RU2694826C1 - Method of treating chronic ischemia of lower extremities of atherosclerotic genesis with shin arteries occlusion - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a method of treating chronic ischemia of lower extremities of atherosclerotic genesis accompanying shin arteries. That is ensured by conducting standard conservative treatment of patients with grade II of pelvic limbs chronic ischemia according to the classification A. V. Pokrovsky and additional, introducing 1.2 mg of Neovasculgen preparation, dissolved in 10 ml of water for injections, twice every two weeks, wherein the preparation is administered paravasally, under the control of ultrasonic Doppler sonography, in fractions, 1 ml of the solution in the muscles of the shin in the projection of the posterior and anterior tibial artery, through five pricks along the path of each of the arteries, at distance of 4–5 cm from each other, at 2 cm in depth at angle of 90 degrees to skin.

EFFECT: invention provides higher clinical effectiveness in chronic ischemia of lower extremities of atherosclerosis and reduced traumatism of treatment.

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Description

The inventive method relates to medicine, namely to therapeutic treatment of ischemic disease of the lower extremities of atherosclerotic genesis in the occlusion of the arteries of the leg.

Atherosclerotic lesion of the arteries of the lower extremities occupies an important place in the structure of cardiovascular morbidity. The prevalence of this pathology among the population over 50 years old is 5-8%, and in the presence of such risk factors as hyperlipidemia, smoking, arterial hypertension or diabetes mellitus reaches 30%. Atherosclerosis of the lower limb arteries affects about 5% of elderly people in the Russian Federation, i.e. about 2 million people [See Gavrilenko A.V., Skrylev S.I., Kuzubova E.A. Modern opportunities and prospects for the surgical treatment of patients with critical lower limb ischemia // Angiology and Vascular Surgery. - 2002. - Vol. 8, No. 4. - S. 80-86.]. In 50% of patients, the disease may be asymptomatic, 40% suffer from intermittent claudication, and 5-10% develop critical ischemia. Thus, the number of patients in need of constant specialized treatment and observation in the Russian Federation is at least 1 million people. The progression of chronic ischemia of the lower extremities (CINK) leads to amputation with the same frequency as 30 years ago.

Known methods of conservative treatment of chronic lower limb ischemia according to the "National guidelines for the management of patients with pathology of the arteries of the lower extremities" [See National guidelines for the management of patients with lower limb artery disease [Text] // Angiology and Vascular Surgery. - 2013. - Vol. 19, No. 2 (Appendix). - S. 1-67.]. With standard conservative treatment, the following are provided: taking statins under the control of blood cholesterol and LDL (low density lipoprotein); disaggregant therapy; dosed load walking; the elimination of risk factors for the progression of atherosclerosis (i.e., it is necessary to quit smoking, correct hypertension and diabetes mellitus if present). Coursework drugs pentoxifylline, sulodeksid.

The disadvantages of this method include its low efficiency, which consists in a slight change in the main manifestation of the disease - intermittent claudication. An increase in this indicator is fixed at a value of 50-70 meters (V. Girolami, 1999; J. Regensteiner, 2002; A.V. Pokrovsky, 2013).

Known methods of treatment of this category of patients is an open vascular reconstruction and endovascular intervention - operations aimed at restoring the arterial blood flow in the affected limb [Vascular surgery. National leadership. Moscow, GEOTAR-Media Publishing Group, 2014, p. 139-140].

The disadvantages of these methods are that, in a number of patients, performing reconstructive arteries on the arteries is either technically impossible (for example, in distal forms of arterial lesions), or is associated with too high operational risk due to the presence of severe concomitant pathology. Adequate surgical revascularization of the arterial bed of the lower extremities is possible in 37-58% of patients [S.V. Lebedev, A.V. Karasev, V.V. Kungurtsev et al. // Bulletin of the Russian Academy of Medical Sciences. - 2013. - №3. - S. 1-44]. In addition, surgical treatment does not stop the progression of the disease, and 1-2 years after endovascular intervention, 4-5 years after open surgery, arterial blood flow obliteration and thrombosis of the reconstruction zone occur again, which is accompanied by a high risk of gangrene formation and amputation [I. AND. Zatevakhin, V.N. Shipovskiy, V.N. Zolkin et al. / / Angiology and Vascular Surgery .- 2011. - Vol. 17, No. 3. - pp. 59-62].

Known selected as the closest analogue method of combined treatment of patients with obliterating lesions of atherosclerosis of the arteries of the lower extremities [see patent RU 2505300, publ. 01/27/2014]. The method consists in performing revascularizing surgery, while twice, with an interval of 14 days and a day before surgical treatment, the Neovasculgen gene preparation is injected intramuscularly at a dose of 1.2 mg.

The disadvantages of this method include the fact that the method is traumatic, since surgical intervention is performed. In addition, the localization of arterial occlusion in chronic ischemia of the lower extremities is extremely diverse (femoral artery, popliteal artery, lower leg arteries; various combinations of lesions of these arteries are also possible). Therefore, a simple intramuscular injection of the same type of the drug does not allow to achieve maximum effectiveness of treatment. For each localization of arterial occlusion requires its own method of introducing a gene preparation.

The technical result of the claimed invention is to increase the effectiveness of treatment of chronic ischemia of the lower extremities of atherosclerotic genesis and reduce the morbidity of treatment.

This technical result is achieved due to the fact that the method of treatment of chronic ischemia of the lower extremities of atherosclerotic genesis in occlusion of the arteries of the leg includes intramuscular injection of 1.2 mg of the drug "Neovasculgen", dissolved in 10 ml of water for injection, twice with an interval of two weeks. The administration of the drug "Neovasculgen" is performed paravasally, under the control of Doppler ultrasound, fractionally, 1 ml of solution into the calf muscles in the projection of the posterior and anterior tibial artery, after five shots along each of the arteries, at a distance of 4-5 cm from each other, 2 cm deep at a 90 degree angle to the skin.

Such an administration of the drug is not just "blindly" into the muscles of the leg, but paravasally, under the control of Doppler ultrasound, fractionally, 1 ml of solution into the muscles of the leg in the projection of the posterior and anterior tibial artery, after five injections along each of the arteries, at a distance of 4 5 cm apart, at a depth of 2 cm at a 90 degree angle to the skin, a large number of small intervascular messages (anastomoses) can be formed, which leads to a significant improvement in the blood supply to the limb, which increases the effectiveness of treatment and does not require operati intervention, which reduces the invasiveness of treatment. In addition, in the claimed method, the introduction of the drug into the muscles is carried out depending on the level of arterial occlusion, i.e. carry out an individual approach to the patient, which increases the effectiveness of treatment.

FIG. 1 shows the change in the mean values of the distance of painless walking in patients 2B of the subgroup after the introduction of the gene preparation according to this method depending on the observation time, Fig.2 shows a comparison of changes in the average values of the distance of painless walking in 1B (with standard conservative treatment) and 2B subgroups (with addition of gene therapy) at different times of observation.

A method for the treatment of chronic ischemia of the lower extremities of atherosclerotic genesis in occlusion of the arteries of the leg is the following.

Conduct standard conservative treatment of patients with HINK II degree according to the classification of A.V. Pokrovsky (1979). according to the “National Recommendations ...” [See “National guidelines for the management of patients with pathology of lower limb arteries” [Text] // Angiology and Vascular Surgery. - 2013. - Vol. 19, No. 2 (Appendix). - S. 1-67.]. Additionally, patients receive double administration of the drug "Neovasculgen" 1.2 mg in the muscles of the affected limb with an interval of 2 weeks.

The drug "Neovasculgen" is a highly purified super-twisted form of the plasmid pCMV-VEGF165, which encodes the vascular endothelial growth factor (VEGF-vascular endothelial growth factor) under the control of a promoter (DNA control region), designed to improve the quality of their life due to a significant increase in the possibility of self-service, improved mobility. In 2011, the drug with the trade name "Neovasculgen" was included in the State Register of Medicinal Products; registration number LP-000671.

The drug "Neovasculgen" in the amount of 1.2 mg is dissolved in 10 ml of water for injection. The introduction of the drug "Neovasculgen" into the muscles is performed paravasally (along the main arteries of the lower leg), under the control of Doppler ultrasound, fractionally, into the muscles of the lower leg in the projection of the posterior and anterior tibial artery, after five injections along each artery, at a distance of 4-5 cm each from a friend, 2 cm in depth at an angle of 90 degrees to the skin.

Such a targeted administration of the drug near the arteries under the control of Doppler ultrasound, allows you to control the ingestion of the drug directly into the necessary treatment area, allows you to form a large number of small intervascular messages (anastomoses), which leads to a significant improvement in the blood supply to the limb, and increases the effectiveness of treatment. The effect of the treatment is achieved in terms of 4 to 6 months and further surgery is not required. In addition, in the claimed method, the introduction of the drug into the muscles is carried out depending on the level of arterial occlusion, i.e. an individual approach to the patient is carried out, which further increases the effectiveness of treatment.

An example of the method.

Conducted treatment and monitoring of 73 patients with CIDI PB degree classification A.V. Pokrovsky (1979). The group of patients was divided into 2 subgroups. In subgroup 1B (n = 36), only standard conservative therapy was used according to the “National guidelines ...” [See "National guidelines for the management of patients with pathology of the arteries of the lower extremities" [Text] // Angiology and Vascular Surgery.- 2013. - Vol. 19, No. 2 (Appendix). - S. 1-67.]. In subgroup 2B (n = 37), in addition to a similar conservative treatment, the genetic therapy construct, the preparation Neovasculgen, was introduced into the muscles of the ischemic limb according to the method presented. Then an aseptic dressing was applied to the injection sites.

The introduction of the gene therapy construct was moderately painful, but did not require additional analgesia. Restrictions on physical stress and motor regimen after treatment were not. Local or systemic reactions to the introduction of the drug in the near and distant periods are not marked. Repeated courses of gene treatment in the same lower limb for 5 years was not carried out.

The main parameters of the subgroups were similar, which allowed us to further compare them (see table number 1).

Patients underwent outpatient treatment and observation on the basis of LLC Medical Center Diagnostics and Prevention, Yaroslavl. Standard conservative therapy included an anti-atherosclerotic diet; taking statins, in dosages selected individually, depending on the values of total cholesterol (OH) and its fractions (target values of OH less than 4.0 mmol / l, low-density lipoproteins less than 1.8 mmol / l); constant intake of antiplatelet agents (preparations of acetylsalicylic acid 75-100 mg per day, or clopidogrel at a dosage of 75 mg per day); metered exercise walking at a distance of 3 to 5 km per day at an average pace. Also, all patients during the study took medications recommended for the treatment of comorbidities in therapeutic doses, according to individual indications. Patients were recommended categorical cessation of smoking.

The main criteria for effectiveness were: survival of patients, safety of the limb, according to which the patient was included in the study, and change in the distance of painless walking (DBH). DBH is a fundamental element of the classification of CLLI, a criterion for assessing the quality of life of patients, an indication for surgical treatment. This indicator was determined during the treadmill test (walking on a flat track, the tilt angle is 0 °, with a track speed of 3 km / h). Secondary effectiveness criteria were recorded and evaluated, which included: the ankle-brachial index (ABI); mean linear blood flow velocity (LSC) according to ultrasound Doppler and duplex angioscanning of the posterior tibial artery, and when occluded throughout, on the anterior tibial artery. Clinical and laboratory parameters were studied in all patients prior to the administration of the drug, and then annually after carrying out gene therapy.

According to the results of a five-year observation of patients with 1B subgroups with standard conservative therapy for 5 years of observation, moderate improvement was observed only in 1 case (3%), where the distance passed without pain increased by 100 m (from 150 m initially to 250 m). In 12 patients (33%), a satisfactory result was recorded without any dynamics; DBH remained at the same level as when included in the study. In 10 cases (28%), progression of the disease was noted with an increase in stenosis of the main arteries of the lower extremities or occlusion of them, as well as a decrease in DBH by 50–100%, which can be regarded as moderate deterioration. A significant deterioration in the clinical course was observed in 4 patients (11%), who by the end of the study had III degree of chronic ischemia with an average DBH of 20 m, that is, with the formation of critical lower limb ischemia, leg pain alone and a high risk of amputation legs. Unsatisfactory results with standard treatment received 25% (9 people - 9 deaths not related to chronic ischemia of the leg (one of them after amputation). The initial DBH value in 1B subgroup when included in the study was 128 ± 49 m, by the end of the fifth year, reliably decreased by 49 m, reaching 79 ± 51 m (p = 0.01), the changes are significant only in the fourth and fifth years of observation. Initially, the ABI was 0.56 ± 0.11, reliably decreasing by the end of the observation by 0.1, making 0.46 ± 0.1 (p = 0.01). The LSV value when included in the study was 21.0 ± 4.4 m / s, and for five years there was a significant decrease in the indicator to 16.5 ± 6.4 m / s (p = 0.04).

In subgroup 2B using gene therapy, in 22 patients, the degree of ischemia decreased to IIA, which amounted to 59% and is regarded as a significant improvement. Of these, I degree of chronic ischemia was registered in 4 people (DBH 1000 or more meters), in 18 patients IIA degree of ischemia was noted (DBH from 250 to 700 m). A moderate improvement was observed in 3 patients (8%) with an increase in DBH of 50–100%), amounting to 200 m. In 16% of cases (5 patients), a satisfactory treatment result was recorded with the same degree of ischemia as in study without dynamics in dbh. In one case (2.5%), a significant deterioration was noted - weighting of ischemia to the III degree. In another case, a patient with severe form of diabetes mellitus type 2 developed foot gangrene, followed by limb amputation. As a result, the unsatisfactory outcome of treatment, taking into account the deceased patients, was 16% (6 people - 5 deaths unrelated to chronic ischemia and 1 amputation). The initial average distance traveled without pain in the 2B subgroup was 115 ± 55 m. By the end of the observation, it increased to 559 ± 349 m (p = 0.007) (the increase was 444 m, the changes are significant in all years of observation). A significant increase in ABI was noted from 0.52 ± 0.16 initially, to 0.6 ± 0.17 in the fifth year of observation (p = 0.04). A significant increase in the LSV from 16.9 ± 9.8 m / s to 21.3 ± 14.6 m / s (p = 0.02) was recorded.

The survival rate of patients during the 5 years of observation in group 1 was 74%, in the second - 80%. The safety of the limb in both groups was 97%.

The method is low-impact, does not require surgery, i.e. treatment is translated in the category of conservative, but with significantly greater efficiency and duration of action. In addition, in the claimed method, the introduction of the drug into the muscles is carried out depending on the level of arterial occlusion, i.e. carry out an individual approach to the patient, which increases the effectiveness of treatment. The treatment method significantly reduces the risk of progression of limb ischemia in the long-term period of at least 5 years compared with standard treatment. The use of this drug as part of complex treatment of patients with CIDI II degree significantly influences an increase in the average distance of painless walking (up to 500%) (p = 0.007), which is one of the main clinical indicators of the reduction of chronic ischemia of the lower extremities. The claimed therapy allows to improve the quality of life of patients with CLLI due to a significant increase in their physical activity, the possibility of self-care.

The proposed method is easily reproducible in polyclinic and hospital conditions with the help of existing equipment with available technical means.

Claims (1)

A method for the treatment of chronic ischemia of the lower extremities of atherosclerotic genesis in occlusion of the arteries of the lower leg, including the standard conservative treatment of patients with grade II OECD according to the classification of A.V. Pokrovsky and the additional administration of 1.2 mg of the drug Neovasculgen, dissolved in 10 ml of water for injection, twice with an interval of two weeks, characterized in that the administration of the drug is performed paravasally, under the control of Doppler ultrasound, fractionally, 1 ml of solution into the calf muscles in the projection of the posterior and anterior tibial artery, after five injections along each of the arteries, at a distance of 4-5 cm from each other, 2 cm in depth at an angle of 90 degrees to the skin.

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