Clinical data | |
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Trade names | Seromycin |
Other names | D-cycloserine, 4-amino-3-isoxazolidinone |
AHFS/Drugs.com | Monograph |
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Pharmacokinetic data | |
Bioavailability | ~70% to 90% |
Metabolism | Liver |
Elimination half-life | 10 hrs (normal kidney function) |
Excretion | Kidney |
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ECHA InfoCard | 100.000.626 |
Chemical and physical data | |
Formula | C3H6N2O2 |
Molar mass | 102.093 g·mol−1 |
3D model (JSmol) | |
Melting point | 155 to 156 °C (311 to 313 °F) (dec.) |
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Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. [1] [2] Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. [2] It is given by mouth. [2]
Common side effects include allergic reactions, seizures, sleepiness, unsteadiness, and numbness. [2] It is not recommended in people who have kidney failure, epilepsy, depression, or are alcoholics. [2] It is unclear if use during pregnancy is safe for the baby. [2] Cycloserine is similar in structure to the amino acid D-alanine and works by interfering with the formation of the bacteria's cell wall. [2]
Cycloserine was discovered in 1954 from a type of Streptomyces . [3] It is on the World Health Organization's List of Essential Medicines. [4]
For the treatment of tuberculosis, cycloserine is classified as a second-line drug. 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). [5] [6] Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures. [6] Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.[ citation needed ]
A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015. [7] Another review found preliminary evidence of benefit. [8] Evidence for use in addiction is tentative but also unclear. [9]
Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria. [10] [11] 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). [11] The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. [11] 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. [11] If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined. [11] This effectively leads to inhibition of peptidoglycan synthesis. [11]
Psychiatric use is suggested based on partial NMDA receptor agonism, which improves neural plasticity in lab animals. The degree of clinical usefulness is, as aforementioned, very unclear and still being explored. [8]
Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine. [12] [13] Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.[ citation needed ]
Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5. [12]
Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis from DL‐β‐aminoxyalanine ethyl ester. In 1957, Platter et al. managed to synthesis the pure D-enantiomer by cyclizing the corresponding α‐amino‐β‐chlorohydroxamic acids. Chemical synthesis of the compound was revolutionized in the 2010s, when several approaches starting with the cheap D-serine (mirror form of normal L-serine) were published by different groups. [14]
The biosynthesis of the compound is defined by a ten-gene cluster. L-serine and L-arginine are converted to O-ureido-L-serine, flipped to O-ureido-D-serine, then turned into the final compound by cyclization. In 2013, Uda et al. successfully used recombinant versions of three enzymes in the cluster to produce the compound. [15]
A 1963 patent describes industrial production of the drug by bacterial fermentation. [16] It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.[ citation needed ]
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. [17] The same team prepared the molecule synthetically. [18] Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine. [19]
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. [20]
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. [21]
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. [21]
Some experimental evidence suggests that D-cycloserine aids in learning by helping form stronger neural connections. [22] It has been investigated as an aid to facilitate exposure therapy in people with PTSD and anxiety disorders, [23] [24] [25] and treatment with schizophrenia. [26] In a clinical trial, a course of D-cycloserine combined with a single dose of ketamine was investigated for treatment resistant bipolar depression. When administered for 8 weeks after a ketamine infusion, cycloserine appeared to potentiate the antidepressant effects in all trial participants. [27] However, a 2019 clinical trial showed no statistically significant difference between the D-cycloserine and placebo groups when it came to maintaining the antidepressant effect of a single ketamine infusion. The authors suggest several possible explanations for this nonsignificance, namely the inclusion of high-risk or severely treatment-resistant participants as well as a possible confounding carryover effect from the ketamine infusion phase. Although the results point to D-cycloserine having a stronger antisuicidal effect than placebo, the authors caution that this difference might be attributed to the placebo group feeling worse than the D-cycloserine feeling better. [28] A combination drug, cycloserine/lurasidone, containing D-cycloserine and the atypical antipsychotic lurasidone is being developed for acute suicidal ideation/behavior. [29]
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management. It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.
Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally as a treatment for severe Clostridium difficile colitis. When taken orally it is poorly absorbed.
Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is primarily used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.
Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle.
Glycopeptide antibiotics are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin, corbomycin, complestatin and the antitumor antibiotic bleomycin. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.
4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.
Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment-resistant depression vary, and they do not include a resistance to psychological therapies. Inadequate response has most commonly been defined as less than 50% reduction in depressive symptoms following treatment with at least one antidepressant medication, although definitions vary widely. Some other factors that may contribute to inadequate treatment are: a history of repeated or severe adverse childhood experiences, early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, cognitive impairment, low income and other socio-economic variables, and concurrent medical conditions, including comorbid psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people with treatment-resistant depression are resistant to. In treatment-resistant depression adding further treatments such as psychotherapy, lithium, or aripiprazole is weakly supported as of 2019.
Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.
D-amino acid oxidase is an enzyme with the function on a molecular level to oxidize D-amino acids to the corresponding α-keto acids, producing ammonia and hydrogen peroxide. This results in a number of physiological effects in various systems, most notably the brain. The enzyme is most active toward neutral D-amino acids, and not active toward acidic D-amino acids. One of its most important targets in mammals is D-Serine in the central nervous system. By targeting this and other D-amino acids in vertebrates, DAAO is important in detoxification. The role in microorganisms is slightly different, breaking down D-amino acids to generate energy.
2-Oxazolidone is a heterocyclic organic compound containing both nitrogen and oxygen in a 5-membered ring.
Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs. It is generally used together with bedaquiline and linezolid. It is taken by mouth.
Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato, Ketanest, among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.
Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.
Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder. Its effectiveness is viewed as similar to that of other antidepressants. It is taken by mouth.
Delamanid, sold under the brand name Deltyba, is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.
Rislenemdaz is an orally active, selective NMDA receptor subunit 2B (NR2B) antagonist which is under development by Cerecor in the United States as an adjunctive therapy for treatment-resistant depression (TRD). In November 2013, phase II clinical trials were initiated, and in the same month, rislenemdaz received Fast Track Designation from the Food and Drug Administration for TRD.
Cycloserine/lurasidone, developmental code name NRX-101 and tentative brand name Cyclurad, is a combination formulation of the antibiotic D-cycloserine, an antagonist of the glycine site of the NMDA receptor, and lurasidone, an atypical antipsychotic, which is under development by NeuroRx for the treatment of acute suicidal ideation/behavior (ASIB). As of May 2016, it has completed a phase II clinical trial for bipolar depression. In September 2017, the drug received fast track designation for bipolar depression from the United States Food and Drug Administration.
Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including Ketamine, MDMA, Scopolamine, and the serotonergic psychedelics, including LSD, psilocin, DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.
Ketamine-assisted psychotherapy(KAP) is the use of prescribed doses of ketamine, the drug, as an adjunct to psychotherapy sessions. KAP shows significant potential in treating mental disorders such as treatment-resistant depression (TRD), anxiety, obsessive–compulsive disorders (OCD), post-traumatic stress disorders (PTSD), and other conditions. It can also be used for those experiencing substance abuse and physical pain. While it is primarily used as a veterinary anaesthetic, ketamine has also been found to have rapid analgesic and hallucinogenic effects, which has sparked interest in its use as an antidepressant. Despite initial trials of its use in the treatment of mental disorders focussing primarily on its antidepressant effects, newer studies are attempting to harness its psychedelic effects to bring about altered states of consciousness, which will augment the adjunct psychotherapy. Ketamine's neuroplasticity-promoting effects strengthen the cognitive restructuring that takes place through traditional psychotherapy, thereby leading to long-lasting behavioural change. KAP offers promising directions for research on new antidepressant alternatives, but is still not sufficiently defined or evaluated as a treatment combination.