Biology subjects

Javitt, J. C.

Publications and source records attributed to Javitt, J. C..

3 recordsLinked to original sources

bioRxiv2024

NRX-101 (D-Cycloserine + Lurasidone) , a Qualified Infectious Disease Product, is Active Against Drug-Resistant Urinary Pathogens In Vitro

BackgroundD-Cycloserine (DCS) is a broad-spectrum antibiotic that is currently FDA-approved to treat tuberculosis (TB) disease and urinary tract infection. Despite numerous reports showing good clinical efficacy, DCS fell out of favor as a UTI treatment because of its propensity to cause side effects. NRX-101, a fixed dose combination of DCS and lurasidone, has been awarded Qualified Infectious Disease Product and Fast Track Designation by the US Food and Drug Administration and is being developed for various CNS indications because of its unique synergistic effect; each component mitigates side effects of the other. MethodsIn this study, we tested NRX-101 against the urinary tract pathogens E. coli, P. aeruginosa, K. pneumoniae, and A. baumannii in Mueller Hinton broth (caMHB) and artificial urine media (AUM). Several strains were multidrug resistant. Test compounds were serially diluted in broth/media. Minimum inhibitory concentration (MIC) was defined as the lowest concentration of test compound at which no bacterial growth was observed. ResultsDCS exhibited antibacterial efficacy against all strains tested while lurasidone did not appreciably affect the antibacterial action of DCS in vitro. In AUM, the MICs ranged from 128 to 512 mcg/ml for both DCS and NRX-101. In caMHB, MICs ranged from 8 to 1024 mcg/ml for NRX-101 and 32 to 512 mcg/ml for DCS alone. ConclusionsOur data confirm that DCS as antibacterial activity against reference and drug-resistant urinary pathogens. Furthermore, lurasidone does not interfere with DCSs anti-microbial action in vitro. These results support the clinical development of NRX-101 as a treatment for complicated urinary tract infection.

microbiology↗

bioRxiv2022

D-cycloserine, a mixed NMDAR agonist/antagonist is Not Susceptible to Self-administration, unlike S-ketamine Using an Intravenous Self-administration Model in Naive and Ketamine-habituated Sprague-Dawley Rats

OBJECTIVEN-methyl D-aspartate Receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a self-administration paradigm in which DCS was tested in its efficacy in substituting for ketamine in ketamine-dependent rats. METHODSA standard Intravenous self-administration study was conducted in Male adult Sprague-Dawley rats. model to study compounds abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15mg/kg per lever press. RESULTSS-Ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in any self-administration at any of the test doses. The self-infusion behavior of DCS was the same as that of saline. CONCLUSIONC-cycloserine, an a mixed agonist/antagonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies has no apparent potential for abuse liability in a standard rodent self-administration model.

neuroscience↗

bioRxiv2022

NRX-101, A RAPID-ACTING ANTI-DEPRESSANT, DOES NOT CAUSE NEUROTOXICITY FOLLOWING KETAMINE ADMINISTRATION IN PRECLINICAL MODELS

BackgroundNMDA (N-Methyl-D aspartate) receptor antagonists have gained increasing attention as rapid-acting antidepressants. However, their use has been limited by potential neurotoxicity (Olney Lesions) and recent FDA guidance requires demonstration of safety on histologic parameters prior to initiation of human studies. D-cycloserine is a mixed NMDA agonist/antagonist awarded Breakthrough Therapy Designation and currently in clinical trials for the treatment of bipolar depression with suicidal ideation. The current study was designed to investigate the neurologic safety profile of D-cycloserine by itself and in combination with ketamine and lurasidone. MethodsSprague Dawley female rats (n=106) were randomly divided into 7 study groups. Ketamine was administered via tail vein infusion. D-cycloserine and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with three different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E and Fluorojade stains. ResultsNo fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 positive control group. ConclusionNRX-101, a fixed-dose combination of D-cycloserine/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at maximum-tolerated doses of D-cycloserine. HIGHLIGHTSO_LINRX-101, a fixed dose combination of D-cycloserine and lurasidone does not exhibit histologic neurotoxicity, even at maximum-tolerated doses C_LI

pharmacology and toxicology↗