Preclinical Dose-Escalation Study of ZSJ-0228, a Polymeric Dexamethasone Prodrug, in the Treatment of Murine Lupus Nephritis.
Mol Pharm
; 18(11): 4188-4197, 2021 11 01.
Article
en En
| MEDLINE
| ID: mdl-34569234
ABSTRACT
Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in â¼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Nefritis Lúpica
/
Dexametasona
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Mol Pharm
Asunto de la revista:
BIOLOGIA MOLECULAR
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FARMACIA
/
FARMACOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos