Cadmium teratogenesis in the chick: Period of vulnerability using the early chick culture method, and prevention by divalent cations

Cadmium (Cd) is teratogenic in chick embryos following treatment in ovo or in shell-less culture. We investigated the ability of other divalent cations (Mn, Ni, Se, Mg and Ca) to influence the effects of Cd. As the proposed mechanism of protection of these ions is prevention of Cd influx by blocking or competing for Ca channels, we also assessed verapamil, a Ca-channel blocker. We used a new, completely ex ovo method, explanting the embryos onto an agar–albumen substrate (0.6% agar diluted 1:1 with thin albumen) to which test substances were added. Following 48–96 h incubation, chicks were explanted onto medium containing 7.5 μM Cd acetate or equimolar sodium acetate. Morphology and somite numbers were assessed at explantation, and again following 24 h incubation on the culture media. In addition, 60-h embryos were explanted onto media containing various concentrations of the aforementioned agents, alone or in combination with 7.5 μM Cd. Chicks were vulnerable to Cd teratogenesis between Hamburger–Hamilton stages 13 and 18. Co-treatment with Se, Mn and Ni prevented malformation at 2×, 50× and 100× the molar dose of Cd, respectively. Ca, Mg and verapamil failed to protect. These results indicate that some, but not all, divalent cations protect against Cd malformation, but the mechanism of rescue remains unresolved.     

Quantitative drug interactions prediction system (Q-DIPS): a computer-based prediction and management support system for drug metabolism interactions

Objective: Drug biotransformation and interactions are a major source of variability in the response to drugs. The superfamily of cytochromes P450 plays a key role in this phenomenon but, because of the complexity of interactions between drugs and isozymes, it becomes more and more difficult for clinicians to master the knowledge required to predict the occurrence of such drug interactions. To predict and help manage the occurrence of cytochrome P450-dependent interactions, we developed an original computer application: Q-DIPS (quantitative drug interactions prediction system). Methods: A multidisciplinary work team was created, associating clinical pharmacologists, pharmacists and a computer scientist. Major steps of investigation were: (1) the creation of a database to collect qualitative and quantitative data describing substrates, inhibitors and inducers of specific cytochrome P450 isozymes, with quality assessments; (2) the development of multi-access to these data and (3) their incorporation into extrapolation systems allowing the prediction of in vivo drug interactions on the basis of in vitro data. As an example, prediction and validation studies of CYP3A4 inhibition by ketoconazole and fluconazole will be discussed. Results: Q-DIPS gives up-to-date information, in dynamic tables, describing which specific P450 isozymes metabolise a given drug, as well as which drugs may inhibit or induce a given isozyme. To better answer common clinical questions and help to rapidly evaluate the risk of interactions, it is possible to obtain an overview of substances causing interactions with a specific drug or to focus on drugs taken by a patient (“clinical case”). For each question, key references, relevant quantitative data and quality indices are easily accessible. Two modules allowing input with commercial names and the anatomical therapeutic chemical classification were also included. On the basis of enzymatic and pharmacokinetic data generated in vitro or collected in vivo, the extrapolation module integrates quantitative models to predict the impact of a treatment on enzymatic activities. The simplest model predicted a strong but fluctuating inhibition of CYP3A4 by ketoconazole, whereas the impact of fluconazole was lower. Validations with published in vivo data suggested an appropriate prediction of the risk. Conclusion: The current Q-DIPS prototype shows promising potential for helping to improve the management of drug interactions involving metabolism. Validation of extrapolation techniques need to be completed, in view of including important factors such as intrahepatocyte drug accumulation, contribution of metabolites to inhibition as well as in vitro non-specific binding to microsomal proteins. The final goal will be to help select the most judicious clinical studies to be performed so as to avoid useless, expensive and unethical investigations in man. Received: 9 November 1998 / Accepted in revised form: 2 March 1999     

氟尿嘧啶类抗肿瘤药物与华法林相互作用研究现状

以氟尿嘧啶类药物如5-氟尿嘧啶、卡培他滨和替吉奥等为基础的化疗方案广泛应用于各种实体瘤治疗。肿瘤患者是血栓形成的高危人群,对已发生血栓或合并血栓形成高危因素者推荐抗凝治疗。华法林是目前广泛应用的口服抗凝药。5-氟尿嘧啶、卡培他滨和替吉奥与华法林联用存在相互作用,可能导致国际标准化比值升高和出血症状,华法林停用、减量或换用低分子肝素后多数患者可恢复,少数可能需要输血治疗。氟尿嘧啶类药物与华法林相互作用的机制尚不明确,可能与5-氟尿嘧啶或其代谢产物抑制华法林代谢酶---肝细胞色素P4501C9酶活性有关。     

Quantity and quality of potential drug interactions with coumarin anticoagulants in the Netherlands

Objective Coumarin anticoagulants are prone to potentially life-threatening drug-drug interactions due to a combination of unfavorable properties. However, real life data on the actual occurrence are scarce. The aim of this study was to quantify and qualify potential drug interactions with coumarin anticoagulants in daily practice. Methods A cohort study including all users of phenprocoumon or acenocoumarol during the period 1991–2003 in the PHARMO Record Linkage System. All 24 individual drugs and 11 drug groups interacting with coumarins according to central database used in the Dutch pharmacies were considered. Main outcome measure Frequency and type of potential drug interactions during anticoagulant therapy with coumarins. Results 48,627 out of 76,455 mainly acenocoumarol-users (64%) were dispensed at least one potentially interacting drug (PID) during anticoagulant therapy. About 35% of these cases were dispensed a (very) strongly interacting drug, whereas 3% were dispensed a contraindicated drug. Antibacterial drugs and NSAIDs (39% and 37% of all users, respectively) were the most frequently dispensed PIDs. Conclusion Potential drug interactions with coumarins frequently occur in daily practice, confronting two-thirds of patients with an increased risk of bleeding. To a large part, this is attributable to commonly prescribed medication like antibacterial drugs and NSAIDs. This situation substantiates the need for proper monitoring or new anticoagulants with less drug–drug interactions.     

A comparison of the relative sensitivities of factor VII and prothrombin time measurements in detecting drug interactions with warfarin

Summary We have studied the comparative abilities of the prothrombin time and factor VII clotting activity, measured using a chromogenic assay, to detect drug interactions with warfarin. Pharmacokinetic and pharmacodynamic data were collected from studies involving the single administration of 25 mg of warfarin in the absence and presence of fengabin, cimetidine, ranitidine, and enoxacin. Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin, whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general, factor VII clotting activity showed greater sensitivity but also greater variability than the prothrombin time to changes in clotting activity. Consequently, factor VII clotting activity did not have greater discriminatory power than the prothrombin time in detecting drug interactions involving warfarin.     

Lamotrigine in children and adolescents: the impact of age on its serum concentrations and on the extent of drug interactions

Objective To investigate the impact of age and co-treatment with other drugs on the serum concentrations of lamotrigine in children and adolescents. Methods A review of routine serum concentration measurements of lamotrigine performed in our laboratory yielded a total of 744 serum samples from 296 subjects (110 males, 186 females, age: 2–19 years) suitable for statistical analysis. The primary outcome variable was the dose-corrected lamotrigine serum concentration, expressed as the lamotrigine concentration/dose (C/D) ratio. A linear mixed model that allowed multiple observations from the same patient was used to identify and quantify the effect of factors influencing the lamotrigine C/D ratio. Results According to the model, the lamotrigine C/D ratio decreases by 6% per year of age. Valproate and levetiracetam were found to raise the lamotrigine C/D ratio, whereas the following co-medications reduced it: carbamazepine, clobazam, fluoxetine, clonazepam and ethinyl estradiol. The effect of carbamazepine decreased with increasing age. No gender difference was detected. Conclusions Age is an important factor with respect to the pharmacokinetics and the extent of drug interactions of lamotrigine in children and adolescents. In this population, older individuals will need higher doses than younger ones in order to achieve the same serum concentrations.     

单胺氧化酶抑制剂及其药物相互作用研究

目的了解单胺氧化酶抑制剂(MAOIs)及其与其他药物的相互作用。方法调查本院及其他医疗机构的药品说明书,检索中英文文献数据库,对涉及MAOIs的重点记录,进行整理归纳、分析总结。结果有11种常用药品属于MAOIs,近40种药品与MAOIs存在药物相互作用。结论上述药品应尽可能避免与M AOIs合用,或合用时减少用药剂量,以避免或减轻药物不良反应。     

毛细管电泳技术在研究生物分子间相互作用和药物筛选中的应用

毛细管电泳技术是八十年代初发展起来的一种新型分离分析技术。由于其分析时间短，样品消耗少，分离度高，应用灵活，能够在生理条件或者接近生理条件的缓冲液中运行等优点，广泛应用于研究生物分子间的相互作用。本文就毛细管电泳研究生物分子间相互作用的基本原理，及其在生物分子间相互作用和药物筛选中的应用进行了综述。对不同的分子间相互作用体系，如蛋白质-蛋白质／多肽，蛋白质-DNA／RNA，蛋白质-糖，抗原-抗体，蛋白质-药物，脂质体-蛋白质／药物等进行了论述。同时也探讨了毛细管电泳从组合化学库中筛选先导药物及其在药物筛选中的应用。     

Current progress in identifying endogenous biomarker candidates for drug transporter phenotyping and their potential application to drug development

Drug transporters play important roles in the elimination of various compounds from the blood. Genetic variation and drug–drug interactions underlie the pharmacokinetic differences for the substrates of drug transporters. Some endogenous substrates of drug transporters have emerged as biomarkers to assess differences in drug transporter activity—not only in animals, but also in humans. Metabolomic analysis is a promising approach for identifying such endogenous substrates through their metabolites. The appropriateness of metabolites is supported by studies in vitro and in vivo, both in animals and through pharmacogenomic or drug–drug interaction studies in humans. This review summarizes current progress in identifying such endogenous biomarkers and applying them to drug transporter phenotyping.     

Potential drug interactions associated with glycyrrhizin and glycyrrhetinic acid

Glycyrrhizin (GZ), the main active component of licorice, is a widely used therapeutic in the clinic. Depending on the disease, the treatment may involve a long course of high dose GZ. Another component of licorice, glycyrrhetinic acid (GA), is the main active metabolite of GZ and is thought to be responsible for the majority of the pharmacological properties of GZ. Therefore, GZ and GA are both used for therapeutic purposes. In addition, GZ and GA are also widely used to sweeten and flavor foods. Due to this widespread, multifaceted use of these substances, potential drug interactions with GZ and GA have recently gained attention. Along these lines, this review covers the known effects of GZ and GA on drug-metabolizing enzymes and efflux transporters. We conclude that both GZ and GA may have an effect on the activity of CYPs. For example, GZ may induce CYP3A activity through activation of PXR. Also, GZ and GA may affect glucuronidation in rats and humans. Furthermore, 18β-GA is a potent inhibitor of P-gp, while GZ and GA are inhibitors of MRP1, MRP2 and BCRP. The pharmacokinetics and pharmacodynamics of many medications may be altered when used concurrently with GZ or GA, which is also covered in this review. Overall, GZ, GA or related products should be taken with caution when taken with additional medications due to the possible drug interactions.     

Methylphenidate and d-amphetamine: Effects and interactions with alphamethyltyrosine and tetrabenazine on DRL performance in rats

The effects of d-amphetamine and methylphenidate and their interactions with amine-depleting drugs were examined in rats trained to press a lever to obtain water reinforcement on a schedule that differentially reinforced responding at low rates (DRL). Both methylphenidate (2.5–20.0 mg/kg) and d-amphetamine (0.375–3.0 mg/kg) increased the rate of responding and decreased the frequency of reinforcement on the DRL schedule. Both drugs also shifted the interresponse time (IRT) distributions to the left such that the modal IRT occurred well below the minimum IRT required for reinforcement (d-amphetamine was about eight times more potent than methylphenidate for each of these effects). The effects of both d-amphetamine and methylphenidate on DRL performance were attenuated by administration of alpha-methyltyrosine (AMT) (150 mg/kg) and both drugs attenuated the response rate-suppressing effects of tetrabenazine (TBZ) (4.0 mg/kg). The similarity of the drug interactions between methylphenidate or amphetamine and AMT or TBZ suggest that the doses of methylphenidate and d-amphetamine examined act on similar catecholaminergic pools with the central nervous system to influence DRL performance.     

瑞舒伐他汀药代动力学及与其他药物的相互作用研究进展

瑞舒伐他汀是新一代他汀类药物,相对之前的他汀类药物,肝选择性更好;肝代谢少、消除半衰期长,具有更强的降脂作用,临床应用前景广泛;其耐受性良好,不良反应发生率与同类其他药物相似。本文对瑞舒伐他汀的药代动力学及与其他药物相互作用作一综述。以期为指导瑞舒伐他汀的临床用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正实现临床上的个体化给药。     

Review of the safety,tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole

SUMMARY

Managing invasive fungal infections often presents a challenge for clinicians in the treatment of immunocompromised patients. Two very different systemic antifungal agents, voriconazole and caspofungin, have recently been introduced into the market place. Voriconazole is a new triazole antifungal, while caspofungin is the first echinocandin antifungal. Voriconazole acts by inhibiting the synthesis of ergosterol in the fungal cell membrane. Caspofungin inhibits β-1,3-D-glucan synthesis in the cell wall, a target present in fungal cells, but absent from mammalian cells. Both agents are broad-spectrum, with efficacy against invasive Aspergillus and Candida infections. The safety and tolerability profile of caspofungin presented with a low incidence of adverse events in clinical trials. Pending further data, coadministration of cyclosporine has been recommended only if the benefit outweighs the risk for patients. Voriconazole has three important side-effects that the clinician must consider: liver abnormalities, skin abnormalities and visual disturbances. Liver abnormalities in particular should be monitored very carefully. The drug interaction profile of voriconazole also warrants a careful evaluation of the concomitant medication, mainly due to cytochrome P450 metabolism. This article reviews the available data concerning the safety and tolerability profiles of each drug, as well as drug interactions and contraindications.     

The chlordiazepoxide/pentylenetetrazol discrimination: characterization of drug interactions and homeostatic responses to drug challenges

Rats were trained to discriminate chlordiazepoxide (CDP) from pentylenetetrazol (PTZ) in a two-lever food motivated discrimination task. Training drug doses were adjusted until subjects emitted approximately 50% of their responses on each of the two drug-appropriate levers during saline injection tests. Tests that followed injection of CDP/PTZ combinations illustrated a reciprocal antagonism between the two drugs. Saline-injection tests that followed large dose injections of CDP revealed a period of predominantly PTZ-appropriate responding that persisted after the initial period of predominantly CDP-appropriate responding. These data are interpreted to suggest that, unlike some other drugs that have been shown to antagonize the behavioral and CNS effects of benzodiazepines, the interoceptive stimulus generated by PTZ occupies a position opposite to that of CDP along some single affective continuum. In addition, these data suggest that drug/drug (DD) discriminations are capable of characterizing the interactions between training drugs. Finally, the data suggest that the CDP/PTZ discrimination is a sensitive detector of bidirectional shifts in interoceptive stimulus state along the CDP/PTZ continuum.     

Carrier-mediated transport in the hepatic distribution and elimination of drugs,with special reference to the category of organic cations

Carrier-mediated transport of drugs occurs in various tissues in the body and may largely affect the rate of distribution and elimination. Saturable translocation mechanisms allowing competitive interactions have been identified in the kidneys (tubular secretion), mucosal cells in the gut (intestinal absorption and secretion), choroid plexus (removal of drug from the cerebrospinal fluid), and liver (hepatobiliary excretion). Drugs with quaternary and tertiary amine groups represent the large category of organic cations that can be transported via such mechanisms. The hepatic and to a lesser extent the intestinal cation carrier systems preferentially recognize relatively large molecular weight amphipathic compounds. In the case of multivalent cationic drugs, efficient transport only occurs if large hydrophobic ring structures provide a sufficient lipophilicity-hydrophilicity balance within the drug molecule. At least two separate carrier systems for hepatic uptake of organic cations have been identified through kinetic and photoaffinity labeling studies. In addition absorptive endocytosis may play a role that along with proton-antiport systems and membrane potential driven transport may lead to intracellular sequestration in lysosomes and mitochondria. Concentration gradients of inorganic ions may represent the driving forces for hepatic uptake and biliary excretion of drugs. Recent studies that aim to the identification of potential membrane carrier proteins indicate multiple carriers for organic anions, cations, and uncharged compounds with molecular weights around 50,000 Da. They may represent a family of closely related proteins exhibiting overlapping substrate specificity or, alternatively, an aspecific transport system that mediates translocation of various forms of drugs coupled with inorganic ions. Consequently, extensive pharmacokinetic interactions can be anticipated at the level of uptake and secretion of drugs regardless of their charge.     

Comparison of interactions of D<Subscript>1</Subscript>-like agonists,SKF 81297, SKF 82958 and A-77636, with cocaine: locomotor activity and drug discrimination studies in rodents

RATIONALE: Recent data suggest that dopamine (DA) D1-like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D1-like agonist, A-77636, has not been well characterized and may prove to be useful as such an agent. OBJECTIVES: The interactions of cocaine and A-77636 were compared to those obtained with the better investigated benzazepine D1-like dopamine agonists, SKF 82958 and SKF 81297. The alterations in the locomotor stimulant and discriminative-stimulus effects of cocaine by the full D1-like dopamine receptor agonists were investigated across a full range of doses in order to characterize their interactions. METHODS: Drug-naive Swiss-Webster mice were pretreated with SKF 81297, SKF 82958 or A-77636 (1-10 mg/kg) and cocaine (5-56 mg/kg) prior to a 30-min period in which locomotor activity was assessed. Rats were trained on a fixed ratio 20 (FR20) schedule to discriminate IP saline from cocaine (10 mg/kg) injections. Cocaine alone (1-10 mg/kg) and with either A-77636 (0.56-1.7 mg/kg), SKF 82958 (0.01-0.1 mg/kg) or SKF 81297 (0.1-0.56) were injected IP 5 min prior to a 15-min test session. RESULTS: Cocaine maximally stimulated activity at 20-40 mg/kg with higher and lower doses stimulating activity less. Each D1-like agonist produced a dose-related decrease in cocaine-induced locomotor activity and lowered its maximal rate. Each of the D1-like agonists partially substituted for cocaine, with maximal substitution approximating 49, 35, and 24% for SKF 81297, SKF 82958, and A-77636, respectively. SKF 82958 significantly shifted the cocaine dose-effect curve approximately 3-fold to the left. With SKF 81297, there was a trend towards a leftward shift of cocaine dose effects, however the change was not statistically significant. In contrast to the other two D1-like agonists, A-77636 either did not affect the cocaine dose-effect curve or shifted it to the right. CONCLUSIONS: All three agonists produced similar effects on cocaine-induced locomotor activity, however the discriminative-stimulus effects of cocaine were affected differently by the D1 agonists. These results suggest fundamental differences in the actions of these D1 agonists. Because A-77636 consistently attenuated the present effects of cocaine, it may prove more useful than the others as a pharmacotherapy to treat cocaine abuse.     

银杏叶提取物对CYP酶的影响及与其他药物的相互作用

综述了近年来银杏叶提取物(Ginkgo biloba extract)与其他药物相互作用的研究进展。研究表明银杏叶提取物在大鼠体内和人体内外对CYP酶的影响不一致。人体内银杏叶提取物对药物代谢酶CYP 2C19和CYP 2E1有诱导作用,分别增强了美芬妥因、奥美拉唑和氯唑沙宗的代谢。银杏叶提取物通过降低血中超氧化物歧化酶水平而发挥抗氧化作用,提高了抗精神病药物的疗效。银杏叶提取物还可能与阿司匹林、华法林和曲唑酮等发生药效学方面的相互作用,在临床应用中要引起重视。因此,需要进一步在人体内研究银杏叶提取物与其他药物的相互作用。