SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Several derivatives of cycloserine (1) were prepared and it was found that (R)-4-[(1-methyl-3-oxo-1-butenyl)-amino]-3-isoxazolidinone (11), the condensation product of acetylacetone and cycloserine (1), was an efficacious prodrug of increased stability under aqueous conditions.
The effects of a muscarinic antagonist (scopolamine), a muscarinic agonist (oxotremorine), an agonist at the N-methyl-D-aspartate receptor site (D-cycloserine), and a GABAa antagonist (bicuculline) on working memory were compared using rats performing a delayed matching-to-sample task. When administered on their own, oxotremorine, D-cycloserine, and bicuculline had no effect on performance in the current task. When administered concurrently with scopolamine, oxotremorine (at 1 dose) and bicuculline (at 2 doses) improved accuracy (in terms of percentage correct) by ameliorating the scopolamine-induced increase in response bias. None of the drugs, however, were successful in ameliorating the scopolamine-induced impairment in bias-free recognition performance per se (as measured by Log d). Therefore, none of the drugs examined were able to fully ameliorate all aspects of the memory impairment caused by scopolamine.
The administration of the N-methyl-D-aspartate (NMDA)-associated glycine recognition site agonist D-cycloserine (DCS) to rats inhibited the head shakes and the forepaw treading induced by the serotonin (5HT) precursor, L-5-hydroxy-tryptophan [(-)5HTP], as well as the forepaw treading and motility elicited by the selective 5HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The head shakes typically induced by the 5HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), were unaffected by DCS pretreatment. The results are consistent with reduced serotonergic transmission produced by NMDA activation, as suggested by other authors. Due to the important role played in the pathogenesis of schizophrenia by glutamate deficiency/serotonin activation, the results support the view that positive modulators of NMDA receptors, activating glutamate receptors and reducing serotonergic tone, might be useful in the alleviation of psychotic symptoms. However, because of its partial agonist properties at the glycine recognition site, D-cycloserine shows some effects that might make it unsuitable for clinical use.
(+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one], a functional antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex, was evaluated in amygdala-kindled rats, a model of epilepsy recently shown to exhibit enhanced susceptibility to the adverse effects of competitive and non-competitive NMDA receptor antagonists. Since (+)-HA-966 displays weak partial agonistic effects at the glycine site (approximately 10% efficacy of glycine), D-cycloserine, a glycine ligand with much higher intrinsic activity, was evaluated in kindled rats for comparison. Following drug administration, electrographic activity was recorded from the basolateral amygdala (i.e. the focal site) as well as the ipsilateral piriform cortex, ventral hippocampus and nucleus accumbens. In addition to the evaluation of original recordings, power spectrum analysis was used to delineate drug effects. (+)-HA-966 (20-40 mg/kg i.p.) induced marked alterations in electrographic recordings, including increases in amplitude and isolated spiking, i.e. signs of paroxysmal activity. The severity or duration of fully kindled seizures was not changed by (+)-HA-966, but the drug dramatically increased the duration of immobilization and limbic seizure activity following a kindled motor seizure. In contrast to (+)-HA-966, D-cycloserine did not induce any electrographic changes, even when administered in much higher doses than (+)-HA-966. The changes in electrographic recordings seen after administration of (+)-HA-966 in kindled rats were almost absent in non-kindled rats, indicating that kindling had increased the sensitivity to the paroxysmal effects of the glycine/NMDA receptor ligand. The data indicate that functional glycine/NMDA antagonists with low intrinsic efficacy may bear the risk of proconvulsant activity.
Contrary to its effect on rich medium, D-cycloserine showed no bactericidal effect on Zymomonas mobilis cells cultured on mineral medium. Addition of a mixture of glycine and glutamic acid to the mineral medium restored its bactericidal action. However, mutant enrichments run in these conditions were biased, with mostly methionine mutants isolated. A decrease of the D-cycloserine concentration only reduced the bias.
Dissolving dehydrated tryptose-sulfite-cycloserine agar by only boiling or microwaving was found to inhibit Clostridium perfringens colony development in pour plates when compared with C. perfringens recovery in tryptose-sulfite-cycloserine agar prepared by autoclaving.
D-cycloserine is a partial agonist on the glycine site of the N-methyl-D-aspartate glutamate receptor. This double-blind crossover study of 15 mg D-cycloserine in Alzheimer's disease patients did not demonstrate clinical benefit. Higher medication dosage or long-term treatment may be required.
An antibiotic which seems to be a cell wall synthesis-inhibitor was isolated from a bacteria strain identified as Erwinia uredovora. The antibiotic was identified with L-cycloserine from its physico-chemical properties. This is the first example for isolation of L-cycloserine as a microbial product.
A select series of N(2)-substituted D,L-cycloserine derivatives were prepared a ndevaluated for inhibitory activity against purified alanine racemases (alr gene product) from Escherichia coli, Staphylococcus aureus, and Mycobacterium tuberculosis, as well as in a growth inhibition assay. N(2)-Modification led to loss of enzymatic inhibitory activity in most cases consistent with a recent proposal for cycloserine function.
Some fluoroacylderivatives at the side chain NH2 of D-cycloserine were synthesized and evaluated in vitro for antimicrobial activity against bacteria and tubercular or non-tubercular mycobacteria. Against the used Gram-positive and Gram-negative strains only trifluoroacetamide 1 exhibited comparable MIC values and lower MBC values than those of parent antibiotic. Other fluoroacycloserines, inactive at all on these bacteria, were found to inhibit the growth of mycobacteria when tested in liquid media. The in vitro anti-Herpex Simplex virus type-2 (HSV-2) activity was also investigated on HEp-2 and Vero cells. The obtained results demonstrated an antiviral activity of the compounds 1 and 3 when tested on Vero cell-lines, whereas the same cycloserine is inactive.
Gross deterioration of cycloserine during transit and storage in the tropics is reported from the Tuberculosis Chemotherapy Centre, Madras. Laboratory experiments suggest that high humidity, rather than high temperature, is the main cause of the deterioration. Further investigations undertaken at the Centre indicate that deterioration can be prevented by storing the drug in tightly closed glass bottles in an air-conditioned room (18 degrees C); if such facilities are not available, and the drug has to be stored at ambient temperature and humidity, the use of air-tight polyethylene bottles will serve to delay the deterioration. The findings also suggest that, when cycloserine is dispensed to patients, individual doses should be heat-sealed in polyethylene strips and that not more than a week's supply should be given at any one time. The authors discuss various measures that could be employed by manufacturers and by shipping and clearing agents to minimize the possibility of deterioration.
We report a case of cycloserine-induced Stevens-Johnson syndrome (SJS) in a 38-year-old male with the acquired immune deficiency syndrome (AIDS) and multidrug resistant tuberculosis (MDR-TB). The patient developed a cutaneous reaction after 60 days of therapy with ofloxacin, streptomycin (SM), pyrazinamide (PZA), ethambutol (EMB), and cycloserine (CSN). All drugs were stopped and the rash improved. Due to the severity of his disease, anti-tuberculosis drugs were resumed, one at a time. The patient developed a recurrent rash consistent with SJS, which began when CSN was restarted. CSN was stopped and the SJS began to gradually resolve with palliative treatment despite continuation of the other anti-tuberculosis drugs. However, the patient's overall condition gradually deteriorated and he died. To our knowledge, this is the first case of probable CSN-related SJS.
The aearance of tritium in plasma water was measured after i.p. injection of 2-tritio-L-alanine as an index of alanine transamination in rats. L-Cycloserine (10 mg/kg) and D-cycloserine (150 mg/kg) inhibited tritium release, whereas theophylline (100 mg/kg) stimulated tritium release.
There is evidence that ethanol is able to influence central functions through the antagonism of the NMDA-receptor system. It has been shown that this system is also involved in the modulation of anxiety-related behavior in rats. Recently, we observed gender- and age-related behavioral influences in rats tested on the elevated plus-maze apparatus The present study was undertaken in order to investigate: (1) the effects of ethanol (0.8, 1.0 or 1.2 g/kg, i.p.) on the behavior of male and female rats tested on the elevated plus-maze at 2, 3, 4 or 5 months of age; (2) the effect of the pre-treatment with D-cycloserine (3.0 or 6.0 mg/kg), an agonist of the glutamate NMDA-receptor system, 30 min before the ethanol (1.2 g/kg) injections, in rats tested in the elevated plus-maze at 2 months or 4 months of age. The results demonstrated that ethanol did not affect the time spent and the frequency of entries on the open arms of the elevated plus-maze in rats tested at 2 months of age, but increased these parameters in older animals. Moreover, the results showed that D-cycloserine, at doses that did not affect the behavior of control animals, antagonized the increased frequency of entries and time spent on open arms produced by ethanol in rats tested at 4 months of age. Our results suggest an age-related influence on the anxiolytic action of ethanol in rats tested in the elevated plus-maze. Moreover, the results suggest that the NMDA-receptor system can be involved in this effect, and strengthens the evidence for the participation of the NMDA-receptor system in anxiety-related behavior.
BACKGROUND: Traditional pharmacological approaches to treating psychiatric disorders focus on correcting presumed biochemical abnormalities. However, some disorders, particularly the anxiety-related disorders exemplified by specific phobia, have an emotional learning component to them that can be facilitated with psychotherapy. OBJECTIVE: To determine whether D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor that has previously been shown to improve extinction of fear in rodents, will also improve extinction of fear in human phobic patients undergoing behavioral exposure therapy. DESIGN: Randomized, double-blind, placebo-controlled trial examining DCS vs placebo treatment in combination with a precisely controlled exposure paradigm. SETTING: Participants were recruited from the general community to a research clinic. PARTICIPANTS: Twenty-eight subjects with acrophobia diagnosed by the Structured Clinical Interview for DSM-IV were enrolled. INTERVENTIONS: After we obtained pretreatment measures of fear, subjects were treated with 2 sessions of behavioral exposure therapy using virtual reality exposure to heights within a virtual glass elevator. Single doses of placebo or DCS were taken prior to each of the 2 sessions of virtual reality exposure therapy. Subjects, therapists, and assessors were blind to the treatment condition. Subjects returned at 1 week and 3 months posttreatment for measures to determine the presence and severity of acrophobia symptoms. MAIN OUTCOME MEASURES: Included were measures of acrophobia within the virtual environment, measures of acrophobia in the real world, and general measures of overall improvement. An objective measure of fear, electrodermal skin fluctuation, was also included during the virtual exposure to heights. Symptoms were assessed by self-report and by independent assessors at approximately 1 week and 3 months posttreatment. RESULTS: Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome measures. Subjects receiving DCS had significantly more improvement compared with subjects receiving placebo within the virtual environment (1 week after treatment, P</=.001; 3 months later, P</=.05). Subjects receiving DCS also showed significantly greater decreases in posttreatment skin conductance fluctuations during the virtual exposure (P</=.05). Additionally, subjects receiving DCS had significantly greater improvement compared with subjects receiving placebo on general measures of real-world acrophobia symptoms (acrophobia avoidance [P</=.02], acrophobia anxiety [P</=.01], attitudes toward heights [P</=.04], clinical global improvement [P</=.01], and number of self-exposures to real-world heights [P</=.01]); the improvement was evident early in treatment and was maintained at 3 months. CONCLUSION: These pilot data provide initial support for the use of acute dosing of DCS as an adjunct to exposure-based psychotherapy to accelerate the associative learning processes that contribute to correcting psychopathology.
d-Cycloserine (DCS), a partial agonist of the glycine recognition site of the N-methyl d-aspartate receptor, has beneficial effects on learning and memory. In order to investigate its potential to influence learning and memory of both the response and the stimulus attributes of training, male Sprague-Dawley albino rats were trained in a one-trial inhibitory avoidance task following an acute intraperitoneal injection of DCS (3 mg/kg) or an equal volume of saline. In order to measure memory for stimulus attributes, testing involved a context shift paradigm, in which subjects are tested in either the environment of training or a different one. Good memory for the contextual attributes of training is indicated by poor performance in the alternate context. Retention was assessed either 1, 7, or 14 days after training. At 1 day, Saline subjects were affected by a change in context, while DCS subjects were not. In subjects tested 1 week following training, Saline subjects were no longer affected by a change in context, in that they performed the avoidance response in both contexts. This indicates the forgetting of stimulus attributes in Saline subjects. DCS subjects did show the context shift effect at 1 week, indicating the retention of stimulus attributes. Finally, Saline subjects demonstrated the context shift rebound at 14 days, while DCS subjects performed equivalently in both contexts. Taken together, these data suggest that DCS may enhance retention of fear and slow the forgetting of stimulus attributes.
A short historical review and pharmacological data indicating the suitability of cycloserine for long-term low-dose prophylaxis of urinary tract infection are presented.
D-Cycloserine (DCS) has been reported to affect the central nervous system in man. To investigate whether the compound produces specific behavioural effects, DCS was administered to male mice in a resident-intruder situation and the behaviour of the interacting mice assessed using ethological analysis. Resident mice given DCS (32.0-320.0 mg/kg PO, 60 min before testing) showed dose-dependent increases in social investigation, smaller increases in sexual behaviour and decreased aggressiveness. Defensive and flight behaviour were not affected. Intruder mice showed slight increases in sexual behaviour that were not dose-dependent, and small increases in social investigation. The increases in social investigation induced by DCS (320.0 mg/kg) in resident mice were not reversible with R-HA 966 (32.0 mg/kg IP, 30 min before testing), a blocker of the strychnine-insensitive glycine modulatory site associated with the N-methyl-D-aspartate receptor, but were blocked by the GABA antagonist bicuculline (0.56 mg/kg IP, 5 min before testing). The small DCS-induced increase in sexual behaviour in residents was reversed by R-HA 966. Within the parameters of the resident-intruder situation, DCS exerts socio-sexual behaviour-enhancing effects which are dependent upon the role of the interactant, and which are mediated by an action upon multiple substrates. DCS may be regarded as another example of a sociotropic (approach-promoting) agent.