Long-term and subcutaneous administration of a low dose of L-cycloserine to mice significantly reduces the level of brain cerebrosides with little effect on other sphingolipids

Absorption, Distribution and Excretion
Following oral administration, cycloserine is rapidly and almost completely (70% to 90%) absorbed from the gastrointestinal tract. The value of cycloserine lies in its ability to diffuse into cells and cross the blood-brain barrier, even in the absence of disease. After oral administration, 70% to 90% of cycloserine is rapidly absorbed. Peak plasma concentrations are reached 3 to 4 hours after a single dose; in children, peak plasma concentrations range from 20 to 35 μg/ml after a 20 mg/kg dose; only trace amounts of drug remain after 12 hours. Cycloserine is distributed in body fluids and tissues. The drug has virtually no blood-brain barrier effect; cerebrospinal fluid concentrations are approximately the same as plasma concentrations in all patients. Following injection, approximately 50% of cycloserine is excreted unchanged in the urine within the first 12 hours; a total of 65% of cycloserine is recovered in its active form within 72 hours. Metabolism/Metabolites Approximately 35% of the antibiotic is metabolized into unidentified substances.

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Biological Half-Life
The half-life in patients with normal kidney function is 10 hours, while the half-life is prolonged in patients with impaired kidney function.
Normal kidney function - 10 hours. Impaired kidney function - prolonged.

Hepatotoxicity
Cycloserine has been reported to be associated with a low incidence of elevated serum transaminases, which are usually transient, asymptomatic, and do not require dose adjustment. Cycloserine is often used in combination with drugs more clearly associated with liver dysfunction, while it itself usually has little or no effect on these abnormalities. Cycloserine has not been definitively proven to be associated with clinically significant liver injury, but it is frequently used in combination with known hepatotoxic drugs, so its potential effect cannot be completely ruled out. Probability Score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Limited information from an early study suggests that a pregnant woman taking 1 gram of cycloserine daily may produce moderate levels of cycloserine in breast milk. This is not a reason to discontinue breastfeeding if the mother needs to take cycloserine, especially if the infant is older than 2 months. If this medication is taken while breastfeeding, exclusively breastfed infants should be monitored, and serum drug concentrations may be measured if necessary to rule out toxicity.
◉ Effects on Breastfed Infants
No adverse reactions were observed in 5 breastfed infants (age not specified) whose mothers took 250 mg of cycloserine orally four times daily.
5 women with multidrug-resistant tuberculosis received multidrug therapy; 4 of them took cycloserine during pregnancy and postpartum, and the other took it only postpartum. All of these infants were breastfed (feeding extent and duration not specified). At 1.25, 1.8, 3.9, 4.6, and 5.5 years of age, these children were developmentally normal, with only one child having mild language delay and another having ADHD.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

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Interactions
Isoniazid should not be used concomitantly with cycloserine due to the potential for additive central nervous system toxicity.
Cycloserine may increase the risk of seizures, especially in cases of chronic alcoholism; patients should be advised to avoid concomitant use.
Concomitant use with isoniazid may increase the incidence of central nervous system adverse reactions (such as dizziness or drowsiness); dose adjustment may be necessary, and patients should be monitored for signs of central nervous system toxicity.
Cycloserine may cause anemia or peripheral neuritis by antagonizing pyridoxine or increasing renal excretion of pyridoxine; patients receiving cycloserine treatment may have an increased need for pyridoxine.

Neurochem Res.1989 Mar;14(3):245-8;J Lipid Res.1987 Dec;28(12):1478-81.

D-Cycloserine is a 4-amino-1,2-oxazolidin-3-one with an R configuration. It is an antibiotic produced by Streptomyces garyphalus or Streptomyces orchidaceus, commonly used in multidrug regimens for tuberculosis to treat tuberculosis that has developed resistance or toxicity to first-line drugs. As an analogue of D-alanine, D-Cycloserine interferes with bacterial cell wall synthesis in the cytoplasm by competitively inhibiting L-alanine racemic enzyme (catalyzing the conversion of L-alanine to D-alanine) and D-alanine-D-alanine ligase (incorporating D-alanine into the pentapeptides required for peptidoglycan formation and bacterial cell wall synthesis). D-Cycloserine possesses multiple functions, including anti-tuberculosis, anti-infective, anti-metabolic, metabolic, and NMDA receptor agonist effects. It is an organic-oxygen heterocyclic antibiotic, an organic-nitrogen heterocyclic antibiotic, and a 4-amino-1,2-oxazolidin-3-one. It is the conjugate base of D-Cycloserine (1+). It is the enantiomer of L-cycloserine. It is the zwitterion tautomer of D-cycloserine. It is an antibiotic produced by Streptomyces garyphalus. Cycloserine is a broad-spectrum antibiotic used as a second-line treatment for drug-resistant tuberculosis, often in combination with other anti-tuberculosis drugs. Cycloserine appears to have little hepatotoxicity, but it is often used in combination with drugs known to be hepatotoxic, so its role in reported cases of liver injury due to combination therapy cannot be completely ruled out. Cycloserine has been reported to be present in Streptomyces garyphalus and Streptomyces lavendulae, and relevant data are available. Cycloserine is an analogue of the amino acid D-alanine and possesses broad-spectrum antibacterial and glycineric activity. D-Cycloserine impairs the formation of peptidoglycan, a necessary component for bacterial cell wall synthesis, by competitively inhibiting two enzymes—L-alanine racemic enzyme and D-alanine:D-alanine ligase. Depending on its concentration at the site of infection and the susceptibility of the pathogen, this drug may have bactericidal or bacteriostatic effects. Furthermore, D-Cycloserine is an excitatory amino acid and a partial agonist of the glycine-binding site of NMDA receptors in the central nervous system (CNS); binding to central NMDA receptors may alleviate neuropathic pain. It is an antibiotic substance produced by Streptomyces garyphalus. Drug Indications It can be used in combination with up to five other drugs for the treatment of Mycobacterium avium complex (MAC) infections and also for the treatment of tuberculosis (TB). Mechanism of Action Cycloserine is an analogue of the amino acid D-alanine. It interferes with early steps of bacterial cell wall synthesis in the cytoplasm by competitively inhibiting two enzymes—L-alanine racemase (which converts L-alanine to D-alanine) and D-alanylalanine synthase (which incorporates D-alanine into the pentapeptides required for peptidoglycan formation and bacterial cell wall synthesis). Tuberculosis patients treated with clinical doses of D-cycloserine show increased excretion of β-alanine and D-β-aminoisobutyric acid. Cycloserine has inhibitory effects on Mycobacterium tuberculosis at in vitro concentrations of 5 to 20 μg/ml. There is no cross-resistance between cycloserine and other anti-tuberculosis drugs. Although this antibiotic is effective against experimental infections caused by other microorganisms, in vitro studies have shown that bacteria cultured in conventional media containing D-alanine do not exhibit growth inhibition; this amino acid blocks the antibacterial activity of cycloserine. …Cycloserine inhibits D-alanine-mediated bacterial cell wall synthesis. Using D-alanine-free culture media, this antibiotic inhibited the growth of Enterococcus, Escherichia coli, Staphylococcus aureus, Nocardia spp., and Chlamydia in vitro.

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Therapeutic Uses
Anti-infectious agent, urinary tract; antibiotic, anti-tuberculosis; antimetabolite
Inhibits a variety of Gram-positive and Gram-negative bacteria, including mycobacteria. …Successfully used to treat refractory urinary tract infections caused by Streptococcus, Staphylococcus, Escherichia coli, and Enterobacter aerogenes.
Cycloserine is indicated for the treatment of tuberculosis after failure of first-line anti-tuberculosis drugs (pyrazinamide, streptomycin, isoniazid, rifampin, and ethambutol). /Included on US Product Label/
Cycloserine is used to treat atypical mycobacterial infections, such as Mycobacterium avium complex infections. /Not Included on US Product Label/
For more complete data on the therapeutic uses of cycloserine (6 in total), please visit the HSDB record page.

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Drug Warnings
Patients with a history of mental illness usually tolerate cycloserine exceptionally well, while seemingly stable individuals may develop psychotic reactions shortly after starting treatment, sometimes even before reaching therapeutic serum concentrations.
Mostly compatible maternal medications for breastfeeding: Cycloserine: Infant-reported signs or symptoms or effects on lactation: None. /Excerpt from Table 6/
This drug may accumulate to toxic concentrations in patients with renal impairment; it can be removed from the bloodstream by dialysis.
Because cycloserine is excreted by the kidneys, it may accumulate in patients with impaired renal function, increasing the risk of side effects; this drug is contraindicated in patients with impaired renal function (creatinine clearance <50 mL/min (0.83 mL/s)).
For more complete data on drug warnings for cycloserine (of 10), please visit the HSDB record page.

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Pharmacodynamics
Cycloserine is a broad-spectrum antibiotic; its bactericidal or bacteriostatic effect depends on the concentration at the site of infection and the susceptibility of the pathogen. Cyclic serine works by blocking the formation of peptidoglycan. This weakens the bacterial cell wall, ultimately leading to bacterial death.

C3H6N2O2

102.09

102.043

339-72-0

6234

White to off-white solid powder

1.278

147ºC

-1.5

2

3

0

7

92.9

1

C1[C@H](C(=O)NO1)N

DYDCUQKUCUHJBH-UWTATZPHSA-N

InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1

(4R)-4-amino-1,2-oxazolidin-3-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1.25 mg/mL (12.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.25 mg/mL (12.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.25 mg/mL (12.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (979.53 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)