Subacute toxicological evaluation of AT‑533 and AT‑533 gel in Sprague‑Dawley rats

Abstract

As a novel heat shock protein 90 inhibitor, AT-533 exhibits various biological activities in vitro, including anti-viral, anti-tumor and anti-inflammatory activities. Moreover, AT-533 gel, a gel dosage form of AT-533, has been suggested to have anti-keratitis and herpes simplex virus type-1 infection-induced effects on the skin lesions of animals. However, the safety evaluation of AT-533 and AT-533 gel has, to the best of our knowledge, not been examined in in vivo toxicological tests. Therefore, these toxicological tests were carried out in the present study. A 30-day subacute toxicity test for AT-533 was conducted at doses of 1, 2 and 4 mg/kg in Sprague-Dawley rats, while that for AT-533 gel was conducted using a single dose of 5 g/kg. The toxicological tests showed that a high-dose of AT-533 caused lethality and side effects in Sprague-Dawley rats. However, no mortality, loss of appetite and body weight, adverse reactions, or toxicologically relevant alterations in hematology, biochemistry and macroscopic findings (except for skin) occurred in rats exposed to low-dose AT-533 and single-dose AT-533 gel (5 g/kg) during a 30-day subacute dermic toxicity study. The aforementioned results suggested that AT-533 gel is non-toxic for Sprague-Dawley rats, as shown by a dermic subacute toxicity test and that except for slight skin irritation, AT-533 gel had almost no side effects when administered percutaneously for 30 days.

Acute toxicological evaluation of AT-533 and AT-533 gel in Sprague-Dawley rats

“…Ninety specific pathogen‑free (SPF) male and female 6-8-week old SD rats were obtained from the Experimental Animal Center of Southern Medical University (Guangzhou, China) under the license number SCXK(YUE)20160041. Feeding conditions are consistent with what we described earlier [ 26 ]. Simply, every 5 rats was kept in a plastic cage with labels attached for identification.…”

“…20180520) and AT-533 gel (Lot No. 20180706) were acquired according to previous reports [ 25 , 26 ]. AT‑533 was dissolved in propyleneglycol, PEG400 and sterile water for skin absorption.…”

Herpes simplex keratitis: A brief clinical overview

“…The use of certain chemical compounds that can modulate the chromatin state of the viral genome resulting in the enhancement of antiviral immunity or suppression of infection and recurrence is another option; novel therapeutic techniques such as CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) have significant potential to make changes in the latent viral DNA in sensory neurons and as such cure the neuronal location of the infection[ 328 - 333 ]. Wu et al [ 334 ] have also reported on AT-533, a heat shock protein-90 antagonist that expressed inhibitory effects on HSV keratitis.…”