The inhibition of TNK-t-PA by C1-inhibitor

Sulikowski, T.; Patston, Philip A.

doi:10.1097/00001721-200101000-00011

Cited by 12 publications

(7 citation statements)

References 15 publications

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“…[17][18][19][20][31][32][33][34][35] An effect of C1INH on the balance between coagulation and fibrinolytic proteases is expected to take place at the time that C1INH activity levels in the circulation are increased after infusion of rhC1INH, which is within the first few hours after infusion. [17][18][19][20][31][32][33][34][35] An effect of C1INH on the balance between coagulation and fibrinolytic proteases is expected to take place at the time that C1INH activity levels in the circulation are increased after infusion of rhC1INH, which is within the first few hours after infusion.…”

Section: Discussionmentioning

confidence: 99%

“…4. Similarly, plasminogen activator inhibitor-1 (PAI-1), a main inhibitor of tPA in vivo, has a second order rate inhibition constant of 1.1 · 10 7 M -1 s -1 [40] compared with that of 0.45 · 10 1 M -1 s -1 for the interaction of tPA and C1INH, [20] which predicts that only at very low PAI-1 concentrations C1INH may contribute to some extent to the inhibition of tPA. Data are median and interquartile range (bars) of levels relative to baseline levels, which were set to 100% in each individual patient.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant C1-Inhibitor

et al. 2012

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Coagulation and fibrinolytic systems are activated in HAE patients suffering from an acute angioedema attack. Treatment with rhC1INH at 50 or 100 U/kg had no effect on parameters reflecting activation of these systems except for a significant effect on aPTT, which likely reflects a pharmacodynamic effect of rhC1INH, and a reduction on plasma levels of the prothrombin activation fragment F1+2. We conclude that these results argue against a prothrombotic effect of treatment with this rhC1INH product in HAE patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Recombinant C1-Inhibitor

et al. 2012

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“…, asymptomatic patients; , healthy volunteers; , symptomatic patients pathways, besides activated C1s. Also, several mediators of the haemostatic and fibrinolytic pathways are target proteases of C1INH, specifically Factor XIIa, kallikrein and Factor XIa and, to a lesser extent, tissue plasminogen activator, thrombin and plasmin [16][17][18][19][20].…”

Section: Figurementioning

confidence: 99%

Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

Farrell¹,

Hayes²,

Relan

et al. 2013

Brit J Clinical Pharma

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AIMSTo characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients. METHODSPlasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme. RESULTSA one-compartment model with Michaelis-Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839-0.968] and 0.176 U ml -1 (95% CI: 0.154-0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68-3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml -1 h -1 (95% CI: 1.41-1.88) and 1.60 U ml -1 (95% CI: 1.14-2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml -1) for at least 94% of all patients. CONCLUSIONSThe population PK model for C1INH supports a dosing scheme on a 50 U kg -1 basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration.

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“…C1 inhibitor also can inactivate several other proteases, including plasmin and tissue plasminogen activator (tPA)(Harpel and Cooper, 1975; Huisman et al, 1995; Ranby et al, 1982; Ratnoff et al, 1969; Sulikowski and Patston, 2001). Although C1 inhibitor does not appear to play a significant role in the inactivation of plasmin in vivo , it may, under some circumstances, contribute to inactivation of tPA (Aoki et al, 1977; Harpel, 1981; Huisman et al, 1995).…”

Section: Activities Of C1 Inhibitormentioning

confidence: 99%

Biological activities of C1 inhibitor

Davis

Mejia

2008

Molecular Immunology

262

202

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Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.

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The inhibition of TNK-t-PA by C1-inhibitor

Cited by 12 publications

References 15 publications

Recombinant C1-Inhibitor

Recombinant C1-Inhibitor

Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

Biological activities of C1 inhibitor

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