Cycloserine

Clinical data
Trade names	Seromycin
Synonyms	4-amino-3-isoxazolidinone
AHFS/Drugs.com	Monograph
License data	US FDA: Seromycin
Pregnancy category	C
ATC code	J04AB01 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	~70% to 90%
Metabolism	liver
Elimination half-life	10 hrs (normal kidney function)
Excretion	kidney
Identifiers
IUPAC name (R)-4-Amino-1,2-oxazolidin-3-one
CAS Number	68-41-7 Y
PubChem CID	6234
DrugBank	DB00260 Y
ChemSpider	5998 Y
UNII	95IK5KI84Z
KEGG	D00877 Y
ChEBI	CHEBI:40009 Y
ChEMBL	ChEMBL771 Y
NIAID ChemDB	007654
ECHA InfoCard	100.000.626
Chemical and physical data
Formula	C3H6N2O2
Molar mass	102.092 g/mol
3D model (JSmol)	Interactive image
SMILES O=C1NOC[C@H]1N
InChI InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1 Y Key:DYDCUQKUCUHJBH-UWTATZPHSA-N Y
.mw-parser-output .nobold{font-weight:normal}   (verify)

Cycloserine, sold under the brand name Seromycin, is an antibiotic used to treat tuberculosis.^[1] Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis.^[1] It is given by mouth.^[1]

Common side effects include allergic reactions, seizures, sleepiness, unsteadiness, and numbness.^[1] It is not recommended in people who have kidney failure, epilepsy, depression, or are alcoholics.^[1] It is unclear if use during pregnancy is safe for the baby.^[1] Cycloserine is similar in structure to the amino acid d-alanine and works by interfering with the formation of the bacteria's cell wall.^[1]

Cycloserine was discovered in 1954 from a type of Streptomyces.^[2] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] The wholesale cost in the developing world is about US$29.70–51.30 per month.^[4] In 2015, the cost in the United States was increased to US$3,150 a month and then decreased to US$1,050 per month.^[5]

Medical uses[edit]

Tuberculosis[edit]

For the treatment of tuberculosis, cycloserine is classified as a second-line drug, i.e. its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors).^[6][7] Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures.^[7] Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.

Psychiatry[edit]

A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015.^[8] Another review found preliminary evidence of benefit.^[9] Evidence for use in addiction is tentative but also unclear.^[10]

Mechanism of action[edit]

Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria.^[11][12] As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).^[12] The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.^[12] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules.^[12] If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together.^[12] This effectively leads to inhibition of peptidoglycan synthesis.^[12]

Chemical properties[edit]

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine.^[13][14] Cycloserine can be thought of a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.

Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.^[13]

History[edit]

The compound was first isolated nearly simultaneously by two teams. Workers at Merck isolated the compound, which they called oxamycin, from a species of Streptomyces.^[15] The same team prepared the molecule synthetically.^[16] Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine.^[17]

Economics[edit]

In the U.S., the price of cycloserine increased from $500 for 30 pills to $10,800 in 2015 after the Chao Center for Industrial Pharmacy and Contract Manufacturing changed ownership to Rodelis Therapeutics in August 2015.^[18]

The price increase was rescinded after the previous owner, the Purdue University Research Foundation, which retained "oversight of the manufacturing operation" intervened and Rodelis returned the drug to an NGO of Purdue University. The foundation now will charge $1,050 for 30 capsules, twice what it charged before". Eli Lilly has been criticised for not ensuring that the philanthropic initiative continued. Due to US antitrust laws however, no company may control the price of a product after it is outlicensed.^[5]

Research[edit]

There is some experimental evidence to suggest that D-cycloserine aids in learning by helping form stronger neural connections.^[19] It has been investigated as an aid to facilitate exposure therapy in people with PTSD and anxiety disorders^[20][21] as well as treatment with schizophrenia.^[22]

References[edit]