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

BMC Pharmacology & Toxicology · 7 authors, 6 centres

AI SUMMARY

FIDELITY 100%

POPULATIONSprague-Dawley rats (6-8 weeks old, both sexes)

INTERVENTIONSingle transdermal administration of AT-533 (5, 50, 250, 500 mg/kg) or AT-533 gel (5 g/kg)

COMPARISONVehicle (solvents) or blank gel and sterile saline controls

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TL;DR

This study evaluated the acute toxicity of AT-533, a novel HSP90 inhibitor, and its gel formulation in rats. The median lethal dose (LD50) of AT-533 was 228.382 mg/kg, while AT-533 gel showed no toxicity at doses up to 5 g/kg. These findings support the safety of AT-533 at low doses and the gel formulation for potential topical use.

Full summary

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**Background:** AT-533 is a novel heat shock protein 90 (HSP90) inhibitor with demonstrated anti-inflammatory, antiviral, and antitumor activities. Its gel formulation (AT-533 gel) has shown efficacy in repairing keratitis and dermatitis caused by herpes virus infection. Despite these therapeutic potentials, the acute safety profile of AT-533 and its gel had not been established. This study aimed to evaluate the acute toxicity of AT-533 and AT-533 gel in Sprague-Dawley (SD) rats to determine non-toxic doses and potential adverse effects.

**Methods:** Ninety SPF SD rats (6-8 weeks old, both sexes) were used. For AT-533, 60 rats were divided into 6 groups (n=10 each, 5 males and 5 females): control (sterile saline), vehicle (solvents), and AT-533 at 5, 50, 250, and 500 mg/kg. For AT-533 gel, 30 rats were assigned to control, blank gel, and AT-533 gel (5 g/kg) groups. All substances were applied transdermally once for 24 hours. Observations over 15 days included mortality, body weight, food consumption, and clinical signs. On day 16, blood was collected for hematology (WBC, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, NE, LY, EO, BA, MO) and serum biochemistry (TP, ALB, ALT, AST, T-Bil, D-Bil, I-Bil, ALP, CRE, BUN, UA, TG, GLU, CHO, HDL, LDL, Na, K, Cl). Organs (brain, heart, liver, spleen, lung, kidneys, skin) were weighed and examined histopathologically. LD50 was calculated using Karber's method.

**Key Results:** In the AT-533 study, 5 deaths occurred in the 250 mg/kg group (1 male, 4 females) and 8 deaths in the 500 mg/kg group (4 males, 4 females). The LD50 of AT-533 was 228.382 mg/kg. Rats in the 250 and 500 mg/kg groups showed appetite loss for 1-5 days and reduced body weight. No deaths or abnormal symptoms were observed in the AT-533 gel study, with LD50 > 5 g/kg. Hematology: In the 500 mg/kg AT-533 group, PLT was significantly higher (933.5 ± 92.631 ×10^9/L) vs vehicle (520.667 ± 201.604 ×10^9/L, p<0.05). No significant differences were seen in other AT-533 groups or in the AT-533 gel groups. Biochemistry: In the 250 mg/kg AT-533 group, ALP was significantly elevated (329.4 ± 71.835 U/L vs 227.7 ± 78.370 U/L, p<0.05). In the 500 mg/kg group, ALP (343.0 ± 78.632 U/L, p<0.05), CHO (2.140 ± 0.234 μmol/L, p<0.05), HDL (0.900 ± 0.124 μmol/L, p<0.01), and K+ (6.790 ± 0.649 μmol/L, p<0.05) were significantly higher vs vehicle. No significant biochemical changes were noted in the AT-533 gel groups. Organ weights and coefficients showed no significant differences between low-dose AT-533 groups (5, 50 mg/kg) and vehicle, or among AT-533 gel groups. Histopathology revealed no pathological lesions in heart, liver, spleen, lung, kidneys, or skin in the AT-533 gel group.

**Clinical Implications:** This study establishes that AT-533 is non-toxic at doses ≤50 mg/kg in rats, while AT-533 gel is safe at doses up to 5 g/kg. The LD50 of AT-533 (228.382 mg/kg) provides a safety margin for its therapeutic use, as effective concentrations in prior studies were much lower. The gel formulation's lack of toxicity supports its potential as a topical treatment for herpes-related keratitis and dermatitis. These findings justify further subchronic and chronic toxicity studies and pave the way for clinical development of AT-533 gel as a safe dermatological medication.

PICO

PPOPULATION

Sprague-Dawley rats (6-8 weeks old, both sexes)

IINTERVENTION

Single transdermal administration of AT-533 (5, 50, 250, 500 mg/kg) or AT-533 gel (5 g/kg)

OOUTCOME

Mortality, body weight, food consumption, hematology, serum biochemistry, organ weights, histopathology, and LD50

STUDY TYPE

other

SPECIALTY

veterinary medicine

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10576390

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

BMC Pharmacology & Toxicology

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ABSTRACT

Background AT-533 is a novel heat shock protein 90 inhibitor that exerting anti-inflammatory, antiviral, and antitumor efficacy. Furthermore, the gel made of AT-533 as raw material named AT-533 gel has the function of repairing keratitis and dermatitis caused by herpes virus infection. However, the acute safety evaluation of AT-533 and AT-533 gel has not been conducted. Methods and results Herein, we performed acute toxicological studies of AT-533 and AT-533 gel in Sprague-Dawley rats. Fifteen-day acute toxicity study of AT-533 was conducted in both male and female Sprague-Dawley rats at doses of 5, 50, 250 and 500 mg/kg and AT-533 gel at 5 g/kg in the study. During experiment, food consumption and mortality were observed and body weight, hematology, serum biochemistry and histopathological assessment of rats were carried out. No abnormal changes were observed in rats percutaneously treated with AT-533 at 5 mg/kg and 50 mg/kg and AT-533 gel. However, loss of appetite and body weight, adverse reactions, toxicologically relevant alterations in hematology and biochemistry were found in rats percutaneously treated with AT-533 at 250 mg/kg and 500 mg/kg during 15-day acute dermic toxicity study. Conclusions The aforementioned results suggested that the LD 50 of AT-533 is 228.382 mg/kg and the LD 50 of AT-533 gel is greater than 5 g/kg. These findings indicated that AT-533 is non-toxic in rats when the dose less than 50 mg/kg and AT-533 gel can be considered a gel with no toxicity at doses less than 5 g/kg.

CITATION EXPORT

Lishan Zhong, Yanting Wu, Chen Huang et al.. Acute toxicological evaluation of AT-533 and AT-533 gel in Sprague-Dawley rats. BMC Pharmacology & Toxicology. (2023). https://doi.org/10.1186/s40360-023-00696-5

AUTHORS

7 · 6 CENTRES

Lishan Zhong, Yanting Wu, Chen Huang, Kaisheng Liu, Cui-fang Ye, Zhe Ren, Yifei Wang

1https://ror.org/02xe5ns62grid.258164.c0000 0004 1790 3548Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
2Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
3Guangdong Provincial biotechnology drug and Engineering Technology Research Center, Guangzhou, China
4Guangzhou (Jinan) Biomedical Research and Development Center Co. Ltd, Guangzhou, China
5grid.440218.b0000 0004 1759 7210Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics,Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong China
6grid.263817.90000 0004 1773 1790Shenzhen People’s Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong China