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Background: A consensus guideline on salicylate poisoning recommends referring patients to the emergency department if they ingested 150 mg/kg of aspirin. The dose of aspirin associated with severe poisoning in pediatric patients has not been investigated. Objective: This study aims to associate medical outcomes with aspirin overdoses in patients 5 years old and younger. Methods: A retrospective review of data on pediatric patients with single substance aspirin exposures reported from poison centers across the country was conducted. The primary endpoint was to associate aspirin doses with medical outcomes. Secondary endpoints included evaluation of the signs, symptoms, and treatments of ingestion and their association with medical outcomes. Results: There were 26 488 included exposures with aspirin exposures resulting in no effect (92.5%), minor effect (6.0%), moderate effect (1.4%), major effect (0.2%), and death (0.02%). There were 8921 cases with available weight-based dosing information. Median doses associated with no effect, minor effects, moderate effects, major effects, and death ranged between 28.4 and 40.9 mg/kg, 52.5 and 82.3 mg/kg, 132.1 and 182.3 mg/kg, 132.3 and 172.8 mg/kg, and 142.2 and 284.4 mg/kg, respectively. Minor effect and moderate effect exposures were more likely to have alkalinization documented compared to no effect exposures (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.41-2.17; OR = 1.79, 95% CI = 1.12-2.86). There was no difference in rates of alkalinization between minor and moderate exposures (OR = 1.02, 95% CI: 0.61-1.7). Conclusions and relevance: Reevaluation of the current recommendation of 150 mg/kg for referral to a healthcare facility is necessary for pediatric acute salicylate overdoses. [ABSTRACT FROM AUTHOR]

Background: Benzonatate is a commonly prescribed medication that can be lethal in acute overdose of a small number of capsules. Objective: This was a systematic review to describe the course of severe poisoning and deaths from benzonatate supplemented with the National Poison Data System (NPDS) fatalities module. Methods: The NPDS was queried from 2000 to 2018 for benzonatate fatalities. Pubmed, Cochrane, Embase, and Google Scholar were searched for combinations of benzonatate and "poisoning," "overdose," and "toxicity." References of relevant articles were searched for additional publications. Articles were included if they described the clinical course of at least one patient suffering from benzonatate poisoning and available in English. Dual independent review and extraction were performed. Results: Seventeen cases from NPDS and 19 published reports met the inclusion criteria resulting in 36 cases, mostly (28/36) self-harm ingestions. Most patients were young [17 (11–29), median (IQR)] and female (22). Onset of toxicity was rapid at <5 min (9). Most common symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Return of spontaneous circulation was achieved in 23/28 patients, but most had significant neurologic deficits or other end organ damage and 5 survived with a good neurologic outcome. Conclusion and relevance: Overdose ingestions of benzonatate can cause significant toxicity with a rapid onset. Interventions performed were generally supportive in nature. Duration of directly toxic effects is short, but dramatic with neurologic devastation and resuscitated patients often still have a poor outcome. [ABSTRACT FROM AUTHOR]

This symposium synopsis summarizes key points discussed related to clinical pathology data interpretation for reproduction and juvenile toxicology studies. In pregnant and growing animals, several changes in clinical pathology parameters linked to growth/maturation of organ and physiological functions can occur, and understanding these changes is important to enable accurate interpretation of clinical pathology data. A brief overview of the general approach to clinical pathology data analysis according to contemporary practices is provided, followed by a discussion focused specifically on reproductive and juvenile clinical pathology. In this context, the approach to recognize and differentiate changes that may be related to pregnancy and growth as opposed to those that may be related to test article effects is highlighted. [ABSTRACT FROM AUTHOR]

Background: Currently, there are no national guidelines for antenatal drug testing. At Colchester Hospital, we use a strategy of screen-only using point-of-care testing to detect illicit drug use in pregnancy. To determine the suitability of this approach, we have compared the results of urine analysis by point-of-care testing with another NHS specialist clinical toxicology service that uses confirmation mass spectrometry. Methods: A total of 482 anonymized random urine specimens from antenatal clinics were tested for six drug classes: amphetamine, benzodiazepines, buprenorphine, cocaine, methadone and opiates using the Alere™ Drug Screen Urine Test Cup. The manufacturer's claims for positive cut-off and result stability were verified using spiked blank urine. Confirmatory testing was performed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for detection of 26 individual drugs. Results: Of 473 urine samples with adequate volume for point-of-care screening, 4.4% tested positive: 19 opiate and 2 cocaine. Concordance between point-of-care screening and UPLC-MS/MS confirmation was 97.9% for all drugs and 78.9% for opiates. Using spiked urine, only positive results for opiates were stable when read up to the manufacturer's recommended time of 60 min. Conclusions: The key advantages of using point-of-care devices to detect drug use in pregnancy are that is convenient and cheap. However, the clinical utility of point-of-care testing is limited by its poor sensitivity. Best practice is to confirm results using a more specific and sensitive method. As a result of this study, we are now reviewing our own procedures to consider introducing routine confirmation by mass spectrometry. [ABSTRACT FROM AUTHOR]

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation. [ABSTRACT FROM AUTHOR]

Though rare due to measures and practices to control the risk, infections can occur in research and toxicology studies, especially in nonhuman primates (NHPs) exposed to xenobiotics, particularly immunomodulatory drugs. With such xenobiotics, immunocompromised or immunosuppressed animals will not be able to mount a protective response to infection by an opportunistic pathogen (bacteria, virus, parasite, or fungus) that might otherwise be nonpathogenic and remain clinically asymptomatic in immunocompetent animals. The respiratory tract is one of the most commonly affected systems in clinic, but also in toxicology studies. Pulmonary inflammation will be the main finding associated with opportunistic infections and may cause overt clinical disease with even early sacrifice or death, and may compromise or complicate the pathology evaluation. It is important to properly differentiate the various features of infection, to be aware of the range of possible opportunistic pathogens and how they may impact the interpretation of pathology findings. This review will present the most common bacterial, viral, parasitic, and fungal infections observed in the respiratory tract in NHPs during research and/or toxicology studies. [ABSTRACT FROM AUTHOR]

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article. [ABSTRACT FROM AUTHOR]

Background: Antimuscarinic delirium is associated with significant morbidity, and its management requires substantial resource allocation, including intubation, restraint, and intensive care unit (ICU) placement. There is controversy over the management of these patients. Physostigmine can rapidly reverse antimuscarinic delirium but has been associated with adverse effects. Objective: This study aims to assess the effect of physostigmine use on resource allocation and adverse events. Methods: This is a retrospective chart review of patients with an antimuscarinic toxidrome at a single hospital approved by the local institutional review board. A blinded abstractor recorded data from patient charts. Whether the patient was given physostigmine, intubated, restrained, or admitting to critical care was recorded. We recorded instances of seizure, vomiting, or bradycardia. The primary aim was to compare frequency of intubation as a function of physostigmine administration. Results: A total of 141 patients were identified. We found no difference between the groups in age, gender, or initial heart rate; 65 (46%) were given physostigmine, 45 (32%) were admitted to the ICU, and 29 (20%) were intubated. Patients who received physostigmine in the first 24 hours were less likely to be intubated and less likely to be admitted to an ICU. The instance of bradycardia (n = 16), vomiting (n = 27), and seizures (n = 7) was limited, and there were no significant differences between the groups. There were no associations noted between physostigmine administration and adverse effects. Conclusion and Relevance: This study demonstrated that physostigmine use is associated with decreased resource utilization (including intubation and ICU placement) without increasing rates of bradycardia, vomiting, or seizures. [ABSTRACT FROM AUTHOR]

National Toxicology Program (NTP) pathologists are engaged in important initiatives that have significant global impact. These initiatives build on its leadership in pathology peer review and publications in the areas of toxicologic pathology, clinical pathology, and laboratory animal medicine. Over the past decade, NTP/National Institute of Environmental Health Sciences research initiatives have focused on cancer and noncancer hazard identification, with the goal of understanding cellular and molecular mechanisms of disease. New initiatives of significant global impact include the web-based nonneoplastic lesion atlas and an NTP partnership with international scientists to investigate molecular mechanisms at the whole genome level, which will be used to inform potential mechanisms of environmental exposures in human cancers. Also, we are dedicated to contributing to pathology and toxicology organizations through service on executive committees and editorial boards, participating in international projects and symposiums, and providing training for future leaders in toxicologic pathology. Herein, we provide highlights of our global contributions. [ABSTRACT FROM AUTHOR]

Real-time telepathology for use in investigative and regulated preclinical toxicology studies is now feasible. Newly developed microscope-integrated telepathology systems enable geographically remote stakeholders to view the live histopathology slide as seen by the study pathologist within the microscope. Simultaneous online viewing and dialog between study pathologist and remote colleagues is an efficient and cost-effective means for consultation, pathology working groups, and peer review, facilitating good science and economic benefits by enabling more timely and informed clinical decisions. [ABSTRACT FROM AUTHOR]

Introduction Legal highs also known as novel psychoactive substances mimic the effects of classic drugs of abuse. Challenges to developing screening services for novel psychoactive substances include identifying which novel psychoactive substances are available to target. Using new techniques such as exact mass time of flight can help identify common novel psychoactive substances to target for screening patient samples by routine methods such as tandem mass spectrometry. We demonstrate this strategy working in our own clinical toxicology laboratory after qualitative analysis of 98 suspect materials for novel psychoactive substances by ultra-performance liquid chromatography with time of flight mass spectrometry. Results From July 2014 to July 2015 we received 98 requests to test a range of different suspect materials for novel psychoactive substances including herbs, tobacco, liquids, pills and powders. Overall, 87% of the suspect materials tested positive for novel psychoactive substances, and 15% for controlled drugs. Three common novel psychoactive substances were present in 74% of the suspect materials: methiopropamine, a methamphetamine analogue; ethylphenidate, a cocaine mimic; and the third generation synthetic cannabinoid 5F-AKB-48. For the 55 branded products we tested only 24% of the stated contents matched exactly the compounds we detected. Conclusion Testing suspect materials using ultra-performance liquid chromatography with time of flight mass spectrometry has identified three common novel psychoactive substances in use in the UK, simplifying the development of a relevant novel psychoactive substances screening service to our population. By incorporating this into our routine liquid chromatography tandem mass spectrometry drugs of abuse screen, then offers a clinically relevant novel psychoactive substances service to our users. This strategy ensures our clinical toxicology service continues to remain effective to meet the challenges of the changing drug use in the UK. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO) is a colourless and odourless gas appearing as a result of incomplete combustion of carbon-containing fuels. Many domestic or occupational poisonings are caused by CO exposure. Malfunctioning heating systems, improperly ventilated motor vehicles, generators, grills, stoves and residential fires may be listed in the common sources of CO exposure. The aim of this study was to emphasize the significance of early diagnosis of CO poisoning with non-invasive measurement of CO levels of the patients with non-specific symptoms using a pulse oximeter device in the triage. Our study was a cross-sectional study. Patients who presented to the emergency department (ED) due to non-specific symptoms and had a Canadian Triage and Acuity scale level of 4 or 5 were included in the study; 106 (5.9%) of 1788 patients admitted during the study period were diagnosed with CO poisoning. Patients with CO poisoning and the other patients had statistically significant differences in terms of presenting symptoms, namely, headache, dizziness, nausea, and vomiting. More CO poisoning cases were admitted in the fall and winter compared to the spring and summer. The number of CO poisoning victims can be decreased if preventive measures like CO monitoring systems and well-designed ventilation systems are generalized at homes and workplaces. Measurement of carboxyhaemoglobin levels of patients presenting to ED due to non-specific symptoms like headache and dizziness during cold seasons and winter months using a pulse CO-oximeter should be a part of the routine of emergency medicine triage. [ABSTRACT FROM AUTHOR]

Introduction: ST segment elevation myocardial infarction (STEMI) due to coronary artery occlusion caused by intracoronary thrombosis in the setting of acute carbon monoxide (CO) poisoning is a very rare presentation. We present a case of intracoronary large and mobile thrombus formation after CO poisoning. Case presentation: A previously healthy 50-year-old woman was referred for CO poisoning. She had chest pain after exposure to CO. Her initial mental status was preoccupied with chest pain. Her initial CO fraction was 28.1%, and initial laboratory data showed creatine kinase–myocardial isoenzyme of 134 U/L (upper limit 25 U/L) and troponin I of >50 ng/mL (upper limit 0.06 ng/mL). Electrocardiography was carried out on admission, revealing an ST segment elevation in the inferolateral leads. After initial evaluation, coronary angiography was performed and an intracoronary large mobile thrombus was seen in the proximal left anterior descending (LAD) artery with no significant stenosis. We administered tenecteplase with heparin. After the thrombolytic therapy, ST elevation in the inferolateral leads resolved. Repeat angiography was performed after 24 h; the thrombus in LAD had resolved. The patient was discharged after 5 days, with persistent Q wave in the inferior leads and mild hypokinesia of the inferoposterior wall suggesting myocardial injury. Conclusion: We describe intracoronary thrombus formation induced by CO poisoning. Because intracoronary thrombus can result in myocardial infarction, its consideration following CO poisoning is important. Patients with CO poisoning who have symptoms of STEMI should be carefully evaluated with serial electrocardiograms, cardiac biomarkers, and an echocardiogram. When there is evidence of acute myocardial injury, a primer in coronary angiography can determine which patients could benefit from intervention. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is widely used in preclinical research and drug development and is a powerful noninvasive method for assessment of phenotypes and therapeutic efficacy in murine models of disease. In vivo MRI provides an opportunity for longitudinal evaluation of tissue changes and phenotypic expression in experimental animal models. Ex vivo MRI of fixed samples permits a thorough examination of multiple digital slices while leaving the specimen intact for subsequent conventional hematoxylin and eosin (H&E) histology. With the advent of new compact MRI systems that are designed to operate in most conventional labs without the cost, complexity, and infrastructure needs of conventional MRI systems, the possibility of MRI becoming a practical modality is now viable. The purpose of this study was to investigate the capabilities of a new compact, high-performance MRI platform (M2™; Aspect Imaging, Israel) as it relates to preclinical toxicology studies. This overview will provide examples of major organ system pathologies with an emphasis on how compact MRI can serve as an important adjunct to conventional pathology by nondestructively providing 3-dimensional (3-D) digital data sets, detailed morphological insights, and quantitative information. Comparative data using compact MRI for both in vivo and ex vivo are provided as well as validation using conventional H&E. [ABSTRACT FROM AUTHOR]

Examination of H&E-stained tongue samples from a 26-week intravenous infusion study of Beagle dogs, utilizing a compound with no recognized effect on mineral metabolism, exhibited superficial stratum corneum calcification in both treated and control animals. This resulted in the search for possible causes of the finding to help clarify confounding issues. Retrospective examination of 11 studies performed before the signal case indicated that the problem existed in the testing facility but was not recognized. Prior to 2008, this finding was not observed, perhaps indicating the requirement for a change in procedures or suppliers. Based on the hypothesis that the calcium salts were deposited from bone during processing, a series of tests was performed by fixing tongue and femur along with different tissues, processed routinely to slide, and stained with H&E and von Kossa stains. We conclude that the presence of superficial stratum corneum calcification of the tongue in dogs demonstrated in toxicology studies is an artifactual change related to the processing of tissues, specifically the fixation of tongue in the same container as bone and stomach. This change should not be confused with compound-related effects, even when the incidence varies between controls and treated animals. [ABSTRACT FROM AUTHOR]

The article discusses the restrospective observational study on the misuse of methylphenidate (MPH) by adult patients in Denmark. The study involved data from the Danish Poison Information Centre in Copenhagen, Denmark from January 2006 to July 2012. The results reportedly revealed that increase of MPH exposures is significantly parallel to the increase in therapeutic use and that most MPH exposure were intentional.

The article discusses the use of several volatile compounds as biomarkers of diseases or acute intoxications which include methanol, acetone, ethanol and acetaldehyde. It emphasizes the quantification of methanol for the diagnosis of criminal or accidental methanol poisoning. It highlights the use of gas chromatography mass spectrometry (GC-MS) techniques for analyzing the volatile compounds.

Prolonged infusion of dexmedetomidine, an α2-adrenoreceptor agonist anesthetic used in the intensive care unit, produces a withdrawal syndrome of sympathetic over-activity, characterized by tachycardia, hypertension and agitation, but there is no recommended standard treatment for this syndrome. We describe two patients with a clinical diagnosis of acute dexmedetomidine withdrawal and its management with oral clonidine. We utilized the principle of managing acute drug withdrawal with longer acting medications. These two cases demonstrated the benefit of using oral, longer acting clonidine to manage acute withdrawal from shorter-acting, intravenous dexmedetomidine. [ABSTRACT FROM AUTHOR]

Atropa belladonna L. is a plant long known to cause poisoning. But no cases of acute subdural hematoma resulting from such poisoning have been reported so far. Care must also be taken in terms of acute pancreatitis and rhabdomyolysis in cases of such poisoning. The plant may sometimes be mistaken for the Caucasian blueberry, V. arctostaphylos L. At least one anti-cholinesterase toxidrome finding was determined in all the nine cases of belladonna poisoning in this series. No elevated creatine kinase was reported in one case with acute subdural hematoma and hyperamylasemia. [ABSTRACT FROM AUTHOR]

The aim of this retrospective epidemiological study was to investigate the demographical, etiological and clinical characteristics of acute drug poisonings in Iasi County, Romania. All patients were referred and admitted in the Toxicology Clinic of “Sf. Ioan” Emergency Clinic Hospital Iasi, Romania. Between 2003 and 2009, 811 cases of acute drug poisonings were recorded, counting for 28.43% from the total number of poisonings. The majority of these poisonings resulted in mild (51.94%) and medium (28.35%) clinical forms, while 19.71% were coma situations. In all, 63.51% of patients originated from urban areas, 39.94% were unemployed and the patients were predominantly women (66.46%). A high percentage (97.27%) were suicide attempts, using only one type of drug (65.88%) and the 21–30 years group (29.8%) records the highest incidence, for both women and men. The most frequently involved drugs were benzodiazepines 13.69%, anticonvulsive drugs 8.63%, barbiturates 8.51% and cardiovascular drugs 5.92%. Drugs combinations were recorded in 32.92% of cases and 1.2% were combinations between drugs and other substances. Mortality was the outcome in 0.3% of the total registered number of acute drug poisonings. This study underlines that in order to provide a proper management of these situations, a Regional Poison Information Center is absolutely necessary. [ABSTRACT FROM AUTHOR]

This report describes the first known case in the literature of acute exposure to a mixture of spinosad and flonicamid that resulted in a substantial clinical toxicities. An 80-year-old depressed female attempted suicide by drinking a mixture of 80-mL Conserve (Dow AgroSciences, Taipei, Taiwan) and 2–3 gram powder of flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan). Spinosad was the main compound ingested. The clinical manifestations were mostly neurological, i.e. consciousness disturbance, shock, respiratory failure, pneumonitis and urinary retention. Endoscopic examination found grade 2a corrosive esophageal injury. After resuscitation, detoxification procedures and intensive care, the patient recovered fully without leaving any chronic sequels. An emerging question arising from this report is, why are the clinical symptoms so severe, given that both compounds were claimed safe in laboratory animals? The answer is unclear. One possible explanation is, the amount of spinosad ingested was far beyond the physiological safety dose that can be handled by human body. Other potential contributors to the clinical toxicities in this patient are the solvent compositions that were found in the Conserve insecticide formulation. [ABSTRACT FROM PUBLISHER]

Organophosphate (OP) poisoning continues to represent an important medical issue through its high prevalence among toxic pathologies and through its severity. In diagnosing this toxicological disorder, the most frequently utilized and available laboratory test remains the assessment of plasma cholinesterase – butyrylcholinesterase (BChE) – activity. Despite the reluctance of many researchers on the usefulness of serum BChE for kinetic analysis in OP intoxications, we have tested a recently proposed protocol, which is safe, non-expensive, easy to perform, appropriate to distinguish between an aged cholinesterase and a still reactivable one. Our aim was to validate the usefulness of this protocol, studying a series of 23 consecutive patients acutely intoxicated with OP, admitted in a regional Emergency Hospital, over a 1-year period. Introducing the proposed test in the routine of monitoring OP-intoxicated patients has resulted in the identification of a pattern with a funnel aspect, consequence of the initial possibility to increment the degree of BChE activity. This funnel shape defines the presence of reactivability, while its absence demonstrates the lack of obidoximes effect, due to cholinesterase’s ageing process. This method consisted in an advantage for the diagnosis, having the potential of improving prognostic evaluation and therapeutic orientation in OP intoxications. [ABSTRACT FROM PUBLISHER]

There are no controlled human studies to determine the efficacy of benzodiazepines or antipsychotic medications for prevention or treatment of acute cocaine toxicity. The only available controlled data are from animal models and these studies have reported inconsistent benefits. The objective of this study was to quantify the reported efficacy of benzodiazepines and antipsychotic medication for the prevention of mortality due to cocaine poisoning. We conducted a systematic review to identify English language articles describing experiments that compared a benzodiazepine or antipsychotic medication to placebo for the prevention of acute cocaine toxicity in an animal model. We then used these articles in a meta-analysis with a random-effects model to quantify the absolute risk reduction observed in these experiments. We found 10 articles evaluating antipsychotic medications and 15 articles evaluating benzodiazepines. Antipsychotic medications reduced the risk of death by 27% (95% CI, 15.2%–38.7%) compared to placebo and benzodiazepines reduced the risk of death by 52% (42.8%–60.7%) compared to placebo. Both treatments showed evidence of a dose-response effect, and no experiment found a statistically significant increase in risk of death. We conclude that both benzodiazepines and antipsychotic medications are effective for the prevention of lethality from cocaine toxicity in animal models. [ABSTRACT FROM PUBLISHER]

Drugs containing 5-acetylsalicylic acid (5-ASA) have been commonly used for inflammatory bowel diseases for more than half a century, but no case about overdose of suppository form of mesalazine which was taken both orally and rectally has been reported in the related literature up to now. In the present case, a 20-year-old male patient who took 14.5 g of mesalazine rectally and orally for suicide purpose is discussed. He was an ulcerative colitis patient and depressed about his illness and routine life traffic. Although it was hard for him to take the suppository form orally because of its bad taste and structure, he took it with the help of water. In the patient’s colonoscopy, diffuse hyperemia and edema extending from the anal channel to the proximal rectal mucosa and a 1.5 cm diameter ulcer expanding from anal channel through the rectum were identified. No pathology was found in the upper gastrointestinal endoscopy. Routine laboratory examination was performed and no abnormality was identified in the patient’s total blood account, biochemical parameters and full-urine examination. In the control rectoscopy applied to the patient 15 days later, recovery of the ulcer was observed and he was discharged to be followed in the psychiatry clinic. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) can cause acute lung injury in humans and experimental animals. However, the role of growth factors in the progression of injury has not been clearly established. We developed an animal model of PQ-induced lung injury using Wistar rats. One milliliter of PQ solution (30, 60, and 120 mg/kg) was applied through the lavage, while the same amount of vehicle was applied to control rats. Based on histopathology, the lungs of some animals exposed to PQ showed acute fulmination, resulting in death, while others showed a more protracted injury, resulting in typical pulmonary fibrosis at 21 days. Using this PQ-poisoned rat model, we examined the intrapulmonary gene expression and circulatory level of cytokines and growth factors at 8 hours, 24 hours, 3 days, 7 days, 14 days, and 21 days after PQ administration. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the gene expression levels of interleukin-1 beta and interleukin-6 were significantly increased at 21 days after PQ challenge compared with the controls. The mRNA expression of tumor necrosis factor-alpha was also significantly increased except on days 14 and 21 after PQ treatment. Moreover, PQ-treated rats showed enhanced gene expression of growth factors such as platelet-derived growth factor-A and insulin-like growth factor-1 at 21 days and transforming growth factor-beta 1 at 14 days. ELISA results showed the circulatory level of cytokines and growth factors coincided with intrapulmonary gene expression. The synergistic effects of these molecules are presumed to cause pulmonary damage due to PQ challenge and may become targets of treatment. [ABSTRACT FROM PUBLISHER]

We report a case of a 51-year-old woman who was admitted to the hospital after ingestion of large doses of dipyridamole (12 g), temazepam (1 g) and oxazepam (0.2 g) with suicidal intent. The highest dipyridamole concentration that was measured in serum was 9.2 mg/L, which was paralleled by impaired platelet activation. For temazepam and oxazepam, peak serum concentrations were 8.5 and 1.3 mg/L, respectively. The patient was treated with activated charcoal, magnesium sulfate and aminophylline and could be discharged in good physical condition within 17 hours. This is the first report that provides toxicokinetic data and a corresponding pharmacodynamic effect after an intoxication with dipyridamole. [ABSTRACT FROM AUTHOR]

This paper presents the case that certain types of homeopathic medicine may represent a form of hormesis, that is, either pre- or post-conditioning hormesis. An example of a post-conditioning model by van Wijk and colleagues demonstrated successful enhancement of adaptive responses using below-toxic threshold doses (i.e. hormetic doses) of inducing agents when administered subsequent to a highly toxic chemical exposure, thus satisfying a basic experimental biomedical standard. Of note is that this model uses exposures within a measurable predicted hormetic range, unlike most forms of homeopathy. This experimental framework (along with a pre-conditioning model developed by Bellavite) provides a possible vehicle by which certain aspect(s) of homeopathy may be integrated into mainstream biomedical assessment and clinical practice. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate effectiveness of the poisoning severity score (PSS), Glasgow coma scale (GCS), and corrected QT (QTc) interval in predicting outcomes in acute organophosphates (OP) poisoning. Over a period of 2 years, 62 patients with OP poisoning were admitted to emergency department (ED) of Erciyes University Medical School Hospital. The age, sex, cause of contact, compound involved, time elapsed between exposure and admission to the ED, duration of hospital stay, and cardiac manifestations at the time of presentation were recorded. GCS and poisoning severity score (PSS) was calculated for each patient. Electrocardiogram (ECG) analysis included the rate, rhythm, ST-T abnormalities, conduction defects, and measurement of PR and QT intervals. Sixty-two patients with OP poisoning presented to our ED from January 2007 to December 2008 from which 54 patients were included in the study. The mean age was 34.1 ± 14.8 years. Of the cases, 53.7% were female. Twenty-six patients had a prolonged QTc interval. Mean PSS of men and women was 1.8 ± 1.0. No statistically significant correlation was found between the PSS and QTc intervals of the cases. A significant correlation was determined between the GCS and PSS of grade 3 and grade 4 cases. GCS is a parameter that helps clinician to identify advanced grade OP poisoning patients in the initial assessment in the ED. However, ECG findings, such as prolonged QTc interval, are not effective in determination of short-term prognosis and show no relationship with PSS. [ABSTRACT FROM AUTHOR]

The increasing demands on toxicology of large-scale risk assessment programmes for chemicals and emerging or expanding areas of chemical use suggest it is timely to review the toxicological toolbox. Like in clinical medicine, where an evidence-based medicine (EBM) is critically reviewing traditional approaches, toxicology has the opportunity to reshape and enlarge its methodology and approaches on the basis of compounded scientific knowledge. Such revision would have to be based on structured reviews of current practice, ie, assessment of test performance characteristics, mechanistic understanding, extended quality assurance, formal validation and the use of integrated testing strategies. This form of revision could optimize the balance between safety, costs and animal welfare, explicitly stating and, where possible, quantifying uncertainties. After a self-critical reassessment of current practices and evaluation of the thus generated information, such an evidence-based toxicology (EBT) promises to make better use of resources and to increase the quality of results, facilitating their interpretation. It shall open up hazard and also risk assessments to new technologies, flexibly accommodating current and future mechanistic understanding. An EBT will be better prepared to answer the continuously growing safety demands of modern societies. [ABSTRACT FROM AUTHOR]

Kampo (Japanese traditional herbal) medicines have been produced by combining multiple crude drugs, almost all of plant origin but with some of animal or mineral origin, and contain a great many substances. Their effect is a combination of the various interactions of the constituent substances, whether they are enhancing, synergistic or suppressive. Kampo medicine has an overall effect that is different from the combined effects of individual crude drugs, and several side effects such as anorexia, slight fever and nausea have been reported in the treatment of certain disorders and disease states with Kampo medicines. Among 210 medical formulations used in Japan, some relevant information on the clinical uses, pharmacology and toxicology of six manufactured Kampo medical formulations, Shosaikoto, Daisaikoto, Saikokeishito, Hochuekkito, Saibokuto and Saireito, containing Bupleurum root are reviewed. Studies of some potential interactions between Kampo medicine and western drugs are also considered. [ABSTRACT FROM AUTHOR]

The influence of lipopolysaccharide (LPS) and the nitric oxide synthase (iNOS) inhibitor – N-nitro-L-arginine methyl ester (L-NAME) – on the formation of N-nitrosodimethylamine (NDMA) by HepG2 cells, engineered to overexpress CYP2E1, was assessed and compared with data from empty vector-transfected cells. HepG2 cells produced significant amounts of NDMA but its levels in the culture media of cells overexpressing CYP2E1 was significantly lower than in empty-vector transfected cells. LPS increased the formation of NDMA, the expression of the iNOS and the production of the nitric oxide (NO). On the other hand, L-NAME significantly decreased NDMA levels. The results above indicate that the synthesis of NDMA by HepG2 cells depends on NO production. Furthermore, ethanol did not affect iNOS expression but decreased NDMA levels in CYP2E1-transfected cells below the detection limit. It is probably caused by the increased N-nitrosodimethylamine metabolism. In conclusion, HepG2 cells' ability to synthesize NO with simultaneous CYP2E1 activation may lead to an increase of carcinogenic products of the NDMA metabolism. [ABSTRACT FROM AUTHOR]

Econazole is an antifungal drug with different in vitro effects. However, econazole's effect on osteoblast-like cells is unknown. In human MG63 osteosarcoma cells, the effect of econazole on intracellular Ca2+ concentrations ([Ca2+]i) was explored by using fura-2. At a concentration of 0.1 μM, econazole started to cause a rise in [Ca2+]i in a concentration-dependent manner. Econazole-induced [Ca2+]i rise was reduced by 74% by removal of extracellular Ca2+. The econazole-induced Ca2+ influx was mediated via a nimodipine-sensitive pathway. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a [Ca2+]i rise, after which the increasing effect of econazole on [Ca2+]i was abolished. Pretreatment of cells with econazole to deplete Ca2+ stores totally prevented thapsigargin from releasing Ca2+. U73122, an inhibitor of phospholipase C, abolished histamine (an inositol 1,4,5-trisphosphate-dependent Ca2+ mobilizer)-induced, but not econazole-induced, [Ca2+]i rise. Econazole inhibited 76% of thapsigargin-induced store-operated Ca2+ entry. These findings suggest that in MG63 osteosarcoma cells, econazole increases [Ca2+]i by stimulating Ca2+ influx and Ca2+ release from the endoplasmic reticulum via a phospholipase C-independent manner. In contrast, econazole acts as a potent blocker of store-operated Ca2+ entry. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA) is a nephrotoxic mycotoxin produced by species of the genus Penicillium and Aspergillus that is present in food and feed as a natural contaminant. It modifies the immune function in animals and inhibits the proliferative response of lymphocytes in vitro. The toxic effect of OTA (0.5, 2, 20 μM) in lymphoproliferative response, natural killer (NK) cell activity, cytotoxic T lymphocytes (CTL) activity and macrophages' bacteriolytic capability was studied in vitro after 1 hour of treatment. The proliferative response of lymphocytes to concanavalin A and lipopolysaccharide was not affected by OTA; the cytotoxic activity of NK cells was dose-dependent decreased; the CTL activity was significantly decreased at the lowest concentration; the bacteriolytic activity of macrophages varied only slightly. These in vitro results reproduced, at least in part, some effects detected previously in vivo. The protein synthesis inhibition and the oxidative metabolism of OTA coupled to the prostaglandin synthesis are probably implicated in NK cells' toxicity, because the effects were reverted by the addition of phenylalanine or piroxicam to the culture medium. The induction of apoptosis seems to be the principal mechanism of action in the CTL effect. The intracellular concentration of OTA after 1 hour was analysed by HPLC and was found to be proportional to the quantity of OTA added to the culture medium for the three cell types; the presence of phenylalanine and piroxicam on the culture medium did not change the intracellular OTA concentration. [ABSTRACT FROM AUTHOR]

We examined the effect of all-trans retinoic acid (ATRA) on the androgen-induced growth of mouse seminal vesicles (SVs) in vivo and its mechanisms. Testosterone propionate (TP) alone or with ATRA was injected daily into adult castrated BALB/c mice. Injections of ATRA significantly inhibited the TP-induced growth of SVs in terms of wet weight and DNA synthesis by a pair of SVs evaluated by [3H]thymidine uptake. The bromodeoxyuridine labelling index showed that ATRA inhibited the proliferation of both epithelial and stromal cells. Immunoreactivity for retinoic acid receptor-α was found in the basal epithelial cells. Injections of ATRA affected neither 5α-reductase activity nor the expression of mRNAs for TGF-β1, 2 and 3 and TGF-β receptor 1 and 2 in the SVs. However, androgen receptor (AR) binding assays and Western blotting revealed a decrease in AR without a change in ligand-binding affinity. The present study showed that retinoid inhibited the androgen-induced growth of mouse SVs in vivo, and suggests that a decrease in AR is one of its mechanisms. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) is a known herbicide that causes acute cell injury by undergoing redox cycling. In previous reports, it has been reported that melatonin reduces PQ-induced hepatic toxicity in vivo, but, at the moment, there is no evidence that this effect occurs in this organ in vitro. In the present study we examined the effect of melatonin on PQ-induced oxidative damage in the liver using a hepatocyte suspension as a biological model. Preincubation of hepatocytes with melatonin (0.5, 1 or 2 mM), 30 min prior to PQ (10 mM) addition, prevented in a dose-and time-dependent manner the loss of viability, the leakage of lactate dehydrogenase, depletion of intra-cellular glutathione and malondialdehyde accumulation induced by the herbicide. Melatonin at the highest dose assayed (2 mM) completely prevented cell damage caused by PQ. These effects of melatonin are similar to those described in studies carried out in vivo. These results confirm that melatonin confers protection against PQ-induced hepatic oxidative stress and show that freshly isolated hepatocyte suspension is an adequate in vitro system for evaluating the cytoprotective effects of melatonin on oxidative injury caused by xenobiotics. [ABSTRACT FROM AUTHOR]

Septic arthritis and toxic synovitis are clinical conditions that can develop in association with various causes and involve symptoms such as pain, swelling, redness, sensitivity and restricted movement in the joint. A 42-year-old male presented to the emergency department with severe joint pain and nausea after injecting a 1-cc mixture of turpentine oil, eucalyptus oil, mint oil and thyme oil, which he purchased from an alternative medicine store, into his right knee with a syringe because of chronic knee pain. Ballottement and sensitivity were present at physical examination. Knee puncture yielded 60 cc of cloudy fluid. There was no growth in the material obtained. Improvement was observed following subsequent arthroscopic washing of the joint space and IV antibiotherapy, and the patient was discharged on day 21 of hospitalization with oral antibiotic and analgesic therapy. Intra-articular injection of foreign bodies into the knee joint space for therapeutic purposes, as in this case report, is a very rare occurrence, but may lead to potentially complicated arthritis. [ABSTRACT FROM PUBLISHER]

Sodium hypochlorite (NaClO) is used extensively as a disinfectant or bleaching agent. Most studies describe ingestion or inhalation route of this product with rare complication and fatalities. Despite global daily exposures, data about bleach injection is limited. Here we report intentional infusion of 20 mL, sodium hypochlorite 5% diluted in 500 mL normal saline 1.5 h prior admission. Clinical manifestation included local pain and edema. There were no laboratory abnormalities in the patient. Doppler sonography revealed thrombosis in superficial (antecubital and basilic) veins. Limb elevation, warm compress, and ibuprofen relived pain and edema after 3 days. [ABSTRACT FROM AUTHOR]

The article presents a clinical case of aminoglycoside-induced metabolic abnormalities involving a male patient, aged 72, who was hospitalized due to fever and symptoms of urinary tract infection lasting for five days. Urine and blood cultures showed him to be infected with Escherichia coli. The patient's renal proximal tubular function improved after stopping aminoglycoside treatment.