A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects

Abstract

Aim: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. Methods: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0, each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. .3% (range, 4.6%-12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E 0 , E max , and EC 50 were 68 bpm, 73 bpm and 8.1 μg/L, respectively. Conclusion: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.

A beating heart cell model to predict cardiotoxicity: Effects of the dietary supplement ingredients higenamine, phenylethylamine, ephedrine and caffeine

“…In animal and human studies, higenamine generally increased the heart rate. Blood levels were not measured in these studies, except for the study published by Feng et al (2012), which we used to set our blood levels for the iCell experiments. One possible explanation for the consistency of higenamine in increasing heart rate in humans and various other models is its lack of a presser effect.…”

“…Higenamine administered intravenously in a human clinical study, resulted in a Cmax level of 31.3 ng/ml, producing an average pulse rate of 126 bpm (Feng et al, 2012). This concentration, plus 10 times lower or higher concentrations (3.13 and 313 ng/ml), were used in the present study.…”

“…First, published data suggest they may enhance heart rate. Higenamine and PEA both have been documented to increase heart rate with in vivo experiments (Dunlop and Shanks, 1969;Feng et al, 2012;Liang and Sprecher, 1979;Praman et al, 2012). Ephedrine is known to increase heart rate, and was banned in 2004 because it was associated with deaths and severe cardiac adverse events.…”

Protective effect of higenamine ameliorates collagen-induced arthritis through heme oxygenase-1 and PI3K/Akt/Nrf-2 signaling pathways

“…Ranunculaceae Aconitum is a traditional Chinese medicine that is used as a long-term cardiotonic drug, whose active constituent is a type of alkaloid named higenamine, which is extracted from Ranunculaceae Aconitum's rhizome (9,10). However, the mechanism underlying the protective effect of higenamine on CIA has, to the best of our knowledge, never been investigated.…”

Pharmacometrics: a quantitative tool of pharmacological research

“…since 1979, the Professional Committee of Mathematical Pharmacology (PCMP) led by the Chinese Society of Pharmacology has been devoting to promote research, education and training of Chinese scientists in academia, industry and regulatory agencies with regard to the use of PK/PD modeling to help drug development and to optimize drug application in clinical therapies [5,6] . The papers organized by PCMP in this Special Issue of Acta Pharmacologica Sinica are focused on phase I trial design [7] , phase I PK study [8,9] , physiologically based PK modelling (PBPK) [10] , PK/ PD linking [11][12][13][14] , population approach [15][16][17] , dose finding [18] , and stochastic simulation [19] . We hope that these papers serve as an introduction for the readers in academia, regulatory authorities and pharmaceutical industry to understand the role of pharmacometrics in drug development and approval processes, which will improve the success rate in drug development, and the beneficiaries will ultimately be the patients in need.…”