RU2190404C1 - Preparation for treatment of obliterating atherosclerosis of lower limb vessels and method for its treatment - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: one should additionally inject 2-ethyl-6-methyl-3-oxypyridine succinate for 10 d at the dosage of 400 mg/d: intravenously twice daily at the dosage of 200 ml 0.9%- sodium chloride. The method correlates the main pathogenic links of the disease. EFFECT: higher efficiency of therapy. 1 cl, 2 ex, 4 tbl

Description

 The invention relates to medicine and can be used in cardiac surgery. Atherosclerosis is the most common cause of morbidity and death from cardiovascular disease. The commonality of etiology and pathogenesis determines the high frequency of combined lesions by the stenosing process of arteries of all vascular regions (coronary, cerebral and vessels of the lower extremities (Kukhtevich I.I., 1998; Samoday V.G. et al. 1999; Mirolyubov B.M., 2000. Tsarev OA, 2000) This circumstance determines the need for the development of a coordinated management strategy for patients with multiple lesions of stenosing atherosclerosis of various sections of the vascular bed by specialists of various fields - cardiologists, neuropathologists, angiochir However, the problem of pharmacological correction of combined occlusive lesions of the arterial system is not sufficiently developed.Occlusive atherosclerotic arteriopathy is the main cause of ischemic damage to the vessels of the lower extremities.

 According to various authors, 15% of patients with atherosclerosis have occlusion of all three leg arteries, with obliterating endarteritis pathology occurs in 40% of patients (Samoday V.P. et al. 1999). According to D.V. Pokrovsky (1986), 600-1000 people per 1 million people have critical lower limb ischemia. Despite the successes of reconstructive vascular surgery, the development of endovascular methods of treatment for obliterating atherosclerosis is the cause of amputation of the lower extremities in 10% of cases (Andrukhova I.V., 1988; Zusmanovich F.N., 1999). In addition, the long-term results of surgical treatment remain unsatisfactory due to the development of restenosis and reocclusion of arteries due to the progression of the main pathological process that affects both new sections of arteries and shunts (Belov Yu.V., 1999).

 Taking into account the role of activation of lipid peroxidation (LP) processes in atherosclerosis, we can suggest a possible beneficial effect of antioxidants on the course of ischemic damage to the vessels of the lower extremities. Since the water-soluble antioxidant, Mexidol, has a wide spectrum of pharmacological action, exhibiting not only antioxidant, antihypoxic, membrane-protective, but also lipid-lowering, anti-aggregation, anti-inflammatory and nootrotropic effects, it can be used as an angioprotective agent for the treatment of atherosclerosis.

As the compared drugs, drugs were chosen - nicotinic acid and trental, proposed by S.A. Drozdov (1998). As angioprotective agents, patients received combined treatment with enduracin 3 g per day and trental - 400 (1200 mg / day) and aspirin 0.33 mg per day for 24 months. A significant decrease in atherogenic shifts in the lipid spectrum of blood serum and an improvement in regional blood circulation were revealed. However, long-term use of a prolonged form of nicotinic acid with enduracin at a dose of 3 g per day is accompanied by side effects, among which are dangerous such as toxic liver damage, ulcerogenic effects, gout, hyperuricemia, tachycardia, arrhythmia, including atrial fibrillation, vasodilation, hypotension, fainting ( Kukes V.G. 1999). A large number of adverse reactions in trental (pentoxifylline): administration of the drug to the elderly and patients with heart failure enhances decompensation, tachycardia, increases myocardial demand for O ₂ , and provokes myocardial ischemia.

 The use of aspirin is fraught with the development of bleeding, ulcerative lesions of the stomach and duodenum, the development of bronchospasm, allergic reactions.

 In this regard, the prolonged use of a combination of 3 drugs (trental, enduracin and aspirin) dramatically increases the likelihood of side effects, including and life-threatening.

 The aim of the present invention was the rationale for the use of a derivative of 3-hydroxypyridine-2-ethyl-6-methyl-3-hydroxypyridine succinate as an angioprotective agent for atherosclerosis obliterans of the lower extremities.

 The study was conducted on 21 male rabbit chinchilla breed.

 As our studies have shown, in rabbits, serum cholesterol levels increase by 25.3% of the initial level, α-tocopherol and mexidol correct the development of hypercholesterolemia (Table 1). The concentration of α-cholesterol did not change, and the atherogenic index increased by 327% from the initial level. The reference drug α-tocopherol did not correct the increase in the atherogenic index.

 Against the background of Mexidol, which was administered at a dose of 5 mg / kg intravenously for 10 days, the atherogenicity index was the lowest and exceeded the initial data by 97%.

 Experimental hyperlipidemia was accompanied by an increase in the concentration of triglycerides by 54% compared with intact animals. α-Tocopherol and Mexidol eliminated the development of hypertriglyceridemia. The concentration of beta-lipoproteins on the background of hyperlipidemia did not change.

 Thus, Mexidol effectively corrected the development of lipid metabolism disorders in experimental hyperlipidemia in rabbits, reducing the total cholesterol, the atherogenic index of triglycerides in blood serum.

 The use of mexidol against the background of experimental hyperlipidemia modeling reduces the level of MDA in plasma to 63.3%, and in red blood cells - to 81% of the initial data. The comparison drug α-tocopherol was inferior in antioxidant activity to mexidol, since the level of MDA in blood plasma decreased only to 88% of the initial level. Unlike mexidol, α-tocopherol enhanced lipid peroxidation in erythrocytes - the MDA level increased by 132.6% from the initial level. Mexidol limited the activation of LP in the aorta - the level of MDA in the aorta decreased to 88.2% when exposed to mexidol and to 76% - α-tocopherol. Thus, the use of Mexidol had a beneficial effect on the processes of lipid peroxidation in biological media during experimental hyperlipidemia in rabbits. Unlike the comparison drug α-tocopherol, Mexidol did not increase the lipid peroxidation activity of erythrocytes, and more effectively inhibited the growth of MDA in plasma and aorta. The ability of mexidol to correct the activation of lipid peroxidation in the aorta opens the prospect of its use as an angioprotective agent with anti-atherogenic effect.

 Mexidol corrected microcirculatory disorders that develop during experimental hyperlipidemia in rabbits, as indicated by an increase of up to 70-80% in the number of functioning capillaries, normalization of the arterio-venular ratio, and a decrease in the total index of microcirculatory disorders from 3.3 to 0.4 points.

 Comparison drug α-tocopherol enhanced microcirculatory disorders in experimental hyperlipidemia, as evidenced by a decrease in the number of functioning capillaries to 25-30%, an uneven narrowing of the lumen of the arterioles, an increase in the arteriovenous ratio and the index of microcirculatory disorders to 8.55 points.

 Thus, mexidol effectively affects the main pathogenesis links of vascular disorders developing during experimental hyperlipidemia, correcting the development of hypercholesterolemia, hypertriglyceridemia, increasing the atherogenicity index, inhibiting the excessive activation of lipid peroxidation and improving the state of microcirculation.

 The inclusion of mexidol in a dose of 200 mg twice a day (5% solution of 2 ml) intravenously in 250 ml of isotonic sodium chloride solution in the complex treatment of patients with atherosclerosis obliterans of the lower extremities had a positive effect on the dynamics of clinical, biochemical parameters and the state of microcirculation.

 Example 1. Patient N., 74 years old, was admitted to the 1st surgical department of MRKB 09/28/99 with a diagnosis of Obliterating atherosclerosis of the vessels of the lower extremities II-III Art. Hk II a. Diabetes mellitus, type II, moderate. Diabetic angiopathy of the vessels of the lower extremities.

 The patient considers himself for 8 years, when he first began to notice chilliness in the lower extremities and paresthesia in the form of tingling in the toes, a sensation of creeping goosebumps. At the end of time, pains in the lower extremities joined, alternating claudication during the passage of 200 meters. Before admission to the hospital, she was treated twice inpatiently, with slight improvement.

 Complaints on admission: pain, intermittent claudication, cramps in the calf muscles, chilliness, tingling sensation. Hospitalized in 1 department of MRKB. On the basis of the department, conservative vascular therapy was performed: 0.9% sodium chloride 400.0 + 0.25% novocaine solution 150.0; saline + trental 2% - 5.0, reopoliglukin 400 intravenously. Nicotinic acid intravenously according to the scheme (from 1.0 to 10.0 iv and from 10.0 to 1.0 iv), myotropic antispasmodics + analgesics (analgin 50% - 20 + papaverine 2% - 4.0 on 200.0 - 0.9% NaCl) intravenously, xanthinol nicotinate 15% - 2.0 intramuscularly 2 times a day, vitamin B1 and B6 1.0 intramuscularly, alternating with vitamin B12 500 g intramuscularly once a day. Antiplatelet agents: 0.5 aspirin once daily orally. After conservative therapy, the condition improved slightly. Therefore, it was decided to use a derivative of 3-hydroxypyridine (Mexidol), which was administered intravenously dropwise with 200 0.9 NaCl + 5% - 2.0 Mexidol once a day for 10 days. On the third day, paresthesia disappeared. On the fifth day, the cramps stopped, on the 8th day the chilliness in the lower extremities disappeared, and complaints of pain, intermittent claudication after 10 days of the course of mexidol began to distinguish when passing 1000 meters. The patient is discharged in satisfactory condition without any special complaints, under the supervision of a surgeon in a clinic at the place of residence.

 Mexidol had a beneficial effect on the dynamics of biochemical parameters in this patient.

In the general analysis of blood at admission, it was characterized by a decrease in HB to 111 g / l, leukopenia 3.2 • 10 ⁹ / l, acceleration of ESR to 27 mm / h. The glycemic profile testified to uncompensated hyperglycemia: blood glucose at 12 hours - 12.0 mmol / L, at 16 hours - 11.2, 22 hours - 11.2, 6 hours - 10.0 mmol / L. The content of total cholesterol was 6.02 mmol / L, α-cholesterol - 1.8 mmol / L, β-lipoproteins 40 IU, triglycerides 1.8 mmol / L; fibrinogen - 3,552 g / l, the atherogenic index was 5.33 units.

 The concentration of total protein was 84 g / l, albumin 36.6%, α1 3.3%, α2 12.1%, β 15%, γ 33%.

 After the complex therapy, which included mexidol infusion, this patient increased HB to 119 g / l, ESR decreased to 12 mm / h, blood sugar decreased to 8.0 mmol / l, total cholesterol decreased to 4 , 58 mmol / L (24% of the outcome), the level of α-cholesterol increased to 1.98 mmol / L; the atherogenic index was only 1.31 srvc. units , i.e. decreased almost 4 times, the content of β lipoproteins was 25 IU (38% lower than the initial data), the concentration of triglycerides decreased to 0.9 mmol / L (2 times the initial data); fibrinogen from the source data); fibrinogen decreased to 2444 mg / l (32% of the outcome), B. fibrinogen disappeared.

 Doppler ultrasonography at admission: According to the ultrasound dopplerographic examination of the vessels of the lower extremities upon admission, the blood flow through the femoral arteries is not changed. According to the tibia and the rear of the foot, left stenosis is up to 25%.

 USDG at discharge: the main blood flow in the arteries of the proximal and distal parts of both limbs is not changed, collateral is reduced by 7%.

 Thus, the inclusion of Mexidol in complex therapy made it possible to achieve significant positive dynamics in clinical and biochemical parameters even in a elderly patient (74 years old). Mexidol corrected lipid, carbohydrate, and protein metabolism disorders, exerted an anti-atherogenic effect, reduced the atherogenic index, and increased exercise tolerance.

 Example 2. Improving the volumetric blood flow with the introduction of Mexidol contributed to the more rapid healing of trophic ulcers. We give an example from the medical history of 7106/1022 patient X. 76 years. He entered the 1st surgical department of MRCB on November 1, 1999, was discharged on November 26, 1999, with a diagnosis of obliterating atherosclerosis of the vessels of the lower extremities II-III art. Nk P b. Trophic ulcer of the V toe of the left foot. He considers himself sick for 9 years, when he first began to notice aches in the calf muscles, tired legs when walking, cooling in the lower extremities. After the lapse of time, burning sensation in the toes, crawling creeps, intermittent claudication began to join. For a long time did not seek medical help. The last 4 years undergoes constant inpatient treatment 2-3 times a year. 10/23/99 turned to the advisory clinic, from where the ICRC was sent. 11.11.99 hospitalized in 1 surgical department.

 Complaints upon admission: pains in the lower extremities, aggravated by walking, intermittent claudication when walking a distance of 150 meters, burning, numbness, tingling in the fingers of both feet of the lower extremities, chilliness, cramps, trophic ulcer on the fourth toe of the left foot. On the basis of the department, conservative therapy was carried out: iv infusion therapy 4: reopoliglukin 400.0 iv 10; 0.9% NaCl 200.0 + trental 5.0 10, iv nicotinic acid according to the scheme (from 2.0 to 10.0 iv and from 10.0 to 1.0 iv), glucose-cocaine mixture : 5% glucose 400.0 + 0.25% novocaine 150.0, w / v papaverine per 200.0 ml nat. solution. Also, intramuscularly nicotinol xanthinate 15% - 2.0 ml 2 times a day 20, vitamin B1 and B6 at 1.0 v / m once a day, alternating with vitamin B12 at 500 mcg / m once a day, antiaggregant therapy: chimes at 0.025 per os 4 times a day, trombonyl at 1 t. 3 times a day per os. After the conservative therapy, the condition improved significantly: the parasthesia disappeared, but the pains remained, alternating claudication when passing 400 meters. Trophic ulcer with a tendency to healing (marginal epithelization). It was decided to use the drug Mexidol in 200 ml of saline + Mexidol 5% 2.0 (100 mg) for 10 days. On the 5th day of application, chilliness in the lower extremities disappeared, on the 8th day a sensation of warmth appeared, the trophic ulcer was epapitalized. On the 10th day of the use of the drug, the pains passed, intermittent claudication was noted when passing 600-700 meters. The patient is discharged in satisfactory condition without any particular complaints.

 In patient X. the use of Mexidol had a positive effect on the dynamics of laboratory parameters.

Upon receipt in the analysis of peripheral blood, a decrease in hemoglobin level to 118 g / l, ESR of 13 mm / h, leukocytes of 7.5 • 10 ⁹ / l was observed. Blood sugar 6.0 mmol / g, total cholesterol 3.17 mmol / l, alpha cholesterol 0.88 mmol / g, atherogenic index was 2.6 conventional units, beta-lipoproteins - 44 units, triglycerides 1.82 mmol / l; total protein 78 g / l, albumin 48.1% α1 - 5%, α2 - 15%, β - 12.5%, γ - 19.4%, fibrinogen 2664 mg%.

 When conducting ultrasound on November 9, 1999, the following was revealed: the main blood flow through the femoral arteries is unchanged. On popliteal: on the left - the main unchanged, on the right - an altered stenosis of up to 50%. In the posterior tibial arteries and arteries of the rear foot, left - collateral stenosis up to 75%, right - collateral stenosis over 75%.

After the treatment, which included the infusion of mexidol, the HB content increased to 125 g / l, the number of leukocytes decreased to 4.8 • 10 ⁹ , ESR to 7 mm / h; blood sugar to 4.67 mmol / g, total cholesterol decreased to 2.38 mmol / g, triglycerides to 0.8 mmol / g, beta lipoproteins to 33 conventional units, alpha-cholesterol increased 1.73 mmol / g ( by 96%), the atherogenic index decreased to 0.32 srvc. (almost 8 times), the concentration decreased to 2220 mg% fibrinogen.

 UZDG November 22, 1999, compared with the data of November 9, 1999, collateral high stenosis of up to 65% is recorded in the arteries of the distal section on the right.

 The rapid regeneration of trophic ulcers in patient X. is due to several factors: improved microcirculation due to improved rheological properties of blood due to a decrease in the concentration of total cholesterol, triglycerides, fibrinogen, an increase in alpha-cholesterol, as well as the ability of mexidol to increase resistance to ischemic tissue limbs hypoxia.

 Example 3. From the medical history of 7753/1126 patient Zh. 56 years old indicates the possibility of correction of ischemic changes in severe arterial blood flow disorders in the vessels of the lower extremities.

 Patient J., 56 years old, was hospitalized in 1 surgical department of MRCB from 29.11. on 12/15/99, with a diagnosis of obliterating atherosclerosis of the vessels of the lower extremities III-IV Art. Hk III b.

 He considers himself sick for 16 years, when he first began to notice chilliness of the lower extremities and paresthesia in the form of tingling in the toes, burning sensation, crawling sensation, pain in the calf muscles. For a long time did not seek medical help, was not treated. 6 years ago, he was transferred to group II disability with a diagnosis of obliterating atherosclerosis of the vessels of the lower extremities. Constantly undergoing inpatient conservative treatment 2-3 times a year.

 11.29.99g. He turned to the consultative clinic, from where he was sent to the MRCB, was hospitalized in 1 surgical department. Complaints on admission to systematic pains in the lower extremities, aggravated by the passage of 50 meters, a burning sensation, tingling, numbness in the toes of both feet, coldness. On the basis of the department, conservative therapy was carried out: infusion therapy: reopoliglukin 400.0 iv, isotonic sodium chloride solution 0.9% - 200.0 + pentoxifylline 2% 5.0; iv nicotinic acid according to the scheme (from 1.0 to 10.0 and from 10.0 to 1.0), Actovegin 6.0 per 200 ml of 0.9% sodium chloride solution; v / m papaverine 3 times a day 2% - 2.0; xantinol nicotinate 15% - 2.0 IM 2 times a day, vitamin B1 and B6 IM 1 time a day, alternating with vitamin B 12 at 500 mcg IM 1 time a day, oral antiplatelet agents: chimes 0.025 per os 4 times a day. After conservative therapy, improvement began to be noted, although the pain syndrome persisted, intermittent claudication after passing 250 meters, convulsions disappeared, chills, burning, tingling, numbness. In this regard, it was decided to use a derivative of 3-hydroxypyridine (Mexidol), which was administered iv for 10 days; Sol. Mexidoli 5% -2.0 to 200 0.9% NaCl once daily. On the third day of treatment, numbness and chilliness disappeared. On the 5th day of treatment, the burning sensation of tingling numbness in the lower extremities disappeared. On day 8, there was a feeling of warmth in the lower extremities, the pain stopped. I began to notice dull pain in the lower extremities and intermittent claudication only when passing 600 meters. The patient is discharged in satisfactory condition without complaint.

 We present the results of laboratory and instrumental examination of this patient.

 Upon admission: HB 136 g / l, 5x10; ESR 10 mm / h. There was an increase in blood sugar to 6 mmol / l, cholesterol to 6.78 mmol / l, beta-lipoproteins to 53 units. The content of alpha-cholesterol was 1.3 mmol / L, triglycerides 0.89 mmol / L, fibrinogen was 4218 mg / L. The atherogenic index was 4.2 units. Total protein 82 g / l, albumin 50.8%, alpha-1 globulin 4%. Alpha-2 globulins 12.2%, beta-globulins 13.4%, gamma globulins - 19.6%. ALT activity 0.82: ACT 0.82 mmol / L. The plasma MDA was 11.86 mmol / L, erythrocytes 17 mmol / L.

 After complex therapy, including mexidol, positive dynamics were also observed in laboratory studies: HB was 146 g / l, α 4.3 • 10, ESR 5 mm / h, blood sugar decreased to 3.5 mmol / l, total cholesterol decreased to 4.78 mmol / l (by 30%), the atherogenic index decreased to 3.68 units. , triglycerides decreased to 0.75 mmol / l, the fibrinogen content decreased to 3330 mg / l (by 21%); the concentration of albumin increased, the serum protein spectrum improved (33% α1, 10.1% α2, 13.5% β, 14.4% γ). The level of MDA in plasma decreased to 7.3, and in red blood cells to 10.3 mmol / L.

 Thus, the inclusion of Mexidol in the complex therapy of patients with obliterating atherosclerosis positively influenced the dynamics of the pathological process: accelerated the regression of the main clinical symptoms and improved blood circulation in the vascular pool of the arteries of the lower extremities.

 Mexidol favorably influenced the dynamics of the main clinical symptoms, accelerating their regression (Table 2). Significant differences in the severity of clinical symptoms were noted already by the 5th day from the start of treatment. The severity of convulsive syndrome, pain and weakness in the legs decreased by 27%, 51% and 72%, respectively, on the 5th, 8th and 10th days from the start of treatment, while in the group without mexidol the decrease in intensity was significantly less pronounced and amounted to 8, 33 and 70%, respectively. The fastest positive dynamics with the introduction of Mexidol underwent neurovegetative symptoms (numbness, paresthesia, chilliness). By 5 days from the beginning of the course, the severity of this symptom decreased by 64.7%, while in the group without mexidol there was no positive dynamics. The skin temperature in the area of the affected limbs was significantly faster restored.

 The improvement of arterial blood flow in the vessels during the use of Mexidol was also confirmed by the data of ultrasound dopplerographic examination of the vessels of the lower extremities (Table 3).

 The increase in volumetric blood flow was maximally expressed in the distal vessels of the foot, where the increase was 12%, while in the group without mexidol, an increase in this indicator was not detected.

 The use of Mexidol in the complex therapy of patients with obliterating atherosclerosis of the vessels of the lower extremities had a positive effect on the dynamics of lipid metabolism. In patients of the control group, against the background of standard therapy, the level of cholesterol remained unchanged, while against the background of mexidol, there was a reliable dynamics of a decrease in cholesterol content by 25% from the initial data (Table 4), a similar trend was also found in the study of β-lipoproteins - a decrease their concentration amounted to 19% of the initial data, while in the control group the concentration of β-lipoproteins significantly increased by 13%. High-density lipoprotein cholesterol against the background of standard therapy tended to decrease, while in the comparison group its concentration significantly increased. A change in the ratio in the lipid spectrum under the influence of Mexidol was reflected in the value of the atherogenicity index. So, in the control group, an increase in the atherogenic index was observed on average by 33%, while in the comparison group it decreased by 24% from the initial level. The content of triglycerides in the control group significantly increased by 28%, while against the background of Mexidol, their concentration decreased by 28%. The introduction of Mexidol decreased by 24% the concentration of glucose in the blood, while the level of standard therapy did not change its level.

 Mexidol exhibits pronounced antioxidant activity in patients with obliterating atherosclerosis, decreasing the concentration of malondialdehyde by 43% from the initial level, while in the control group there was a tendency to increase this indicator (Table 4).

 Mexidol corrects an increase in the concentration of fibrinogen in the blood (table. 4).

 Thus, the inclusion of Mexidol in the complex therapy of patients with obliterating atherosclerosis of the vessels of the lower extremities has a beneficial effect on clinical, functional and metabolic parameters, correcting the main pathogenetic links of this disease. Mexidol corrects atherogenic shifts, reducing the atherogenic index, the level of triglycerides, fibrinogen, and blood glucose. Of significant importance in the implementation of the angioprotective action of Mexidol is its high antioxidant potential. Normalization of metabolic changes is an important factor in the positive effect of mexidol on microcirculatory blood flow in atherosclerotic lesions of the vessels of the lower extremities. The total effect of Mexidol is manifested in improving blood supply in the ischemic zone in patients with obliterating atherosclerosis.

LITERATURE
1. Drozdov S.A. The use of nicotinic acid and pentoxifylline for the treatment and prevention of the progression of occlusive atherosclerotic arteriopathies // Cardiology .-1998. 9. S.16-19.

 2. Mirolyubov B.M., Zamaleev Z.A. Autovenous deep femoral popliteal shunting // Thoracic and cardiovascular surgery. 1.2000. - S. 43-45.

 3. Pokrovsky VV Surgical tactics for lesions of the abdominal aorta and lower limb arteries in young patients // Surgery.- 1986.- 5.- p. 89-95.

 4. Samoday V.G., Zvyagin A.V., Ivanov A.A. Surgical treatment of patients in the terminal stages of occlusive diseases of the peripheral arteries of the lower extremities // Bulletin of Surgery. 15. T. 158. 1999.-C.29-30.

 5. Tsarev O. A. Intraarterial laser exposure as an addition to traditional methods of direct revascularization of the limbs // Angiology and cardiovascular surgery. 1998.- 2.- S. 220-221.

Claims (1)

 A method for the treatment of atherosclerosis obliterans of the lower extremities, including the use of antiplatelet agents, anticoagulants, vasodilators, characterized in that for an additional 10 days, 2-ethyl-6-methyl-3-hydroxypyridine succinate is administered at a dose of 400 mg per day: intravenously twice a day in 200 ml of 0.9% sodium chloride.

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