Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.

Ceftazidime induced liver injury

A 65-year-old woman with type II diabetes mellitus complicated by non-healing ulcers with recurrent osteomyelitis was admitted for progression of cellulitis after treatment failure with an outpatient course of amoxicillin-clavulanate. She was found to have persistent osteomyelitis and started on ceftazidime for a culture documented Pseudomonas aeruginosa infection. After two parenteral doses, she had a rapid rise in liver function tests (LFTs) in a hepatocellular pattern. Due to rapid identification, all medications with potential hepatotoxicity, including ceftazidime, were discontinued and the LFTs promptly returned to baseline over 3 days. Of note, the patient did not experience any symptoms of liver injury. Other causes of acute liver injury were effectively ruled out, but the case was confounded by usage of other potential hepatotoxic medications. Still, the most likely culprit was ceftazidime, a rare cause of drug induced liver injury with very few reports in the literature.

Synthesis of radioiodinated carnosine for hepatotoxicity imaging induced by carbon tetrachloride and its biological assessment in rats

The imaging of organs is very important in the field of diagnosis especially in case of liver diseases. In the present work, carnosine was successfully labeled with iodine-131 at room temperature in acidic medium using chloramine-T (Ch-T) as moderate oxidizing agent. The parameters affecting labeling of carnosine such as amount of oxidizing agent, amount of substrate, pH value of the reaction mixture, reaction temperature and reaction time, were investigated. The best conditions for formation of 131I-carnosine (131I-CAR) complex were 40 μg of chloramine-T (Ch-T), 75 μg of carnosine, pH 4 and 45 min reaction time at room temperature. The radiochemical yield for 131I-CAR complex was (91 ± 0.11) % at optimum conditions and the labeled complex was stable for 2 h after labeling process. Biodistribution study was achieved using three groups of rats (normal, treated by inactive carnosine and hepatotoxicity rats induced by CCl4). Hepatotoxicity of liver was evaluated using different biochemical markers such as ALT, AST and ALK.P. The 131I-CAR complex showed selective bio-localization in stomach and liver and its selectivity increases in acquired hepatotoxicity. The biological distribution indicates that the suitability of 131I-CAR as a potential hepatotoxicity imaging to detect hepatitis and medical prognosis.

Arum conophalloides Aqueous Extract Induced Hepatotoxicity in Rat; Histopathological, Biochemical, and mir-122 Assessments

Background: Arum conophalloides (A. conophalloides) is a wild edible delicate plant, widely used in traditional medicine. Objective: This study aimed to examine the effects of A. conophalloides extracts on biochemical, molecular, and histopathological changes in the rat. Methods: Fifty adult male Sprague-Dawley rats were divided into 5 groups (10 each) as follows: G1 or control, received distilled water; G2 and G3, treated with the aqueous extract at doses of 200 and 400 mg/kg; G4 and G5, treated with the hydroalcoholic extract at doses of 200 and 400 mg/kg. Prior to and at the end of the experiments, the serum levels of biochemistry parameters and the relative expression of miR-122 were assessed. Moreover, the liver and kidney tissues were examined microscopically. Results: Liver and kidney tissues showed normal structure in all groups. There were no significant changes in biochemical indices or the expression of miR-122 in the extract-treated groups at the dose of 200 mg/kg. However, the group that received the aqueous extract at the dose of 400 mg/kg exhibited a significantly lower level of HDL, LDL, ALT, and ALP in comparison to the control. Additionally, miR-122 expression in this group exhibited a 10-fold increase (P=0.009). Conclusion: The serum level of hepatocyte-specific miR-122 will be more helpful in detecting hepatic changes in early stages than ALT and AST activity or histopathological evaluations of liver sections. Our findings highlight the potential hepatotoxicity of A. conophalloides aqueous extract in a rat model.

Is cannabidiol hepatotoxic or hepatoprotective: A review

Questions have been raised regarding the potential hepatotoxicity of cannabidiol (CBD). Conversely, several animal studies have demonstrated the hepatoprotective effects of CBD against bile duct ligation, cocaine, thioacetamide, alcohol, and several other chemicals. This review summarizes the current literature concerning the hepatic effects of CBD in humans and animals. Based on the available data, it may be concluded that there is a low probability of serious hepatotoxicity at the high therapeutic doses that are used and a much lower risk of adverse hepatic effects and a potential for hepatoprotection effects at the lower doses commonly used in dietary supplements and food products. However, a detailed safety study in rats using highly purified CBD rather than enriched Cannabis extracts is needed, enabling the determination of hepatic as well as other tissue effects and potential margin of safety.

A microfluidic 3D hepatocyte chip for hepatotoxicity testing of nanoparticles

Aim: To develop a practical microfluidic 3D hepatocyte chip for hepatotoxicity testing of nanoparticles using proof of concept studies providing first results of the potential hepatotoxicity of superparamagnetic iron oxide nanoparticles (SPION) under microfluidic conditions. Methods: A microfluidic 3D hepatocyte chip with three material layers, which contains primary rat hepatocytes, has been fabricated and tested using different concentrations (50, 100 and 200 μg/ml) of SPION in 3-day (short-term) and 1-week (long-term) cultures. Results: Compared with standard well plates, the hepatocyte chip with flow provided comparable viability and significantly higher liver-specific functions, up to 1 week. In addition, the chip recapitulates the key physiological responses in the hepatotoxicity of SPION. Conclusion: Thus, the developed 3D hepatocyte chip is a robust and highly sensitive platform for investigating hepatotoxicity profiles of nanoparticles.