Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary angioedema is a rare disease resulting from a lack of functional C1 esterase inhibitor (C1 INH). Several genetic defects can cause decreased production of the protein or the synthesis of a biologically inactive form. A similar, acquired condition is occasionally seen, associated with malignancies or as an autoimmune process. Disease severity varies greatly among affected individuals. Most patients have cutaneous, laryngeal, or gastrointestinal edema, often in combinations. The symptoms may appear spontaneously or result from a stimulus, usually trauma. When clinical suspicion exists, measurement of the C4 level screens for the disease. An assay showing low serum C1 INH function confirms the diagnosis. When disease severity warrants, symptoms can be controlled with anabolic steroids or antifibrinolytics. Doses should be increased before symptom-provoking events. Emergencies are treated with plasma infusions, fluids, and pain control. Where available, C1 INH concentrate is the treatment of choice. Therapy can usually be monitored by control of symptoms. With appropriate therapy, most cases remain well controlled.
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PMID:Hereditary angioedema. 143 45

Bradykinin (BK), an important mediator of allergic reactions and pain induction, is released by the activation of the plasma kallikrein-kinin (K-K) cascade. Neurotropin is a biological material obtained from inflamed rabbit skin inoculated with vaccinia virus and is widely used clinically in Japan as an effective agent for these disorders. Since its mechanism of action is not clearly known, we have investigated the effects of Neurotropin on the human plasma K-K system. In dextran sulfate-activated plasma, Neurotropin inhibited the formation of BK, the cleavage of high molecular weight kininogen (HK) and the formation of kallikrein-C1 inhibitor and activated coagulation factor XII (FXIIa)-C1 inhibitor complexes. Experiments using purified enzyme of the K-K cascade indicated that Neurotropin inhibited surface-mediated activation of coagulation factor XII (FXII) and the activation of prekallikrein by FXIIa. Neurotropin also inhibited the binding of FXII and HK to the activating surface. These data suggest that the ameliorating effects of Neurotropin in allergic disorders and pain syndromes may be related to this ability to inhibit activation of the K-K cascade and consequently the formation of BK.
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PMID:Effect of Neurotropin on the activation of the plasma kallikrein-kinin system. 156 87

The hereditary angioedema (HAE) is an autosomal dominant transduced illness. Patients suffer from severe attacks with circumscribed swellings of the skin, or of the gastro-intestinal mucosa, or of whole organs. Laryngeal edema is responsible for airway obstruction and often for sudden death. Very often the abdominal symptoms are leading to false diagnosis and treatment. The diagnosis is proved by estimation of lowered C1-inhibitor (C1-INH) activity. The defect of C1-INH is responsible for the activation of the start phases of the complement system and of the kinin system. The liberation of vasoactive peptides and kinins induces the edematous swellings and severe pain. The acute symptoms of HAE are promptly resolved by intravenous application of C1-inhibitor concentrate.
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PMID:[Pathogenesis of hereditary angioedema]. 361 44

In vitro complement activation has been detected during passage of blood through tubing used in hemodialysis and cardiopulmonary bypass surgery, in addition to tubing being investigated for vascular grafts. Because tubing from arterial lines and central venous catheters are composed of similar materials and are used when blood is withdrawn from patients for complement assays, a study was undertaken to assess the degree of complement activation in blood obtained from these sites. Complement activation was determined by a terminal complement complex enzyme-linked immunosorbent assay (ELISA), C1rC1s-C1 inhibitor complex ELISA, and 50% complement hemolytic activity (CH50) assay. Blood simultaneously obtained from the arterial lines and central venous catheters had identical terminal complement complex, C1rC1s-C1 inhibitor complex, and CH50 levels when compared with blood withdrawn by antecubital phlebotomy. Because blood may be obtained from the arterial lines and central venous catheters for complement assays, the pain and possible bruising from antecubital phlebotomy could be eliminated. Furthermore, blood may now be withdrawn from indwelling catheters without fear of in vitro complement activation causing a misinterpretation of results.
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PMID:Identical complement concentrations in blood obtained from central venous catheters, arterial lines, and antecubital phlebotomy. 365 27

Angioneurotic oedema is a rare disease caused by Cl esterase inhibitor deficiency. Hereditary angioneurotic oedema includes type I (quantitative and functional) deficiency and type 11 (functional) deficiency. Its prophylactic treatment during pregnancy, based on danazol therapy if the fetus is male, may avoid acute attacks of generalized or laryngeal oedema. It must be instituted before delivery and carried into the postpartum period. If the fetus is female, epsilon aminocaproic acid may be used. The acquired form of angioneurotic oedema can be due to antibodies to C1 esterase inhibitor. A prophylactic therapy is not well established, but high doses of corticosteroids are recommended. Operative delivery is best avoided when possible. Regional analgesia is indicated for labour or caesarean section to prevent pain and stress and to avoid the difficulties associated with laryngeal oedema and tracheal intubation. In the treatment of an acute attack, Cl esterase inhibitor concentrates (1500 units) may be given i.v. We present two cases, one of hereditary and one of acquired angioneurotic oedema, both presenting during pregnancy and both delivered vaginally under epidural analgesia with successful outcome.
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PMID:Parturition and angioneurotic oedema. 1532 Nov 58

Neuroinflammatory and neuroimmune mechanisms, as exemplified by infiltrating immune cells and activation of resident endothelial/glial cells, respectively, are known to be involved in the establishment and maintenance of chronic pain. An immune system pathway that may be involved in the activation of both immune and glial cells is complement. The complement pathway is made up of a large number of distinct plasma proteins which react with one another to opsonize pathogens and induce a series of inflammatory responses to help fight infection. Cleaved products and complexes produced by complement activation are responsible for a range of effects including mediation of immune infiltration, activation of phagocytes, opsonization/lysis of pathogens and injured cells, and production of vasoactive amines such as histamine and serotonin. Gene-expression microarray-analysis performed on the rat spinal nerve ligation (SNL) model of neuropathic pain revealed that multiple complement components including the C1 inhibitor, C1q alpha, beta, and gamma, C1r, C1s, C2, C3, C4, C7, and factors B, D, H, and P, were up-regulated while DAF was down-regulated. Regulation of C3 and DAF was confirmed by real-time RT-PCR and in situ hybridization. To test the hypothesis that complement plays a role in neuropathic pain, SNL rats were treated with cobra venom factor (CVF) to deplete plasma of complement component C3. Pain behavior was significantly attenuated in SNL rats treated with CVF as was complement activity at the ipsilateral dorsal root ganglia. Our results suggest the complement pathway might be a novel target for the development of neuropathic pain therapeutics.
Pain 2008 Jul
PMID:Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain. 1816 Feb 18

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.
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PMID:New treatments addressing the pathophysiology of hereditary angioedema. 1841 Jun 89

Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed.
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PMID:Treatment of hereditary angioedema: current perspectives. 1907 6

Hereditary and acquired angioedema (HAE/AAE) are the clinical translation of a qualitative or a quantitative deficit of C1 esterase inhibitor (C1 INH). The frequency and severity of clinical manifestations vary greatly, ranging from a moderate swelling of the extremities to obstruction of upper airway. Anaesthesiologists and intensivists must be prepared to manage acute manifestations of this disease in case of life-threatening laryngeal edema. Surgery, physical trauma and labour are classical triggers of the disease. The anaesthesiologists should be aware of the drugs used as prophylaxis and treatment of acute attacks when considering labour and caesarean section. Androgens are contraindicated during pregnancy. If prophylaxis is required, tranexamic acid may be used with caution. The safest obstetric approach appears to be to administer a predelivery infusion of C1 INH concentrate. It is important to avoid manipulation of the airway as much as possible by relying on regional techniques. We report the case of a patient suffering from an HAE discovered during pregnancy. The management included administration of C1 INH during labor and early epidural analgesia for pain relief. A short review of the pathophysiology and therapeutic options follows.
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PMID:[Anaesthesic management of vaginal delivery in a parturient with C1 esterase deficiency]. 1935 29

The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK) and high molecular weight kininogen (HK). The conversion of plasma prekallikrein to kallikrein by the activated FXII and in response to numerous different stimuli leads to the generation of bradykinin (BK) and activated HK (HKa, an antiangiogenic peptide). BK is a proinflammatory peptide, a pain mediator and potent vasodilator, leading to robust accumulation of fluid in the interstitium. Systemic production of BK, HKa with the interplay between BK bound-BK receptors and the soluble form of HKa are key to angiogenesis and hemodynamics. KKS has been implicated in the pathogenesis of inflammation, hypertension, endotoxemia, and coagulopathy. In all these cases increased BK levels is the hallmark. In some cases, the persistent production of BK due to the deficiency of the blood protein C1-inhibitor, which controls FXII, is detrimental to the survival of the patients with hereditary angioedema (HAE). In others, the inability of angiotensin converting enzyme (ACE) to degrade BK leads to elevated BK levels and edema in patients on ACE inhibitors. Thus, the mechanisms that interfere with BK liberation or degradation would lead to blood pressure dysfunction. In contrast, anti-kallikrein treatment could have adverse effects in hemodynamic changes induced by vasoconstrictor agents. Genetic models of kallikrein deficiency are needed to evaluate the quantitative role of kallikrein and to validate whether strategies designed to activate or inhibit kallikrein may be important for regulating whole-body BK sensitivity.
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PMID:Human plasma kallikrein-kinin system: physiological and biochemical parameters. 1968 62


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