Acute exposure and biomarkers assessment in rainbow trout exposed to selected pharmaceuticals.

Pharmaceuticals released from municipal effluents discharges pose a risk to aquatic organisms. The toxicity of 5 pharmaceuticals with distinct therapeutic actions were assessed in rainbow trout: olanzapine (antipsychotic), erythromycin (antibiotic), mycophenoate (immunosuppression), pinaverium (anti-inflammatory) and trazodone (sedative). Juveniles were exposed to these drugs for 96 h at concentrations between 64 µg/L up to 40 mg/L to reach lethality. Survival was determined and a suite of biomarkers was analyzed for drug biotransformation, oxidative stress/damage and metabolic activity at sublethal concentrations. The data revealed the following toxicity: olanzapine >trazodone>mycophenolate>pinaverium∼erythromycin based on mortality. The data also revealed that toxicity was associated to mass, pKa and hydrophobicity and the following sublethal effects: GST, LPO and DNA strand breaks. Pharmaceuticals with lower molecular weight, physiological pKa, moderate hydrophobicity, low biotransformation and DNA strand breaks were generally more toxic to fish. However, this should be considered as a general guide in identifying toxic pharmaceuticals in non-target organisms.

Geopersonality of Preventable Death in the United States: Anger-Prone States and Opioid Deaths.

BACKGROUND: Opioid overdoses have reached epidemic levels in the United States and have clustered in Northeastern and "Rust Belt" states. Five Factor Model (FFM) personality traits also vary at the state level, with anger-prone traits clustered in the Northeast region. This study tested the hypothesis that state-level anger proneness would be associated with a greater increase in rates of opioid overdose death. METHODS: This was a secondary analysis of state-level data on FFM traits, opioid overdose deaths, and other classes of preventable death. Robust mixed models tested whether change in rates of opioid overdose death from 2008 to 2016 was moderated by state-level anger proneness. RESULTS: State-level anger proneness was significantly associated with greater increases in rates of opioid overdose deaths (B = 1.01, standard error = 0.19, P < .001, 95% confidence interval: 0.63-1.39). The slope of increase in opioid overdose death rates was 380% greater in anger-prone states and held after adjustment for potential confounders such as state-level prevalence of major depressive disorder, number of mental health facilities, and historical patterns of manufacturing decline. A similar pattern was observed between state-level anger proneness and benzodiazepine overdose deaths but was not significant for the latter after adjustment for potential confounders. CONCLUSION: These findings suggest that states characterized as more anger prone have experienced greater increases in opioid overdose deaths.

Sociodemographic factors, prescription history and opioid overdose deaths: a statewide analysis using linked PDMP and mortality data.

BACKGROUND: Opioid overdose deaths have continued to rise in Tennessee (TN) with fentanyl emerging as a major contributor. Current data are needed to identify at-risk populations to guide prevention strategies. We conducted a large statewide observational study among TN adult decedents (2013-2016) to evaluate the association of sociodemographic factors and prescribing patterns with opioid overdose deaths. METHODS: Among drug overdose decedents identified using death certificate data (n = 5483), we used logistic regression to estimate adjusted odds ratios and 95% confidence intervals for characteristics associated with prescription opioid (PO) (excluding fentanyl), fentanyl, and heroin alone overdoses. Among decedents linked to TN's Prescription Drug Monitoring Database using deterministic algorithms, we obtained prescription history in the year before death (n = 3971), which was evaluated by type of overdose using descriptive statistics. RESULTS: Younger, non-White decedents had lower odds of PO overdose, while females and benzodiazepines as a contributing cause were associated with increased odds of PO overdose. Younger age, Non-Hispanic Black race/ethnicity, greater than high school education, and cocaine/other stimulants as a contributing cause were associated with increased odds of fentanyl or heroin overdoses. Over 55% of PO, 39.2% of fentanyl, and 20.7% of heroin overdoses had an active opioid prescription at death. For PO, fentanyl, and heroin decedents, respectively, 46.0%, 30.5%, and 26.2% had an active prescription for benzodiazepines at death. CONCLUSIONS: Prescription opioid overdose deaths were associated with different sociodemographic profiles and prescribing history compared to fentanyl and heroin overdose deaths in TN. Data can guide prevention strategies to reduce opioid overdose mortality.

Reaction of diazepam and related benzodiazepines with chlorine. Kinetics, transformation products and in-silico toxicological assessment.

In this work, the reaction of four benzodiazepines (diazepam, oxazepam, nordazepam and temazepam) during water chlorination was studied by means of liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-QTOF-MS). For those compounds that showed a significant degradation, i.e. diazepam, oxazepam and nordazepam, parameters affecting to the reaction kinetics (pH, chlorine and bromide level) were studied in detail and transformation products were tentatively identified. The oxidation reactions followed pseudofirst-order kinetics with rate constants in the range of 1.8-42.5 M-1 s-1, 0.13-1.16 M-1 s-1 and 0.04-20.4 M-1 s-1 corresponding to half-life values in the range of 1.9-146 min, 1.8-87 h and 2.5-637 h for oxazepam, nordazepam and diazepam, respectively, depending of the levels of studied parameters. Chlorine and pH affected significantly the reaction kinetics, where an increase of the pH resulted into a decrease of the reaction rate, whereas higher chlorine dosages led to faster kinetics, as expected in this case. The transformation of the studied benzodiazepines occurs mainly at the 1,4-diazepine 7-membered-ring, resulting in ring opening to form benzophenone derivatives or the formation of a 6-membered pyrimidine ring, leading to quinazoline derivatives. The formation of these by-products was also tested in real surface water samples observing kinetics of oxazepam degradation slower in river than in creek water, while the degradation of the two other benzodiazepines occurred only in the simpler sample (creek water). Finally, the acute and chronical toxicity and mutagenicity of precursors and transformation products were estimated using quantitative structure-activity relationship (QSAR) software tools: Ecological Structure Activity Relationships (ECOSAR) and Toxicity Estimation Software Tool (TEST), finding that some transformation products could be more toxic/mutagenic than the precursor drug, but additional test would be needed to confirm this fact.

Fertility and Embryo-Fetal Development Assessment in Rats and Rabbits with Evacetrapib: A Cholesteryl Ester Transfer Protein Inhibitor.

BACKGROUND: The purpose of these studies was to evaluate the effects of evacetrapib on male and female fertility and on embryo-fetal development (EFD). METHODS: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was administered daily by oral gavage starting 2 weeks (for female) or 4 weeks (for male) before mating, during cohabitation, and until necropsy in the male rat fertility study or through gestation day (GD) 17 in the female rat combined fertility/EFD study. For rabbit EFD studies, animals were dosed from GDs 7 to 19 or from 1 week before mating through GD 19. Dose levels of evacetrapib ranged from 60 to 600 mg/kg for rats and from 1 to 100 mg/kg/day for rabbits. RESULTS: Parental findings in rats included decreased body weight and food consumption and moribund euthanasia in animals given 600 mg/kg/day and decreased food consumption at 300 mg/kg/day. There were no adverse effects on estrus cycling, fertility indices, sperm parameters, maternal reproductive parameters, male reproductive tissue, or fetal viability, growth, or external/visceral morphology. An increase in the incidence of 14th rudimentary ribs, a minor, transient variation considered nonadverse, was the only significant developmental finding in rats given 600 mg/kg/day. Slight decreases in body weight and food consumption at 100 mg/kg/day were the only maternal effects observed in rabbits with no adverse developmental effects noted. CONCLUSION: No adverse effects on fertility or EFD were observed in rats at doses up to 600 mg/kg/day and no adverse effects on EFD were noted in rabbits at doses up to 100 mg/kg/day. Birth Defects Research 109:513-527, 2017. © 2017 Wiley Periodicals, Inc.

Prenatal and Postnatal Assessment in Rabbits with Evacetrapib: A Cholesteryl Ester Transfer Protein Inhibitor.

BACKGROUND: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was under development for the treatment of cardiovascular (CV) disease. The purpose of this pre-postnatal study in rabbits was to evaluate the effects of evacetrapib on pregnancy, parturition, and lactation of the maternal animals and on the growth, viability, development, and reproductive performance of the first filial (F1) offspring. The rabbit is considered a relevant species for toxicity testing with evacetrapib as it demonstrates significant CETP expression, whereas mice and rats do not express significant levels of CETP. METHODS: Evacetrapib was administered daily by oral gavage from gestation day (GD) 7 through lactation day (LD) 41 at dose levels of 0, 10, 30, and 100 mg/kg/day. RESULTS: There were no adverse effects on maternal survival, clinical signs, gestation length, parturition, and litter size. There were no effects on F1 clinical observations, body weight, sexual maturation, conditioned eye blink, functional observational battery, or pathology findings. Treatment-related decreases in F1 postnatal survival and equivocal reductions in F1 mating, fertility, and copulation/conception indices without changes in sperm parameters or pathology of reproductive organs were noted in F1 animals. CONCLUSIONS: The maternal no observed adverse effect level (NOAEL) after evacetrapib administration in female rabbits was 100 mg/kg/day. Based on the decreased F1 postnatal survival and equivocal changes in F1 fertility, the NOAEL for F1 neonatal developmental was 30 mg/kg/day. Birth Defects Research 109:486-496, 2017.© 2017 Wiley Periodicals, Inc.

A 3-Year Comparison of Overdoses Treated in a Military Emergency Department-Complications, Admission Rates, and Health Care Resources Consumed.

BACKGROUND: Drug overdose has become a leading cause of death in the United States and is a growing issue in civilian and military populations. Increasing prescription drug misuse and poisonings translate into greater utilization of medical resources. Our objective was to describe the incidences of overdoses and their associated events and outcomes following emergency department consult. METHODS: We performed a retrospective cohort study on cases evaluated in 2 military hospital emergency departments over 3 years. Subjects were identified using International Classification of Diseases, 9th Revision codes 960-970. Variables collected included demographics, military service, method of arrival, vital signs, clinical complications, and hospital admission, if overdose was documented as intentional or unintentional and drug ingested. RESULTS: Over 3 years, 342 overdoses were treated. Mean age was 35 ± 19 and gender was 53% female. 47% were active duty and 32% were dependents. 21% of overdoses involved benzodiazepines and 20% opioids. Active duty and benzodiazepine overdoses were more likely to arrive by ambulance (p = 0.0006, p = 0.03), were more likely to have overdosed intentionally (p = 0.02, p = 0.009), and were more likely to be admitted (p = 0.04, p = 0.007). Active duty had a longer length of stay (p = 0.02). CONCLUSION: Overdoses involving the active duty population and benzodiazepines consume greater military health care resources than other overdoses.

On hygienic regulation of benzodiazepines.

Experimental studies covered risk of possible toxic influence by medications - derivatives of 1.4-benzodiazepine - in single and multiple intake by intragastric way, inhalation and skin application. The authors give recommendations on hygienic regulation of 1.4-benzodiazepine derivatives - alprazolam, diazepam, mezapam and nozepam. The study results served as a base for specifying approximate safe level of exposure to alprazolam at level of 0.1 mg/m³, diazepam - 0.2 mg/m³, mezapam - 0.3 mg/m³ and nozepam at level of 1.0 mg/m³ in the air of workplace.