RU2199320C1 - Method for treating rheumatoid arthritis - Google Patents

Abstract

FIELD: medicine, rheumatology. SUBSTANCE: one should intravenously inject metotrexate at the dosage of 10 mg weekly along with prospidine 200-300 mg weekly, moreover, the latter should be introduced by drops. The method provides earlier and pronounced therapeutic effect at decreased number of complications in case of immunosuppressive therapy. EFFECT: higher efficiency of therapy. 2 ex, 6 tbl

Description

 The invention relates to medicine, namely to rheumatology, and can be used as a method of treating rheumatoid arthritis (RA).

 There are treatments for RA. One of them is the use of prospidine [1]. Prospidine is an antitumor drug with significant therapeutic breadth, good tolerance, and the absence of an inhibitory effect on the hematopoiesis system. The drug acts mainly on cellular receptors and membranes and has not only immunocorrective, but also anti-inflammatory effect [2]. Open controlled trials have proven its effectiveness in RA and developed a supportive therapy technique [4]. Compared with other basic drugs, the clinical efficacy of prospidine is expressed at the earlier stages of treatment (1-3 months), the anti-inflammatory effect of the drug appears already at the end of 1 - beginning of 2 weeks of therapy [4].

 The main disadvantage of prospidin therapy: the drug loses its effectiveness with prolonged use in connection with the development of resistance.

 The prototype is methotrexate (MT) therapy. MT belongs to the group of antimetabolites, has anti-inflammatory and immunomodulatory effects and is considered the "gold standard" of RA therapy as the most effective and least toxic drug [5]. The effectiveness of MT at a dose of 7.5-25 mg per week with RA compared with placebo and other antirheumatic drugs has been confirmed in many controlled studies [3]. MT is central to combination therapy for RA [3, 5].

 However, despite the well-known advantages, treatment with MT has its drawbacks: complete remission develops rather rarely, exacerbation usually occurs during withdrawal of the drug, therapy often has to increase the dose of the drug, since the absorption of MT decreases over time, some patients are resistant to MT therapy , especially in low doses, the effect of the drug begins to appear in 2-3 months [3, 5].

 The essence of the proposed method of treatment is that to increase the effectiveness of RA treatment, the combined use of MT and prospidine is used. Based on modern ideas about the mechanisms of action of anti-rheumatoid basic drugs, their combined purpose seems to be quite reasonable [5]. This creates the possibility of simultaneous exposure to different pathogenetic links of the disease, which allows to increase clinical efficacy, and the use of lower doses of each of the drugs reduces the risk of drug resistance [3].

 The method of combination therapy of MT and prospidine in RA: at the stationary stage, MT is prescribed at a dose of 10 mg / week i / m, prospidine - 300 mg / week iv / drop per 200 ml of 5% glucose 3-4, in the future, patients receive MT orally at a dose of 7.5-10 mg per week, prosidin 100-200 mg per week i / m as maintenance therapy. A dose of MT of 10 mg per week was selected as the least effective and least toxic [3, 5]. Prospidine is prescribed at a dose of 300 mg per week, which is 50-60% of the dose used in monotherapy [4].

 To assess the effectiveness and tolerability of the proposed method of treatment, the authors conducted a series of studies.

 Combination therapy with MT and prospidin was prescribed to 29 patients with reliable active RA, most of them had systemic manifestations and steroid dependence (Table 3). The severity of clinical efficacy was evaluated according to the criteria [6] of the American College of Rheumatology (ACR): improvement of more than 20%, 50%, 70% of the count of painful and swollen joints and improvement of at least 3 of 5 indicators: total activity according to the patient and the doctor visual analogue scale (VAS), pain according to the patient’s assessment (VAS), ESR, CRP (C - reactive protein) and functional status assessment according to HAQ (Stanford scale of life quality assessment). When evaluating the effectiveness of therapy, the effect of therapy on the daily need for steroids in case of steroid dependence was also taken into account. The generally accepted criteria of the American Rheumatological Association (ARA) were used to assess disease remission.

 Testing results. Combination therapy with MT and prospidine led to clinical improvement in most patients (93.1%) already at the stationary stage, and in 17 patients (58.6%) the clinical effect was more than 50% according to ACR criteria (Table 4) and was combined with a decrease in the need for glucocorticoids and intraarticular punctures (tab. 5, 6). The effect of therapy began to manifest itself very quickly - at 1-2 weeks and reached a maximum by 4 weeks of treatment. By the 6th month of treatment, clinical improvement continued in all patients, including 4 patients (25%) who had a remission of the disease according to the ARA criteria, in 12 patients (75%) the clinical effect was estimated at 50% or more according to the ACR criteria (table . 4). In the whole group, there was a significant (p <0.05) decrease in the daily requirement for steroids (Table 5). Noteworthy was the good tolerability of combination therapy with MT and prospidine. Side effects (Table 6) were identified in 7 patients (24.1%), which required cancellation of treatment in 2 of them (6.8%). Cancellation due to the lack of effect of combination therapy was not.

Clinical examples
Example 1: Patient P. 48 years old, medical history 1344. He was admitted to the hospital on February 12, 2001 with a diagnosis of Rheumatoid arthritis, polyarthritis with systemic manifestations (weight loss, rheumatoid nodules, Sjogren's syndrome, episcleritis), seropositive, rapidly progressing course, II degree activity , II stage, FTS II. Steroid addiction.

 Upon receipt of a complaint of pain in the small joints of the hands, feet, wrist, shoulder and elbow joints, morning stiffness before lunch, nodules in the elbow joints, feeling of “sand” in the eyes, dry mouth, general weakness, weight loss over the past year 6 kg He suffers from RA for 1.5 years, over the past 6 months he has been taking methotrexate at a dose of 10 mg per week and prednisone 10 mg / day without noticeable improvement: pain, swelling and stiffness in the joints persist, systemic manifestations of the disease appeared. Attempts to increase the dose of methotrexate led to an increase in the level of liver enzymes and bilirubin. The patient was prescribed combination therapy with methotrexate at a dose of 10 mg iv weekly and prosidin 300 mg weekly iv drip on 5% glucose 4. The patient showed positive dynamics of clinical parameters during treatment (Table 1). The pain and stiffness in the joints, the phenomena of episcleritis and Sjogren's syndrome disappeared, the dose of prednisolone was reduced by 50%. Clinical efficacy of therapy ≥70 according to ACR criteria.

 The presented clinical example shows that in a patient with therapy-resistant methotrexate RA, a distinct positive effect was observed when conducting combination therapy already at the stationary stage. Side effects were not identified. In addition, the patient in the course of treatment managed to reduce the daily dose of prednisolone by 2 times.

 Example 2: Patient G., 44 years old, medical history 5998. Was admitted to the hospital on December 20, 2000 with a diagnosis of Rheumatoid arthritis, polyarthritis with systemic manifestations (anemia), seropositive, slowly progressing course, activity of the II degree, III stage, FTS II . Steroid addiction.

 Received complaints of pain and swelling in the small joints of the hands and feet, wrist, ankle, morning stiffness for about 5 hours, general weakness.

 The illness experience is 20 years. Over the past 3 years, he has been taking methotrexate 7.5-10 mg per week with insufficient effect, and therefore, prednisolone 10 mg / day was added to therapy a year ago.

 In the hospital, the patient was prescribed combination therapy with methotrexate 10 mg per week and prosidin 300 mg per week iv 4. By the end of the inpatient phase of treatment, pain in the joints decreased significantly, the number of painful and swollen joints decreased by more than 50%, morning stiffness disappeared (table 2). The dose of prednisone was halved.

Upon discharge from the hospital, the patient was prescribed methotrexate 10 mg per week orally and prosidin 200 mg per week intramuscularly. When observing by the 6th month of treatment, there was no pain and stiffness in the joints, ESR = 10 mm / hour, CRP 2 mg / ml, RF was not detected. NSAIDs and prednisone do not take. The effectiveness of the therapy was evaluated more than 70% according to ACR criteria. The patient’s condition during the last 3 months is regarded as remission according to the ARA criteria
This clinical example shows that in a patient with long-term RA experience resistant to MT therapy with steroid dependence, a good response was obtained to the combined therapy of MT and prospidine at the stationary stage, which was maintained during maintenance therapy. Side effects are not registered. In addition, the patient managed to cancel the NSAIDs and prednisone already at 2 months of therapy.

 In general, the results of testing and the given clinical examples demonstrate high efficiency, satisfactory tolerance and low toxicity of combination therapy with MT and prospidine. Clinical efficacy can be traced by the rapid onset of anti-inflammatory effect (1-2 weeks), by good overall treatment results by the 6th month of therapy (in 25% of patients - remission, in 75% of patients - improvement of more than 50% by ACR), by a noticeable decrease in daily requirement in corticosteroids in case of steroid dependence.

 The authors conducted a comparative analysis of the combination therapy of MT and prospidine and MT monotherapy in equal treatment periods in comparable groups of patients (Table 3). Compared to MT monotherapy, the clinical efficacy of combination therapy was expressed at the earlier stages of observation (1 month), had a more noticeable anti-inflammatory effect during maintenance therapy (Table 4) and reduced the daily requirement for glucocorticoids in case of steroid dependence (Table 5) ) MT monotherapy revealed instability of the clinical effect in relation to the joint syndrome, which required an increase in the daily dose of prednisolone (Table 5).

 Compared to MT monotherapy, combination therapy with MT and prospidin did not lead to an increase in the frequency of side effects and discontinuation of treatment due to drug toxicity, and treatment was not canceled due to the lack of effect (Table 6).

 Thus, in comparison with existing methods of treatment, the proposed method has an earlier and pronounced clinical effect. Significant clinical effect appeared already at the end of the 1st - the beginning of the 2nd week of therapy, was expressed at the end of the inpatient phase of treatment, and was maintained during maintenance therapy. The proposed method can significantly reduce the daily need for steroids in case of steroid dependence and achieve remission in a larger number of patients (Tables 4, 5). In this case, there is no increase in the frequency and severity of side effects and related cancellations (Table 6).

 During the information and patent search, the authors in the available literature did not find similar developments.

 Scope: rheumatology departments of the regional, city and district level.

Literature
1. Benenson E.V., Nemtsov B.F. "Anti-rheumatoid drug Prospidinum". A.S. USSR 1235502, 1986.

 2. Mashkovsky M.D. Medicines - 12th ed. - 1993.T.II. - C.502-504.

 3. E.L. Nasonov, S.K. Soloviev. The use of methotrexate in rheumatology, Moscow, 2000, 128 p.

 4. B.F. Nemtsov, E.V. Benenson, O.V. Timina. "Comparative efficacy of pulse therapy with prosidin and methotrexate in rheumatoid arthritis (12-month controlled study)." // Clinical medicine, 8, 1998, p. 25-28.

 5. Ya.A. Sigidin, G.V. Lukina. "Basic (pathogenetic) therapy of rheumatoid arthritis", Moscow, 2000, p.100 - prototype.

 6. Felson D.T. et al. The American College of rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727-735.

Claims (1)

 A method of treating rheumatoid arthritis consisting in the fact that methotrexate is administered at a dose of 10 mg per week, characterized in that prospidine is added at a dose of 200-300 mg / week intravenously.

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