Histamine 48/80-induced

Histamine H2 Receptor Antagonists. In 1972 a new class of histamine antagonists was described that was capable of antagonizing histamine-induced gastric acid secretion (6). The H2 antagonists are divided into five stmctural classes, some of which are shown in Table 3. A more complete review can be found in Reference 25. 

In addition, Pfister and coworkers investigated 3-hydroxyflavone-6-carboxylic acids as histamine induced gastric secretion inhibitors. After condensing 3-acetyl-4-hydroxybenzoic acid (45) with a variety of aldehydes 46 to deliver the chalcones 47, these purified chalcones were then subjected to the standard AFO conditions to afford flavonols 48 in 51-80% yield. Subsequent alkylation of 48 with methyl iodide or isopropyl iodide followed by saponification of the corresponding esters gave the target compounds. 

Kenakin, T. P., and Cook, D. A. (1976). Blockade of histamine-induced contractions of intestinal smooth muscle by irreversibly acting agents. Can. J. Physiol. Pharmacol. 54 386-392. 

FIGURE 11 Duration of bronchodilator activity in an animal model Anesthesized guinea pigs received 1 ymol/kg of terbutaline, free or in liposomes, via intracheal instillation at time zei o. Bronchodilator activity was measured as the reduction in histamine-induced airway resistance. Histamine (10 yg/kg) was administered i.v. prior to each resistance measurement, o saline (n = 3) free drug (n = 3) a liposomal drug (n = 4). (Courtesy of Liposome Technology, Inc., Menlo Park, California.)... 

Clough GF, Boutsiouki P, Church MK Comparison 57 of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy 2001 56 985-988. 58... 

Grant JA, Riethuisen JM, Moulaert B, DeVos C A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo sup- 59 pression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. 

Schaefer U, Schneider A, Rixen D, Neugebauer E (1998) Neutrophil adhesion to histamine stimulated cultured endothelial cells is primarily mediated via activation of phospholipase C and nitric oxide synthase isozymes. Inflamm Res 47(6) 256-264 Schaefer U, Schmitz V, Schneider A, Neugebauer E (1999) Histamine induced homologous and heterologous regulation of histamine receptor subtype mRNA expression in cultured endothelial ceUs. Shock 12(4) 309-315... 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

A series of novel l-substituted-4-phenyl-l,2,3-triazolo(4,3-a)quinazolin-5(4H)-ones 1 were synthesized by the cyclization of 2-hydrazino-3-phenyl-quinazolin-4(3H) 2 with various one carbon donors. The starting material 2-hydrazino-3-phenylquinazolin-4(3H)-one 2, was synthesized from aniline 7 by a novel innovative route. When tested for their in vivo Hi-antihistaminic activity on conscious guinea pigs all the test compounds protected the animals from histamine-induced bronchospasm significantly, whereas the compound l-methyl-4-phenyl-l,2,3-triazolo(4,3-a)quinazolin-5(4H)-one lb (percentage protection 70.7%) was found to be equipotent with the reference standard chlorpheniramine maleate (percentage protection 71%). These compounds show negligible sedation (5%) when compared to the reference standard (26%). Hence they could serve as prototype molecules for future development [1,4,5]. 

The in vivo antihistaminic activity results indicate that all test compounds protected the animals from histamine-induced bronchospasm significantly. Structural activity relationship (SAR) studies indicated that different alkyl substituents on the first position of the triazoloquinazohne ring exerted varied biological activity. 

Cockcroft, D.W., Killian, D.N., Mellon, J.J. and Hargreave, F. (1977). Protective effects of drugs on histamine-induced asthma. Thorax 32, 429-437. 

Kriesman, FI., Mitchell, C. and Bouhuys, A. (1977). Inhibition of histamine-induced airway constriction negative results with oxtriphylline and ascorbic acid. Lung 154, 223-229. 

Kalivas, P. W. (1982). Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. J. Pharmacol Exp. Then 222, 37-42. 

Vizuete, M. L Dimitriadou, V., Traiffort, E. et at (1995). Endogenous histamine induces c-fos expression within paraventricular and supraoptic nuclei. Neuroreport 6, 1041-4. 

Nogami-Itoh, M., I.Yakuo, D.M.Hammerbeck, R.I.Miller, and K.Takeyama. 1997. The equivalent bronchodilator effects of salbutamol formulated in chlorofluorocarbon and hydrofluoroalkane-134a metered dose inhalers on the histamine-induced pulmonary response in dogs. Pharmaceut. Res. 14 208-212. 

Taggart, S.C.O., A.Custovic, D.H.Richards, and A.Woodcock 1994. An alternative metered dose inhaler propellant GR106642X comparison to chlorofluorocarbon 11 and 12 in the attenuation of histamine-induced bronchoconstriction by salbutamol. Eur. Resp. J. (Suppl. 18) 400s. 

Cetrizine The PK-PD modeling characterized the time course of cetirizine effect on histamine-induced skin reactions (wheal and flare). The histamine-induced flare was at least 80% inhibited at the start of the second administration. Thereafter, on successive administrations, the inhibition was even more pronounced and the response control was nearly total... 

Histamine induces intracellular Ca " flux, actin polymerization, and chemotaxis in immature DCs due to stimulation of HRl and HR3 subtypes. Maturation of DCs results in loss of these responses. In maturing DCs, however, histamine dose-dependently enhances intracellular cAMP levels and stimulates IL-10 secretion, while inhibiting production of IL-12 via HR2 [16]. Interestingly, although human monocyte-derived dendritic cells have both histamine Hj and H2 receptors and can induce CD86 expression by histamine, human epidermal Langerhans cells express neither H nor Hj receptors [72]. 

Jeannin P, Delneste Y, Gosset P, Molet S, Lassalle P, Hamid Q, Tsicopoulos A, Tonnel AB Histamine induces interleukin-8 secretion by endothelial cells. Blood 1994 84 2229-2233. 

Kubes P. Kanwar S Histamine induces leukocyte rolling in post-capillary venules. A P-selectin-mediated event. J Immunol 1994 152 3570-3577. 

Yamaki K, Thorlacius H. Xie X. Lindbom L, Hedqvist P. Raud J Characteristics of histamine-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery. Br J Pharmacol 1998 123 390-399. 

Schaefer U, Schmitz V. Schneider A. Neugebauer E Histamine induced homologous and heterologous regulation of histamine receptor subtype mRNA expression in cultured endothelial cells. Shock 1999 12 309-315. 

Buckland KF, Williams TJ, Conroy DM Histamine induces cytoskeletal changes in human eosinophils via the H4 receptor. Br J Pharmacol 2003 140 1117-1127. 

Caron G, Delneste Y, Roelandts E Histamine induces CD86 expression and chemokine production by human immature dendritic cells. J Immunol 2001 166 6000-6006. 

Gantner F, Sakai K, Tusche MW, Cruikshank WW, Center DM, Bacon KB Histamine h4 and h2 receptors control histamine-induced interleukin-16 release from human CD8+ T cells. J Pharmacol Exp Ther 2002 303 300-307. 

Considerable evidence has emerged to suggest that histamine participates in the immune regulation of the inflammatory response in several diseases. Histamine interferes with the peripheral tolerance induced during SIT in several pathways. Histamine induces the production of IL-10 by DCs [184]. In addition, histamine induces IL-10 production by Th2 cells [188]. Furthermore, histamine enhances the suppressive activity of... 

---