RU2157208C2 - Preparation for treatment of freezing patients - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention relates to agents used for treatment of patients with freezings. Invention proposes xymedone that is N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidione-2. Use of xymedone in clinic results to improvement of microcirculation, acceleration of processes of reparative regeneration in patients with freezings. EFFECT: enhanced effectiveness of preparation, decreased treatment and hospitalization period. 1 tbl

Description

 The invention relates to medicine, namely to the treatment of frostbite.

 In the outcome of frostbite, an important role belongs to the nature of the medical care provided in the pre-reactive and reactive periods of lesions. The most rational is the integrated use of drugs acting on various parts of the pathogenetic chain of the disease resulting from frostbite.

 Of great importance is the appointment of drugs that lead to the restoration of metabolic processes in cells by improving microcirculation in the tissues. The complex of therapeutic measures, especially at the first stages of treatment, includes ganglion blockers, vitamins, low molecular weight dextrans, glucose-containing solutions with insulin, mono- and polyionic salt solutions, corticosteroids.

 At present, conservative frostbite therapy aimed at restoring peripheral blood circulation by eliminating vascular spasm, improving blood rheological properties, and preventing vascular thrombosis has gained widespread acceptance in the pre-reactive and early reactive periods. In addition, given the fact of inhibition of metabolic processes, the use of drugs that enhance the processes of reparative regeneration is pathogenetically justified, which is of particular importance in the late reactive period.

 Of the anticoagulants, heparin is most often administered up to 60,000 - 80,000 units per day for 7-10 days / Vikhriev B.C., Kichemasov S. X., Skvortsov Yu.R. Problems of treatment of frostbite // Kazan honey. Journal. - 1987. -N 6.- S. 411-414 /. However, the drug has significant disadvantages, which include limiting the time of its use, the absence of immunostimulating properties, and the inability to activate cell regeneration processes. If the introduction of heparin is possible in the pre-reactive and early reactive periods in the absence of a wound surface, then in the late reactive period, after necrotomy and ectomy with the formation of a wound surface, it is contraindicated because of the risk of external bleeding. Increased bleeding significantly worsens, and sometimes negates the results of a plastic-plastic surgery.

 Also known is the preparation of the pyrimidine series 4-methyluracil, which stimulates the course of tissue regenerative processes in various forms of pathology / The use of pyrimidine and purine derivatives in surgery and other fields of medicine. -Rostov-on-Don, 1970 /, especially in cases with a torpid course of healing of tissue defects. The drug is taken by us for the prototype of the present invention. Numerous in-house experimental and clinical studies indicate that various purine and pyrimidine derivatives, i.e. Compounds close in their chemical structure to the corresponding bases of nucleic acids have a stimulating effect on the course of recovery processes. When analyzing the positive effect of mechanisms on regenerative processes, one should take into account not only the local, but also the general effect of pyrimidine derivatives, in particular, their possible effect on the state of hemostasis.

The main disadvantages of the prototype include:
- lack of pharmacological properties that improve regional peripheral blood circulation;
- does not affect the normalization of the blood coagulation system, which is necessary during frostbite;
- low stimulating effect of the healing processes of tissue defects.

 Thus, even with the traditional therapy of frostbite started in a timely manner, the proper effect is not always achieved and subsequently in such patients eating disorders in the deep layers of the tissues often develop, necrosis develops and persistent suppression of the processes of reparative regeneration sets in.

 Given the leading role in the pathogenesis of frostbite thrombus formation, the state of microcirculation and inhibition of intracellular regenerative processes, we propose to use a new pyrimidine derivative - Xymedon N- (β-hydroxyethyl) - 4,6-dimethyldihydropyrimidone-2, which is ordered by the Ministry of Health RF 07.12.93, N 287 approved for industrial production and use in medical practice.

 The active substance is xymedon / powder substance / belongs to the class of pyrimidines / 4-methyluracil also belongs to this group. Dosage form - tablets. Low toxic drug that does not have cumulative properties.

 The purpose of the invention is improving therapeutic efficacy, expanding indications for the use of Xymedon, reducing treatment time.

 This goal is achieved by the fact that all victims underwent comprehensive treatment, including, along with generally accepted various conservative and surgical methods of treatment, the appointment of Xymedon.

 Xymedon was used both in isolation and in combination with heparin in the complex treatment of frostbite of the 3-4th degree of the lower extremities in 18 patients aged 26 to 42 years / 16 men and 2 women. Victims were admitted to the clinic on days 2-5 from the moment of injury. The drug was prescribed from the 1st day of admission, 0.5 g 4 times a day by mouth for 2-5 weeks / for a course of 30-70 g /.

 All patients observed by us were divided into 3 groups: the 1st / control / group included people who received conventional treatment, including heparin + methyluracil / 15 people /; in the 2nd, who received with conventional treatment xymedon / 9 people /, in the 3rd / 9 people / - xymedon using heparin.

In the vast majority of patients, moderate hypoproteinemia / 56 ± 7 g / l /, leukocytosis / from 5 to 12.5 • 10 ⁹ / l with a neutrophilic shift of the formula to the left was observed. The number of T and B lymphocytes was significantly reduced. An increase in fibrinogen concentration, a decrease in blood coagulation time, and an increase in prothrombin time were noted. At the same time, inhibition of anticoagulant factors was noted - a decrease in the level of free heparin and fibrinolytic activity of the blood.

 The obtained data testified to the intensification of intravascular coagulation, which is also reported by other authors // Kotelnikov V.P. // Wedge. chir. -1987. -N 12. -C. 1-4; Yukhtin V.I. et al. // Surgery. -1988. -N 8.- S. 93-97 /.

Subjectively, there were severe pains in the distal extremities, which were cold to the touch, swollen, of increased density. Sites of dark cyanotic color with sharply reduced tactile and pain sensitivity were determined. The pulsation of blood vessels in the feet was not determined. The state of regional blood circulation of the affected limbs was assessed by rheovasography, the results of the latter indicated a persistent violation of peripheral blood circulation: a decrease in the elevation angle in the ascending part of the rheogram L _j in degrees, a decrease in the average blood supply rate / SSC /, anacrot increase / α /, ratio α to catocrot / β /, the propagation time of the rheographic wave / Q - A /, the relative indicator of elasticity / OPE / vascular wall.

 During treatment, the clinical signs of frostbite in the 2nd and 3rd groups of patients disappeared much faster than in the 1st group. In patients treated with xymedon in combination with heparin and in isolation, body temperature returned to normal on 4-5 days / in control on 7-8 days. /, 2-3 days earlier signs of intoxication stopped faster compared to control, general condition and appetite improved.

 During therapy, the content of total protein and leukocytes earlier returned to normal in patients of the 2nd and 3rd groups with a decrease in neutrophilic shift. An increase in the number of T-active lymphocytes, T- and B-lymphocytes was observed.

The inclusion of xymedon in the complex of therapeutic measures led to an improvement in blood circulation in the limbs, as evidenced by rheovasography parameters. On the 12-15th day after treatment in the experimental group, compared with the control, such indicators as the rheographic index (RI), tonic stress index (PTN), SSC, T _j were much larger, and the vascular wall OPE, α and Q- A- less than before treatment. In the experiment, a higher intensity of arterial blood filling was observed than in the control group of patients. The pronounced positive dynamics of the functional state of peripheral blood circulation in the limbs in patients with cold trauma under the influence of xymedon is due to a number of reasons. One of them must be considered that biologically active substances play a certain role. A search in this direction was determined by the quite convincing data available in the literature on the effect of serotonin and histamine on inflammation and the course of the wound process.

 Biogenic amines are not only one of the triggers of the initial manifestations of any tissue injury, but also subsequently they have a noticeable effect on the course of recovery processes. Local injections of serotonin and histamine cause pain, swelling. A large role for serotonin and histamine belongs to maintaining a normal level of microcirculation / Chernuk A.M. et al. Microcirculation. -M .: Medicine, 1975. -456 p. /. Our studies of the content of serotonin and histamine in the blood by fluorimetric method with orthophalic aldehyde / Methodology Loboda EG and Makarova Yu.A. in modification, Kolb V.G. and Kamyshnikova B.C. Clinical biochemistry. -Minsk, 1976, S. 271-276 / showed an increase in the content of serotonin and histomine simultaneously in blood taken in close proximity to a tissue defect (flowing blood from the site of frostbite), as well as from a vein of an unaffected contralateral limb, respectively from 5.3 up to 6.7 and from 4.1 to 6.7 μmol / L (in the control, serotonin: 0.6-2.4 μmol / L, histamine 0.06-0.3 μmol / L), with an improvement in the general condition of patients and local status (mummification of dead sites, formation of a demarcation line) there was a decrease in free seratonin and histamine, which is the same scarlet with improved rheology.

 Significant changes were found in the coagulogram, indicating a decrease in the intensity of intravascular coagulation, as evidenced by an increase in blood coagulation time, a decrease in the concentration of fibrinogen, prothrombin / table /. These shifts are more pronounced in patients receiving xymedon and heparin. During therapy with xymedon / group 2 / more pronounced changes were observed in the immunogram, while when using xymedon together with heparin - in the coagulogram / group 3 /.

 However, the clinical results of therapy in these patients were approximately the same and significantly better than in the group without the use of Xymedon. It should be noted that heparin should be included in complex therapy only for patients with an increased risk of thrombosis (elderly and senile age, blood diseases, etc., for example, obliterating atherosclerosis and endarteritis, diabetic angiopathy).

 Of great importance in evaluating the coagulation and anticoagulation systems of the blood is the pathological fraction of fibrinogen “B”, the appearance of which in the blood of severely frostbitten coincides with the inhibition of fibrinolysis and an increase in the concentration of total fibrinogen. Fibrinogen "B" is detected in the blood during massive tissue breakdown and the release of thromboplastin / Machabeli M.S. Labor.-1973. -N 9; Chernobrovy N.P. et al. Wedge. surgeon -1978. -N 3 /. Fibrinogen “B” is attributed to an intermediate product during the transition of fibrinogen to fibrin under the influence of thrombin / Lomazova X. D. Labor. business. -1971. -N 12 /. Fibrinogen "B" disappears during the period of convalescence / Kuzmuk V.V. et al. // Labor. business. -1973. -N 9 /. We studied the dynamics of fibrinogen "B" in the blood of patients with frostbite by the Kumman-Lienza method / Cummine Lyons / in the modification of Smith et al. based on a specific reaction between fibrinogen “B” and β-naphthol showed that a decrease in its amount in the blood of this patient constituent is parallel to the normalization of the blood coagulation system / table. /, improving the local status and functions of the liver. The data obtained show the beneficial effect of xymedon / a decrease in the concentration of fibrinogen in the blood /, expressed in a weakening of the readiness of the blood for thrombosis. The drug prevents the formation of a fibrin oligomer, which is a factor that reduces the tension of the blood coagulation system and reduces the ability of the plasma to form a complete fibrin polymer.

 Xymedon had a noticeable effect on increasing the concentration in patients with frostbite of the fibrin-stabilizing factor / XIII / - fibrinase contained in plasma, serum and platelets. It is known that FSF insufficiency disrupts the normal course of the formation of insoluble fibrin during hemocagulation and leads to impaired wound healing / Izmailov S.G. // Auto-allodermoplasty in clinical practice. Kazan, 1980, p. 14-17 /. We can assume that the decrease in the concentration of FSF in these patients occurs due to the direct influence of the waste products of microbes and the end products of the decay of dead tissue on the liver, followed by a violation of its fibrinazosynthetic function.

 A clearly pronounced positive dynamics of the functional state of peripheral blood circulation in persons of the 2nd and 3rd groups was noted already on the 5th day of treatment / in the control - on the 9th day / - the intensity of arterial blood filling increased, there was a decrease in the OPE of the vascular wall.

 When frostbite of the 3rd degree, the administration of Xymedon facilitated faster healing of damaged tissues, and in the 4th degree, conditions were created for better healing of wounds after necrectomy. In the 2nd and 3rd groups, 1-2 days earlier compared with the control, necrectomy was used at 1.5-2 cm / in the control 3-4 cm / distal to the demarcation line. The amount of purulent discharge, which was judged by the time the standard dressings were wet, was almost the same in all patients, but pink granulations appeared faster in the groups treated with Xymedon, edge epithelization started earlier, the wound surface became suitable for autoplasty for a shorter time than in control.

 Different types of local treatment in the early reactive period did not have fundamental advantages. The main principle of local therapy was to prevent the genesis of favorable conditions for the development of wet necrosis. Wet-drying dressings, predominantly alcohol ones, were preferred. If secondary amputations in the 1st group were performed in 3 patients, then in the 2nd and 3rd - persistent results were obtained after the primary amputation.

 In patients treated with Xymedon, the first autoplasty was done on average after 24 days, and in the control after 28. Of the 7 observations of free dermoplasty in the experimental group, engraftment took place in all operated, while in the control - out of 6 - only in 3.

 The average length of hospital stay in the 2nd and 3rd groups, respectively, was 29, and in the control - 35 days.

 As an illustration, we present the following clinical observation. Patient P., 39 years old, was admitted to the General Surgery Clinic of the Kazan Medical Institute on 01.20.1989, 4 hours after a cold injury / about 5 hours was in the street at night in a state of intoxication / with a diagnosis of frostbite of both feet of the IV degree. Intensive complex therapy was started with the inclusion of Xymedon 0.5 g 4 times a day. On the 3rd day, the general condition of the patient improved significantly. After 9 days, a demarcation line was formed at the level of the metatarsal-tarsal lines of both feet. Under general anesthesia, amputation was performed along the Lisfranc line, tangential necrectomy with subsequent successful free autodermoplasty. Donor wounds healed completely and the patient in satisfactory condition 02/18/1989 was discharged home.

 The convincing results of the clinical trials showed that Xymedon has a significant pharmacological effect on the acceleration of the reparative regeneration processes in patients with frostbite, reducing the time of their treatment and hospital stay.

 Thus, the solution claimed in the claims is not obvious, since the mechanism of healing of trophic ulcers is different than with frostbite.

 In the latter, the primary in violation of hemomicrocirculation is not vascular thrombosis, but their spasm, i.e. their dysfunction. Therefore, it was not obvious that Xymedon would be effective in frostbite.

Claims (1)

 The use of Xymedon for the treatment of frostbite as a drug that improves blood circulation in the limbs.

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