Novel actions of oxazolidinones: in vitro screening of a triazolyloxazolidinone for anticonvulsant activity

To test the hypothesis that a triazolyloxazolidinone [PH084] has anticonvulsant activity by examining its effects on in vitro seizure models in the rat hippocampus. Whole-cell synaptic currents, action potentials and extracellular population spikes [PS] were recorded in the cell body area of rat hippocampal CA1 region in acutely prepared slices. Chemical [picrotoxin [100 micro m] and zero magnesium] and electrical seizures were induced and the effect of PH084 [10 micro M] was tested on cellular responses, multiple spikes and spontaneous bursting frequencies. PH084 depressed evoked excitatory postsynaptic currents, action potential firing frequency and PS amplitude. All of these responses did not recover to baseline after 15-20 min washout of PH084. Perfusion with zero magnesium ion [Mg[2+]]-containing buffer converted a single PS to multiple PS [mPS] accompanied by spontaneous burst. PH084 suppressed the mPS and the spontaneous burst frequency and it also suppressed the picrotoxin-induced mPS number. However, it did not affect the frequency of stimulus train-induced after discharge or bursts. Furthermore, 8-10 min pretreatment with PH084 did not affect the ability of zero Mg[2+] buffer, picrotoxin or stimulus train to induce epileptiform activity. Thus, while PH084 may have potential for anticonvulsant activity against chemically induced seizures, it has little or no potential against electrically induced seizures or in preventing epileptiform discharge

Assessment of the stability of novel antibacterial triazolyl oxazolidinones using a stability-indicating high-performance liquid chromatography method

To evaluate the stability of 12 triazolyl oxazolidinone [TOZ] derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 +/- 1°C. A stability-indicating high-performance liquid chromatography [HPLC] procedure with a C8 column [250 +/- 40 mm, 5 micro m particle size] and a mobile phase of acetonitrile/H2O [50/50 v/v] at 1.0 ml/min was used. Accelerated stability studies were conducted at 37 +/- 1°C in 0.1 M HCl solution as simulated gastric fluid and in phosphate buffer solution [pH about 7.4] as simulated intestinal fluid. The stability of TOZs in human plasma at a simulated biological temperature of 37 +/- 1°C was evaluated as well. The stability studies indicated that the examined TOZs were stable in the above media, with the exception of compounds 1a [tert- butyl 4-[4-[[R]-5-[[1H-1,2,3-triazol-1-yl]methyl]-2-oxooxazolidin-3-yl]-2-fluorophenyl]piperazine-1-carboxylate] and 1b [tert-butyl 4-[2-fluoro-4-[[R]-5-[[4-methyl-1H-1,2,3-triazol- 1-yl]methyl]-2-oxooxazolidin-3-yl]phenyl] piperazine-1-carboxylate], which underwent degradation in simulated gastric fluid. The degradation kinetics revealed degradation parameters [kdeg, t1/2, t90] of 0.180 h-1, 3.85 h, and 0.58 h for 1a and of 0.184 h-1, 3.76 h and 0.57 h for 1b, respectively. Furthermore, the degradation products were identified by mass-spectrometric analysis at mass-to-charge ratios 347.5 and 361.5, respectively, and proton nuclear magnetic resonance analysis. With the exception of compounds 1a and 1b, the TOZs are stable in simulated gastric and intestinal fluids as well as in human plasma. Being carbamate derivatives, compounds 1a and 1b underwent fast and complete degradation in simulated gastric fluid. The obtained results should be considered for future studies of formulation of structurally related TOZs in oral dosage forms