Abstract
The treatment of seizure disorders with currently available pharmacotherapeutic agents is not optimal due to the failure of some patients to respond, coupled with occurrences of side effects. There is therefore a need for research into the development of new chemical entities as potential anticonvulsant agents, which are different structurally from the existing class of drugs. We recently identified a novel triazolyl-oxazolidinone derivative, PH-192, as a potential anticonvulsant agent. PH-192 demonstrated protection comparable to phenytoin against both chemically- and electrically-induced seizures in rodents with little or no central nervous system side effects. However, PH-192 did not exhibit protection beyond 30 min; therefore, we decide to investigate a stability-indicating assay of PH-192 in plasma and other solutions. A reliable and validated analytical method was developed to investigate the stability of PH-192 for 90 min in human plasma, acidic, basic, and oxidative conditions, using a Waters Acquity ultra high-performance liquid chromatography (UHPLC) system with a quaternary Solvent Manager (H-Class). A simple extraction method indicated that PH-192 was stable in human plasma after 90 min at 37 °C, with more than 90% successfully recovered. Moreover, stress stability studies were performed, and degradants were identified using LC-QToF-MS under acidic, basic, and oxidative simulated conditions.
Highlights
Seizure disorders arise when brain nerve cells inappropriately and spontaneously fire action potentials, synchronously resulting in alterations in the sensory, motor, autonomic and psychological function of the afflicted individual
The oxazolidinone-containing antibacterial agents, namely, linezolid 1 and tedizolid (2, Figure 1), have demonstrated clinical success with regards to their efficacy and safety profiles against susceptible and resistant Gram-positive cocci [16,17,18,19]. Based on these pharmacological properties, we previously reported the effects of a series of oxazolidinone derivatives on neuronal responses, which may correspond to their potential use as anticonvulsant agents with new pharmacophores [13,14,15]
The amount of PH-192 was calculated from the calibration curve equation and was found to be equivalent to 9.44 μg/mL out of 10 μg/mL of PH-192, which was spiked in the human plasma
Summary
Seizure disorders arise when brain nerve cells inappropriately and spontaneously fire action potentials, synchronously resulting in alterations in the sensory, motor, autonomic and psychological function of the afflicted individual. This manifestation of neuronal firing is called convulsion and the recurrent episodes of seizures result in a syndrome called epilepsy. Several anticonvulsant agents with different pharmacophores and chemical structures have been developed to control seizure disorders. There is considerable interest in the development of newer and more effective anticonvulsant agents that may cover several seizure types or treat currently untreatable seizures and with fewer side effects [5]
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