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)

The mast cell, equipped with enzymes, chemotactic factors, a vasoactive amine, an anticoagulant, and lipid-derived proinflammatory products, may be essential in tissue modeling as well as in defense. Its primarily perivascular location in skin and the mucosa of the respiratory tract and the gut assures its availability to counter parasites. By the same token, the mast cell is responsible for interactions with inhaled, ingested, and injected antigens that comprise IgE-mediated allergic reactions. Abnormally high numbers of mast cells in the skin, either localized or generalized, result in urticaria pigmentosa or generalized cutaneous mastocytosis, respectively. Tissue infiltration by excessive mast cells, primarily in gut, bone, liver, and spleen, results in systemic mastocytosis; this may be accompanied by myelodysplasia or lymphoma and may eventuate in mast cell leukemia. Until the etiology of mastocytosis is understood, the treatment is symptomatic: histamine antagonism by H1 +/- H2 blockade for flushing, itching, and gastric distress; cyclooxygenase inhibition to prevent prostaglandin D2 (PGD2)-induced hypotension when indicated; and oral cromolyn to prevent gastrointestinal symptoms and bone pain.
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PMID:Mast cell disease. 149 Jun 22

Twenty-eight ragweed-allergic patients with hay fever participated in a clinical trial that examined the pattern of symptom relief resulting from addition of a cyclooxygenase-inhibiting drug to standard antihistamine therapy. In the first week antihistamine use by the subjects was standardized, and subjects were oriented to use of the hay fever symptom diary. They were then allocated, according to symptom severity, to two treatment groups. One group received 120 mg of terfenadine and 300 mg of flurbiprofen (a cyclooxygenase-inhibiting drug) per day. Members of the other group received terfenadine and a placebo that looked like flurbiprofen. This treatment lasted 1 week. Subjects recorded severity of congestion, drainage, running, nose blowing, itching, and sneezing four times each day. The flurbiprofen-treated patients experienced less severe symptoms, demonstrating maximum benefit 3 to 5 days into the drug trial with some loss of effect thereafter. Secretion-related symptoms appeared to benefit most. Combined blockade of histamine and cyclooxygenase products appears to offer improved symptom control in ragweed hay fever.
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PMID:Hay fever treatment with combined antihistamine and cyclooxygenase-inhibiting drugs. 289 86

Leukotriene D4 (LTD4) increased the blood flow rate in human skin, equipotent to histamine in the dose range of 3.1-200 pmol. The vasodilatation lasted for up to 60 min, and no late reactions occurred. Indomethacin did not affect the LTD4-induced blood flow rate. H1 and H2 antagonists reduced the increase in blood flow rate, but did not abolish the response to LTD4. Local nerve block inhibited the axon reflex-mediated flare component of the LTD4-induced blood flow rate, leaving a local red reaction. This local red reaction was not affected by H1 and H2 antagonists. These results indicate histamine as a mediator of the axon reflex, and show that LTD4 causes a direct vasodilatory effect that is not mediated via histamine or cyclooxygenase products. The laser-Doppler flowmeter was applied for dynamic studies of the vasopressor response in the skin during a Valsalva maneuver, and the relative changes in blood flow were confirmed by control estimates of the blood flow rate by a 133xenon washout method. The pressor response to a Valsalva maneuver was reversed by local nerve block, but not affected by LTD4. Therefore LTD4 did not interfere with the sympathetic activity on the cutaneous vessels. Leukotriene D4 caused a dose-dependent wheal reaction, equipotent to histamine in the dose range of 0.2-200 pmol. Only minor whealing occurred when the vasculature to the test arm was occluded before injection of LTD4 and the circulation restored 30 min later. Most of the LTD4 was apparently metabolized within this period. Subsequent injections of LTD4 into the same sites demonstrated the development of tachyphylaxis with respect to whealing. This evidence suggests that LTD4 cannot mediate sustained inflammation. The injections of LTD4 caused neither pain nor itching. In conclusion, the elucidated properties point to LTD4 as a possible mediator of microvascular changes during acute inflammation.
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PMID:Vascular effects of leukotriene D4 in human skin. 380 52

The studies described herein characterize animal behavioral models for conjunctival and cutaneous itch. Histamine was used as the reference stimulus for model development because it is firmly established as a pruritogen in both conjunctiva and skin. Itching evokes the desire to scratch in human subjects, so hind limb scratching at the afflicted area was used to identify pruritogenic stimuli. Under optimized environmental conditions, hind limb scratching behavior yielded substantial and highly reproducible responses. The conjunctival itch-scratch response was delineated from pain and foreign body sensations by using appropriate stimuli. Examination of a large and diverse variety of autocoids revealed that only histamine, platelet-activating factor (PAF) and arachidonic acid and its cyclooxygenase metabolite prostaglandin E2 possessed meaningful pruritogenic activity. PAF-induced ocular pruritus did not involve histamine release, according to studies with appropriate antagonists. Thus PAF-induced ocular pruritus was unaffected by the histamine H1-receptor antagonist pyrilamine but was substantially attenuated by the PAF antagonists WEB 2086 and CV-6209 and was virtually abolished by E-6123. Similar itch-scratch behaviors were quantified in hairless guinea pig skin following the application of cowhage or the iontophoretic administration of histamine and PAF. Findings from these newly developed itching models suggest that PAF could be an important mediator of the pruritic sensation by activating a population of nerve endings responsible for encoding the itch sensation.
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PMID:Characterization of a behavioral model for peripherally evoked itch suggests platelet-activating factor as a potent pruritogen. 785 91

The therapeutic utility of cyclooxygenase (CO) inhibitors, such as ketorolac, in reducing the inflammatory events associated with allergic conjunctivitis is not unexpected since prostanoids (PG) elicit conjunctival redness (PGD2, PGE2, PGF2 alpha), edema (PGD2, TxA2), eosinophil infiltration (PGD2, PGJ2) and mucous cell discharge (PGD2, PGJ2, TxA2). Recently, topically administered ketorolac has also been reported to alleviate the itching associated with allergic conjunctivitis. This was viewed as intriguing since CO inhibitors are not regarded as useful for treating itching dermatoses and PGs do not elicit itching when applied to the skin. In order to investigate the antipruritic activity of ketorolac, we developed a model for reproducibly measuring ocular surface itch responses. The model involves itch-scratch responses to pruritogens applied locally to the ocular surface. Painful and foreign body stimuli do not produce an itch-scratch response. Unlike reported skin studies, PGE2 was a potent itch-producing substances in the conjunctiva. PGD2 was weakly pruritogenic but PGF2 alpha and the TxA2-mimetic U-46619 were inactive. The PG precursor arachidonic acid was also a potent pruritogen and its effects were inhibited by ketorolac pretreatment. Ketorolac also dose-dependently inhibited the itching associated with experimental allergic conjunctivitis. It appears that PGs are potent itch-producing substances in the conjunctiva and the anti-itch efficacy of ketorolac in allergic conjunctivitis appears to involve inhibition of conjunctival PG biosynthesis from arachidonic acid.
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PMID:The pruritogenic and inflammatory effects of prostanoids in the conjunctiva. 859 Feb 66

Exposure of the eye to airborne particles in patients predisposed to allergy often results in the signs and symptoms of allergic conjunctivitis such as red, itchy eyes and ocular discharge. The mediators of these allergic symptoms include histamine, inflammatory substances such as prostaglandins, and other products of arachidonic acid metabolism (ie, leukotrienes). Ketorolac tromethamine is a nonsteroidal anti-inflammatory agent that inhibits the activity of cyclooxygenase, one of the two major enzymes responsible for the conversion of arachidonic acid to inflammatory substances. A multicenter patient survey was performed to evaluate the effectiveness of topical ketorolac tromethamine in treating the symptoms of allergic conjunctivitis. After ocular administration of ketorolac tromethamine, 90% (246/272) of patients reported that their eyes felt better. Eighty-four percent (173/206) of respondents rated ketorolac tromethamine as good to excellent in relieving their overall symptoms of ocular allergy, and 86% (217/251) of patients found the study drug produced good to excellent relief of their ocular itching usually within minutes to 1 hour of administration. Results of this survey found ketorolac tromethamine is effective in relieving ocular itching, the hallmark symptom of allergic conjunctivitis. In addition, these results provide further evidence that the products of arachidonic acid metabolism contribute to the symptoms of allergic conjunctivitis.
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PMID:Results of a survey of patients with ocular allergy treated with topical ketorolac tromethamine. 859 40

Topically administered ketorolac (Acular), a cyclooxygenase inhibitor, has recently been reported as clinically beneficial for treating allergic conjunctivitis. The ability of ketorolac to relieve the itching associated with allergic conjunctivitis is intriguing because cyclooxygenase inhibitors are not regarded as useful in treating allergic dermatoses and prostaglandins (PG) do not elicit an itch response in human skin. To gain further insight into the mechanisms involved in the antipruritic activity of ketorolac, we used a method of reproducibly assessing ocular surface itch responses in the guinea pig. The measurement of conjunctival pruritus involved a recently developed behavioral model whereby hind limb scratching episodes directed toward the afflicted area were quantified. Itch-scratch episodes have previously been delineated from foreign body and pain sensations, which do not evoke such a behavioral response. Ketorolac significantly inhibited the itching associated with experimental allergic conjunctivitis. The basis of this antipruritic activity may be ascribed to preventing the biosynthesis of itch-producing PGs because ketorolac inhibited arachidonic acid-induced pruritus. In contrast to skin studies, PGE2 and PGI2 were found to be potent pruritogens at the guinea pig ocular surface. PGD2 was a weak pruritogen, and PGF2 alpha and the thromboxane-mimetic U-46619 produced no meaningful response. Further studies involving selective agonists and antagonists suggested that EP1 receptors, IP receptors and PGD2-sensitive receptors may mediate prostanoid-induced conjunctival itching. No evidence for the involvement of other prostanoid receptor subtypes was obtained. Although the EP1 receptor antagonist AH 6809 and the DP receptor antagonist BW A868C inhibited PGE2- and PGD2-induced itching, respectively, neither antagonist alone significantly affected the itching associated with experimental allergic conjunctivitis. A combination of AH 6809 and BW A868C, however, did exhibit antipruritic activity. It appears that for effective relief of itching in allergic conjunctivitis, it is not sufficient to block the effects of a single pruritogenic PG. It is preferable to reduce the participation of all pruritogenic PGs by either using combined receptor antagonists or by using a cyclooxygenase inhibitor such as ketorolac to block their biosynthesis.
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PMID:Characterization of receptor subtypes involved in prostanoid-induced conjunctival pruritus and their role in mediating allergic conjunctival itching. 885 86

Intradermal injection of substance P elicits an itch sensation in human subjects and an itch-associated response in mice. The substance P-induced itch-associated response in mice is not inhibited by antihistamine. Therefore, the mechanisms of substance P-induced itch-associated response are unclear. In this study, we demonstrated one of the mechanisms. Substance P induces an arachidonate cascade to produce prostaglandins and leukotriene. In this study we considered whether arachidonate metabolites are involved in the substance P-induced itch-associated response. A phospholipase A(2) inhibitor arachidoryltrifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pre treatment with the glucocorticoids betamethasone and dexamethasone also produced inhibition of the substance P-induced itch-associated response in mice as well as humans. The 5-lipoxygenase inhibitor zileuton, but not the cyclooxygenase inhibitors indomethacin and diclofenac, suppressed substance P-induced itch-associated response. The leukotriene B(4) receptor antagonist 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid produced inhibition, whereas pranlukast (leukotriene C(4)/D(4)/E(4) receptor antagonist) and 5(Z)-7-[1S,2S, 3S,5R-3-(trans-b-styren)sulfonamido-6,6-dimethylbi cyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP(1) receptor antagonist) were without effect. Furthermore, when the production of leukotriene B(4) and prostaglandin E(2) was measured in skin injected with substance P and in mouse keratinocytes applied with substance P, the level of both products increased. As leukotriene B(4), but not prostaglandin E(2), also induces the itch-associated response in mice, these results suggest that leukotriene B(4) and keratinocytes, cutaneous cells which produced leukotriene B(4), play an important role in substance P-induced itch-scratch response in mice. Leukotriene B(4) receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.
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PMID:Involvement of leukotriene B(4) in substance P-induced itch-associated response in mice. 1188 31

Aspirin and all nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that share the ability to inhibit the enzyme cyclooxygenase (COX). This inhibitory effect, especially of COX-1, is suggested as the mechanism underlying NSAID-induced hypersensitivity reactions. In this study, we evaluated the safety and convenience of a single full-dose challenge with nabumetone, a selective COX-2 inhibitor, in patients with hypersensitivity to nonselective NSAIDs (ns-NSAIDs). Twenty-four subjects with a history of hypersensitivity reactions to at least two different ns-NSAIDs on two different occasions were enrolled in the study. The patients were otherwise healthy and did not suffer from NSAID- or aspirin-induced asthma or urticaria. All subjects were orally challenged by a single full dose (1000 mg) of nabumetone, monitored closely in the hospital for the next 4 hours and contacted by telephone the next morning and 3-12 months afterward. Twenty-two patients tolerated nabumetone without any reaction during and after the challenge. One patient had a single urticarial lesion and one patient reported mild pruritus without objective signs, both of which resolved spontaneously. Thirteen patients, including the patient who responded with pruritus to the challenge, used nabumetone on several occasions during the follow-up period without any adverse reaction. Our study shows that in patients with a history of aspirin- and ns-NSAID-induced hypersensitivity reaction, a rapid one-step challenge with nabumetone was well tolerated. These initial data support the possibility that a single full dose of nabumetone can be tried as a safe alternative in most patients with a hypersensitivity reaction to ns-NSAIDs.
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PMID:Safe full-dose one-step nabumetone challenge in patients with nonsteroidal anti-inflammatory drug hypersensitivity. 1297 96

Histamine is known to excite a subset of C-fibers and cause itch sensation. Despite its well-defined excitatory action on sensory neurons, intracellular signaling mechanisms are not understood. Previously, we demonstrated that bradykinin excited sensory neurons by activating TRPV1 via the phospholipase A(2) (PLA(2)) and lipoxygenase (LO) pathway. We, thus, hypothesized that histamine excited sensory neurons via the PLA(2)/LO/TRPV1 pathway. Application of histamine elicited a rapid increase in intracellular Ca(2+) ([Ca(2+)](i)) that desensitized slowly in cultured dorsal root ganglion neurons. Histamine-induced [Ca(2+)](i) was dependent on extracellular Ca(2+) and inhibited by capsazepine and by SC0030, competitive antagonists of TRPV1. Quinacrine and nordihydroguaiaretic acid, a PLA(2) and an LO inhibitor, respectively, blocked the histamine-induced Ca(2+) influx in sensory neurons, while indomethacin (a cyclooxygenase inhibitor) did not. We thus conclude that histamine activates TRPV1 after stimulating the PLA(2)/LO pathway, leading to the excitation of sensory neurons. These results further provide an idea for potential use of TRPV1 antagonists as anti-itch drugs.
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PMID:Histamine-induced Ca(2+) influx via the PLA(2)/lipoxygenase/TRPV1 pathway in rat sensory neurons. 1513 18


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