MEDtube science最新文献

Introduction: Numerous studies have emerged over the course of several decades describing the properties of drugs eliciting vasodilatory or vasoconstrictor responses in the human vasculature. During drug development, decisions to move forward with testing with a new chemical entity are very costly. To fund or not to fund development, go or no-go, decisions are often limited by efficacy comparisons with the current products on the market. The primary aim of this paper is to use dose-response modeling and simulations to quantify differences in blood flow to Acetylcholine, Albuterol, ATP, Bradykinin, 17β-Estradiol, Glyceryl Trinitrate, L-NMMA, Nevibolol, Norepinephrine, Sodium Nitroprusside, Substance P, and Verapamil.

Methods: Five studies were identified in the literature that included a total of 12 compounds. Infusion doses were normalized to nmol/min and forearm blood flow values were normalized and scaled to the percent increase or decrease in forearm blood flow from baseline resting values. The original published studies were mathematically modeled using the Emax model or Sigmoid Emax model equation parameters. Lastly, dose-response simulations of higher doses using a virtual population were produced to account for population variability.

Results: The gender difference between the Emax estimates, interpreted as the %Change from Baseline resting forearm blood flow, were found to be: Albuterol 253%, Acetylcholine 231%, Substance P 159%, Verapamil 145%, Bradykinin 42%, Sodium Nitroprusside 41%, and Glyceryl Trinitrate 26%. Contrastingly, Norepinephrine and L-NMMA Emax gender difference resulted in a 6% and 7% difference, respectively.

Conclusion: These results provide insight into the differences in men and women seen in anti-hypertensive patient management. Further, the modeling estimates provide pharmacometricians evaluating new compounds with mathematical parameters for comparative efficacy studies through the various phases of drug development.

Objective: This article seeks to test the hypothesis that repeated 1mg intravenous epinephrine dosing intervals of 3-minutes and 5-minutes results in differences in the total drug exposure and the maximum epinephrine concentration using simulated cardiopulmonary resuscitation (CPR) dosing.

Methods: Published population pharmacokinetic parameters were identified in the literature and pharmacokinetic dosing simulations were conducted according to the 2015 American Heart Association guidelines for CPR in adults. The stochastic pharmacokinetic simulations were conducted in MATLAB and R for statistical programming.

Results: A total of 5000 simulations were conducted in MATLAB while 90,000 data points for the 3-minute dosing interval and 150,000 data points for the 5-minute epinephrine dosing interval resulted from pharmacokinetic simulations in R. The difference between the 3-minute and 5-minute dosing intervals for patients with a SAP score of 30, were found to be: Male ΔAUC=2416 and ΔCmax=71, Female ΔAUC=1422 and ΔCmax=41, and for a 70kg patient ΔAUC=2968 and ΔCmax=90. While in virtual healthy participants, the differences were calculated to be ΔAUC=2658 and ΔCmax=81 for 3-minute and 5-minute dosing frequencies.

Conclusions: Epinephrine plasma levels during a simulated CPR scenario in a virtual patient population are dependent upon intravenous dosing intervals of either 3-minutes or 5-minutes. Based on the results of this clinical trial simulation, implications may exist that may require clinical studies investigating the influence of the 1mg epinephrine dosing frequency on the return of spontaneous circulation.