Cardiac conduction abnormalities and atrial arrhythmias associated with salicylate toxicity

Cardiac side effects from aspirin are uncommon; however, severe acid-base imbalance, pulmonary edema, ventricular ectopic activity and cardiopulmonary arrest have been reported in patients with toxic serum salicylate concentrations. We saw a patient with salicylate toxicity who developed a variety of sinus and atrioventricular nodal conduction disturbances and atrial arrhythmias with a relatively low toxic serum salicylate concentration. The cardiac rhythm returned to normal as the serum salicylate concentration decreased, and results of subsequent electrophysiologic testing and Holter monitoring were normal. A low serum albumin level may have resulted in altered salicylate binding in this patient, thereby increasing the availability of unbound (active) drug for toxic effects.     

The sea within us: disorders of body water homeostasis

The use of a sensitive radioimmunoassay to measure plasma vasopressin led to the clarification of the role of vasopressin in most clinical hyponatremic states, an advance that had been impossible with the less sensitive bioassay for antidiuretic hormone. The cloning of the V2 vasopressin receptor on the basolateral membrane of the principal cells of the collecting duct demonstrated that the majority of congenital nephrogenic diabetes insipidus (NDI) was caused by mutations in this V2 receptor gene. The Nobel Prize discovery of the first membrane water channel by Agre and colleagues allowed for the molecular understanding of many disorders of water homeostasis, several of which are discussed in this review. Mutations of the vasopressin-regulated water channel on the principal cells of the collecting duct, namely aquaporin (AQP)2, account for a minority of cases of congenital NDI. Downregulation of AQP2 expression has subsequently proved important in an array of clinically significant causes of acquired NDI. Most important clinically, has been the discovery of several orally active, non-peptide V2 receptor antagonists, which have significant implications in the treatment of hyponatremic states. This review discusses the major advances that have increased our understanding of the mechanisms of renal water regulation in health and disease. The relationship between osmotic and non-osmotic regulation of antidiuretic hormone (arginine vasopressin) release is discussed.     

Application and toxicity of CNTs in human body

This review addressed the recent advances in CNT researches for many pharmaceutical applications. The attractive properties of CNT have paved the way for the construction of a wide range of biosensors and energy storage devices, exhibiting attractive analytical behaviors and semiconducting industry, respectively. The review discussed the potential toxicity of CNT on various human and animal cells, including blood proteins like binding with hemoglobin. Till date, no result was reported on chronic toxicity of CNT. If no or minimal toxicity would be proven with human cells and tissues in future, CNTs could be utilized for neurodegenerative disease like Alzheimer’s and Parkinson’s diseases using its BBB transpermeability.     

Active transport across the human placenta: impact on drug efficacy and toxicity

The human placenta expresses a large number of transport proteins. The ATP-binding cassette (ABC) family of active efflux pumps, predominantly localised to the maternal-facing syncytial membrane of placental microvilli, comprise the major placental drug efflux transporters. A variety of other transporters are also expressed in the placenta that can facilitate xenobiotic transfer in both the maternal and fetal directions. Many drugs administered in pregnancy are ABC transporter substrates, and many are either teratogenic or fetotoxic. The in vitro, in vivo and clinical evidence reviewed in this article argues that active efflux of drugs by placental transporters helps to maintain its barrier function, reducing the incidence of adverse fetal effects. ABC transporter polymorphisms may explain the wide variability observed in fetal drug concentrations, incidence of teratogenesis or drug failure in pregnancies exposed to therapeutic agents. Although our understanding of the molecular mechanics and dynamics of placental drug transfer is advancing, much work is needed to fully appreciate the significance of placental drug transporters in the face of increasing drug administration in pregnancy.     

Hematologic abnormalities associated with vidarabine

A report of hematologic abnormalities associated with administration of vidarabine in a neonate is presented. High doses of vidarabine (30 mg/kg/d) for the treatment of herpes simplex infection may have caused a decrease in hematocrit and platelet count. This case demonstrates the need to monitor hematologic indices during administration of vidarabine. The use of doses greater than 15 mg/kg/d is questioned.     

垂体后叶素相关电解质异常

1例19岁男性肺结核患者因大咯血入院。入院当日血电解质检查示钾3.5 mmol/L、钠137 mmol/L、氯104 mmol/L。给予其甲磺酸酚妥拉明20 mg、垂体后叶素24 U分别加入0.9%氯化钠注射液50 ml中以5 ml/h速度每日持续静脉泵入,同时给予抗结核治疗(对氨基水杨酸异烟肼+左氧氟沙星+阿米卡星)。入院第5天患者出现乏力、头痛,血电解质检查示钾3.1 mmol/L、钠122 mmol/L、氯88 mmol/L、磷0.65 mmol/L。垂体后叶素减量至18 U,1次/12 h,同时补充电解质,其他药物维持不变。第6天检查示血钾2.8 mmol/L、钠117 mmol/L、氯83 mmol/L、磷0.54 mmol/L、钙1.99 mmol/L。停用垂体后叶素,补充电解质。入院第10天,患者电解质恢复正常:钾4.3 mmol/L、钠136 mmol/L、氯101 mmol/L、钙2.17 mmol/L、磷0.82 mmol/L。     

Clinical toxicity associated with tiazofurin

Summary Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23–36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity ( grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity.     

Changes in zinc and copper homeostasis in human livers and kidneys associated with exposure to environmental cadmium

This study was undertaken to assess changes in zinc and copper homeostasis in human tissues that could be attributed to human exposure to environmental cadmium, using samples of lung, liver and kidney cortex of 61 Queensland residents, aged 2 to 89 years, who had died of accidental causes. None of the subjects were exposed to cadmium in the workplace. Levels of zinc in liver and kidney cortex samples showed inverse associations with donor age whereas zinc in lung only showed inverse association with gender. Lung zinc levels in females were 14% lower than in males. Zinc in liver and kidney cortex samples were found to exist in at least two pools; one was associated with cadmium that bound to metallothionein (MT) and the other was associated with non-MT bound copper. In liver, the amounts of zinc in the MT pool were smaller compared to those in non-MT pool given that only 7% of zinc variations were explained by cadmium whereas 22% of the liver zinc variations were accounted for by non-MT bound copper. In sharp contrast, larger amounts of zinc in kidney cortex samples were in the MT pool, compared to those in the non-MT pool given that cadmium was found to explain 69% of total zinc variation whereas copper explained only 17% of kidney zinc variations. The levels of copper in liver were found to be increased by 45-50% in subjects with high cadmium exposure level, compared to subjects of similar ages with medium exposure level. The levels of zinc and copper in kidney cortex samples in the subjects with high cadmium exposure were both found to be significantly elevated compared to those found in the medium-exposure group whereas copper contents were about 19-23% greater than in medium- as well as low-exposure groups. Taken together these results indicate increased sequestration of zinc and copper in liver and kidney cortex samples. The increases in metal sequestrations were observed in liver samples having cadmium contents of greater than 1 microg/g wet weight and in kidney cortex having cadmium contents of greater than 26 microg/g wet weight. Zinc and copper contents in lung of this sample group, however, were not associated with cadmium due probably to lower exposure levels compared to those of liver and kidney.     

癃必舒胶囊致血氨基转移酶异常

患者男,69岁。于2003年10月14日例行体检时发现前列腺Ⅰ度肥大,当时未予治疗。2004年出现尿频、尿急、尿不净等症状约半年,再次体检发现列腺肥大增至Ⅱ度。两年体检时检测ALT正常,B超:肝胆胰脾双肾未见异常。当年9月16日开始在我院外科治疗,给予非那雄胺片5mg口服,1次/d;癃闭舒胶囊0.9g口服,2次/d。2周后病人症状好转,并按上述药物剂量继续服用治疗前列腺肥大。病人因自觉“胸腹部不适半年”,于2005年3月2日来我院中医科诊治。查心电图正常,仍服用非那雄安、癃闭舒胶囊,先后加服心可舒胶囊、舒肝和胃丸、加味逍遥丸等药治疗,但效果欠佳,胃…     

Renal toxicity associated with tenofovir use

Importance of the field: Tenofovir (TFV) is a nucleotide analogue widely used for the treatment of HIV infection. Despite its proven efficacy and safety, cases of kidney tubular dysfunction have increasingly been reported and concern exists about the risk of nephrotoxicity associated with the long-term use of TFV.

Areas covered in this review: Evidences about the renal toxicity associated with TFV use as well as predictors are examined. The most relevant publications assessing TFV safety and those which have reported cases of tubular dysfunction were identified and carefully revised.

What the reader will gain: Renal damage of clinical significance caused by TFV is uncommon in the short-mid-term. It occurs more frequently in subjects with underlying kidney conditions. TFV primarily results in kidney tubular dysfunction and less frequently in glomerular abnormalities. Kidney damage may progress over time under long-term TFV exposure but is reversible in most cases on drug discontinuation.

Take home message: Severe renal damage associated with TFV use is uncommon and of multifactorial origin. However, mild tubular dysfunction is recognized in a substantial proportion of TFV-treated individuals and tends to increase with cumulative exposure.     

Pulmonary toxicity associated with fludarabine monophosphate

Summary Fludarabine monophosphate (FAMP), the 2-fluoro, 5phosphate derivative of 9--D-arabinofuranosyl adenine (ara-A), is a purine nucleoside antimetabolite presently undergoing clinical testing for the treatment of a variety of malignancies including lymphoproliferative disorders and acute leukemia. We report a case of diffuse interstitial pneumonitis during treatment of chronic lymphocytic leukemia with FAMP. This resolved quickly with high dose steroids, recurred with steroid withdrawal, and abated with further steroid therapy. To our knowledge, this is the first reported case of fludarabine monophosphate associated pulmonary toxicity.     

镁离子导致人体对机械刺激以及热辐射刺激感觉异常的研究

目的：观察Mg^2＋对周围神经元的影响。方法：通过双盲法,分别给20名健康志愿者皮下注射0．5M、0．05M硫酸镁成皮丘,然后分别测试皮丘区域皮肤的触觉、触压觉与热痛觉,并设生理盐水组作为对照。结果：注射Mg^2＋后皮丘区域皮肤出现触觉、触压觉迟钝,而热痛觉过敏的现象。结论：发现Mg^2＋。可以抑制周围神经触觉、触压觉的传导,但提高热痛觉的敏感性。     

Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines

Tyrosine kinase inhibitors have revolutionized the treatment of certain cancers. They are usually well tolerated, but can cause adverse reactions including liver injury. Currently, mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors are only partially clarified. We therefore aimed at investigating the toxicity of regorafenib, sorafenib, ponatinib, crizotinib, dasatinib and pazopanib on HepG2 and partially on HepaRG cells. Regorafenib and sorafenib strongly inhibited oxidative metabolism (measured by the Seahorse‐XF24 analyzer) and glycolysis, decreased the mitochondrial membrane potential and induced apoptosis and/or necrosis of HepG2 cells at concentrations similar to steady‐state plasma concentrations in humans. In HepaRG cells, pretreatment with rifampicin decreased membrane toxicity (measured as adenylate kinase release) and dissipation of adenosine triphosphate stores, indicating that toxicity was associated mainly with the parent drugs. Ponatinib strongly impaired oxidative metabolism but only weakly glycolysis, and induced apoptosis of HepG2 cells at concentrations higher than steady‐state plasma concentrations in humans. Crizotinib and dasatinib did not significantly affect mitochondrial functions and inhibited glycolysis only weakly, but induced apoptosis of HepG2 cells. Pazopanib was associated with a weak increase in mitochondrial reactive oxygen species accumulation and inhibition of glycolysis without being cytotoxic. In conclusion, regorafenib and sorafenib are strong mitochondrial toxicants and inhibitors of glycolysis at clinically relevant concentrations. Ponatinib affects mitochondria and glycolysis at higher concentrations than reached in plasma (but possibly in liver), whereas crizotinib, dasatinib and pazopanib showed no relevant toxicity. Mitochondrial toxicity and inhibition of glycolysis most likely explain hepatotoxicity associated with regorafenib, sorafenib and possibly pazopanib, but not for the other compounds investigated.