Antibiotic Cycloserine is the last hope. Instructions for use. Cycloserine - instructions, use, indications, contraindications, action, side effects, analogs, dosage, composition Cycloserine release form

Cycloserine is formed during the life of Streptomyces orchidaceus and other microorganisms or is formed synthetically. Cycloserine disrupts cell wall synthesis. Cycloserine is a competitive antagonist and analogue of D-alanine. Cycloserine inhibits the activity of two enzymes that are involved in the formation of bacterial cell walls in the early stages: D-alanyl-D-alanine synthetase (ensures the inclusion of D-alanine in the pentapeptide, which is necessary for the formation of peptidoglycans) and L-alanine racemase (converts L-alanyl into D -alanine). Cycloserine is effective against Mycobacterium tuberculosis, gram-negative, gram-positive bacteria, and other microorganisms. Cycloserine exhibits a bactericidal or bacteriostatic effect depending on the sensitivity of microorganisms and concentration at the site of infection. Cycloserine is active against gram-negative microorganisms at a concentration of 10 - 100 mg/l - Rickettsia spp., Treponema spp., the minimum inhibitory concentration against Mycobacterium tuberculosis is 3 - 25 mg/l in liquid and 10 - 20 mg/l or more - on a solid nutrient medium. Cycloserine is active against Klebsiella spp., Enterobacter spp., Eschevichia coli. Resistance of Mycobacterium tuberculosis to cycloserine develops rarely and slowly; after six months of treatment, up to 20 - 30% of drug-resistant strains are isolated. Cycloserine has not shown cross-resistance with other anti-tuberculosis drugs. The effectiveness of cycloserine has been shown in chronic forms of tuberculosis, which are caused by mycobacteria that are resistant to other anti-tuberculosis drugs, atypical mycobacterioses, which are caused by the Mycobacterium xenopi complex, Mycobacterium avium-intracellulare and others.
When taken orally, cycloserine is quickly and almost completely (70 - 90%) absorbed from the gastrointestinal tract. The maximum concentration of cycloserine in the blood is achieved after 3 to 8 hours. When taken at a dose of 250 mg every 12 hours, the maximum concentration of cycloserine in the blood is 25 - 30 mcg/ml. Cycloserine almost does not bind to plasma proteins. Cycloserine is well distributed throughout body fluids and tissues, including cerebrospinal, synovial, ascitic and pleural fluids, sputum, bile, lungs, and lymphoid tissue. Cycloserine penetrates the blood-brain and placental barrier and is excreted in breast milk. The concentration of cycloserine in pleural, cerebrospinal fluid, breast milk and fetal blood approaches plasma concentrations. Cycloserine is partially (35%) biotransformed in the liver to unidentified metabolites. The half-life of cycloserine is 8 - 12 hours. Cycloserine is excreted mainly by the kidneys (by glomerular filtration) unchanged (66% within 24 hours and another 10% excreted over the next 2 days) and in small amounts with feces. Repeated doses of cycloserine may be accompanied by accumulation. In renal failure, the half-life of cycloserine increases.
No studies have been conducted to evaluate the carcinogenicity of cycloserine.
The nonreparative deoxyribonucleic acid synthesis test and the Ames test were negative.
Studies on two generations of rats have shown no impairment of fertility during the first mating and a slight decrease in fertility during the second mating. Studies on two generations of rats that received doses of up to 100 mg/kg per day did not reveal the teratogenic effect of cycloserine. The ability of cycloserine to cause harm to the fetus when taken by pregnant women has not been established.

Indications

Active form of pulmonary tuberculosis, extrapulmonary tuberculosis (including kidney damage) with sensitivity of microorganisms to cycloserine and after unsuccessful adequate therapy with the main anti-tuberculosis drugs (isoniazid, streptomycin, ethambutol, rifampicin) only in combination with other anti-tuberculosis drugs; chronic forms of tuberculosis; combination of tuberculosis with acute urinary tract infections, which are caused by sensitive strains of gram-negative and gram-positive microorganisms, especially Enterobacter spp., Klebsiella spp., Eschevichia coli with the ineffectiveness of basic drugs (it is necessary to use cycloserine for the treatment of these infections only when all conventional drugs for treatment and the sensitivity of microorganisms to it was determined); atypical mycobacterial infections (including those caused by Mycobacterium avium); urinary tract infections.

Method of administration of cycloserine and dose

Cycloserine is taken orally immediately before meals; if the mucous membrane of the gastrointestinal tract is irritated, the drug is taken after meals.
For adults, the initial dose is 250 mg 2 times a day with an interval of 12 hours during the first two weeks, then, if necessary, taking into account tolerability, the dose is carefully increased to 250 mg every 6 to 8 hours under monitoring the concentration of cycloserine in the blood, the maximum daily dose is 1 d. For children (over 3 years old), the usual dose is 10 mg/kg per day in 2 to 3 doses, then the dose varies depending on the concentration of cycloserine in the blood and the therapeutic effect; a larger dose is given only if smaller doses are insufficiently effective or in the acute phase of the tuberculosis process; The daily dose for children should not exceed 750 mg. For patients over 60 years of age, as well as for patients weighing less than 50 kg, cycloserine is prescribed 250 mg twice a day.
Before starting therapy, it is necessary to isolate cultures of microorganisms and determine the sensitivity of microorganism strains to cycloserine and other anti-tuberculosis drugs.
During therapy you should not drink alcohol.
Elderly patients with impaired renal function are prescribed lower doses of cycloserine.
During therapy, it is necessary to monitor the concentration of cycloserine in the blood (the concentration of cycloserine in the blood should not exceed 30 mg/l; at concentrations above 30 mg/ml toxicity is likely), renal and liver function, and hematological parameters.
To prevent symptoms of neurotoxicity (including convulsions, tremor, agitation), sedative or anticonvulsant medications may be used.
Careful monitoring of patients receiving cycloserine at a dose of more than 500 mg per day is necessary to identify signs of toxic effects of the drug on the central nervous system.
The use of cycloserine should be discontinued or the dose should be reduced if the patient develops allergic dermatitis or symptoms of intoxication from the central nervous system: convulsions, drowsiness, psychosis, confusion, depression of consciousness, headache, hyperreflexia, tremor, paresis, dizziness, dysarthria.
The risk of developing a seizure syndrome increases in patients with chronic alcoholism, therefore the use of cycloserine in this condition is contraindicated.
When treating patients with reduced renal function who are taking a daily dose of more than 500 mg and in whom signs and symptoms of overdose are suspected, the concentration of cycloserine in the blood should be determined at least once a week. The dose of cycloserine should be adjusted to maintain the drug concentration in the blood below 30 mg/l. Such patients should be under the direct supervision of a physician due to the possible development of toxicity symptoms.
In some cases, the use of cycloserine and other anti-tuberculosis drugs can cause a deficiency of folic acid and cyanocobalamin (vitamin B12) in the body, the development of megaloblastic anemia. If anemia develops during therapy, it is necessary to conduct appropriate examination and treatment of the patient.
The toxic effects of cycloserine can be reduced or prevented by prescribing glutamic acid 500 mg 3 - 4 times a day (before meals) during therapy, and daily intramuscular administration of the sodium salt of adenosine triphosphoric acid (1 ml of 1% solution), pyridoxine 200 - 300 mg per day.
During treatment with cycloserine, it is necessary to limit the mental stress of patients and eliminate possible factors of overheating (hot shower, exposure to the sun).
During treatment with cycloserine, it is necessary to refrain from performing potentially hazardous activities that require rapid psychomotor reactions and increased concentration (including driving, working with machinery).

Contraindications for use

Hypersensitivity, depression, epilepsy, severe agitation, chronic renal failure (creatinine clearance less than 25 ml/min), psychosis, alcoholism, mental disorders (psychosis, anxiety, depression, including a history), organic diseases of the central nervous system, chronic heart failure, convulsive seizures (including history), age under 3 years, pregnancy, breastfeeding.

Restrictions on use

Chronic renal failure (creatinine clearance more than 25 ml/min), age under 18 years.

Use during pregnancy and breastfeeding

The use of cycloserine is contraindicated during pregnancy. It has not been established whether cycloserine causes fetal harm when used in pregnant women. Cycloserine should be given to pregnant women only when absolutely necessary. During lactation, during cycloserine therapy, it is necessary to stop breastfeeding or stop taking cycloserine during breastfeeding, taking into account the significance of drug treatment for the mother.

Side effects of cycloserine

Nervous system and sensory organs: tremor, headache, dysarthria, convulsions, epileptic convulsions, dizziness, drowsiness, semi-consciousness, disorientation, confusion, memory loss, psychosis, anxiety, insomnia, stupor, suicidal behavior, peripheral neuritis, euphoria, suicide attempts, change in character, aggressiveness, increased irritability, paresis, paresthesia, depression, attacks of clonic convulsions, hyperreflexia, coma.
Digestive system: nausea, heartburn, increased serum aminotransferase levels (especially in elderly patients with liver disease).
Cardiovascular system and blood (hematopoiesis, hemostasis): congestive heart failure, exacerbation of chronic heart failure, megaloblastic anemia, sideroblastic anemia.
Allergic reactions: skin rash, itching.
Others: fever, increased cough.

Interaction of cycloserine with other substances

Cycloserine helps reduce resistance to streptomycin, isoniazid, para-aminosalicylic acid.
Isoniazid and ethionamide (including as part of combination drugs) when used together with cycloserine mutually increase neurotoxicity.
Cycloserine is incompatible with alcohol (the risk of developing epileptic seizures increases).
Azithromycin slows down elimination, increases the concentration of cycloserine in the blood and increases the risk of toxicity.
Cycloserine mutually enhances the effect of the combined drugs amoxicillin + clavulanic acid, amoxicillin + sulbactam.
In a placebo-controlled clinical trial in patients with multidrug-resistant tuberculosis, no significant pharmacokinetic interaction between bedaquiline and cycloserine was observed.
There may be an interaction between cycloserine and the combination of benfotiamine + pyridoxine.
Resistance of the BCG vaccine to cycloserine has been observed.
Cycloserine weakens the effect of pyridoxine (including in various combinations) by increasing the rate of pyridoxine excretion by the kidneys (can cause the development of anemia, peripheral neuritis, an increase in the dose of pyridoxine is necessary).
In the combination treatment of tuberculosis, it is necessary to take into account the additive effect on the central nervous system of prothionamide (as part of the combination pyrazinamide + prothionamide + rifabutin + [pyridoxine]) and cycloserine.
Prothionamide (as part of the combinations lomefloxacin + pyrazinamide + prothionamide + ethambutol, lomefloxacin + pyrazinamide + prothionamide + ethambutol + pyridoxine) is compatible with cycloserine.
Cycloserine reduces the effect of pyridoxal phosphate.
The combination of pyridoxine + thiamine + cyanocobalamin + [lidocaine] may interact with cycloserine.
Concomitant use of pyridoxine with cycloserine may cause neuropathy and anemia.
When prothionamide and cycloserine are used together, seizures become more frequent.
When used together, folic acid reduces the effects of cycloserine.

Overdose

Acute overdose can be observed when using cycloserine in a dose of more than 1 g. Signs of overdose can be observed when the content of cycloserine in the blood serum is 25 - 30 mg/ml (taking high doses, if more than 500 mg of cycloserine is introduced into the body daily, impaired renal clearance). In case of an overdose of cycloserine, headache, increased irritability, dizziness, paresthesia, paresis, dysarthria, convulsions, semi-consciousness, psychosis, confusion, coma develop.
taking activated carbon (may be more effective than inducing vomiting and gastric lavage); symptomatic and supportive treatment; for seizures, the use of antiepileptic drugs; To prevent neurotoxic effects, pyridoxine (200 - 300 mg per day), nootropic drugs (piracetam, glutamic acid), and benzodiazepine drugs (diazepam) are used. Hemodialysis removes cycloserine from the blood, but does not exclude the development of life-threatening intoxication.

Trade names of drugs with the active ingredient cycloserine

Combined drugs:
Cycloserine + Pyridoxine: Coxerine Plus, Cyclo plus, Cyclomycin® plus.

J.04.A.B Antibiotics

J.04.A.B.01 Cycloserine

Cyclocarine, Cyclovalidin, Closin, Farmiserina, Novoserin, Orientomycin, Oksamycin, Serocycline, Seromycin, Tebemycin, Tizomycin

Recipe (international)

Rp.: Tab. Cycloserini 0.25
N. 40
D.S. 1 tablet 3 times a day (before meals)

pharmachologic effect

The drug has a wide spectrum of antibacterial action: it inhibits gram-positive and gram-negative bacteria. The most valuable property is its ability to inhibit the growth of Mycobacterium tuberculosis (the causative agent of tuberculosis). Its activity is inferior to streptomycin, isoniazid and ftivazid, but it acts on mycobacterium tuberculosis that is resistant to these drugs and para-aminosalicylic acid.

Mode of application

For adults: Orally, immediately before meals (if irritation of the gastrointestinal mucosa - after meals), for adults - 0.25 g of Cycloserine every 12 hours for the first 12 hours, then, if necessary, taking into account tolerance, the dose is carefully increased to 250 mg every 6-8 hours under monitoring the concentration of the drug in the blood serum.

The maximum daily dose is 1 g. For patients over 60 years of age, as well as with a body weight of less than 50 kg, 0.25 g 2 times a day. The daily dose of Cycloserine for children is 0.01-0.02 g/kg (not higher than 0.75 g/day).

Indications

Cycloserine is considered as a “reserve” anti-tuberculosis drug, i.e. prescribed to patients with chronic forms of tuberculosis in whom the previously used main drugs have ceased to have an effect
.
Cycloserine can also be combined with essential drugs to prevent the development of resistance (drug resistance) in mycobacteria. It is also possible to combine cycloserine with other second-line drugs, ethionamide, pyrazinamide, etc.

Contraindications

Hypersensitivity, epilepsy, depression, severe agitation, psychosis, severe renal failure, alcoholism.

Side effects

From the nervous system: headache, dizziness, insomnia or drowsiness, nightmares, anxiety, irritability, memory loss, paresthesia, peripheral neuritis, tremor, euphoria, depression, suicidal ideation, psychosis, epileptiform convulsions.

From the digestive system: nausea, heartburn, diarrhea.

Other: fever, increased cough.

Overdose.

Overdose is observed when the concentration of Cycloserine in plasma is 25-30 mg/ml - taking high doses, impaired renal clearance; Acute poisoning can occur when more than 1 g/day is ingested.

Symptoms of chronic intoxication with long-term use at a dose of more than 500 mg/day: headache, dizziness, confusion, increased irritability, paresthesia, psychosis, dysarthria, paresis, convulsions, coma.
Treatment of overdose with Cycloserine: symptomatic, activated charcoal, antiepileptic drugs. To prevent neurotoxic effects, pyridoxine is administered at a dose of 200-300 mg/day, anticonvulsants and sedatives.

Release form

Tablets or capsules, 0.25 g.

ATTENTION!

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COMPOUND
Each capsule contains: active substance: cycloserine - 250 mg. Excipients: talc, capsule composition: sunset yellow dye E110 (EP), quinoline yellow dye E104 (EP),

titanium dioxide E171 (EP), gelatin (EP).

DESCRIPTION
Hard gelatin capsules No. 0 are white with an orange cap.

The contents of the capsules are white or almost white powder.

Pharmacotherapeutic group: antibiotic

ATX code: .

PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Cycloserine is a broad-spectrum bactericidal antibiotic. Cycloserine inhibits the synthesis of the cell membrane of sensitive strains of gram-positive and gram-negative bacteria and Mycobacterium tuberculosis. Active against gram-negative microorganisms, at a concentration of 10-100 mg/l - Rickettsia spp., Treponema spp.. MIC against Mycobacterium tuberculosis is 3-25 mg/l in liquid and 10-20 mg/l or more in solid nutrient medium. Drug resistance occurs slowly (after 6 months of treatment observed in 20-60% of cases).

Pharmacokinetics
Cycloserine is rapidly absorbed from the gastrointestinal tract after oral administration, reaching detectable concentrations in plasma within one hour, freely distributed in body fluids and tissues. Cycloserine penetrates the BBB, concentrations in the cerebrospinal fluid are approximately the same as in blood plasma. In patients with tuberculosis, Cycloserine is found in sputum, as well as in pleural and ascitic fluids, bile, amniotic fluid and fetal blood, in breast milk, lung tissue and lymphoid tissue.
About 66% of the drug dose is excreted unchanged in the urine within
24 hours. 10% - within the next 48 hours. Excreted in small amounts with feces. About 35% is metabolized, but the metabolites have not yet been identified.
The half-life of cycloserine is between 8-12 hours.
Cycloserine crosses the placenta. The abdominal and pleural cavity contains
50-100% of the concentration of the drug in the blood serum. T1/2 with normal renal function - 10 hours. With chronic renal failure, cumulation phenomena may occur after 2-3 days.

INDICATIONS FOR USE
Active pulmonary tuberculosis; extrapulmonary tuberculosis (including kidney disease), provided that microorganisms are sensitive to this drug and after ineffective treatment with adequate doses of basic drugs (streptomycin, isoniazid, rifampicin and ethambutol). The drug should be used in combination with other chemotherapeutic agents, and not as monotherapy. Atypical bacterial infections (including those caused by Mycobacterium avium).
Acute urinary tract infections caused by sensitive
strains of gram-positive and gram-negative bacteria, especially
Klebsiella/Enterobacter and Escherichia coli species. When treating infections
urinary tract infections caused by bacteria other than mycobacteria,
Cycloserine is usually as effective as other antimicrobials.
Cycloserine should be used to treat these infections only after
all conventional means of treatment have been exhausted, and when the sensitivity of microorganisms to this drug has been established.

CONTRAINDICATIONS
Hypersensitivity to cycloserine; Epilepsy, epileptic seizures (including a history);
Depression;
Severe states of agitation or psychosis;
Heart failure;
Severe renal failure;
Alcohol abuse; Children under 3 years of age.

CAREFULLY
Children's age (see section "Dosage and Administration"). Treatment with cycloserine should be discontinued or the dose should be reduced if the patient develops allergic dermatitis or symptoms of damage to the central nervous system, such as convulsions, psychosis, drowsiness, depression, confusion, hyperreflexia, headache, tremor, dizziness, paresis or dysarthria.
Poisoning is usually observed when the drug concentration in the blood is more than 30 g/ml, which may be the result of an overdose or impaired renal clearance.
The therapeutic index of this drug is low. The risk of developing seizures increases in patients with chronic alcoholism.
When taking the drug, hematological parameters, renal excretory function, blood levels of the drug and the state of liver function should be monitored.
Before starting treatment with cycloserine, it is necessary to isolate a culture of microorganisms and determine the sensitivity of the strains to this drug. In the case of tuberculosis infection, it is necessary to determine the sensitivity of the strain to other anti-tuberculosis drugs.
When treating patients with reduced renal function taking a daily dose of more than 500 mg who are suspected of showing signs and symptoms of poisoning, drug levels in the blood should be monitored at least once a week. The dose must be adjusted to maintain blood levels of the drug below 30 mg/ml.
Anticonvulsants or sedatives may be effective in preventing symptoms of central nervous system toxicity, such as seizures, agitation, or tremors.
Patients receiving more than 500 mg of cycloserine per day should be closely monitored due to the possible development of similar symptoms. The value of pyridoxine in preventing CNS poisoning with cycloserine has not been established. In some cases, the use of cycloserine and other anti-tuberculosis drugs caused the development of vitamin B12 and/or folic acid deficiency, megaloblastic and sideroblastic anemia. If anemia occurs during treatment, it is necessary to conduct appropriate examination and treatment of the patient.

USE DURING PREGNANCY AND BREASTFEEDING
Use during pregnancy. Concentrations in fetal blood approach those found in serum. Studies on 2 generations of rats receiving doses up to 100 mg/kg body weight/day showed no teratogenic effect in newborns. It has not been established whether cycloserine causes fetal harm when administered to pregnant women only when absolutely necessary. Use during breastfeeding. Concentrations in human milk approach those found in serum. The decision to discontinue breastfeeding or discontinue drug treatment must be made taking into account the significance of drug treatment for the mother.

METHOD OF APPLICATION AND DOSES
Orally, immediately before meals (if irritation of the gastrointestinal mucosa - after meals), adults - 0.25 g every 12 hours for the first 12 hours, then, if necessary, taking into account tolerance, the dose is carefully increased to 250 mg every 6-8 hours under the control of drug concentration in blood serum.
The maximum daily dose is 1 g. For patients over 60 years of age, as well as with a body weight of less than 50 kg, 0.25 g 2 times a day. The daily dose for children is 0.01-0.02 g/kg (not higher than 0.75 g/day).

SIDE EFFECT
Most of the side effects observed during treatment with cycloserine were associated with the nervous system or were manifestations of hypersensitivity to the drug. From the nervous system (due to high doses of the drug (more than 500 mg per day)): convulsions, drowsiness, insomnia, nightmares dreams, semi-consciousness, headache, tremor, dysarthria, dizziness, confusion and disorientation accompanied by memory loss, anxiety, peripheral neuritis, psychosis, possibly with suicide attempts, character changes, euphoria, depression, increased irritability, aggressiveness, paresis, hyperreflexia, paresthesia, large and small attacks of clonic convulsions and coma.
From the digestive system: nausea, heartburn, diarrhea.
Other established side effects include allergic reactions, pruritus, megaloblastic anemia, and increased serum aminotransferases, particularly in elderly patients with pre-existing liver disease.
Sudden development of congestive heart failure has been observed in patients taking 1 to 1.5 g of cycloserine per day. Other: fever, increased cough.

OVERDOSE
In case of overdose, symptomatic treatment is recommended. Interaction with other drugs. Cycloserine increases the rate of excretion of pyridoxine by the kidneys (can cause the development of anemia and peripheral neuritis, which requires an increase in the dose of pyridoxine). Alcohol and cycloserine are incompatible, especially when treated with high doses of cycloserine. Alcohol increases the possibility and danger of epileptic seizures. Patients receiving cycloserine and isoniazid should be monitored for signs of CNS toxicity, such as dizziness and somnolence, as these drugs cause additive CNS toxicity. Ethionamide increases the risk of CNS side effects, especially seizures.

SPECIAL INSTRUCTIONS
The toxic effect of cycloserine can be prevented or reduced by prescribing glutamic acid 0.5 g 3-4 times a day (before meals) during treatment, and daily intramuscular administration of the sodium salt of ATP (1 ml of 1% solution), pyridoxine 200- 300 mg/day. It is necessary to limit the mental stress of patients and exclude possible factors of overheating (staying in the sun with bare head, hot shower). Due to the rapid development of resistance during monotherapy with cycloserine, its combination with other anti-tuberculosis drugs is recommended.
Effect on the ability to drive a car and use machinery. Not established.

RELEASE FORM
Capsules 250 mg. 100 capsules per bottle made of high-density polyethylene with a screw cap (with a schematic drawing showing instructions for opening the bottle), equipped with first-opening protection in the form of a ring and induction sealing of foil. 1 bottle along with instructions for use in a cardboard pack.

BEST BEFORE DATE
2 years. Do not use after the date indicated on the package.

STORAGE CONDITIONS
List B. In a dry place, protected from light, at a temperature not exceeding 25 ° C.

VACATION CONDITIONS
On prescription.

MANUFACTURER
JSC "Biocom", Russia,

• Instructions for use Cycloserine
• Composition of the drug Cycloserine
• Indications for the drug Cycloserine
• Storage conditions for the drug Cycloserine
• Shelf life of the drug Cycloserine

ATX code: Antimicrobials for systemic use (J) > Drugs active against mycobacteria (J04) > Antituberculosis drugs (J04A) > Antibiotics (J04AB) > Cycloserine (J04AB01)

Release form, composition and packaging

Capsules hard gelatin, white, size No. 0.

Excipients: calcium stearate, sodium lauryl sulfate, lactose monohydrate.

Shell composition capsules: gelatin, titanium dioxide.

10 pieces. - contour cell packaging (3) - cardboard packs.

Description of the drug CYCLOSERINE based on officially approved instructions for use of the drug and made in 2013. Update date: 03/18/2015

pharmachologic effect

Cycloserine has a wide spectrum of antibacterial action:

• inhibits gram-positive and gram-negative bacteria, including Escherichia coli and Staphylococcus aureus, at a concentration of 10-100 mg/l - Rickettsia spp., Treponema spp. It acts bacteriostatically or bactericidal depending on the concentration at the site of infection and the sensitivity of microorganisms. The most valuable property of Cycloserine is its ability to inhibit the growth of Mycobacterium tuberculosis (anti-tuberculosis antibiotic). The MIC in relation to Mycobacterium tuberculosis is 3-25 mg/l in liquid and 10-20 mg/l or more in solid nutrient medium. It is inferior in activity to streptomycin, tubazid and ftivazid, but acts on mycobacterium tuberculosis resistant to these drugs and PAS. Resistance of M. tuberculosis to cycloserine develops slowly and rarely; after 6 months of therapy, up to 20-30% of resistant strains are isolated. No cross-resistance with other anti-tuberculosis drugs has been detected. Active regarding Mycobacterium avium.

The mechanism of action is to inhibit the synthesis of the Mycobacterium cell wall. At an early stage, D-alanine molecules are joined together. Cycloserine, being an analogue of the amino acid D-alanine, competitively inhibits the activity of the enzymes L-alanine racemase, which converts L-alanine into D-alanine, and B-alanyl-B-alanine synthetase, which includes D-alanine into pentapeptide, which is necessary for the formation of peptidoglycans and synthesis bacterial walls.

Pharmacokinetics

Cycloserine is quickly and almost completely (70-90%) absorbed from the gastrointestinal tract after oral administration, creating detectable concentrations after 1 hour. It is slightly bound to plasma proteins (<20%), свободно распределяется по биологическим жидкостям и тканям организма. Циклосерин проникает через гематоэнцефалический и плацентарный барьеры. У больных туберкулезом циклосерин обнаруживается в мокроте, а также в плевральной и асцитической жидкостях, а также в крови плода, в грудном молоке, тканях легких и лимфоидной ткани, в мокроте, желчи.

Moreover, the concentration in cerebrospinal fluid, pleural and ascitic fluid is approximately the same as in blood plasma. After taking a dose of 250 mg, peak plasma concentrations of approximately 10 mg/l are achieved within 3-4 hours; after taking a dose of 250 mg every 12 hours, Cmax is 25-30 mcg/ml. Doubling the dose results in doubling the peak plasma concentration, indicating dose proportionality. Then the concentration of the drug in plasma decreases rapidly, 50% of the drug is eliminated within 12 hours.

About 60-70% of an oral dose of cycloserine is excreted by the kidneys (glomerular filtration) in an unchanged active form within 24 hours. The other 10% is excreted in the next 48 hours. About 35% of the dose taken is metabolized in the liver, but the metabolites are not identified, and are excreted in the urine. It is excreted with feces in small quantities.

It has been established that T1/2 of the drug ranges from 8 to 12 hours, on average 10 hours. In case of renal failure, T1/2 increases.

Repeated doses may be accompanied by accumulation.

Indications for use

As part of complex therapy:

• active pulmonary tuberculosis, extrapulmonary tuberculosis (including kidney damage) in case of microorganism sensitivity to the drug and after unsuccessful adequate treatment with basic drugs, chronic forms of tuberculosis;
• combination of tuberculosis with acute urinary tract infections caused by sensitive strains of gram-positive and gram-negative bacteria, especially Klebsiella spp., Enterobacter coli with the ineffectiveness of basic drugs.
• atypical mycobacterial infections (including those caused by Mycobacterium avium);
• urinary tract infections.

Dosage regimen

Orally, immediately before meals (if irritation of the gastrointestinal mucosa - after meals).

Adults: the usual dose is from 500 mg to 1 g/day. The initial dose for adults is most often 250 mg 2 times / day with a 12-hour interval during the first two weeks, then, if necessary, taking into account tolerability, the dose is carefully increased to 250 mg every 6-8 hours under monitoring the concentration of the drug in the blood serum. The daily dose should not exceed 1 g.

Patients over 60 years of age, as well as with a body weight of less than 50 kg, the drug is prescribed at a dose of 250 mg 2 times a day.

In children over 3 years old The initial dose of cycloserine is 10-20 mg/kg body weight per day in 2-3 doses (not higher than 750 mg/day; a large dose is given only in the acute phase of the tuberculosis process or if smaller doses are insufficiently effective).

Side effects

When treating with cycloserine, side effects may be observed, mainly due to the toxic effect on the nervous system when taking the drug in high doses, more than 500 mg/day: headache, dizziness, insomnia (sometimes, on the contrary, drowsiness), anxiety, aggressiveness, increased irritability, confusion of thoughts, disorientation, accompanied by memory loss, memory impairment, peripheral neuritis, paresis, hyperreflexia, paresthesia, tremor, attacks of clonic convulsions. Sometimes more severe symptoms are possible:

• feelings of fear, psychosthenic states, hallucinatory phenomena, psychosis with suicidal attempts, character changes, epileptiform seizures, semi-consciousness or loss of consciousness.

From the gastrointestinal tract: nausea, heartburn, diarrhea, especially in elderly patients with pre-existing liver disease.

From the cardiovascular system: There was a sudden development of congestive heart failure in patients taking the drug at a dose of 1-1.5 g/day.

From the hematopoietic system: in some cases - megaloblastic and sideroblastic anemia.

Others: allergic reactions, skin rash, itching, deficiency of cyanocobalamin and folic acid, increased transaminase activity (especially in elderly patients with liver disease), exacerbation of CHF was observed when used at a dose of 1000-1500 mg/day.

These phenomena usually resolve with dose reduction or drug discontinuation. The toxic effect of cycloserine can be prevented or reduced by prescribing glutamic acid 0.5 g 3-4 times a day (before meals) during the treatment period; It is also recommended to administer the sodium salt of adenosine triphosphoric acid intramuscularly - 1 ml of a 1% solution daily. Sometimes the administration of pyridoxine is effective (1-2 ml of 5% solution intramuscularly per day). If necessary, you can take anticonvulsants, sedatives, and antidepressants.

To reduce adverse reactions, it is necessary to limit the mental stress of patients and exclude possible factors of overheating (staying in the sun with bare head, hot shower, etc.), which can provoke complications.

Use during pregnancy and breastfeeding

Use during pregnancy:

• It has not been established whether cycloserine causes fetal harm when used in pregnant women. Cycloserine should be prescribed to pregnant women only when absolutely necessary.

Use during breastfeeding:

• concentrations in human milk approach those found in maternal serum. The decision to stop breastfeeding or discontinue drug treatment must be made taking into account the significance of drug treatment for the mother.

Use for renal impairment

When treating patients with reduced renal function who are taking a daily dose of more than 500 mg and who are suspected of showing signs and symptoms of overdose, drug levels in the blood should be monitored at least once a week. The dose must be adjusted so as to maintain the drug level in the blood below 30 mg/l.

Patients (especially elderly) with impaired renal function are prescribed lower doses.

Use is prohibited in patients with chronic renal failure (creatinine clearance less than 50 ml/min).

special instructions

Before starting treatment with cycloserine, cultures of microorganisms should be isolated and the sensitivity of the strains to cycloserine should be determined. In the case of tuberculosis infection, it is necessary to determine the sensitivity of the strain to other anti-tuberculosis drugs. Patients receiving more than 500 mg of cycloserine per day should be under the direct supervision of a physician due to the possible development of side effects from the central nervous system.

Treatment with cycloserine should be discontinued or the dose should be reduced if the patient develops allergic dermatitis or symptoms of central nervous system intoxication, for example: convulsions, psychosis, drowsiness, depression or confusion, hyperreflexia, headache, tremor, dizziness, paresis or dysarthria. Risk of developing convulsions syndrome increases in patients with chronic alcoholism, therefore the use of cycloserine in this condition is contraindicated. Anticonvulsants or sedatives may be effective in preventing neurotoxic reactions, for example:

• convulsions, agitation or tremors.

When taking the drug, hematological parameters, renal excretory function, the concentration of cycloserine in the blood and the state of liver function should be monitored. The concentration of cycloserine in the blood should not exceed 30 mg/ml. When treating patients with reduced renal function who are taking a daily dose of more than 500 mg and who are suspected of showing signs and symptoms of overdose, drug levels in the blood should be monitored at least once a week. The dose must be adjusted so as to maintain the drug level in the blood below 30 mg/l. Such patients should be under the direct supervision of a physician due to the possible development of toxicity symptoms. Patients (especially elderly) with impaired renal function are prescribed lower doses.

Cumulation of the drug can also develop in patients with normal renal function, which makes it necessary to reduce the dose of the drug. In some cases, the use of cycloserine and other anti-tuberculosis drugs can cause a deficiency of cyanocobalamin (vitamin B 12) and folic acid in the body, and the development of megaloblastic anemia. If anemia occurs during treatment, it is necessary to conduct appropriate examination and treatment of the patient.

The toxic effect of cycloserine can be prevented or reduced by prescribing glutamic acid 0.5 g 3-4 times a day (before meals) during treatment, and daily intramuscular administration of sodium salt of adenosine triphosphoric acid (1 ml of 1% solution), pyridoxine 200 -300 mg/day.

It is necessary to limit the mental stress of patients and exclude possible factors of overheating (staying in the sun with bare head, hot shower).

During the treatment period, avoid drinking alcohol.

Impact on the ability to drive vehicles and other potentially dangerous mechanisms.

Because Since cycloserine has a toxic effect on the central nervous system, while taking the drug it is recommended to avoid driving, operating machinery and performing other work that requires concentration.

Overdose

Symptoms: toxic effects include mainly central nervous system symptoms: headache, dizziness, irritability, paresthesia, dysarthria, paresis, convulsions, psychosis, confusion or loss of consciousness (coma).

An overdose is observed when the concentration of cycloserine in plasma is 25-30 mg/ml (taking high doses, impaired renal clearance; acute poisoning can occur when ingesting more than 1 g / day). Symptoms of chronic intoxication with long-term use at a dose of more than 500 mg/day.

Treatment: All activities are carried out against the background of cycloserine withdrawal:

• intake of activated carbon and maintenance therapy, hemodialysis, administration of 200-300 mg/day of pyridoxine in order to stop the development of neurotoxic effects, anticonvulsants and sedatives are prescribed if necessary.

Drug interactions

Concomitant use of cycloserine and ethionamide potentiates side neurotoxic effects.

Simultaneous intake of alcohol and cycloserine, especially at high doses of the latter, increases the possibility and risk of developing epileptic seizures. Patients receiving concomitant cycloserine and isoniazid should be closely monitored to avoid the development of symptoms of CNS toxicity, such as dizziness and drowsiness, because These drugs have a combined toxic effect on the central nervous system. Dose adjustment may be necessary.

Simultaneous use of cycloserine and other anti-tuberculosis drugs can lead to deficiency of vitamin B 12 and/or folic acid, megaloblastic anemia, sideroblastic anemia. Increases the rate of excretion of pyridoxine by the kidneys (may cause the development of anemia and peripheral neuritis, an increase in the dose of pyridoxine is required).