NOLTREX™ — A DRUG FOR THE TREATMENT OF OSTEOARTHRITIS OF JOINTS

ABOUT THE DRUG

NOLTREX™ is an artificial endoprosthesis based on a three-dimensional polyacrylamide mesh polymer with the addition of silver ions. The drug serves to replace the synovial fluid of the joints (the fluid that fills the joint cavity and acts as an intra-articular lubricant). Used to treat osteoarthritis.

MOLECULAR WEIGHT NOLTREX™ > 10,000,000 DALTON

Compound:

3-dimensional polyacrylamide, % 4.0 ± 1.5

Purified water, % 96.0 ± 1.5

Silver ions, % 0.0001 - 0.0025

Each disposable syringe of NOLTREX™ contains 2.5 ml of gel for injection into the joint cavity.

Unlike other intra-articular injections commonly used in the treatment of osteoarthritis, NOLTREX™ does not contain hyaluronic acid, as well as other components that are broken down by enzymes present in the human body, which ensures its long-term presence at the injection site.

NOLTREX™ is a biocompatible material that has neither immunogenic nor antigenic properties, and does not cause an allergic reaction due to its synthetic nature.

NOLTREX™ is not a pharmacological drug from the group of antibiotics or antimicrobial agents, therefore it cannot be used as the main therapeutic agent for bacterial arthritis.

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RESULTS AND DISCUSSION

Before the study, 303 patients were screened, of whom 236 met the criteria and were included in the study. All 236 patients received a single intra-articular injection of Noltrex™. 186 patients reached the end of the study, 18 people stopped participating before the end point (14 withdrew voluntarily, 4 took NSAIDs for at least two weeks). At the final stage, 32 patients stopped participating: three of them due to the development of pathological conditions not related to the treatment, 12 returned to their original state, the rest stopped the study at will, without explanation. The average age of the patients was 65.3±11.56 years; the ratio of men to women was 1:2. The ratio of patients with stages II, III and IV of gonarthrosis in the groups was 5.8:6.2:1 in men and 4.9:4.1:1 in women. Demographic characteristics and distribution of patients by stage of the process and number of affected knee joints are presented schematically (Fig. 1).

In the one-sample Kolmogorov-Smirnov test, the distribution of values ​​does not obey the score, but the distribution of the total index does not obey the normal distribution, therefore, the score characteristics were assessed using nonparametric criteria, and the index values ​​using parametric ones. In the diagram presented in Fig. Figure 2 shows the dynamics of the value of the average “total Lequesne index” and its standard error for conditional groups according to the stages of gonarthrosis.

Patients with stage II arthrosis tend to have a more rapid decrease in the index and, accordingly, an improvement in clinical indicators. In patients with stages III and IV, a gradual decrease in the index was revealed. When conducting a multivariate ANOVA analysis with Bonferroni correction in the overall group, statistically significant differences were found between all groups at different times. In pairwise comparisons in the Post Hoc test, among male patients there were no significant differences between groups with stages III and IV on day 0 and in the first week (which does not have a significant effect on the results of the study), and among women there were differences in all cases . The data obtained indicate a significant difference in the values ​​of the Lequesne index within the group at different times and between groups at the same time periods of the study.

Pearson correlation analysis revealed the presence of a medium to strong positive statistically significant correlation between the age of patients and the stage of arthrosis, as well as between age and the value of the Lequesne index at different periods of the study. These data correspond to the fact that at older ages there are more patients with more severe forms of gonarthrosis and, naturally, with more pronounced clinical manifestations. This relationship between phenomena only reflects the regularity of the process in gonarthrosis. A strong and very strong positive relationship was revealed between the stage of arthrosis and the values ​​of the Lequesne index, calculated at different periods of the study for the general group, as well as for men and women separately. This is confirmed by the fact that the Lequesne index, regardless of the period of determination, significantly increased in the group with more severe manifestations of arthrosis (see table). When comparing the number of affected joints and the index value, the relationship is significant, but weak. Consequently, the number of affected joints has an unexpressed effect on the result of the treatment, although there is a tendency towards this.

Descriptive statistics in the form of frequency characteristics of some features of the Lequesne questionnaire score are shown graphically in histograms. In the group of female patients, night pain initially prevails, which nevertheless goes away faster than in men; the sign of “morning stiffness in the joints” at time zero is also more pronounced in women (Fig. 3). This also applies to changes in the maximum walking distance without pain, especially since women are less likely to use crutches or a cane. Already by the first week after the injection, a significant part of the group with stage II of the disease was freed from pain, while in the group with stage III, improvement in most cases occurred more often by the sixth week, and with stage IV, the pain subsided, but did not disappear. In the group of patients with stage II, the maximum distance by the end of the first week after the injection increased by an average of 500 m, and after six weeks it was 1 km, and the achieved distance without pain after 24 weeks remained the same and became so in most cases. For groups with stages III and IV, the starting distance was smaller (100–300 m), and the increase in distance was more extended over time - by the sixth week the peak distance was 300–500 m. However, in the group with stage III, by the 24th week it improved and in some cases reached 1 km, and in patients with stage IV there was only a tendency to achieve a distance of 500–900 m. For the group with stage II, the position “walking with a cane” was irrelevant, since most patients in this group walked without devices (Figure 3 D). Already one week after the injection, patients with stage III began to refuse to use a cane (usually women), and by the 24th week the majority were moving without it. In the group with stage IV with a more pronounced and long-standing pathology, where 9 patients walked with a cane or a crutch, and 8 with two crutches, by the sixth week 7 patients abandoned one crutch, and by the 24th week everyone was walking with either a cane , or with one crutch.

Pairwise and group comparisons of the values ​​of all characteristics from the questionnaire were carried out using the Mann-Whitney test and the Kruskal-Wallis median test. During all periods of observation, when comparing values ​​between pairs of groups with stages II and III and with stages II and IV, significant differences were identified. When comparing patients with stages III and IV, on day 0 there were no differences in the signs of “night pain” and “pain when walking”, in the first week - in four signs, in the sixth week - in five, at the end of the study - in half of the signs no differences were noted between the groups. When conducting a univariate Friedman analysis with a χ2 test, the influence of the timing of the study on the scores in all groups was revealed, with the exception of the signs of “pain when standing up” in the first week and “going down the stairs” in the 24th.

Spearman's correlation analysis showed:

• the absence of a significant connection between the manifestation of 36 of 48 signs and the gender of the patients, the remaining connections were weak and heterogeneous;
• the presence of a weak connection between the number of joints and the manifestation of 27 out of 48 signs and its absence in other cases, more often at the end of the first week;
• the presence of a significant medium, strong and very strong positive relationship between the manifestation of 45 of 48 signs and the age of the patients, as well as between the manifestation of all signs and the stage of gonarthrosis.

At the same time, in the analysis of the relationship between stage and clinical manifestations, the most pronounced signs were “maximum walking distance without pain” (0–1–6 weeks), “walking on stairs” (0–6–24 weeks), as well as “pain when standing up” , “pain when standing”, “walking with a cane” (sixth week).

As a result of a multicenter clinical study, in most cases we obtained a stable clinical effect after a single intra-articular injection of Noltrex™, and none of the 186 patients developed complications or adverse reactions, or hypersensitivity to the polymer.

There was a direct relationship between the stages of the process and the rate of relief (or weakening) of the pain syndrome and improvement in the functional state of the knee joint, which, naturally, appeared faster in the group with stage II and was slightly delayed in the groups with stage III and IV. This effect to some extent also affected patients with bilateral gonarthrosis compared to unilateral ones, as well as representatives of the older age group. There was no significant difference when comparing the results of the male and female groups. Obvious clinical improvement in the group with stage II occurred already by the end of the first week after injection, while in the groups with stages III and IV, the full effect of viscosupplementation occurred between the first and sixth weeks.

In the course of the study, we came to the conclusion that the endoprosthesis, in addition to its main effect as a VST, also has an indirect effect: due to the long duration of the protective action, such a long-term unloading of the joint and the muscles compensating for its function is achieved that the isometric and dynamic capabilities of the lower legs are restored. limbs.

In conclusion, we present data from a partial follow-up survey of 20 patients from the study group who were not included in the study. Patients were interviewed 3 years after Noltrex™ injection. In 4 people, the effect lasted no more than 6 months, and 1 patient noted only a slight temporary improvement; several patients showed noticeable or significant improvement over 1–1.5–2 years (2–6–6 patients, respectively). In two people, the effect of a single injection of Noltrex™ lasted about 3 years, and only recently, with almost completely restored function, pain began to return.

Analysis of the data obtained as a result of the clinical study showed the pronounced and prolonged effectiveness of the polyacrylamide synovial fluid prosthesis Noltrex™ in patients with gonarthrosis of stages II–IV, which makes the use of this product a new competitive method of viscosupplementation therapy for idiopathic forms of degenerative joint disease.

NATURAL OR SYNTHETIC?

There is a misconception that the use of drugs based on hyaluronic acid is preferable to completely artificial drugs. Many people appeal to the fact that preparations based on hyaluronic acid are similar in composition to human synovial fluid. However, the trouble is that the similarity is not absolute and this is what qualitatively reduces their effectiveness. Made from raw materials of animal origin, these drugs are easily detected by the body's immune cells (phagocytes), destroyed and excreted from the body. At the same time, the use of raw materials of animal origin often provokes the development of allergic reactions and inflammatory processes inside the joint. In addition, the high rate of resorption results in a very short recommended interval between repeated injections.

Administration of NOLTREX™ is required no more than once every six months to one and a half years1. This is due to the fact that the macromolecules of the network polymer are practically invisible to phages and are excreted from the body extremely slowly, allowing the therapeutic effect to prolong as much as possible. The synthetic origin of the drug completely eliminates allergic reactions.

Thus, the answer to the question of choosing a drug for the treatment of arthrosis becomes obvious. At the moment, among the means to combat arthrosis, NOLTREX™ is the absolute leader in effectiveness and safety.

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MATERIALS AND METHODS

A multicenter uncontrolled (open) clinical trial was conducted at MONIKI named after. M.F. Vladimirsky, Moscow Regional Hospital for War Veterans and municipal hospitals of the Moscow Region (MU Dzerzhinskaya GB, MU Ivanteevskaya Central District Hospital, MU Domodedovo Central District Hospital). The study was planned and carried out in accordance with the national standard GOST R 52379-2005 “Good Clinical Practice”. The study involved patients of both sexes aged from 43 to 89 years with unilateral or bilateral gonarthrosis. Criteria for inclusion in the study:

1. clinically verified idiopathic gonarthrosis;
2. radiologically verified gonarthrosis II–IV according to Kellgren;
3. the duration of the disease is at least 1 year.

Exclusion criteria:

• secondary gonarthrosis;
• chronic active fibromyalgia;
• skin damage around the joint;
• intercurrent diseases in the stage of decompensation;
• injection of HA into the joint under study no more than 6 months before the study;
• administration of corticosteroids and/or arthroscopic treatment no more than 3 months before the study;
• a course of NSAIDs less than 1 month before the study and during the entire 24-week period;
• administration of Noltrex™ less than 2 years before the study.

The drug was administered at a time into the cavity of the knee joint in an amount of 5 ml into the upper inversion, from the outside, in the supine position;
Before administering the drug, exudate was evacuated from the joint. For bilateral lesions, the drug was injected simultaneously into both joints. Clinical and functional assessment of the condition was carried out before administration and at the 1st, 6th and 24th week after injection of the drug. Data collection was performed by completing the Lequesne questionnaire. In case of bilateral damage (in case of its asymmetry), the assessment of the condition was carried out with an emphasis on the joint with initially more pronounced pathological symptoms. The results were processed using the SPSS 13.0 package. The analysis was carried out using parametric and non-parametric methods: the values ​​of individual characteristics (scores for each question in the Lequesne questionnaire) and the total Lequesne index were assessed; At the same time, patients were divided into conditional groups according to gender and stage of joint damage.