The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats. After a single oral dose of racemic warfarin (2 mg kg-1), treatment with oral Danshen extract (5 g kg-1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0.2 mg kg-1 day-1 for 5 days) the 3-day treatment of Danshen extract (5 g kg-1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin. The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.
Danshen is a Chinese folk medicine commonly used in the Chinese population. The effects of Danshen on the pharmacokinetics and pharmacodynamics of warfarin were studied in rats. In the pharmacokinetic study, single oral doses of warfarin were administered to rats or after 3 days treatment with Danshen intraperitoneally twice daily. Plasma warfarin concentrations were measured for 48 after each of two warfarin doses by high performance liquid chromatography (HPLC). In the pharmacodynamic study, the treatments were similar to the pharmacokinetic study, the prothrombin time (PT) was measured daily both in the Danshen treatment period and after the warfarin doses for 4 days. The absorption rate (Ka), volume of distribution (Vd) and elimination half-life (T1/2) of warfarin were significantly decreased while Cmax and Tmax were significantly increased after treatment with Danshen. There was no significant change in PT during the Danshen treatment period while the PTs were increased significantly in the first two days after warfarin doses. Our results suggested that Danshen can increase the initial bioavailability of warfarin and also affect the elimination of warfarin. It can also increase the PT further after the warfarin doses. The pharmacokinetic and pharmacodynamic interactions observed in this study indicate a clinically important interaction between Danshen and warfarin if these two agents are taken together.
Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self-medicate with Danggui or other TCM products while on chronic treatment with warfarin.
Propofol, an intravenous anesthetic, has been shown to offer superior analgesic effect clinically. Whether propofol has preventive analgesic property remains unexplored. The present study investigated the antinociceptive effect of propofol and underlying molecular and cellular mechanisms via pre-emptive administration in a formalin-induced inflammatory pain model in rats. Male adult Sprague–Dawley rats were randomly allocated into four groups: naïve (Group Naïve), formalin injection only (Group Formalin), and formalin injection at 30 min (Group P-30 min) or 2 h (Group P-2 h) after intravenous infusion of propofol (0.6 mg kg−1 min−1) for 1 h. Nociceptive responses and protein expression of phosphorylated- or pan-GluN2B, ERK1/2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in the spinal dorsal horn were evaluated. Alteration of intracellular Ca2+ concentration induced by N-methyl-D-aspartate (NMDA) receptor agonists with or without pre-treatment of propofol was measured using fluorometry in SH-SY5Y cells while neuronal activation in the spinal dorsal horn by immunofluorescence. Pre-emptive propofol reduced pain with a delayed response to formalin and a reduction in hypersensitivity that lasted at least for 2 h. The formalin-induced activation of spinal GluN2B and ERK1/2 but not p38 or c-Jun N-terminal kinase was also diminished by propofol treatment. Preconditioning treatment with 3 µM and 10 µM of propofol inhibited Ca2+ influx mediated through NMDA receptors in SH-SY5Y cells. Propofol also reduced the neuronal expression of c-Fos and p-ERK induced by formalin. This study shows that pre-emptive administration of propofol produces preventive analgesic effects on inflammatory pain through regulating neuronal GluN2B-containing NMDA receptor and ERK1/2 pathway in the spinal dorsal horn.
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