Gender effect on the pharmacokinetics of thymoquinone: Preclinical investigation and in silico modeling in male and female rats.

Thymoquinone is the most biologically active constituent of Nigella sativa (black seed). A monoterpene compound chemically known as 2-methyl-5-isopropyl-1, 4-quinone. In this study, the gender-dependent pharmacokinetic behavior of thymoquinone in rats was investigated. Thymoquinone was administered orally (20 mg/kg) and intravenously (5 mg/kg) to male and female rats and blood samples were collected at specific time points. Plasma concentration-time curves were plotted and pharmacokinetic parameters were determined using the non-compartmental analysis. In addition, simulations of steady state concentrations of thymoquinone in male and female rats were performed using GastroPlus PK software. After oral administration, the maximum plasma concentration (Cmax) of thymoquinone was 4.52 ±â€¯0.092 µg/ml in male rats and 5.22 ±â€¯0.154 µg/ml in female rats (p = 0.002). Similarly, after intravenous administration, the Cmax was 8.36 ±â€¯0.132 µg/ml in males and 9.51 ±â€¯0.158 µg/ml in females (p = 0.550). The area under the plasma concentration-time curve (AUC)0-∞ following oral dosing was 47.38 ±â€¯0.821 µg/ml·h in females and 43.63 ±â€¯0.953 µg/ml·h in males (p = 0.014). Pharmacokinetics and plasma concentration vs. time profiles for multiple oral doses of thymoquinone in rats were predicted using a simulation model to compare the simulation results with the experimental plasma pharmacokinetic data. The differences observed in thymoquinone pharmacokinetics between male and female rats after a single dose were not evident for the simulated steady-state parameters. The findings suggest that the gender difference does not seem to play a significant role in thymoquinone disposition at steady state.

The Resuscitative and Pharmacokinetic Effects of Humeral Intraosseous Vasopressin in a Swine Model of Ventricular Fibrillation.

Introduction The American Heart Association (AHA; Dallas, Texas USA) and European Resuscitation Council (Niel, Belgium) cardiac arrest (CA) guidelines recommend the intraosseous (IO) route when intravenous (IV) access cannot be obtained. Vasopressin has been used as an alternative to epinephrine to treat ventricular fibrillation (VF). Hypothesis/Problem Limited data exist on the pharmacokinetics and resuscitative effects of vasopressin administered by the humeral IO (HIO) route for treatment of VF. The purpose of this study was to evaluate the effects of HIO and IV vasopressin, on the occurrence, odds, and time of return of spontaneous circulation (ROSC) and pharmacokinetic measures in a swine model of VF. METHODS: Twenty-seven Yorkshire-cross swine (60 to 80 kg) were assigned randomly to three groups: HIO (n=9), IV (n=9), and a control group (n=9). Ventricular fibrillation was induced and untreated for two minutes. Chest compressions began at two minutes post-arrest and vasopressin (40 U) administered at four minutes post-arrest. Serial blood specimens were collected for four minutes, then the swine were resuscitated until ROSC or 29 post-arrest minutes elapsed. RESULTS: Fisher's Exact test determined ROSC was significantly higher in the HIO 5/7 (71.5%) and IV 8/11 (72.7%) groups compared to the control 0/9 (0.0%; P=.001). Odds ratios of ROSC indicated no significant difference between the treatment groups (P=.68) but significant differences between the HIO and control, and the IV and control groups (P=.03 and .01, respectively). Analysis of Variance (ANOVA) indicated the mean time to ROSC for HIO and IV was 621.20 seconds (SD=204.21 seconds) and 554.50 seconds (SD=213.96 seconds), respectively, with no significant difference between the groups (U=11; P=.22). Multivariate Analysis of Variance (MANOVA) revealed the maximum plasma concentration (Cmax) and time to maximum concentration (Tmax) of vasopressin in the HIO and IV groups was 71753.9 pg/mL (SD=26744.58 pg/mL) and 61853.7 pg/mL (SD=22745.04 pg/mL); 111.42 seconds (SD=51.3 seconds) and 114.55 seconds (SD=55.02 seconds), respectively. Repeated measures ANOVA indicated no significant difference in plasma vasopressin concentrations between the treatment groups over four minutes (P=.48). CONCLUSIONS: The HIO route delivered vasopressin effectively in a swine model of VF. Occurrence, time, and odds of ROSC, as well as pharmacokinetic measurements of HIO vasopressin, were comparable to IV. Burgert JM , Johnson AD , Garcia-Blanco J , Fulton LV , Loughren MJ . The resuscitative and pharmacokinetic effects of humeral intraosseous vasopressin in a swine model of ventricular fibrillation. Prehosp Disaster Med. 2017;32(3):305-310.