Table 2.
Laboratory and clinical studies of C1-esterase inhibitor
| Type of study | Indication | Model/Study type | Objective | Findings | Reference |
|---|---|---|---|---|---|
| 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. | [18] |
| 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. | [24] | ||
| Mouse | Effect on survival | C1 INH blocked LPS-binding protein-dependent binding and suppressed LPS-induced TNF-a mRNA expression. | [25] | ||
| Mouse | Effect on survival | C1 INH enhanced the bactericidal activity of blood neutrophils and peritoneal exudate leukocytes. Survival increased with C1 INH. | [26] | ||
| 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. | [19] | |
| 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. | [20] | ||
| 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. | [21] | ||
| 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 | [22] | ||
| 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. | [23] | ||
| Ischemia- reperfusion injury | Cat | Cardioprotective Effect | C1 INH improved recovery of cardiac contractility and preservation of coronary vascular endothelial function. | [27] | |
| Rat | Cardioprotective Effect | C1 INH attenuated myocardial injury and neutrophil infiltration even after 48 hours of reperfusion. | [28] | ||
| Rat | Effect on C3 activity in ischemic myocardial tissue | C1 INH suppressed C3 mRNA expression and protein synthesis and prevented myocardial cell injury. | [32] | ||
| Rat | Protection against myocardial cell injury | C1 INH improved cardiac function and hemodynamics and reduced myocardial infarct size. | [31] | ||
| Mouse | Role and mechanism of C1 INH in alleviating intestinal injury | C1 INH reduced intestinal tissue injury and attenuated leukocyte infiltration and improved survival. | [33] | ||
| 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. | [35] | |
| Xenotrans- plantation | Pig | Inhibition of complement-mediated cytotoxicity and activation of endothelial cells | C1 INH inhibited C1 activation. | [38] | |
| 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. | [39] | ||
| Laboratory | Xenotrans- plantation | Pig | Effect on hyperacute rejection | C1 INH attenuated hyperacute rejection by decreasing the activation of adhesion molecules. | [41] |
| 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. | [42] | ||
| Pig | Effect on hyperacute rejection | C1 INH improved pulmonary function but not survival. | [40] | ||
| Pig/Monkey | Effect on hyperacute rejection | C1 INH therapy with standard immunosuppressive regimen prevented rejection but did not improve survival. | [43,44] | ||
| Thermal injury | Pig | Effect on capillary leak syndrome and inflammatory tissue destruction | C1 INH reduced complement activation and improved clinical outcome. | [45] | |
| Meningitis | Mouse/Rat | Effect on clinical illness, bacterial clearance, and inflammatory response | C1 INH increased bacterial clearance. | [47] | |
| Clinical | Sepsis | Case series | Effect on functional levels on C1 INH | C1 INH may attenuate complement and contact activation. | [49,50] |
| 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. | [51] | ||
| Case series | Effect on neutrophil activation | Elastase-alpha(1)-antitrypsin complex and lactoferrin levels were reduced. | [52] | ||
| Open-label | Efficacy and safety of C1 INH | Complement activity was inhibited, and survival was improved. | [53] | ||
| 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. | [54] | ||
| Ischemia-reperfusion injury | Case series | C1 INH as rescue therapy | C1 INH restored myocardial function. | [55] | |
| Open-label | Effect of C1 INH following reperfusion | 48-hour infusion of C1 INH was safe and inhibited complement activation. | [56] | ||
| 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 | [58] | ||
| 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. | [57] | |
| Transplantation | Comparative, open-label | Efficacy | In C1 INH patients, plasma levels of C5a and C4 d and fluid levels were normalized. | [59] | |
| Case studies | - | 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. | [60] |
C1 INH, C1-esterase inhibitor; CABG, coronary artery bypass grafting; LPS, lipopolysaccharide; RCT, randomized controlled trial; TNF-α, tumor necrosis factor-alpha.