Studies on the heparin sulphamidase activity from rat spleen. Intracellular distribution and characterization of the enzyme

Friedman, Yochanan; Arsenis, Charalampos

doi:10.1042/bj1390699

Cited by 52 publications

(9 citation statements)

References 23 publications

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“…4) (26) intravenously, while the urinary excretion of 3H-labeled material is found to be almost completed within 5 hr after the dose (23). The desulfation is most likely a result of the action of endogenous heparin N-desulfatases, previously demonstrated in rat spleen and liver (26,27), from which the released sulfate is either excreted into the urine or transferred to endogenous mucopolysaccharides via the sulfate pool (28). The anticoagulant activity of heparin has been shown to be dependent both on size and on the sulfate groups, particularly the N-sulfated ones (29).…”

Section: Resultsmentioning

confidence: 99%

Oral heparin results in the appearance of heparin fragments in the plasma of rats.

Larsen¹,

Lund²,

Langer³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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We have previously shown that angiogenesis inhibition and tumor regression can be accomplished by combinations of heparin or heparin fagments with cortisone [Folkman, J., Langer, R., Linhardt, R. J., Haudenschild, C. & Taylor, S. (1983) Science 221,[719][720][721][722][723][724][725]. Oral heparin was also effective in combination with cortisone. We now show that a single oral dose of [35S]heparin or [3H]heparin (15,000 units/kg) results in continuous release of radioactive material into the bloodstream for at least 12 hr. This is associated with the presence of anti-factor Xa activity at a level of "0.1 unit/ml. The radioactive material is Identified as oligo-, di-, and monosaccharides by its behavior in chromatographic systems, its possession of anti-factor Xa activity, and the effect of treatment with bacterial heparinase. The heparin fragments are extensively metabolized to fragments without anti-factor Xa activity that are readily subject to urinary excretion.We have previously demonstrated that the combination of heparin, or a heparin fragment, and cortisone inhibited angiogenesis, including the chicken chorioallantoic membrane and the rabbit corneal pocket assay (1). When the combination was used to inhibit tumor growth by parenteral administration to mice, a high rate of hemorrhagic complications was encountered because of the anticoagulant effect of heparin. Other methods of heparin administration were tried, and it was found that the anti-angiogenic effect was maintained when heparin was given orally even though the anticoagulant complications did not occur. This oral regimen inhibited tumor growth and metastasis in some animal tumor models. In an initial experiment to study the absorption of oral heparin, mice were given [35S]heparin in their drinking water. Serum obtained 24 hr later yielded 0.4% of the radioactivity that was present in the drinking water. However, gel filtration chromatography failed to demonstrate radiolabeled heparin fragments with biological activity (1).The anti-angiogenic activity of oral heparin was somewhat surprising. The literature contains numerous reports of attempts to administer heparin orally (2-4), with little success in achieving clinically useful anticoagulant activity. Attempts have been made to improve enteral absorption in a number of ways: (i) use of adjuvants such as EDTA (5), citric acid (6), or dimethyl sulfoxide (7); (ii) oral administration in micellar solutions (8) or in liposomes (9); (iii) rectal administration with bile salts (10); or (iv) administration of low molecular weight heparins (4). No such technique has yet achieved clinical usefulness.As a result of finding anti-angiogenic activity with oral heparin plus cortisone without anticoagulant activity, we decided to examine the fate of radiolabeled heparin given enterally. Furthermore, by examining two differently labeled heparins (35S and 3H), we sought to gain information about metabolism of the drug by desulfation and by depolymerization. We now show that a single oral dose of hepari...

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Section: Resultsmentioning

confidence: 99%

Oral heparin results in the appearance of heparin fragments in the plasma of rats.

Larsen¹,

Lund²,

Langer³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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“…UFH binds to a number of plasma proteins, which reduces its anticoagulant activity, contributing to its variable anticoagulant response (Hirsh et al , 2008). UFH also binds to endothelial cells (Mahadoo et al , 1977; Glimelius et al , 1978; Barzu et al , 1985) and macrophages (Friedman & Arsenis, 1974), which further complicates its pharmacokinetic profile.…”

Section: Unfractionated Heparinmentioning

confidence: 99%

Anticoagulating obese patients in the modern era

2011

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The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.

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“…Again, they can be "cnred" by the Sanfilippo A Factor from normal tissnes and nrine which in this case appears to be a heparan sulphate A'-suIphatase (a snlphamatase, catalysing reaction 2) distinct from other sniphatases {Kresse and Nenfeld, 1972). The relationship of this sulphutase to the known, bnt nnpurified, heparin snlphamatases of mammalian tissnes (Dietrich, 1970) is unknown but at least some of these enzymes are lysosomal (Friedman and Arsenis, 1974). …”

Section: Hunter Sijmlronie: Mucopohjsaccharidosis Ilmentioning

confidence: 99%

Sulphatases, Lysosomes and Disease

1976

Aust J Exp Biol Med

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Studies on the heparin sulphamidase activity from rat spleen. Intracellular distribution and characterization of the enzyme

Cited by 52 publications

References 23 publications

Oral heparin results in the appearance of heparin fragments in the plasma of rats.

Oral heparin results in the appearance of heparin fragments in the plasma of rats.

Anticoagulating obese patients in the modern era

Sulphatases, Lysosomes and Disease

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