Cycloserine

(BAN, rINN)
Cycloserine Chemical formula
Synonyms: Cicloserina; D-Cycloserin; Cyclosérine; D-Cycloserine; Cycloserinum; Cykloserin; SC-49088; Sikloserin; Sykloseriini. (+)-(R)-4Aminoisoxazolidin-3-one.
Cyrillic synonym: Циклосерин.

💊 Chemical information

Chemical formula: C3H6N2O2 = 102.1.
CAS — 68-41-7.
ATC — J04AB01.
ATC Vet — QJ04AB01.

Description.

Cycloserine is an antimicrobial substance produced by the growth of certain strains of Streptomyces orchidaceus or S. garyphalus, or obtained by synthesis.

Pharmacopoeias.

In Jpn and US.

USP 31

(Cycloserine). A white to pale yellow, crystalline powder, odourless or has a faint odour. It is hygroscopic and deteriorates upon absorbing water. Freely soluble in water. pH of a 10% solution in water is between 5.5 and 6.5. Store in airtight containers.

💊 Adverse Effects and Treatment

The most frequent adverse effects with cycloserine involve the CNS and include anxiety, confusion, disorientation, depression, psychoses possibly with suicidal tendencies, aggression, irritability, and paranoia. Vertigo, headache, drowsiness, speech difficulties, tremor, paresis, hyperreflexia, dysarthria, paraesthesia, coma, and convulsions may also occur. Neurological reactions are dose related and may be reduced by keeping plasma concentrations below 30 micrograms/mL. It has been reported that up to 30% of patients have experienced adverse effects. These reactions usually subside when cycloserine is stopped or the dosage is reduced. Pyridoxine has been used in an attempt to treat or prevent neurological reactions but its value is unproven. Hypersensitivity reactions including skin reactions and photosensitivity occur rarely. Serum aminotransferase values may be raised, especially in patients with a history of liver disease. Folate and vitamin B12 deficiency, megaloblastic anaemia, and sideroblastic anaemia have been reported occasionally when cycloserine has been used with other antituberculous drugs. Heart failure has occurred in patients receiving daily doses of 1 g or more.

💊 Precautions

Cycloserine is contra-indicated in patients with epilepsy, depression, psychosis, severe anxiety, severe renal impairment, or in those who misuse alcohol. Cycloserine should be stopped, or the dose reduced, if skin reactions or symptoms of CNS toxicity develop. Cycloserine has a low therapeutic index, and dosage should be adjusted according to plasma concentrations, which should be monitored at least weekly in patients with renal impairment, in those taking doses greater than 500 mg daily, and in patients showing signs of neurotoxicity. Plasma concentrations should be maintained below 30 micrograms/mL. Haematological, renal, and hepatic function should be monitored. Patients with mild to moderate renal impairment require lower doses.

Breast feeding.

No adverse effects have been seen in breastfed infants whose mothers were receiving cycloserine,1 and the American Academy of Pediatrics considers2 that it is therefore usually compatible with breast feeding.
1. Morton RF, et al. Studies on the absorption, diffusion, and excretion of cycloserine. Antibiot Annu 1955-56; 3: 169–72
2. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 03/10/07)

Porphyria.

Cycloserine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

💊 Interactions

Patients receiving cycloserine and taking alcohol are at increased risk of convulsions; for reference to increased blood-alcohol concentrations in patients receiving cycloserine. Neurotoxic effects may be potentiated by use of cycloserine with ethionamide, and concurrent use of cycloserine and isoniazid may result in increased CNS toxicity, such as dizziness and drowsiness.

💊 Antimicrobial Action

Cycloserine interferes with bacterial cell wall synthesis by competing with D-alanine for incorporation into the cell wall. It has variable activity against Gram-positive and Gram-negative bacteria including Escherichia coli and Staphylococcus aureus. Cycloserine is active against Mycobacterium tuberculosis and some other mycobacteria. Resistance develops if cycloserine is used alone.

💊 Pharmacokinetics

Cycloserine is readily and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations of 10 micrograms/mL have been obtained 3 to 4 hours after a dose of 250 mg, rising to 20 to 30 micrograms/mL on repeating the dose every 12 hours. The plasma half-life is about 10 hours and is prolonged in patients with renal impairment. Cycloserine is widely distributed into body tissues and fluids, including the CSF, placenta, and breast milk, producing fetal blood concentrations approaching those in maternal serum. Cycloserine is excreted largely unchanged by glomerular filtration. About 50% of a single 250-mg dose is excreted unchanged in the urine within 12 hours and about 70% is excreted within 72 hours. As negligible amounts of cycloserine appear in the faeces, it is assumed that the remainder of a dose is metabolised to unidentified metabolites. It is removed by haemodialysis.

Pregnancy and breast feeding.

Cycloserine has been shown to pass to the fetus, into amniotic fluid,1 and into breast milk.2Concentrations in breast milk after 250 mg four times daily have been reported to range from 6 to 19 micrograms/mL.2
1. Holdiness MR. Transplacental pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1987; 13: 125–9
2. Morton RF, et al. Studies on the absorption, diffusion, and excretion of cycloserine. Antibiot Annu 1955-56; 3: 169–72.

💊 Uses and Administration

Cycloserine is a second-line antimycobacterial that may be used in the treatment of tuberculosis as part of a multidrug regimen when resistance to primary drugs has developed. It has been used in urinary-tract infections, although less toxic drugs are preferred. The usual adult oral dose in tuberculosis is 250 mg twice daily for 2 weeks, followed by 0.5 to 1 g daily in divided doses. Dosage in patients with mild to moderate renal impairment should be reduced and doses for all patients should be adjusted by monitoring plasma concentrations (see Precautions, above). For details of doses in infants, children, and adolescents, see below. Cycloserine has been tried for the adjunctive treatment of schizophrenia. L-Cycloserine has been investigated for the treatment of Gaucher disease.

Administration in children.

Use of cycloserine is licensed in both the UK and USA for children, although age ranges are not specified in licensed product information. For the treatment of drug-resistant tuberculosis the American Academy of Pediatrics (AAP) suggests a dose of 5 to 10 mg/kg twice daily, to a maximum dose of 1 g daily. The BNFC suggests the following doses:
children aged 2 to 12 years; 5 mg/kg twice daily
children aged 12 to 18 years; 250 mg twice daily for 2 weeks then adjusted to a maximum dose of 1 g daily Doses are adjusted according to blood concentrations and response.

💊 Preparations

USP 31: Cycloserine Capsules.

Proprietary Preparations

Austral.: Closina; Gr.: D-cycloserin; Seromycin; Hong Kong: Seromycin; India: Cyclorine; Thai.: Proserine; Turk.: Siklocap; UK: Cycloserine; USA: Seromycin.
Published January 30, 2019.