小诺霉素在小鼠的时辰毒性及时辰药代动力学

小鼠自实验前２Ｗｋ置于标准的明期和暗期下饲养，自由进食饮水。急性毒性昼夜节律实验剂量为小诺霉素７５０ｍｇ．ｋｇ－１，ｉｐ，于１ｄ中６个不同时间给药；选择９：００和２１：００做昼夜ＬＤ５０实验和昼夜药动学实验（剂量为１００ｍｇ．ｋｇ－１，ｉＰ）。结果：小诺霉素的急性毒性呈昼夜节律性变化，明期毒性大于暗期，９：００死亡率（０．７）最高，１７：００死亡率（０．２５）最低。９：００组和２１：００组ＬＤ５０±Ｌ９５分别为５６２．２±４８．４ｍｇ·ｋｇ－１和６７８．１±５３．８ｍｇ·ｋｇ－１。与２１：００组比较，９：００组在用药后０．５和１ｈ血药浓度较高，ＡＵＣ较大，提示小诺霉素毒性的昼夜节律性变化与其药动学昼夜节律变化有关。     

曲马多在小鼠体内的时间药理学

目的　研究曲马多对小鼠的急性毒性、药效学及药代动力学的昼夜节律性。方法　小鼠在08:00 ,12:00 ,16:00,20:00 ,24:00和04:00 ip曲马多后,观察其急性死亡率、对热板和压尾刺激的反应及药代动力学的变化。结果曲马多对小鼠的急性毒性有明显的昼夜节律,且与血药浓度的昼夜节律呈正相关,毒性作用峰值在暗中期;曲马多对小鼠的镇痛作用存在昼夜节律性差异,作用峰值在暗后期;曲马多在小鼠体内的药代动力学有用药时间依赖性。结论　曲马多对小鼠的急性毒性、镇痛作用及药动学均存在昼夜节律性     

硝苯吡啶时辰药动学的实验研究

本文报道了硝苯吡啶在家兔体内不同给药时间的药动学变化。家兔7只,于0:00,6:00,12:00,18:00四个不同的时间给药,剂量为10mg╱kg,血药浓度用HPLC法测定。结果表明硝苯吡啶的血药浓度在0:00最高,AUC最大,为156.90μg·(ml·min)~(-1);MRT最长为4.39h。     

时辰药理学与合理用药

目的 论述时辰药理学与昼夜节律的关系,为临床选择最佳用药时间提供参考.方法 查阅相关文献,结合临床用药实际进行汇总、分析给药时辰的重要性.结果 同一药物在1 d中不同的时间给药,疗效和毒性不同结论根据机体自身的节律变化,选择合适的用药时机,能以最小的剂量达到最佳疗效和最小毒性,从而提高治疗效果,改善患者的生活质量.     

时辰药代动力学在药物治疗中的应用

目的：通过阐明影响口服药物药代动力学的时辰因素,以指导临床合理用药。方法从药物的吸收、分布、代谢和排泄四方面讨论药物在人体内的时辰变化。结果药物在体内的药代动力学过程受到生理活动周期昼夜节律变化的影响。结论结合药物的时辰药代动力学和人体生理功能的节律变化制订合理的给药方案,从而提高疗效,减少药品不良反应。     

苯巴比妥对小鼠的敏感性及药物代谢动力学的昼夜差异

苯巴比妥对ICR小白鼠的急性毒性及药效均呈明显的昼夜节律性差异,夜间用药的毒性高于白昼用药,死亡峰值时在21:29,反之,白昼用药催眠作用起效快,维持时间久,血药浓度高,半衰期短,在较低的血药浓度下仍能维持有效的催眠作用,结果表明苯巴比妥的毒性及药效的昼夜节律性差异并非完全取决于其药物动力学的昼夜差异,而可能是主要依赖于动物的敏感性的昼夜差异。     

临床用药切勿忽视时辰药理

时辰药理学是研究与时间相关的机体对药物的反应,包括药理效应与毒性、药代动力学和生物利用度等随时间发生变化的规律.人体的激素分泌、酶的活性都呈节律性变化,机体对药物的生物利用度、血药浓度、代谢排泄也是有节律性的改变.根据机体自身的节律变化选择合适的用药时机及新型智能型药物,以达到最小剂量、最佳疗效、最小毒性来保障用药安全有效,对改善患者的生存质量很有意义.     

临床用药切勿忽视时辰药理

时辰药理学是研究与时间相关的机体对药物的反应,包括药理效应与毒性、药代动力学和生物利用度等随时间发生变化的规律.人体的激素分泌、酶的活性都呈节律性变化,机体对药物的生物利用度、血药浓度、代谢排泄也是有节律性的改变.根据机体自身的节律变化选择合适的用药时机及新型智能型药物,以达到最小剂量、最佳疗效、最小毒性来保障用药安全有效,对改善患者的生存质量很有意义.     

甲氨蝶呤时辰药动学研究

目的:探讨早、晚静滴甲氨蝶呤(MTX)时,其血药浓度及药动学参数的时辰变化,为制定我国患者的MTX给药方案提供依据.方法:应用高效液相色谱法,测定6例肿瘤患者接受早晚两个疗程化疗后的不同时间的血药浓度,并用3P97软件进行模拟.结果:静滴MTX后,其血药浓度存在明显的节律性,早上给药组药时曲线下面积AUC高于晚上给药组,其余药动学参数变化不明显.结论:上午8∶00～12∶00用药具有较好的效果.     

应用时辰药理学指导临床合理用药

目的体内生理活动的昼夜节律与药物作用的时间节律密切相关,用以指导临床合理用药.方法参考有关资料,进行分析汇总,加以阐述.结果同一药物在1天中不同的时间给药,其疗效和毒性不同.结论根据人体生理活动的昼夜节律与药物作用的时间节律来指导临床制定最佳用药方案,可以更有效地提高疗效,减轻毒副作用.充分体现时辰用药的优越性.     

Chronopharmacological study of sodium valproate in mice: dose-concentration-response relationship

Effects of the time-of-day of drug administration on the pharmacokinetics electroshock seizure (ES) threshold and acute toxicity were investigated in mice with sodium valproate (VPA). ICR male mice, housed under a light-dark (12:12) cycle, were orally administered 600 mg/kg VPA for anticonvulsant effect studies and administered 1500 mg/kg VPA for acute toxicity studies. A significant circadian rhythm was demonstrated for the ES threshold at 30 min after VPA administration, with the highest value in the light phase and the lowest in the dark phase, although no rhythm was shown in the nondrugged state. A significant circadian rhythm was also shown for plasma and brain VPA concentrations. This finding nicely corresponded to the circadian rhythm in the ES threshold. The positive relationship between the brain VPA concentration and the ES threshold was not different between the light phase and the dark phase. There was also a significant circadian rhythm in the acute toxicity induced by VPA, with the highest mortality in the light phase and the lowest in the dark phase. The results suggest the importance of time in the circadian stage at which VPA is administered in the experimental studies in mice and the significance of circadian rhythm in VPA kinetics in relation to the rhythm of ES threshold.     

渗透压微泵恒速给药丙戊酸在小鼠体内的时间药物动力学

以渗透压微泵植入小鼠皮下恒速给予丙戊酸钠，在达到理论稳态浓度时间后，血浆药浓呈昼夜变化，白昼高于夜间，峰值位于明期末。药动学研究揭示丙戊酸血药浓度的昼夜差异可能与其清除率及分布容积的昼夜变化有关。     

An animal model for the study of chronopharmacokinetics of drugs and application to methotrexate and vinorelbine

An animal model was designed to study the chronopharmacokinetics of intravenous drugs and applied to anticancer agents vinorelbine (VNB) and methotrexate (MTX). Each experiment was performed on four pigs housed in a standardized light-dark cycle (12:12). Four pigs received a 0.16-mg bolus of VNB, followed by a 60-h continuous infusion at 0.48 mg/h. After hydration and urine alkalinization, four other pigs received a 2 mg/kg bolus of MTX, followed by two concomitant 60-h continuous infusions, one with MTX (8 mg/kg/h) and the other for hydration and folinic acid rescue (1.5 mg/kg/24 h). Serum cortisol was determined in each blood sample collected in these pigs. Blood samples were collected each hour for 60 h. The infusion flow rates and drug solution concentrations were controlled throughout the experiments. Analysis of VNB serum concentrations did not show any circadian rhythm of VNB serum concentrations. One pig administered MTX exhibited severe toxicity. Interestingly, no circadian rhythm of serum cortisol concentration was observed in this pig, whereas the three others exhibited a statistically significant cortisol circadian rhythm with a peak secretion in the morning. Two of these three pigs showed a significant 24-h rhythm of MTX with acrophase occurring at approximately 1:00 PM in both. The maximal concentration was found at 12:00 AM in the third pig. After the data were pooled, a highly significant (P < 0.01) circadian rhythm in MTX serum concentrations (57%) was found, with acrophase at midday. The pig represents a useful model for the study of chronopharmacokinetics of drugs given intravenously in human. The MTX chronokinetic variation found herein may be of interest for the improvement of chemotherapy in cancer patients.     

Factors influencing circadian rhythms in acetaminophen lethality

Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.     

Modulation of nonprotein sulphydryl compounds rhythm with buthionine sulphoximine: relationship with oxaliplatin toxicity in mice

The relationship between the rhythm in tissue nonprotein sulphydryl groups (NPSH) and that in 1,2-diamine (trans-I)-cyclohexane oxalatoplatinum (l-OHP) toxicity was investigated in a total of 266 male B₆D₂F1 mice, using buthionine sulphoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase. Mice were synchronized with an alternation of 12 h light (L) and 12 h darkness (D; LD 12:12), and circadian time was expressed in hours after light onset (HALO). NPSH was measured in liver, jejunum and bone marrow at 0, 8 and 16 HALO. Dosing l-OHP at these times achieved intermediate, high or low toxicity respectively. The physiological circadian rhythm in NPSH content was statistically significant in all tissues studied, with a maximum at the transition from D to L (0 HALO). BSO administration (450 mg/kg i.p., 4 h before sampling) induced a large depletion in liver and jejunum NPSH at their physiological peak (0 HALO), but exerted no significant effect at their trough (8 HALO). As a result, 24 h rhythm was suppressed in liver and jejunum, but remained similar to the physiological one in bone marrow. BSO enhanced l-OHP-induced mortality and jejunal toxicity, but exerted no significant effect upon bone marrow toxicity. Despite these differences, l-OHP remained least toxic at 16 HALO, near the middle of the dark span, which corresponds to maximum activity in the circadian rest/activity cycle. Our results show that mean NPSH levels in liver seem to account for the mean level of l-OHP toxicity, while jejunal NPSH rhythm plays an important role in the intestinal toxicity rhythm of this drug. Received: 19 January 1998 / Accepted: 18 June 1998     

XK的镇痛作用及急性毒性的时间药理学研究

目的研究XK对小鼠的急性毒性、药效学及药动学的昼夜节律性。方法小鼠分别在0400、0800、1200、1600、2000和2400灌胃XK后,观察其急性死亡率,用热板法、扭体法了解XK镇痛作用的时间变化,同时用高效液相色谱法测定不同时间点的血药浓度。结果XK对小鼠的急性毒性呈明显的昼夜节律,毒性作用的峰值在明中期;镇痛作用存在昼夜节律性差异,但作用峰值在明中后期,这恰是血药浓度的达峰时间。结论XK有良好的镇痛作用,其急性毒性和镇痛作用均呈现昼夜节律性,急性毒性与血药浓度的昼夜节律性有关。     

Circadian variation in methamphetamine- and apomorphine-induced increase in ambulatory activity in mice

The existence of circadian variation in methamphetamine- and apomorphine-induced change in ambulatory activity in mice was investigated. Adult male mice of dd strain, which had been housed on a 12 hr light-dark schedule (light period; 6:00–18:00) for 4 weeks, received injections of either methamphetamine HCl 1 or 2 mg/kg SC at one of six times of day (3:00, 7:00, 11:00, 15:00, 19:00 and 23:00), or apomorphine HCl 0.5 or 1 mg/kg SC at one of six times of day (3:30, 7:30, 11:30, 15:30, 19:30 and 23:30). The control animals were administered a physiological saline vehicle alone at the corresponding times of day. The ambulatory activity of each mouse was measured by a tilting-type activity cage for 3 hr after methamphetamine, and for 1 hr after apomorphine. A circadian variation in the ambulatory activity was observed after the administration of the saline, methamphetamine and apomorphine. Here, the highest activity counts were found when the saline, methamphetamine and apomorphine were administered during the late dark period (3:00 or 3:30), while the lowest activity counts were found when the saline and apomorphine 1 mg/kg were administered during the mid light period (11:00 or 11:30), and methamphetamine 1 and 2 mg/kg and apomorphine 1 mg/kg were administered during the late light period (15:00 or 15:30). The circadian variation in methamphetamine-induced increase in the activity was abolished by a pretreatment with reserpine 2 mg/kg SC 4 hr before, but that of apomorphine was maintained even by the pretreatment with reserpine. The present results suggest that the methamphetamine- and apomorphine-induced increase in the ambulatory activity in mice is dependent on the time-of-day 3f the drug administration, and the occurence is mainly due to a circadian variation in activity of the catecholaminergic systems in the brain.