Comparison of Anticoagulant Effects and Safety of Argatroban and Heparin in Healthy Subjects

Swan, Suzanne K.; Peter, John; Lambrecht, Lawrence J.; Hursting, Marcie J.

doi:10.1592/phco.20.9.756.35194

Cited by 92 publications

(76 citation statements)

References 25 publications

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“…Argatroban must be used intravenously due to its lack of oral bioavailability and short half-life (t 1/2 = 40 min) [57]. Argatroban is primarily cleared through the liver after metabolism by CYP3A4, or excretion through bile [58,59]. The intravenous administration and short half-life do not make argatrobanan ideal drug.…”

Section: Serine Protease Inhibitors In the Clinicmentioning

confidence: 99%

Proteases: Nature’s Destroyers and the Drugs that Stop Them

Veltri¹

2015

PPIJ

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Proteases are found in all life forms and regulate many cellular pathways. Proteases have been proven as viable drug targets. This paper reviews the mechanism of hydrolysis of the amino acid based aspartic, cysteine, serine and threonine proteases and will also highlight the current anti protease therapeutics in the clinic. the oxygen of the carbonyl drive the cleavage of the peptide bond, which abstracts hydrogen from the general base. Water then releases the second half of the product from the active site residue. The oxyanion hole generated during the transition state is stabilized through hydrogen bonding with amino groups of the backbone. The role of the oxyanion hole is not fully understood [18]. While the chemistry of the mechanism of hydrolysis is similar for serine, aspartic, cysteine and threonine proteases, the amino acids involved in catalysis are what define the various classes. The different classes of proteases are discussed below. Serine ProteasesSerine proteases [19][20][21] use an active site serine to hydrolyze a peptide bond. The other amino acids involved in catalysis vary between the different serine protease groups. The Ser-His-Asp triad can be replaced with Ser-His-Glu, Ser-His-His or Ser-Lys depending on the family of serine protease [20,21]. The serine proteases are categorized by tertiary structures into the super families of the trypsin-like or subtilisin-like [2,19,20]. Examples of the trypsin-like serine proteases, the larger of the super families, are trypsin, chymotrypsin, thrombin, factor IX a, and factor Xa [2,19,20]. Interestingly, some cysteine proteases adopt the trypsin-like structure [22]. Examples of the subtilisin-like serine proteases are proteinase K and thermitase [2,19,20]. Proteases: Nature's Destroyers and the Drugs that Stop Them 3/11Copyright: ©2015 Veltri Citation: Veltri CA (2015) Proteases: Nature's Destroyers and the Drugs that Stop Them. Pharm Pharmacol Int J 2(6): 00044. DOI: 10.15406/ ppij.2015.02.00044Along with tertiary structure, serine proteases are designed against the nature of the P 1 residue recognized by the protease types. The trypsin-like proteases cleave positively charged residues (Lys or Arg are preferred at P 1 ), elastase-like proteases prefer small hydrophobic residues (Ala or Val are preferred at P 1 ) while chymotrypsin-like proteases prefer large hydrophobic residues (Phe, Tyr, or Leu) [2,19,20]. Aspartic ProteasesAspartic proteases [19,[23][24][25][26] use two aspartic acid residues to hydrolyze a peptide bond. These proteases are categorized into the super families of pepsin-like or viral retropepsin-like due to the tertiary structure [23,24,26,27]. The pepsin-like include pepsin, cathepsin D and chymosin [23,27]. The viral retropepsinlike include the retro pepsins of the immune viruses HIV, FIV and SIV [24,26].Aspartic proteases are unique in the fact they do not have a His residue in their active site. The general acid-base mechanism proposed for peptide hydrolysis involves two Asp residues and uses water to attack the targe...

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Section: Serine Protease Inhibitors In the Clinicmentioning

confidence: 99%

Proteases: Nature’s Destroyers and the Drugs that Stop Them

Veltri¹

2015

PPIJ

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“…Argatroban reaches its steady-state plasma levels, measured by its activated partial thromboplastin time (aPTT) anticoagulant effect, 1-3 h after initiation of intravenous administration (faster when a loading bolus is administered) [14,15]. Low intra-and intersubject variability is observed.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Argatroban is rapidly metabolized in the liver and excreted through the bile into the feces [14,15,17,18]. There are three known metabolites of argatroban (M1, M2 and M3) ( fig.…”

Section: Metabolismmentioning

confidence: 99%

“…If lifethreatening bleeding occurs and excessive plasma argatroban levels are suspected, argatroban should be discontinued immediately, and the patient provided symptomatic and supportive therapy. Anticoagulant parameters generally return to baseline within 2-4 h after argatroban discontinuation [14,15]. This reversal may take at least 6 h and perhaps more than 20 h in hepatically impaired patients [17].…”

Section: Antidotementioning

confidence: 99%

“…Higher levels of anticoagulation such as required during interventional procedures are monitored using the activated clotting time (ACT) [15,24,27]. Argatroban also increases the thrombin time and ecarin clotting time (ECT) in a dose-dependent fashion [24].…”

Section: Monitoringmentioning

confidence: 99%

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An Overview of the Direct Thrombin Inhibitor Argatroban

Walenga¹

2002

Pathophysiol Haemos Thromb

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Argatroban is a small molecule direct thrombin inhibitor. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, absence of antibody formation and no need for initial dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT); and it is approved in Japan and Korea for treatment of various thrombotic disorders. Argatroban has been shown in limited trials to provide reliable anticoagulation during percutaneous coronary interventions on HIT and non-HIT patients. Preliminary reports document the feasibility of using argatroban for anticoagulation during peripheral vascular interventions, hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the activated partial thromboplastin time for low doses and the activated clotting time for high doses. The ease of monitoring argatroban, its ‘turn-on/turn-off’ characteristic and its consistent safety profile provide the rationale to continue studies of argatroban as an anticoagulant in clinical settings.

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