Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema.

Quastel, Michael R.; Harrison, Richard A.; Cicardi, Marco; Alper, Chester A.; Rosen, Fred S.

doi:10.1172/jci110831

Cited by 129 publications

(56 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At these high doses, disappearance as a result of complex formation will play only a relatively minor role, as compared with hepatic removal of functional C 1-INH. This could reveal the observed FCR value of 0.011 h -1 • A similar low FCR value was found by Quastel et al 18 for a dysfunctional Cl-INH protein, Ta. They reported that Cl-INH Ta scarcely binds to Cl.…”

Section: Possible Explanations For Discrepancies In Fcr Valuessupporting

confidence: 84%

Pharmacokinetics of C1‐inhibitor protein in patients with acute myocardial infarction

Diris

2002

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Objectives: Cl-inhibitor protein (Cl-INH) purified from pooled human plasma is used for the treatment of patients with hereditary angioedema. Recently, the beneficial effects of high-dose Cl-INH treatment on myocardial ischemia or reperfusion injury have been reported in various animal models and in humans. We investigated the pharmacokinetic behavior of Cl-INH in patients with acute myocardial infarction to calculate the amount ofCI-INH required for optimal efficacy. Methods: Twenty-two patients received an intravenous loading dose, followed by 48 hours of continuous infusion of Cl-INH. Changes in the endogenous production of Cl-INH were evaluated in 16 control patients with acute myocardial infarction. A 2-compartment model was used to estimate the fractional catabolic rate constant (FCR), transcapillary escape rate constant (TER), and extravascular return rate constant (ERR) of Cl -INH. Software designed to analyze and fit measured data to unknown parameters in a system of differential equations was used to fit the experimental data against the 3-parameter model. Maastricht and Amsterdam, The NetherlandsCl-inhibitor protein (Cl-INH), a protein of approximately 104 kd, regulates the classical activation pathway of the complement system. 1 Patients with hereditary angioedema (HAE), in whom there is a congenital lack of Cl-INH, have attacks of uncontrolled complement activation that may lead to life-threatening laryngeal obstruction or swelling of the gastrointestinal mucosa.2 Depending on the severity of the edematous attack, treatment of patients with HAE usually consists of one or more bolus injections of CI-INH purified from pooled human plasma.

show abstract

Section: Possible Explanations For Discrepancies In Fcr Valuessupporting

confidence: 84%

Pharmacokinetics of C1‐inhibitor protein in patients with acute myocardial infarction

Diris

2002

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

show abstract

“…6 h, respectively. Both these values reflect faster plasma clearance rates than the t ½ of 20 h reported earlier by Quastel et al [22] for the turnover of human C1INH in humans. This discrepancy between the turnover rates of intact human C1INH in humans and in guinea pigs is probably explained on the basis of the host used.…”

Section: Discussionsupporting

confidence: 63%

The catabolism of intact, reactive centre-cleaved and proteinase-complexed C1 inhibitor in the guinea pig

Malek

Aulak

Davis

1996

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARYClearance rates in the guinea pig were determined for intact guinea pig and human C1 inhibitor, the complexes of both inhibitors with human C1s,¯factor XIIa and kallikrein, and for each inhibitor cleaved at its reactive centre with trypsin. Intact human and guinea pig C1 inhibitor were cleared from the circulation more slowly (t ½ s of 9 . 7 h and 12 . 1 h and fractional catabolic rates (FCRs) of 0 . 09 and 0 . 117) than any of their cleaved or complexed forms. The reactive centre-cleaved inhibitors were cleared with half-lives of 6 . 75 h for humans and 10 . 1 h for the guinea pig. The complexes with target proteases were catabolized much more rapidly, with half-lives ranging from 3 . 08 h to 4 . 3 h. The complexes with kallikrein were cleared more slowly than those with C1s and¯factor XIIa. Complexes prepared with the guinea pig and human inhibitors were cleared at equivalent rates. The free inactivated proteases were cleared at rates similar to the equivalent complexes, except for kallikrein, which was cleared more rapidly than its complex. The fact that the complexes with different target proteases differed in their catabolism and that protease and complex catabolism were similar suggests that protease may play a direct role in clearance.

show abstract

“…Typically, in HAE functional values of C1 inhibitor are less than 50%. 9 This patient had idiopathic urticaria.…”

Section: Discussionmentioning

confidence: 93%

A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency

Gompels¹,

Lock²,

Morgan³

et al. 2002

Journal of Clinical Pathology

View full text Add to dashboard Cite

Aim: To determine the diagnostic efficiency of assays routinely used in the investigation of hereditary angiooedema. Methods: Over a four year period, 1144 samples were received for analysis from 907 patients suspected of C1 inhibitor deficiency. Analyses were performed for C4 and C1 inhibitor (functional and immunochemical). Notes were reviewed retrospectively on patients with low serological indicators to determine diagnosis. Results: These are the first data to indicate the sensitivity, specificity, and predictive values of the assays most frequently used to screen for C1 inhibitor deficiency. A combination of low C4 and low C1 inhibitor function has 98% specificity for C1 inhibitor deficiency in this population and a 96% negative predictive value, and is thus a very effective screen. All patients with untreated C1 inhibitor deficiency had a low C4 value. Conclusions: All patients considered for a diagnosis of C1 inhibitor deficiency should have serum examined to measure both C4 and functional C1 inhibitor. If either is normal at presentation this essentially excludes a diagnosis of C1 inhibitor deficiency. These tests can be performed sequentially. If C4 is normal it is not necessary to proceed to C1 inhibitor analysis. If C1 inhibitor function and C4 are both low then a repeat sample should be obtained to confirm the findings. C 1 inhibitor is a serine protease inhibitor that is involved in the regulation of several enzymes including C1r, C1s, plasmin, kallikrein, factor XIa, factor XIIa, and factor XIIf. 1 Deficiency results in recurrent oedema affecting primarily the extremities, face, larynx, and gastrointestinal mucosa. Insufficient normal C1 inhibitor leads to uncontrolled activation of the classical complement pathway, with subsequent reduction of serum C4 and C2 concentrations. 1 C1 inhibitor deficiency may be either hereditary (hereditary angio-oedema; HAE) or acquired. 1 2 HAE has two major variants. In type 1, the classic form, found in 85% of patients, concentrations of C1 inhibitor are low at presentation. The remaining 15% have type 2 HAE, where a dysfunctional C1 inhibitor is produced in normal or increased amounts. 3 The disorder is rare, with HAE affecting around 1 in 10 000-50 000 of the population, 4 and the acquired form affecting a 10th of that number. The diagnosis is important because there is a high associated morbidity and mortality. There are potent and effective treatments available, particularly the androgenic drugs. These may result in serum concentrations of C1 inhibitor and C4 reaching normal values, 5 but the side effects are potentially serious and include hepatocellular adenoma. 6 To our knowledge, there are no data in the literature to indicate the sensitivity, specificity, and predictive values of the assays most frequently used to screen for C1 inhibitor deficiency (C1inhD); namely, serum C4, C1 inhibitor protein, and C1 inhibitor function. We reviewed the data from two laboratories over four years on samples referred from three centres for C1 inhibitor values and reviewe...

show abstract

Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema.

Cited by 129 publications

References 14 publications

Pharmacokinetics of C1‐inhibitor protein in patients with acute myocardial infarction

Pharmacokinetics of C1‐inhibitor protein in patients with acute myocardial infarction

The catabolism of intact, reactive centre-cleaved and proteinase-complexed C1 inhibitor in the guinea pig

A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency

Contact Info

Product

Resources

About