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At least 19 recordsLinked to original sources
PubMed2026

Efficacy and Safety of the C3 Inhibitor Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of the complement C3 inhibitor pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies reporting pegcetacoplan use in PNH. Outcomes included transfusion-requirement, hemoglobin normalization, mean hemoglobin levels, lactate dehydrogenase normalization, reticulocyte count normalization, and safety endpoints. Pooled proportions with 95% confidence intervals were calculated using random-effects models, and heterogeneity was assessed using the I2 statistic. RESULTS: Five studies comprising 271 patients were included. Transfusion avoidance was observed in 80.6% of patients, with a pooled transfusion-requirement rate of 19.4%. LDH normalization occurred in 68.5% of patients (I2 = 0%). Hemoglobin normalization was observed in 42.9%, while reticulocyte count normalization reached 66%. Any-grade adverse events occurred in 83.5% of patients, most commonly pyrexia, headache, and dizziness. Serious adverse events occurred in 16.6%, decreasing to 12% after sensitivity analysis. Breakthrough hemolysis was reported in 14.8%, and infections in 17%. CONCLUSION: Pegcetacoplan demonstrates consistent efficacy signals across key hematologic endpoints and an acceptable safety profile, supporting its potential role as an important therapeutic option, particularly in patients with persistent extravascular hemolysis despite C5 inhibition.

Humans↗
PubMed1979

Proteinase inhibitors in severe inflammatory processes (septic shock and experimental endotoxaemia): biochemical, pathophysiological and therapeutic aspects.

Plasma levels of antithrombin III, alpha 2-macroglobulin and inter-alpha-trypsin inhibitor, as well as those of various clotting, complement and other plasma factors, were significantly decreased in 18 patients suffering from hyperdynamic septic shock. A similar statistically significant reduction of the concentrations of several plasma factors (prothrombin and antithrombin III, plasminogen and alpha 2-plasmin inhibitor, complement factor C3 and clotting factor XIII) was observed in experimental endotoxaemia. In this model the reduction in the plasma levels of these factors was considerably diminished by the intravenous injection of a granulocytic elastase--cathepsin G inhibitor of lower molecular weight from soybeans. The results of both studies indicate that consumption of plasma factors in the course of Gram-negative sepsis proceeds not only via the classical routes (by activation of the clotting, fibrinolytic and complement cascades by system-specific proteinases such as thrombokinase or the plasminogen activator) but also to an appreciable degree of unspecific degradation of plasma factors by neutral proteinases such as elastase and cathepsin G. The endotoxin-induced release of both sorts of proteinases, the system-specific ones and the unspecific lysosomal proteinases from leucocytes and other cells, is likely to be mainly responsible for the consumption of antithrombin III and alpha-2-macroglobulin via complex formation (followed by elimination of the complexes) and the increased turnover of the inter-alpha-trypsin inhibitor as observed in the clinical study. The therapeutic use of an exogenous elastase--cathepsin G inhibitor in the experimental model was stimulated by the observation that human mucous secretions contain and acid-stable inhibitor of the neutral granulocytic proteinases, called HUSI-I or antileucoproteinase. This inhibitor protects mucous membranes and soluble proteins against proteolytic attack by leucocytic proteinases released in the course of a local inflammatory response. Preliminary results indicate that HUSI-I, which is produced by the epithelial cells of mucous membranes, does not belong to any known structural type of acid-stable proteinase inhibitor. The search for other candidates suitable for medication in humans led to the discovery of a potent elastase--cathepsin G inhibitor, called eglin, in the leech Hirudo medicinalis. This acid-stable inhibitor with a molecular weight close to 8100 has an unusual structural property in that the structure of the molecule is not stabilized by any disulphide bridge.

Adolescent↗
PubMed1975

Protease inhibitors in plasma of patients with chronic urticaria.

The hypothesis that deficiencies of plasma protease inhibitors might play a role in the pathogenesis of chronic urticaria was evaluated. Plasma levels were measured in patients with urticaria and a matched control group for alpha1-antitrypsin, alpha2-macroglobulin, total trypsin-inhibiting capacity, kallikrein-inhibiting capacity, and the complement factors C1 esterase inhibitor, C3, and C4. A total of 92 patients with chronic urticaria or more than three months' duration was studied. Patients with acquired cold urticaria had significantly decreased levels of alpha1-antitrypsin and total antitrypsin activity. In patients with acquired angioneurotic edema, alpha1-antitrypsin levels and antichymotrypsin activities were lowered, with less significant decreases in anti-trypsin and antikallikrein activities. Levels of C1 esterase inhibitor , C3, and C4 were normal in all groups. There was no correlation between the increased sensitivity to intracutaneously administered kallikrein injection and deficiencies of of protease inhibitors.

Adolescent↗
PubMedDate not supplied

Humoral and cellular immunity in chronic urticaria.

In chronic recurrent urticaria of months' or years' duration, it is difficult to identify the causative factor. From an immunological point of view, various authors have attempted to demonstrate alterations in levels of immunoglobulins and complement fractions. We do not know of any previous studies of cellular immunity in this disorder. Fifty-one patients with chronic urticaria were studied, 22 females and 29 males, with ages ranging from 8 to 70 years. The patients were considered to be affected by recurrent or chronic urticaria with no clear allergic etiology. In all subjects a determination was made of serum levels of immunoglobulins G, A, M and E and of the complement fractions: C1 inhibitor, C1q, C3, C4 and C5. In addition, a study of cellular immunity was carried out on these patients. The results of tests of humoral immunity in the group of chronic urticarial patients studied showed only an increase of IgM in 41.7%. No significant changes were noted among the complement fractions. The study of cellular immunity gave normal figures for total and for B and T lymphocytes. The only finding which may be worthy of is a slight decrease in active T lymphocytes. The lymphocyte transformation test also gave a normal response to PHA and overall a normal cellular immunity was shown in these patients. At present we do not consider that the increased IgM in 40 to 45% of the cases has any pathogenic diagnostic value.

Adolescent↗
PubMed1978

Translocation of a hydrocarbon fluorescent probe between Epstein-Barr virus and lymphoid cells: an assay for early events in viral infection.

Translocation of the hydrocarbon fluorescent probe diphenylhexatriene (DPH) between membranes was studied by fluorescence polarization (P) analysis. First, using a model system, the high P value (0.324) of DPH-labeled cholesterol/phosphatidylcholine liposomes and the low P value (0.157) of DPH-labeled phosphatidylcholine liposomes allowed detection of DPH translocation between interacting liposomes. This was monitored by the change in P in either direction. Early events during cell-virus interactions were similarly studied by monitoring DPH translocation. The P value of DPH-labeled Epstein-Barr Virus (EBV) was significantly higher (0.350-0.392) than the P value of DPH-labeled lymphoid cells (0.238-0.289). Hence, DPH translocation could be detected by changes in P following incubation of DPH-labeled EBV and nonlabeled cells. A marked decrease in P was observed after incubation of DPH-labeled EBV with either nonlabeled lymphoblastoid Raji cells or fresh human B lymphocytes. However, only a slight decrease in P was obtained when DPH-labeled EBV was incubated with either nonlabeled fresh human T lymphocytes or fresh T or B rabbit lymphocytes. Moreover, incubation of fresh human B lymphocytes with the purified C3 component of complement (a putative inhibitor for the EBV receptor) prior to the addition of DPH-labeled EBV abolished the observed decrease in the P value. Most of these experiments were carried out with both the P3HR-1 and the B95-8 strains of EBV. DPH translocation, as determined by fluorescence polarization analysis, is, therefore, measuring some early event during interaction of this enveloped virus and mammalian cells. The potential applicability of this technique to other viruses is illustrated by an experiment with Semliki Forest virus.

Cells, Cultured↗
PubMed1978

Serum proteins in heavily burnt patients.

Several serum proteins, such as prealbumin, protease inhibitors, immunoglobulins, metalloproteins and inflammatory glycoproteins were determined in the sera of heavily burnt patients by radial immunodiffusion. An increase of acute phase reactant glycoproteins (orsomucoid, haptoglobin, haemopexin, C-reactive protein), C3-complement, immunoglobulins, prealbumin and of the protease inhibitors (a1-antitrypsin, a2-macroglobulin) was found. For some proteins, such as prealbumin, haemopexin, immunoglobulins, this increase was preceeded by a decrease on days 3 to 5 post-burn. The time course of the increase was variable, faster for some patients and slower for others: orosomucoid, C-reactive protein, C3-complement reached peak values between days 6 and 8; immunoglobulins and hemopexin decreased then towards normal values. No significant increase was found for ceruloplasmin, transferrin, beta2-glycoprotein, a2-SH glycoprotein and GC-globulin. It is proposed that the selective overproduction of the above mentioned proteins may be related to the stimulation of acute-phase reactant protein synthesis by the liver as a result of tissue breakdown produced by the circulating proteases and especially by elastases and collagenases as was shown previously (Miskulin et al., 1978; Moati et al., 1978a).

Blood Proteins↗
PubMed1975

Phylogeny of complement components in non-human primates.

The antigenic properties and functional activities of complement components were analyzed in primates to determine their relative evolutionary development. The sera of eight different sub-human primate species were examined by double diffusion in agar and compared to a pool of human serum with rabbit and goat antisera to human complement components Clq, Cls, C4, C2 C3, C5, C6, C8, C9, properdin, factor B (B), and C1 inhibitor. There are no apparent antigenic differences in complement proteins between man and the apes except for C1q. Old world monkeys are antigenically deficient in Clq,C1s, C9, and variably deficient in C4, C3, and C8. New World monkeys are antigenically deficient in all components (measured) except C5, C6, and properdin factor B. Prosimians are antigenically deficient in all components. Functional analyses of complement components showed similar levels in man and primates, except in prosimians. There is a dissociation between hemolytic assays and antigenic analyses, suggesting that functional sites may be separate from antigenic sites.

Absorption↗
PubMed1977

A second case of human C3b inhibitor (KAF) deficiency.

The second case of C3b inhibitor deficiency is described in an 11-year-old girl who presented with recurrent attacks of meningitis, in between which she was well. Her serum showed all of the complement component changes noted in the first described case, although showing only a relatively slight defect in its ability to opsonize bacteria for phagocytosis and killing by polymorphonuclear leucocytes. This correlated with the patient's freedom from other infections.

Chemotaxis, Leukocyte↗
PubMed1977

[Serum concentrations of proteinase inhibitors, complement components and of acid alpha-1-glucoprotein in children with myocarditis (author's transl)].

We examined 4 panels of children and 40 control patients for their serum levels of the complement components C3, C4 and the C3 activator, the proteaseinhibitors alpha-1-antitrypsin, alpha-2-macroglobulin and acid alpha-1-glycoprotein. Children of the group with active myocarditis revealed the consumption of the complement system, increased protease inhibitors and elevated acid alpha-1-glycoprotein. Group 2, children with the clinical diagnosis chronic myocarditis or status post myocarditis showed in six of seven cases low complement levels and elevated alsGP. 4 children showed increased A1AT and five increased A2MG. In the third panel: status post myocarditis, we estimated in five of eight patients complement activation, 4 children showed increased A2MG and alsGP and in 3 cases elevated A1AT levels were detected. Group 4 children revealed no complement consumption and showed no increased levels for the other proteins estimated, with the only exception of 1 case with increased alsGP. The children of the control group showed normal levels for the six proteins. By means of the examinations an inflammatory process can be detected, tissue injury can be indicated and the participation of the immune system can be shown.

Adolescent↗
PubMed1976

Collagenase and elastase released during peritonitis are complexed by plasma protease inhibitors.

Peritoneal fluids from patients with diffuse peritonitis secondary to perforation of the appendix contained large quantities of collagenase and elastase. The enzymes, which existed in the form of complexes with plasma protease inhibitors, probably had been released from the granulocytes. The two enzymes had linked almost half of the alpha 1-antitrypsin and four fifths of the alpha 2-macroglobulin in the fluid. Evidence that regional defense against protease had failed was obtained by finding the C3 component of complement completely converted. Toxic peptides probably had been released. Recognition of plasma protease inhibitors as an important part of the regional defense against protease also suggested use for therapy. We lavaged the peritoneum postoperatively with fluid that did not contain plasma inhibitors but with volumes large enough to eliminate the accumulation of enzymes for the granulocyte.

Adult↗
PubMed1976

Separation of six bovine complement components and one inactivator (1, 2).

Six components (C1, C5, C6, C7, C8 and C9) of bovine complement and one inactivator (C3 in) could be separated from bovine serum. Bovine C1 was separated by precipitation at low molarity (0.03 M of relative salt concentration) other components by DEAE-cellulose chromatography using 0.005 M sodium phosphate buffer, pH 7.5, as a base for solvents having the relative salt concentration adjusted by addition of NaCl from 0.03 to 0.3 M. The separated bovine complement components could be tested using intermediates formed from sheep erythrocytes, rabbit hemolysin, guinea pig C1 and remaining human complement components. C2, C3 and C4 of bovine origin remained undetected either because of incompatibility with the intermediates used or interference of inhibitors or inactivators.

Animals↗
PubMed1975

Alternate complement pathway induction of aggregation and release of 5-hydroxytryptamine and adenosine diphosphate by rabbit platelets.

The present studies investigated patterns of rabbit platelet aggregation and release of 5-hydroxytryptamine (5HT) utilizing nine variables: three different types of challenge, soluble antigen and antibody (AG-AB), zymosan (Z), an agent known to activate the alternate complement pathway (ACP), and Z preincubated in lightly heparinized plasma so as to become coated with complement (ZC); three different types of platelet-rich plasma (PRP), lightly heparinized PRP in which both complement pathways are active, ethylene glycol tetraacetic acid-PRP (EGTA-PRP) in which only the ACP is active, and ethylene diamine tetraacetic acid PRP (EDTA-PRP), which inhibits both complement pathways; three different types of inhibitors, cobra venom factor (CoF), which causes activation of C3 proactivator (C3PA) to C3 activator (C3A) and fluid phase decomplementation of C3 and C5 through C9, adenosine monophosphate (AMP), a specific antagonist of ADP, and tosyl arginine methyl ester (TAME), an inhibitor thought to act not only on the first component of complement, but also on a platelet membrane site of mediating complement-induced platelet injury as well as on C3PAse. In heparinized PRP, both AG-AB and Z produced biphasic aggregation and prompt and extensive 5HT release. A brief lag period noted with both AG-AB and Z challenge was not observed with ZC challenge, indicating that this lag period represented time required for generation of the necessary complement-dependent membrane-injuring activity. Prior decomplementation by CoF entirely prevented both aggregation and release by either AG-AB or Z but by ZC, indicating first that fluid-phase ACP activation did not produce platelet injury, and second that ZC had on its surface an activity capable of producing immediate biphasic aggregation and prompt 5HT release without the further participation of later acting complement components. Both AMP and TAME eliminated the second phase of aggregation and diminished or eliminated 5HT release with all three challenges, suggesting that both inhibitors might be operative on similar or identical platelet membrane receptors mediating complement-dependent platelet injury. In EGTA-PRP, AG-AB and Z produced delayed monophasic aggregation and delayed and diminished 5HT release, whereas ZC produced immediate although monophasic aggregation but delayed and diminished 5HT release. This suggested that all three challenges were capable of producing ACP-mediated platelet injury.

Adenosine Diphosphate↗
PubMed1979

Effect of a streptococcal preparation on the complement system.

Streptococcal preparation OK-432 (Picibanil), clinically being used as an immunopotentiator, has been shown to activate the complement system either through the classical or the alternative pathway in vitro [15]. In this experiment, OK-432 was found to increase serum complement level in guinea pigs, and in human without malignancy, when investigated by hemolytic assay using sensitized sheep erythrocytes (EA) for the classical pathway activity and unsensitized rabbit erythrocytes (RaE) for the alternative pathway activity. Assay of complement components revealed a significant increase in C3, but decrease in Clq, while no specific tendency was observed in C4, C5, C9, properdin, C3 activator and Cl-inhibitor. These evidences suggested that OK-432 might potentiate immune response of the host by elevating serum complement level, in addition to activate the complement system.

Aged↗
PubMedDate not supplied

[Hereditary angioedema by defict of C1 esterase. Our experience in 8 cases].

Eight cases of hereditary angioedema, all of them with low values of C1-sterase inhibitor are analyzed. In 7 cases the C3 and C4 components of the complement were assessed; the results showed marked descent of C4. The 8 patients came from 4 different families; only 2 of them were males. Six patients presented digestive disorders, reporting colic pain, nausea and vomiting. In 1 of them the abdominal picture was the only evidence of the disease. In 5 patients the angioedema episodes occurred following traumatisms and in 3 because of emotional states. The duration of the attacks varied from several hours to six days. There was a familial history in all cases. Three of the patients had repeated episodes of pharyngolaryngeal angioedema, two of them requiring emergency tracheotomy because of suffocating crisis. Six patients were treated with Epsilon aminocaproic acid (16 to 20 gr daily) or with tranexamic acid (1 to 3 gr. daily). In 4 cases the results were excellent with either of these antifibrinolytic drugs. No side effects were observed in the tranexamic acid therapy whilst they were frequent in the treatment with Epsilon aminocaproic acid.

Adolescent↗