RU2312667C1 - Method for treatment of adverse neurotoxic response caused by antituberculosis preparations - Google Patents

Abstract

FIELD: medicine, phthisiology.

SUBSTANCE: method involves both administration of antituberculosis preparations and using cortexin in the dose 10 mg in physiological solution. Cortexin is administrated by intramuscular route, 10 injections for treatment course. Method provides enhancing effectiveness and reducing treatment period. Invention can be used in treatment of adverse neurotoxic responses caused by effect of antituberculosis preparations.

EFFECT: improved method of treatment.

3 tbl, 2 ex

Description

The invention relates to medicine, in particular to phthisiology, and can be used in the treatment of adverse neurotoxic reactions associated with the use of anti-TB drugs.

Combined etiotropic chemotherapy is the main component of the treatment of tuberculosis, when several anti-TB drugs are used simultaneously for a rather long time.

Chemotherapy regimens for tuberculosis patients include isoniazid, the main, most effective anti-TB drug. Isoniazid, disrupting the metabolism of B vitamins, glutamic acid, penetrating the blood-brain barrier, has a pronounced neurotoxic effect, which is manifested by symptoms of damage to the central and peripheral nervous system. Ethambutol can lead to the development of optic neuritis, possible neurological disorders (headache, paresthesia, frequent epileptic seizures). Streptomycin causes damage to the VIII pair of cranial nerves, neuromuscular blockade.

Many of the reserve drugs also have a neurotoxic effect. Thioamide preparations (ethionamide, protionamide) are similar in chemical structure to isoniazid, as a result of which they have a neurotoxic effect, which is manifested by symptoms of central nervous system damage. In the treatment with fluoroquinolones, a side effect is most often noted on the part of the central nervous system. Cycloserine has an inhibitory effect on the metabolism of pyridoxine, disrupts the metabolism of nicotinic acid and riboflavin, resulting in neuropsychiatric disorders. Ethionamide and isoniazid potentiate the neurotoxic effect of cycloserine. Kanamycin and capreomycin are also capable of causing neurotoxic reactions.

There is a method of treating adverse neurotoxic reactions developing during chemotherapy for tuberculosis by increasing the dose of pyridoxine to a maximum daily dose (200 mg), treating tricyclic antidepressants such as amitriptyline 25-75 mg per night. It is also necessary to reduce the dose of the suspected drug, or its complete cancellation. If there is no improvement, gabapentin 300 mg is prescribed. Perhaps the use of carbamazepine 200 mg 2 times a day. (Guidelines for the treatment of multidrug-resistant tuberculosis. Edited by A. Pasechnikov, M. R. Rich - Partners in Health, 2003. - 173 p.).

The disadvantages of this method is the need for constant monitoring by a psychiatrist, the manifestation of a cholinolytic effect when using tricyclic antidepressants, which limits the possibility of its use, the need to cancel anti-TB drugs.

A known method of treating adverse neurotoxic reactions that develop on the background of chemotherapy for tuberculosis through the use of glycine and limontara, which are metabolites of a wide spectrum of action. Glycine was prescribed in tablets of 0.1 g sublingually 4 times a day and limontar - orally, 1 tablet (0.25 g) per day during the intensive phase of chemotherapy. (Bogadelnikova I.V., Perelman M.I. Antibacterial therapy of pulmonary tuberculosis. // Textbook. - M. - MMA named after I.M.Sechenov. - 1997. - 80 p.).

The disadvantages of this method is the low efficiency of its use, the use of glycine and limontara allows you to stop the developed side effects in 54% of cases and reduce their clinical manifestations in 35%, in 11% of cases the effect of the use of drugs is not observed.

The objective of the invention is to increase the efficiency and reduce the time of treatment of neurotoxic reactions caused by anti-TB drugs.

A method of treating adverse neurotoxic reactions caused by anti-TB drugs involves the use of 10 mg cortexin in saline intramuscularly for a course of 10 injections. Cortexin is a complex of polypeptides isolated from the cerebral cortex of calves or piglets by the method of acetic acid extraction. The drug has a tissue-specific effect and stimulates reparative processes in the brain, has an effective neuroprotective, nootropic and anticonvulsant effect, reduces the toxic effects of neurotropic substances, accelerates the restoration of brain functions after stressful effects. The drug regulates the ratio of inhibitory and excitatory amino acids, the level of serotonin and dopamine, has a GABAergic effect, has antioxidant activity and the ability to restore the bioelectric activity of the brain.

We observed 22 patients with developed neurotoxic reactions: 12 patients with central neurotoxic reactions of moderate severity and 10 patients with peripheral polyneuropathies. The average age of the patients was 49.2 years, among them there were 16 men (72.7%) and 6 women. Patients were distributed according to the forms of tuberculosis as follows: infiltrative tuberculosis - 17, disseminated tuberculosis - 2, focal - 1, tuberculosis - 1, fibro-cavernous - 1. Early neurotoxic reactions in the first month of treatment developed in 6 patients (27.3%). The reasons were: alcohol abuse before the onset of the disease (in 4 patients - 18.2%) and diabetes mellitus (2-9.1%). In the remaining patients, neurotoxic reactions developed at 3-4 months of chemotherapy.

All patients (n = 22) underwent a course of cortexin therapy. Cortexin was administered 10 mg intramuscularly in physiological saline for a course of 10 injections. All patients were examined by a neurologist and psychiatrist before prescribing cortexin, during and after treatment. The follow-up period was 2 months.

The manifestations of central neurotoxic reactions of moderate severity included a long-lasting headache, dizziness, weakness, fatigue, a severe state of depression, intellectual-mnestic depression, and sleep disorder. The neurological status of patients was represented by cerebroasthenic, diencephalic syndromes, often in combination with the syndrome of intellectual-mnestic disorders (Table 1).

The effectiveness of cortexin in the treatment of central neurotoxic reactions was evaluated by the results of an EEG study. The results of a study of the effectiveness of treatment of central neurotoxic reactions using cortexin are shown in Table 2.

In newly diagnosed pulmonary tuberculosis patients with neurotoxic reactions of moderate severity developed during chemotherapy, the bioelectric activity of the brain was characterized by polymorphism and instability of the background rhythm. Most of the patients showed a predominance of the alpha rhythm on the EEG, which in most cases had a pointed shape and was interspersed with numerous fast and sharp potentials and irregular slow fluctuations. Fast potentials in the beta rhythm range were recorded in most patients. Slow delta activity was represented by single, irregular waves. The presence of a theta rhythm on the EEG, which was recorded as groups of bilateral synchronous waves with an amplitude predominance in the anterior regions of the cortex, reflecting the existing dysfunction of the bilateral stem structures of the brain, turned out to be characteristic. Analysis of EEG changes showed that after the use of cortexin, the regularity and severity of the alpha rhythm increased. Fast potentials in the beta rhythm range were recorded less frequently; in a number of patients, slow fluctuations in the range of both delta and theta waves disappeared. The general character of EEG in patients with neurotoxic reactions after taking cortexin improved significantly more than in the comparison group.

Table 1 Clinical manifestations of central neurotoxic reactions CNS lesion syndromes abs. number % Diencephalic syndrome 12 one hundred Cerebroasthenic syndrome 9 75 Depressive syndrome 6 fifty Mental Disorder Syndrome 7 58.3 Sleep disorders 10 83.3

table 2 Changes in electroencephalographic parameters in patients with tuberculosis with chemotherapy-developed and treated central neurotoxic reactions EEG rhythm Diagnosed neurotoxic reaction, before treatment n = 12 20 days after the end of treatment with cortexin n = 12 abs. % abs. % number number Regular alpha rhythm 9 75 eleven 91.6 Beta rhythm 9 75 5 41.7 Delta rhythm 7 58.3 four 33.3 Theta rhythm 8 66.7 3 25.0

As a result of treatment with the use of cortexin, an improvement in the general condition, disappearance of complaints, and a clear positive dynamics in neurological status were noted in all patients. In all patients, isoniazid therapy was continued. During the 2-month observation period, there were no indications for drug withdrawal.

The clinical manifestations of peripheral neurotoxic reactions that develop while taking anti-TB drugs include pain along the nerve trunks of the lower extremities, numbness, creeping creeps, burning along the nerve trunks. In the neurological status of patients, motor, sensory, autonomic and trophic disorders were detected (Table 3). A good effect of the use of cortexin was observed in 80% of patients and was accompanied by a regression of neurological symptoms, the disappearance of a feeling of numbness and "goose bumps", and restoration of motor and sensory functions. During the 2-month observation period, there was no deterioration in the neurological status of patients; patients continued to use isoniazid.

The use of cortexin in the treatment of neurotoxic reactions gives a positive result and allows you to continue taking neurotoxic drugs and the most effective anti-TB drug isoniazid. Cortexin can be used to treat the effects of neurotoxic drugs at a dose of 10 mg intramuscularly daily for 10 days.

Table 3 Clinical manifestations of peripheral neurotoxic reactions Main symptoms abs. number % Subjective neurological symptoms: pain, burning along the nerve trunks, numbness, "crawling creeps" 10 one hundred Violation of motor functions in the form of hypotension of the muscles of the lower extremities, a decrease in knee and Achilles reflexes 2 twenty 9 90 Sensitive disorders in the lateral region of the lower leg 7 70 Trophic disorders in the form of dry skin, hypotrichosis 6 60

EXAMPLE 1: Patient U., 57 years old, hospital patient card No. 26/0404, was admitted to the GKPTD No. 4 02/10/04. for treatment. Clinical diagnosis: Infiltrative pulmonary tuberculosis, 2-sided. Office

Upon receipt complained of shortness of breath, cough, fever.

From the anamnesis of the disease: pulmonary tuberculosis was detected for the first time in 2003. She received treatment according to the I chemotherapy regimen, is in the phase of continuing treatment. Last month, deterioration in well-being in the form of the appearance of bronchopulmonary and intoxication syndromes. This condition is regarded as an exacerbation of the process, the patient is hospitalized.

Upon receipt, the state of moderate severity. Consciousness is clear. The position is active. Low power. Hard breathing, scattered dry rales, moist finely bubbling rales in the upper right are heard. Respiratory rate 20 per minute. Heart sounds are muffled, rhythmic. Heart rate 90 per minute. HELL 110/90. The abdomen is soft, painless. No peripheral edema.

X-ray: increase in infiltration, areas of enlightenment in the upper part on the right.

He was prescribed treatment according to the II regimen of chemotherapy: isoniazid - 0.45, ethambutol - 1.2, rifampicin - 0.6, pyrazinamide - 1.5 per day. After 1.5 months. Therapy noted an improvement in the general condition in the form of normalization of temperature, a decrease in cough. The patient has complaints of weakness in the legs, pain along the nerve trunks, a feeling of numbness, creeping "goose bumps".

Examined by a neurologist: impaired motor function in the form of hypotension of the muscles of the lower extremities, decreased knee and Achilles reflexes, sensitive disorders in the lateral region of the lower leg, trophic disorders in the form of dry skin. Diagnosed with peripheral polyneuropathy with impaired function of the lower extremities while taking anti-TB drugs. Recommended: withdrawal of isoniazid, cortexin 10 mg intramuscularly 10 injections.

After the course of treatment, the patient's condition improved, in neurological status, a clear positive dynamics was noted. Isoniazid therapy was continued. In the next 2 months of observation, there was no indication for drug withdrawal.

EXAMPLE 2: Patient M., 54 years old, inpatient card No. 573/142, was admitted to GKPTD No. 4 05/19/04. for treatment. Clinical diagnosis: Infiltrative pulmonary tuberculosis, right-sided, upper lobar. Office + (epidemiological No. 14569/64). Concomitant diseases: Diabetes mellitus, type II, moderate.

Upon admission, she complained of weakness, loss of appetite, cough with sputum, sweating at night.

From the anamnesis of the disease: the disease was detected for the first time during a physical examination in 2003. It was not treated as an outpatient. In late April, I felt weak. Upon examination in the analysis of sputum revealed KUM - 5 per 100 p / sp. In this connection, hospitalized. Objectively: the general condition is satisfactory, of sufficient nutrition, the skin is of a normal color, peripheral lymph nodes are not enlarged. In the lungs, percussion is a blunting in the upper right. Hard breathing on the right, dry and single wet rales are heard. Respiratory rate 18 per minute. Heart sounds are muffled, rhythmic. Heart rate 82 per minute. HELL 130/90 mm Hg The abdomen is soft, painless. The liver is not enlarged. No peripheral edema.

On the radiograph of the OGK: on the right there is a low-intensity focus in S2 and fuzzy foci on the background of fibrosis. Left without features.

He was prescribed treatment according to the I chemotherapy regimen: isoniazid - 0.6, rifampicin - 0.45, pyrazinamide - 1.5, streptomycin - 1.0 g per day. During treatment, a positive clinical and radiological dynamics was obtained - intoxication decreased, moist rales ceased to be heard, on the x-ray at the first rib and below, isolated foci were clear, small. Fibrosis is expressed.

A month after the start of treatment, the patient has complaints of dizziness, headache, irritability, and poor sleep.

Examined by a neurologist: revealed violations of the type of diencephalic and cerebroasthenic syndromes. The EEG was performed on 06/17/04. Protocol No. 895863: alpha rhythm prevails with the correct zonal distribution, amplitude of 50 μV, against this background, single sharp waves of the alpha range with an amplitude of 70 μV are recorded, bilateral synchronous discharges of the alpha range are recorded as paroxysmal activity. Beta activity in the form of fast potentials.

Conclusion: signs of irritation of secondary structures are recorded. Recommended: cortexin 10 mg intramuscularly 10 injections; phenazepam 10 mg at night.

After the course of treatment, a clear positive dynamics was obtained in the neurological status of the patient, no complaints.

Control EEG (20 days after the end of treatment with cortexin) 07/17/04. Protocol No. 920468: alpha rhythm prevails with the correct zonal distribution, amplitude of 60 μV, sharp waves are not recorded, paroxysmal activity is not recorded in the background recording, beta activity is reduced, in response to hyperventilation - bilateral synchronous discharges of the alpha range with a tendency to generalization.

Conclusion: there is a positive trend compared with the EEG from 06.17.04. - there are no sharp waves.

Isoniazid therapy was continued. There were no indications for drug withdrawal in the next 2 months of observation.

RESULTS. Of great clinical importance is the treatment of neurotoxic reactions. The use of cortexin in the treatment of neurotoxic reactions gives a positive result, allows you to continue taking anti-TB drugs with neurotoxic effects and leave isoniazid as the most effective anti-TB drug in the chemotherapy regimen. Cortexin can be used to treat the effects of neurotoxic drugs at a dose of 10 mg intramuscularly daily for 10 days.

Moreover, our proposed technique is easy to use, does not require high material costs, and the absence of contraindications to the appointment of cortexin and side effects allows it to be widely used.

Claims (1)

A method of treating adverse neurotoxic reactions caused by anti-TB drugs, characterized in that, along with the introduction of anti-TB drugs, 10 mg cortexin is used in saline, which is administered intramuscularly, for a course of 10 injections.