In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171–578 mg/kg, and increased in over proportion to the EH dose in the range of 578–1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619–1300 times of the proposed clinical equivalent dose).

Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic side effects are known to be more likely to occur in women. In the present study, we investigated and tested the hypothesis that olanzapine induces oxidative stress in the hypothalamus and induces metabolic side effects. We also examined its association with sex differences. Olanzapine was administered intraperitoneally to male and female C57BL/6 mice, and the expression levels of oxidative stress-responsible genes in the hypothalamus and cerebral cortex were measured by qRT-PCR. In addition, olanzapine was administered intraperitoneally to C57BL/6 and Nrf2 KO mice, and the expression level of total glutathione was measured. Gene expressions induced by the Keap1-Nrf2-regulated system showed different responses to olanzapine for each gene. Under the conditions of this experiment, cystine-glutamate transporter was decreased although heme oxygenase-1 and γ-glutamylcysteine synthetase were increased. It was also clear that these responses were not hypothalamus-specific. Long-term feeding with olanzapine suppressed weight gain in males but not females. No glucose intolerance was observed at 13 weeks of administration. Furthermore, deaths occurred only in females. In conclusion, this study failed to provide evidence that olanzapine induces oxidative stress in a hypothalamic-specific manner. Instead, sex differences were observed in response to long-term and high-dose olanzapine administration, suggesting that individual susceptibility to olanzapine toxicity occurred in female mice.

Acetamiprid (ACE), a neonicotinoid chemical, is widely used as a pesticide due to its rapid insecticidal activity. Although neonicotinoids exert very low toxicity in mammals, the effects of early exposure to neonicotinoids on the adult central nervous system are poorly understood. This study investigated the effects of ACE exposure in early life on brain function in adult mice. We exposed male C57BL/6N mice to ACE (10 mg/kg) orally when they were two (postnatal lactation) or 11 weeks old (adult). We examined the effects of ACE on the central nervous system using the mouse behavioral test battery, consisting of the open field test, light/dark transition test, elevated plus-maze test, contextual/cued fear conditioning test, and pre-pulse inhibition test at 12–13 weeks old. In the mouse behavioral test battery, learning memory abnormalities were detected in the mature treatment group. In addition, learning memory and emotional abnormalities were detected in the postnatal lactation treatment group. These results suggest that the behavioral effects of postnatal lactation treatment with ACE were qualitatively different from the behavioral abnormalities in the mature treatment group.

Products used in daily life contain multiple chemicals capable of inducing endocrine disruption in animals, including humans. One such typical substance is bisphenol A (BPA). BPA has been widely used in epoxy resins and polycarbonate plastics and can exert several adverse effects. Furthermore, given their structural similarity to BPA, phenolic analogs of BPA, i.e., synthetic phenolic antioxidants (SPAs), are considered to exhibit similar toxicity; however, the effects of early SPA exposure on the adult central nervous system remain poorly clarified. In the present study, we aimed to evaluate and compare the neurobehavioral effects of early life exposure to BPA and two selected SPAs, 4,4'-butylidenebis (6-tert-butyl-m-cresol) (BB) and 2,2'-methylenebis (6-tert-butyl-p-cresol) (MB). We exposed mice to low levels of these chemicals through drinking water during prenatal and postnatal periods. Subsequently, we examined the adverse effects of these chemicals on the central nervous system using a mouse behavioral test battery, comprising the open field test, light/dark transition test, elevated plus-maze test, contextual/cued fear conditioning test, and prepulse inhibition test, at 12-13 weeks old. Based on the behavioral analysis, SPAs, like BPA, may cause affective disorders even at low doses, although qualitative differences were noted in anxiety-related behaviors. In conclusion, our findings could be valuable for clarifying the potential adverse developmental risks of SPA exposure in early life.

In China, the extensive use of the pesticide chlorfenapyr has led to an increase in chlorfenapyr poisoning. However, there are limited reports on chlorfenapyr poisoning, and most of them are fatal cases. This study retrospectively analyzed four patients admitted to the emergency room after chlorfenapyr intake and detected different concentrations of chlorfenapyr in their plasma. Among them, one patient died and three patients survived. Case 1 suffered respiratory and circulatory failure with a deep coma shortly after oral administration of 100 mL of a the chlorfenapyr-containing mixture and died 30 min after admission. Case 2 experienced transient nausea and vomiting after oral administration of chlorfenapyr (50 mL). The patient had normal laboratory results and was discharged with no further treatment. Case 3 developed nausea and vomiting and a light coma after taking 30 mL of chlorfenapyr orally. He underwent blood perfusion and plasma exchange in the intensive care unit (ICU) and was discharged with recovery. A two-week follow-up visit, however, revealed hyperhidrosis. Case 4 (advanced age with severe underlying disease) developed a light coma after oral intake of 30 mL of chlorfenapyr. Subsequently, pulmonary infection and gastrointestinal bleeding were developed. The patient experienced blood perfusion and mechanical ventilation in the ICU and finally survived after treatment. The present study provides the basic information, plasma concentration of toxins, onset of poisoning and treatment process of the four patients mentioned above, providing novel insights into the clinical diagnosis and treatment of chlorfenapyr poisoning.