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Abstract Background Leaves of Lomatia hirsuta are used in traditional medicine in Chile under the common name of "radal". A tea of radal is traditionally used for treatment of cough, bronchial troubles, and asthma. In a preliminary screening, extracts of the leaves revealed antifungal activity, and the present phytochemical study was undertaken to explain this activity and support the traditional use. Methods Along with the traditional tea, extracts of the leaves were screened for antifungal and toxic activities. The profile of secondary constituents was obtained using GC-MS. Results 2-Methoxyjuglone was isolated from the leaves of Lomatia hirsuta and found to be active against the pathogenic fungus Candida albicans (MIC = 8 μg/mL). Cinnamic acid and vanillic acid were identified as major constituents in the tea by GC-MS. The tea was found not to be toxic against Artemia salina. Conclusion The presence of phenolic acids with antimicrobial properties supports the traditional use of Radal, and encourages further studies.

The obese rodent serves as an indispensable tool for proof-of-concept efficacy and mode-of-action pharmacology studies. Yet the utility of this disease model as an adjunct to the conventional healthy animal in the nonclinical safety evaluation of anti-obesity pharmacotherapies has not been elucidated. Regulatory authorities have recommended employing disease models in toxicology studies when necessary. Our study investigated standard and exploratory toxicology parameters in the high-fat diet (HFD)-induced obese, polygenic Sprague-Dawley rat model in comparison to chow diet (CD)-fed controls. We sought to establish feasibility of the model for safety testing and relevance to human obesity pathophysiology. We report that both sexes fed a 45% kcal HFD for 29 weeks developed obesity and metabolic derangements that mimics to a certain extent, common human obesity. Minor clinical pathologies were observed in both sexes and considered related to CD versus HFD differences. Histopathologically, both sexes exhibited mild obesity-associated findings in brown and subcutaneous white fat, bone, kidneys, liver, lung, pancreas, salivary parotid glands, and skeletal muscle. We conclude that chronic HFD feeding in both sexes led to the development of an obese but otherwise healthy rat. Therefore, the diet-induced obese Sprague-Dawley rat may serve as a suitable model for evaluating toxicity findings encountered with anti-obesity compounds.

New insulin analogues with a longer duration of action and a 'peakless' pharmacokinetic profile have been developed to improve efficacy, safety and convenience for patients with diabetes. During non-clinical development, according to regulatory guidelines, these analogues are tested in healthy euglycaemic rats rendering them persistently hypoglycaemic. Little is known about the effect of persistent (24 hr/day) insulin-induced hypoglycaemia (IIH) in rats, complicating interpretation of results in pre-clinical studies with new longer-acting insulin analogues. In this study, we investigated the effects of persistent IIH and their reversibility in euglycaemic rats. Histopathological changes in insulin-infused animals included partly reversible axonal and reversible myofibre degeneration in peripheral nerve and skeletal muscle tissue, respectively, as well as reversible pancreatic islet atrophy and partly reversible increase in unilocular adipocytes in brown adipose tissue. Additionally, results suggested increased gluconeogenesis. The observed hyperphagia, the pancreatic, peripheral nerve and skeletal muscle changes were considered related to the hypoglycaemia. Cessation of insulin infusion resulted in transient hyperglycaemia, decreased food consumption and body-weight loss before returning to control levels. The implications for the interpretation of non-clinical studies with long-acting insulin analogues are discussed., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Humans are simultaneously exposed to several chemicals that act jointly to induce mixture effects. At doses close to or higher than no-observed adverse effect levels, chemicals usually act additively in experimental studies. However, we are lacking knowledge on the importance of exposure to complex real-world mixtures at more relevant human exposure levels. We hypothesised that adverse mixture effects occur at doses approaching high-end human exposure levels. A mixture (Mix) of 14 chemicals at a combined dose of 2.5 mg/kg bw/day was tested in combination with perfluorononanoic acid (PFNA) at doses of 0.0125 (Low PFNA), 0.25 (Mid PFNA) and 5 (High PFNA) mg/kg bw/day by oral administration for 14 days in juvenile male rats. Indication of a toxicokinetic interaction was found, as simultaneous exposure to PFNA and the Mix caused a 2.8-fold increase in plasma PFNA concentrations at Low PFNA. An increase in testosterone and dihydrotestosterone plasma concentrations was observed for Low PFNA + Mix. This effect was considered non-monotonic, as higher doses did not cause this effect. Reduced LH plasma concentrations together with increased androgen concentrations indicate a disturbed pituitary-testis axis caused by the 15-chemical mixture. Low PFNA by itself increased the corticosterone plasma concentration, an effect which was normalised after simultaneous exposure to Mix. This combined with affected ACTH plasma concentrations and down-regulation of 11β HSD mRNA in livers indicates a disturbed pituitary-adrenal axis. In conclusion, our data suggest that mixtures of environmental chemicals at doses approaching high-end human exposure levels can cause a hormonal imbalance and disturb steroid hormones and their regulation. These effects may be non-monotonic and were observed at low doses. Whether this reflects a more general phenomenon that should be taken into consideration when predicting human mixture effects or represents a rarer phenomenon remains to be shown.

There is growing concern of permanent damage to the endocrine and nervous systems after developmental exposure to endocrine disrupting chemicals. In this study the permanent reproductive and neurobehavioral effects of combined exposure to five endocrine disrupting pesticides, epoxiconazole, mancozeb, prochloraz, tebuconazole and procymidone, were examined. Pregnant and lactating rat dams were dosed with a mixture of the five pesticides at three different doses, or with the individual pesticides at one of two doses. Adverse effects were observed in young and adult male offspring from the group exposed to the highest dose of the mixture. These included reduced prostate and epididymis weights, increased testes weights, altered prostate histopathology, increased density of mammary glands, reduced sperm counts, and decreased spatial learning. As no significant effects were seen following single compound exposure at the doses included in the highest mixture dose, these results indicate cumulative adverse effects of the pesticide mixture., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Disseminated intravascular coagulation (DIC) is a severe clinical condition with activation of coagulation and fibrinolysis. Its diagnosis is based on the International Society of Thrombosis and Haemostasis (ISTH) scoring system of DIC. Animal models of DIC, used to investigate pathophysiology and evaluate treatments, have not been developed in a standardized way, which impedes comparison between models and translation to the human setting. In the current review of animal models of DIC an overview of species, inducers, and dosing regimens is provided. Diagnostic approaches are compared in the light of the ISTH score and treatments tested in animal models of DIC are summarized. Systematic analysis revealed that the rat is by far the preferred species amongst animal models of DIC and lipopolysaccharides (LPS) the preferred inducer of DIC. An overview of the reporting of ISTH DIC score parameters elucidated that only about 25% of the studies measure all of the four parameters necessary for the implementation the ISTH scoring system. Furthermore, most therapeutic interventions tested in animal models of DIC are administered prophylactically, which may be irrelevant to the clinical setting and could explain why compounds effective in preclinical animal models often fail in clinical trials. It is concluded that Implementation of a scoring system in animal models of DIC may increase the ability to compare DIC amongst animal models and improve the translational aspect of treatment effect., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, and we have previously established a rabbit model of non-overt DIC based on the ISTH classification of non-overt DIC. In this rabbit model, we used purified rabbit brain thromboplastin to induce DIC and test applicability of ISTH classifications of overt human DIC. Cardiovascular and haematological parameters from rabbits, either saline-injected or administered a 2.5 mg thromboplastin/kg bolus and a 15 minutes 1.25 mg thromboplastin/kg infusion, were determined at four time points over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH classifications of overt DIC. Despite the fact that injection of purified thromboplastin resulted in decreased platelet count, increased prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes and fibrin degradation products, and pulmonary micro-thrombosis, none of the rabbits were diagnosed as having overt DIC according to ISTH classification. We conclude that purified thromboplastin causes haemostatic abnormalities in the rabbit but this experimental model was not diagnosed as overt DIC., (Copyright © 2010 Elsevier Ltd. All rights reserved.)