Distribution of [14C]suramin in tissues of male rats following a single intravenous dose

McNally, W.; DeHart, Peter D.; Lathia, Chetan; Whitfield, Lloyd R.

doi:10.1016/s0024-3205(00)00767-0

Cited by 23 publications

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“…Linkage analysis studies, however, have recently shown that nearly half of these patients' family members have segregation of hematuria at the COLA3/A4 locus (36%) or the COLA5 locus (10%), the same loci for autosomal recessive and X-linked Alport syndrome, respectively (37,38). These data suggest that 50% of patients who have a diagnosis of TBMD actually have Alport syndrome, but the cause of the GBM abnormality in the remaining cases has, as yet, not been determined.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that PI-88 may affect normal Golgi or tubular lysosomal turnover. Administration of suramin, a polysulfonated napthylurea and known inhibitor of heparanase, is associated with the formation of lysosomal accumulations and lamellar inclusions in kidney tubular cells (37,38). The renal toxicity of suramin has limited its clinical usage (41), and the induced lysosomal changes make it an ideal agent to study lysosomal storage diseases (37,42).…”

Section: Discussionmentioning

confidence: 99%

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A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Levidiotis

Freeman

Punler³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The ␤-D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by acting to selectively degrade the negatively charged side chains of heparan sulfate proteoglycans (HSPG) within the glomerular basement membrane (GBM). A loss of the negatively charged HSPG may result in alteration of the permselective properties of the GBM, loss of glomerular epithelial and endothelial cell anchor points, and liberation of growth factors. This study examined the effect of PI-88, a sulfated oligosaccharide heparanase inhibitor, on renal function, glomerular ultrastructure, and proteinuria. Continuous PI-88 infusion at 25 mg/kg per d did not adversely affect animal behavior, growth, or GFR. Cortical tubular vacuolation, however, was observed by light microscopy, and GBM thickness was significantly reduced in these animals (P Ͻ 0.0002). Tissue distribution studies using [35 S]-labeled PI-88 revealed high levels of radioactivity in the kidney after a single subcutaneous injection of 25 mg/kg, suggesting protracted accumulation; moreover, active PI-88 was detected in urine. In passive Heymann nephritis, PI-88 delivered as a continuous infusion at 25 mg/kg per d significantly reduced autologous-phase proteinuria, at day 14 (P Ͻ 0.009), in the absence of altered sheep antibody deposition, C5b-9 deposition, and circulating rat anti-sheep antibody titers. Glomerular vascular endothelial growth factor and fibroblast growth factor expression was unaffected by PI-88 administration. However, PI-88 administration significantly prevented glomerular HSPG loss as demonstrated by quantitative immunofluorescence studies (P Ͻ 0.0001) in the absence of altered agrin distribution. These data therefore confirm the importance of heparanase in the development of proteinuria.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Levidiotis

Freeman

Punler³

et al. 2004

Journal of the American Society of Nephrology

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“…Suramin was reported to be mostly accumulated in the kidney after injection and has a half-life of 21 days. 35,39 Therefore, we speculate that the actual concentration of suramin in the kidney may be higher than in the blood and that a low dose would result in a therapeutic effect. Indeed, we observed that suramin at 5 mg/kg, a dose that is sixfold lower than the dose used for treating patients with tumors (usually 30 mg/kg), 40 decreased expression of ␣-SMA and fibronectin and suppressed expression of collagen 1 and deposition of ECM.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 98%

“…Because suramin has a half-life of at least 21 days, 35 mice were given a single dose of suramin immediately after surgery, and kidneys were collected on days 7 and 21 after the treatment. Western blot analysis of whole kidney lysates indicated increased expression of ␣-SMA and fibronectin on day 7 that persisted at day 21 after unilateral urethral obstruction (UUO) injury (Figure 2 and Supplemental Figure 3).…”

Section: Suramin Inhibits Expression Of ␣-Sma and Fibronectin In The mentioning

confidence: 99%

Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

Liu

Tolbert

Pang

et al. 2011

Journal of the American Society of Nephrology

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The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the interaction of several cytokines and growth factors with their receptors, but whether suramin inhibits the progression of renal fibrosis is unknown. Here, treatment of cultured renal interstitial fibroblasts with suramin inhibited their activation induced by TGF-␤1 and serum. In a mouse model of obstructive nephropathy, administration of a single dose of suramin immediately after ureteral obstruction abolished the expression of fibronectin, largely suppressed expression of ␣-SMA and type I collagen, and reduced the deposition of extracellular matrix proteins. Suramin also decreased the expression of multiple cytokines including TGF-␤1 and reduced the interstitial infiltration of leukocytes. Moreover, suramin decreased expression of the type II TGF-␤ receptor, blocked phosphorylation of the EGF and PDGF receptors, and inactivated several signaling pathways associated with the progression of renal fibrosis. In a rat model of CKD, suramin abrogated proteinuria, limited the decline of renal function, and prevented glomerular and tubulointerstitial damage. Collectively, these findings indicate that suramin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.

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“…An added advantage of using these low doses is the minimal suramin systemic exposure of less than 1 μg/ml. Finally, in view of the long retention of suramin in tissues, e.g., up to >12 weeks in rats (29), a routine weekly dose schedule would cause drug accumulation. Additional studies to address the post-treatment suramin retention in bladder tissues and the dosing frequency are warranted.…”

Section: Pharmacokinetic Interactions Between Intravesical MMC and Sumentioning

confidence: 99%

Bladder Tissue Pharmacokinetics of Intravesical Mitomycin C and Suramin in Dogs

Wientjes

et al. 2010

AAPS J

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Abstract. Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy.

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Distribution of [14C]suramin in tissues of male rats following a single intravenous dose

Cited by 23 publications

References 0 publications

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

Bladder Tissue Pharmacokinetics of Intravesical Mitomycin C and Suramin in Dogs

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