Identification

Name
Sulodexide
Accession Number
DB06271
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Thrombolytic agents
Description

Sulodexide is a mixture of glycosaminoglycans (GAGs) composed of dermatan sulfate (DS) and fast moving heparin (FMH).

Protein chemical formula
Not Available
Protein average weight
6500.0 Da (range 5000-8000)
Sequences
Not Available
Synonyms
  • Sulodexida
External IDs
KRX-101
International/Other Brands
Sulonex / Vessel
Categories
UNII
75HGV0062C
CAS number
57821-29-1

Pharmacology

Indication

Sulodexide has been used clinically for the prophylaxis and treatment of vascular diseases with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarc-tion. Also investigated in the treatment of diabetic kidney disease and diabetic neuropathy. New anti-inflammatory properties have also extended its use in venous disease.

Pharmacodynamics

The low molecular weight of both sulodexide fractions allows for extensive oral absorption compared to unfractionated heparin. The pharmacological effects of sulodexide differ substantially from other glycosaminoglycans and are mainly characterized by a prolonged half-life and reduced effect on global coagulation and bleeding parameters. Due to the presence of both glycosaminoglycan fractions, sulodexide potentiates the antiprotease activities of both antithrombin III and heparin cofactor II simultaneously. It is capable of inhibiting both anti-IIa and anti-Xa. It promotes fibrinolytic activity by releasing tissue plasminogen activator and reduces plasminogen activator inhibitor. The drug also blocks platelet adhesion and platelet function induced by cathepsin G and thrombin. Research has also shown that Sulodexide had endothelial protective properties by inducing the overexpression of growth factors important for the protection of organs. It has anti-inflammatory properties via its effect on the release of inflammatory mediators from macrophages. This results in anti-proliferative effects such as the regulation of growth factors like VEGF and FGF. The intravenous administration has also been shown capable of releasing tissue factor pathway inhibitor from the endothelium, which also contributes to the anti-thrombotic effects of Sulodexide. Lastly, this drug is known for its ability to inhibit the secretion of MMPs, particularly MMP-9, from leukocytes in a dose dependent manner, resulting in the restoration of the balance with their tissue inhibitors.

Mechanism of action

Thrombin inhibition produced by sulodexide is due to the additive effect of its components, namely, heparin cofactor II (HCII) catalysis by dermatan sulfate and antithrombin-III catalysis by fast moving heparin (FMH).

TargetActionsOrganism
AHeparin cofactor 2
agonist
Human
AAntithrombin-III
potentiator
Human
Absorption

Sulodexide can be administered via the oral route, IV and IM routes. After oral dosing, the absorption rate being equivalent, the bioavailability is 40-60%. either calculated from the fast-moving heparin fraction or from the dermatan fraction. Bioavailability following IM administration is approximately 90%. After a rapid absorption in the intestine, the dermatan and heparin components start to appear in the plasma. Sulodexide is degraded after ingestion and loses its sulfate groups and both sulfated and unsulfated groups circulate in the blood for up to 24hours. AUC=22.83+/-4.44mg.h/L.

Volume of distribution

Cmax=516+/-77.54ng/mL, Tmax=1.33+/-0.58h, Vd=71.24+/-14.06L (b phase). Sulodexide reaches high concentrations in the plasma and is widely distributed in the endothelial layer. Binding to endothelial cell receptors in arteries and veins contributes to its rapid distribution profile.

Protein binding
Not Available
Metabolism

It is mainly metabolized in the liver.

Route of elimination

Sulodexide is eliminated via the renal, fecal and bile routes. The main clearance occurs renally and accounts for elimination of 55+2.9% of the drug over 96 hours. The fecal and bile routes remove the rest of the drug over 48 hours, which accounts for 23.5+/-2.5% for both routes.

Half life

The elimination half-life was 11.7 +/- 2.0 h after intravenous administration, 18.7 +/- 4.1 h after 50 mg per os, and 25.8 +/- 1.9 h after 100 mg per os.

Clearance

2.70+/-0.58L/h

Toxicity

Sulodexide seems to be well tolerated. Most adverse effects reported are related to the GI system and seem to be transient in nature. Among others adverse reactions are diarrhea, epigastralgia, dyspepsia, heartburn and dizziness. Allergic reactions, such as skin rash, have also been reported but are very rare.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Sulodexide can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Sulodexide is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Sulodexide is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Sulodexide can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Sulodexide can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Sulodexide is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Sulodexide can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Sulodexide can be increased when used in combination with 5beta-dihydrotestosterone.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Sulodexide.
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Sulodexide.
Food Interactions
Not Available

References

General References
  1. Cosmi B, Cini M, Legnani C, Pancani C, Calanni F, Coccheri S: Additive thrombin inhibition by fast moving heparin and dermatan sulfate explains the anticoagulant effect of sulodexide, a natural mixture of glycosaminoglycans. Thromb Res. 2003 Mar 15;109(5-6):333-9. [PubMed:12818259]
  2. Harenberg J: Review of pharmacodynamics, pharmacokinetics, and therapeutic properties of sulodexide. Med Res Rev. 1998 Jan;18(1):1-20. [PubMed:9436179]
  3. Lasierra-Cirujeda J, Coronel P, Aza M, Gimeno M: Use of sulodexide in patients with peripheral vascular disease. J Blood Med. 2010;1:105-15. doi: 10.2147/JBM.S10558. Epub 2010 Jun 15. [PubMed:22282689]
  4. Hoppensteadt DA, Fareed J: Pharmacological profile of sulodexide. Int Angiol. 2014 Jun;33(3):229-35. [PubMed:24936531]
External Links
KEGG Drug
D08547
PubChem Substance
347910343
ChEMBL
CHEMBL2108086
Therapeutic Targets Database
DAP000866
PharmGKB
PA164746343
Wikipedia
Sulodexide
ATC Codes
B01AB11 — Sulodexide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1WithdrawnPreventionDense Deposit Disease1
2CompletedTreatmentRetinopathy, Diabetic1
2CompletedTreatmentTinnitus, Subjective1
3CompletedTreatmentDiabetic Nephropathies1
3Not Yet RecruitingTreatmentPeripheral Arterial Obstructive Disease1
3TerminatedTreatmentDiabetic Nephropathies1
3Unknown StatusTreatmentChronic Kidney Disease (CKD)1
4TerminatedOtherPost-Thrombotic Syndrome1
4TerminatedTreatmentDiabetic Nephropathies1
4WithdrawnTreatmentDiabetic Nephropathy Type 21

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT...
Gene Name
SERPIND1
Uniprot ID
P05546
Uniprot Name
Heparin cofactor 2
Molecular Weight
57070.16 Da
References
  1. Cosmi B, Cini M, Legnani C, Pancani C, Calanni F, Coccheri S: Additive thrombin inhibition by fast moving heparin and dermatan sulfate explains the anticoagulant effect of sulodexide, a natural mixture of glycosaminoglycans. Thromb Res. 2003 Mar 15;109(5-6):333-9. [PubMed:12818259]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Potentiator
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory a...
Gene Name
SERPINC1
Uniprot ID
P01008
Uniprot Name
Antithrombin-III
Molecular Weight
52601.935 Da
References
  1. Cosmi B, Cini M, Legnani C, Pancani C, Calanni F, Coccheri S: Additive thrombin inhibition by fast moving heparin and dermatan sulfate explains the anticoagulant effect of sulodexide, a natural mixture of glycosaminoglycans. Thromb Res. 2003 Mar 15;109(5-6):333-9. [PubMed:12818259]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  3. Harenberg J: Review of pharmacodynamics, pharmacokinetics, and therapeutic properties of sulodexide. Med Res Rev. 1998 Jan;18(1):1-20. [PubMed:9436179]

Drug created on March 19, 2008 10:20 / Updated on November 05, 2018 17:48