Dexamethasone prodrug treatment prevents nephritis in lupus‐prone (NZB × NZW)F1 mice without causing systemic side effects

Fang, Yuan; Nelson, Richard Κ.; Tabor, Dana E.; Zhang, Yijia; Akhter, Mohammed P.; Gould, Karen A.; Wang, Dong

doi:10.1002/art.34667

Cited by 42 publications

(56 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Results from studies of animal models of inflammatory diseases, including LN, have indicated that this dexamethasone formulation provides sustained resolution of inflammation [62, 63]. Studies have not yet been reported in patients with RA.…”

Section: Discussionmentioning

confidence: 99%

Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis

Kavanaugh

Wells

2014

Rheumatology

View full text Add to dashboard Cite

Glucocorticosteroids (GCs) have been employed extensively for the treatment of rheumatoid arthritis (RA) and other autoimmune and systemic inflammatory disorders. Their use is supported by extensive literature and their utility is reflected in their incorporation into current treatment guidelines for RA and other conditions. Nevertheless, there is still some concern regarding the long-term use of GCs because of their potential for clinically important adverse events, particularly with an extended duration of treatment and the use of high doses. This article systematically reviews the efficacy for radiological and clinical outcomes for low-dose GCs (defined as ≤10 mg/day prednisone equivalent) in the treatment of RA. Results reviewed indicated that low-dose GCs, usually administered in combination with synthetic DMARDs, most often MTX, significantly improve structural outcomes and decrease symptom severity in patients with RA. Safety data indicate that GC-associated adverse events are dose related, but still occur in patients receiving low doses of these agents. Concerns about side effects associated with GCs have prompted the development of new strategies aimed at improving safety without compromising efficacy. These include altering the structure of existing GCs and the development of delayed-release GC formulations so that drug delivery is timed to match greatest symptom severity. Optimal use of low-dose GCs has the potential to improve long-term outcomes for patients with RA.

show abstract

Section: Discussionmentioning

confidence: 99%

Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis

Kavanaugh

Wells

2014

Rheumatology

View full text Add to dashboard Cite

show abstract

“…In an attempt to address this problem, we have developed macromolecular prodrugs of anti-inflammatory agents, which passively target to inflammation. This approach is based on a mechanism involving the prodrug's e xtravasation through l eaky v asculature and i nflammatory cell-mediated s equestration (ELVIS) and has been validated in several inflammatory disease models [13, 14, 28]. …”

Section: Discussionmentioning

confidence: 99%

“…In a previous study we employed a murine calvaria particle implant model and demonstrated the utility of the HPMA copolymer system to detect early particle-induced inflammation [13]. Though the murine calvaria osteolysis model reflects many biological features of the wear debris-associated osteolysis [10, 29], the lack of a prosthetic implant and a prosthesis/medullar canal interaction does not recapitulate the actual clinical setting associated with peri-implant osteolysis after total joint replacement.…”

Section: Discussionmentioning

confidence: 99%

“…In order to address the problem related to high off-target GC concentrations and associated systemic toxicity, we developed a N -(2-Hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) [12, 13]. In previous studies, we have found that HPMA copolymer conjugated with an imaging probe could preferentially target to the sites of particle-induced inflammation prior to detectable osteolysis in a murine calvaria osteolysis model [14].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects

Ren

Dusad

Fang

et al. 2014

Journal of Controlled Release

Self Cite

View full text Add to dashboard Cite

Aseptic implant loosening related to implant wear particle-induced inflammation is the most common cause of failure after joint replacement. Modulation of the inflammatory reaction to the wear products represents a rational approach for preventing aseptic implant failure. Long-term treatment using anti-inflammatory agents, however, can be associated with significant systemic side effects due to the drugs' lack of tissue specificity. To address this issue, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) was developed and evaluated for prevention of wear particle-induced osteolysis and the loss of fixation in a murine prosthesis failure model. Daily administration of free dexamethasone (Dex) was able to prevent wear particle-induced osteolysis, as assessed by micro-CT and histological analysis. Remarkably, monthly P-Dex administration (dose equivalent to free Dex treatment) was equally effective as free dexamethasone, but was not associated with systemic bone loss (a major adverse side effect of glucocorticoids). The reduced systemic toxicity of P-Dex is related to preferential targeting of the sites of wear particle-induced inflammation and its subcellular sequestration and retention by local inflammatory cell populations, resulting in sustained therapeutic action. These results demonstrate the feasibility of utilizing a macromolecular prodrug with reduced systemic toxicity to prevent wear particle-induced osteolysis.

show abstract

“…Micro-CT scanning parameters were identical to those described previously [4]. Femoral BMD, BV/TV and trabecular number and thickness were quantified with CTAn software (Skyscan).…”

Section: Methodsmentioning

confidence: 99%

A Dexamethasone Prodrug Reduces the Renal Macrophage Response and Provides Enhanced Resolution of Established Murine Lupus Nephritis

et al. 2013

Self Cite

View full text Add to dashboard Cite

We evaluated the ability of a macromolecular prodrug of dexamethasone (P-Dex) to treat lupus nephritis in (NZB × NZW)F1 mice. We also explored the mechanism underlying the anti-inflammatory effects of this prodrug. P-Dex eliminated albuminuria in most (NZB × NZW)F1 mice. Furthermore, P-Dex reduced the incidence of severe nephritis and extended lifespan in these mice. P-Dex treatment also prevented the development of lupus-associated hypertension and vasculitis. Although P-Dex did not reduce serum levels of anti-dsDNA antibodies or glomerular immune complexes, P-Dex reduced macrophage recruitment to the kidney and attenuated tubulointerstitial injury. In contrast to what was observed with free dexamethasone, P-Dex did not induce any deterioration of bone quality. However, P-Dex did lead to reduced peripheral white blood cell counts and adrenal gland atrophy. These results suggest that P-Dex is more effective and less toxic than free dexamethasone for the treatment of lupus nephritis in (NZB × NZW)F1 mice. Furthermore, the data suggest that P-Dex may treat nephritis by attenuating the renal inflammatory response to immune complexes, leading to decreased immune cell infiltration and diminished renal inflammation and injury.

show abstract

Dexamethasone prodrug treatment prevents nephritis in lupus‐prone (NZB × NZW)F1 mice without causing systemic side effects

Cited by 42 publications

References 28 publications

Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis

Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis

Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects

A Dexamethasone Prodrug Reduces the Renal Macrophage Response and Provides Enhanced Resolution of Established Murine Lupus Nephritis

Contact Info

Product

Resources

About