The history of poisoning in the future: lessons from Star Trek

BACKGROUND: The Arts are replete with examples of presaged events of the future. Since a unique glimpse of the 23rd century is afforded by the television series Star Trek, a survey of the toxin-related events as chronicled by the crew of the USS Starship Enterprise may provide insight to prepare toxicologists for the future. METHODS: An investigation of the logs of the Enterprise was undertaken for the years 2266 to 2269 which were part of its first 5-year mission. Internet sites, published databases, and selected recorded episodes from the original Star Trek television series were searched for poisonings or toxin-related incidents. RESULTS: Out of the 79 Star Trek episodes, 28 (35%) involved toxin-related incidents. A total of 31 poisoning incidents were documented with 13 environmental, 9 intentional, 5 unintentional, and 4 homicidal circumstances. Biotoxins (10 incidents) were the most frequently involved toxin followed by neurotoxins (9), radiation (3), cytotoxins (3), temporal toxins (3), acids (2), and phytotoxins (1). Of these cases, 2 involved hazardous materials incidents, 1 was contamination of food, and 3 involved therapeutic misadventures. CONCLUSIONS: Many of the circumstances encountered in poisonings of the future will likely be similar to contemporary reasons, but the nature of the toxins will differ. Clinical toxicologists should prepare for the future by increasing their study of molecular biology, comparative medicine, physics, and history.     

中毒暴露监测系统的应用研究

目的建立中毒暴露监测系统,实时掌握中毒的流行病学特征。方法对本市各市级、区级、镇级医院第一手接收或由下级卫生院社区卫生站转入的有明确中毒史患者的资料,通过监测系统指定详尽录入．进行归类分析。结果2011年1月～2012年3月共报告急性中毒952例,死亡45例,占4．73％。中毒种类中以酒精中毒最为常见。占24．3％,其次为药物中毒及农药;中毒年龄段以青年为首,依次为中年、儿童、老年。结论建立中毒暴露监测系统,可及时了解时期急性中毒人群的年龄、毒物种类、原因及病死率等流行病学特征,为指导临床快速救治和预防控制提供依据。     

Applying pharmaceutical lessons: learning lessons from the past

Systematic evaluation of a project, product or other successes, and failures, is an important method for improving the performance of a company, as well as that of an individual. One should evaluate and determine if lessons learned can be applied to the systems and procedures being used in the company. Even if the company does not have to adjust its strategies, procedures, portfolio or systems as a result of lessons it has learned, there may be pointers to communicate to staff. It is easy for many aspects of a system to become outdated, particularly in an organization that is growing or changing rapidly. It is therefore generally appropriate to evaluate the company's regulatory compliance, toxicology compliance, clinical auditing practices and other appropriate systems on an annual or biannual basis. Most lessons of success or failure are specific to a single situation because of the combination of people, drug, competition, priorities and many other factors involved, and cannot be extrapolated to other situations. Some general lessons and principles are presented that will facilitate drug discovery, development and marketing.     

The tobacco epidemic: lessons from history

Tobacco has caused the greatest epidemic of the twentieth century, which is beginning to wane in the United States, but is still growing in much of the world. The epidemic developed as a result of innovations in the tobacco industry and larger cultural changes over the 75 years prior to the introduction of Camel cigarettes in 1913. Factors that set the stage for the epidemic include the development of flue-cured and Burley tobaccos, the mechanization of cigarette production with its consequent concentration of capital in a few companies, the safety match, efficient transportation systems, and innovative advertising. Between 1913 and 1963, the cigarette industry experienced almost unbroken growth in the United States. However, since the early 1950s, increasing evidence that cigarettes cause lung cancer and other diseases has dictated that product innovation concentrate on the appearance of safety. In the late 1960s and for a sustained period since 1973, cigarette consumption has declined in the United States, but in the developing world the epidemic curve of cigarette use is still on the upswing. As tobacco use declines in the United States, it is crucial that the production of tobacco products as well as their consumption be reduced. Otherwise, attempting to control the problem in the United States will not result in a net reduction in mortality around the world.     

Effect of dioxin exposure on aromatase expression in ovariectomized rats

Because of their persistence in the environment dioxins are one of the most concerned classes of carcinogens. Displaying both pro- and anti-agonistic properties to some hormone receptors, the pollutants are also known to be endocrine disruptors. Humans can be exposed to this pollutant through contaminated food, air, drinking water, etc. The female hormone estrogen may initiate various physiological functions, and excessive exposure to this hormone is a documented risk factor for carcinogenesis. Cyp19 (aromatase) catalyses the last step of estrogen biosynthesis, while cyp1a1 can hydroxylate and deactivate the hormone. In the present study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) on aromatase expression in the brain and adipose tissue in ovariectomized Sprague Dawley rats. Female rats were given 2.5 microg/kg TCDD p.o. before and after ovariectomy. Real-time PCR and western blot analysis indicated that pre-ovariectomy administration of TCDD could significantly reduce aromatase expression in the brain but increase the expression in the adipose tissue. In addition, increased plasma estrogen level and uterine weight were observed in these rats. These parameters did not change in rats with post-ovariectomy TCDD treatment. Our results suggested that the timing of exposure to the toxicant could determine the estrogenicity of TCDD. No correlation between cyp1a1 and cyp19 expression was observed.     

Tyrothricin powder in the treatment of cutaneous lesions

BACKGROUND AND OBJECTIVES: The efficacy and tolerance of an antiseptic wound powder based on the antibiotic tyrothricin was investigated in a prospective, randomized multicenter trial in patients with posttraumatic and surgical cutaneous lesions. PATIENTS AND METHODS: In 5 centers, 131 male and female patients from 18-85 years were included with posttraumatic or surgical cutaneous lesions with infection or in danger of infection (area > or = 200 mm2). In a double-blind study, tyrothricin (n = 62; 0.1 g tyrothricin per 100 g of vehicle) or placebo powder (n = 69) was applied to the wound twice daily for 9 days. The primary aim was to evaluate the average daily reduction of the radius from the lesion area between the start and end of the randomized treatment (alpha = 0.025; one-sided). Secondly, a wound index (range 0-15) was calculated from the assessments of rubor, crusting, exudation, pain and functional impairment. RESULTS: The treatment groups were comparable at baseline. During randomized treatment, the radius of the lesions was reduced at an average of 0.55 +/- 0.31 mm/day (mean +/- SD) for tyrothricin and 0.47 +/- 0.30 mm/day for placebo (p = 0.016; one-sided; intention-to-treat data set). The wound index decreased at an average of 4.2 +/- 1.7 and 3.3 +/- 1.9 points for tyrothricin and placebo, respectively (p = 0.0048; one-sided). 4 adverse events occurred in each group. A causal relationship with the investigational drug could not be excluded in 3 of the placebo group. CONCLUSION: The results confirm the tendency to an acceleration of wound healing by tyrothricin powder (Tyrosur Powder) in case of infection or danger of infection. A superior efficacy compared to placebo was demonstrated. Due to its good tolerability and the absence of a systemic effects tyrothricin powder is appropriate for the treatment of superficial skin lesions.     

Cardiovascular gene expression profiles of dioxin exposure in zebrafish embryos.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant that causes altered heart morphology, circulatory impairment, edema, hemorrhage, and early life stage mortality in fish. TCDD toxicity is dependent, in large part, on the aryl hydrocarbon receptor (AHR), but understanding of the molecular mechanism of cardiovascular embryotoxicity remains incomplete. To identify genes potentially involved in cardiovascular effects, we constructed custom cDNA microarrays consisting of 4896 zebrafish adult heart cDNA clones and over 200 genes with known developmental, toxicological and housekeeping roles. Gene expression profiles were obtained for 3-day-old zebrafish after early embryonic exposure to either 0.5 or 5.0 nM TCDD. In all, 516 clones were significantly differentially expressed (p < 0.005) under at least one treatment condition; 123 high-priority clones were selected for further investigation. Cytochromes P450 1A and 1B1, and other members of the AHR gene battery, were strongly and dose-dependently induced by TCDD. Importantly, altered expression of cardiac sarcomere components, including cardiac troponin T2 and multiple myosin isoforms, was consistent with the hypothesis that TCDD causes dilated cardiomyopathy. Observed increases in expression levels of mitochondrial energy transfer genes also may be related to cardiomyopathy. Other TCDD-responsive genes included fatty acid and steroid metabolism enzymes, ribosomal and signal-transduction proteins, and 18 expressed sequence tags (ESTs) with no known protein homologs. As the first broad-scale study of TCDD-modulated gene expression in a non-mammalian system, this work provides an important perspective on mechanisms of TCDD toxicity.     

A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation.

Many ligands for the aryl hydrocarbon receptor (AhR) are considered endocrine disruptors and carcinogens, and assessment of adverse health effects in humans exposed to such chemicals has often focused on malignancies, including breast cancer. Mammary tissue contains the AhR, and inappropriate activation of the AhR during fetal development causes defects in mammary development that persist into adulthood. However, it is not known whether the extensive differentiation of mammary tissue that occurs during pregnancy is also sensitive to disruption by AhR activation. To examine this, we exposed pregnant C57Bl/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on days 0, 7, and 14 of pregnancy. Examination of mammary glands on days 9, 12, and 17 of pregnancy and on the day of parturition showed severe defects in development, including stunted growth, decreased branching, and poor formation of lobular alveolar structures. This impaired differentiation was biologically significant, as expression of whey acidic protein in the gland was suppressed, and all pups born to TCDD-treated dams died within 24 h of birth. Analysis of circulating progesterone, prolactin, and estradiol suggest that hormone production was slightly impaired by inappropriate activation of the AhR. However, hormone levels were affected only very late in pregnancy. Given that the observed defects in gland development preceded these hormonal effects, altered hormone levels are an unlikely mechanistic explanation for impaired mammary development. This novel finding that AhR activation during pregnancy disrupts mammary gland differentiation raises questions about the susceptibility of mammary tissue to direct injury by endocrine disrupting agents and the potential for AhR-mediated signaling to adversely affect lactation and breast tissue development in human populations.     

The double-edged sword of autoimmunity: lessons from multiple sclerosis

The relationship between immune responses to self-antigens and autoimmune disease is unclear. In contrast to its animal model experimental autoimmune encephalomyelitis (EAE), which is driven by T cell responses to myelin antigens, the target antigen of the intrathecal immune response in multiple sclerosis (MS) has not been identified. Although the immune response in MS contributes significantly to tissue destruction, the action of immunocompetent cells within the central nervous system (CNS) may also hold therapeutic potential. Thus, treatment of MS patients with glatiramer acetate triggers a protective immune response. Here we review the immunopathogenesis of MS and some recent findings on the mechanism of glatiramer acetate (GA).     

美国仿制药行业发展头25年的经验教训

本文回顾了自《1984年药品价格竞争与专利期补偿法案》实施、创立美国仿制药行业以来,美国仿制药行业的发展经验和教训。对仿制药丑闻、仿制药审批制度发展、生物等效性与可替代性、复杂剂型的生物等效性方法、专利常青、授权仿制药、仿制药安全性、仿制药审评、仿制药替代、4美元仿制药等美国仿制药行业发展中的关键性事件和过程进行了系统回顾与分析。美国仿制药行业在头25年发展历程中的经验教训,对其他希望建立或重新建立国内仿制药行业的国家有借鉴作用。     

Losartan: lessons learned from the RENAAL study

Renal and cardiovascular diseases associated with Type 2 diabetes are increasing at rapid rates, and are significant burdens to patients and healthcare systems. The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study was conducted from 1996 to 2001. This landmark clinical trial provided the opportunity to study renal and cardiovascular outcomes, as well as risk predictors, in a relatively large number of patients with Type 2 diabetes and nephropathy. The RENAAL study also provided information that will be valuable to those designing future clinical trials in this patient population. This review highlights key findings from the RENAAL study.     

Drug discovery: lessons from evolution

A common view within the pharmaceutical industry is that there is a problem with drug discovery and we should do something about it. There is much sympathy for this from academics, regulators and politicians. In this article I propose that lessons learnt from evolution help identify those factors that favour successful drug discovery. This personal view is influenced by a decade spent reviewing drug development programmes submitted for European regulatory approval. During the prolonged gestation of a new medicine few candidate molecules survive. This process of elimination of many variants and the survival of so few has much in common with evolution, an analogy that encourages discussion of the forces that favour, and those that hinder, successful drug discovery. Imagining a world without vaccines, anaesthetics, contraception and anti-infectives reveals how medicines revolutionized humanity. How to manipulate conditions that favour such discoveries is worth consideration.     

Neuropsychological sequelae from acute poisoning and long-term exposure to carbamate and organophosphate pesticides

This research examines the effects of different degrees of pesticide exposure on neuropsychological performance. Exposures varied from acute poisoning coupled with chronic exposure to low or high levels of chronic exposure (defined by years of exposure). A cross-sectional neuropsychological and biochemical study was conducted in greenhouse farmers from southern Spain: data from 24 acutely poisoned workers and 40 non-poisoned but chronically (low or high) exposed sprayers were compared to 26 controls. We examined performance on 21 neuropsychological tests that assessed attention, memory, praxis, gnosis, motor coordination, naming and reasoning and also examined values of plasmatic cholinesterase. Results indicated statistically significant neuropsychological deficits in the acute poisoning and high chronic exposure groups after controlling for confounds, whereas similar performance was seen in the low chronic exposed subjects and controls. Subjects who were acutely poisoned performed worse than the other groups on perceptual, visuomotor, visual memory and mood state domains. Both the acutely poisoned and the chronically high exposed subjects obtained significantly lower scores in the perceptual, verbal memory and visuomotor domains. Levels of butyrylcholinesterase were related to the seasonal sprayer activity except in the case of acutely poisoned subjects. Conclusions: Both acutely poisoned long-term workers and chronically high (> 10 years) exposed workers exhibited similar disturbances in perception and visuo-motor processing, in the absence of any related acute effect of butyrylcholinesterase inhibition. In the case of acutely poisoned subjects, verbal and perceptive learning and recall and constructive abilities were also impaired. These results point to the need for follow-up studies to assess the possible sequelae of chronic and acute exposure to pesticides and their interactions.