RU2412701C2 - Method of reducing intolerance to antituberculous preparations - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to phthisiology, and can be used in treating tuberculosis by antituberculous preparations (ATP). That is ensured by chemotherapy supplemented with daily introduction of the preparation taurin for at least 2 months.

EFFECT: method provides good tolerance to dosages of primary and reserve ATP required for therapy in various clinical forms of tuberculosis, reducing or eliminating various adverse reactions of therapy.

4 cl, 5 ex

Description

The invention relates to medicine, phthisiology, and can be used in the treatment of various forms of tuberculosis using chemotherapy.

In the treatment of tuberculosis, the main role is played by chemotherapy (XT), which includes at least 4-5 primary or reserve anti-TB drugs (PTP), which often have a negative side effect on the human body. In a number of patients (an average of 17-28%), XT is accompanied by intolerance to PTP. Drug intolerance is an increased sensitivity of the body to certain medicinal substances, which, when introduced into the body even in minimal therapeutic doses, cause undesirable side reactions. The frequency of drug complications in patients with tuberculosis varies widely. In this case, intolerance reactions (PH) of PTP have various manifestations: hepatotoxic reactions are manifested by an increase in the level of transaminases, bilirubin, and the presence of dyspepsia; nephrotoxic - increased intoxication, increased creatinine and urea; cardiotoxic - by a change in heart rhythm, the appearance of shortness of breath, pain, ECG changes, neurotoxic - by headache, dizziness, toxico-allergic - by skin itching, urticaria; etc. The appearance of pH requires a reduction in the dose of anti-TB drugs or the complete abolition of XT, which adversely affects the course of a specific process, slowing down the time of abacilation, provoking the development of multiresistance or disease progression, which significantly reduces the effectiveness of treatment.

Currently, the most effective anti-TB drugs are drugs of the isonicotinic acid hydrazide group (GINC) - isoniazids, which are the main ones in the treatment of tuberculosis and are included in all treatment regimens in optimal doses (M. Mashkovsky. Medicines. M., Medicine, 1993, C .367-369). The disadvantage of using GINC drugs is the formation of some fairly toxic metabolites in the body, which leads to undesirable side effects of the drugs. There is a method of limiting complications and side effects in the treatment of tuberculosis with GINC drugs (RU 2217137 C1, 11/27/2003), in which iron oxide sulfate is used in therapeutic doses to reduce intolerance to the drugs used, which is taken previously for at least two days , before the onset of TB XT, then continue its administration with the GINC preparation until the end of treatment.

However, this method stops the pH caused only by drugs of the GINC group, without reducing the pH of other PTP, which often leads to the need for correction or cancellation of XT. In addition, delaying the onset of XT also reduces the effectiveness of treatment for tuberculosis.

It is known to use the drug Glutoxim for the prevention of toxic complications of XT tuberculosis (RU 2197984 C1, 02/10/2003). However, the use of Glutoxim allows you to stop only hepatotoxic reactions caused by drugs of the GINC group and rifampicin. Thus, various other manifestations of pH caused by both these and other anti-TB drugs remain unaffected, as a result of which there remains the need for XT correction to continue treatment and the effectiveness of treatment is reduced.

Closest to the claimed is a method of reducing intolerance to PTP, including the addition of XT agent that reduces adverse reactions XT (RU 2314113 C1, 10.01.2008). In this method, the herbal preparation Populin (an aqueous extract of aspen bark and hillwort), which reduces and prevents hepatotoxic PTP reactions, is used as an additional tool. However, Populin suppresses only the hepatotoxic effect of PTP and does not affect other manifestations of drug intolerance, which, if present, leads to the need to change or cancel XT, reducing the effectiveness of treatment. Reducing the hepatotoxic effects of PTP with Populin is shown in this method only in the treatment of pulmonary tuberculosis.

The objective of the invention is to increase the effectiveness of the treatment of tuberculosis.

The technical result is the expansion of the range of stopping pH that occurs when taking anti-TB drugs, with various clinical forms of tuberculosis.

This result is achieved by the fact that in the method of reducing PTP intolerance, including the addition of XT with an agent that reduces side reactions of XT, the authors proposed to use taurine daily for at least two months as an additional means. Taurine can be used in the form of a solution of taufon, administered intramuscularly, or in tablet form, as well as in the form of a dibicor preparation.

Taurine is a natural aminosulfonic acid (b-aminoethanesulfonic acid, H ₂ NCH ₂ CH ₂ SO ₃ H), widely used in healthcare practice in various dosage forms: ampoules (in 1 ml of 40 mg of taurine), taufon tablets and dibicor containing 0, 25 and 0.5 g of taurine, eye drops. It is known that taurine normalizes metabolic processes, has a regenerative, reparative, membrane-protective effect. It plays a large role in lipid metabolism, optimization of energy and metabolic processes, preservation of the electrolyte composition of the cytoplasm (due to the accumulation of potassium and calcium ions), and is a part of paired bile acids, which contribute to the emulsification of fats in the intestine. In the brain, it performs the function of a neurotransmitter inhibiting synaptic transmission, has anticonvulsant and cardiotonic activity. It causes the normalization of eye tissue metabolism. Increases performance during physical exertion (Encyclopedia of drugs. Register of medicines of Russia. M., 2003, p.797). The tuberculostatic properties of taurine (RU 2207126 C1) were established, and the experiment showed that taurine increases the effectiveness of treatment with isoniazid tuberculosis (RU 2207127 C1).

However, the pharmacological properties of taurine do not directly imply the possibility of its effect on adverse reactions of XT tuberculosis. Also, taurine has never been used to stop the pH of the main and reserve anti-tank vehicles. This allows us to conclude that the novelty and inventive step of the claimed invention.

The authors conducted clinical studies of the effect of taurine on the relief of adverse reactions of XT, including primary and backup PTP. In this case, taurine was used in ampoule (taufon preparation) and tablet (taufon or dibicor preparations) forms. Studies were performed on 20 patients with various clinical forms of the tuberculosis process: pulmonary (infiltrative, multiple tuberculomas, fibrocavernous tuberculosis), extrapulmonary (female genital tuberculosis, kidney tuberculosis). Previously, in all these patients, treatment with the PTP complex was accompanied by a variety of pHs from various organs and systems, because of which XT had to be corrected or interrupted. To a greater extent, this was characteristic of fibrocavernous tuberculosis (FCT) and tuberculosis of the female genital organs. In these cases, due to the abolition of XT, the duration of treatment averaged only half the duration of the disease.

Supplementation of XT with taurine, applied daily for 2 months, improved the general condition of patients and led to a relief of pH, which made it possible to conduct an XT course without adjusting the regimen and dose of PTP, providing effective treatment for tuberculosis. Taurine, possessing membrane-stabilizing, hepatoprotective, cardiotropic and neurotropic properties, apparently has a stopping effect on pH caused by various anti-TB drugs. It was found that the addition of XT tuberculosis with taurine expands (compared with the prototype) the spectrum of stopping adverse reactions that occur with XT: not only hepatotoxic adverse reactions were eliminated or decreased, but also cardio-, nephro- and neurotoxic, as well as toxic-allergic.

Manifestations of PTP intolerance were completely stopped in 7 patients every other day, in 7 patients - in 5-7 days. In the remaining 6 patients, pH decreased to tolerable. These effects were obtained in patients with various clinical forms of the tuberculous process: infiltrative pulmonary tuberculosis - 3 patients, cavernous tuberculosis - 3 patients, FCT - 9 patients, renal tuberculosis - 2 patients, female genital tuberculosis - 3 patients, while taurine was used throughout not less than two months. The use of taurine for less than 2 months did not give a lasting effect of stopping the pH. At the same time, with prolonged XT in patients who received a two-month course of treatment with taurine, in some cases, 3-4 weeks after stopping taurine, pH was resumed. However, these reactions were expressed to a much lesser extent, did not require XT correction and were eliminated by a repeated course of taurine.

The method is as follows. If PTP intolerance reactions occur during XT, daily intramuscular or oral administration of taufon or dibicor in a therapeutic dose is prescribed for at least 2 months, without interrupting or correcting the prescribed XT. The relief of pH is assessed by the absence of patient complaints and by clinical and laboratory dynamics. After the cancellation of taufon or dibikor XT continue in the same volume. With the resumption of pH, the course of treatment with taurine is repeated without interrupting or correcting XT.

Example 1. Patient C, born in 1986: infiltrative tuberculosis of the upper zone of the right lung. Conducting intensive XT at the place of residence was complicated by pH in the form of nausea, repeated vomiting, dizziness, and a persistent increase in transaminases (ACT 2.36 mmol / L h, ALT 3.68 mmol / L h). This necessitated the abolition of anti-TB drugs, which stopped these reactions within 1-2 weeks. However, they appeared again during the subsequent renewal of XT, which again caused its cancellation. As a result, during the year, due to the impossibility of carrying out a continuous XT course, the process progressed: the infiltration of the upper lobe of the right lung increased and seeding appeared in the 6th segment.

After a year of treatment, she was admitted to the clinic of UNIIF. XT was prescribed: rifampicin 0.45 g, tubazide 0.6 g, pyrazinamide 1.0 g, ethambutol 0.8 g, avelox 400 mg and amikacin 1.0 ml. In addition to PTP, taufon was prescribed at a dose of 80 mg per day intramuscularly daily. The patient tolerated this XT well. And although during the first week noted periodic nausea, however, there was no need to cancel the anti-TB drugs. Indicators of transaminases remained within normal limits. Using taufon allowed to conduct a continuous course of XT for 2 months. A positive clinical and radiological dynamics was obtained in the form of resorption of infiltrative changes in the upper lobe of the right lung. When the taufon was canceled and XT continued, the PTP intolerance reactions resumed after 3 weeks, however, they were expressed to a much lesser extent, did not require the PTP cancellation and were stopped 1 day after the start of the second taufon course, which lasted 2 months. The patient in satisfactory condition was discharged to continue treatment at the place of residence.

Example 2. Patient G., born in 1973, was admitted to the UNIIF clinic with a diagnosis of Infiltrative tuberculosis of the upper lobe of the right lung in the phase of decay and bilateral contamination, MBT (+), multidrug resistance (MDR). Upon admission, he complained of weakness, dizziness, weight loss, lack of appetite, pain in the right hypochondrium, loose stools up to 4-5 times a day. Sick for 2 years. He received inconsistent treatment at the place of residence in connection with the manifestations of toxic reactions. Upon admission to the UNIIF clinic, sputum was examined (biochip - mutations of resistance to rifampicin and isoniazid were detected), and therefore an individual XT course was prescribed: intramuscular tubazide 5.0 ml, 0.5 g cycloserine, 1.5 g pyrazinamide, capreomycin 1, 0 g, avelox 400 mg. On the 4th day, the patient began to complain of dizziness, abdominal pain, loose stools up to 6-8 times a day. Laboratory indicators were within normal limits. In addition to PTP, taufon was prescribed at a dose of 80 mg intramuscularly for 2 months. On the 2nd day, the patient noted a significant improvement (stool reduction, relief of headache), and after 7 days the pH was completely stopped, which allowed the XT course to be carried out continuously for 2 months. A distinct positive radiological dynamics was obtained in the form of resorption of infiltrative changes and the formation of fibrosis. The patient was discharged to continue treatment at the place of residence with a diagnosis of Infiltrative tuberculosis of the upper lobe on the right with decay and seeding of the middle lobe in the phase of the formation of cirrhosis of the upper lobe, MBT (-).

Example 3. Patient Ch., Born in 1948, was admitted to the clinic of the UNIIF with a diagnosis of Tuberculosis of the urinary system: polycavernous tuberculosis of the right kidney, MBT (+), chronic kidney disease grade 1 according to Ryabov. Admission laboratory parameters: hemoglobin 123 g / l, red blood cells 3.2 × 10 ¹² , white blood cells 4.5 × 10 ⁹ , urea 8.7 mmol / l, creatinine 0.997 mmol / l, ACT 0.35 mmol / l, ALT 0.67 mmol / L. An XT course was prescribed - the 1st regimen (intensive phase), which the patient tolerated satisfactorily for 4 weeks. In the future, nephro- and hepatotoxic reactions appeared: the patient began to complain of weakness, dry mouth, and nausea. At the same time, a change in laboratory parameters was noted - hemoglobin 100 g / l, red blood cells 3.4 × 10 ¹² , white blood cells 6.0 × 10 ⁹ , urea 12.1 mmol / l, creatinine 2.15 mmol / l, ACT 1.8 mmol / l, ALT 2.9 mmol / l. XT was canceled, a course of infusion therapy was prescribed. After 5 days, XT was again appointed, but complaints resumed on the 2nd day, which forced the abolition of the anti-TB drugs. After 7 days, a second course of XT was prescribed, while the patient was additionally intramuscularly injected daily with taufon at a dose of 80 mg for 2 months, which allowed for a continuous course of XT. Laboratory indicators during this period remained within normal limits. At the end of the intensive phase of treatment, the patient was discharged in satisfactory condition to continue treatment at the place of residence.

Example 4. Patient K., born in 1980, diagnosis: genital tuberculosis, tuberculous adnexitis, active phase. Sick of tuberculosis for 4 years. During this period, XT courses were complicated by cardio-, hepato- and neurotoxic reactions: nausea, headache, pain in the precardial region, tachycardia up to 110-120 beats per minute at rest. Received planned for the XT prophylactic course, during which she received: rifampicin 0.3 g, tubazide 0.6 g, pyrazinamide 1.0 g per day. After 6 days from the onset of XT, complaints of headache, tachycardia appeared. An ECG recorded rhythm disturbances in the form of tachycardia of 110 beats per minute with pronounced dystrophic changes. XT was canceled, the drug Magne B6 was prescribed. On the 3rd day, headaches and pains in the precardial region ceased, the pulse was 70 beats per minute, the ECG values were normal. With the resumption of XT, pH appeared again, as a result of which, in addition to XT, dibicor was prescribed at a dose of 750 mg per day for 2 months. The pH disappeared, which allowed for the full course of XT prophylaxis.

Example 5. Patient K., born in 1958 Sick of tuberculosis for 2 years. If detected, infiltrative tuberculosis of the upper lobe of the right lung, MDR. During the first year, treatment was effective: a decrease in infiltrative changes was observed. However, after a year, pH appeared in the form of skin itching, rashes of the type of urticaria, which did not allow continuing the XT course without a break and led to the progression of tuberculosis. Upon admission to the UNIIF clinic, she was diagnosed with FCT of the upper lobe of the right lung in the phase of infiltration and seeding, MBT (+), MDR, chronic hepatitis B, C. XT was prescribed according to the individual regimen: pyrazinamide 1.5 g, ofloxacin 800 mg, cycloserine 500 mg , PASK 9.0 g, tubazide 0.6 g, protionamide 0.5 g. After 1.5 months from the onset of XT, pH developed in the form of nausea, itching of the skin, and headache. In addition to XT, taufon was prescribed at a dose of 80 mg intramuscularly daily. After 7 days, all manifestations of pH were stopped. There was no need for XT correction, the course of treatment with taufon was continued for 2 months. As a result of a full XT, the patient was abacilated for 2 months.

Thus, the inventive method provides good tolerance of the main and backup PTP in patients with different clinical forms of the tuberculosis process, eliminating or reducing a variety of adverse reactions of XT. At the same time, the possibility of using the necessary dosages of anti-TB drugs and the continuity of their administration is achieved, which increases the effectiveness of treatment of tuberculosis.

Claims (4)

1. A method of reducing intolerance to anti-TB drugs, including the addition of chemotherapy with a drug that reduces the adverse reactions of chemotherapy, characterized in that taurine is administered daily as an additional agent for at least two months. 2. The method according to claim 1, characterized in that taurine is used as a solution of the taufon preparation administered intramuscularly. 3. The method according to claim 1, characterized in that taurine is used in the form of a taufon preparation in tablet form. 4. The method according to claim 1, characterized in that taurine is used in the form of a dibicor preparation.