Nicardipine Hydrochloride

Tamoxifen, a selective estrogen receptor modulator (SERM) used in breast cancer therapy, requires metabolic activation by CYP3A4 to exert its biological effects. This study evaluated the effects of calcium channel blockers nimodipine, nitrendipine and felodipine on tamoxifen metabolism by studying their interactions with tamoxifen in vitro and in vivo. Rat liver microsomes (RLM) and human liver microsomes (HLM) were used in this study to evaluate the inhibitory potential of nimodipine, nitrendipine and felodipine on tamoxifen metabolism in vitro. A total of 28 cardiovascular drugs, including calcium channel blockers, were screened in an RLM incubation system in vitro. In RLM, nimodipine, nitrendipine and felodipine had half-maximum inhibitory concentration (IC₅₀) values of 5.55 µM, 11.86 µM and 7.71 µM, respectively. In HLM, the IC₅₀ values were increased to 20.38 µM, 30.06 µM, and 44.45 µM for nimodipine, nitrendipine and felodipine, respectively. The kinetic assays indicated that nimodipine and felodipine inhibited the metabolism of tamoxifen in a competitive way, whereas nitrendipine showed non-competitive inhibition in RLM. However, felodipine exhibited non-competitive inhibition, and nimodipine and nitrendipine showed competitive inhibition in HLM. Pharmacokinetic studies in rats revealed that pretreatment with nimodipine and nitrendipine significantly increased the systemic exposure of tamoxifen, as demonstrated by increasing the area under the curve (AUC), the maximum concentration (C_max) and decreasing the clearance (CL_z/F). Finally, molecular docking studies supported these findings, showing potential interactions at the active site of CYP3A4. These results suggested the necessity for careful monitoring and possible dose adjustments of tamoxifen when co-administered with calcium channel blockers in clinic.

General anesthesia is a promising method for advanced Parkinson's disease patients unable to tolerate awake deep brain stimulation (DBS) surgery. However, anesthetic agents must be kept at relatively low levels to preserve the quality of intraoperative microelectrode recordings, which can lead to unstable hemodynamic conditions. Remifentanil, with its sedative and analgesic properties, could offer a solution. This study retrospectively analyzed microelectrode recordings of the subthamic nucleus (STN) and hemodynamic responses in patients with Parkinson's disease who received deep brain stimulation surgery under controlled volatile anesthesia with/without remifentanil infusion. From October 2017 to June 2019, 24 patients with Parkinson's disease who received bilateral subthalamic deep brain stimulation surgery in Hualien Tzu Chi Hospital with (n = 12) or without remifentanil infusion (n = 12) were enrolled in this study. We conducted a comprehensive spike analysis, examining frequency, inter-spike interval properties, modified burst index, modified pause index, and modified pause ratio. Additionally, we performed spike frequency spectrum analysis to investigate oscillatory activity in high-frequency, multi-unit, and single-unit neuronal activity. Our findings revealed no differences in STN firing characteristics, while a significant decrease in high beta power was observed in multi-unit activity in the remifentanil group. Notably, nine patients in the non-remifentanil group required additional nicardipine, whereas none in the remifentanil group did. Conclusively, for patients with advanced Parkinson's disease sensitive to external stimulation at low minimum alveolar concentration, remifentanil co-administration is an option to avoid unstable hemodynamic conditions during subthalamic deep brain stimulation surgery.