Biomedical Engineering Reference
In-Depth Information
33
AMEDIPLASE
S TEFANO E VANGELISTA AND S TEFANO M ANZINI
Menarini Ricerche SpA, Preclinical Development, Florence, Italy
33.1 Introduction
33.2 Source, physico-chemical properties and formulation
33.3 Preclinical studies
33.4 Human studies
33.5 Historical comparison with other thrombolytics
33.6 Conclusions and future perspectives
Acknowledgment
References
anistreplase (APSAC). On the other hand, fibrin-specific
agents (i.e., agents whose proteolytic activity is greatly
enhanced by fibrin binding) are alteplase (rt-PA), saruplase
(unglycosylated human rscu-PA), reteplase, and tenececte-
plase (TNK-t-PA) differing for tPA length, glycosylation sites,
and some crucial amino acids. See their schematic structure in
Figure 33.1.
Even if thrombolytic efficacy of all these drugs has been
established; each agent has different advantages and dis-
advantages in terms of time-to-reperfusion, reocclusion rate,
systemic fibrinolysis, immunogenicity, and so on [5].
Different approaches have been explored to improve
thrombolytic treatment, including the construction of mutants
and variants of t-PA and u-PA and of chimeric PAs. t-PA is a
single chain molecule that can be converted to a two-chain
structure by a specific plasmin cleavage at Arg 275 -Ile 276 bond.
The NH 2 -terminal heavy chain (A chain) comprises four
structural/functional domains: a finger region (F), a region
similar to human EGF (E); and two kringles (K 1 and K 2 ).
These domains are autonomous entities that regulate plasma
clearance (E and F), lysine binding (K 1 andK 2 ), fibrin binding
(F and K 2 ), while the protease activity resides in the COOH-
terminal chain (B chain) [6]. Pro-urokinase, or single-chain u-
PA (scu-PA) is a single chain glycoprotein that, at variance
with t-PA, is enzymatically active only after limited cleavage
(by plasmin or kallikrein) at the Lys 158 -Ile 159 bond to give
two-chain u-PA (tcu-PA). The catalytic center is located in the
COOH-terminal part of scu-PA. Although it has no affinity for
fibrin, scu-PA preferentially cleaves fibrin-bound plasmino-
gen, and the sites responsible for the formation of the func-
tional complex appear also to be located in the COOH
terminus of scu-PA [7].
Amediplase (K 2 tu-PA, product code MEN 9036) was
constructed as a hybrid PA comprising just the kringle 2
33.1
INTRODUCTION
Acute myocardial infarction (AMI) is the leading cause of
cardiovascular mortality in the Western countries [1]. In the
United States, the incidence of new myocardial infarction is
high; accounting as 25.4% of the total annual deaths [2].
More than 250,000 people die within 1 h from the onset of
symptoms and before ever reaching a hospital. The rapid
restoration of coronary patency is the main goal of critical
care therapy in subjects with AMI [3]. Thrombolytics
represent the main pharmacological tool for rapid induction
of coronary recanalization [4].
Amediplase is the result of a project aimed to identify and
develop a recombinant plasminogen activator (PA) with
outstanding fibrinolytic activity, high level of fibrin speci-
ficity, prolonged half-life, and no immunogenicity to be used
as a single bolus agent in AMI.
All fibrinolytic agents act, directly or indirectly, as PAs, but
they can be subdivided according to the fibrin dependency of
their action in nonfibrin-specific and fibrin-specific agents.
Nonfibrin-specific agents are streptokinase (SK), urokinase
(u-PA, also known as two-chain urokinase, tcu-PA), and
Search WWH ::




Custom Search