Population pharmacokinetics of oxcarbazepine in Chinese epilepsy patients / 药学学报

Oxcarbazepine (OXC) is a common antiepileptic drugs. In this study, one hundred and eighty four epilepsy patients with 196 observations of oxcarbazepine's active metabolite, 10,11-dihydro-10-monohydroxy carbazepine (MHD) were collected prospectively from routine clinical monitoring. Nonlinear mixed effect modeling was employed to develop a population pharmacokinetic model of oxcarbazepine in Chinese patients with epilepsy to investigate the impact of gender, age, weight, co-medications and genetic polymorphisms of UGT2B7 c.802T>C, ABCC2 c.1249G>A, ABCC 23972C>T on pharmacokinetic characteristics of OXC. The population estimate of apparent clearance (CL/F) and apparent volume of distribution (V/F) was 1.84 L·h−1 and 275 L, respectively. Gender and UGT2B7 c.802T>C affected the clearance rate of MHD significantly. The established model was:CL/F=1.84×0.848UGT2B7×1.17GENDER. Where the genotype of UGT2B7 c.802T>C was CC, UGT2B7=0, otherwise UGT2B7=1. When the patient was male, GENDER=1, otherwise GENDER=0. The final model was evaluated by normalized predictive distribution error (NPDE) and bootstrap method. The model was stable and reliable, which offers a powerful approach for rational use of OXC in epilepsy patients.

Development of decision system for individualization of vancomycin dosage / 药学学报

Vancomycin has been widely prescribed as the first-line antibiotic in the treatment of methicillin-resistant Staphylococcus aureus and other serious Gram-positive infections. Due to its large pharmacokinetic (PK) variability and narrow therapeutic range, it requires optimization of dosage to achieve target exposure. In this study, SmartDose, a decision support system for individualization of vancomycin dosage is developed using the maximum a posterior Bayesian estimation (MAPB) by the open-source language R combined with the population PK characteristics of vancomycin in Chinese patients. It provides initial design and adjustment of dose regimens based on the therapeutic drug monitoring (TDM) results, as well as a user-defined module to facilitate optimal vancomycin therapy. SmartDose has a high computational reliability, which is validated by NONMEM, the golden standard PK software. Meanwhile, SmartDose is established as a web-based application and its operational flexibility makes it an efficient tool for vancomycin dose optimization in routine clinical settings.

[Effect of beta-adrenoceptor on NO-induced attenuation in spontaneous contractions of ileum in mice].

AIM: To investigate the influence of L-arginine (NO donors, L-Arg) on spontaneous contractions of ileum in mice and study the effects of activation of beta-adrenoceptor on NO-induced inhibition in spontaneous contractions of ileum. METHODS: The method of spontaneous contractions recording was used to investigate the effect of L-NNA, ODQ, Isoprenaline( beta-adrenoceptor agonist) and Propranolol (beta-adrenoceptor antagonist) on NO-induced inhibition in spontaneous contractions of ileum. RESULTS: (1) L-Arg inhibited the spontaneous contractions of ileum and had concentration-response relationship. (2) L-NNA (3 x 10(-4) mol/L), ODQ (3 x 10(-6) mol/L) relieved the inhibitory effect of L-Arg in ileum . (3) Propronalol (3 x 10(-6) mol/L) decreased significantly the inhibitory effect of L-Arg. (4) Iso (1 x 10(-7) mol/L) increased the inhibitory effect of L-Arg. After Iso (1 x 10(-7) mol/L) and Propronalol (3 x 10(-6) mol/L) being coapplied, the inhibitory effect of L-Arg was not changed. CONCLUSION: NOS catalyzed L-Arg and produced NO. NO exerted its inhibitory effect by the cGMP pathway, the activation of beta-adrenoceptor was partly involved in NO-induced relaxation in ileum.

5-HT2 receptor mediated the potentiation of GABA-activated current in the membrane of the dorsal root ganglion neurons of rat.

AIM: To explore the modulation of 5-HT on GABA-activated current (I(GABA)) in the membrane of rat dorsal root ganglion (DRG) neurons and its mechanism. METHODS: Rat DRG neurons were isolated mechanically and enzymatically, on which whole-cell patch clamp recording and repatch technique for intracellular dialysis were performed. RESULTS: In the majority of neurons examined (92.0%, 69/75) GABA induced a concentration-dependent inward current. In neurons sensitive to GABA preapplication of 5-HT produced potentiation effect (82.6% , 57/69) on I(GABA). Preapplication of 5-HT at concentrations of 1 x 10(-6), 1 x 10(-5), 1 x 10(-4) and 1 x 10(-3) mol x L(-1) potentiated I(GABA) by (35 +/- 8)% (n=8), (47 +/- 11)% (n=10), (65 +/- 17)% (n=9) and (75 +/- 18)% (n=11), respectively. This effect was mimicked by alpha-methyl-5-HT (1 x 10(-6) mol x L(-1)), a specific 5-HT2 receptor agonist, and reversed by cyproheptadine, a selective 5-HT2 receptor antagonist. The potentiation of I(GABA) by 5-HT was irrespective to whether the I(5-HT) presents or not in a subset of neurons. The concentration-response curves for GABA before and after pretreatment with 5-HT manifested the same threshold value and similar EC50 (2.0 x 10(-5) and 1.9 x 10(-5) mol x L(-1), respectively) , while the maximal value of I(GABA) for the latter was 33.6% higher than that for the former. Intracellular dialysis with GDP-beta-S or H-7 abolished the potentiation of I(GABA) by 5-HT, while H-9 did not. CONCLUSION: 5-HT can potentiate GABA-activated current via PKC-dependent phosphorylation of GABA(A) receptor following the activation of 5-HT2 receptor.

Effect of sildenafil citrate on penile erection of rhesus macaques.

AIM: To examine the effect of sildenafil citrate on penile erection of male rhesus macaque. METHODS: Twenty Macaca mulatta were divided into the sildenafil treated and the control groups of 10 animals each. The penile size, the corpus cavernosal electromyogram (EMG) and the intra-corpus cavernosal pressure (ICP) were determined. RESULTS: The diameter of penis and the ICP were significantly increased and the corpus cavernosal EMG significantly reduced in the sildenafil group. CONCLUSION: Sildenafil citrate increases the penile size and ICP and reduces the corpus cavernosal EMG in male rhesus macaque.