Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oral administration of 50 mg tartrazine to 122 patients with a variety of allergic disorders caused the following reactions: general weakness, heatwaves, palpitations, blurred vision, rhinorrhoea, feeling of suffocation, pruritus and urticaria. There was activation of the fibrinolytic pathway as shown by reduction of plasminogen with high pre-kallikrein and low kallikrein values. Reduction in complement activity (CH50) was seen in three out of sixteen reactions.
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PMID:The danger of "yellow dyes" (tartrazine) to allergic subjects. 62 44

The effects of oral cetirizine on spontaneous and provoked urticaria were evaluated in two studies. In a double-blind crossover trial, 30 patients with idiopathic urticaria received 10 or 20 mg of cetirizine or placebo. Cetirizine was significantly more effective than placebo in reducing the incidence of erythema, wheals, and pruritus. No serious side effects were reported. In the second study of ten patients with chronic urticaria, immediate and delayed reactions to injected autologous serum, histamine, kallikrein, and synthetic platelet-activating factor (PAF)-acether were inhibited by 10 mg of cetirizine. These results suggest that the mechanism of action of cetirizine may involve inhibition of PAF-induced influx of eosinophils.
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PMID:Cetirizine in the treatment of chronic urticaria. 182 14

Allergic rhinitis is a classic example of a type I immunological reaction. After allergic provocation tests a biphasic reaction is seen in the respiratory tract that is more pronounced in the lower than in the upper respiratory tract due to the physiological changes during the nasal cycle. The early phase of the immediate reaction starts some minutes after allergen provocation. After 5-10 h the nasal symptoms (discharge, blockage, sneezing and itching of the nose) reappear, a phenomenon which is called the "late-phase response" (LPR). The LPR is of great clinical importance in the pathophysiology of perennial allergic rhinitis and phenomena such as nasal priming and nasal hyper-reactivity. The most important effector cell of the early phase of the immediate reaction is the mast cell, whereas basophils, eosinophils and neutrophil granulocytes seem to be more important for the LPR. There is also evidence for morphological and functional heterogeneity of mast cells in man. The role of the chemotactically immigrated eosinophils in allergic reactions has not been clear until now: the eosinophil-derived mediators may enhance or inhibit the allergic reaction. Also the eosinophils show different morphological and functional states (so-called hypo- and hyperdense eosinophils). The symptoms of allergic rhinitis (sneezing, discharge, blockage, itching of the nose) are caused by different mediators, of which the most important is histamine. Other mediators or modulators of the allergic reactions are leucotrienes, prostaglandins, PAF, serotonin, and the kallikrein-kinine and complement systems. In recent years many regulatory peptides have been detected in the human nasal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Current pathophysiologic aspects of allergic rhinitis. I]. 226 46

Eight substances (histamine, compound 48/80, kallikrein, trypsin, papain, substance P, serotonin and platelet activating factor) were injected intradermally (volume 50 microl) into the rostral back (neck) of rats in order to establish an animal model for peripherally elicited pruritus. While serotonin induced excessive scratching at the site of injection, the other substances were weak or inactive. The dose-response relationship of serotonin was sigmoid, EC50=2.1 mg/ml (95% confidence interval: 1.0 to 4.3 mg/ml). Injections of serotonin 1 mg/ml into the caudal back elicited no scratching at all, i.e. neither at the site of injection nor elsewhere, so the experiment indicated no systemic effect of serotonin 1 mg/ml intradermally. Scratching was probably elicited histamine-independently, since histamine itself did not elicit scratching. The intra- and inter-observer variations were 3-4%. We conclude that serotonin is a reproducible local pruritogen eliciting scratching in the rat. The model may be useful in research and development of topical antipruritics of the nonhistaminic type as well as for various other purposes in pruritus research.
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PMID:Scratch induction in the rat by intradermal serotonin: a model for pruritus. 1172 Jan 70

Proteinase-activated receptor-2 (PAR2) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR2 is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR2 is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand. The endogenous activators of PAR2 on keratinocytes have not been identified as of yet. Potential candidates are kallikrein-related peptidases (KLKs) expressed by epidermal cells. Therefore, the ability of four human skin-derived KLKs was examined with regard to their capacity to activate PAR2 in vitro. PAR2 cleavage was followed by immunofluorescence analysis and functional activation by measurements of changes in intracellular calcium levels. We found that KLK5 and KLK14, but neither KLK7 nor KLK8, induced PAR2 signalling. We conclude that certain, but not all, epidermal KLKs are capable of activating PAR2. We could also show the coexpression of KLK14 and PAR2 receptor in inflammatory skin disorders. These in vitro results suggest that KLKs may take part in PAR2 activation in the epidermis and thereby in PAR2-mediated inflammatory responses, including epidermal barrier repair and pruritus. The role of KLKs in PAR2 activation in vivo remains to be elucidated.
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PMID:Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. 1762 93

Hereditary angioedema (HAE) is an inherited disorder characterized by recurrent, circumscribed, non-pitting, non-pruritic, and rather painful subepithelial swelling of sudden onset, which fades during the course of 48-72 hours, but can persist for up to 1 week. Lesions can be solitary or multiple, and primarily involve the extremities, larynx, face, esophagus, and bowel wall. Patients with HAE experience angioedema because of a defective control of the plasma kinin-forming cascade that is activated through contact with negatively charged endothelial macromolecules leading to binding and auto-activation of coagulation factor XII, activation of prekallikrein to kallikrein by factor XIIa, and cleavage of high-molecular-weight kininogen by kallikrein to release the highly potent vasodilator bradykinin. Three forms of HAE have currently been described. Type I and type II HAE are rare autosomal dominant diseases due to mutations in the C1-inhibitor gene (SERPING1). C1-inhibitor mutations that cause type I HAE occur throughout the gene and result in truncated or misfolded proteins with a deficiency in the levels of antigenic and functional C1-inhibitor. Mutations that cause type II HAE generally involve exon 8 at or adjacent to the active site, resulting in an antigenically intact but dysfunctional mutant protein. In contrast, type III HAE (also called estrogen-dependent HAE) is characterized by normal C1-inhibitor activity. The diagnosis of HAE is suggested by a positive family history, the absence of accompanying pruritus or urticaria, the presence of recurrent gastrointestinal attacks of colic, and episodes of laryngeal edema. Estrogens may exacerbate attacks, and in some patients attacks are precipitated by trauma, inflammation, or psychological stress. For type I and type II HAE, diminished C4 concentrations are highly suggestive for the diagnosis. Further laboratory diagnosis depends on demonstrating a deficiency of C1-inhibitor antigen (type I) in most kindreds, but some kindreds have an antigenically intact but dysfunctional protein (type II) and require a functional assay to establish the diagnosis. There are no particular laboratory findings in type III HAE. Prophylactic administration of either 17alpha-alkylated androgens or synthetic antifibrinolytic agents has proven useful in reducing the frequency or severity of attacks. Plasma-derived C1-inhibitor concentrate, recombinant C1-inhibitor, ecallantide (DX88; a plasma kallikrein inhibitor) and icatibant (a bradykinin B(2) receptor antagonist) have demonstrated significant efficacy in the treatment of acute attacks, whereas the C1-inhibitor concentrate has also provided a significant benefit as long-term prophylaxis. However, these drugs are not licensed in all countries and are not always readily available.
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PMID:Hereditary angioedema in childhood: an approach to management. 2059 9

Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable, episodic, incapacitating attacks of well-demarcated angioedema in the absence of urticaria and pruritus. HAE is due to deficient or dysfunctional C1-esterase inhibitor activity, which results in unopposed activation of plasma kallikrein, resulting in increased levels of bradykinin. Ecallantide is a potent and specific plasma kallikrein inhibitor approved for the treatment of acute attacks of HAE affecting any anatomic site. In Phase III clinical trials, subcutaneously administered ecallantide demonstrated significant, rapid and durable symptom relief. Ecallantide was effective for all attack types, including potentially life-threatening laryngeal attacks. The main safety concern is potentially serious hypersensitivity reactions, including anaphylaxis. Ecallantide represents an important treatment option for the management of acute attacks of HAE.
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PMID:Prospective, double-blind, placebo-controlled trials of ecallantide for acute attacks of hereditary angioedema. 2214 37

Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein-related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmosomal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.
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PMID:Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. 2453 91

Little is known about the role of the kallikrein-kinin system in chronic spontaneous urticaria (CSU). Kallikrein 5 (KLK5), a trypsin-like enzyme, is the most abundant in the skin and plays a role in itching and inflammatory reaction. In this study, we determined plasma KLK5 concentration, and its associations with acute phase response in CSU patients. Concentrations of KLK5 in plasma and CRP in serum were measured in patients with CSU of varying severity and in the healthy subjects. Plasma KLK5 concentrations were significantly lower in CSU (all) and moderate-severe CSU patients, as compared with the controls. There were no significant differences in KLK5 concentration in mild CSU patients as compared with the healthy subjects and moderate-severe CSU patients. No correlation was observed between KLK5 and CRP concentrations in the patients. It may be considered that circulating kallikrein 5 is down-regulated in CSU patients, however its potential role and the possible underlying mechanism are unknown.
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PMID:Decreased plasma kallikrein 5 concentrations in patients with chronic spontaneous urticaria. 2868 45

Identifying the function of kallikrein-related peptidases (KLKs) in the epidermis has elicited great interest over recent decades. KLKs comprise 15 serine proteases, and their activities are regulated by complex and fine-tuned mechanisms involving the proteolytic activation cascade, endogenous inhibitors, and environmental factors. When the balance is disrupted, excessive or insufficient protease activity can impair epidermal barrier homeostasis. KLKs are involved in various events, such as skin inflammation, wound healing, pruritus, anti-bacterial activity, and viral susceptibility. One of the primary roles of KLKs, mainly KLK5 and KLK7, is physiological desquamation. Both proteases are also involved in the development of inflammatory skin diseases with barrier abnormalities, e.g., Netherton syndrome and atopic dermatitis (AD). In Netherton syndrome, unrestricted activity of KLK5 due to loss of the major endogenous inhibitor, lymphoepithelial Kazal-type-related inhibitor (LEKTI), destroys the component molecules of corneodesmosome, leading to Th2 and Th17 inflammation. Meanwhile, the increased activity of KLK7 in the hyperkeratotic lesions of chronic AD is suppressed by upregulated LEKTI. The functions and implications of other KLKs including KLK6 and KLK8 in healthy and diseased skin such as psoriasis represent an exciting but relatively unexplored area. Clarifying the function of epidermal KLKs will enable development of disease-specific biomarkers and new therapeutic strategies.
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PMID:Physiological and pathological roles of kallikrein-related peptidases in the epidermis. 3127 1


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