Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of cetirizine in comparison with meclizine, another piperazine H1 receptor antagonist, in rat pleurisy caused by allergen or autacoid was investigated. Sensitization was achieved by subcutaneous injection of a mixture of ovalbumin and aluminium hydroxide. Fourteen days later, the animals were challenged with an intrathoracic injection of ovalbumin (12 micrograms/cavity), which caused drastic mast cell degranulation, followed by pleural oedema and leucocyte influx. Cetirizine and meclizine (2.5-30 mg/kg i.p.), 1 h before challenge, inhibited the exudatory response evoked by antigen, under conditions where neutrophil and eosinophil accumulation was affected only by the former. When administered intrathoracically 22 h after allergen, i.e. using a curative approach, cetirizine (15 micrograms/cavity) drastically reduced the pleural eosinophilia noted 24 h post-challenge, indicating that this drug can reverse an already established eosinophilia. Cetirizine (15 mg/kg i.p.) also restored, to about 39% (P < 0.001), the number of uninjured mast cells recovered from the pleural cavity following allergen stimulation. In normal rats, cetirizine (5-15 micrograms/cavity) completely inhibited the pleural exudation elicited by histamine and only partially the exudation caused by 5-hydroxytryptamine or bradykinin, but was quite inactive against platelet-activating factor. We conclude that the pleural exudation triggered by allergen, vasoactive amines or bradykinin is clearly sensitive to cetirizine. In addition, the ability of the drug to interfere with pleural neutrophil or eosinophil mobilization and mast cell degranulation seems not to be associated with its ability to block the histamine H1 receptor.
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PMID:Suppression by cetirizine of pleurisy triggered by antigen in actively sensitized rats. 136 60

Small intestinal histopathology and absorption were examined in Beagle puppies infected with either a moderate or a low burden of Toxocara canis. Infection with T. canis significantly reduced absorption of xylose, but only slightly delayed absorption of para-aminobenzoic acid. Fat assimilation was reduced and faecal proteolytic activity was increased. A significant reduction in villous height occurred and was inversely related to the extent of the infection. Villous goblet cell numbers, particularly those in the luminal third of the villus, were lowest and crypt goblet cell numbers were highest in the most heavily infected of the puppies. Villous goblet cell numbers increased rapidly after treatment of the puppies with piperazine or after the spontaneous elimination of the T. canis infection while crypt goblet cell numbers were less affected by elimination of the parasites. Intra-epithelial lymphocyte numbers were lowest in 33- to 37-day-old puppies infected with greater than 127 T. canis and highest in 44- to 46-day-old puppies losing their infection. Infection with T. canis had no apparent effect on mast cell numbers or pyroninophilic cell numbers in the lamina propria.
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PMID:Intestinal changes in puppies infected with Toxocara canis. 191 55

The acute incubation of mouse bone marrow-derived mast cells with low concentrations of agents known to activate protein kinase C [phorbol myristate acetate (PMA), 1,2-dioctanoyl-sn-glycerol (diC8), and 1-oleoyl-2-acetyl-glycerol (OAG)] caused an enhancement of beta-hexosaminidase release stimulated by the calcium ionophore A23187. Higher concentrations of protein kinase C activators tended to inhibit A23187- or antigen-induced preformed mediator release. All concentrations studied induced a striking mast cell hyporesponsiveness to the mediator release augmenting effect of adenosine. Agents that have been reported to block protein kinase C activity [1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride (H-7) and sphingosine] demonstrated diverse responses in this system. Up to 100 microM H-7 failed to affect mast cell beta-hexosaminidase release in the presence or absence of PMA and secretagogue. Sphingosine (10 microM) was a potent inhibitor of antigen- or A23187-induced mediator release as well as adenosine responsiveness. Sphingosine also blocked the effects of PMA noted above in a dose-dependent fashion. The generation of leukotriene C4 (LTC4) by stimulated mast cells surprisingly was not affected by concentrations of diC8 that significantly inhibited granule-associated mediator release. Translocation of protein kinase C activity from the cytosol to the mast cell membrane was evident in cells briefly pretreated with A23187, adenosine alone, and diC8 in the presence of Tyrode's buffer, A23187, or adenosine. These findings lend further support to the contention that signal transduction from mast cell adenosine receptors to processes that regulate degranulation may involve protein kinase C.
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PMID:Modulation of mast cell responses to adenosine by agents that alter protein kinase C activity. 214 Dec 57

The effect of mepyramine, ketotifen and picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) on anaphylactic histamine release from lungs, heart, stomach, and intestine of guinea pigs in response to antigen was examined in vivo. When sensitized animals were pretreated intraperitoneally with a single dose of these compounds 60 min before i.v. antigen challenge (native ovalbumin 20 mg/kg), a dose related inhibition of immunological histamine release from the lung was established. After pretreatment of the animals with 3 mg/kg of mepyramine, 10 mg/kg of ketotifen, and 6 mg/kg of picumast dihydrochloride, the inhibitory effect on histamine release from the lung was so marked that both the acute and the protracted anaphylactic shock were completely suppressed. The corresponding histamine levels in blood plasma, regularly measured 1.5 min after antigen stimulation, had dropped to about 40%, 50%, and 35%, respectively (p less than 0.05), whereas lung histamine content increased by about 60%, 150%, and 90% compared with unpretreated, shocked controls. According to these findings the number of lung mast cells in protected animals was significantly increased. In addition, ketotifen significantly reduced histamine release from heart and intestine. In contrast the compound injected intravenously 1 min before antigen challenge had no effect on mast cell degranulation and on histamine liberation, thus only decreasing the acute anaphylactic bronchospasm. These data suggest that all three drugs were acting as H1-antagonists when administered immediately prior to the antigen-provoked anaphylactic reaction. The property of these drugs to inhibit mast cell degranulation and the reduction of mediator release, however, appears to depend on their prolonged action on these cells. Together with their histamine antagonism anaphylactic death is thus prevented.
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PMID:Inhibition of immunological histamine release from guinea pig lungs and other organs by mepyramine, ketotifen, and picumast in vivo. 248 12

Picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) was compared with cromoglycate, ketotifen and mepyramine as an inhibitor of allergic and anaphylactoid reactions. 1. In guinea-pigs, pretreatment with picumast dihydrochloride given intravenously, orally or by inhalation prevented bronchospasm induced by antigen or histamine. The fraction of the bronchospasm remaining after mepyramine pretreatment was further reduced by picumast dihydrochloride. 2. Systemic administration of picumast dihydrochloride inhibited antigen-induced conjunctivitis, whereas mepyramine and ketotifen were inactive. 3. Intravenous and oral pretreatment with picumast dihydrochloride inhibited the antigen-induced mast cell degranulation in rat mesentery. The effective doses of cromoglycate given intravenously were twice as high as those of picumast dihydrochloride. Picumast dihydrochloride did not inhibit antigen-induced bronchoconstriction in rats. 4. The cutaneous reaction induced with Ascaris antigen in atopic monkeys was insensitive to the antihistaminic action of ketotifen, whereas it was inhibited by low doses of picumast dihydrochloride. Both compounds suppressed skin reactions induced by histamine. 5. Picumast dihydrochloride decreased IgE production in atopic high responder mice. It did not prevent autoimmune nephritis in NZB/W mice. 6. In rats, picumast dihydrochloride did not reduce cotton pellet granuloma, nor adjuvant arthritis. The inhibition of carrageenin oedema is presumably due to its anti-oedematous properties rather than to an antiproliferative activity. In conclusion, the inhibition of allergic and anaphylactoid reactions by picumast dihydrochloride can be attributed to a combined inhibition of liberation and action of histamine and other mediators.
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PMID:Antiallergic activity of picumast dihydrochloride in several animal species. 257 54

In a small range finding study a number of N-benzylpiperazino derivates of 3-nitro-4-hydroxycoumarin have been shown to combine potent H1-antihistamine activity with that of mast cell stabilization as demonstrated by their activity as antagonists of histamine on guinea pig ileum and by their inhibition of the release of histamine in rat passive peritoneal anaphylaxis (PPA). The most potent compound, 1-[2-hydroxy-3-[(4-hydroxy-3-nitrocoumarin-7-yl)oxy]propyl]-4- (4-chlorobenzyl)piperazine, 30, had a pA2 of 9.0 against histamine on guinea pig ileum and inhibited histamine release in the rat PPA test with a potency similar to that of disodium cromoglycate.
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PMID:N-benzylpiperazino derivatives of 3-nitro-4-hydroxycoumarin with H1 antihistamine and mast cell stabilizing properties. 620 60

Hydroxyzine is a piperazine, tricyclic, H1-receptor antagonist with unique properties, especially the inhibition of mast cell and neuronal secretion. Preliminary results indicate is has an unusual ability to reduce interstitial cystitis symptoms. The long history, lack of major side effects, wide availability, low cost, and apparent effectiveness of hydroxyzine compel presentation of these preliminary results.
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PMID:Hydroxyzine in the treatment of interstitial cystitis. 828 34

Experimental allergic encephalomyelitis (EAE) has been used as an animal model for the human demyelinating disease multiple sclerosis (MS). In acute MS or EAE, early disruption in the integrity of the blood-brain-barrier (BBB) precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cells. We investigated the number and degree of activation of brain mast cells in EAE and the effect of the heterocyclic histamine-1 receptor antagonist hydroxyzine, a piperazine compound known to also block mast cells. Acute EAE was induced in Lewis rats by immunization with whole guinea pig spinal cord homogenate and complete Freund's adjuvant (CFA). A second group of animals were treated orally with hydroxyzine for one day before immunization and then continuously for 14 days. Control rats were treated with CFA or hydroxyzine alone. The clinical progression of EAE was assessed on days 10, 12 and 14 after immunization. The number of metachromatic mast cells and the degree of degranulation was assessed in the thalamus with light microscopy. At day 14, there was a three-fold increase in the number of brain mast cells with EAE, as compared to controls. These cells were positive for the immunoglobulin E binding protein (FcepsilonRI), while those from control rats were not. Over 40% of all thalamic mast cells studied in EAE showed partial staining or extruded secretory granule indicative of secretion. Hydroxyzine treatment inhibited (p<0.05) the progression and severity of EAE by 50% and the extent of mast cell degranulation by 70% (p<0.05). These findings indicate that brain mast cells are associated with EAE development and that inhibition of their activation correlates positively with the clinical outcome.
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PMID:Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation. 1088 88

The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and investment before we can reap the rewards of highly potent and selective pharmacological modulators.
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PMID:In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels -- mirage or pot of gold? 2376 62