Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid-acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well-characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography-mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non-compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co-administration with the SOC following nerve agent exposure in animal models.
cytoreduction. 43 patients received IDS with HIPEC and 80 patients had IDS without HIPEC. The median follow-up period was 34.4 months. Results No differences in baseline characteristics in patients were found between the 2 groups. The IDS with HIPEC group had fewer median cycles of chemotherapy (P = 0.002) than IDS group. The IDS with HIPEC group had higher rate of high surgical complexity score (P = 0.032) and higher rate of complete resection (P = 0.041) compared to IDS group. The times to start adjuvant chemotherapy were longer in IDS with HIPEC group compared to IDS group (P < 0.001). Postoperative grade 3 or 4 complications were similar in the two groups (P = 0.237). Kaplan-Meier analysis showed that HIPEC with IDS group had better progression-free survival (PFS) (P = 0.010), while there was no difference in overall survival between two groups (P = 0.142). In the multivariate analysis, HIPEC was significantly associated with better PFS (HR, 0.60; 95% CI, 0.39 -0.93). Conclusions The addition of HIPEC to IDS resulted in longer PFS than IDS without HIPEC not affecting safety profile. Further research is needed to evaluate the true place of HIPEC in the era of targeted treatments.
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