盐酸小檗碱与环孢素A合用对大鼠肝P450同工酶和mdr1的影响

目的　阐明盐酸小檗碱 (berberinechloride ,Ber)及其与环孢素A (cyclosporin ,CsA)合用对大鼠肝脏P4 5 0同工酶和多药耐药基因的影响。方法　采用分光光度法测定大鼠肝微粒体红霉素N 脱甲基酶 (ERD)、氨基比林N 脱甲基酶(ADM )的活性 ,采用RT PCR法测定大鼠肝脏CYP3A1、CYP1A1、CYP2E1、mdr1a和mdr1b基因的水平。结果　灌胃给药 6d后 ,除外 10 0mg·kg-1Ber组 ,其余各组对ERD活性有明显的抑制作用 ;给药 12d时 ,所有用药组对ERD活性均有抑制作用。给药 6d后 ,CsA单用组、Ber与CsA合用组对ADM均有抑制作用 ;给药 12d后 ,除了 15 0mg·kg-1酮康唑组和 10 0mg·kg-1Ber组外 ,其余各用药组对ADM均有抑制作用。给药 12d时 ,除了 10 0mg·kg-1Ber组外 ,其余各用药组对大鼠肝脏CYP3A1、CYP2E1、mdr1a、mdr1b基因均有抑制作用。各组的CYP1A1基因均未能检出。结论　抑制CYP3A基因的表达及酶的活性 ,抑制mdr1a、mdr1b基因的表达 ,从而减少CsA在肝脏的代谢及消除 ,可能是Ber增加CsA血浓度的重要机制     

联苯双酯与环孢素合用对大鼠肝药物代谢酶的影响

目的:阐明联苯双酯与环孢素合用对药物代谢酶的影响.方法:采用分光光度法测定联苯双酯、环孢素及两者合用时大鼠肝微粒体红霉素N-脱甲基酶(erythromycin demethylase,ERD)、氨基比林Ⅳ-脱甲基酶(aminopyrence N-demethylase,ADM)和谷胱甘肽s转移酶(glutathione S transferenase,GST)的含量或活性.结果:灌胃给药8 d,联苯双酯(200 mg·kg-1)对ADM和GST没有明显诱导作用,但对ERD有显著诱导作用(P<0.01);环孢素(20 mg·kg-1)对ERD和GST没有显著抑制作用(P<0.01);但对ADM有显著抑制作用;联苯双酯与环孢素合用对ADM和GST均有明显抑制作用(P<0.01).结论:BFD是药物代谢酶ERD(CYP3A4)的诱导剂,是ADM(CYP1A1,281,2C11)的抑制剂;BFD与环孢素合用可以抑制ADM(CYP1A1、2B1、2C11)和GST的活性.     

琥乙红霉素和阿司匹林合用对大鼠肝脏细胞色素P450酶的影响

目的：阐明基于药物代谢酶的药物相互作用机制，选择临床常用抗菌药物琥乙红霉素和预防心脑血管疾病的药物阿司匹林作为研究对象，研究两者合用对大鼠肝细胞色素P450（CYP450）含量、氨基比林N-脱甲基酶（ADM）、红霉素N-脱甲基酶（ERD）、谷胱甘肽S-转移酶（GST）活性的影响。方法：体内实验分空白对照组、琥乙红霉素组、阿司匹林组、琥乙红霉素和阿司匹林合用组，每日灌胃给药一次，连续7d。制备大鼠肝微粒体，采用紫外-可见分光光度法测定CYP450含量及ADM、ERD、GST活性。结果：琥乙红霉素、阿司匹林合用后CYP450酶活性均有不同程度的降低，与对照组比较有显著性差异（P〈0．05）。结论：两药合用对药物代谢酶有影响，可能使药物的体内代谢特征发生改变，产生药物代谢性相互作用，从而影响药物疗效。     

年龄对大鼠肝脏生物转化功能及膜流动性的影响

通过与青年(3～4月)及中年(14月)组比较,研究了老年(24月)大鼠肝脏生物转化酶活性改变及膜流动性变化。结果表明,老年大鼠肝微粒体P-450含量、NADPH-细胞色素C还原酶活性无明显改变,但氨基比林N-脱甲基酶、苯胺羟化酶活性明显降低,且微粒体及胞浆GST、胞浆GSH-Px活性也明显下降;同时肝微粒体膜脂区流动性明显降低,膜Ch/PL值显著增大。研究提示,微粒体膜脂质环境及流动性变化与上述生物转化功能改变可能有一定的联系。     

盐酸小檗碱及其与环孢素A合用对大鼠肝脏和小肠CYP3A1的影响

目的 :阐明盐酸小檗碱 (berberinechloride ,Ber)及其与环孢素A (cyclosporin ,CsA)合用对大鼠肝脏和小肠CYP3A1的影响。方法 :实验分 7组 :溶媒对照组、15 0mg·kg-1酮康唑组、10 0mg·kg-1Ber组、2 0 0mg·kg-1Ber组、4 5mg·kg-1CsA组、10 0mg·kg-1Ber 45mg·kg-1CsA组、2 0 0mg·kg-1Ber 45mg·kg-1CsA组 ,采用RT PCR和Westernblot等方法测定大鼠肝脏和小肠CYP3A1的表达水平。结果 :RT PCR结果显示 :灌胃给药 12d后 ,除了 10 0mg·kg-1Ber组外 ,其余各用药组对大鼠肝脏CYP3A1基因表达均有明显的抑制作用。Westernblot结果显示 :给药 6d后 ,2 0 0mg·kg-1Ber 45mg·kg-1CsA组对大鼠肝脏CYP3A1的表达有明显抑制作用 ;给药 12d后 ,10 0mg·kg-1Ber 45mg·kg-1CsA ,2 0 0mg·kg-1Ber 45mg·kg-1CsA组对大鼠肝脏和小肠CYP3A1的表达均有明显抑制作用。结论 :通过增强CsA对肝脏和小肠CYP3A1基因表达的抑制作用 ,从而减少CsA在肝脏和小肠的代谢及消除 ,可能是Ber增加CsA血浓度的重要机制。     

石榴皮鞣质对大鼠肝药酶活性的影响

摘 要 目的：研究石榴皮鞣质对正常大鼠肝药酶活性的影响。方法: 将30只Wistar大鼠随机分为5组：空白对照组,石榴皮鞣质高、中、低剂量组,苯巴比妥钠阳性对照组。空白对照组给予生理盐水,石榴皮鞣质高、中、低剂量组分别按150,100,75 mg·kg^-1·d^-1连续灌胃给药7 d,苯巴比妥钠组给予苯巴比妥钠注射液,按80 mg·kg^-1·d^-1连续腹腔给药5 d。实验结束后采用UV法测定各组大鼠肝脏微粒体中Ⅰ相代谢酶和Ⅱ相代谢酶活性。结果: 与空白对照组相比,石榴皮鞣质高、中、低剂量组均能降低细胞色素P450（CYP450）总蛋白和细胞色素b5（CYPb5）含量及抑制氨基比林N-脱甲基酶（ADM）活性,差异有统计学意义（P<0.01）;石榴皮鞣质高、中剂量组能显著抑制红霉素N-脱甲基酶（ERD）活性,差异有统计学意义（P<0.01）;石榴皮鞣质高剂量组能显著降低谷胱甘肽S 转移酶（GST）活性,差异有统计学意义（P<0.01）。结论: 石榴皮鞣质对正常大鼠肝药酶活性具有一定抑制作用,能降低CYP3A 和 CYP2E1的表达,且与给药剂量有关。     

灯盏细辛注射液对小鼠肝微粒体细胞色素P450含量的影响

目的:研究灯盏细辛注射液对小鼠肝微粒体细胞色素P450含量的影响。方法:小鼠分为空白对照组、阳性对照组(苯巴比妥钠80mg/kg,i.p.,共7d)、灯盏细辛注射液正常剂量组、高剂量组(10、30mg/kg,i.p.,共14d)。用紫外分光光度法测定细胞色素P450及其同工酶的活性。结果:灯盏细辛注射液两剂量组小鼠肝微粒体的蛋白含量和细胞色素P450含量较空白对照组增高,对肝重指数基本无影响;可抑制红霉素-N-脱甲基酶(ERD)的活性(P<0.01),而对氨基比林-N-脱甲基酶(AMD)基本无影响(P>0.05);苯巴比妥钠组肝重指数、蛋白含量和细胞色素P450含量与其他各组比较均升高(P<0.05),对氨基比林-N-脱甲基酶、红霉素-N-脱甲基酶活性均有诱导作用(P<0.01)。结论:灯盏细辛注射液对小鼠肝微粒体蛋白、细胞色素P450含量有一定影响,对CYP3A可能有抑制作用,对氨基比林-N-脱甲基酶活性基本无影响。     

辛伐他汀对大鼠肝微粒体药物代谢酶活性的影响

目的研究辛伐他汀(simvastatin, SV)对大鼠肝脏药物代谢酶活性的影响。方法大鼠口服给予SV,qd×7,超速离心法分离肝微粒体,一氧化碳示差光谱法测定细胞色素P450(CYP)含量,以红霉素、苯胺、CDNB、利尿酸、7-羟基-4-甲基香豆素和对羟基联苯为底物分别测定肝微粒体红霉素脱甲基酶(CYP3A4)、苯胺羟化酶(CYP2E1)、谷胱甘肽-S-转移酶(glutathione S transferase, GST)及其π亚型 (πGST)、尿苷二磷酸葡萄糖醛酸转移酶(uridine diphosphoglucuronyl transferase, UGT1和UGT2)活性。结果大鼠口服给予SV可明显降低大鼠肝微粒体CYP含量及CYP3A4活性,对CYP2E1则没有显明影响。同时,SV 则可显著增高大鼠肝微粒体GST、πGST及UGT1和UGT2活性。结论SV可降低大鼠肝微粒体CYP3A4活性,而增高肝微粒体Ⅱ相代谢酶的活性。     

辛伐他汀对大鼠肝微粒体药物代谢酶活性的影响

目的 研究辛伐他汀(simvastatin, SV)对大鼠肝脏药物代谢酶活性的影响。方法 大鼠口服给予SV,qd×7,超速离心法分离肝微粒体,一氧化碳示差光谱法测定细胞色素P450(CYP)含量,以红霉素、苯胺、CDNB、利尿酸、7-羟基-4-甲基香豆素和对羟基联苯为底物分别测定肝微粒体红霉素脱甲基酶(CYP3A4)、苯胺羟化酶(CYP2E1)、谷胱甘肽-S-转移酶(glutathione S transferase, GST)及其π亚型 (πGST)、尿苷二磷酸葡萄糖醛酸转移酶(uridine diphosphoglucuronyl transferase, UGT1和UGT2)活性。结果 大鼠口服给予SV可明显降低大鼠肝微粒体CYP含量及CYP3A4活性,对CYP2E1则没有显明影响。同时,SV 则可显著增高大鼠肝微粒体GST、πGST及UGT1和UGT2活性。结论 SV可降低大鼠肝微粒体CYP3A4活性,而增高肝微粒体Ⅱ相代谢酶的活性。     

细胞色素P450 3A在胎肾上腺和胎肝中的表达

采用酶学和逆转录聚合酶链式反应 ( RT-PCR)技术 ,研究与药物代谢密切相关的细胞色素P450 3A( CYP3A)在胎肾上腺和胎肝中的表达 .结果表明 ,胎肾上腺微粒体中苄非他明 ,氨基比林 ,红霉素 N-脱甲基酶和睾酮 6β-羟化酶活性分别为胎肝微粒体的 2 1 % ,2 60 % ,1 0 5%和 33% .CYP诱导剂苯巴比妥能显著增加体外培养胎肾上腺细胞中苄非他明和氨基比林 N-脱甲基酶活性 ,诱导剂地塞米松也能明显诱导红霉素 N-脱甲基酶活性 .RT- PCR表明胎肾上腺和胎肝中存在 CYP3A7m RNA表达 .说明胎肾上腺和胎肝中存在 CYP3A亚族 .上述结果提示处于发育时期的肾上腺具有与胎肝能力相当的药物代谢功能 .     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Isolation and characterization of glycosylated and non-glycosylated prolactins from alligator and crocodile

Two molecular forms of prolactin (PRL). glycosylated and non-glycosylated, were isolated from pituitary glands of two reptiles, alligator and crocodile. The reptilian PRLs were extracted under alkaline conditions from the precipitate obtained after pituitaries were first extracted with 0.25 m sucrose, 1 mM NH₄HCO₃, pH 6.3. Purification was performed by ion exchange chromatography on DE-52, gel filtration on Sephadex G-75 superfine, and reversed phase high performance liquid chromatography. Two forms of both alligator and crocodile PRL, designated PRLI and PRLII, with molecular weights of 26000 and 24000 were isolated. Alligator and crocodile PRLI and PRLII were stained specifically in immunoblots with anti-sea turtle PRL and anti-ostrich PRL. Sequence analysis revealed that both forms of alligator and crocodile PRLs consisted of 199 amino acid residues with a glycosylation consensus sequence (Asn-Ala-Ser) at position 60 in alligator and crocodile PRLs with a molecular weight of 26000 (PRLI). In contrast, Thr was substituted for Asn at position 60 in the PRLs with a molecular weight of 24000 (PRLII). The sequences of alligator PRLs differed from crocodile PRLs only in position 134: Val for alligator PRLs and He for crocodile PRLs. There is a high degree of structural conservation between the reptilian PRLs isolated in this study and avian PRL; each showed 92% sequence identity with chicken PRL and 89% with turkey PRL.