http://www.ncbi.nlm.nih.gov/pubmed/18278032?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum1: Nature. 2008 Feb 28;451(7182):1076-81. Epub 2008 Feb 17. Links
Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets.Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B, Robinson WH, Baranzini SE, Grinnell BW, Raine CS, Sobel RA, Han DK, Steinman L.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.
Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. This is fundamental for the leeches’ alimentary habit of hematophagy, since it keeps the blood flowing after the initial phlebotomy performed by the worm on the host’s skin.
In 1884, the British physiologist John Berry Haycraft discovered that the leech secreted a powerful anticoagulant, which he named hirudin, though it was not isolated until the 1950s, nor its structure fully determined until 1976. Full length, hirudin is made up of 65 amino acids. These amino acids are organised into a compact N-terminal domain containing three disulfide bonds and a C-terminal domain which is completely disordered, when the protein is un-complexed in solution. Natural hirudin contains a mixture of various isoforms of the protein. However, recombinant techniques can be used to produce homogeneous preparations of hirudin.A key event in the final stages of blood coagulation is the conversion of fibrinogen into fibrin by the serine protease enzyme thrombin. Thrombin is produced from prothrombin, by the action of an enzyme, prothrombinase, in the final states of coagulation. Fibrin is then cross linked by factor XIII to form a blood clot. The principal inhibitor of thrombin in normal blood circulation is antithrombin III. Similar to antithrombin III, the anticoagulatant activity of hirudin is based on its ability to inhibit the pro-coagulant activity of thrombin.
Hirudin is the most potent natural inhibitor of thrombin. Unlike antithrombin III hirudin binds to and inhibits only the activity of thrombin forms with a specific activity on fibrinogen. Therefore, hirudin prevents or dissolves the formation of clots and thrombi (i.e. it has a thrombolytic activity), and has therapeutic value in blood coagulation disorders, in the treatment of skin hematomas and of superficial varicose veins, either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such as heparin, as it does not interfere with the biological activity of other serum proteins and can also act on complexed thrombin.
It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using recombinant biotechnology has been developed. This has led to the development and marketing of a number of hirudin based anticoagulant pharmaceutical products such as lepirudin (Refludan) and Desirudin (Revasc/Iprivask). Several other direct thrombin inhibitors are derived chemically from hirudin.
Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme (EC 220.127.116.11) that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. It should not be confused with C peptide or c-reactive protein or protein kinase C.
The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti-inflammatory and anti-apoptotic activities. Its actions are related to development of thrombosis and ischemic stroke. The protein C pathway of the coagulation of the blood involves the influences of lipids and lipoproteins and the study of the strong epidemiologic association between hyperlipidemia and hypercoagulability.[
http://www.ncbi.nlm.nih.gov/pubmed/11302416?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum1: Ann Pharmacother. 2001 Apr;35(4):501-4. Links
Interaction between warfarin and danshen (Salvia miltiorrhiza).Chan TY.
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories. firstname.lastname@example.org
OBJECTIVE: To discuss the potential for an adverse interaction between the Chinese herb danshen, the dry root and rhizome of Salvia miltiorrhiza Bge, and warfarin. DATA SOURCES: A MEDLINE search was performed (from January 1966 through October 2000) using the key words danshen and Salvia miltiorrhiza. All articles written in English or with an English extract were considered for review. STUDY SELECTION AND DATA EXTRACTION: All studies of antithrombotic effects of danshen or interaction between danshen and warfarin were evaluated. Previous case reports of an adverse interaction between danshen and warfarin were reviewed. DATA SYNTHESIS: Danshen is commonly used in mainland China for the treatment of atherosclerosis-related disorders such as cardiovascular and cerebrovascular diseases. Danshen can affect hemostasis in several ways, including inhibition of platelet aggregation, interference with the extrinsic blood coagulation, antithrombin III-like activity, and promotion of fibrinolytic activity. Single-dose and steady-state studies in rats indicated that danshen increased the absorption rate constants, AUCs, maximum concentrations, and elimination half-lives, but decreased the clearances and apparent volume of distribution of both R- and S-warfarin. Consequently, the anticoagulant response to warfarin was exaggerated. Three cases have previously been published reporting gross overanticoagulation and bleeding complications when patients receiving chronic warfarin therapy also took danshen. CONCLUSIONS: Because of both pharmacokinetic and pharmacodynamic interactions, danshen should be avoided in patients taking warfarin.
PMID: 11302416 [PubMed - indexed for MEDLINE]
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