Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · Apr 2019
Preclinical safety evaluation of the adrenomedullin-binding antibody Adrecizumab in rodents, dogs and non-human primates.
Adrenomedullin (ADM) is a vasoactive peptide in sepsis. The non-neutralizing ADM-binding antibody Adrecizumab improved outcome in animal models of systemic inflammation and sepsis. Herein, we evaluated the preclinical safety of Adrecizumab in various animal species. ⋯ Toxicokinetic analyses showed immediate and dose-dependent peak concentrations, slow elimination and no gender differences. In conclusion, intravenous, repeated administration of high doses of Adrecizumab appeared well-tolerated across species. These results pave the way for further investigation of Adrecizumab in humans (intended dose of 2 mg/kg).
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Toxicol. Appl. Pharmacol. · Apr 2019
Evidence for the involvement of opioid and cannabinoid systems in the peripheral antinociception mediated by resveratrol.
Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. ⋯ Peripheral antinociception of RES intermediate-dose (50 μg/paw) was increased by: (i) bestatin, inhibitor of endogenous opioid degradation involved-enzymes; (ii) MAFP, inhibitor of anandamide amidase; (iii) JZL184, inhibitor of 2-arachidonoylglycerol degradation involved-enzyme; (iv) VDM11, endocannabinoid reuptake inhibitor. Acute and peripheral administration of RES failed to affect the amount of μOR, CB1R and CB2R. Experimental data suggest that RES induces peripheral antinociception through μOR and CB1R activation by endogenous opioid and endocannabinoid releasing.