Difference between 1 2 chain forms Differences between

Difference between 1 & 2 chain forms Differences between binding of one-chain and two-chain tissue plasminogen activators to non-cross-linked and cross-linked fibrin clots, Husain SS, Hasan AA, Budzynski AZ, Blood, 1989 Aug 15; 74(3): 999 -1006

STEMI • An occlusion of a coronary artery by a thrombus or an embolus. * Sinus Rhythm with ST Elevation Normal Sinus Rhythm

Tenecteplase • The kringle 1 domain Asn 103 (←Thr), Gln 117 (←Asn) • The protease domain Ala 296– 299 * * PDB 1 BDA

Alteplase 2007311872 La Jinhwan

t-PA (Alteplase)

Contents • • • What is t-PA? Mechanism of the action Clinical Applications Pharmacokinetics Commercialized products

t-PA(tissue-Plasminogen Activator) • Glycoprotein, 527 amino acids • 68 k. Da, Single chain * • PLAT gene 32. 4 kb, 92% intron (human chromosome 8 p 12 -q 11. 2) Single m. RNA 2. 5 kb → t-PA PDB 1 A 5 H

t-PA(tissue-Plasminogen Activator) • Serine protease (endothelial cells)

Enzyme mechanism • His 322, Asp 371, Ser 478 (Catalytic Site) • Cleavage of Arg 561 -Val 562 (Plasminogen) His 322 Ser 478 Asp 371 Water

Clinical Applications • Myocardial infarction with ST-elevation (STEMI) * • Acute ischemic stroke (AIS) • Acute massive pulmonary embolism

t-PAs • Alteplase recombinant t-PA • Reteplase contains 357 of the 527 amino acids of the original protein • Tenecteplase 527, but 6 amino acids modified *

Pharmacokinetics Parameters Alteplase Tenecteplase Clearance [m. L/min] 620 ± 70 105 (mean value) t 1/2 α [min] 4. 4 ± 0, 3 17 – 24 t 1/2 β [min] 39 ± 2. 6 65 – 132 Alteplase → 05 min, 50% of dose eliminated in plasma → 10 min, 80% “ TNK-t. PA: IV injection / t-PA: IV infusion (90 min)

Products Alteplase Actilyse® Tenecteplase Metalyse® Actilyse® 318, 560 20 mg/20 m. L 794, 856 50 mg/50 m. L Vial 158, 9712 50 mg/10 m. L Metalyse®