The percentage collagen loss was high in skin when compared with tail. This may be due to the site of application where in the nano zinc oxide may be passed through skin due to their small size and may induce oxidative stress. Hence, we suggest that regulators and industry need to address the toxicity of nanomaterials with a realistic exposure assessment rather following conventional dose measurements following existing protocols.
As an alternative to the standard Draize eye irritation test, the potential irritancy of compounds was evaluated by observing adverse changes that occur in chorioallantoic membrane CAM) of the hen egg (HECAM) after exposure to a test chemical placed directly on the CAM. The occurrence of hemorrhage, coagulation, and lysis in response to a test compound is the basis for employing this technique to evaluate its potential for in vivo damage to mucous membrane, in particular the eye. Irritancy is scored according to the severity and speed at which damage occurs. In the present study, five different classes of pesticides were screened for irritation potential. There was good correlation between the HECAM assay and the in vivo Draize eye irritation test. The proposed HECAM assay, which reduces the requirement for laboratory animals, could be a painless alternative to the Draize test.
Voltage-gated sodium channel Na V 1.7 is a genetically validated target for pain. Identification of Na V 1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure−activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and statedependent Na V 1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over Na V 1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.
The skin irritation test is designed for the prediction of acute skin irritation of nanoparticles by measurement of its cytotoxic effect, as reflected in the MTT assay, on the Reconstructed Human Epidermis (RHE) model. RHE tissues are commercially available.
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