animals without treatment, there was no decrease in the content of LPO products. On the contrary, their content increased and by the 30th minute exceeded that in animals without treatment by 2.2 times.

In the pancreas, unlike the liver, the use of oxygenated perftoran in chronic pancreatitis is accompanied by a restriction of prooxidant activity, mobilization of antioxidant defense and prevention of its depletion. The more pronounced beneficial effect of perftoran on lipoperoxidation processes in the pancreas compared with that in the liver is apparently due to its specific effect on metabolism in the primary focus of inflammation, compared to the effect on secondary changes in the liver, as well as metabolic characteristics of the studied organs.

At the final stage, the effectiveness of combined correction (antioxidant - fridox, emoxipin, and metabolic - perftoran) changes in lipoperoxidation processes in the liver and pancreas in chronic pancreatitis was studied.

It was found that the content of lipid peroxidation products in the liver in vivo during combined correction did not significantly change compared to the use of perfluorane alone.

However, the dynamics of their accumulation in incubated homogenates changed, approaching that in the control series — an initial decrease (by the 15th minute of incubation) and a subsequent increase to the initial values. In animals without treatment, the content of LPO products decreased throughout the incubation period of homogenates.

At the same time, in the first 15 minutes of incubation, the content of lipid peroxidation products in homogenates decreased 2 times faster than in the control, and in the next 15 minutes increased at a rate of 0.03 ± 0.001 n / mol / ml / min, which was slightly less than the control values. For comparison, the content of lipid peroxidation products in animal homogenates using only perfluorane increased during the entire period of incubation of homogenates at a rate of 2-2.5 times greater than in combination with antioxidants.

The use of the combination: oxygenated perftoran, fridox, and emoxipin was not accompanied by any significant changes in the activity of SOD in the liver in vivo and in incubated homogenates in vitro compared with those using perftoran.

In the pancreas, the content of lipid peroxidation products in vivo decreased in the same way as when using perftoran. However, their accumulation in the incubated homogenates changed in such a way that the average speed approached that in the control.

At the same time, the activity of SOD in vivo decreased on average by 30–40% of that when using perftoran. Within 30 minutes of incubation, it decreased by 2 times, while when using perftoran - by 1.5 times.

In the uncomplicated course of CP, conservative treatment is indicated. The main objective of the conservative treatment of CP is a constant and long-term effect on the pathological process with the aim of slowing the progression of fibrosis, as well as correcting excretory and incretory pancreatic insufficiency (Yu.G. Bozhenkov, A.N. Scherbyuk, S.A.Shalin. Practical pancreatology // M .: Medicine. - 2003. - P.93).

In chronic pancreatitis, the combined use of perftoran and antioxidants is accompanied by the development of a somewhat paradoxical situation in the pancreas, as well as in the liver: despite the potentially prooxidant effect of these drugs, lipoperoxidation status is normalized, i.e. the excess activity of prooxidant systems decreases and antioxidant activity is restored. This may be the result of normalization of oxygenation, metabolic support of cells and phospholipid composition of cell membranes.

The inventive method is one of the promising methods for correcting the lipid peroxidation status of the liver and pancreas in chronic pancreatitis. The normalization of metabolism using perfluorane in combination with antioxidant drugs with an inhibitory effect can reduce complications and mortality in chronic pancreatitis by increasing antioxidant activity and suppressing pancreatic hypoxia.

Claims (1)

A method of treating chronic pancreatitis, which consists in eliminating provoking factors, prescribing a diet, conducting enzyme replacement therapy, suppressing pain, administering anabolic steroids, phosphodiesterase inhibitors, administering infusion therapy, administering antioxidants and antidiarrheal drugs, characterized in that they use fridox and emoxipin, and also use perftoran, while these drugs are administered intravenously once a day at a dose of: per Toran - 2 ml / kg, fridoks - 3-9 mg / kg, emoksipin - 3 mg / kg, and the administration is daily for at least 3 but no more than 7 days.