10 Aptamers for Thrombotic Diseases
285
basis for a more rational design of new TBA molecules with improved therapeutic
action [33].
After then, 31TBA, HD1-22, NU172, RA-36, RE31, and some other aptamers are
modified and extended the initial 15-mer DNA aptamer with improved activity and
in vivo stability.
10.2.1.2 ARC183
Presently heparin is the only approved post-operation anticoagulant for CABG
surgery. However, heparin-protamine treatment has a number of serious side
effects, especially, asymptomatic bleeding and thrombocytopenia often result in
life-threatening arterial or venous thromboemboli [34].
ARC183 (Archemix and Nuvelo), also named TBA or HD1, is thrombin-specific
aptamer with a desirable affinity for thrombin (K d = 2 nM) and prothrombin
(K d = 50 nM) [35]. In vitro experiments showed that incubation of platelet-poor
plasma, thrombin, and ARC183 at nM concentrations resulted in prolongation
of thrombin time in a significant concentration-dependent manner. Furthermore,
ARC183 dose-dependently inhibited thrombin-catalyzed cleavage of fibrinogen and
platelet thrombin receptor (PAR-1) [36], significantly reduced thrombin-mediated
platelet degranulation and platelet aggregation in platelet-rich plasma. Therefore,
ARC183 is a strong anticoagulant that can inhibit thrombin-catalyzed activation of
fibrinogen and platelet aggregation.
A linear dose–response pharmacologic relationship between the infusion rate of
a novel thrombin aptamer and plasma PT was observed in cynomolgus monkeys.
This novel aptamer had an extremely short half-life, estimated to be 108 ± 14 s.
In addition, the aptamer inhibited thrombin-induced platelet aggregation in plateletrich plasma ex vivo but did not inhibit collagen-induced aggregation, suggesting
that the inhibition of aptamer was specific. The ability of regional anticoagulation
and the half-life of the aptamer in an extracorporeal hemofiltration circuit in sheeps
were evaluated. The authors concluded that the rapid onset of action and short halflife make the aptamer a useful anticoagulant for extracorporeal circuits and certain
acute clinical settings compared to current anticoagulant therapy [37]. Furthermore,
it prolonged activated clotting time (ACT) in a dose-related manner without acute
toxicities in monkey and dog models of CPB [29, 37]. Preliminary results of the phase
I trial showed that ARC183 resulted in a rapid onset of anticoagulation and the blood
coagulation effects could be rapidly reversed after the aptamer infusion stopped.
However, the phase I trial was closed for a sub-optimal dosing profile resulting from
the amount of drug needed to achieve the desired anticoagulation for use in CABG
surgery (limited literature information is available).
285
basis for a more rational design of new TBA molecules with improved therapeutic
action [33].
After then, 31TBA, HD1-22, NU172, RA-36, RE31, and some other aptamers are
modified and extended the initial 15-mer DNA aptamer with improved activity and
in vivo stability.
10.2.1.2 ARC183
Presently heparin is the only approved post-operation anticoagulant for CABG
surgery. However, heparin-protamine treatment has a number of serious side
effects, especially, asymptomatic bleeding and thrombocytopenia often result in
life-threatening arterial or venous thromboemboli [34].
ARC183 (Archemix and Nuvelo), also named TBA or HD1, is thrombin-specific
aptamer with a desirable affinity for thrombin (K d = 2 nM) and prothrombin
(K d = 50 nM) [35]. In vitro experiments showed that incubation of platelet-poor
plasma, thrombin, and ARC183 at nM concentrations resulted in prolongation
of thrombin time in a significant concentration-dependent manner. Furthermore,
ARC183 dose-dependently inhibited thrombin-catalyzed cleavage of fibrinogen and
platelet thrombin receptor (PAR-1) [36], significantly reduced thrombin-mediated
platelet degranulation and platelet aggregation in platelet-rich plasma. Therefore,
ARC183 is a strong anticoagulant that can inhibit thrombin-catalyzed activation of
fibrinogen and platelet aggregation.
A linear dose–response pharmacologic relationship between the infusion rate of
a novel thrombin aptamer and plasma PT was observed in cynomolgus monkeys.
This novel aptamer had an extremely short half-life, estimated to be 108 ± 14 s.
In addition, the aptamer inhibited thrombin-induced platelet aggregation in plateletrich plasma ex vivo but did not inhibit collagen-induced aggregation, suggesting
that the inhibition of aptamer was specific. The ability of regional anticoagulation
and the half-life of the aptamer in an extracorporeal hemofiltration circuit in sheeps
were evaluated. The authors concluded that the rapid onset of action and short halflife make the aptamer a useful anticoagulant for extracorporeal circuits and certain
acute clinical settings compared to current anticoagulant therapy [37]. Furthermore,
it prolonged activated clotting time (ACT) in a dose-related manner without acute
toxicities in monkey and dog models of CPB [29, 37]. Preliminary results of the phase
I trial showed that ARC183 resulted in a rapid onset of anticoagulation and the blood
coagulation effects could be rapidly reversed after the aptamer infusion stopped.
However, the phase I trial was closed for a sub-optimal dosing profile resulting from
the amount of drug needed to achieve the desired anticoagulation for use in CABG
surgery (limited literature information is available).