小鼠体液免疫功能的昼夜节律性

小鼠体液免疫功能的昼夜节律性黄丰阳李经才为探索体液免疫功能的昼夜节律性，昆明种雌性小鼠置于１２∶１２的明暗周期交迭的环境中饲养，在０４∶００，０８∶００，１２∶００，１６∶００，２０∶００和２４∶００时分别取样测定．结果表明，正常小鼠和初次致敏小鼠的...     

正常小鼠免疫功能的昼夜节律性

本文用雌性小鼠研究免疫成分的昼夜节律性。动物自实验前一周置于标准的明暗周期交迭的环境中饲养，自由摄食饮水．在昼夜０４：００，０８：００，１２：００，１６：００，２０：００，２４：００时分别取样测定。结果表明，小鼠血液白细胞（ＷＢＣ）数、淋巴细胞百分率（Ｌｙｍ％），Ｌ－淋巴细胞百分率（Ｔ－Ｌｙｍ％）、碳粒廓清能力以及血清溶血素水平等各项指标均呈现明显的昼夜节律特征，按平均余弦法拟合可得其峰值位相时间分别为０４：０８，０７：５８，０７：５７，２１：１９，０２：５９时。     

氯氰菊酯对淋巴细胞信使昼夜节律的影响

本研究表明，Ｔ淋巴细胞中ｃＡＭＰ和ｃＧＭＰ含量具有昼夜节律，表现其峰值相分别位于－１８５°（１２∶２０）和－１８°（１∶１２），中值相差３．１２倍。氯氰菊酯染毒后，ｃＡＭＰ含量升高而ｃＧＭＰ含量降低，ｃＡＭＰ／ｃＧＭＰ比值增大。但这些变化只发生在部分昼夜时点（０４∶００，０８∶００，２０∶００和２４∶００），呈现明显的时间－效应。经在１／３ＬＤ５０和１／３０ＬＤ５０两种剂量染毒后，ｃＡＭＰ和ｃＧＭＰ含量的昼夜节律均消失，表明氯氰菊酯可破坏生理性节律系统。由于ｃＡＭＰ与ｃＧＭＰ节律的峰值和谷值相之间表现相互倒置的关系，使氯氰菊酯对Ｔ淋巴细胞的毒效应出现相应的时相性差异。这些结果提示，氯氰菊酯通过改变淋巴细胞内ｃＡＭＰ和ｃＧＭＰ的含量以及破坏其生理性昼夜节律，可导致免疫功能的降低。     

松果体对小鼠痛觉敏感性昼夜节律的影响

小白鼠置于标准光－暗条件中饲养２ｗｋ后，采用热板法，在昼夜６个时间点测痛阈值，结果呈现明显的昼夜节律，峰、谷时间在２４：００和１２：００时分别为（２７．８土３．０）ｓ和（１９．６土２．８）ｓ．热辐射刺激鼠尾痛阈也存在昼夜节律，峰、谷时间仍在２４：００和１２：００时，痛阈分别是（１８．３±３．０）ｓ和（１０．９±０．８）ｓ．扭体实验亦证明有昼夜节律．用切除松果体（Ｐｉｎｅａｌｅｃｔｏｍｙ，Ｐｘ）的小鼠重复上述实验，痛阈值减小，痛觉敏感性增强，而且昼夜节律消失，对动物进行持续光照或黑暗２ｗｋ，均明显改变其痛觉敏感性．结果表明：痛觉敏感性有昼夜节律．Ｐｘ使痛觉昼夜节律消失．说明松果体参予痛觉过程，而且与痛觉昼夜节律的形成有关．     

褪黑素对下丘脑氨基酸神经递质的影响

应用纸电泳一双波长薄层扫描法测定了雄性小鼠下丘脑天冬氨酸（Ａｓｐ）．谷氨酸（Ｇｉｎ），及γ－氨基丁酸（ＧＡＢＡ）３种神经递质的含量和褪黑素（ＭＴ）对其影响。结果发现；下丘脑内３种氨基酸神经递质含量均呈明显的昼夜节律性变化，ＭＴ使Ａｓｐ、ＧＡＢＡ的昼夜节律曲线上移，在１２：００及２０：００ｈ升高Ａｓｐ、ＧＡＢＡ作用明显。不同剂量的ＭＴ腹腔注射能够升高Ａｓｐ．ＧＡＢＡ含量，以５μｇ·ｋｇ－１剂量为强，脑室注射ＭＴ的效果更佳。然而，不同浓度，不同时ＩＭＭＴ给药均不影响下丘脑Ｇｌｕ水平。利血平化小鼠的Ａｓｐ、ＧＡＢＡ含量升高，Ｇｌｎ含量则下降、给利血平化动物注射ＭＴ，则ＭＴ对Ａｓｐ，ＧＡ－ＢＡ的影响消失，而使Ｇｌｎ含量进一步下降。提示：ＭＴ对Ａｓｐ、ＧＡＢＡ昼夜节律产生影响，这种影响可能通过单胺神经递质介导。     

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。     

反相高效液相色谱法测定5—氨基水杨酸及其代谢物在人血浆 …

研究５－氨基水杨酸及其代谢物在人血浆及尿中的浓度。方法：反相高效液相色谱法为测定方法。结果：血浆测定两者线性范围为０．０８－８．００μｇ．ｍｌ＾－１，最低检出浓度均为０．０４μｇ．ｍｌ＾－１，两者平均回收率分别为８７．３％，９１．４８％，日内ＲＳＤ分别为６．０４％，５．５１％，日间ＲＳＤ分别为７．９８％，４．３％。     

丙戊酸恒速约药在小鼠体内时间药物动力学及进食条件的影响

研究丙戊酸药物动力学昼夜节律变化及进食条件对节律的影响。方法：对自由进食及限定进食的ＩＣＲ小鼠分别以渗透压微泵技术（１．０６２ＭＧ．Ｈ＾－１及ｉｖ（５０ｍｇ．ｋｇ＾－１）给予戊酸钠，并测定ＶＡ动力学的时间依赖性变化。结果：血浆ＶＡ浓度及清除率在稳态时呈昼夜节律性变化限定进食时间影响ＶＡ动力学的节律，使峰值位相移动约１２ｈ。     

高效液相色谱法测定复方克霉唑霜中克霉唑和盐酸达克罗宁含量

本文用高效液相色谱法在ＹＷＧ－Ｃ１８柱上，以甲醇－ｐＨ３．６的缓冲液（含０．０１５ｍｏｌ／Ｌ的四丁基溴化铵）为流动相，在２８０ｎｍ和２３７ｎｍ处分别测定了盐酸达克罗宁和克霉唑的含量。结果平均回收率和相对标准偏差分别为：９８．９３％，１．０４％；９９．１２％，１．１５％。醋酸地塞米松及霜剂基质均无干扰。     

高效液相色谱法测定犬血浆和小鼠组织,体液中的紫杉醇

建立了犬血浆和小鼠组织、尿和粪中紫杉醇的ＨＰＬＣ检测法。生物样品用乙醚提取后在Ｃ１８柱上以０．０１ｍｏｌ／Ｌ磷酸二氢钠－甲醇（４０：６０，ｐＨ＝４．３）为流动相，安定为内标，检测波长为２３３ｎｍ条件下进行检测。线性范围为１８．７￣３６００μｇ／Ｌ，最低检测浓度为１０μｇ／Ｌ。紫杉醇在犬血浆和小鼠肝、尿、粪中的回收率分别为８６．０４％￣９１．７３％，８７．６２％￣９２．１２％，８６．７８％￣９２．１     

四种药物毒性的昼夜节律变化

本文依据时间药理学的原理和方法,对抗肿瘤药苦参总碱、皮质激素类药氢化可的松、强心药洋地黄毒甙和镇静催眠药戊巴比妥钠对小白鼠的急性毒性进行测定。结果表明,四种药物 LD_(50)值具有明显的昼夜节律变化,均依照一天中的时辰呈现一定的数学函数曲线。每种药物毒性最强和最低出现的时刻不尽相同,但将其 LD_(50)值进行比较皆有显著性差异。文末对药物毒性昼夜节律变化的原因作了分析,强调时间毒性(chronotoxicity)在药学研究和临床用药中的意义和作用。     

Circadian rhythm of lithium toxicity in mice

The existence of cyclical (circadian) variations in lithium toxicity in mice was determined. Mice, standardized to a light-dark cycle, were injected with lithium chloride (940 mg/kg) at one of six times (20:00, 24:00, 4:00, 8:00, 12:00, and 16:00) and subsequently observed for mortality over 28 h. A significant (P<0.01) time-of-day effect was found for lithium-induced lethality, with highest lethality following injection at 12:00.     

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.     

Circadian rhythm of apomorphine-induced stereotypy in rats

The existence of circadian variations of apomorphine-induced stereotypy was determined. Male Wistar rats, standardized to a light-dark cycle (lights on from 7:00–19:00) for three weeks, were injected with apomorphine hydrochloride (1 mg/kg or 3 mg/kg) at one of six times (9:00, 13:00, 17:00, 21:00, 1:00 and 5:00). A significant time-of-day effect was found for apomorphine-induced stereotypy, with highest stereotypic score following injection at 13::00 or 17:00. The circadian rhythm of apomorphine-induced stereotypy was significantly fitted to a single cosine curve with a 24-hr cycle using the least squares method.     

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。     

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。