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
Rapidly and almost completely absorbed (70 to 90%) from the gastrointestinal tract following oral administration.
VALUE OF CYCLOSERINE IS ENHANCED BY FACT THAT IT DIFFUSES INTO CELLS & CROSSES BLOOD-BRAIN BARRIER, EVEN IN ABSENCE OF DISEASE.
When given orally, 70% to 90% of cycloserine is rapidly absorbed. Peak concentrations in plasma are reached 3 to 4 hours after a single dose and are in the range of 20 to 35 ug/ml in children who receive 20 mg/kg; only small quantities are present after 12 hours.
Cycloserine is distributed throughout body fluids and tissues. There is no appreciable blood-brain barrier to the drug, and CSF concentrations in all patients are approximately the same as those in plasma. About 50% of a parenteral dose of cycloserine is excreted unchanged in the urine in the first 12 hours; a total of 65% is recoverable in the active form over a period of 72 hours.

---

Metabolism / Metabolites
APPROX 35% OF ANTIBIOTIC IS METABOLIZED TO AS-YET-UNIDENTIFIED SUBSTANCE.

---

Biological Half-Life
Half-life in patients with normal renal function is 10 hours, and is prolonged in patients with impaired renal function.
Normal renal function - 10 hours. Impaired renal function - prolonged.

Hepatotoxicity
Cycloserine is reported to be associated with a low rate of serum aminotransferase elevations that are usually transient and asymptomatic and do not require dose modification. Cycloserine is usually used in combination with agents that are more clearly linked to liver test abnormalities, and it generally plays little or no role in these abnormalities. Cycloserine has not been definitely linked to instances of clinically apparent liver injury, but is often used with agents that are known hepatotoxins and its possible contribution cannot always be excluded.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information from an old study indicates that maternal doses of cycloserine of 1 gram daily produce moderate levels in milk. If cycloserine is required by the mother, it is not a reason to discontinue breastfeeding, especially if the infant is older than 2 months. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.
◉ Effects in Breastfed Infants
No adverse effects were noted in 5 in breastfed infants (ages not stated) whose mothers were taking oral cycloserine 250 mg 4 times daily.
Cycloserine was used as part of multi-drug regimens to treat 5 women with multidrug-resistant tuberculosis, 4 throughout pregnancy and postpartum and the other postpartum only. The infants were breastfed (extent and duration not stated). At age 1.25, 1.8, 3.9, 4.6 and 5.5 years, the children were developing normally except for a mild speech delay in one and hyperactivity in another.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Interactions
ISONIAZID SHOULD NOT BE GIVEN WITH CYCLOSERINE BECAUSE OF POSSIBLE ADDITIVE CENTRAL NERVOUS SYSTEM TOXICITY.
/Cycloserine/ may increase the risk of seizures, especially in chronic alcohol abuse; patients should be advised to avoid concurrent use.
Concurrent use /with isoniazid/ may result in increased incidence of CNS effects such as dizziness or drowsiness; dosage adjustments may be necessary, and patients should be monitored for signs of CNS toxicity.
Cycloserine may cause anemia or peripheral neuritis by acting as a pyridoxine antagonist or increasing renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving cycloserine.

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 that has R configuration. It is an antibiotic produced by Streptomyces garyphalus or S. orchidaceus and is used as part of a multi-drug regimen for the treatment of tuberculosis when resistance to, or toxicity from, primary drugs has developed. An analogue of D-alanine, it interferes with bacterial cell wall synthesis in the cytoplasm by competitive inhibition of L-alanine racemase (which forms D-alanine from L-alanine) and D-alanine--D-alanine ligase (which incorporates D-alanine into the pentapeptide required for peptidoglycan formation and bacterial cell wall synthesis). It has a role as an antitubercular agent, an antiinfective agent, an antimetabolite, a metabolite and a NMDA receptor agonist. It is an organooxygen heterocyclic antibiotic, an organonitrogen heterocyclic antibiotic and a 4-amino-1,2-oxazolidin-3-one. It is a conjugate base of a D-cycloserine(1+). It is an enantiomer of a L-cycloserine. It is a tautomer of a D-cycloserine zwitterion.
Antibiotic substance produced by Streptomyces garyphalus.
Cycloserine is a broad spectrum antibiotic used as a second line agent for treatment of drug resistant tuberculosis, always in combination with other antituberculosis agents. Cycloserine is appears to have little or no hepatotoxic potential, but it is usually used in combination with agents that are known to be hepatotoxic, and its role in the reported cases of liver injury with combination therapy cannot always be excluded.
Cycloserine has been reported in Streptomyces garyphalus and Streptomyces lavendulae with data available.
Cycloserine is an analogue of the amino acid D-alanine with broad-spectrum antibiotic and glycinergic activities. D-cycloserine interferes with bacterial cell wall synthesis by competitively inhibiting two enzymes, L-alanine racemase and D-alanine:D-alanine ligase, thereby impairing peptidoglycan formation necessary for bacterial cell wall synthesis. This agent may be bactericidal or bacteriostatic, depending on its concentration at the infection site and the susceptibility of the organism. In addition, D-cycloserine is an excitatory amino acid and partial agonist at the glycine binding site of the NMDA receptor in the central nervous system (CNS); binding to the central NMDA receptor may result in amelioration of neuropathic pain.
Antibiotic substance produced by Streptomyces garyphalus.

---

Drug Indication
Used in combination with up to 5 other drugs as a treatment for Mycobacterium avium complex (MAC) and is also used to treat tuberculosis (TB).

---

Mechanism of Action
Cycloserine is an analog of the amino acid D-alanine. It interferes with an early step in bacterial cell wall synthesis in the cytoplasm by competitive inhibition of two enzymes, L-alanine racemase, which forms D-alanine from L-alanine, and D-alanylalanine synthetase, which incorporates D-alanine into the pentapeptide necessary for peptidoglycan formation and bacterial cell wall synthesis.
EXCRETION OF B-ALANINE & D-BETA-AMINOISOBUTYRIC ACID WAS INCR IN PT WITH TUBERCULOSIS RECEIVING CLINICAL DOSES OF D-CYCLOSERINE.
Cycloserine is inhibitory for Mycobacterium tuberculosis in concentrations of 5 to 20 ug/ml in vitro. There is no cross-resistance between cycloserine and other tuberculostatic agents. While the antibiotic is effective in experimental infections caused by other microorganisms, studies in vitro reveal no suppression of growth in cultures made in conventional media, which contain D-alanine; this amino acid blocks the antibacterial activity of cycloserine. ... Cycloserine inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis. The use of media free of D-alanine reveals that the antibiotic inhibits the growth in vitro of enterococci, E. coli, Staph. aureus, Nocardia species, and Chlamydia.

---

Therapeutic Uses
Anti-Infective Agents, Urinary; Antibiotics, Antitubercular; Antimetabolites
INHIBITS WIDE VARIETY OF BOTH GRAM-POSITIVE & GRAM-NEGATIVE BACTERIA, INCL MYCOBACTERIA. ... IT HAS BEEN USED SUCCESSFULLY AGAINST STUBBORN URINARY TRACT INFECTIONS CAUSED BY STREPTOCOCCI, STAPHYLOCOCCI, E COLI & AEROBACTER AEROGENES.
Cycloserine is indicated in combination with other antituberculars in the treatment of tuberculosis after failure of the primary medications (pyrazinamide, streptomycin, isoniazid, rifampin, and ethambutol). /Included in US product labeling/
Cycloserine is used in the treatment of atypical mycobacterial infections, such as mycobacterium avium complex. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for CYCLOSERINE (6 total), please visit the HSDB record page.

---

Drug Warnings
PATIENTS WITH HISTORY OF MENTAL ILLNESS OFTEN TOLERATE CYCLOSERINE UNUSUALLY WELL, WHEREAS APPARENTLY STABLE INDIVIDUALS MAY DEVELOP PSYCHOTIC REACTION SOON AFTER INITIATION OF TREATMENT, SOMETIMES BEFORE THERAPEUTIC SERUM LEVELS ARE ACHIEVED.
Maternal Medication usually Compatible with Breast-Feeding: Cycloserine: Reported Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/
The drug may accumulate to toxic concentrations in patients with renal insufficiency; it may be removed from the circulation by dialysis.
Because cycloserine is renally excreted, cycloserine may accumulate in patients with renal function impairment, leading to an increased risk of side effects; the medication should not be given to patients with renal function impairment (creatinine clearance of < 50 ml per minute (0.83 ml per second)).
For more Drug Warnings (Complete) data for CYCLOSERINE (10 total), please visit the HSDB record page.

---

Pharmacodynamics
Cycloserine, a broad-spectrum antibiotic, may be bactericidal or bacteriostatic, depending on its concentration at the site of infection and the susceptibility of the organism. Cycloserine works by blocking the formation of these peptidoglycans. By doing this the walls of the bacteria become weak and it results in the death of the bacteria

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.

---

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.

---

View More

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.

---

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.

---

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