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Greg L. Plosker – 1st expert on this subject based on the ideXlab platform
Recombinant Human C1 Inhibitor (Conestat Alfa)BioDrugs, 2012Co-Authors: Greg L. PloskerAbstract:
Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation.
Recombinant Human C1 Inhibitor (Conestat Alfa)BioDrugs, 2012Co-Authors: Greg L. PloskerAbstract:
Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation. The therapeutic efficacy of conestat alfa in the treatment of angioedema attacks in patients with HAE was evaluated in two similar randomized, double-blind, placebo-controlled trials conducted in North America and Europe. The randomized controlled phases of both studies were closed after interim analyses provided compelling evidence of statistically significant positive efficacy findings and showed no apparent adverse safety findings. Results of the pooled analysis of the two trials showed that conestat alfa provided significantly faster initial relief of symptoms than placebo. The median time to the beginning of relief of symptoms (primary endpoint) was 66 minutes with conestat alfa 100 units/kg, 122 minutes with conestat alfa 50 units/kg, and 495 minutes with placebo. Conestat alfa was also statistically superior to placebo for the secondary endpoint of median time to minimal symptoms, with values of 266, 247, and 1210 minutes for the respective treatment groups. On the basis of data from open-label extension studies and integrated analyses of clinical trial data, conestat alfa has demonstrated efficacy in the treatment of repeated HAE attacks and in patients with potentially life-threatening HAE attacks with involvement of the upper airways. Conestat alfa was generally well tolerated in clinical trials, with the most frequently reported adverse event being headache. In the two randomized controlled trials, headache and vertigo were the only adverse events deemed to be related to study treatment.
Marco Cicardi – 2nd expert on this subject based on the ideXlab platform
C1 Inhibitor AutoantibodiesAutoantibodies, 2020Co-Authors: Andrea Zanichelli, Marco Cicardi, Chiara Suffritti, Roberto PerriconeAbstract:
Abstract Autoantibodies to C1 inhibitor (C1-INH) bind to epitopes on the reactive center of the C1-INH molecule. As a consequence of this binding, C1-INH is converted into an inactive substrate that can be cleaved by proteases. C1-INH is a serine protease inhibitor that plays a role in the complement, contact, fibrinolytic, and coagulation cascades. Autoantibodies to C1-INH cause acquired C1-INH deficiency, activation of the classical complement pathway, and defective control of the contact-kinin system. This eventually leads to recurrent bradykinin release with increased vascular permeability and symptoms of angioedema involving subcutaneous tissue, gastrointestinal mucosa, and the upper respiratory tract. Autoantibodies inactivate C1-INH protein and may dramatically reduce efficacy of replacement therapy with plasma derived C1 inhibitor. Autoantibodies to C1-INH have also been described in absence of angioedema symptoms. They have been found in patients with systemic lupus erythematosus (SLE), with lupus-like syndrome and anticardiolipin antibodies and in a patient with primary antiphospholipid syndrome: their effect on C1-INH function in these conditions is only partially defined.
C1 inhibitor: molecular and clinical aspectsSpringer Seminars in Immunopathology, 2005Co-Authors: Marco Cicardi, Andrea Zanichelli, Lorenza Zingale, Emanuela Pappalardo, Benedetta CicardiAbstract:
C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three β-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia–reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.
Molecular defects in hereditary angioneurotic edema.Proceedings of the Association of American Physicians, 1997Co-Authors: John J Bissler, Kulwant S. Aulak, Virginia H Donaldson, Fred S. Rosen, Marco Cicardi, Harrison Ra, Davis AeAbstract:
Thirty-eight previously unreported, unrelated patients with hereditary angioneurotic edema were studied, and each was found to have a single mutation in the C1 inhibitor gene. On the basis of serine protease inhibitor crystal structure, these and published mutations affect critical domains in the reactive center loop, alpha-helices A, B, C, E, and F, and beta-sheets A and C. Almost all mutations, other than in the reactive center loop, occur at residues that are highly conserved among serine protease inhibitors, and the others are likely to interfere with molecular movement. These mutations begin to identify residues critical for molecular function of the C1 inhibitor molecule.
Alvin E. Davis – 3rd expert on this subject based on the ideXlab platform
BIOLOGICAL ACTIVITIES OF C1 INHIBITORMolecular Immunology, 2008Co-Authors: Alvin E. Davis, Pedro Mejia, Fengxin LuAbstract:
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.
New treatments addressing the pathophysiology of hereditary angioedemaClinical and Molecular Allergy, 2008Co-Authors: Alvin E. DavisAbstract:
Hereditary angioedema is a serious medical condition caused by a deficiency of C1-Inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-Inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low – between 1:10,000 to 1:50,000 – the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation. Subnormal levels of C1-Inhibitor are associated with the inappropriate activation of a number of pathways – including, in particular, the complement and contact systems, and to some extent, the fibrinolysis and coagulation systems. Current findings indicate bradykinin, a product of contact system activation, as the primary mediator of angioedema in patients with C1-Inhibitor deficiency. However, other systems may play a role in bradykinin’s rapid and excessive generation by depleting available levels of C1-Inhibitor. There are currently no effective therapies in the United States to treat acute attacks of hereditary angioedema, and currently available agents used to treat hereditary angioedema prophylactically are suboptimal. Five new agents are, however, in Phase III development. Three of these agents replace C1-Inhibitor, directly addressing the underlying cause of hereditary angioedema and re-establishing regulatory control of all pathways and proteases involved in its pathogenesis. These agents include a nano-filtered C1-Inhibitor replacement therapy, a pasteurized C1-Inhibitor, and a recombinant C1-Inhibitor isolated from the milk of transgenic rabbits. All C1-Inhibitors are being investigated for acute angioedema attacks; the nano-filtered C1-Inhibitor is also being investigated for prophylaxis of attacks. The other two agents, a kallikrein inhibitor and a bradykinin receptor-2 antagonist, target contact system components that are mediators of vascular permeability. These mediators are formed by contact system activation as a result of C1-Inhibitor consumption.
C1 Inhibitor-Mediated Protection from SepsisJournal of Immunology, 2007Co-Authors: Fengxin Lu, Stacey M. Fernandes, Jinan Li, Alvin E. DavisAbstract:
C1 inhibitor (C1INH) protects mice from lethal Gram-negative bacterial LPS-induced endotoxin shock and blocks the binding of LPS to the murine macrophage cell line, RAW 264.7, via an interaction wi …