Preparation and anticoagulant activity of the phosphosulfomannan PI-88

Yu, Guangli; Gunay, Nur Sibel; Linhardt, Robert J.; Toida, Toshihiko; Fareed, Jawed; Hoppensteadt, Debra; Shadid, Hazar; Ferro, Vito; Li, Caiping; Fewings, Kym; Palermo, Maria C; Podger, Denis

doi:10.1016/s0223-5234(02)01347-8

Cited by 71 publications

(76 citation statements)

References 27 publications

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“…Prior studies have shown that PI-88 prolongs the APTT by potentiating heparin cofactor II -mediated inhibition of thrombin activity. PI-88 has no effect on the prothrombin time (14,18).…”

Section: Discussionmentioning

confidence: 91%

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A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

Basche

Gustafson

Holden

et al. 2006

Clinical Cancer Research

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Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis.The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C max correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for z6 months. Conclusion:The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

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“…Prior studies have shown that PI-88 prolongs the APTT by potentiating heparin cofactor II -mediated inhibition of thrombin activity. PI-88 has no effect on the prothrombin time (14,18).…”

Section: Discussionmentioning

confidence: 91%

“…PI-88 is a mixture of highly sulfated oligosaccharides derived from the yeast Pichia (Hanensula) holstii NRRL Y-2448 (14,15). It was selected for development because it is a potent inhibitor of heparanase.…”

mentioning

confidence: 99%

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

Basche

Gustafson

Holden

et al. 2006

Clinical Cancer Research

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“…(30). The purity of the end product was identified using capillary electrophoresis (31). Fifteen male Sprague Dawley rats that weighed 279 to 328 g at the time of dosing were used.…”

Section: Light and Electron Microscopymentioning

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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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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“…Additionally, monophosphorylated trisaccharide and tetrasaccharylamine are present (5.5% combined) (Fig. 11) [50]. PI-88 is a promising inhibitor of tumor growth and metathesis [51].…”

Section: Pi-88mentioning

confidence: 99%

“…PI-88 is currently undergoing Phase II clinical evaluation in cancer patients. (29), (30), (31 The anticoagulant activity of PI-88 and its fractions PK1 (hexa-and pentasaccharides), PK3 (penta-and tetrasaccharides) PK4 (tetra) and PK5 (tri-and disaccharides) were assessed using various assays [50] (Table 5). Studies demonstrated concentration dependence [50] as well as chain length dependence [50,53] for PI-88 anticoagulant activities.…”

Section: Pi-88mentioning

confidence: 99%

Synthetic Oligosaccharides as Heparin-Mimetics Displaying Anticoagulant Properties

Avci¹,

Karst²,

Linhardt³

2003

CPD

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Heparin and low molecular weight heparins are major clinical anticoagulants and the drugs of choice for the treatment of deep venous thrombosis. The discovery of an antithrombin binding domain in heparin focused interest on understanding the mechanism of heparin's antithrombotic/ anticoagulant activity. Various heparin-mimetic oligosaccharides have been prepared in an effort to replace polydisperse heparin and low molecular weight heparins with a structurally-defined anticoagulant. The goal of attaining a heparin-mimetic with no unwanted side-effects has also provided motivation for these efforts. This article reviews structure-activity relationship (SAR) of structurally-defined heparin-mimetic oligosaccharides.

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Preparation and anticoagulant activity of the phosphosulfomannan PI-88

Cited by 71 publications

References 27 publications

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Synthetic Oligosaccharides as Heparin-Mimetics Displaying Anticoagulant Properties

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