Effect of Reserpine,Desipramine and Phenytoin on Digoxin Induced Arrhythmias and Myocardial Uptake of Digoxin in Guinea Pigs

Abstract: Digoxin was infused intravenously 27.5 μg/min. to guinea pigs. By means of the ECG doses of digoxin needed to cause ventricular extrasystoles (VES), ventricular fibrillation (VF), and asystole (AS) were determined in a control group without any premedication. Three groups were given a pre-treatment with desipramine, phenytoin and reserpine. After AS digoxin concentrations in the heart muscle and in the kidneys were determined by radioimmunoassay. The concentrations of adrenaline and noradrenaline were also determined in these tissues. After reserpine and phenytoin the doses of digoxin needed to induce VF and AS were increased. Desipramine had no effect on digitalis-induced arrhythmias. The relative uptake of digoxin in the heart muscle was decreased after all of the three premedications; there was no change in the kidney. The tissue catecholamine concentrations were decreased after reserpine and desipramine, but remained unchanged after phenytoin. The lethal dose of digoxin seemed not to correlate to the myocardial digoxin concentration after different premedications. The mechanism of the uptake in the heart muscle seemed to be different from that in the kidney. There was no correlation between the catecholamine concentration in myocardium and the ar-rhythmogenic effect of digoxin in the different groups.     

Inotropic Action and Myocardial Uptake of Digoxin and Betamethyldigoxin in Isolated Guinea Pig Atria

Abstract: The chronotropic and inotropic effects as well as the tissue levels of digoxin and methyldigoxin were studied in isolated guinea pig atria. Higher concentrations of methyldigoxin than of digoxin were required to cause arrhythmias. The inotropic potencies of the two glycosides did not differ from each another in equimolar concentrations in the organ bath. The increase in contractility correlated with the level of the glycoside in the organ bath and in the tissue. Digoxin was more effectively taken up by the heart tissue than methyldigoxin. Thus, when the tissue levels of the glycosides were the same, the contractility was greater after methyldigoxin than after digoxin.     

Mechanism of inhibitory effect of citalopram on isolated guinea-pig atria in relation to adenosine receptor

The effect of citalopram (CTP), a selective serotonin reuptake inhibitor antidepressant was studied on the rate and force of contractions of isolated guinea-pig atria. CTP (2-32 microg/ml) caused a dose-dependent decrease in the contractile force (7%-62%) and in the rate of contractions (11%-72%). These negative inotropic and chronotropic effects of CTP (8 microg/ml) were not prevented by atropine (1 microg/ml) and 3,7 dimethyl-1-propargylxanthine (DMPX; 1.5 microg/ml), an adenosine A(2) receptor antagonist, but 1,3 dipropargyl-8-cyclopentylxanthine (DPCPX; 12 microg/ml), a specific adenosine A(1) receptor antagonist significantly blocked these effects (p < 0.001) and theophylline (30 microg/ml) a non-selective adenosine A(1)/A(2A) receptor antagonist also prevented the inotropic and chronotropic effects of CTP. These results suggest that the negative inotropic and chronotropic effect of CTP on isolated guinea-pig atria is probably mediated through an inhibition of the uptake of adenosine or the A(1) receptor mechanism.     

MDR1 Genotype-Related Pharmacokinetics of Digoxin After Single Oral Administration in Healthy Japanese Subjects

Purpose. To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacokinetics of digoxin after single oral administration in healthy subjects. Methods. The MDR1 genotype at exon 26 was determined in 114 healthy volunteers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single oral administration at a dose of 0.25 mg. Results. It was found that 35.1 % (40/114) of subjects were homozygous for the wild-type allele (C/C), 52.6 % (60/114) were compound heterozygotes with a mutant T-allele (C3435T) (C/T), and 12.3 % (14/114) were homozygous for the mutant allele (T/T). There was no effect of gender or age on the distribution. The serum concentration of digoxin after a single oral administration increased rapidly, attaining a steady state in all subjects; however, it was lower in the subjects harboring the T-allele. AUC_{0-4 h} values (±SD) were 4.11 ± 0.57, 3.20 ± 0.49, and 3.27± 0.58 ng h/ml, respectively, with a significant difference between C/C and C/T or T/T. Conclusions. The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.     

婴儿口服地高辛醑剂后血药浓度监测结果分析

目的 探讨婴儿口服地高辛醑剂后血药浓度与临床疗效、给药剂量、合并用药情况、性别、年龄和体重的相关性.方法 查阅广东省人民医院2005 ～2009年口服地高辛醑剂的婴儿病历,记录疗效、用药情况、性别、体重、年龄、血药浓度监测结果等,用统计软件SPSS 13.0进行分析.结果 415例婴儿口服地高辛醑剂血药浓度测定值在治疗浓度0.8～2.2 ng/ml的共270例,占65.1％;低于治疗浓度范围下限(＜0.8 ng/ml)的共107例,占25.8％;高于治疗浓度范围上限(＞2.2 ng/ml)的共48例,占11.6％.婴儿地高辛血药浓度值与性别不存在明显相关性,但与给药剂量、年龄、体重、合并用药和具体病情有关.结论 地高辛血药浓度受个体因素与具体病情影响,药物剂量的制订和调整,应考虑可能影响地高辛血药浓度的各种因素,结合婴儿自身情况来决定最佳给药方案.     

影响地高辛血药浓度的生物统计因素

本文随机选择100例地高辛血药浓度监测病人的病案记录，分别就性别、年龄、疾病状态、合并用药诸因素对用药者体内地高辛血药浓度的影响进行了生物统计分析。数据应用POMS医用统计学软件进行方差分析，结果显示：性别、肝功能、肺心病及合并用药对地高辛血药浓度无显著影响（P＞0.05）;年龄老化及疾病状态中肾功能不全、糖尿病、肺部感染对地高辛血药浓度有显著影响（P＜0.01）。     

Effect of citalopram on ouabain-induced arrhythmia in isolated guinea-pig atria

The effect of citalopram (CTP) a selective serotonin reuptake inhibitor agent was studied on ouabain-induced arrhythmia in spontaneously beating isolated guinea-pig atria. CTP (2-32 microg/ml) produced a dose-dependent decrease in the force of contractions (7-62%), and in the rate of contractions (11-72%). Pre-administration of the atria with CTP inhibited the ouabain-induced arrhythmia in isolated atria. Ouabain alone (1.2 microg/ml) produced arrhythmia at 4.5 min, and asystole at 20.7 min. Pretreatment with CTP (8 microg/ml) significantly increased the time of onset of arrhythmia to 9.5 min. In addition CTP prolonged the beating of atria (survival time) to more than 56 min, and inhibited the occurrence of asystole. These findings indicate that CTP produces direct cardiac action, probably due to the inhibition of cardiac Na(+) and Ca(2+) channels. Moreover our results suggest that CTP may reduce the membrane conductance through inhibition of ionic channels which decrease ouabain-induced arrhythmia.     

前胡丙素对豚鼠心房和兔主动脉条的钙拮抗作用

前胡丙素(Pra—C)非竞争性抑制CaCl_2和高钾除极化所致兔主动脉条的收缩,pD’_2值分别为4.9和5.0;抑制5—HT诱导的依外钙性收缩,但不影响依内钙性收缩及NE诱导的收缩;Pra—C5～50μmol/L浓度依赖性地抑制豚鼠左房收缩力和阶梯现象;Pra—C抑制血管与心脏的IC_(50)之比为1:8。结果提示Pra—C对血管和心脏的抑制作用可能与拮抗Ca~(2+)有关,且主要影响经PDCs的外钙内流。     

Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide

AIMS: Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide. METHODS: Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC. RESULTS: The C(max) and AUC(0,infinity) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t(1/2) of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in t(max) values among the three genotypic groups was not statistically significant. CONCLUSIONS: Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.     

乙肝核酸疫苗安全性的初步研究

目的:研究乙肝核酸疫苗对小鼠和豚鼠的长期毒性.方法:健康小鼠和豚鼠分别按体重随机分为低、中、高剂量组(小鼠剂量分别为0.5,1.5,4.5 mg·kg-1,豚鼠剂量分别为0.1,0.4,0.8 mg·kg-1)和溶媒对照组.2种动物均每周后肢肌内注射2次,共8周.末次给药后24 h和停药后30 d分别测血液学、血液生化、病理检查和小鼠的各项免疫指标(包括IgG 1和IgG 2a亚型血清水平、血清抗核抗体、血清抗体总水平、γ-干扰素(IFN-γ)和白介素-4(IL-4)血清水平、外周血中各淋巴细胞亚群的分布情况和染色体整合检测).结果:两种动物各剂量组的各项常规检测指标均未见有任何异常变化,与空白及溶媒对照组相比均无显著性差异.小鼠免疫指标未出现与治疗目的无关的改变.结论:受试疫苗在两种动物未观察到明显的生化、病理学、免疫学指标异常.小鼠和豚鼠肌内注射乙肝核酸疫苗的安全剂量分别为4.5和1.2 mg·kg-1.     

MDR1 Genotype-Related Duodenal Absorption Rate of Digoxin in Healthy Japanese Subjects

Purpose. Recent clinical studies suggest the importance of the MDR1 genotype at position 3435 (C3435T) in terms of pharmacokinetics, but there is still no consensus in reports on the relationship between the genotype and plasma/serum concentration-time profiles of drugs after conventional oral administration. This study was performed to elucidate the effects of C3435T on the rate of duodenal absorption of digoxin in healthy Japanese subjects. Methods. Digoxin solution was sprinkled directly over the surface of the duodenum using an endoscope, and its absorption rate was evaluated by serial monitoring of the serum concentration and by analysis of its initial 15-min increasing phase. Results. The duodenal absorption rates of digoxin were 911 ± 91 ng/min and 506 ± 76 ng/min for C/C and T/T, respectively (±SE, p = 0.007). Conclusions. The C3435T mutation of the MDR1 gene is associated with suppression of duodenal absorption of digoxin.     

Inotropic Effect of Digoxin in Humans: Mechanistic Pharmacokinetic/Pharmacodynamic Model Based on Slow Receptor Binding

Purpose. The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response. Methods. On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II. Results. The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC₅₀, E _max and delay time ) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time that were dependent on the digoxin administration schedule. Conclusions. The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.     

齐墩果酸对OATP1B1介导药物转运功能的关联性影响

目的 探讨齐墩果酸对有机阴离子转运多肽1B1（organic anion transporting polypetide1B1,OATP1B1）转运功能的关联性影响。方法 利用稳定表达人OATP1B1的人胚胎肾293（hunan embyonic kindney293,HEK293）细胞株,以氟伐他汀为底物进行OATP1B1摄取反应,观察齐墩果酸对OATP1B1摄取功能的影响。结果 齐墩果酸对OATP1B1摄取氟伐他汀的功能有竞争性抑制作用,抑制常数Ki值为（20.3±2.1）mmol·L^-1。结论 齐墩果酸对肝脏药物转运体OATP1B1转运抑制作用可诱导中西药相互作用。     

Intravenous Infusion of RMP-7 Increases Ocular Uptake of Ganciclovir

Purpose. The ability of intravenous (i.v.) infusions of the bradykinin agonist, RMP-7, to permeabilize the blood-ocular barriers (BOB) to the antiviral agent ganciclovir was investigated in guinea-pigs. Methods. Different i.v. dosing regimens included pre-treatment with RMP-7 (0.2 g/kg/min for 5 min) followed by either [³H]-ganciclovir (1 Ci/0.2 ml/min) alone, and/or co-infusion with RMP-7 and [³H]-ganciclovir. At specific times the animals were sacrificed, their eyes removed, and the retina and lens epithelium dissected and analyzed for the amount of radioactivity. Results. Using the ratio of tissue vs. integrated plasma radioactivity concentration, a two-fold increase in ganciclovir steady-state levels were observed in the retina as well as lens epithelium following RMP-7 pretreatment. Peak uptake effects were achieved with a 4.5 min ganciclovir infusion. Neither longer infusions of ganciclovir alone, nor co-infusions of RMP-7 and ganciclovir further enhanced the uptake effects. Kinetic analysis indicated that RMP-7 increased the rate of ganciclovir entry (K _IN) in studied ocular tissues, while the efflux of drug (K _OUT) was not affected by this treatment. Finally, ganciclovir retina:plasma ratios elevated by RMP-7 pre-treatment, remained higher than control ratios within 60 min following cessation of 4.5 min ganciclovir infusion. Conclusions. These data offer further evidence that BOB and in particular the blood-retinal barrier can be permeabilized via bradykinin receptor stimulation. As the i.v. infusions of RMP-7 enhanced the retinal uptake of ganciclovir, it is suggested that a combination of RMP-7 and ganciclovir may provide a novel approach for treating cytomegalo-virus retinis.     

槐果碱对哇巴因诱发豚鼠室性心律失常的影响

目的观察槐果碱的抗室性心律失常作用。方法将哇巴因诱发的室性心律失常豚鼠,分为对照组与不同剂量槐果碱组(5、2.5和1.25 mg·kg~(-1))。通过心电图仪连续观察记录室性早搏(室早)、室性心动过速(室速)、室扑、室颤及心脏停搏出现时间,计算哇巴因的累积量。结果槐果碱各组与对照组相比,仅5 mg·kg~(-1)组能增加出现室早、室速、室扑、室颤及心脏停搏的哇巴因累积量(P<0.01)。结论槐果碱对哇巴因诱发的豚鼠室性心律失常有一定的抑制作用,以5 mg·kg~(-1)的剂量为佳。     

抗癌药细胞色素P450 1B1抑制剂的研究进展

介绍了有关人细胞色素P450 1B1(CYP1B1)抑制剂的研究概况。CYP1B1是一类在导致癌变的雌激素代谢和激活芳香烃化合物致癌性中起重要作用的酶，在正常组织中通常不表达而在许多肿瘤组织中表达活跃，同时对许多抗癌药物的代谢具有重要影响。这表明CYP1B1抑制剂有望成为又一类肿瘤治疗药物。     

尼卡地平在异丙肾上腺素扩张气管中的作用

目的:探讨尼卡地平(Nic)对异丙肾上腺素(Iso)舒张气管的增强作用.方法:在豚鼠离体气管上观察Nic对Iso的增强作用,并与Nic对茶碱(Theo)和硝普钠(SNP)的作用进行比较.结果;(1)Nic能增强Iso豚鼠离体气管的舒张作用.此增强作用具剂量依赖性.表现在Iso量-效曲线随Nic剂量增高而逐渐左移;(2)Theo浓度大于Nic1000倍时,也增强Iso的作用;(3)相同条件下,SNP合用Nic或Theo后对SNP引起的气管舒张无增强作用.结论:Nic和Theo一样,可能通过抑制磷酸二酯酶而增高Iso对气管平滑肌的舒张作用.     

马布特罗对豚鼠支气管平滑肌松弛作用和平喘作用的影响

目的 :观察马布特罗对豚鼠的平喘作用和离体豚鼠支气管平滑肌的松弛作用。方法 :用 2 %氯化乙酰胆碱和 0 .1 %组胺等容积混合液喷雾诱发哮喘 ,观察马布特罗 (0 .0 6～ 1mg·kg-1)平喘作用的半数有效量(ED50 )及对引喘潜伏期的影响。用离体豚鼠肺支气管灌流法观察马布特罗 (1 0 -9,1 0 -7,1 0 -3 kg·L-1)对组胺 1 0 -4kg·L-1引起肺支气管灌流量减少的影响。结果 :马布特罗对致痉剂诱发豚鼠哮喘有明显抑制作用 ,减少哮喘诱发抽搐动物数 ,其ED50 为 0 .2mg·kg-1及 95 %可信限为 0 .0 8～0 .49mg·kg-1;马布特罗可剂量依赖性对抗组胺减少肺支气管灌流量作用 ,并显著缩短组胺灌流达固定流量时间。结论 :马布特罗对药物致豚鼠哮喘具有明显平喘作用 ,此作用与其松弛支气管平滑肌作用有关。     

有机阴离子转运多肽1B1的遗传药理学进展

人体存在多种类型的药物转运体,对于药物的吸收、分布和排泄起重要作用。参与药物跨膜转运的转运体功能受影响,将可能导致诸多临床药物的疗效、毒副作用甚至药物相互作用的发生。在各种影响因素中,遗传多态性所起的作用最为重要,可导致基因表达和蛋白功能发生改变。目前,阐明转运体基因的多态性以及基因型与表型之间的相互关系已成为应用遗传信息指导临床个体化用药的必要步骤。本文就肝脏有机阴离子转运多肽1B1（OATP1B1[OATP-C],编码基因SLCO1B1）基因多态性对药代动力学和药效动力学的影响及其临床意义等方面的进展作一综述。     

Effect of TCDD exposure on CYP1A1 and CYP1B1 expression in explant cultures of human endometrium.

Endometriosis is a debilitating disease estimated to affect 10% of reproductive-age women and characterized by the growth of endometrial tissue outside of the uterus. The present study characterizes a human endometrial explant culture model for studying the direct effects of TCDD exposure by assessing the expression of CYP1A1 and CYP1B1 mRNA (Northern blotting), protein (Western blotting), and activity (7-ethoxyresorufin-O-deethylase; EROD) in explants cultured with and without TCDD. Explants were obtained at laparoscopy or laparotomy from women undergoing surgery for tubal ligation, endometriosis, or pelvic pain unrelated to endometriosis. The explants were cultured with 10 nM estradiol (E(2)) or 1 nM E(2) plus 500 nM progesterone (P(4)) with or without TCDD (first 24 h). The expression of CYP1A1 and CYP1B1 mRNA was greatest with 10 nM TCDD and increased up to 72 h after initial exposure. EROD activity increased up to 120 h. Explants from a secretory phase biopsy became reorganized in culture and formed a new epithelial membrane, while maintaining basic endometrial morphology and viability for up to 120 h. At 24 h, TCDD significantly increased CYP1A1 and CYP1B1 mRNA, and at 72 h, TCDD significantly increased EROD activity and CYP1B1 protein compared to explants cultured without TCDD for similar times. CYP1B1 protein also exhibited substantial constitutive expression that was similar in uncultured biopsies, where CYP1B1 protein was immunolocalized in the cytoplasm of epithelial glands, with only occasional patches of protein in the surface epithelial membrane. In explants cultured with and without TCDD exposure, CYP1B1 protein was localized in the cytoplasm of the new surface epithelial membrane and glands closest to the surface. CYP1A1 protein was not detected in uncultured biopsies or explants. Both younger age (age 30 and under) and proliferative phase were associated with higher TCDD-induced EROD activity in specimens treated with E(2):P(4). No significant endometriosis-related differences were observed for any of the biomarkers, but the detection of disease-specific change was limited by small sample size and variability in tissue-cycle phase. The human endometrial explant culture model will be useful for future studies of the effects of dioxin-like compounds on human endometrium in relationship to cycle phase and hormonal exposure.