Pharmacokinetics and Tolerability of LC28-0126, a Novel Necrosis Inhibitor, After Multiple Ascending Doses: A Phase I Randomized, Double-blind, Placebo-controlled Study in Healthy Male Subjects.

PURPOSE: LC28-0126 is a reactive oxygen species scavenger being developed for the treatment of various conditions caused by oxidative stress, such as oral mucositis, graft-versus-host disease, and lethal reperfusion injury in acute myocardial infarction. The aim of this study was to assess the tolerability and pharmacokinetic properties of LC28-0126 with multiple IV administrations in healthy male subjects. METHODS: A dose-block-randomized, double-blind, placebo-controlled, multiple ascending-dose study was conducted. Subjects received 3-, 10-, 20-, or 30-mg doses of LC28-0126 or inactive control vehicle, infused over 30 min, once daily for 7 days. Blood and urine samples were collected for pharmacokinetics assessment. Tolerability was assessed by the documentation of adverse events, including abnormal findings on physical examination, vital sign measurements, blood oxygen saturation monitoring, 12-lead ECG, continuous ECG monitoring, and clinical laboratory testing. FINDINGS: A total of 32 subjects completed the study. After multiple dosing, the plasma concentration of LC28-0126 showed a steep decrease after infusion, followed by slow elimination. Systemic exposure of LC28-0126 was increased proportionally to doses ranging from 3 to 30 mg. The accumulation ratios were 2.58-2.79 on multiple dosing. The fractions excreted unchanged in urine were found to be <5%. All reported drug-related adverse events were injection-site reactions, and no serious adverse events were reported. IMPLICATIONS: Multiple administrations of LC28-0126 exhibited a dose-proportional pharmacokinetic profile and were well tolerated at a dose range of 3-30 mg. ClinicalTrials.gov identifier: NCT03196804.

Computer and electronic duster spray inhalation (huffing) injuries managed at emergency departments.

Background: Computer and electronic duster sprays contain halogenated hydrocarbon gases. Intentional inhalation of computer and electronic duster sprays to induce intoxication, also known as huffing, may cause serious adverse effects and even death.Objectives: Describe computer and electronic duster spray inhalation-related injuries managed at United States (US) emergency departments (EDs).Methods: Data were obtained from the National Electronic Injury Surveillance System (NEISS), a database of consumer product-related injuries collected from the EDs of approximately 100 hospitals in the US. Cases were computer and electronic duster spray inhalation-related injuries included in NEISS during 2001-2017. The distribution by selected variables was determined for the resulting cases as well as a weighted estimate.Results: A total of 320 computer and electronic duster spray inhalation-related injuries were identified, resulting in a national estimate of 14,715 (95% confidence interval 11,120-18,311) such injuries. The annual estimated number of injuries remained low during 2001-2008 then increased during 2008-2017. Of the estimated injury patients, 3.2% were aged 6-12 years, 20.3% 13-19 years, and 76.5% 20-59 years; 65.4% of the patients were male. The disposition of the patient was 71.4% treated and examined and released, 6.9% treated and transferred, 11.6% treated and admitted or hospitalized, 0.7% held for observation, and 8.7% left without being seen.Conclusion: This study suggests that computer and electronic duster spray inhalation (huffing) may be an increasing issue of which hospital EDs and other clinicians should be aware. The pattern of injuries observed may be useful for targeting education, prevention and management activities.

El escándalo de los productos sanitarios y el problema de los perfluorocarbonados líquidos / The health products scandal and the problem of perfluorocarbon fluids

No disponible

Contaminants in Atlantic walruses in Svalbard part 1: Relationships between exposure, diet and pathogen prevalence.

This study investigated relationships between organohalogen compound (OHC) exposure, feeding habits, and pathogen exposure in a recovering population of Atlantic walruses (Odobenus rosmarus rosmarus) from the Svalbard Archipelago, Norway. Various samples were collected from 39 free-living, apparently healthy, adult male walruses immobilised at three sampling locations during the summers of 2014 and 2015. Concentrations of lipophilic compounds (polychlorinated biphenyls, organochlorine pesticides and polybrominated diphenyl ethers) were analysed in blubber samples, and concentrations of perfluoroalkylated substances (PFASs) were determined in plasma samples. Stable isotopes of carbon and nitrogen were measured in seven tissue types and surveys for three infectious pathogens were conducted. Despite an overall decline in lipophilic compound concentrations since this population was last studied (2006), the contaminant pattern was similar, including extremely large inter-individual variation. Stable isotope ratios of carbon and nitrogen showed that the variation in OHC concentrations could not be explained by some walruses consuming higher trophic level diets, since all animals were found to feed at a similar trophic level. Antibodies against the bacteria Brucella spp. and the parasite Toxoplasma gondii were detected in 26% and 15% of the walruses, respectively. Given the absence of seal-predation, T. gondii exposure likely took place via the consumption of contaminated bivalves. The source of exposure to Brucella spp. in walruses is still unknown. Parapoxvirus DNA was detected in a single individual, representing the first documented evidence of parapoxvirus in wild walruses. Antibody prevalence was not related to contaminant exposure. Despite this, dynamic relationships between diet composition, contaminant bioaccumulation and pathogen exposure warrant continuing attention given the likelihood of climate change induced habitat and food web changes, and consequently OHC exposure, for Svalbard walruses in the coming decades.

Mechanisms of Cardioprotection of Halogenated Agents During Extracorporeal Circulation in Cardiac Surgery.

The implementation of cardioprotective strategies involving pre-, intra-, and postoperative interventions is key during cardiac surgery requiring extracorporeal circulation (ECC). The primary goal of this study was to review the physiopathology and protection strategies against myocardial damage secondary to ECC during cardiac surgery. The administration halogenated anesthetics for cardiac anesthesia is common place due to their well-known cardioprotective effects and their capacity to ensure hypnosis. An optimal myocardial protection strategy requires that a comprehensive approach should be adopted to cover pre-, intra-, and post-operative interventions. Pre-conditioning and post-conditioning share numerous pathways, mainly based on mitochondrial signaling, antiapoptotic pathways, and reduced inflammatory mediators. However, volatile anesthetic can also be administered during ECC, in which mechanism of action has been scantly investigated, during this period and its biology is still unknown.

Halogenated Agents and Cardiovascular Surgery: Has Mortality Really Decreased?

Halogenated anesthetic agents (desflurane, isoflurane and sevoflurane) may have cardioprotective properties at therapeutic doses against myocardial intraoperative ischemia-reperfusion injury. Cardioprotection mechanisms are related to mitochondrial and anti-apoptotic signaling pathways. Experimentals and human studies have proven that their use may reduce morbidity and mortality in the setting of cardiac surgery, including a reduction in myocardial infarct size and mechanical ventilation needs. In contrast, total intra-venous propofol based anesthesia may be detrimental. In the present review, we show the rationale for the perioperative use of halogenated anesthetics based on mechanisms of action, experimental research and human studies. Considerations and major concerns regarding their use, the present evidence for their use in other areas, such as major non-cardiac surgery and intensive care unit patients, and future perspectives are also discussed.

An approach for the development of emergency response levels for halogenated hydrocarbons.

Emergency exposure guidance levels have been developed for many halogenated hydrocarbons. These can be employed in the event of accidental releases or terrorist actions. However, for a chemical release involving a substance without existing guidance levels, there is a need to be able to develop one rapidly. Two data sources are available, the Acute Exposure Guideline Levels (AEGL) and Emergency Response Guideline Levels (ERPG). The subset of halogenated hydrocarbons and related substances included in these data sources represent 30 chemicals and 41 risk assessments. The ratios for serious toxicity/annoyance level and for potential lethality/serious toxicity were calculated. On reviewing the results, the geometric means provided the best basis for extrapolation. When the geometric means of the ratios of ERPG-3/ERPG-2 and AEGL-3/AEGL-2 were calculated their combined mean was 4.40. The geometric standard deviation for the combined data set was 2.00 suggesting the data were homogeneous. Likewise, calculation of the geometric means for ERPG-2/1 and AEGL-2/1 the combined ratio was 3.93. The geometric standard deviation for the combined set was 1.46, again suggesting homogeneity of the data. The review described in this paper confirmed that the time default "n" values of 3 and 1 (ten Berge et al., 1986) are appropriate for extrapolation to shorter and longer exposure times, respectively.

Catechins in tea suppress the activity of cytochrome P450 1A1 through the aryl hydrocarbon receptor activation pathway in rat livers.

Polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) develop various adverse effects through activation of an aryl hydrocarbon receptor (AhR). The suppressive effects of brewed green tea and black tea on 3-methylcholanthrene (MC)-induced AhR activation and its downstream events were examined in the liver of rats. Ad-libitum drinking of green tea and black tea suppressed MC-induced AhR activation and elevation of ethoxyresorufin O-deethylase activity in the liver, whereas the teas themselves did not induce them. Tea showed a suppressive fashion on the expression of cytochrome P450 1A1 (CYP1A1). Tea suppressed the AhR activation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) ex vivo. A part of catechins and theaflavins was present in plasma and liver as conjugated and intact forms. The results of this study suggested that active component(s) of tea are incorporated in the liver and suppress the activity of CYP1As through the AhR activation pathway.

Persistent organic pollutants and male reproductive health.

Environmental contaminants such as persistent organic pollutants (POPs) are man-made bioaccumulative compounds with long half-lives that are found throughout the world as a result of heavy use in a variety of consumer products during the twentieth century. Wildlife and animal studies have long suggested adverse effects of exposure to these compounds on human reproductive health, which, according to the endocrine disrupter hypothesis, are ascribed to the compounds' potential to interfere with endocrine signaling, especially when exposure occurs during certain phases of fetal and childhood development. An extensive number of epidemiological studies have addressed the possible effects of exposure to POPs on male reproductive health, but the results are conflicting. Thus far, most studies have focused on investigating exposure and the different reproductive health outcomes during adulthood. Some studies have addressed the potential harmful effects of fetal exposure with respect to malformations at birth and/or reproductive development, whereas only a few studies have been able to evaluate whether intrauterine exposure to POPs has long-term consequences for male reproductive health with measurable effects on semen quality markers and reproductive hormone levels in adulthood. Humans are not exposed to a single compound at a time, but rather, to a variety of different substances with potential divergent hormonal effects. Hence, how to best analyze epidemiological data on combined exposures remains a significant challenge. This review on POPs will focus on current knowledge regarding the potential effects of exposure to POPs during fetal and childhood life and during adulthood on male reproductive health, including a critical revision of the endocrine disruption hypothesis, a comment on pubertal development as part of reproductive development and a comment on how to account for combined exposures in epidemiological research.

Effects of polychlorobiphenyls, polybromodiphenylethers, organochlorine pesticides and their metabolites on vitamin A status in lactating grey seals.

Polychlorobiphenyls (PCBs), polybromodiphenylethers (PBDEs) and organochlorine pesticides (OCPs), such as dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene (HCB), are considered as endocrine disruptors in laboratory and wild animals. This study investigated whether these compounds and their hydroxylated metabolites (HO-PCBs and HO-PBDEs) may affect the homoeostasis of vitamin A, a dietary hormone, in the blubber and serum of twenty lactating grey seals sampled at early and late lactation on the Isle of May, Scotland. The effect of naturally produced compounds such as the methoxylated (MeO)-PBDEs was also examined. Vitamin A levels in inner blubber (37±9 µg/g wet weight (ww) and 92±32 µg/g ww at early and late lactation, respectively) and serum (408±143 and 390±98 ng/ml at early and late lactation, respectively) appeared to be positively related to ΣPCBs, ΣPBDEs and several individual PCB and PBDE congeners in inner blubber and serum. These findings may suggest enhanced mobilisation of hepatic retinoid stores and redistribution in the blubber, a storage site for vitamin A in marine mammals. We have also reported that serum concentrations of ΣHO-PCBs and 4-OH-CB107 tended to increase with circulating vitamin A levels. Although the direction of the relationships may sometimes differ from those reported in the literature, our results are in agreement with previous findings highlighting a disruption of vitamin A homoeostasis in the blubber and bloodstream following exposure to environmental pollutants. The fact that vitamin A and PCBs appeared to share common mechanisms of mobilisation and transfer during lactation in grey seals (Debier et al., 2004; Vanden Berghe et al., 2010) may also play a role in the different relationships observed between vitamin A and lipophilic pollutants.

On mechanisms of reactive metabolite formation from drugs.

Idiosyncratic adverse drug reactions (IADRs) cause a broad range of clinically severe conditions of which drug induced liver injury (DILI) in particular is one of the most frequent causes of safety-related drug withdrawals. The underlying cause is almost invariably formation of reactive metabolites (RM) which by attacking macromolecules induc eorgan injuries. Attempts are being made in the pharmaceutical industry to lower the risk of selecting unfit compounds as clinical candidates. Approaches vary but do not seem to be overly successful at the initial design/synthesis stage. We review here the most frequent categories of mechanisms for RM formation and propose that many cases of RMs encountered within early ADME screening can be foreseen by applying chemical and metabolic knowledge. We also mention a web tool, SpotRM, which can be used for efficient look-up and learning about drugs that have recognized IADRs likely caused by RM formation.

Inhalation cancer risk associated with exposure to complex polycyclic aromatic hydrocarbon mixtures in an electronic waste and urban area in South China.

Atmospheric particulate matter samples were collected from May 2010 to April 2011 in a rural e-waste area and in Guangzhou, South China, to estimate the lifetime inhalation cancer risk from exposure to parent polycyclic aromatic hydrocarbons (PAHs), high molecular weight PAHs (MW 302 PAHs), and halogenated PAHs (HPAHs). Seasonal variations in the PAH concentrations and profiles within and between the e-waste and urban areas indicated different PAH sources in the two areas. Benzo[b]fluoranthene, benzo[a]pyrene, dibenz[ah]anthracene, and dibenzo[al]pyrene made the most significant contribution to the inhalation cancer risk. MW 302 PAHs accounted for 18.0% of the total cancer risk in the e-waste area and 13.6% in the urban area, while HPAHs made a minor contribution (<0.1%) in both the areas. The number of lifetime excess lung cancers due to exposure to parent PAHs, MW 302 PAHs, and HPAHs ranged from 15.1 to 1198 per million people in the e-waste area and from 9.3 to 737 per million people in Guangzhou. PAH exposure accounted for 0.02 to 1.94% of the total lung cancer cases in Guangzhou. On average, the inhalation cancer risk in the e-waste area was 1.6 times higher than in the urban area. The e-waste dismantling activities in South China led to higher inhalation cancer risk due to PAH exposure than the urban area.

Sex-related differences in renal toxicodynamics in rodents.

INTRODUCTION: An issue yet to be addressed, in the investigation of the xenobiotic toxicity, is a detailed characterization of the sex differences in toxicological responses. The 'sex issue' is particularly significant in nephrotoxicology as the kidney is a relevant target organ for xenobiotics and few studies have approached this subject in the past. There is a strong need to improve our understanding regarding the influence of sex in toxicology, given their increased requirement to establish the limits of exposure to chemicals in the environment and at work. AREAS COVERED: In this review, the authors provide the reader with the current knowledge of sex differences in kidney toxicity for rats and mice. To make the review easier to consult, these studies have been organized according to the class of xenobiotic. EXPERT OPINION: From the analysis of the present knowledge emerges a dramatic need for information on sex differences in xenobiotics toxicity. Although animals are reasonably good predictors of adverse renal effects in patients, there is need to identify alternative methods (e.g. in vitro/ex vivo) to better study sex differences in organ toxicity.

Optimal design for the precise estimation of an interaction threshold: the impact of exposure to a mixture of 18 polyhalogenated aromatic hydrocarbons.

Traditional additivity models provide little flexibility in modeling the dose-response relationships of the single agents in a mixture. While the flexible single chemical required (FSCR) methods allow greater flexibility, its implicit nature is an obstacle in the formation of the parameter covariance matrix, which forms the basis for many statistical optimality design criteria. The goal of this effort is to develop a method for constructing the parameter covariance matrix for the FSCR models, so that (local) alphabetic optimality criteria can be applied. Data from Crofton et al. are provided as motivation; in an experiment designed to determine the effect of 18 polyhalogenated aromatic hydrocarbons on serum total thyroxine (T(4)), the interaction among the chemicals was statistically significant. Gennings et al. fit the FSCR interaction threshold model to the data. The resulting estimate of the interaction threshold was positive and within the observed dose region, providing evidence of a dose-dependent interaction. However, the corresponding likelihood-ratio-based confidence interval was wide and included zero. In order to more precisely estimate the location of the interaction threshold, supplemental data are required. Using the available data as the first stage, the Ds-optimal second-stage design criterion was applied to minimize the variance of the hypothesized interaction threshold. Practical concerns associated with the resulting design are discussed and addressed using the penalized optimality criterion. Results demonstrate that the penalized Ds-optimal second-stage design can be used to more precisely define the interaction threshold while maintaining the characteristics deemed important in practice.

AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents.

RATIONALE: The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia. OBJECTIVE: These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs). METHODS: The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential. RESULTS: AVE1625 (1, 3, and 10 mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects. CONCLUSIONS: These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments.

Polyhalogenated aromatic hydrocarbons and metabolites: Relation to circulating thyroid hormone and retinol in nestling bald eagles (Haliaeetus leucocephalus).

Polyhalogenated aromatic hydrocarbons are global contaminants that are often considered to be endocrine disruptors and include 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p'-DDE), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). The present study examined these compounds and their hydroxylated metabolites or analogues and relationships with circulating thyroid hormones and retinols in plasma from nestling and adult bald eagles in British Columbia, Canada, and California, USA. We also compared our results with published data. Thyroxine (T4) decreased with summation operatorPCB and CB153 in nestling bald eagles, which was congruent with results from nine of 14 other published avian laboratory and field studies. Free thyroid hormone levels also decreased with CB-153 and hydroxylated PCBs (OH-PCBs). Retinol increased with CB118 and CB180 in nestling eagles, decreased with OH-PCBs in a subset of nestlings, and decreased in 7 of 12 PCB published studies. Thyroxine decreased with p,p'-DDE for nestlings and with data reported in one of five other published studies. In our samples, plasma retinol, triiodothyronine (T3), and T4 were independent of summation operatorPBDEs, whereas summation operatorOH-PBDEs were weakly but significantly correlated with increases in T3 and retinol. Adult bald eagles showed no relationship between contaminants and thyroid hormones, which is consistent with other studies of long-lived birds, perhaps because adult birds have time to adjust to contaminant levels. Measurement of circulating thyroid hormones appears to be a more useful biomarker than retinols, given the more consistent response of T4 to PCBs here and reported in the literature. We conclude that current environmental exposures to PCBs in British Columbia and in southern California are associated with significant decreases in T4, suggesting a potential negative effect on the endocrine system of nestling bald eagles.

Environmental agents involved in the cause of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an immune mediated chronic cholestatic liver disease with a slowly progressive course It is a universal disease with a reported latitudinal gradient in prevalence and incidence. The aetiology of primary biliary cirrhosis is still unknown. It is characterized by a 60% concordance in monozygotic twins and is considered an autoimmune disease because of several features common to other autoimmune conditions and the relatively homogeneous serological and biochemical features. However geoepidemiological and clinical studies strongly imply that environmental factors also play an important role. It is accepted that the disease is clearly the result of a combination of genetic and environmental factors. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics. This review will attempt to place such factors in perspective.

Cevipabulin (TTI-237): preclinical and clinical results for a novel antimicrotubule agent.

Antimitotic agents are among the most effective drugs for the treatment of solid tumors and metastatic cancer. These drugs promote cell death by interfering with the crucial structural and regulatory function of microtubules in cells. Most of the agents of clinical relevance are natural products or semisynthetic derivatives thereof, and they fall into two major classes: microtubule stabilizers such as the taxanes, which enhance tubulin polymerization, and microtubule destabilizers such as the Vinca alkaloids, which lead to the depolymerization of existing microtubules. While these drugs are effective in inhibiting the progression of certain types of tumors, their utility is limited in part by incomplete tumor responses and/or significant side effects. In addition, inherent resistance is encountered in many tumor types, or acquired resistance may occur as a result of multiple cycles of therapy. Cevipabulin (TTI-237) is a novel, small synthetic molecule with an unusual biological mode of action. It appears to bind at the vinca site, but exhibits some properties similar to those of taxane-site ligands, such as enhancing tubulin polymerization. The compound works against a variety of tumors, including those resistant to paclitaxel and vincristine. Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development.