RU2200007C2 - Method for treating patients for nonspecific ulcerating colitis - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves administering Ethymizol at a daily dose of 0.3-0.8 g for 10-30 days after having determined in advance diurnal morning and evening serum cortisol level and the value occurred to be lower than the physiological level. EFFECT: enhanced effectiveness of treatment; stable clinical remission; reduced drug consumption; avoided abstinence syndrome occurrence.

Description

 The invention relates to medicine, namely to proctology, and can be used in the treatment of patients with ulcerative colitis.

 There are various methods of treating patients with ulcerative colitis, including basic drug therapy - the introduction of drugs 5-aminosalicylic acid (5-ASA), immunomodulators / 1 / and the use of glucocorticosteroid drugs (GCSP) / 2 /.

 In the treatment of ulcerative colitis, prednisone and hydrocortisone related to HKSP are administered at a dose of 1-2 mg / kg of the patient’s weight (based on prednisolone) 1-2 times a day, the course of treatment depending on the severity of the disease is from several weeks to six months / 3 /.

 The disadvantages of the known methods, including the use of HKSP in the treatment of ulcerative colitis, include a number of undesirable side effects of glucocorticosteroids - Itsenko-Cushing's symptom complex, hyperglycemia, osteoporosis, slower regeneration processes, exacerbation of gastric ulcer and duodenal ulcer, growth retardation, myopathy, posterior subcapsular cataract, changes in the nervous system - cause adrenal suppression / 4 /.

 With prolonged use of HSCP, the possibility of suppressing the function of the adrenal cortex with suppression of hormone biosynthesis and atrophy of it, as well as the inhibition of the formation of gonadotropic and thyroid-stimulating pituitary hormone, is taken into account. In patients receiving glucocorticosteroid-type drugs, a decrease in the level of serum cortisol by 2-3 times from the initial one was observed, which indicates adrenal suppression. The sudden cessation of the administration of HKSP can cause an exacerbation of the pathological process, so the completion of the course of treatment is carried out by gradually reducing the dose.

 Closest to the proposed one is a method of treating patients with ulcerative colitis, including basic therapy using rapidly metabolizing synthetic glucocorticosteroid analogs - budesonide, tixocortol pivalate, beclomethasone dipropinate, prednisolone metasulphobenzoate / 5 /.

 The essence of the known method is as follows.

 A 9-week, randomized, double-blind, controlled study of 10 mg of budesonide related to HSCP, but not adrenal suppression, was performed compared to 40 mg of prednisolone. Doses were gradually reduced. It was established that in the group of patients taking prednisone for treatment, the morning plasma cortisol level was reduced 3 times from the initial one, and in the group with budesonide cortisol remained at the initial level. Positive endoscopic dynamics in both groups was without significant differences.

 Based on this, the authors of the known method propose to use, against the background of basic therapy, budesonide instead of prednisone as a drug that does not suppress plasma cortisol levels.

 The disadvantages of this method include the occurrence of side effects characteristic of drugs of the glucocorticosteroid series / 4 /. The sudden cessation of the administration of HKSP can cause an exacerbation of the pathological process, so the completion of the course of treatment is done by gradually reducing the dose.

 The objective of the invention is to develop a method of treatment that allows you to obtain clinical remission during ulcerative colitis, by restoring the level of serum cortisol.

 The technical result of this proposal is to restore the level of serum cortisol to a physiological norm.

 This problem is solved by the method consisting in the fact that the treatment of patients with ulcerative colitis includes the introduction of drugs 5-aminosalicylic acid, glucocorticosteroid and immunomodulating drugs.

 Distinctive techniques of the proposed method are a preliminary determination of the morning and evening daily levels of serum cortisol. When its values are below the physiological norm, etymizole is administered in a daily dose of 0.3-0.8 g for 10-30 days.

 A comparative analysis of the proposed solution and the prototype shows that the proposed method differs from the known preliminary determination of morning and evening daily levels of serum cortisol; at its values below physiological norms, etymizole is administered in a daily dose of 0.3-0.8 g for 10-30 days.

 From the above comparative analysis it follows that the claimed method meets the criteria of the invention of "novelty."

 The method comprising the claimed invention is intended for use in healthcare. The possibility of its implementation is confirmed by the methods and means described in the application.

 The claimed method ensures the achievement of the objectives set by the applicant: obtaining clinical remission during ulcerative colitis by restoring the level of serum cortisol to a physiological norm.

 From the above it follows that the claimed invention meets the condition of patentability "industrial applicability".

 The basis of the proposed method are clinical trials conducted by the author, which showed that the level of serum cortisol in some patients who received an acute attack of ulcerative colitis was initially below normal / within <10.0 nmol / l to 201.0 nmol / l /. We also found that the use of basic therapy (5-ASA, GKSP, immunosuppressive drugs) against this background only aggravates the situation - the level of cortisol decreases from the initial by 2–3 times / from <10.0 nmol / l to 35.0 nmol / l /.

 In addition, we did not find any data on the initially reduced level of serum cortisol in patients with ulcerative colitis / ULC / (in the acute period) in the available literature.

 Also, in the available literature, we did not find data on the use of drugs that increase the level of serum cortisol in patients with ulcerative colitis.

 Etymizole (aethimizolum) belongs to the group of respiratory analeptics, however, it activates the adrenocorticotropic function of the pituitary gland, which leads to an increase in the level of glucocorticosteroids in the blood, and also has a mild antidepressant effect. In connection with the stimulation of the adrenocorticotropic function of the pituitary gland, etimizol is used as an anti-inflammatory and anti-allergic agent for polyarthritis and some forms of bronchial asthma. The drug has antispasmodic properties / 7 /.

 Therefore, the analysis of known methods revealed a lack of information about the influence of the distinguishing features of the method to achieve a technical result, which allows us to consider the claimed invention meets the criterion of "inventive step".

 The inventive method is as follows.

 Upon admission, the patient determines the dynamics of the minimum and maximum daily levels of serum cortisol. During exacerbation, serum cortisol levels range from <10.0 nmol / L to 201.0 nmol / L in the morning (normal 250.0-650.0 nmol / L) and in the evening from <10.0 to 73.0 nmol / L (norm 50.0-280.0 nmol / L).

 To determine serum cortisol, test systems CIS bio international, France (morning norm - 154-638 nmol / l, evening - 80-388 nmol / l) and Immunotech a coulter company, Czech Repablic (morning norm - 250-650 nmol / l, evening - 50-280 nmol / l) / the amount of cortisol is calculated on const /.

 As a rule, incoming patients take basic therapy, including 5-ASA, GKSP, immunomodulators, immunosuppressants / salofalk, salosinal, sulfasalazine, prednisolone, hydrocortisone, azathioprine /.

 When determining the values of the level of serum cortisol below the physiological norm, etimizol is administered. Depending on the severity of the disease, etimizol is administered in tablet form at 0.3 g per day for 30-40 days, or 0.6-0.8 g per day for 10-15 days.

 If the patient is operated on, then in the postoperative period, 1.5% of etimizole is prescribed intravenously in an isotonic solution of sodium chloride in a dose of 6.0-15.0 ml per day, drip, with subsequent transfer to a tablet form.

 When the serum cortisol level was restored to normal values, all patients experienced a complete and long-term remission (from 6 months to 2 years), which was expressed in positive subjective feelings, in the absence of complaints, which was confirmed by objective examination data (endoscopic picture, laboratory parameters).

 It should also be noted that in the stage of incomplete remission in patients receiving etimizol, the level of serum cortisol approached the norm and then its normal level was recorded during remission.

 The essence of the proposed method is illustrated by clinical examples.

 Example 1

 Patient Smorodinov V.A., 68 years old, medical history 8505, on December 25, 1997, was admitted to the proctology department of the Regional Clinical Hospital 1. Diagnosis: Nonspecific ulcerative colitis / ULC /, first detected, subtotal lesion, moderate degree of endoscopic activity, moderate gravity.

Serum Cortisol Level:
* upon admission - morning - 193.0 nmol / l (normal 250.0-650.0 nmol / l);
- evening - 39.0 nmol / l (norm 50.0-280.0).

Upon receipt, intravenous prednisone was prescribed at 120 mg / day, sulfosalazine 3 g / day, salofalk 4 g / day in microclysters. Etymizole is prescribed at a dose of 0.6 g / day, when prednisone was reduced to 10 mg / day for the entire withdrawal period, and then for 10 days after the withdrawal of prednisolone. The dose of prednisolone was reduced by 5 mg per week, the dose of etimizole - by 0.1 g until it was completely canceled. At discharge on January 15, 1998, prednisone 35 mg / day in tablets;
* after 2 weeks on the background of taking GKSP:
- morning - 77.0 nmol / l (normal 250.0-650.0);
- evening - <10.0 nmol / l (norm 50.0-280.0).

* After taking etimizole - after 2.5 months - in remission, the level of serum cortisol was:
- morning - 405.0 nmol / l (norm 250.0-650.0);
- evening - 65.0 nmol / l (norm 50.0-280.0).

 Currently, the patient is under our control. Inspection is made 1 time in 3 months. There are no complaints, stool 1 time per day without visible pathological impurities. According to sigmoidoscopy, the rectal mucosa is pink, shiny, vascular pattern is traced, there are no neoplasms. The last inspection was on December 3, 1998. The level of serum cortisol: in the morning - 453.0 nmol / l (normal 250.0-650.0); in the evening - 81.0 nmol / l (normal 50.0-280.0 nmol / l). The patient has persistent remission for 11 months.

 Example 2

 Patient Ivanova N.A., 38 years old, medical history 18270, January 23, 1998 was admitted to the proctology department of the Regional Clinical Hospital 1. Diagnosis: UC, left-sided lesion, continuously recurring severe course, pronounced degree of endoscopic activity. Cicatricial deformity of the perineum, insufficiency of the anal pulp 4 tbsp., Colostomy.

Serum Cortisol Level:
* upon admission - morning - 110.0 nmol / l (norm 250.0-650.0);
- evening - <10.0 nmol / l (norm 50.0-280.0);
* after 2 weeks on the background of taking GKSP:
- morning - 18.0 nmol / l (norm 250.0-650.0);
- evening - 73.0 nmol / l (norm 50.0-280.0).

 After left-sided hemicolproctectomy (with a reduction in the dosage of prednisolone and the administration of etimizole in a dose of 1.5% solution, 6.0 ml on a 0.9% sodium chloride solution of 200% intravenously, drip, for 7 days, and then 0.3 g each / day in tablet form for 15 days with a gradual cancellation of 0.1 g / day).

* February 18, 1998 at discharge:
- morning - 103.0 nmol / l (normal 154.0-638.0);
- evening - 35.0 nmol / l (normal 80.0-389.0).

* 1.5 months after the course of treatment and discontinuation of drug therapy:
- morning - 210.0 nmol / l (normal 154.0-638.0);
- evening - 75.0 nmol / l (normal 80.0-388.0).

During the dynamic observation for 10 months, from the remaining right half of the colon - clinical endoscopic remission. Fecal matter, decorated and half-formed / depending on the food taken /, the colostomy functions well. In November 1998, the patient underwent sphincterolevateroplasty; reconstructive surgery is planned (reduction of the right half). Serum Cortisol Levels November 30, 1998:
- morning 458.0 nmol / l (normal 154.0-638.0);
- evening 97.0 nmol / l (normal 80.0-388.0).

 Example 3

Patient Shaposhnikova Yu.B., 29, medical history 14054, was admitted to the proctology department of the Regional Clinical Hospital 1. She was treated from June 28, 1997 to August 8, 1997. Upon receipt of the diagnosis: Nonspecific ulcerative colitis, first detected, total damage, a pronounced degree of endoscopic activity, a severe course with extraintestinal manifestations. Upon receipt, serum cortisol levels:
- morning - 36.0 nmol / l (norm 250.0-650.0);
- evening - <10.0 nmol / l (norm 50.0-280.0).

 Basic therapy: intravenous drip prednisone - 225 mg / day, salofalk 4 g / day, antibacterial, anti-inflammatory therapy, symptomatic, cryoplasmapheresis, iv infusion therapy.

After 6 months, in the stage of stable remission (after the course of etymizole according to the proposed scheme):
- morning - 345.0 nmol / l (154.0-638.0);
- evening - 80.0 nmol / l (80.0-388.0).

 Example 4

 Patient A. Zhilyakova, 24 years old, medical history 9605, was admitted to the proctology department of the Regional Clinical Hospital 1. She was treated from April 20, 1998 to May 13, 1998. Diagnosis: Ileostomy according to Brook, a continuously recurring process in the cult rectum (subtotal colectomy in August 1997).

Serum Cortisol Level
*on admission:
- morning - <10.0 nmol / l (normal 250.0-650.0 nmol / l);
- evening - <10.0 nmol / L (normal 50.0-280.0 nmol / L).

Against the background of the use of microclysters with prednisone and salofalk, as well as etymizole per os: tabletted etymizole 0.6 g / day with a gradual withdrawal of 0.1 g / week. Microclysters with prednisone were canceled after 3 weeks from receipt. During treatment, the level of serum cortisol:
- morning - 24.0 nmol / l (normal 154.0-638.0);
- evening - 85.0 nmol / l (normal 80.0-388.0).

In remission / June 15, 1998 - 1 month after discharge /:
- morning - 387.0 nmol / l (normal 250.0-650.0);
- evening - 65.0 nmol / l (norm 50.0-280.0).

 In August 1998, a transanal proctectomy was performed as planned (in remission). The patient is preparing for reconstructive surgery - the creation of an intra-pelvic reservoir.

 A total of 36 patients were examined and treated. In all the studied, regardless of the stage of the process, the levels of adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), follitropin (FSH), lutropin (LH) corresponded to the physiological norm.

 A decrease in the level of serum cortisol was noted in patients during the period of pronounced activity of the process in the colon.

 In the control group - patients with other various proctologic diseases / 40 patients /, their serum cortisol level was within the physiological norm.

 Thus, the claimed method allows to reduce the time of taking HKSP, respectively, to reduce the undesirable effects of these drugs and save patients from the "withdrawal syndrome", helps to restore the level of serum cortisol to physiological norm and provides a stage of remission. It is important that this isol is affordable and manufactured in Russia.

Literature
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 2. Starkova N.T. Diseases of the adrenal gland // Clinical endocrinology. - M.: Medicine, 1991 .-- S. 278-344.

 3. Fedorov V.D., Vorobev G.I., Rivkin V.L. Features of operations in ulcerative colitis and Crohn’s disease // Clinical surgical coloproctology. - M., 1994 .-- S. 289-297.

 4. Trusov V.V., Zelenin A.A., Marizin S.A. Application of the method of radioimmunological analysis in endocrinology. Cortisol // Radioimmunological analysis in biology and medicine. - Bitter. - 1987. - S. 61-63.

 5. Lofberg R., Danitlsson A., Suhr O. et al. "Oral Budesonide compared with prednisolone in treatment of active to tole and left side ulcerative colitis (Oral budesonide compared with prednisolone in patients with active total and left-sided ulcerative colitis // Gastroenterology. - 1996. 110. - P. 1713-1718.

 6. Gary R. Lichtenstein, Medical therapies for inflammatory bowel disease // Lichtenstein G.R., Cohen R. D., Hanauer S.B. Current Opinion in Gastrenterology. - 1994. Vol. 10. - P. 390-403: Russel D. Cohen, Stephen B. Hanauer.

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Claims (1)

 A method of treating patients with ulcerative colitis, including basic therapy, characterized in that the morning and evening daily levels of serum cortisol are preliminarily determined, and when its value is lower than the physiological norm, etimizol is administered in a daily dose of 0.3-0.8 g for 10-30 days.