pyrimidinones and Anaphylaxis

Although many studies have suggested a relation between allergy and Ménière's disease, the pathophysiology of this condition remains controversial. The aim of this study was to clarify whether an anaphylactic reaction in the inner ear can disturb hearing and equilibrium, and whether such disturbances recur in response to repeated anaphylactic reactions. Increases in audiological threshold, nystagmus, and endolymphatic hydrops were observed in response to a single exposure to antigen administered to actively sensitized guinea pigs. The increase in audiological threshold was maximal 10 h after antigen challenge (p < 0.005) and returned to the baseline level after 7 days. Nystagmus and the increase in audiological threshold induced by antigen exposure were inhibited by prior administration of pemirolast potassium (p < 0.05), an inhibitor of chemical mediator release from mast cells. A second challenge with antigen 7 days after the first also induced an increase in audiological threshold (p < 0.05) and nystagmus. These results suggest that studies of repeated antigen challenge in actively sensitized animal models may increase our understanding of the pathophysiology of Ménière's disease.

Topics: Anaphylaxis; Animals; Cochlea; Dinitrophenols; Ear, Inner; Endolymphatic Hydrops; Guinea Pigs; Hearing Loss, Bilateral; Histamine Antagonists; Male; Nystagmus, Pathologic; Postural Balance; Pyridines; Pyrimidinones; Vaccination

A series of 6-substituted [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one derivatives 4a--z were synthesized from 5-substituted 1,3,4-thiadiazol-2-amines 5 by the following consecutive reactions: pyrimidine ring closure with bis(2,4,6-trichlorophenyl) malonate, nitration, chlorination, amination, hydrogenation and diazotization. The structure of 4 was confirmed by an alternate synthesis of 4, involving reaction of 5-substituted 2-azido-1,3,4-thiadiazole 13 with ethyl cyanoacetate, followed by the Dimroth rearrangement and ring closure. The antiallergic activities (anti-passive peritoneal anaphylaxis, anti-passive cutaneous anaphylaxis and anti-slow reacting substance of anaphylaxis activities) of the products were evaluated.

Topics: Anaphylaxis; Animals; Male; Passive Cutaneous Anaphylaxis; Pyrimidinones; Rats; Rats, Inbred Strains; SRS-A; Thiadiazoles; Triazoles

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbox yli c acid (1) in the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of an (arylamino)methylene moiety into position 9 of the pyridopyrimidine ring. Compound 34, (+)-6(S)-methyl-9-[(m-methylphenyl)-hydrazono]-4-oxo-4H-pyrido[1,2 -a] pyrimidine-3-carboxylic acid, displayed about 10 000 times the activity of the starting compound 1. A structure-activity relationship study of 9-[(arylamino)methylene]tetrahydropyridopyrimidine-3-carb ox ylic acids resulted in conclusions similar to those found for the 9-(arylhydrazono)tetrahydro-and 9-(arylamino)dihydropyridopyrimidine series. Replacement of the 3-carboxy group of 9-(phenylhydrazono)-tetrahydropyridopyrimidin-4-ones with an acrylic acid moiety caused slight increases in potency. In the 6-methyl-substituted series, a high stereospecificity was observed between the enantiomers with 6S and 6R absolute configurations, the former being responsible for the antiallergic activity. The effects of some 9-[(arylamino)-methylene]tetrahydropyridopyrimidine-3-car box ylic acids on the rat passive peritoneal anaphylaxis test were also investigated.

Topics: Anaphylaxis; Animals; Drug Evaluation, Preclinical; Female; Histamine H1 Antagonists; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Optical Rotation; Passive Cutaneous Anaphylaxis; Pyrimidinones; Rats; Rats, Inbred Strains; Structure-Activity Relationship

BL-5255 inhibited release of preformed mediators from passively sensitized mast cells in the rat peritoneal cavity, chopped monkey lung or human lung tissue. The compound failed to block rat cutaneous reactions elicited by histamine or serotonin. It exhibited weak to no ability, depending on the mediator employed, to block contraction of isolated guinea pig ileum or tracheal tissue. At concentrations of 1 microM or greater, BL-5255 itself was contractile to the ileum but not to the quiescent or submaximally contracted trachea. The compound relaxed spontaneously contracting rabbit jejunum muscle but at doses not likely to be achieved in vivo. Phosphodiesterase activities in extracts of rat and human lung were inhibited at concentrations greater than those required to inhibit mediator release.

Topics: Anaphylaxis; Animals; Female; Guinea Pigs; Histamine Release; Humans; Hypersensitivity, Immediate; Lung; Macaca fascicularis; Male; Muscle Contraction; Muscle, Smooth; Passive Cutaneous Anaphylaxis; Phosphodiesterase Inhibitors; Pyrimidinones; Rabbits; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Serotonin