RU2547791C1 - Method for non-invasive treatment of legg's disease - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: orthopaedic unload is accompanied with prescribing a therapeutic diet promoting weight reduction and adequate feeding of calcium and vitamins C, D, E, K.That is combined with the oral administration of Fosamax® tablets 70 mg once a week for 6 months, Arthrodarin® capsules 50 mg in the morning and evening for 4-6 months and nasal sprayings of Miacalcic® 200 International Units/day in cycles of 2 weeks every 2 weeks for 4-6 months. What is also used is Milgamma® solution for intramuscular injections 2 ml a day, at least 10 times, with a pause of 1 day. Alflutop® 2 ml a day is injected intramuscularly daily within at least 20 days. That is combined with a therapeutic course including 8-10 therapeutic sessions each of which consists of the two stages of procedures following each other. The first of this stages involve the successive one-day abdominal decompression of the lower body from the waist down, pneumocompression massage of legs, manual and vacuum massages. The exposure segments are: hip joints - lateral surface of hips, gluteal region and paravertebral area L2-L5, cervical segment - paravertebral area C7-T1 and sacral bone. A preferred pause between the above procedures is no more than 10-15 minutes. Thereafter, the first stage of the therapeutic session is completed by conducting a hirudotherapy with the use of no more than 8 medicinal leeches per one session to be placed on the cervical paravertebral area C7-T1 and lumbar paravertebral area L2-L5, sacral bone, tail bone, abdomen within the liver, lower abdomen, painful hip segments and/or segments discoloured after the massage. Each therapeutic session is completed by successive procedures of the second stage with a pause of at least 3 days. A magnetic therapy and a barolasertherapy cover the segments: hip joints - lateral surface of hips, gluteal region and paravertebral areas L2-L5. A phonophoresis with the used of karipain gel covers the gluteal, knee and hip segments. Thereafter, 24 hours later the therapeutic session is repeated depending on the patient's state no more than 10 times. That is followed by doing therapeutic physical exercises in the swimming pool within at least 10 days. Kartalax® peptide preparation 1-2 ml in the concentration of at least 100 mcg in 1 ml diluted together with Tymalin® 10 mg is administered daily once a day for 10 days. After the injections are completed, peptide Vezugen® capsules 0.2 g are orally administered in the morning and in the evening 10-15 minutes before meals for 30 days. After the continuous and single course of Fosamax® and nasal sprayings of Miacalcic® are completed, 1-2 months later Osteogenon® tablets 830 mg are administered daily in a dose of 2-4 tablets 2 times a day, and Arthrodarin® capsules are also taken in a dose of 50 mg in the morning and in the evening for 4-6 months. The oral administration of the last-mentioned two preparations is repeated at least three months later.EFFECT: preventing bone absorption and loss, restoring the shape, volume and normal consistence of an intraarticular cartilage that makes it possible to avoid the further progression of the disease and a necessity of surgical management in this group of patients.3 cl, 3 ex

Description

The invention relates to medicine, namely to traumatology and orthopedics, arthrology and physiotherapy, and can be used in the non-surgical treatment of patients suffering from aseptic necrosis of the head of the hip bone.

Aseptic necrosis of the femoral head (ANGBC) is due to the pathogenesis of traumatic and non-traumatic effects.

ANGBK, due to the pathogenesis of the traumatic action, is expressed by ischemia of the femoral head due to mechanical impairment of vascular integrity.

ANGBK, due to the pathogenesis of non-traumatic effects, occurs as a result of taking glucocorticoids, alcohol abuse, smoking, pancreatitis, ionizing radiation, etc.

It is well known that ANGBK affects mainly people of the most working age: 20-50 years. In this sense, the proposed method for the treatment of this disease is relevant, has practical value and has great social significance.

The development of ANGBC is accompanied by a decrease in the number and activity of osteoblasts and osteocytes. At the same time, the activity of osteoclasts increases. This leads to an imbalance between bone formation and resorption. As a result, bone tissue is weakened and its strength is impaired. In this case, the load contributes to the appearance of microfractures of the trabeculae of the femoral head and, due to mechanical compression of the venous channel, venous stasis appears first and then arterial stasis. Bone ischemia exacerbates necrosis and resorption, an impression fracture of the head occurs and deforming coxarthrosis develops. Thus, increased resorption of bone tissue in the lesion is a key point in the pathogenesis of AHBC.

There is a method of treating aseptic necrosis of the femoral head, including perforation of the femoral neck with the introduction of a needle, characterized in that during treatment they reduce intraosseous pressure by 15% from normal twice a day for 10 days through a previously placed intraosseous needle, which allows to exclude postoperative complications, improve blood supply to the femoral head [9].

There is a method of treating aseptic necrosis of the femoral head, the purpose of which is to restore the congruency of the support zone of the femoral head, with the prevention of further progression of the process in it, by capsulotomy and osteotomy of the femur with subsequent anterior rotation and fixation of fragments. In this case, an arcuate basal cervical osteotomy is performed while maintaining the integrity of the greater trochanter and hemicapsulotomy along the anterior surface of the hip joint [6].

There is a method of treating aseptic necrosis of the femoral head, the essence of which is that a double-lumen balloon catheter is inserted into the femoral artery below the discharge of the deep femoral artery and daily temporary increasing embolization of the femoral artery is performed until hypervascularization of the tissue, especially the affected femoral head, takes place during embolization, drugs dipyridamole are selectively administered, which improve the rheological properties of blood and enhance local microcirculation s - prostaglandins-E, which improves the reparative regeneration of bone tissue [8].

There is a method of treating aseptic necrosis of the femoral head, which consists in the fact that by excising the changed tissues from the lesion in the form of a cylinder, the axis of which is directed through the center of the head to the Adams arch and replacing the defect with a bone autograft from the iliac wing in the form of a cylinder, characterized in that form two half-cylinders, one of which is free, and the second on the muscle leg containing a portion of the gluteus maximus muscle and / or tensor of the broad fascia of the thigh, while the free half-cylinder is placed to the medial part of the defect, and the half-cylinder on the leg to the lateral part of it. It is indicated that this method allows for additional blood supply, to prevent squeezing of the muscle bundle of the transplant [7].

The above methods of treating aseptic necrosis of the head of the hip bone with surgery have the following disadvantages:

- high manufacturability and complexity of execution;

- a long period after surgical recovery;

- a significant deterioration in the quality of life in the period after surgical recovery;

- high morbidity and a large amount of surgical intervention;

- a large percentage of disability;

- a large percentage of re-intervention;

In the process of outpatient treatment of ANGBCs, medical rehabilitation procedures are usually used, including:

- compliance with the optimal orthopedic regimen and therapeutic exercises;

- decompression tunneling and prolonged intraosseous blockade;

- intraarticular injection therapy;

- electromyostimulation;

- correction of walking, including using multichannel electromyostimulation;

- physiotherapy (EHF-therapy, laser therapy, magnetotherapy).

There is a method of treating coxarthrosis, which consists in the effect of an alternating magnetic field on the area of the hip joint, as well as in a drug effect, including non-steroidal anti-inflammatory, analgesic agents, as well as vitamins. Cylindrical inductors from the apparatus "Pole-1" or "Pole-2" are placed contact at the front and rear outer surfaces of the hip joint, installing opposite poles to each other. A continuous mode is used, the current is sinusoidal, the magnetic induction of the magnetic field is from 25 to 50 mT (“2” - “4” intensity positions) depending on the stage of the disease. The duration of exposure on one field is 15-20 minutes. The course of treatment includes 12-18 procedures conducted daily or every other day [1]. The therapeutic effects of magnetic fields are: vasodilating, catabolic, anti-inflammatory, trophic, hypocoagulating [11, 16].

Known therapeutic effects from the use of barolaser therapy, which were considered in various works [3, 4, 5, 17]. They note that the use of barolaserotherapy has analgesic, anti-inflammatory, anti-edematous and anti-allergic effects, increases immunity by mobilizing the body’s defenses, normalizes local blood flow, improves microcirculation and activates trophic processes in tissues, improves blood rheological properties and activates regenerative processes in surrounding tissues at the site of exposure.

When barolaserotherapy uses a mutual enhancement of the beneficial effects of two physical factors. The combination of low-intensity laser radiation and local decompression (vacuum) mutually enhances the positive effect on biological tissues with virtually no side effects, allergic reactions and adverse effects, which makes it possible to use it in combination with other traditional methods of treatment.

Known therapeutic effects from phonophoresis procedures: anti-inflammatory, reparative-regenerative, analgesic, catabolic, defibrosing, as well as a specific effect due to the ultrasound-administered drug substance [13].

The therapeutic effects of pneumocompression therapy are known: variable compression affects individual layers of tissue and blood vessels and improves tissue trophism, increases skin elasticity and turgor, increases muscle blood flow, normalizes contractile and plastic tone, improves blood flow to periarticular tissues and activates the secretory function of the synovial membrane, stagnation in tissues is eliminated, pain and swelling are reduced, lymphatic outflow is stimulated, metabolism improves TV and gas exchange; venous blood flow is accelerated and arterial blood flow velocity increases, leading to an increase in systolic and lower diastolic blood pressure [12]. This therapy is free from side effects, which makes it possible to use it in combination with other traditional methods of treatment.

The therapeutic effects of manual massage procedures are known: the flow of lymph and blood is accelerated, which leads to an improvement in metabolic processes in the body at different levels, local tissue nutrition rises, and at the same time, they are freed from harmful elements, overall muscle tone is increased, skin is freed from surface layer, the activity of sweat glands is excited.

The therapeutic effects of vacuum massage procedures are known: the absorption of fatty particles and liquids increases, the toxins are removed and the lymphatic system is cleansed, the pores are cleaned and the dead cells are removed, the skin surface is restored and activated (revitalized), local microcirculation is improved, muscle function is restored, fat conversion is accelerated acids; the exchange of biological fluids (blood, lymph, interstitial fluid) in the microcirculatory system of the skin, subcutaneous tissue and skeletal muscles improves; the process of neovasculogenesis is activated (the formation of new, young microvessels in pathologically altered tissues), which helps to restore and rejuvenate the microvascular network of tissue structures; blood supply and oxygen supply to tissues and organs are significantly increased, tissue metabolism and detoxification are stimulated, and regenerative and reparative cellular reactions are strengthened and accelerated [14].

The use of vacuum massage eliminates sleep disturbances, reduces the negative effects of stress, stabilizes blood pressure, normalizes the functioning of the kidneys and digestive organs, and prevents the development and manifestations of osteochondrosis and scoliosis. Muscle tension and fatigue are quickly relieved. The use of vacuum massage is also effective in cases of impaired fat metabolism, including those accompanied by cellulite.

The therapeutic effects of abdominal decompression procedures are known: microcirculatory blood supply to the lower extremities improves when there is a violation of the main blood flow in them; the mechanism of transmembrane metabolism and direct oxygen transport through the membrane separating capillaries and tissues is activated; blood flow through the capillaries increases; significantly increases the permeability of the capillary endothelium, especially for oxygen; active tissue oxygenation occurs; stimulation of local immunity; the level of saturation of the tissues of the lower extremities with oxygen increases. Abdominal decompression has an anti-inflammatory and vasoactive effect and has a positive effect on the endocrine glands, liver, nervous system and joints [15].

The abdominal decompression procedure can be used in a complex of therapeutic measures for various diseases and pathological conditions.

Known therapeutic effects of occupational therapy procedures associated with the properties of enzymes of the leech saliva (leech secretion), which it injects into the patient’s blood. In this case, the leech is able to find reflexogenic points and acts on them like acupuncture. Leech saliva contains over 100 different enzymes. Biologically active substances of leech secretion have a whole range of therapeutic effects, including: anti-inflammatory, decongestant, analgesic, thrombolytic (destruction of blood clots), anti-ischemic (improvement of blood supply to tissues and organs), antihypoxic (improvement of blood supply to oxygen of tissues and organs), bacteriostatic (death of a microorganism that caused the inflammatory process, “like an antibiotic”), activate the immune system, lower blood pressure, cholesterol and sugar blood, improve fat metabolism, remove toxins. Leech secretion has regenerative and antioxidant effects, expressed anticoagulant (anticoagulant properties) improves microcirculation [2].

Known methods for the treatment of ANGBC (based on clinical observations) based on the use of only medical rehabilitation procedures (including magnetotherapy, laser therapy, phonophoresis, massages, hirudotherapy), taking into account the stages of the process and the orthopedic situation, are not very effective. They provide only a short-term improvement in the condition and, usually, do not lead to the restoration of the joint and do not prevent the accumulation of microfractures of trabeculae due to an increase in the intensity of resorption of the cancellous bone. This is due to the fact that drugs and treatment methods are used, the effectiveness of which is small and, obviously, insufficient.

A known method for the treatment of ANHBK [10], carried out on the background of orthopedic discharge, including the introduction of drugs chimes, ibandronate, an active metabolite of vitamin D3 and osseino-hydroxyapatite complex, and ibandronate is administered intravenously at a rate of 2-4 mg / 2-4 ml once every 3 months, and other drugs are administered orally daily in the following amounts: the active metabolite of vitamin D3 - 0.5-1 mcg / day, osseino-hydroxyapatite complex - 0.6-3.6 g / day and chimes - 75-400 mg / day .

The above method of treatment is the closest analogue of the proposed method and is taken as a prototype of the invention.

The disadvantages of the prototype include:

- side effects of chimes and ibandronate coincide in direction, both on the cardiovascular system (unstable angina and coronary stealing syndrome, an increased risk of heart rhythm disturbances), and on the gastrointestinal tract (esophagitis, gastritis, ulcers);

- the possible development of hypercalcemia due to the use of an active metabolite of vitamin D3 with thiazide diuretics, which are often used as antihypertensive therapy in patients aged 30 to 50 years;

- lack of sequence of application of methods that affect the normalization of the immune and vascular systems, as well as the activation of the regeneration of bone matrix and cartilage.

These disadvantages lead to a decrease in the efficiency of tissue regeneration of the femoral head undergoing necrosis.

Thus, known methods of treating aseptic necrosis are not effective enough.

The objective of the invention is the creation of a non-surgical and more effective method of treatment of ANGBC.

A new method for the treatment of ANHBC differs from the prototype method in systemic treatment of the body, including normalization of the vascular, immune and bone systems, based on the use of drug therapy using: peptides that help normalize cartilage and musculoskeletal system; peptides that regulate the metabolism in the cells of the vascular wall, improve the state of the vascular wall and normalize lipid metabolism; peptides that restore immunological reactivity, regulate the tissue protective forces of the body, stimulate the processes of regeneration (recovery) and hematopoiesis in case of depression, and improve the processes of cellular metabolism - in combination with massages and hirudotherapy, physiotherapy, therapeutic physical exercises and diet.

The proposed method allows to increase the efficiency of non-surgical treatment of ANGBC due to the activation of the process of regeneration of tissues of the femoral head that underwent necrosis up to their recovery, as well as due to the possibility of restoring the shape, volume and normal consistency of articular cartilage, activating trophic processes in the tissues of the joint, normalizing lipid metabolism , regulation of tissue protective forces of the body, stimulating the processes of regeneration (recovery) and hematopoiesis in case of inhibition, and improving their processes of cellular metabolism, as well as improving blood circulation and eliminating its stagnation in the affected organs. Particular attention is paid to the processes of blood circulation restoration of the femoral head, bone tissue and cartilage. The proposed method is preferably used at stages not exceeding the third stage of the disease.

The task is achieved due to the following.

The patient is prescribed diagnostic tests: X-ray, computed tomography (CT), magnetic resonance imaging (MRI), densitometry and scintigraphy to exclude specific processes. In addition, urine and blood tests (clinical and biochemical) are prescribed. A biochemical blood test includes an assessment of the following indicators: C-reactive protein, alanine aminotransferase (ALT), aspartate transferase (ACT), bilirubin, urea, creatinine, sodium, potassium, calcium, magnesium, iron, phosphorus, thyroid hormones, rheumatoid coagulation factor and indicators. Moreover, the volume of the indicated instrumental and laboratory studies is determined individually for each patient. According to the results of the studies, it is important to make sure that the patient does not have autoimmune processes.

Depending on the results of diagnosis, weight assessment (body mass / volume index) and the period of the disease (exacerbation, inflammatory changes, synovitis, cystic restructuring, osteopenia, remission), the patient is prescribed treatment in a hospital, or in an outpatient setting, or as an outpatient. In this case, a diet is prescribed in accordance with the treatment tables and the joint load regimen is selected (partial unloading, full unloading or full load).

Further, the patient is prescribed continuous administration of drugs: oral alendronic acid ("Instructions for the medical use of the drug FOSAMAX ^® / FOSAMAX ^® ". Registration number: Π No. 008977) at the rate of 70 mg once a week for 6 months, diacerein ("Medical instructions the use of the drug ARTRODARIN ^® / ARTRODARIN ^® ". Registration number: LSR-005403/08) 50 mg each 1 pc. in the afternoon and 1 pc. in the evening for 4-6 months, calcitonin ("Instructions for the medical use of the drug MIAKALTSIK ^® / MIACALCIC ^® ". Registration number: Π No. 013245/01) is administered nasally 200 IU / day 2 weeks after 2 weeks for 4-6 months . Along with this, intramuscular injections of the combined preparation are performed ("Instructions for the medical use of the drug MILGAMMA ^® / MILGAMMA ^® ". Registration number: ΠN012551 / 02) containing neurotropic vitamins of group B in the form of a solution for intramuscular use of 2 ml per day, not less than 10 times with a break of 1 day and daily intramuscular administration of a chondroprotector with an active component from a bioactive concentrate from small sea fish containing: amino acids, mucopolysaccharides, peptides, potassium, sodium, calcium, magnesium ions, m unity, iron, zinc ("Instructions for medical use of the drug ALFLUTOP ^® / ALFLUTOP ^® ". Registration number: Π N012210 / 01) - 2 ml per day, for at least 20 days with a break of 24 hours.

The proposed use of these drugs allows you to stop the biosynthesis of inflammatory mediators, reduce capillary permeability, inhibit the processes of bone and cartilage resorption, minimize invasiveness, stimulate bone formation, increase bone mineral density (BMD), improve the quality of its structure and the state of cartilage, which leads to relief pain and inflammatory processes in the hip joints.

At the end of intramuscular injections of a chondroprotector with an active component from a bioactive concentrate from small sea fish (ALFLUTOP®), with an interval of 24-48 hours (while taking the other drugs mentioned above), the patient is prescribed a course of therapeutic treatment aimed at increasing the vascular efficiency system - by improving the rheological properties of the blood, eliminating its stagnation in the affected organs and increasing the immune properties of the body. It includes 8-10 treatment sessions, each of which consists of two successive stages of the procedure.

At the first stage, over the course of one day, the following procedures are sequentially performed: abdominal decompression, pneumocompression massage, manual massage, vacuum massage and occupational therapy. It is preferable that on this day the time intervals between these procedures should not exceed 10-15 minutes. After hirudotherapy, a break of at least 3 days is carried out, depending on the condition of the patient.

Next, carry out the second stage of the session of therapeutic procedures. It is performed within one day and includes a sequence of procedures: magnetotherapy, barolaser therapy and phonophoresis using the karipain gel. Then, with a break of 24 hours, the therapy session is repeated. The number of repetitions depends on the condition of the patient and it is not recommended to exceed 10 times.

The sequence of these steps is not decisive. It is important that the condition is that no other procedures are performed on the day of magnetotherapy, barolaser therapy and phonophoresis using the karipain gel.

The magnetotherapy procedure as one of the options can be performed on the basis of using the ALIMP-1 low-frequency magnetotherapy apparatus manufactured by the Novator State Enterprise (Khmelnitsky, Ukraine), acting for 10-15 minutes on: hip joints (lateral thighs) , gluteal and lumbosacral areas; choosing the modes “frequency 100 Hz” and “intensity 50%” with a duration of working pulses of 12 ± 3 ms, a period of repetition of working pulses of 96 ± 24 ms, the value of magnetic induction in the geometric center of solenoid inductors 2.5 ± 0.6 mT.

The barolaserotherapy procedure can be performed, for example, on the basis of using the ALP-01-Laton-Kombi apparatus manufactured by NII VOLO LLC (St. Petersburg, Russia), acting for 10-15 minutes on: hip joints (lateral) thigh surface), gluteal region, L2-L5 paravertebral zones, sacrum, setting the wavelength to 810 ± 20 nm, pressure 10-12 Pa, laser radiation intensity 20-30 mW, frequency up to 100 Hz.

One of the possible phonophoresis embodiments is a procedure using the PHYSIOSON-Basic apparatus manufactured by PHYSIOMED Elektromedizin AG (Germany) using a karipain gel, the essence of which is to expose for 6-8 minutes to: paravertebral, buttock, knee and the hip area, setting the emitting power of 0.4 W / cm ² , the pulsating wave and the radiation frequency of 1 MHz. In this case, the gel is slowly rubbed in circular motions onto the indicated areas of influence.

The proposed combined use of the procedures of magnetotherapy, barolaserotherapy and phonophoresis leads to: a decrease in blood viscosity, a decrease in the likelihood of blood clots, an improvement in blood circulation and the state of blood vessels, a decrease in reflex muscle spasm, an improvement in cartilage nutrition, normalization of metabolic processes in the body, a decrease in tissue swelling, an improvement in microcirculation and exchange substances, and also promotes faster restoration of damaged tissues in the joint, which increases the effectiveness of echeniya.

   The abdominal decompression procedure can be performed using the KAD-01-AKC Nadezhda equipment set manufactured by AKC Firm LLC (St. Petersburg, Russia), on the basis of which they act on the legs, including feet, for 15-20 minutes lower legs, knees, hips and hips, setting a vacuum pressure of 1.5-1.8 kPa; rarefaction time 10-12 min; pause time 15-25 s - depending on the body mass / volume index.

One of the preferred options for performing the pneumatic compression massage procedure is the use of the Lymphat Digital digital apparatus manufactured by UP LIMPEKS (Minsk, Republic of Belarus), on the basis of which they act on the legs, including feet, legs, for 15-20 minutes , knees, hips and hips, setting a pressure of 20 to 60 mmHg. Art. depending on body mass / volume index.

The manual massage procedure is performed for 30 minutes, affecting: the hip joints (lateral surface of the thighs), the gluteal region and paravertebral zones L2-L5, the cervical region (paravertebral zone C7-T1) and the sacrum. This procedure is performed smoothly and gently, without sudden movements. It should cause the patient a feeling of pleasant warmth and comfort. Muscles need to be washed deep enough and thoroughly, without pain and discomfort.

The vacuum massage procedure, as one of the alternatives, can be performed using the SLIM PROJECT PLUS apparatus manufactured by GENERAL PROJECT S.R.L. (Italy), acting for 10-15 minutes exactly on the same areas that were affected by manual massage, setting the pressure to 10-12 Pa, setting program No. 6 or No. 14.

In the process of hirudotherapy, a leech injects a number of biologically active enzymes into the patient’s blood, including hirudin, destabilase, aeglins, bledinny, hyaluronidase. With ANGBC, enzymes injected with medical leeches improve blood circulation and eliminate its stagnation in the femur damaged in the head. In addition, they dissolve blood clots, improve metabolism and tissue elasticity. Enzymes injected with medical leeches not only contribute to a significant improvement in blood circulation, normalize the rheological properties of blood, but also increase the immune properties of the body.

To achieve the best effect, 2 courses of hirudotherapy per year should be carried out, the interval between which should be at least 3 (three) months. Each course consists of 8-10 sessions. Sessions are carried out with an interval of at least 3 days, depending on the condition of the patient.

Leeches are placed on the gluteal region, L2-L5 paravertebral zones, cervical (C7-T1 paravertebral zone), sacrum, coccyx, on the stomach in the liver, lower abdomen, painful hip areas and / or changed color after massage. In one session, no more than 8 leeches should be used.

At the beginning of treatment with leeches (usually after the first 3-4 sessions), a temporary exacerbation may occur. The improvement effect usually becomes noticeable only after 7-8 sessions of hirudotherapy, and the patient reaches the best form 10-15 days after the end of the full course of treatment.

In order to achieve the best therapeutic effect, together with the course of therapeutic treatment, the patient is prescribed a course of peptidergic regulation, aimed at restoring and normalizing the work of the vascular, immune and bone systems. It includes the use of:

- a peptide complex containing amino acids: alanine, glutamic and aspartic acid, which contribute to the normalization of cartilage and musculoskeletal system ("KARTALAX® - peptide complex". State registration certificate No. RU.77.99.11.003.E.012695.05.11 from May 4, 2011);

- a peptide complex containing amino acids: lysine, glutamic and aspartic acids - that regulate the metabolism in the cells of the vascular wall, improve the condition of the vascular wall and normalize lipid metabolism ("VEZUGEN® - peptide complex". State registration certificate No. RU.77.99.11.003.E .012701.05.11 dated 05/04/2011);

- a preparation containing thymus polypeptides that contribute to the normalization of the thymus gland, restoring immunological reactivity, regulating the number and ratio of T and B lymphocytes and their subpopulations, enhancing phagocytosis, stimulating cellular immunity reactions and regeneration (recovery) and blood formation processes in case of their oppression, as well as improving the processes of cellular metabolism ("Instructions for the medical use of the drug TIMALIN®." Registration number: LS-000267).

The course of peptidergic regulation is carried out in two stages.

At the first stage, daily, for 10 days, the patient is given intramuscular injections. Each injection consists of 1-2 ml of a solution for intramuscular administration of a peptide complex containing amino acids: alanine, glutamic and aspartic acid with a concentration of at least 100 μg in 1 ml (the drug "KARTALAX®"), which is diluted with 10 mg of powder containing polypeptides thymus (drug "TIMALIN®").

In the second stage, with an interval of 24 hours, after the completion of these injections, a peptide complex containing amino acids: lysine, glutamic and aspartic acids (VESUGEN® preparation) and a peptide complex containing amino acids: alanine, is orally administered daily for 30 days glutamic and aspartic acids (KARTALAX® preparation) - 0.2 g capsules per 1 pc. in the morning and 1 pc. in the evening 10-15 minutes before eating each peptide complex, respectively.

The use of peptidergic regulation achieve:

- improving blood supply, including when taking other medications, which increases the effectiveness of treatment;

- normalization of functional and morphological changes in the vascular wall;

- Improvement of trophism of vascular wall tissue cells;

- Improving the processes of cellular metabolism;

- significant smoothing of pathological symptoms, including pain;

- increased range of motion in the affected joints.

The course of therapeutic treatment, including magnetotherapy, barolaser therapy, phonophoresis using karipain gel, abdominal decompression, pneumocompression massage, manual massage, vacuum massage and hirudotherapy is prescribed in the absence of contraindications, preferably with a peptidergic regulation and at least 2 (two) times a year. . If necessary, these courses of treatment can be repeated, but with interruptions of at least 3 (three) months.

After taking alendronic acid (FOSAMAX® preparation) and calcitonin (MIAKALTSIK® preparation), a 1-2-month break is taken. Acceptance of these drugs during treatment is carried out only in one continuous course, without reuse.

Then, the patient is orally administered the osseino-hydroxyapatite compound (“Instructions for the medical use of the drug OSTEOGENON® / OSTEOGENON®.” Registration number: Π N013182 / 01) daily in the form of tablets of 830 mg, 2-4 pcs. 2 times a day for 4-6 months. Along with this, diacerein (“Instructions for the medical use of the drug ARTRODARIN® / ARTRODARIN®.” Registration Number: LSR-005403/08) is administered orally in capsules of 50 mg each. day and 1 pc. in the evening for 4-6 months. The course of taking these drugs can be repeated, with a break of at least 3 (three) months.

In the process of treatment, the process of controlling “excess” weight is important and requiring special attention. Overweight increases the load on the joint and reduces the ability of cartilage to recover. Maintaining a diet that promotes weight loss and passing physical therapy sessions (exercise therapy) can significantly improve the general condition of patients. Dosed physical activity and the implementation of certain therapeutic exercises can reduce the excessive load on the joints and relieve overstrain of muscles and ligaments.

An important goal of the diet is to ensure sufficient intake of calcium and vitamins with food: C, D, E, K. At the same time, it is necessary to reduce consumption or refuse coffee, any alcoholic beverages, smoking, salty foods that remove calcium from the body.

To prevent muscle atrophy, the patient is required, on the basis of recommendations of a specialist, to perform special therapeutic exercises to strengthen leg muscles at least 30 minutes a day. To strengthen the muscles and ligaments - exercises (with aseptic necrosis) must be done either statically, fixing the position for a certain time, or in dynamics, but slowly. It is slow (dynamic and static) correctly selected exercises that strengthen those muscles and ligaments that atrophied in humans due to the disease. At the same time, a set of physical exercises and loads is chosen individually and strictly under the supervision of a doctor.

In order to speed up the process of restoring motor function, in the absence of contraindications, the complex of physical exercises may include classes on mechanotherapeutic apparatuses and classes in the pool for at least 30 minutes a day, under the mandatory supervision of a specialist and individual choice of loads. Physical exercises in water and swimming in the pool have painkillers and relaxing effects, strengthen and increase the efficiency of the cardiovascular system, increase the speed of metabolic processes in which energy is used or calories are burned.

Regular performance of a set of physical exercises allows you to increase the adaptive capabilities of the body, improve the nutrition of joint tissues, reduce muscle tension, promotes uniform development of the muscle system, burning of subcutaneous fat and lowering cholesterol, which, in turn, helps to effectively reduce excess weight, increase mobility and flexibility joints, improve sleep and overall well-being.

Below the invention is accompanied by clinical examples of specific applications.

Example No. 1.

Patient Z., 37 years old, in April 2012 complained of pain in the right hip joint with axial load, limitation of movements in the right hip joint. The patient had a medical history: a traffic accident, a severe combined injury to the femur and pelvis, a fracture of the wing of the right iliac bone, and a fracture of the acetabulum. I did not receive surgical treatment. Treated conservatively. First, by skeletal traction - 2 weeks, then - was discharged under the supervision of a doctor at the community clinic for conservative treatment - bed rest. According to spiral computed tomography (CT) data, aseptic necrosis of the head of the right femur of stage II was diagnosed. A significant increase in bone resorption was found. The patient is vertical with crutches. Can only move on crutches and with extraneous support. Treatment has been started: oral administration of alendronic acid (Fosamax®) at a rate of 70 mg once a week for 6 months and diacerein (Arthrodarin®) 50 mg each. in the afternoon and 1 pc. in the evening for 6 months, calcitonin (“Miacalcic®”) is nasally 200 IU / day, 2 weeks after 2 weeks for 6 months. Along with this, the patient received intramuscular injections of a combined preparation containing neurotropic B vitamins (Milgamma®) 2 ml per day, 10 times with a break of 1 day and daily intramuscular administration of a chondroprotector with an active component from a bioactive concentrate from small sea fish, containing: amino acids, mucopolysaccharides, peptides, potassium, sodium, calcium, magnesium, copper, iron, zinc ions (Alflutop®) - 2 ml per day, for 20 days with a break of 24 hours. At the end of these injections, the patient received a course of therapeutic treatment, which included 10 treatment sessions, each of which consisted of 2 consecutive stages of the procedures.

At the first stage, within one day, the patient consistently received: abdominal decompression, pneumocompression massage, manual massage, vacuum massage and hirudotherapy. After hirudotherapy, the patient took a break of at least 3 days. At the second stage, within one day, the patient consistently received: magnetotherapy, barolaser therapy and phonophoresis using the karipain gel. After this, the patient took a break of 24 hours.

Together with the course of therapeutic treatment, the patient was prescribed a peptidergic regulation course, which was carried out in two stages. At the first stage, daily, for 10 days, the patient received intramuscular injections. Each injection consisted of 1 ml of a solution for intramuscular administration of a peptide complex containing amino acids: alanine, glutamic and aspartic acid with a concentration of at least 100 μg in 1 ml (Kartalax® preparation), which was diluted with 10 mg of powder containing thymus polypeptides ( Timalin® preparation). At the second stage, with a break of 24 hours, after the completion of these injections, the patient took an orally peptide complex containing amino acids: lysine, glutamic and aspartic acid (Vezugen® preparation) and a peptide complex containing amino acids: alanine every day for 30 days , glutamic and aspartic acids (Kartalax® preparation) - 0.2 g capsules per 1 pc. in the morning and 1 pc. in the evening 10-15 minutes before eating each peptide complex, respectively.

After taking alendronic acid (Phosamax® preparation) and calcitonin (Miacalcic® preparation), the patient took a break of 2 months.

Then the patient took the osseino-hydroxyapatite compound (Osteogenon® preparation) orally in the form of tablets of 830 mg daily in 2 pcs. 2 times a day for 6 months. In addition, he took orally diacerein (Arthrodarin®) in 50 mg capsules of 1 pc. day and 1 pc. in the evening for 6 months. After 2 months from the start of taking the osseino-hydroxyapatite compound (Osteogenon® preparation) and diacerein (Arthrodarin® preparation), the patient received a second-defined course of therapeutic treatment together with a course of peptidergic regulation. Along with this, to prevent muscle atrophy, the patient performed special therapeutic exercises to strengthen the leg muscles for 30 minutes a day.

According to SKT, 12 months after treatment, the foci of resorption decreased significantly, deformation of the femoral head is absent. After 14 months, from the moment of treatment, the patient moves independently with the help of one half-chair.

Example No. 2.

Patient B., 42 years old, in February 2012 complained of pain in the projection of the left hip joint, aggravated by exertion, restriction of movements in the left hip joint. History: pain appeared 3 years before treatment, in the last trimester of pregnancy. X-ray images were not performed, a lumbar ischialgia was diagnosed in the clinic at the place of residence, and did not receive treatment. Symptoms increased, after childbirth pain intensified. The patient turned to the clinic of the City Geriatric Medical and Social Center (GGMStsTs). According to magnetic resonance imaging (MRI), aseptic necrosis of the head of the right femur II stage was diagnosed. A biochemical study revealed a significant increase in bone resorption. The patient was placed on crutches and treatment was started: oral administration of alendronic acid (Fosamax®) at a rate of 70 mg once a week for 6 months and diacerein (Arthrodarin) 50 mg each. in the afternoon and 1 pc. in the evening for 6 months, calcitonin (“Miacalcic®”) is nasally 200 IU / day, 2 weeks after 2 weeks, for 6 months. Along with this, the patient received intramuscular injections of a combined preparation containing neurotropic B vitamins (Milgamma®) 2 ml per day, 10 times with a break of 1 day and daily intramuscular administration of a chondroprotector with an active component from a bioactive concentrate from small sea fish, containing: amino acids, mucopolysaccharides, peptides, potassium, sodium, calcium, magnesium, copper, iron, zinc ions (Alflutop®) - 2 ml per day, for 20 days with a break of 24 hours. At the end of these injections, the patient received a course of therapeutic treatment, which included 10 treatment sessions, each of which consisted of 2 successive stages of the procedures.

At the first stage, within one day, the patient consistently received: abdominal decompression, pneumocompression massage, manual massage, vacuum massage and hirudotherapy. After occupational therapy, the patient took a break of at least 3 days. At the second stage, within one day, the patient consistently received: magnetotherapy, barolaser therapy and phonophoresis using the karipain gel. After this, the patient took a break of 24 hours.

Together with the course of therapeutic treatment, the patient was prescribed a course of peptidergic regulation, which was carried out in two stages. At the first stage, daily, for 10 days, the patient received intramuscular injections. Each injection consisted of 1 ml of a solution for intramuscular administration of a peptide complex containing amino acids: alanine, glutamic and aspartic acid with a concentration of at least 100 μg in 1 ml (Kartalax® preparation), which was diluted with 10 mg of powder containing thymus polypeptides ( Timalin® preparation).

At the second stage, with an interval of 24 hours, after the completion of these injections, the patient took an oral peptide complex containing amino acids: lysine, glutamic and aspartic acid (Vezugen® preparation) and a peptide complex containing amino acids: alanine every day for 30 days , glutamic and aspartic acids (Kartalax® preparation) - 0.2 g capsules per 1 pc. in the morning and 1 pc. in the evening 10-15 minutes before eating each peptide complex, respectively.

After taking alendronic acid (Fosamax®) and calcitonin (Miacalcic®), the patient withstood a break of 2 months.

Then the patient took the osseino-hydroxyapatite compound (Osteogenon® preparation) orally in the form of tablets of 830 mg, 2 pcs each day. 2 times a day for 6 months. In addition, she took orally diacerein (the drug "Artrodarin") in capsules of 50 mg, 1 pc. day and 1 pc. in the evening for 6 months.

Along with this, to prevent muscle atrophy, the patient performed special therapeutic exercises to strengthen the muscles of the legs for 30 minutes a day. After 2 months from the start of treatment, joint pain decreased. After 6 months of treatment - no pain, according to MRI, insignificant intraosseous edema remains. After 8 months from the moment of treatment, the patient moves within the apartment without support. 12 months after treatment, the patient walks without support at full load. After 14 months from the time of treatment, clinically and radiologically - a full recovery by the proposed method.

Example No. 3.

Patient I., 37 years old, in 2009 complained of pain in the projection of both hip joints, aggravated by exertion, a sharp restriction of movements in both hip joints. From the anamnesis: pain appeared 3.5 months before treatment. Since February 2008 - Hodgkin’s lymphoma, nodular sclerosis with damage to the cervical and mediastinal lymph nodes. In 2008 - chemoradiotherapy, persistent remission - since December 2008.

11.11.09 - during x-ray of the osteolytic hip joints, destruction of the head of the right femur. Osteolytic type destruction of the head of the left femur.

11/12/09 - according to spiral computed tomography, the diagnosis of aseptic necrosis of the femoral head of stage III was established. A biochemical study revealed an increase in bone resorption. The patient cannot move independently. Treatment has been started: oral administration of alendronic acid (Fosamax®) at a rate of 70 mg once a week for 6 months and diacerein (Arthrodarin®) 50 mg each. in the afternoon and 1 pc. in the evening for 6 months, calcitonin (“Miacalcic®”) is nasally 200 IU / day, 2 weeks after 2 weeks, for 6 months. Along with this, the patient received intramuscular injections of a combined preparation containing neurotropic B vitamins (Milgamma®) 2 ml per day, 10 times with a break of 1 day and daily intramuscular administration of a chondroprotector with an active component from a bioactive concentrate from small sea fish, containing: amino acids, mucopolysaccharides, peptides, potassium, sodium, calcium, magnesium, copper, iron, zinc ions (Alflutop®) - 2 ml per day, for 20 days with a break of 24 hours. At the end of these injections, the patient received a course of therapeutic treatment, which included 10 treatment sessions, each of which consisted of 2 consecutive stages of the procedures.

At the first stage, within one day, the patient consistently received: abdominal decompression, pneumocompression massage, manual massage, vacuum massage and hirudotherapy. After occupational therapy, the patient took a break of at least 3 days. At the second stage, within one day, the patient consistently received: magnetotherapy, barolaser therapy and phonophoresis using the karipain gel. After this, the patient took a break of 24 hours.

Together with the course of therapeutic treatment, the patient was prescribed a peptidergic regulation course, which was carried out in two stages. At the first stage, daily, for 10 days, the patient received intramuscular injections. Each injection consisted of 2 ml of a solution for intramuscular administration of a peptide complex containing amino acids: alanine, glutamic and aspartic acid with a concentration of at least 100 μg in 1 ml (Kartalax® preparation), which was diluted with 10 mg of powder containing thymus polypeptides ( Timalin® preparation). At the second stage, with a break of 24 hours, after the completion of these injections, the patient took an oral peptide complex containing amino acids: lysine, glutamic and aspartic acid (Vezugen® preparation) and a peptide complex containing amino acids: alanine, glutamic and aspartic acids (Kartalax® preparation) - 0.2 g capsules per 1 pc. in the morning and 1 pc. in the evening, 10-15 minutes before eating each peptide complex, respectively.

After taking alendronic acid (Phosamax® preparation) and calcitonin (Miacalcic® preparation), the patient took a break of 2 months. At the end of the 2nd month, the patient is upright and moves with the help of 2 crutches.

Further, the patient took orally the osseino-hydroxyapatite compound (Osteogenon® preparation) daily in the form of tablets of 830 mg in 4 pcs. 2 times a day for 6 months. While taking this drug, the patient also took orally diacerein (Arthrodarin®) in 50 mg capsules of 1 pc. day and 1 pc. in the evening for 6 months. After 3 months of taking the osseino-hydroxyapatite compound (Osteogenon® preparation) and diacerein (Arthrodarin® preparation), the patient received a previously defined course of therapeutic treatment together with a course of peptidergic regulation.

After 12 months from the moment of treatment, the patient moves with the help of two half-wings. At the same time, to prevent muscle atrophy, the patient was prescribed special therapeutic exercises to strengthen the muscles of the legs, which he performed for 30 minutes a day.

In 2011 and in 2012, the patient regularly performed therapeutic physical exercises, which were supplemented by exercises on mechanotherapeutic apparatuses and exercises in the pool. Along with this, the patient took orally the osseino-hydroxyapatiti compound (Osteogenon®) daily in the form of tablets of 830 mg in 2 pcs. 2 times a day for 4 months, against the background of which, the patient also took orally diacerein (the drug "Artrodarin®") in 50 mg capsules of 1 pc. day and 1 pc. in the evening for 4 months. In addition, the patient received a previously defined course of therapeutic treatment together with a course of peptidergic regulation 2 times a year.

At the end of 2012, the patient moves with a cane, within the apartment - without support. 06/12/2013 - according to spiral computed tomography - destruction cavities were completely organized. As a result, the heads took an egg-shaped shape, the articular surfaces of the roofs of the acetabulums tend to restore congruence. The femoral heads are centered correctly. No new outbreaks have been identified. There is no data for synovitis. Significant positive dynamics and improvement in the quality of life of the patient are observed.

These results confirm the promise of using the developed method for the treatment of aseptic necrosis of the femoral head.

The developed new method of treatment, in which all conditions for its implementation are observed, is more effective than the prototype, since it also has a systemic effect on the body, which allows you to: prevent resorption and loss of bone tissue, further disease progression and avoid surgery, including joint replacement; normalize calcium homeostasis and mineralization of newly formed bone tissue; increase the mechanical strength of bones by improving the mineralization and regulation of calcium-phosphorus metabolism; restore the shape, volume and normal consistency of intraarticular cartilage, improve microcirculation and activate trophic processes in the tissues of the joint; normalize lipid metabolism; improve blood circulation, eliminate its stagnation in the affected organs, as well as normalize the functioning of the vascular, immune and bone systems.

When implementing the proposed method, a pronounced analgesic and anti-inflammatory effect is achieved without surgery, with subsequent improvement in functional abilities and an increase in the range of motion in the hip joints, as well as a significant improvement in well-being, which leads to an increase in the quality of life of patients.

INFORMATION SOURCES

1. Bogolyubov V.M., Ponomarsiko G.N. General physiotherapy (manual). T.2. - M.: Medicine, 1985 .-- S. 152-154.

2. Kamenev O.Yu., Baranovsky A.Yu. Medical leeches. Theory and practice. A guide for doctors. - SPb .: Publishing house Ves, 2006. - 356 p.

3. Lazutina G.S., Ovchinnikova N.V., Zherebyatyeva S.R. Laser and regenerative processes in tissues of different genesis. // Modern high technology. - 2005. - No. 9 - p. 57-58.

4. Luton. Apparatus for low-intensity laser therapy. - St. Petersburg: NLP VOLO, 2009 / http://lasermed.volo.ru/docs/laton-katl.pdf.

5. Orlova M.A. The use of barolaserotherapy for gynoid lipodystrophy: the dissertation ... cand. medical Sciences: special. 14.00.51 / Orlova Maria Aleksandrovna, Saint-Petersburg Medical Academy of Postgraduate Education. - SPb., 2009 .-- 97 p.

6. Patent No. 2063719, Russia, IPC АВВ 17/00. A method for the surgical treatment of aseptic necrosis of the femoral head. / Buachidze O.S., Onoprienko G.A., Kael Α.Λ., Voloshin V.P .; declared 07/13/1993; publ. 07/20/1996.

7. Patent No. 2131709, Russia, IPC АВВ 17/00. A method for the treatment of aseptic necrosis of the femoral head. / Ruzanov V.I., Zhadenov I.I., Slaves V.K .; declared 06/23/1995; publ. 06/20/1999.

8. Patent No. 2179833, Russia, IPC АВВ 17/56. A method for the treatment of aseptic necrosis of the femoral head. / Kornilov N.V., Rasulov P.M .; declared 08/17/1999; publ. 02/27/2002.

9. Patent No. 2286735, Russia, IPC АВВ 17/56. A method for the treatment of aseptic necrosis of the femoral head and Perthes disease. / Dudarev V.Α., Kirgizov I.V., Gorbunov N.S., Sinyuk V.P., Kulikov N.N .; declared 05/23/2005; publ. 11/10/2006.

10. Patent No. 2392942, Russia, IPC A61Β 31/663. A method for the treatment of aseptic necrosis of the femoral head. / Mironov S.P., Rodionova S.S., Shumsky A.A .; declared 10/20/2008; publ. 06/27/2010.

11. Ponomarenko G.N. General physiotherapy: a textbook. - SPb .: VMedA, 1998 .-- S. 149-150.

12. Ponomarenko G.N. General physiotherapy: a textbook. - SPb .: VMedA, 1998 .-- S. 265-267.

13. Ponomarenko G.N. Private physiotherapy: study. benefits - M .: Medicine, 2005 .-- S. 119, 120, 225.

14. Ponomarenko G.N. Private physiotherapy: study. benefits - M .: Medicine, 2005 .-- S. 297, 576.

15. Skonichev V.G., Zhichkina L.V. Physiology of local negative pressure. // Abdominal decompression in medicine. Theory and practice. - St. Petersburg, 2004 .-- S. 29-49.

16. Ushakov A.A. Practical Physiotherapy, 2nd ed. M .: MIA, 1996 - p. 63-65.

17. Ushmarov A.K., Rakita D.R., Rondaleva N.A. General physiotherapy: study. allowance / Under the general. ed. V.Ya. Garmash; - Ryazan: Ryazan State Medical University. Academician I.P. Pavlova, 2002 .-- S. 66-72.

Claims (3)

1. The method of non-surgical treatment of aseptic necrosis of the femoral head, carried out on the background of orthopedic discharge, including therapeutic physical exercises, therapeutic diet, physiotherapy and oral administration of an osseino-hydroxyapatite compound, characterized in that against the background of a therapeutic diet that contributes to weight loss and provides sufficient intake with food of calcium and vitamins: C, D, E, K, and oral administration of the drug “Fosamax®” in the form of tablets of 70 mg once a week for 6 months, the drug “Artro arin® "in the form of capsules of 50 mg in the morning and evening for 4-6 months and nasal injection of the drug" Miacalcic "200 IU / day in cycles of 2 weeks after 2 weeks for 4-6 months, the introduction of the drug" Milgamma ® "in the form of a solution for intramuscular injection of 2 ml per day at least 10 times with a break of 1 day and daily intramuscular injection of the drug" Alflutop® "2 ml per day for at least 20 days with a break of 24 hours and produce a course of treatment, comprising 8-10 treatment sessions, each of which consists of two next their successive stages of carrying out the procedures, the first of these stages includes the sequential performance of abdominal decompression with exposure below the waist on the entire lower body, pneumocompression massage with impact on the legs, manual and vacuum massages with impact on the area: hip joints - lateral surface of the thighs, gluteal region and paravertebral zones L2-L5, cervical - paravertebral zone C7-T1 and sacrum, with a preferred interval between these procedures no more 10-15 minutes, after which the first stage of the treatment session is completed with hirudotherapy using no more than 8 medical leeches per session, which are placed on the cervical paravertebral zone C7-T1 and the lumbar, paravertebral zone L2-L5, sacrum, coccyx, on the stomach in the area liver, lower abdomen, painful hip areas and / or areas that changed color after massage, then with a break of at least 3 days, each treatment session is completed by sequential procedures of the second stage: magnetotherapy and barolaser therapy with effects on the region STI: hips - lateral thighs, gluteal region and paravertebral zone L2-L5; phonophoresis using karipain gel and affecting the gluteal, knee and hip areas, after which, with a break of 24 hours, the therapy session is repeated no more than 10 times depending on the patient’s condition, then therapeutic physical exercises in the pool are performed for at least 10 days, together with this is administered intramuscularly with the peptide preparation “Kartalax®” of 1-2 ml with a concentration of at least 100 μg per 1 ml, diluted with 10 mg of the drug “Timalin®”, daily 1 time per day for 10 days, after completion of these injections daily o for 30 days, the peptide preparation “Vezugen®” is administered orally in the form of capsules of 0.2 g and the drug “Kartalax®” in the form of capsules of 0.2 g in the morning and evening 10-15 minutes before meals, then after continuous and a single course of administration of the drug “Fosamax®” and nasal injection of the drug “Miacalcic®” with a break of 1-2 months, the drug “Osteogenon®” is administered orally daily in the form of tablets of 830 mg, 2-4 tablets 2 times a day for 4- 6 months, the drug "Artrodarin®" in the form of 50 mg capsules in the morning and evening for 4-6 months while oral administration of the last pair of drugs is repeated with a break of at least three months. 2. The method according to p. 1, characterized in that the therapy sessions, including magnetotherapy, barolaser therapy, phonophoresis using karipain gel, abdominal decompression, pneumocompression massage, manual and vacuum massages, hirudotherapy are carried out in the absence of contraindications and preferably together with the introduction of peptide complexes at least twice a year and with a break of at least three months. 3. The method according to p. 1, characterized in that the treatment is preferably carried out at a stage not exceeding the third stage of the disease.