Oxygen and Redox-Active Drugs: Shared Toxicity Sites

Oxygen and Redox-Active Drugs: Shared Toxicity Sites. Brown,O.R. and Seither, R.L. (19S3).Fundam. Appl. Toxicol. 3:209-214.Paraquat and nitrofurantoin can accept single electrons and,under appropriate conditions in tissues and cells, can passthese electrons to oxygen, thus participating in redox cycling.Similarities in the response of the target organ (the lung)and in subsequent pathology have also been observed among animalspoisoned by oxygen and by these chemicals. We report evidenceprimarily obtained from Escherichia coli for common biochemicalsites of toxicity for these agents. Common sites for oxygenand paraquat involve biosynthesis of specific amino acids, inductionof genetic stringency via unloaded tRNAs resulting from aminoacid deficiencies, decreased thiamin content, and impaired biosynthesisof pyridine nucleotide coenzyme biosynthesis for paraquat andoxygen. Inhibition of specific amino acid biosynthesis and inductionof stringency also have been observed for nitrofurantoin. RNAand DNA biosynthesis are also impaired by oxygen; this has notbeen examined for paraquat or nitrofurantoin. There is a biochemicalbasis and preliminary data to support inhibition of NAD biosynthesisas a component of mammalian toxicity for these agents. Niacinmay act to circumvent the consequences of the biochemical lesionat quinolinate phosphori-bosyl transferase in NAD biosynthesis.     

常用抗癫痫药物的血液系统毒性

常用抗癫痫药物均有不同程度的血液系统毒性。文章通过综述经典抗癫痫药物和新一代抗癫痫药物的血液系统毒性及相关研究进展,以期为临床抗癫痫药物的合理、安全使用提供参考。     

Marked Differences in the Effect of Antiepileptic and Cytostatic Drugs on the Functionality of P-Glycoprotein in Human and Rat Brain Capillary Endothelial Cell Lines

Purpose

The expression of P-glycoprotein (Pgp) is increased in brain capillary endothelial cells (BCECs) of patients with pharmacoresistant epilepsy. This may restrict the penetration of antiepileptic drugs (AEDs) into the brain. However, the mechanisms underlying increased Pgp expression in epilepsy patients are not known. One possibility is that AEDs induce the expression and functionality of Pgp in BCECs. Several older AEDs that induce human cytochrome P450 enzymes also induce Pgp in hepatocytes and enterocytes, but whether this extends to Pgp at the human BBB and to newer AEDs is not known.

Methods

This prompted us to study the effects of various old and new AEDs on Pgp functionality in the human BCEC line, hCMEC/D3, using the rhodamine 123 (Rho123) efflux assay. For comparison, experiments were performed in two rat BCEC lines, RBE4 and GPNT, and primary cultures of rat and pig BCECs. Furthermore, known Pgp inducers, such as dexamethasone and several cytostatic drugs, were included in our experiments.

Results

Under control conditions, GPNT cells exhibited the highest and RBE4 the lowest Pgp expression and Rho123 efflux, while intermediate values were determined in hCMEC/D3. Known Pgp inducers increased Rho123 efflux in all cell lines, but marked inter-cell line differences in effect size were observed. Of the various AEDs examined, only carbamazepine (100 μM) moderately increased Pgp functionality in hCMEC/D3, while valproate (300 μM) inhibited Pgp.

Conclusions

These data do not indicate that treatment with AEDs causes a clinically relevant induction in Pgp functionality in BCECs that form the BBB.     

Mechanisms and Pathology of Monocrotaline Pulmonary Toxicity

Abstract

Monocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolite of MCT is the dehydro-genation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.     

Idiosyncratic Liver Toxicity of Nonsteroidal Antiinflammatory Drugs: Molecular Mechanisms and Pathology

Abstract

This review explores the clinical hepatic pathology associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs), possible cellular and molecular mechanisms of injury, and future challenges. NSAIDs comprise a group of widely used compounds that have been associated with rare adverse reactions in the liver, including fulminant hepatitis and cholestasis. These reactions are idiosyncratic, mostly independent of the dose administered, and host-dependent. The mechanisms responsible for the initiation and perpetuation of NSAID-induced hepatotoxicity remain poorly understood and have been largely inferred from clinical manifestation. A mounting body of evidence, however, indicates that many acidic NSAIDs are metabolized to reactive acyl glucuronides that can form covalent adducts with plasma proteins and hepatocellular proteins. In hepatocytes co-cultured with lymphocytes, these NSAID-altered proteins can become antigenic. Thus, long-lived, drug-altered proteins may act as immunogens and produce cytotoxic T-cell-mediated or antibody-dependent, cell-mediated toxicity in susceptible patients. Alternatively, individual abnormalities in metabolism or disposition of some NSAIDs may lead to the formation or accumulation of toxic metabolites. Additional work with transgenic animal models is needed to permit better understanding of the general and specific risk factors involved in the pathogenesis of the idiosyncratic liver injuries related to NSAIDs and other drugs.     

呋喃唑酮诱导急性肺部毒性临床病例分析

目的 总结呋喃唑酮诱导急性肺部反应的临床特征、病程和转归,提高呋喃唑酮肺部毒性的认识。方法 回顾性分析9例使用呋喃唑酮后出现急性肺损伤住院患者的临床特征、实验室检查、治疗手段及临床结局。结果 使用呋喃唑酮后发生肺部毒性反应平均时间为(9.78±3.15) d,首发症状均为发热。早期胸部影像特征为双肺小叶间隔增厚、小叶内线状影及小叶内间质增厚等肺间质改变。所有患者就诊时停用呋喃唑酮,其中8例未接受糖皮质激素治疗。总体好转率为100%,5例患者出院前复查CT提示间质改变吸收。结论 治疗幽门螺杆菌的重要药物呋喃唑酮可引起肺间质改变为特征的急性肺毒性,需严密监测以便及时发现和处理。     

聚焦慢性阻塞性肺病治疗药物

慢性阻塞性肺病（COPD）是肺部进行性疾病,需长期治疗。预计到2020年,每年COPD将会导致全球600多万人死亡。尽管对新型药物开发投资不断增加,但该领域的治疗仍以缓解症状的支气管扩张吸入剂为主,而不是治愈性疗法,故应对COPD的创新药的研发仍困难重重。与乳腺癌等疾病领域相比,呼吸系统药物的研发成功率不到50％,但每种获批药物的研发成本却翻倍。因此,制药公司致力于药品生命周期的管理,在当前治疗的基础上进一步改进。其策略包括不同种类药物联用、开发新配方和各种剂量剂型．改善疗效,方便给药。其中以长效β受体激动剂（LABA）／长效毒蕈碱拮抗剂（LAMA）的定量复方药的需求增长最多。领导市场的GSK公司的LABA沙美特罗和吸入型皮质类固醇（ICS）氟替卡松的复方药Advair,就是应用以上方法的典型。虽已出现潜在新型靶标．但这些药物还处于早期开发阶段。吸入型LABA／ICS定量复方药短期内仍是COPD治疗领域的主力军。     

Pulmonary Toxicity of Inhaled Polypropylene Fibers in Rats

This study was initiated to assess the pulmonary toxicity ofpolyolefin fiber composed of polypropylene in male Fischer 344rats after 90 days of inhalation exposure. To increase fiberrespirability in the rodent, polypropylene fibers were size-selectedbefore aerosolization to have a geometric mean diameter of 1.6m (46% <1 µm) and a geometric mean length of 30.3 µm.Three groups of animals were exposed in nose-only inhalationchambers, 6 hr/day, 5 days/week, for 90 days to 15, 30, or 60mg/m³ of polypropylene, or filtered air (negative control).Microscopic examination of the polypropylene fiber-exposed lungsrevealed that, at all time points examined in the study, therewas a dose-dependent increase in pulmonary macrophages. Theseminimal or mild increases in cellularity appeared to be reversible,especially at the lower doses 30 days post exposure. No fibrosiswas observed in any of the groups. A strong correlation wasfound between the external exposure concentration, the timeexposure, and the lung fiber burden. The number of partiallydegraded (segmented) fibers within the lung increased with theexposure concentration and period of exposure, as well as withthe period of recovery after termination of exposure at 90 days.Fibers were recovered from exposed lungs using a hypochloritedigestion technique.     

Two-Dimensional pH Mapping of Release Kinetics of Silica-Encapsulated Drugs

The encapsulation of pharmaceutical drug molecules in silica gels during the sol–gel synthesis andtheir kinetic release profile in aqueous solutions were systematically investigated in dependence of synthesis pH(S) and extraction pH(E) values. Six pH values in the range from 1 to 6 were chosen in a 6 × 6 two-dimensional matrix to screen the first-order initial dissolution rate constant and the total amount of released drug. Characteristic differences are discovered in such two-dimensional pH mapping profiles for the molecules with different ionization behavior and they are explained by surface imprinting and encapsulation processes. Remarkably, these encapsulations must occur either in the particles of the sol solutions or during the rapid liquid–solid transition of the spray-drying process employed in this study. This pH mapping method is suggested as a novel tool to probe noncovalent imprinting and encapsulation processes in sol–gel-derived materials with embedded guest molecules. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4401–4412, 2011     

三聚氰胺急性毒性对临床合理用药的启示

目的：从急性毒性分析三聚氰胺对有肾毒性药物魄影响。方法：以昆明小鼠为对象,1次灌胃给药进行急性毒性试验。连续观察14d。记录小鼠中毒情况及死亡只数,Bliss法计算LD50及95％可信限。对死亡及14d存活动物相关组织做病理观察。结果：小鼠灌胃给药LD50与95％可信限为9899．97mg·kg^-1和7897．22～12410．63mg·kg^-1;其中雌性为11375．00mg·kg^-1,7643．13～16929．01mg·kg^-1,雄性为8385．81mg·kg^-1和6334．49—11101．40mg·kg^-1。中毒动物肾远曲小管、集合管管腔有淡红色析出物及其钙化颗粒．伴上皮细胞变性坏死。结论：三聚氰胺终毒物可能为同系物的聚合体,临床用药应考虑三聚氰胺与有肾毒性药物的联合毒效应。     

A Review on Renal Toxicity Profile of Common Abusive Drugs

Drug abuse has become a major social problem of the modern world and majority of these abusive drugs or their metabolites are excreted through the kidneys and, thus, the renal complications of these drugs are very common. Morphine, heroin, cocaine, nicotine and alcohol are the most commonly abused drugs, and their use is associated with various types of renal toxicity. The renal complications include a wide range of glomerular, interstitial and vascular diseases leading to acute or chronic renal failure. The present review discusses the renal toxicity profile and possible mechanisms of commonly abused drugs including morphine, heroin, cocaine, nicotine, caffeine and alcohol.     

胺碘酮致肺毒性20例文献分析

目的:总结应用胺碘酮致肺毒性的一般规律与特点,为临床合理使用胺碘酮及避免相关不良反应发生提供参考。方法:检索中国知网(CNKI)、中文科技期刊数据库(VIP)、万方数据库收录的1990-2016年间发表的胺碘酮致肺毒性相关个案报道文献,对符合要求的病例进行统计和分析。结果:共收集到19篇相关文献,涉及20例应用胺碘酮致肺毒性的患者。其中,年龄>60岁的患者占75.0%,男女比例为3∶1;75.0%的患者肺毒性发生时的用药时间>1个月;17例患者胺碘酮的口服维持量为200~400mg/d;6例患者死亡,占30.0%。结论:胺碘酮致肺毒性可能与患者的性别、年龄、用药时间、用药剂量等因素有关,其致死率相对较高,应引起广大医务工作者的关注,定期监测,以便及时发现和处理。     

老年人肺部感染性疾病的抗菌药物治疗

目的：探讨有效的治疗老年人肺部感染性疾病的方法和抗菌药物的合理应用。方法：通过对病原的检测与估计、抗菌药物的选择与应用手阐述。结果：为老年人肺部感染性疾病药物治疗提供依据。结论：合理使用抗菌药物对老年人肺部感染性疾病的治疗非常重要。     

New Approaches for the Evaluation of Pulmonary Toxicity: Bronchoalveolar Lavage Fluid Analysis

New Approaches for the Evaluation of Pulmonary Toxicity: BronchoalveolarLavage Fluid Analysis. Henderson, R. F., BENSON, J. M., HAHN,F. F., HOBBS, C. H., JONES, R. K., MAUDERLY, J. L., MCCLELLAN,R. O., AND PICKRELL, J. A., (1985). Fundam. Appl. Toxicol. 5,451–458. Analysis of bronchoalveolar lavage fluid (BAL)is an effective method of detecting an inflammatory responsein the lungs of animals in toxicological studies. Alterationsin BAL that are the most sensitive indications of an inflammatoryresponse are an increased content of serum proteins and an influxof neutrophils (PMNs). Elevation of the cytoplasmic enzyme lactatedehydrogenase (LDH) is a useful indicator of cytotoxicity. Thepulmonary inflammatory response to particles (either mineraldusts or soot) in the lung includes greatly increased activitiesof such lysosomal enzymes as ß-glucuronidase and ß-N-acetylglucosaminidasein BAL. Examination of alterations in BAL in rats and mice duringchronic exposure to high levels of diluted diesel exhaust revealedthat steadily increasing levels of LDH, ß-glucuronidase,and hydroxyproline in BAL correlated better with the developmentof pulmonary fibrosis than did measures of an inflammatory response(protein, PMNs). Analysis of BAL has proven useful, both fordetection of lung injury in toxicological screening tests andfor determination of the mechanisms of developing chronic lungdisease. Future work shows promise of developing assays forBAL analysis to identify the specific site or type of pulmonaryinjury present     

Establishing Cell Models to Understand Cellular Toxicity: Lessons Learned from an Unconventional Cell Type

The syndrome of uremic toxicity comprises a complex toxic milieu in-vivo, as numerous uremic substances accumulate and harm the organ systems. Among these substances, toxic and non-toxic players differently interfere with human cells. However, results from animal experiments are not always compatible with the expected reactions in human patients and studies on one organ system are limited in capturing the complexity of the uremic situation. In this narrative review, we present aspects relevant for cellular toxicity research based on our previous establishment of a human spermatozoa-based cell model, as follows: (i) applicability to compare the effects of more than 100 uremic substances, (ii) detection of the protective effects of uremic substances by the cellular responses towards the uremic milieu, (iii) inclusion of the drug milieu for cellular function, and (iv) transferability for clinical application, e.g., hemodialysis. Our technique allows the estimation of cell viability, vitality, and physiological state, not only restricted to acute or chronic kidney toxicity but also for other conditions, such as intoxications of unknown substances. The cellular models can clarify molecular mechanisms of action of toxins related to human physiology and therapy. Identification of uremic toxins retained during acute and chronic kidney injury enables further research on the removal or degradation of such products.     

Understanding How Data Triangulation Identifies Acute Toxicity of Novel Psychoactive Drugs

Over the last decade, there has been an increase in the availability and use of novel psychoactive substances (also known as ??legal highs??). There is limited information available on the potential acute toxicity (harms) associated with the use of these novel psychoactive substances. Gold standard evidence, such as animal studies or human clinical trials, is rarely available to users or healthcare professionals. However, it is possible to use triangulation of data on the acute toxicity from multiple sources to describe the overall pattern of toxicity associated with a novel psychoactive substance. In this review, we will describe these potential data sources, which include self-reported toxicity on internet discussion fora, data from sub-population user surveys, data from regional and national poisons information services and published case reports and case series. We will then describe how pattern of acute toxicity associated with the use of the cathinone mephedrone (4-methylmethcathinone) was established using triangulation of these different data sources.     

Cytostatic and Antiviral Activity Evaluations of Hydroxamic Derivatives of Some Non‐steroidal Anti‐inflammatory Drugs

Non‐steroidal anti‐inflammatory drugs (NSAID) pharmacophores are interesting in designing potential anticancer drugs. Indeed, numerous experimental, epidemiologic and clinical studies suggest that NSAIDs are promising anticancer drugs. Herein, NSAID hydroxamic acids 3a‐i were prepared by a new synthetic procedure and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts (WI38). Antiviral activity evaluation results indicated that 3f had only a minor activity against the influenza virus A/H1N1 subtype with a selectivity index of 7–10. On the other hand, the results of the in vitro cytostatic activity evaluations revealed that the majority of NSAID hydroxamic acid derivatives 3a – i exhibited a strong non‐specific antiproliferative effect at the highest concentration (100 μm ) on the tested cell line panel. Only compounds 3b , 3e and 3i exerted a differential dose‐dependent inhibitory activity against the growth of HeLa cells (p < 0.05) at concentration 10 μm . Among those three compounds, only compound 3b showed a selective cytostatic effect on HeLa in comparison with normal fibroblasts.     

A Method for Determination of the Absolute Pulmonary Bioavailability of Inhaled Drugs: Terbutaline

Terbutaline sulfate (4 × 0.250 mg) was given to 11 healthy volunteers by inhalation from a metered dose inhaler (MDI), with and without oral administration of a charcoal slurry. Before the inhalations, the adsorbing capacity of the charcoal slurry was tested. Deuterated terbutaline, 0.125 mg, was given intravenously at the same time as the test doses. The charcoal slurry adsorbed 97% of an oral dose. The oral contribution to the overall systemic bioavailability after inhalation, when charcoal was coadministered, could thus be neglected. After inhalation of terbutaline, 9.1% of the dose was deposited in the lungs and an additional 6.7% was systemically available via the oral route. The method presented measures the absolute pulmonary bioavailability after inhalation from a MDI. Since a deuterated analogue is given intravenously together with the inhalations, fewer subjects are needed to obtain reliable data.     

常用抗菌药物治疗肺部感染研究进展

成人肺部感染中 ,细菌占病原体的 80 %以上。据世界卫生组织 (ＷＨＯ)统计 ,目前世界人口死因中感染性疾病 1 3,而急性呼吸道感染 (主要为肺炎 )死亡人数占其中的 1 4。制药界统计表明 ,抗菌药物处方中约 2 3用于呼吸道感染 ,其中最常用药物有 β 内酰胺类、喹诺酮类、大环内酯类。此外 ,革兰阳性 (Ｇ )球菌耐药率上升 ,抗耐药Ｇ 球菌的药物研究进展 ,令人鼓舞。1　β 内酰胺类药物近年来产ＢｕｓｈⅠ型酶和产超广谱 β 内酰胺酶 (ＥＳＢＬｓ)的耐药菌株大量增加。开发第Ⅳ代头孢菌素 ,旨在全面增强抗Ｇ 球菌和Ｇ 杆菌 (特别是对耐药菌 )…