Effects of Berberine on In Vivo Pharmacokinetics of Midazolam and Its Metabolite in Rats / 医药导报

Objective To examine the effect of berberine hydrochloride ( BER ) on the pharmacokinetic profiles of midazolam,a substrate of CYP3A,in rats. Methods The rats were intragastrically given different doses of BER (50,100, 200 mg?kg-1) or ketoconazole (75 mg?kg-1) for 10 days.Single-pass duodenum perfusion of 20 mg?kg-1 MDZ was performed and the inguinal artery was cannulated for blood sampling.Plasma concentrations of MDZ and 1'-OH-MDZ were analyzed by high performance liquid chromatography ( HPLC) with the CYP3A inhibitor ketoconazole serving as positive control. Results BER (50,100,200 mg?kg-1) and ketoconazole (75 mg?kg-1) could significantly increase the AUC(0-t),AUMC(0-t)and Cmax of MDZ in a dose-dependent manner ( P<0.05) ,and reduce the clearance rate ( CLz ) of MDA and its apparent volume of distribution in the body ( Vz ) ( P<0. 05). But they failed to dramatically affect the half-life ( t1/2z ) and the peak time ( tmax ) of MDZ. Additionally,BER ( 100,200 mg?kg-1 ) and ketoconazole ( 75 mg?kg-1 ) could significantly dose-dependently decrease the AUC(0-t),AUMC(0-t)and Cmaxof 1'-OH-MDZ,and profoundly increase the CLz,tmax and Vz of 1'-OH-MDZ (P<0.05),but they had no remarkable influences on the t1/2z.The ratio of AUC(1'-OH-MDZ)/AUC(MDZ) was decreased with the increase of BER concentration. Conclusion BER can inhibit the in vivo metabolism of MDZ in a dose-dependant manner, which is associated with the suppression of the activity of CYP3A.

Interaction between Mivacurium and Nitroglycerin / 대한마취과학회지

BACKGROUND: The neuromuscular blocking effects of a nondepolarizing neuromuscular blocker (NDNM) during a nitroglycerin (NTG) infusion were significantly potentiated and prolonged. NTG reduced the requirement of a NDNM in surgical patients. We investigated the influence of a NTG single bolus injection on a mivacurium nuromuscular blockade. METHODS: We studied 36 adult surgical patients, ASA physical status I or II, between 15 and 53 years old. Neuromuscular monitoring was measured by TOF-GUARD (Biometer Co., Denmark). Anesthesia was induced by thiopental sodium 3-5 mg/kg and fentanyl 3 microgram/kg, and maintained with 3 L/min N2O, 2 L/min O2 and 1 vol.% isoflurane. Patients were randomly assigned to 3 groups: 1) Control group (mivacurium 0.16 mg/kg), 2) N100 group (mivacurium 0.16 mg/kg, NTG 100 microgram), 3) N200 group (mivacurium 0.16 mg/kg, NTG 200 microgram). We measured the train-of-four (TOF) response from the beginning of recovery to the complete regaining of muscle twitch. RESULTS: NTG produced a prolongation of the neuromuscular blocking effect by mivacurium. T1 (contro group: 12.1 +/- 0.5, N100 group: 15.8 +/- 0.4 and N200 group: 11.6 +/- 0.4 min), T25 (16.4 +/- 0.4, 20.5 +/- 0.5 and 14.9 +/- 1.0 min), T75 (22.5 +/- 0.9, 29.4 +/- 0.7 and 20.1 +/- 1.0 min), T95 (27.3 +/- 0.6, 39.6 +/- 0.7 and 24.6 +/- 1.5 min) and the recovery index (6.1 +/- 0.6, 9.0 +/- 0.4 and 5.3 +/- 0.7 min) were significantly prolonged in the N100 and N200 groups (P < 0.05). CONCLUSION: These results suggest that a NTG bolus injection prolonged the neuromuscular blocking effect of mivacurium, dose relatively.

The Compatibility of Mixed Solutions of Ketorolac Tromethamine with Nalbuphine HCl / 대한마취과학회지

BACKGROUND: In patient-controlled analgesia (PCA), ketorolac tromethamine has been mixed with nalbuphine HCL in the same PCA balloon or syringe. The compatibility of mixed drugs is an important factor in determining the effects of the administered drugs, so we examined the compatibility of the mixed solution of the both drugs in various dilutions. METHODS: Ketorolac tromethamine (K1, 3, 7, 19 group; n = 10/group) or nalbuphine HCl (N1, 3, 7, 19 group; n = 10/group) was diluted 1: 1, 3, 7, or 19 with normal saline and then the other drug was added. The presence of precipitates, turbidity by visual and spectrophotometric methods, and the pH of the mixed solutions were evaluated 0, 1, 6, 12 and 24 hours later. RESULTS: Precipitates were observed in all studied solutions except in solutions of nalbuphine HCl diluted 1 : 19 with normal saline plus ketorolac tromethamine at the observed intervals. Turbid changes were observed in N1, 3, K1, 3, and 7, but significantly decreased from 6 hours after mixing. The pH of the K groups were significantly lower than those of the N groups. CONCLUSIONS: The mixed solutions of ketorolac tromethamine with nalbuphine HCl were visually incompatible in almost all studied cases, so careful considerations are needed in mixing ketorolac tromethamine with nalbuphine HCl.

The Neuromuscular Blocking Effect of Mivacurium in Isolated Rat Phrenic-Hemidiaphragm with Long-term Phenytoin Pretreatment / 대한마취과학회지

BACKGROUND: Long-term phenytoin therapy induces resistance to the neuromuscular blocking effects of metocurine, atracurium, doxacurium, and pipecuronium. This study examine neuromuscu-lar blocking effect and recovery of mivacurium in isolated rat phrenic-hemidiaphragm with two-weeks phenytoin pretreatment. METHOD: After the administration of 14 days of phenytoin 40 mg/kg, administered intraperitoneally twice daily (n=10), ED90, antagonism of neostigmine and 4-aminopyridine on the electrically evoked twitch response and train-of-four (TOF) stimulation were compared to control groups in isolated rat phrenic-hemidiaphragm preparation. RESULTS: ED90 was significantly greater in the phenytoin group than in the control group (319 +/- 39.5 g vs. 209.5 +/- 52.2 g, respectively). After the administration of neostigmine 0.75 M, the recovery of the single twitch and TOF ratio were significantly lesser in the phenytoin group than in the control group (single twitch; 19.6 +/- 6.6% vs. 69.2 +/- 9.4%, TOF ratio; 0.258 +/- 0.149 vs. 0.543 +/- 0.1, respectively). After the administration of 4-aminopyridine 40uM, the recovery of the single twitch and TOF ratio were no significant differrence between the phenytoin group and the control group (twitch; 118.1 +/- 25.3% vs. 122.6 +/- 24.8%, TOF ratio; 0.937 +/- 0.051 vs. 0.949 +/- 0.067, respectively). CONCLUSION: Long-term phenytoin therapy induces resistance to the neuromuscular blocking effects of mivacurium.