piperidines and Food-Hypersensitivity

Topics: Antifungal Agents; Attention Deficit Disorder with Hyperactivity; Boron Compounds; Botulinum Toxins, Type A; Bridged Bicyclo Compounds, Heterocyclic; Brimonidine Tartrate; Depression; Dermatitis, Atopic; Food Hypersensitivity; Humans; Immunologic Factors; Ivermectin; Phosphodiesterase Inhibitors; Phototherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinoxalines; Skin Diseases; Societies, Medical; Thalidomide; Triazoles; United States

Topics: Adrenergic beta-Agonists; Albuterol; Amantadine; Analgesics, Non-Narcotic; Androstadienes; Aromatase Inhibitors; Asthma; Bronchodilator Agents; Donepezil; Drug Therapy, Combination; Female; Fluticasone; Food Hypersensitivity; Humans; Indans; Interferons; Latex Hypersensitivity; Letrozole; Mandelic Acids; Middle Aged; Multiple Sclerosis; Nebulizers and Vaporizers; Nitriles; Nootropic Agents; Parasympatholytics; Paresthesia; Piperidines; Respiratory Function Tests; Salmeterol Xinafoate; Thyroxine; Triazoles

1. This in vitro study was designed to determine the potential use of the NK(1) antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimuli on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated. 2. Submucosal and sensory nerve fibre stimulation using electrical field stimulation (1 ms/7 Hz/7 V) and capsaicin (50 microM) respectively, mast cell activation by anti-IgE (1/250 dilution) and granulocyte stimulation using fMLP (50 microM) each released SP and evoked a secretory response. 3. SP and the NK(1) selective agonist, Sar-SP (0.1 - 1000 nM) stimulated an increase in colonic secretion which was antagonized by SR140333 (pD'(2)=6.7 and 7.25 versus SP and Sar-SP respectively). 4. SR140333, at a concentration that blocked NK(1)-mediated secretion (500 nM), also reduced the secretory response to both alphaIgE and capsaicin. This suggests a pathophysiologic role for NK(1) receptors. 5. Capsaicin evoked SP release was increased in tissue taken from Crohn's disease but not ulcerative colitis patients. The response to SP was however reduced by 70 and 89% respectively. 6. Mast cells and sensory afferents contribute to allergic diarrhoea. Since SR140333 reduced the secretory response to mast cell and afferent stimulation this compound may be particularly useful in reducing the symptoms of food allergy.

Topics: Animals; Antidiarrheals; Capsaicin; Colitis, Ulcerative; Colon; Crohn Disease; Epithelial Cells; Food Hypersensitivity; Guinea Pigs; Humans; Immunoglobulin E; Inflammatory Bowel Diseases; Male; Mast Cells; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Receptors, Neurokinin-1; Species Specificity; Substance P; Tachykinins

There is growing evidence for a pivotal role for tachykinins in gut neuroimmune interactions.. To determine whether NK1, NK2, and NK3 tachykinin receptors are involved in milk protein induced allergic sensitisation.. Eight groups of 12 Dunkin-Hartley guinea pigs (250-300 g) were used. Four groups were sensitised to milk proteins for three weeks. During this period, these animals were injected intraperitoneally each day with NK1 (SR 140333; 0.3 mg/kg), NK2 (SR 48968; 5 mg/kg), or NK3 (SR 142801; 5 mg/kg) receptor antagonist or vehicle. The fifth group had water available instead of milk and was used as a non-sensitised control. The three other groups received the NK receptor antagonists for three weeks but were not sensitised to milk proteins.. Sensitised animals treated with NK1 and NK3 receptor antagonists had both lower IgE and IgG serum titres, evaluated by passive cutaneous anaphylaxis, and lower specific IgG serum titres, determined by enzyme linked immunosorbent assay (ELISA), than vehicle treated animals. Sensitisation induced an increase in intestinal mast cell number which was abolished by treatment with the NK1 receptor antagonist. Antigenic challenge-induced jejunal hypersecretion was also blocked by treatment with the NK1 receptor antagonist.. In guinea pigs, NK1 and NK3 but not NK2 receptors are involved in sensitisation to cow's milk. However, NK1 but not NK3 receptor antagonists abolish both the hypermastocytosis induced by food allergy and the hypersecretion induced by antigenic challenge, suggesting different roles for NK1 and NK3 receptors in the mechanisms of sensitisation to beta-lactoglobulin.

Topics: Animals; Benzamides; Female; Food Hypersensitivity; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Jejunum; Lactoglobulins; Mast Cells; Passive Cutaneous Anaphylaxis; Piperidines; Quinuclidines; Receptors, Tachykinin

AHR-13268D (4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1- piperidinyl]propoxy]benzoic acid, sodium salt) is a potent, long-acting water soluble, antiallergic and antihistaminic agent. AHR-13268D protects sensitive guinea pigs from collapse induced by aerosolized antigen; 1, 5, and 24 h ED50s in the test were 0.27, 0.25, 0.93 mg/kg, PO, respectively. AHR-13268D was also active when given as an aerosol, the 1 h ED50 = 0.29%. In the rat passivefoot anaphylaxis test. AHR-13268D was slightly more active (1.55 times) than AHR-5333B when given orally 1 h prior to challenge and equipotent to cromolyn when given intravenously immediately prior to challenge. AHR-13268D displayed potent, long-acting antihistaminic activity in naive guinea pigs; the 1, 5, and 24 h oral ED50s being in the range of 0.3 mg/kg. AHR-13268D (10 to 20 mg/kg, PO) attenuated the skin responses to ascaris antigen in sensitive dogs and did not alter the EEG pattern or sleep/wake patterns of cats at doses in vast excess of its antihistaminic activity. In vitro, AHR-13268D was a potent inhibitor of histamine release from rat peritoneal mast cells (IC50 = 0.51 nM) and was as potent as the reference 5-LO inhibitor phenidone in inhibiting antigen-induced contractions of guinea pig ileum in the presence of pyrilamine, atropine, and imidazole (IC50 approximately 300 microM). AHR-13268B was bioavailable (approximately 88%) from capsules or from oral solutions.

Topics: Aerosols; Anaphylaxis; Animals; Antigens; Ascaris; Benzoates; Biological Availability; Electroencephalography; Female; Food Hypersensitivity; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypersensitivity; Immunoglobulin E; Lung; Male; Piperidines; Rats; Rats, Inbred Strains; Skin Tests