RU2840197C1 - Use of agent for treating arthrological diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to orthopaedics, and can be used in treating arthrological diseases. Application according to the invention refers to course administration of a drug, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulphate every second day.

EFFECT: use of the invention allows to reduce the time to achieve a therapeutic effect, equal or greater clinical effectiveness, as well as higher safety of treatment compared to the standard course of 25–30 injections due to a shorter therapeutic course.

5 cl, 14 tbl, 3 ex

Description

The invention relates to the field of medicine, in particular to the use of chondroitin sulfate medicinal products for the treatment of arthrological diseases.

LEVEL OF TECHNOLOGY

Degenerative joint disease, or osteoarthritis (OA), is the most common form of joint disease, with the knee joint most commonly affected. More than four million new patients seek medical attention each year because of knee pain. An estimated 10% of the population over 55 years of age have signs of loss of knee function, with about 25% of these having serious problems that affect the patient’s quality of life. According to the WHO Global Disease Burden Report, knee OA is one of the leading causes of disability: the fourth leading cause among women and the eighth leading cause among men. Osteoarthritis can affect anyone, regardless of gender, age, race, or skin color. The main manifestation of OA is the disruption of the articular cartilage structure, subchondral bone remodeling, and osteophyte formation (joint ossification). The course of the disease is chronic and progressive, with exacerbations most often occurring under the influence of mechanical factors, and destructive changes progressively increasing. OA occurs not only in old age, but also in the working population, often leading to decreased mobility, up to disability, the socio-economic cost of which is very high. The appearance of OA is closely related to age: up to 50 years, the disease is more common in men, after 50 years - in women, which is the result of a lack of estrogens during menopause. At the same time, the frequency of the disease in women and men becomes the same at about 80 years of age.

An equally dangerous disease is osteochondrosis of the spine. The spine is the basis of the human musculoskeletal system. The spinal column is subject to significant static-dynamic loads, which lead to the fact that degenerative-dystrophic processes develop relatively early in the joints of the spine.

Principles of treatment

Treatment of these diseases is complex and includes a number of preventive and therapeutic measures:

1. Therapy aimed at relieving pain in the form of parenteral or oral administration of analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates;

2. Local therapy - topical steroids, NSAIDs and capsaicin in gels and creams;

3. Intra-articular injections of corticosteroids and hyaluronic acid;

4. Non-drug methods - physiotherapy, aerobics, stretching exercises, transcutaneous electrical nerve stimulation, orthopedic insoles;

5. Surgical methods - joint prosthetics, arthroscopic debridement of affected joints.

Frequent side effects and low efficacy limit the use of many non-surgical therapies.

In recent years, chondroitin, glucosamine, avocado and soybean unsaponifiables, and diacerein have been proposed as new treatments for osteoarthritis.

According to the latest guidelines of the American College of Rheumatology and the European League Against Rheumatism, drugs for the treatment of osteoarthritis are classified as symptom-modifying and structure-modifying, depending on their ability to influence the progression of the disease. Accumulated evidence allows chondroitin (sodium chondroitin sulfate (CS)) to be classified as a symptom-modifying agent, since it primarily relieves pain and improves joint function. One of the main advantages of chondroitin sulfate is its safety profile.

Chondroitin sodium sulfate belongs to the family of heteropolysaccharides called glucosaminoglycans. Chondroitin is found in human cartilage, bone tissue, cornea, skin, and arterial vessel walls. One of the main mechanisms of action of Chondroitin is considered to be the restoration of the extracellular matrix of cartilage tissue, prevention of cartilage degradation, and replenishment of the deficiency of sulfur-containing amino acids, which are essential building blocks for the assembly of molecules of the cartilage extracellular matrix. Many patients with osteoarthritis in Russia and around the world already use chondroitin.

Medicines

Groups

The pharmaceutical market offers the following groups of drugs with the active ingredient sodium chondroitin sulfate:

1. Topical agents are mainly used as part of complex therapy due to low bioavailability associated with the fact that the active substance in ointments or gels needs to overcome the tissue barrier to provide a therapeutic effect. According to Russian and European clinical guidelines, topical forms are most often used together with parenteral agents.

2. Oral medications also have low bioavailability. According to various literary sources, it ranges from 8% to 13%. These medications are mainly represented by biologically active food supplements. They also often use a low-quality substance. These medications are recommended for use as a preventive measure.

3. Parenteral agents with Chondroitin Sodium Sulfate are the most effective. This is due to its high bioavailability. After an intramuscular injection, Chondroitin Sodium Sulfate is detected in the synovial fluid after 15 minutes, then it enters the joint, where it reaches its maximum after 48 hours.

4. Products containing sodium chondroitin sulfate in general and products for parenteral administration in particular are characterized by a long course of therapy.

Commercially available drugs

The drug "Artogistan solution for intramuscular injection" is known. It is used intramuscularly, 100 mg every other day. If well tolerated, the dose is increased to 200 mg, starting with the fourth injection. The course of treatment is 25-35 injections. If necessary, a repeat course of treatment can be carried out after 6 months.

The drug "Drastop solution for intramuscular injection" is known. It is used intramuscularly at 1 ml (100 mg of sodium chondroitin sulfate) every other day. If well tolerated, the dose is increased to 2 ml (200 mg of sodium chondroitin sulfate), starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, a repeat course of treatment can be carried out after 6 months.

The drug " Chondrogard solution for intramuscular and intraarticular administration" is known. It is used intramuscularly, 100 mg every other day. If well tolerated, the dose is increased to 200 mg, starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, a repeat course of treatment can be carried out after 6 months. In case of osteoarthritis of large joints, a combination of intraarticular and intramuscular methods of administration is possible. Up to 5 intraarticular injections of 200 mg are carried out with a 3-day break between injections and 16 intramuscular injections of 200 mg with an interval of 1 day between injections (every other day). Depending on the size of the joint, up to 2 ml of the drug Chondrogard can be injected into the joint cavity.

The drug " Injectran solution for intramuscular and intra-articular administration" is known. It is used intramuscularly, 1 ml every other day. If well tolerated, the dose is increased to 2 ml, starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, a repeat course of treatment can be carried out after 6 months. In osteoarthrosis of large joints, a combination of intra-articular and intramuscular methods of administration is possible. Up to 5 intra-articular injections of 2 ml are carried out with a 3-day break between injections and 16 intramuscular injections of 2 mg with an interval of 1 day between injections (every other day). Depending on the size of the joint, up to 2 ml of Injectran can be injected into the joint cavity.

The drug " Mukosat solution for intramuscular and intra-articular administration" is known. The drug is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, repeated courses can be carried out after 6 months. In osteoarthritis of large joints, a combination of intra-articular and intramuscular routes of administration is possible. Up to 5 intra-articular injections of 200 mg are administered with a 3-day break between injections and 16 intramuscular injections of 200 mg with a 1-day interval between injections (every other day).

Intra-articular administration of the drug is carried out under aseptic conditions by a specialist trained in the technique of intra-articular administration. Depending on the size of the joint, up to 2 ml of the drug Mucosat can be injected into the joint cavity.

After intra-articular administration of the drug, the puncture site is lubricated with an alcohol wipe and a bactericidal plaster is applied.

The drug " Chondroitin-Apex solution for intramuscular injection" is known. Intramuscularly, 1 ml every other day. If well tolerated, the dose is increased to 2 ml, starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, a repeated course of treatment can be carried out after 6 months. The duration of repeated courses of treatment is determined by the doctor.

The drug " Chondroitin-B solution for intramuscular injection" is known. Intramuscularly, 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-35 injections. If necessary, a repeated course of treatment can be carried out after 6 months. The duration of repeated courses of treatment is determined by the doctor.

The drug " Chondroitin-Binergia solution for intramuscular and intra-articular administration" is known. The drug is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-35 injections. If necessary, a repeat course of treatment can be carried out after 6 months. In osteoarthritis of large joints, a combination of intra-articular and intramuscular administration is possible. Up to 5 joint injections of 2 ml are administered with a 3-day break between injections and 16 intramuscular injections of 2 ml with a 1-day interval between injections (every other day).

Intra-articular administration of the drug is carried out under aseptic conditions by a specialist trained in the technique of intra-articular administration. Depending on the size of the joint, up to 2 ml of the drug can be injected into the joint cavity.

After intra-articular administration of the drug, the puncture site is lubricated with an alcohol wipe and a bactericidal plaster is applied.

The drug "Chondroitin sulfate solution for intramuscular injection" is known. The drug is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, repeated courses can be carried out after 6 months.

The drug "Chondrofast solution for intramuscular injection" is known. The drug is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, repeated courses can be carried out after 6 months.

The drug "Khonsat solution for intramuscular injection" is known. The drug is administered intramuscularly at 1 ml (100 mg) every other day. If well tolerated, the dose is increased to 2 ml (200 mg), starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, repeated courses can be carried out after 6 months.

The drug "Chondromed-Lekpharm solution for intramuscular injection" is known. The drug is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-35 injections. If necessary, a repeat course of treatment can be carried out after 6 months.

The drug "ARTRAVIR-TRIVIUM solution for intramuscular injection" is known. It is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-30 injections. If necessary, repeated courses can be carried out after 6 months.

All of the listed drugs have similar side effects: allergic reactions (skin itching, erythema, urticaria, dermatitis, edema), hemorrhages at the injection site, in addition, prolonged administration of the drug is accompanied by pain. A long course of treatment (at least 25 injections) with the above drugs inevitably leads to an increase in the number of these side effects. In addition, long courses are inconvenient for patients, since it is necessary to visit treatment rooms for at least 25 days, not all medical professionals are trained to do these injections. This leads to the fact that patients do not undergo full courses of treatment, reducing the effectiveness of the treatment or not achieving any improvement at all. The need for the first three test injections also reduces the effectiveness of the treatment. Such injections lead to an increase in the duration of treatment and reduce its effectiveness.

Thus, the problem of effective treatment of arthrological diseases has not been solved to date.

DISCLOSURE OF THE ESSENCE OF THE INVENTION

The present invention solves the above problems of the known solutions.

The objective of the present invention is to develop a strategy for the effective treatment of arthrological diseases, comparable in effectiveness or superior to that of known solutions, ensuring greater safety and adherence to treatment compared to known strategies.

The stated task is solved by using a medicinal product with the active substance sodium chondroitin sulfate for the treatment of arthrological diseases selected from the group of osteoarthrosis of peripheral joints, intervertebral osteochondrosis and osteoarthrosis, including a course of administration of the medicinal product, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

The hyaluronan-connective tissue polysaccharide compound is found in blood serum at concentrations < 100 μg/l (on average 30-40 μg/l in middle-aged individuals). In synovial fluid, a high concentration of hyaluronic acid (HA) provides the necessary lubrication for the moving parts of the joint and serves as a shock absorber, reducing friction between moving bones and joint wear. In joint diseases, HA is destroyed, which reduces the viscosity of the synovial fluid and leads to a weakening of the shock absorber and lubrication function. This limits joint mobility, and any movement is accompanied by pain.

The clinical activity of osteoarthritis (OA) depends on pathological changes in the parameters of the synovial fluid. It has been noted that in OA, the enzymatic activity of hyaluronidase (an enzyme that breaks down HA) increases by 3.7 times, and, accordingly, the concentration of hyaluronic acid decreases by 3.7 times, while the content of glucuronic acid increases by 2.3 times. Against the background of a decrease in hyaluronic acid in the synovial fluid and in the joint itself, the concentration of HA in the blood of such patients increases, presumably as a result of its leaching from the joints [Laurent T.S. et al. Serum hyaluronan as a disease marker. Ann Med 1996 Jun; 28 (3): 241-53]. When creating an artificial deficiency of hyaluronidase and exoglycosidase in mice, accumulation of hyaluronic acid and chondroitin sulfate was noted. Experiments have shown that under the influence of chondromodulating therapy there is a reliable increase in the concentration of hyaluronic acid already three months after the start of therapy, on average by 2.6 times [Ryabkov A.B. Abstract of a dissertation in medicine “Biochemical parameters of synovial fluid in clinical and laboratory evaluation of the effectiveness of chondromodulating therapy for osteoarthrosis”, St. Petersburg, 2005, 28 p.].

The generally accepted therapeutic dose of chondroitin sulfate is 800 mg.

It is also well known that OA is characterized by persistent inflammation in joint tissues with the development of chondritis, osteitis and synovitis. Inflammation not only causes pain, rigidity and limited mobility of the affected joint, but also contributes to a chronic progressive course. Therefore, the advisability of anti-inflammatory therapy is beyond doubt. NSAIDs are the main link in symptom-modifying therapy for OA and an integral part of complex treatment. Most standard NSAIDs are considered to be drugs that enhance cartilage degeneration by inhibiting the metabolic activity of chondroblasts and suppressing the synthesis of proteoglycans by chondrocytes, as well as other macromolecules that ensure the normal functioning of hyaline cartilage. Studies on experimental models have shown that NSAIDs can have a negative effect on the metabolism of hyaline cartilage; the nature and strength of such action is determined by the mechanism of the drug, depending on the stage of development of OA and the duration of treatment. It is known that indomethacin has a negative effect on articular cartilage both in the initial and advanced stages of the disease, and diclofenac and naproxen - mainly in the advanced stage [Badokin V.V. Non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis. Modern rheumatology. Pharmacotherapy. No. 1, Vol. 9, Pp. 73-77].

The negative effect of NSAIDs on articular cartilage has given grounds to recommend only short-term use of NSAIDs in OA and only in cases of exacerbation of the disease or severe joint pain and the ineffectiveness of simple analgesics, which causes significant difficulties given the duration and painfulness of the course.

The authors of the present invention have developed a treatment strategy that involves the use of sodium chondroitin sulfate medications as part of a shorter treatment course than the standard one, which allows for the minimization or elimination of the use of NSAIDs for therapy while maintaining or enhancing the therapeutic effect.

This application ensures a reduction in the time to achieve a therapeutic effect, equal or greater treatment effectiveness, as well as greater safety compared to a standard course of 25-30 injections and eliminates the need for the first test injections, which lead to an increase in the course of treatment, an increase in the pain effect and a decrease in the effectiveness of the course.

The present invention relates to the use of a medicinal product with the active substance sodium chondroitin sulfate for the treatment of arthrological diseases selected from the group of peripheral joint osteoarthrosis, intervertebral osteochondrosis and osteoarthrosis, including a course of administration of the medicinal product, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

The present invention also relates to a method for treating arthrological diseases selected from the group of osteoarthrosis of peripheral joints, intervertebral osteochondrosis and osteoarthrosis, comprising a course of administration of a medicinal product with the active substance sodium chondroitin sulfate, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

According to a particular embodiment of the invention, the course may include no more than 20, 19, 18, 17, 16 or 15 intramuscular injections.

According to a particular embodiment of the invention, the course may include 15-20, 16-20, 17-20, 15-16, 15-17, 15-19, 16-18, 16-19 intramuscular injections.

IMPLEMENTATION OF THE INVENTION

Examples of preparation of injection forms with sodium chondroitin sulfate, which are not exhaustive

Example #1

Preparation of solution "A". In 40 l of injection water heated to 50°C, dissolve 10 kg of sodium chondroitin sulfate (in terms of absolutely dry substance). After complete dissolution of sodium chondroitin sulfate, cool the solution to room temperature, bring the volume of the solution to 40 l with injection water and subject it to sterilizing filtration.

Preparation of solution "B". Add 25 liters of injection water to 1000 g of benzyl alcohol and stir until the benzyl alcohol is completely dissolved. Then, while stirring, add 1111.11 mg of iron gluconate dihydrate (containing 8 mg of elemental iron per 1 kg of sodium chondroitin sulfate. The substance is manufactured by Pfizer Inc., Germany).

Preparation of solution “B”. 0.05 g of sodium hydroxide is dissolved in 24 l of water for injection.

Preparation of solution "G". 50 l of solution "B" are sterilely filtered into sterile solution "A" with constant stirring, and then 15-20 minutes after adding solution "B", continuing to stir the solution, 25 l of solution "B" are sterilely filtered. Stirring after adding solution "B" is continued for 15-20 minutes.

Obtaining the preparation. The missing amount (up to 100 l) of injection water is added to a sterile container with solution "G" through a sterilizing filter.

Pouring the drug solution. The solution is poured into 2 ml ampoules. The ampoules are sealed.

Example #2

90.7 l of water for injection at a temperature of 24°C are loaded into a pre-prepared reactor. The water is bubbled with sterile nitrogen at an excess pressure of 0.2±0.1 bar (0.02±0.01 MPa) for at least 10 minutes (then the process is carried out with constant bubbling of the solution with nitrogen).

With the stirrer running (200-300 rpm), 181.41 g of sodium disulfite are loaded into the reactor and stirred for at least 10 minutes until completely dissolved. Then 9.07 kg (in terms of the main substance) of sodium chondroitin sulfate are loaded into the reactor in portions and stirred for at least 60 minutes until completely dissolved.

Next, 45.35 g of methyl parahydroxybenzoate are loaded into the reactor, stirred for at least 20 minutes, and a sample is taken. The pH of the resulting solution is measured, if necessary, its value is brought to 6.8 using 1 M sodium hydroxide solution, the solution is stirred for at least 10 minutes, then 1763.32 mg of iron gluconate dihydrate (in terms of containing 14 mg of elemental iron per 1 kg of sodium chondroitin sulfate. The substance is manufactured by Pfizer Inc., Germany) are added while stirring, then the solution is brought to the calculated volume (20 l) with water for injection and stirred for at least 15 minutes.

After analysis and adjustment (if necessary), the solution is subjected to sterilizing filtration and poured into 2 ml ampoules.

Example #3

Preparation of solution "A". 10.42 kg of sodium chondroitin sulfate (based on the content of the main substance) are dissolved in 52.08 l of injection water heated to 50°C. After the chondroitin sulfate is completely dissolved, the solution is cooled to a temperature no higher than 35°C.

Preparation of solution "B". Add 36.46 l of injection water to 937.5 g of benzyl alcohol and stir until the benzyl alcohol is completely dissolved, add 104.17 g of sodium disulfite and 578.7 mg of iron gluconate dihydrate (in terms of containing 4 mg of elemental iron per 1 kg of sodium chondroitin sulfate. The substance is manufactured by Novartis AG, Switzerland).

Preparation of solution "G". 35 l of solution "B", 0.1 M NaOH solution to pH 6-6.5 and injection water to a volume of 100 l are added to solution "A" with constant stirring. The content of the main substances and the pH of the solution are analyzed; if necessary, the solution is adjusted. Solution "G" is subjected to sterilizing filtration into a sterile container. The solution is poured into 2 ml ampoules and sealed.

CLINICAL STUDIES

The observation involved 74 people diagnosed with osteoarthritis stages 1-3, from 18 to 65 years old, including 49 women and 15 men. The patients were divided into 3 groups: two groups of 27 people each, the control group consisted of 10 patients. All patients had a stable clinical picture of the disease with pain syndrome of at least 40 mm on a 100 mm visual analogue pain scale (VAS).

The first group received Mucosat according to the standard scheme: the first three injections at a subtherapeutic dose of 100 mg intramuscularly every other day, starting with the fourth injection of 200 mg every other day, a total of 30 injections. Nonsteroidal anti-inflammatory drugs (NSAIDs) were prescribed on demand to relieve pain.

The second group received Mucosat according to the regimen of 200 mg intramuscularly every other day, a total of 30 injections, NSAIDs were prescribed on demand to relieve pain.

The third group received standard NSAID therapy for pain relief on demand.

The assessment of pain parameters was carried out at 4 visits.

Visit 1 corresponded to the first visit to the clinic and reflected the indicators before the start of therapy,

Visit 2 corresponded to a period of 14 (±5 days) after the start of treatment,

Visit 3 - 30 (±5 days),

Visit 4 - 60 (±5 days).

At all visits, adverse events were assessed and their relationship with drug administration was established; if an adverse reaction was detected, the patient was observed until it resolved.

The distribution characteristics of the VAS score across visits are presented in Table 1.

Table 1. Characteristics of the distribution of the VAS indicator by visits

Visit N, person Pain scale according to VAS indicator (group boundaries) NSAID withdrawal No pain (0-4) Weak (5-44) Moderate (45-74) Strong (75-100) 1 1 group 27 0 (0%) 0 (0%) 20 (74%) 7 (25%) 0 (0%) 2 group 27 0 (0%) 0 (0%) 19 (70%) 8 (30%) 0 (0%) Control 10 0 (0%) 0 (0%) 7 (70%) 3 (30%) 0 (0%) 2 1 group 27 0 (0%) 12 (45%) 12 (45%) 3 (10%) 12 (45%) 2 group 27 0 (0%) 15 (55%) 12 (45%) 0 (0%) 15 (55%) Control 10 0 (0%) 4 (40%) 4(40%) 2 (20%) 0 (0%) 3 1 group 27 0 (0%) 17 (85%) 3 (15%) 0 (0%) 17 (85%) 2 group 27 3 (10%) 24 (90%) 0 (0%) 0 (0%) 24 (90%) Control 10 0 (0%) 4 (40%) 4(40%) 2 (20%) 4 (40%) 4 1 group 27 4 (15%) 21 (78%) 2 (7%) 0 (0%) 25(93%) 2 group 27 7(26%) 20 (74%) 0 (0%) 0 (0%) 27(100%) Control 10 1 (10%) 5(50%) 3(30%) 1 (10%) 6(60%)

Table 2. Characteristics of adverse events (AE) and relationship with drug intake

1 visit 2 visit 3 visit 4th visit Total number of adverse events 0 2 1 1 Connection established 1 group 0 1 0 0 Connection established 2 group 0 0 0 0 Connection established 3 group 0 1 1 1

At all visits, adverse events were recorded and the relationship between the reaction and the drug intake was assessed.

In total, 5 adverse events were registered during the observation process, in all cases the connection with the intake of drugs was established as definite, i.e. all events were caused by the intake of the drug and were assessed as adverse reactions. In the first group, at the second visit, one of the observed subjects developed a rash similar to urticaria, which was stopped without discontinuing the study drug by prescribing systemic and local desensitizing agents.

In the third group, which took NSAIDs, the greatest number of adverse reactions was noted: at visit 1, one patient noted nausea, which was relieved by changing the non-steroidal agent and prescribing a proton pump inhibitor; at visit 3, one of the patients in group 3 noted an increase in blood pressure over the past week to 135/85 mm Hg (previously, the pressure did not rise above 125/80 mm Hg), which was relieved by prescribing an antihypertensive drug; at visit 4, one of the observed noted increasing insomnia over the past 2 weeks, accompanied by periodic headaches and dizziness. Since the observation period was over by this point, the drug was discontinued, which was followed by normalization and stabilization of the condition.

At the end of the treatment, it was found that the overall VAS pain score was the lowest in the second group, 26% of patients reported no pain, 74% of patients - mild pain. In 7% of patients in the first group, who received the first three injections of chondroitin sulfate in a reduced dosage, moderate pain remained by the end of the treatment and in 78% - mild pain, in the control group by the end of the treatment 10% continued to experience severe pain, and 80% - mild or moderate.

The use of chondroitin sulfate at a dose of 200 mg from the first injection allowed 55% of patients to stop taking NSAIDs after 2 weeks, 90% after a month of therapy, and by the end of treatment all patients stopped taking NSAIDs, in the control group this figure was only 60%, and in the first group - 93%.

All patients had weekly venous blood samples collected.

The blood was centrifuged for 5 minutes and the serum was collected. Hyaluronidase activity in the serum was determined by the Morgan-Elson fluorimetric method modified by T. Takahashi et al. under conditions of 3-hour hydrolysis at 37°C for the final product N-acetylglucosamine. The activity of the accompanying exohydrolases was inhibited by 0.02 M mucus acid added to the mixture. Fluorescence was measured at an excitation wave of 545 nm and an emission wave of 602 nm (Fluorate-2M, LUMEX, St. Petersburg, Russia). The amount of enzyme required under the given reaction conditions to form 1 micromole of terminal glucosamine in 1 min was taken as a unit of hyaluronidase activity [DZGOEVS.G., TOTROV I.N. HYALURONIDASE ACTIVITY OF BLOOD SERUM FROM PATIENTS WITH RHEUMATOID ARTHRITIS. No. 56-12, 2019, P. 53-55; Takahashi T. et al. A fluorimetric Morgan–Elson assay method for hyaluronidase activity. No. 322, T. 15, 2003, PP. 257-263].

The results of the study of hyaluronidase activity by groups (mU/ml) are presented in Table 3.

Table 3. Results of the study of hyaluronidase activity by groups (mU/ml)

Before starting therapy 1 8 15 23 30 1 group 3.43 3.45 3.51 3.58 3.54 3.49 2 group 3.45 3.44 3.35 3.27 3.0 2.72 Group 3 3.45 3.45 3.45 3.46 3.45 3.46

In patients of the second group, a gradual decrease in the activity of serum hyaluronidase was observed; in the first group, against the background of the first three injections at a dose of 100 mg, an increase in the activity of serum hyaluronidase was noted, and then, after increasing the dose of chondroitin sulfate to 200 mg, a gradual decrease in activity, which, however, did not reach the indicators of the 2nd group.

These 3 groups remained without dynamics throughout the entire course of therapy.

Thus, chondroitin sulfate in a subtherapeutic dose of 100 mg promotes a temporary increase in the activity of serum hyaluronidase, which negatively affects the results of chondroitin sulfate therapy, since hyaluronidase is an agent that destroys the administered substance. Dynamic monitoring of pain assessment using the VAS scale showed that the best results in reducing the pain index were achieved with the administration of chondroitin sulfate at a dosage of 200 mg from the first day of therapy - all patients either did not have pain syndrome or noted its mild severity at the end of treatment. In the control group receiving NSAID monotherapy, 40% of patients at the end of treatment indicated severe or moderate pain and only 10% of patients noted its absence. In the first group, which received the first three injections of chondroitin sulfate in a reduced dosage of 100 mg, the absence of pain syndrome at the end of therapy was noted by only 15% of patients versus 26% in the second, moderate pain was experienced by 7%, in the second subgroup there were no patients with moderate pain at the end of the course. It should also be noted that by the last visit, all 100% of those observed in the second group refused to take painkillers (NSAIDs).

The best indicators of the ratio of the effectiveness and safety of therapy were demonstrated by the second group, which received chondroitin sulfate at a dose of 200 mg from the first day of therapy: here, the greatest decrease in the pain index, the lowest activity of serum hyaluronidase and the highest safety profile were noted. In the first group, which received the first 3 injections of chondroitin sulfate at a subtherapeutic dose, the effectiveness of therapy was significantly lower, and the indicators of serum hyaluronidase, an antagonist of chondroitin sulfate, were increased.

Course duration

The observation included 72 women and 51 men aged 50 to 75 years (mean 63.0±7.4 years) with a diagnosis of knee OA of radiographic stage II and III, not requiring surgical treatment. Patients were divided into 6 groups of 19-22 people each.

All patients were examined at visit 1 (inclusion in the study, start of observation and therapy).

The following examination was carried out:

Visit 2 after 15 days±3 days;

Visit 3 after 30 days±3 days;

Visit 4 after 35 days±3 days;

Visit 5 after 40 days±3 days;

Visit 6 after 50 days±3 days;

Visit 7 3 months after the end of therapy, the date of the visit was calculated individually depending on the duration of the course;

Visit 8, 6 months after the end of therapy (telephone notification);

Visit 9 with open date.

All patients received NSAID therapy in standard therapeutic doses and injectable chondroitin sulfate (CS) according to the following regimen:

Group 1 - 1 ml intramuscularly every other day for the first 3 days, then 2 ml intramuscularly every other day, a total of 25 injections;

Group 2 - 2 ml intramuscularly every other day, 25 injections;

Group 3 - 2 ml intramuscularly every other day, 20 injections;

Group 4 - 2 ml intramuscularly every other day, 18 injections;

Group 5 - 2 ml intramuscularly every other day, 15 injections;

Group 6 - NSAIDs.

Visit 1 (beginning of therapy)

Table 4. Visit 1

Indicator, points, M ± d 1 group (1ml) 2 group
(2 ml) Group 3
(2 ml) 4 group
(2 ml) Group 5
(2 ml) Group 6 Pain according to YOU 63.6±10.8 63.5±10.5 62.8±10.1 63.7±10.6 63.2±10.2 59.2±10.1 Lequesne index 9.3±2.2 9.4±2.2 9.3±2.1 9.3±2.2 9.4±2.3 9.1±2.1 WOMAC general 37.2±9.6 38.2±9.4 37.9±9.5 38.2±9.3 37.8±9.6 35.2±9.2

Visit 2

By visit 2, patients in the first group received 3 injections of 1.0 ml and 5 injections of 2.0 ml; in groups 2–5, all patients received 8 injections of 2.0 ml; group 6 did not receive chondroitin sulfate.

Table 5. Visit 2

Indicator, points, M ± d 1 group 2 group Group 3 4 group Group 5 Group 6 Pain according to YOU 59.4±11.8 53.4±9.5 53.6±10.1 53.8±10.8 53.2±10.2 57.9±10.3 Lequesne index 8.6±2.3 7.9±2.2 7.8±2.1 7.8±2.2 7.8±2.3 8.8±2.1 WOMAC general 34.2±9.6 30.2±8.6 30.3±9.5 30.3±9.3 30.2±9.6 35.2±9.2

The reduction in pain and mobility indices by the second visit (after 2 weeks of therapy) was most pronounced in groups No. 2, 3, 4, 5. Positive dynamics were also noted in groups No. 1 and 6, but its severity was significantly less.

Visit 3

By visit 3, group #5 had completed therapy (15 injections).

Table 6. Visit 3

Indicator, points, M ± d 1 group 2 group Group 3 4 group Group 5 (completed therapy) Group 6 Pain according to YOU 50.4±12.6 47.5±10.7 46.8±10.1 46.6±10.3 46.2±10.2 52.1±10.1 Lequesne index 6.6±2.0 5.9±2.3 5.8±2.1 5.8±2.3 5.8±2.2 7.1±2.1 WOMAC general 25.1±13.2 23.2±10.4 22.9±9.3 22.7±9.4 22.9±9.7 29.2±10.1

The reduction in pain and mobility indices continued by the third visit (after 30 days of therapy) and was most pronounced in groups No. 2, 3, 4, 5. Positive dynamics were also noted in groups No. 1 and 6, but its severity was significantly less. Group No. 5 completed the full course of therapy by visit 3 - 15 injections, then the patients were under observation and received only NSAIDs in case of occurrence or intensification of pain syndrome.

Visit 4

By visit 4, group #4 had completed therapy (18 injections).

Table 7. Visit 4

Indicator, points, M ± d 1 group 2 group Group 3 Group 4 (completed therapy) Group 5 (completed therapy) Group 6 Pain according to YOU 47.4±10.9 46.2±11.3 46.1±10.3 46.3±9.8 46.1±10.3 49.1±10.3 Lequesne index 6.1±2.2 5.9±2.1 5.8±2.3 5.8±2.7 5.7±2.1 7.1±2.1 WOMAC general 24.8±10.1 22.8±11.1 22.5±10.2 22.4±10.5 22.7±10.1 26.1±9.5

Visible dynamics of pain and mobility index reduction were observed from visit 3 to visit 4 in groups 2, 3, 4. Group No. 4 completed the full course of therapy by visit 4 - 18 injections, then patients were under observation and received only NSAIDs in case of occurrence or increase of pain syndrome. None of the patients in group No. 5 who completed HS therapy noted an increase in pain syndrome, and NSAIDs were not required.

Visit 5

By visit 5, group #3 had completed therapy (20 injections).

Table 8. Visit 5

Indicator, points, M ± d 1 group 2 group Group 3 (completed therapy) Group 4 (completed therapy) Group 5 (completed therapy) Group 6 Pain according to YOU 46.7±10.4 44.1±10.1 43.4±11.2 45.1±9.6 46.4±11.2 48.8±11.2 Lequesne index 5.9±2.1 5.2±2.2 5.2±2.1 5.7±2.2 5.7±2.1 7.2±2.3 WOMAC general 23.8±12.2 19.5±10.4 19.1±10.3 20.5±10.2 22.9±9.4 29.0±10.4

The most pronounced dynamics of pain and mobility index reduction were observed from visit 4 to visit 5 in groups No. 2 and 3. Group No. 3 completed the full course of therapy by visit 4 - 20 injections, then the patients were under observation and received only NSAIDs in case of occurrence or increase of pain syndrome. In group No. 5, who completed the HS therapy, against the background of the overall positive dynamics of the group, one patient noted an increase in pain syndrome, due to which it was necessary to prescribe NSAIDs.

Visit 6

By visit 6, groups No. 6, No. 1 and No. 2 had completed therapy.

Table 9. Visit 6

Indicator, points, M ± d Group 1 (completed therapy) Group 2 (completed therapy) Group 3 (completed therapy) Group 4 (completed therapy) Group 5 (completed therapy) Group 6
(completed therapy) Pain according to YOU 44.4±10.6 43.1±13.2 43.2±10.1 44.9±10.8 46.9±10.7 47.4±9.4 Lequesne index 5.4±2.3 4.8±2.2 4.9±2.1 5.6±2.1 5.7±2.3 7.0±2.5 WOMAC general 21.2±10.6 18.5±9.8 18.8±13.4 19.6±13.3 22.4±10.5 27.6±9.7

The dynamics of the decrease in pain and mobility indices was noted from visit 4 to visit 5 in groups No. 1, 2, 3. Group No. 4 showed no changes in the indices. In group No. 5, which completed the HS therapy, against the background of the overall positive dynamics of the group, one patient noted the presence of pain syndrome, which required the prescription of NSAIDs. In group No. 3, according to the results of observation, persistent remission with further positive dynamics of pain and mobility indices was noted. Positive dynamics were also noted in groups No. 1 and No. 2, but the indices of group No. 1 significantly lagged behind group No. 2. Group No. 6 demonstrated the worst dynamics at all visits. In group No. 1, one patient developed a rash of the urticaria type with severe itching. Despite desensitizing therapy, itching could not be completely relieved, and chondroitin sulfate therapy was discontinued early. In group #2, extensive hemorrhages at the injection site were detected in two patients at visit #6, and local therapy was prescribed. No additional measures were taken in connection with the end of HS therapy.

Visit 7

3 months after the end of therapy.

Table 10. Visit 7

Indicator, points, M ± d 1 group 2 group Group 3 4 group Group 5 Group 6 Pain according to YOU 42.8 ± 10.3 41.6±10.1 41.7±11.2 44.9±10.8 48.6±10.2 54.0±13.2 Lequesne index 4.8 ± 2.8 4.4±2.2 4.3±2.4 5.6±2.1 6.2±2.1 8.7±2.2 WOMAC general 19.4 ± 13.2 18.3±10.4 18.4±9.2 19.6±13.3 24.3±13.2 29.6±10.2

All patients were examined 3 months after the end of therapy. The worst results were obtained in group #6, in patients taking NSAIDs. After the drug was discontinued, all indices practically returned to the values recorded before the study: almost all patients noted increased pain and decreased mobility against the background of therapy discontinuation. Deterioration of indices was also noted by those observed in group #5. Despite the fact that during HS therapy all patients noted decreased pain and improved mobility, 3 months after the end of therapy 4 patients required NSAIDs, all indices demonstrated some negative dynamics. In patients of group #4, positive dynamics were noted in all indices during therapy, 3 months after the end of therapy, negative dynamics were not revealed, all observed patients had stable remission.

In groups No. 1 and 2, which received the maximum number of injections, the best results were noted in patients who received CS at a dose of 2.0 ml from the first injection. The decrease in indices in group No. 1, in patients who received CS at a subtherapeutic dose of 1.0 ml during the first week of therapy, was less pronounced by the end of therapy and 3 months later.

The best results were observed in group No. 3. All patients showed positive dynamics, none of the patients needed additional NSAIDs by the end of therapy, 3 months after the end of HS therapy, a further decrease in indices and no need for NSAIDs were noted.

In groups No. 2, 3, 4, 5, higher efficiency was noted due to the initiation of therapy with a dose of 2.0 ml of CS versus standard therapy of 1.0 ml in the first three injections and then 2.0 ml up to 25 injections of CS in group No. 1. Groups No. 2 and 3, where patients received 2.0 ml of CS - 20 and 25 injections, respectively, showed comparable dynamics 3 months after the end of therapy, however, in group No. 1, one adverse reaction in the form of urticaria was recorded, and in group No. 2, two cases of hemorrhage at the injection site. Given the identified negative impact of long-term therapy on the safety profile and the lack of impact on the positive dynamics of the indices, it can be considered that additional 5 injections are inappropriate.

Following treatment, patients were surveyed to determine whether they were willing to undergo the next course.

According to experts, long-term adherence to any treatment, regardless of the disease, is low and does not exceed 50%, especially in the treatment of chronic diseases, since they require long-term, often lifelong, medication and compliance with a number of medical recommendations. Lack of adherence to prescribed therapy can cause insufficient therapeutic effect, be accompanied by exacerbation or progression of the disease, lead to hospitalization and / or disability of the patient [Hughes, C.M. Medication non-adherence in the elderly: how big is the problem? / C.M. Hughes // Drugs Aging. - 2004. - Vol. 21, N 12. - P. 793-811]. In osteoarthritis, low adherence to drug therapy is recorded, however, to achieve the maximum effect, patients must follow drug recommendations, it is especially important to avoid missing or changing the regimen of intramuscular administration of symptom-modifying therapy drugs, including chondroitin sulfate. The determining factors in this case are not only proven efficacy and good tolerability of drugs (DR), but also high patient adherence to therapy. Currently, poor adherence is another proven risk factor for any disease, which reduces the effectiveness and increases the cost of treatment, increases the risk of various complications, worsens the prognosis of the disease and life [Chowdhury R., Khan H., Heydon E. et al. Adherence to cardiovascular therapy: a metaanalysis of prevalence and clinical consequences. Eur Heart J 2013; 34: 2940-8. Ho PM, Bryson CL, Rumsfeld JS. Medication adherence. Its importance in cardiovascular outcomes. Curculation 2009; 119: 3028-35].

To assess the patients’ willingness to follow the doctor’s recommendations in all treatment groups, the treatment adherence was assessed using the KOP-25 questionnaire, which was developed in 2008 to assess treatment adherence in patients with arterial hypertension but was subsequently modernized for universal use. In this study, the version for patients with chronic diseases was used [https://clinpharm-journal.ru/articles/2018-1/rossijskij-universalnyj-oprosnik-kolichestvennoj-otsenki-priverzhennosti-k-lecheniyu-kop-25/]. Each technical indicator is a simple sum of points obtained by answering the corresponding questions. The minimum possible value of each technical indicator is 5 points, the maximum is 30 points.

A compliance rate of ≤50% was considered low, from 51 to 75% as average, and >75% as high [Nikolaev N.A. Guide to Clinical Research in Internal Medicine (scientific monograph). Moscow, 2015, 74 p.].

Table 11

Levels of commitment Level Meaning Interpretation High 76% and more Medical recommendations and actions based on them will be followed by patients, or will be followed more often Average 51-75% Medical recommendations and actions based on them are more likely to be followed by patients than not. Short 50% and less Medical recommendations and actions based on them will not be followed by patients, or rather will not be followed

Visit 1

By the time of inclusion in therapy, all groups showed comparable figures for treatment adherence: the average level prevailed, i.e. the greatest number of patients were ready to follow medical recommendations and actions based on them.

Table 12

Commitment Index,
% of number of patients 1 group 2 group Group 3 4 group Group 5 Group 6 Short 7 6 7 5 6 7 Average 59 58 60 59 60 59 High 34 36 33 36 34 34

Visit 7

All subjects were interviewed 3 months after the end of therapy; the date of the visit was calculated individually, depending on the end date of the course of therapy.

The lowest level of adherence was demonstrated by observed groups No. 6, which is probably due to the fact that after almost all patients noted low efficiency of therapy due to increased pain and decreased mobility after discontinuation of NSAIDs. 57% of patients noted that they do not consider it necessary to follow medical recommendations and related actions.

Group No. 5 also showed a decrease in therapy adherence. Despite the fact that during HS therapy all patients noted a decrease in pain and an improvement in mobility, 3 months after the end of therapy 4 patients required the prescription of NSAIDs, all indices demonstrated some negative dynamics, which affected the dynamics of the expectations of the observed: the number of patients with low adherence to treatment more than doubled, the number of patients with a high degree of readiness to follow doctors' recommendations decreased by 1.5 times.

In group No. 4, no significant dynamics of the indicators were noted; a slight decrease in the number of patients with high and medium adherence and an increase in the number of patients with low readiness to follow recommendations were recorded.

In groups No. 1 and No. 2, an increase in the number of patients with low compliance to treatment was also noted, which was probably caused by the development of adverse reactions in the form of urticaria and hemorrhages.

The best results were obtained in group No. 3, which is probably due to the recorded positive dynamics in all patients who received therapy and the absence of the need for additional intake of NSAIDs; 97% of respondents demonstrated a willingness to follow the doctors’ recommendations.

Table 13

Commitment Index,
% of number of patients 1 group 2 group Group 3 4 group Group 5 Group 6 Short 8 8 3 5 14 57 Average 60 57 46 62 62 39 High 32 35 51 34 24 4

After visit 7, all patients in groups 1, 2, 3, 4, and 5 received standard recommendations on the need for regular courses of chondroitin sulfate therapy at intervals of once every six months to maintain remission. After six months, all patients previously observed in the study were notified by telephone to plan their follow-up care. The message contained information on the need to see a doctor to continue therapy.

All patients in group No. 6 were prescribed chondroitin sulfate therapy at 2.0 ml every other day for a total of 20 injections on visit 7 due to pronounced unsatisfactory dynamics and for ethical reasons; NSAID intake was maintained in the “on demand” mode.

Based on the results of the telephone notification, attendance at consultations with a doctor was distributed among groups as follows.

Table 14

Attendance rate for appointments,
% of the number of patients 1 group 2 group Group 3 4 group Group 5 Didn't show up for the appointment 9 8 5 10 14 Attendance at the reception is recorded 73 75 79 73 70 No data (subscriber did not answer the call) 18 17 16 17 16

The best attendance and adherence to therapy was demonstrated by group #3, where only 5% of no-shows were registered, the worst results were demonstrated by group #5 with 14% of patients who did not show up to continue therapy. The reasons for refusing to continue therapy in the groups were: duration and inconvenience of use, presence of adverse reactions, ineffectiveness of therapy.

Based on the above, the best and optimal ratio of efficacy, safety, and compliance (adherence) of therapy was shown by the scheme of group No. 3: 2 ml intramuscularly every other day, 20 injections. An increase in the number of injections did not lead to a linear expected increase in the effect, while contributing to the development of adverse reactions against the background of a plateau of effectiveness, a small number of injections contributed to a decrease in pain syndrome and an increase in joint mobility, but did not allow achieving a stable and long-term remission. The use of small doses of chondroitin sulfate at the start of therapy not only did not show the expected positive effect on the profile of efficacy and safety, but demonstrated a negative effect associated with the effect of small doses of CS on the activation of serum hyaluronidase (an agent that destroys chondroitin), which was recorded in the form of stagnation of the dynamics of pain and mobility indices and in the form of adverse reactions to the administration of CS. NSAIDs as a drug of choice for long-term treatment of pain syndrome in OA did not show any effect on the establishment of long-term remission and its maintenance.

Claims (5)

1. The use of a medicinal product with the active substance sodium chondroitin sulfate for the treatment of arthrological diseases selected from the group: osteoarthrosis of peripheral joints, intervertebral osteochondrosis and osteoarthrosis, consisting of a course of administration of the medicinal product, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day. 2. Use according to paragraph 1, where the course contains no more than 18 intramuscular injections. 3. Use according to paragraph 1, where the course contains no more than 16 intramuscular injections. 4. Use according to paragraph 1, where the course contains no more than 15 intramuscular injections. 5. Use according to paragraphs 1-4, where the course contains 15-20 intramuscular injections.