RU2363455C1 - Method of using dalargin in complex therapy for crohn's disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to clinical gastroenterology and combination therapy for Crohn's disease by administering dalargin. For this purpose there is further intramuscular injection of a 1 mg dose of dalargin twice a day, during the active stage of the disease, in addition to complex therapy. The course lasts 20 days and repeated treatment is done after 3 months.

EFFECT: stimulation of proliferation and reparation processes in the intestinal wall, improved morphological picture 8 weeks after commencement of therapy, reduction of number of relapses and increased remission duration of the disease.

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Description

The invention relates to medicine, in particular to clinical gastroenterology, and for the comprehensive treatment of Crohn's disease.

The constant interest in Crohn's disease (CD) is due, first of all, to the fact that, despite a long history of research, the etiology of the disease remains unknown: the epidemiology, clinic, diagnosis, pathogenetic and symptomatic treatment of CD are well studied, but the information in the available literature often carries controversial. The prevalence of CD in various regions of the world varies widely from 10 to 150 cases per 100 thousand population [Belousova EA Ulcerative colitis and Crohn's disease. - Tver, 2002, pp. 11-12]. The incidence of CD is progressively increasing. From 5 to 10 new cases of the disease per 100 thousand population are registered annually [Yablokova EA, Gorelov AV, Ratnikova MA Inflammatory bowel disease. - Moscow, 2006, p.20-30].

Epidemiological studies of IBD in Russia (in different regions) indicate a lower incidence compared with Central Europe: prevalence of CD 2.3-4.0 per 100 thousand of the population; incidence of CD 0.3-0.6 per 100 thousand of the population. Among the urban population, the incidence is 2-3 times higher in comparison with the inhabitants of the province. There were no significant differences between the incidence rates among men and women. The situation is characterized by extremely negative trends: unsatisfactory, late diagnosis (which explains the low rates in comparison with Europe) and, as a result, the prevalence of severe forms of the disease, high mortality [Belousova E. Epidemiology of inflammatory bowel disease in Russia, Falk Symposium 2006, 31] . The relatively young age of the diseased, their employment in socially useful work, a long stay in the hospital, the need for long-term outpatient monitoring - all this makes the disease one of the most expensive internal diseases in the clinic and indicates significant damage to the BC production area of the Far East and insufficiently effective therapy .

Modern treatment of CD is pathogenetic and, unfortunately, does not always affect the process of the disease. In the best case, only 50% of patients manage to maintain remission. During treatment, the absence of morphological activity is observed in less than 50% of cases. New treatment approaches are needed and need serious clinical research in all possible directions and aspects [Brian G. Feagan, M, Altering the Natural History of Crohn's Disease: How Much Progress Are We Making? Medscape 2006]. The entire course of treatment is divided into intensive and supportive care.

The principle of administering drugs is based on the use of basic (basic) drugs according to the “step-up” scheme and additional (auxiliary) drugs. In CD, basic agents include: steroid hormones, 5-aminosalicylic acid preparations, biological agents and immunosuppressants [Fiocchi C. The multifactorial pathogenesis of IBD, Falk Symposium, 2006, 21]. Since 2003, Western literature began to provide information on the role of mu receptors in inflammatory bowel diseases. Articles on the role of µ receptors in the pathogenesis of human IBD have been published since 2005. The prototype analogue is the work of foreign researchers who used selective synthetic ligands (DALDA, DAMGO), which possess activity against µ receptors, in their work. The expression of μ receptors in the mucous membrane of the colon, small intestine, and peripheral blood was evaluated for the control group and the group of patients with CD. The potential anti-inflammatory effect of the DALDA ligand [Colombel J., Pierre Desreumaux et al. µ-opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation. Gut 2005, 10]. The results of the study allowed us to draw a number of promising conclusions about the advisability of further studying and using synthetic ligands in the complex treatment of Crohn's disease. Unfortunately, a number of factors were not taken into account in the work that made it possible to completely eliminate the additional effect on the described mechanisms: groups of patients received disparate treatment regimens, the control group included patients with organic gastrointestinal diseases, sampling was performed during surgery using morphine in premedication. The question remained why the protective mechanisms of the endogenous opioid system do not work with IBD, what doses and for how long the drug can be used without fear of side effects, whether DALDA is able to penetrate the blood-brain barrier in therapeutic doses. To study this issue, we planned to use the domestic opiate receptor ligand - dalargin, which has the ability to interact with peripheral opiate receptors. It should be borne in mind that dalargin has a cytoprotective effect and regulates the processes of reparative regeneration in the mucous membrane of the small intestine [Tegeder I, Geisslinger G. Opioids as modulators of cell death and survival - unraveling mechanisms and revealing new indications. Pharmacol Rev 2004; 56 (3): 351-69]. Along with the ability to stimulate DNA synthesis, dalargin has a pronounced antioxidant activity. It is of interest how the antioxidant properties of dalargin correlate with the ability to influence tissue homeostasis disorders in CD [David Philippe et al. Anti-inflammatory properties of the µ-opioid receptor support its use in the treatment of colon inflammation. The Journal of Clinical Investigation 2003, Volume 111 / Number 9].

In the literature available to us, we did not find information about the use of dalargin in the treatment of Crohn's disease, its effect on the course of the pathological process in the small intestine and data on the methods of administration, doses and patterns of use of the drug in inflammatory bowel diseases. There is no information regarding the long-term results of the use of the drug in inflammatory bowel diseases.

The objective of the invention is to improve the quality of complex therapy of Crohn's disease. The technical result will increase the duration of remission, will help overcome the disadvantages of standard treatment regimens.

The technical result is achieved by the inclusion in the treatment regimen of a ligand of opiate receptors - dalargin. The ligand affects the increased expression of µ receptors in the mucous membrane of the large and small intestines in patients with CD. Pronounced expression of µ receptors is observed in the lamina propria mucosa, intramural nerve plexuses of the small and large intestines, and CD ⁴⁺ and CD ⁸⁺ peripheral blood T-lymphocytes in patients with CD. Inflammatory cytokines (INF-γ, TNF-α, IL-1β) enhance this process in the mucous membrane, and, conversely, NF-kB inhibitors were suppressed in T-lymphocytes [Colombel J., Pierre Desreumaux et al. µ-opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation. Gut 2005, 10]. All this contributes to the fact that interacting with peripheral opiate receptors, dalargin stimulates the proliferation and repair processes in the damaged intestinal wall.

From a practical point of view, the technical result was achieved as a result of treating 20 patients with the first diagnosis of Crohn’s disease with damage to the terminal ileum, moderate severity, moderate activity according to Best. All cases were confirmed by clinical and laboratory methods and histological verification. In the volume of complex therapy, 10 patients (group No. 1) received salofalk (mesalazine) in a daily dose of 3 grams per os (12 months), dalargin in a daily dose of 2 mg intramuscularly (20 days) and metronidazole intravenously in a daily dose of 1000 mg (5 days) ) The comparison group included 10 patients (group No. 2) who received salofalk in a daily dose of 3 grams per os (12 months) and metronidazole intravenously in a daily dose of 1000 mg (5 days).

Both groups were standardized by age and gender. Only patients with moderate course were included in the development. The severity of patients was evaluated subjectively, based on the clinical manifestations of the disease, and objectively, taking into account instrumental and laboratory parameters. In addition, the BEST activity index and questionnaires SF-36, IBDQ (sample attached) were used for objectification.

In the Excel software shell, a database was compiled containing clinical and laboratory parameters for all patients. Further, in the compared groups, the mean values and their errors were determined. The significance of differences (p) was found using the Student method, considering differences to be significant at p <0.05. Dangerous side effects when using dalargin in a dosage of 2 mg per day have not been identified. The data obtained are shown in table No. 1. The results of the study, shown in table No. 1, show that the duration of symptoms such as increased stool, fever, abdominal pain in the compared groups was significantly different. At the same time, in the group of patients receiving dalargin as part of the complex therapy, the duration of asthenic syndrome did not significantly differ in comparison with the groups of patients receiving only complex therapy. The decrease in the concentration of reactive plasma proteins in the blood group in the dalargin group was significantly higher than in the group without dalargin. The BEST activity index and histological index in the analysis after 8 weeks of treatment were lower in the dalargin group. Analyzing mental and physical health using the SF-36 questionnaire, we found significant differences in the compared groups. The duration of the bed day in the group of patients receiving complex therapy with dalargin was significantly shorter than in the group of patients receiving only complex therapy. Summary: the data obtained indicate that our proposed method using dalargin has advantages over the standard method.

1. The clinical course of the disease improves.

2. The duration of hospital stay is reduced.

3. Improving the quality of life of patients.

4. The time spent on the certificate of incapacity for work is reduced.

The results of the study allowed us to draw a number of promising conclusions about the advisability of further studying and using synthetic ligands in the complex treatment of Crohn's disease.

Clinical example No. 1.

Gorlova G.S. patient, 38 years old. In May 2006, she was hospitalized in general relativity with a fever of unclear origin, observed 2 months before hospitalization. The department conducted a full laboratory and instrumental examination, excluding oncopathology, infectious and systemic diseases. 06/18/06 was performed diagnostic laparoscopy: revealed segmental lesions of the small intestine. Diagnosed with Crohn's disease, small bowel form, moderate, exacerbation. Since that time, therapy with salofalk per os 3 g per day has been started, intravenous metrogil 1000 mg per day in combination with dalargin intramuscularly 2 mg per day; positive dynamics was noted: body temperature returned to normal, abdominal pain decreased. Outpatient after 2 weeks, dalargin was completely canceled, no relapse of the disease was noted. During the follow-up examination after 8 weeks, clinical and laboratory remission, the histological activity index is minimal. Salfalk therapy (2 g per day) is carried out to the present. The patient was discharged with a closed certificate of incapacity for work.

Clinical example No. 2.

Patient Nikitina A.S., 45 years old. Considers herself a patient since April 16, 2006, when, after eating poor-quality food, vomiting, epigastric pain, loose stools 2 times a day, without pathological impurities, were not treated. On April 17, 2006, she began to notice a deterioration in the form of an increase in dyspeptic syndrome, and she turned to a local therapist. She was treated for acute gastritis. After the treatment was prescribed, there was no improvement; in this regard, she was sent for treatment and additional examination to the hospital of the surgical department of the Clinical Hospital. I was in hospital treatment from April 20 to May 2, 2006 due to suspected acute appendicitis. Diagnostic laparoscopy and abdominal drainage were performed. She received treatment in the form of metronidazole 1.5 g / day and salofalk 1.5 g / day due to suspected Crohn's disease. There is no laparoscopy protocol in the statement. Against the background of the therapy, from May 5, I began to note an increase in body temperature in the evening. I turned to a gynecologist, an ultrasound of the uterus and appendages was performed - without pathology. May 12, she was sent for examination after the operation to a surgeon who recommended contacting a gastroenterologist and was discharged to work. Subfebrile temperature and abdominal pains continued, so on May 18 the patient turned for consultation to a gastroenterologist, who sent him to the General Clinical Hospital (in a planned manner). She was hospitalized to verify the diagnosis and behavior of the X-ray examination and the FCC in the General Clinical Hospital. After performing laboratory and instrumental screening for the gastrointestinal tract and histological examination of the patient, she was diagnosed with Crohn's disease with a primary lesion of the terminal ileum, moderate severity, moderate degree of activity (according to Best). Salofalk therapy began per os 3 g per day, intravenously metrogil 1000 mg per day in combination with dalargin intramuscularly 2 mg per day, positive dynamics were noted: body temperature returned to normal, abdominal pain decreased. Outpatient after 2 weeks, dalargin was completely canceled, no relapse of the disease was noted. During the follow-up examination after 8 weeks, clinical and laboratory remission, the histological activity index is minimal. Salofalk therapy (2 g per day) is carried out to the present. The patient was discharged with a closed certificate of incapacity for work.

Clinical example No. 3.

Patient Shishova A.S., 29 years old, 01/23/07 hospitalized urgently in the surgical department of the ICB, taking into account pain in the right iliac region. 01/23/07 diagnostic laparoscopy was performed, the diagnosis was made: Crohn's disease with ileum damage. Secondary mesadenitis. The abdominal cavity is drained. Conservative therapy was carried out (iv metrogil, tramal, salofalk 1.5 g / day), pain and loosening of the stool persisted. For further treatment, 01/25/07, the patient was transferred to general hospital of the Clinical Hospital. In the therapeutic department, the dose of salofalk was increased to 3 g / day, dalargin was prescribed intramuscularly at 2 mg per day. After 1.5 weeks, against the background of relief of pain and restoration of stool, control tests were performed. A complete clinical and laboratory remission has been established. At this point, body temperature for 4 days in the evening to 37.4 ° C due to SARS. Radiography of the sinuses showed the presence of inflammatory changes. The patient was transferred in satisfactory condition to the ENT department for further treatment of sinusitis. During the follow-up examination after 8 weeks, clinical and laboratory remission, the histological activity index is minimal. Salofalk therapy (1.5 g per day) is carried out to the present. The patient was discharged with a closed certificate of incapacity for work.

Comparative characteristics of the effectiveness of complex therapy of Crohn's disease

Table number 1 Symptom / indicator Group No. 2 (n = 10) Group No. 1 (n = 10) Increased stool (duration in days) 6.73 ± 0.25 4.58 ± 0.27 p <0.05 Abdominal pain (duration in days) 5.37 ± 0.17 6.9 ± 0.35 p <0.05 Astheno-vegetative syndrome (duration in days) 9.7 ± 0.33 10.4 ± 0.32 p> 0.05 Fever (duration in days) 9.06 ± 0.19 7.37 ± 0.17 p <0.05 Increased level of reactive plasma proteins (SRV, gamma fraction) (duration in days) 11.42 ± 0.25 8.95 ± 0.27 p <0.05 Best activity index (at 8 weeks of therapy with an initial value> 220) 180-190 150 and < Physical Health SF-36 30 ± 0.28 34.7 ± 0.9 p <0.05 Mental Health by SF-36 33.9 ± 0.2 41.4 ± 0.3 p <0.05 Bed day 15.4 ± 0.45 12.48 ± 0.43 p <0.05 Histological degree of activity (8 weeks after the start of therapy) 100% moderate The minimum in 74% of cases, p <0.05 Note: p <0.05 reflects the degree of confidence when comparing group 1 with group 2

Claims (1)

A method of treating Crohn’s disease, which consists of using dalargin as an adjunct to complex therapy, characterized in that dalargin is administered intramuscularly at a dose of 1 mg 2 times a day for 20 days with a second course after 3 months, which allows you to achieve an earlier clinical effect, significantly improve the morphological picture (up to 74% of cases) 8 weeks after the start of therapy.