Table 2 Laboratory and clinical studies of C1-esterase inhibitor

Laboratory

Sepsis

Rat

Influence of C1 INH on microcirculation and leukocyte-endothelial interaction in the liver

Leukocyte sticking to the endothelial wall in post-sinusoidal venules was reduced in C1 INH rats. Hepatic microcirculatory disturbances may be reduced by C1 INH.

Baboon

Effect of C1 INH on physiologic and inflammatory response

C1 INH did not prevent the hemodynamic/hematologic changes. Activation of fibrinolysis and development of intravascular coagulation were unaffected. C1 INH reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appearance of C4b/c and reduced elaboration of various cytokines.

Mouse

Effect on survival

C1 INH blocked LPS-binding protein-dependent binding and suppressed LPS-induced TNF-a mRNA expression.

Mouse

Effect on survival

C1 INH enhanced the bactericidal activity of blood neutrophils and peritoneal exudate leukocytes. Survival increased with C1 INH.

Experimental endotoxemia

Rat

Effects of C1 INH on arterial oxygenation and tissue oxygenation of jejunal mucosa during endotoxemia

Decrease in arterial oxygenation was attenuated by pre-treatment with C1 INH. Tissue oxygenation decreased in LPS and C1 INH groups without significant difference after 120 minutes of endotoxemia. Endotoxin-induced tissue hypoxia of the intestinal mucosa was not prevented by C1 INH.

Rat

Effects of C1 INH on intestinal functional capillary density, leukocyte adherence, and mesenteric plasma extravasation

C1 INH reduced endotoxemia (9.5%) and attenuated intestinal leukocyte adherence in submucosal venules (35%) and mesenteric plasma extravasation (44%). C1 INH diminished changes in the intestinal microcirculation.

Mouse

Investigate the role of complement in endotoxic shock

C3- and C4-deficient mice were significantly more sensitive to endotoxin. C1 INH had a protective Effect against endotoxin.

Rabbit

Effect of antithrombin III + C1 INH on intravascular organ fibrin deposition and cardiorespiratory changes

Combined treatment was associated with decreased clot formation in lungs and livers. There was no clear dose-dependent Effect

Dog

Effect on cardiovascular and respiratory dysfunction

C1 INH prevented hypoxemia. C1 INH improved recovery of cardiac contractility and preservation of coronary vascular endothelial function.

Ischemia- reperfusion injury

Cat

Cardioprotective Effect

C1 INH improved recovery of cardiac contractility and preservation of coronary vascular endothelial function.

Rat

Cardioprotective Effect

C1 INH attenuated myocardial injury and neutrophil infiltration even after 48 hours of reperfusion.

Rat

Effect on C3 activity in ischemic myocardial tissue

C1 INH suppressed C3 mRNA expression and protein synthesis and prevented myocardial cell injury.

Rat

Protection against myocardial cell injury

C1 INH improved cardiac function and hemodynamics and reduced myocardial infarct size.

Mouse

Role and mechanism of C1 INH in alleviating intestinal injury

C1 INH reduced intestinal tissue injury and attenuated leukocyte infiltration and improved survival.

Acute pancreatitis

Mouse/Rat

Evaluate the Effect of C1 INH

C1 INH slightly ameliorated the degree of histological alterations, but increase in serum amylase was reduced in diet-induced pancreatitis only. C1 INH did not improve survival in taurocholate- and diet-induced pancreatitis.

Xenotrans- plantation

Pig

Inhibition of complement-mediated cytotoxicity and activation of endothelial cells

C1 INH inhibited C1 activation.

Pig

Effect on hyperacute rejection

Survival improved. C1 INH inhibited complement activation, and no contact activation was found. Leukocytes and platelet activation were reduced by C1 INH.

Laboratory

Xenotrans- plantation

Pig

Effect on hyperacute rejection

C1 INH attenuated hyperacute rejection by decreasing the activation of adhesion molecules.

Pig

Effect on hyperacute rejection

C1 INH at 10 U/mL prolonged survival time and diminished complement activation but did not prevent rapid lung injury.

Pig

Effect on hyperacute rejection

C1 INH improved pulmonary function but not survival.

Pig/Monkey

Effect on hyperacute rejection

C1 INH therapy with standard immunosuppressive regimen prevented rejection but did not improve survival.

Thermal injury

Pig

Effect on capillary leak syndrome and inflammatory tissue destruction

C1 INH reduced complement activation and improved clinical outcome.

Meningitis

Mouse/Rat

Effect on clinical illness, bacterial clearance, and inflammatory response

C1 INH increased bacterial clearance.

Clinical

Sepsis

Case series

Effect on functional levels on C1 INH

C1 INH may attenuate complement and contact activation.

Double-blind RCT

Efficacy and safety of C1 INH

C1 INH increased plasma C1 INH antigen and activity levels during days 1 to 4 and lowered serum creatinine concentrations on days 3 and 4. Organ failure was less pronounced. Mortality was unaffected.

Case series

Effect on neutrophil activation

Elastase-alpha(1)-antitrypsin complex and lactoferrin levels were reduced.

Open-label

Efficacy and safety of C1 INH

Complement activity was inhibited, and survival was improved.

Comparative

To measure functional C1 INH levels in newborns with culture-proven sepsis

There was no difference in functional C1 INH levels between treatment group and controls.

Ischemia-reperfusion injury

Case series

C1 INH as rescue therapy

C1 INH restored myocardial function.

Open-label

Effect of C1 INH following reperfusion

48-hour infusion of C1 INH was safe and inhibited complement activation.

Randomized, double-bind

Effects of C1 INH in ST segment elevation myocardial infarction

Arterial pressure, cardiac index, and stroke volume were improved in the C1 INH group. No adverse effects were observed

Emergency CABG

Comparative, open-label

Effect of C1 INH on complement activation, myocardial cell injury, and clinical outcome

Complement activity was reduced. There was no Effect on mortality.

Transplantation

Comparative, open-label

Efficacy

In C1 INH patients, plasma levels of C5a and C4 d and fluid levels were normalized.

Case studies

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In case 1, pleural effusions were reduced within 12 hours, leading to normal graft function within 4 days. In case 2, pleural effusions were reduced from 19 L per day to 300 mL within 3 days of treatment.