A. Gulbenkian

Antiallergic activity of loratadine, a non-sedating antihistamine.

Loratadine is a new non‐sedating antihistamine. The present studies compared loratadine and terfenadine, another non‐sedating antihistamine, for their ability to inhibit the bronchial response to histamine and other autacoids which have been implicated as contributing to the symptoms of an allergic reaction. In addition, the two antihistamines were evaluated in models of immunologically mediated allergic reactions. Loratadine is a more potent inhibitor of histamine‐induced bronchospasm in guinea pigs than is terfenadine. Both antihistamines exhibit marked antiserotonin activity at doses 10 times their antihistamine ED50 values. In contrast, loratadine and terfenadine produce little or no inhibition of the bronchial responses to methacholine, leukotriene C4 or platelet‐activating factor. An allergic bronchospasm in guinea pigs is inhibited by loratadine (ED50= 0.40 mg/kg, p.o.) and terfenadine (ED50= 1.7 mg/kg, p.o.). The bronchospasm associated with allergic anaphylaxis in rats is significantly inhibited by 10 mg/kg, p.o. loratadine and 30 mg/kg, p.o. terfenadine. Loratadine exhibits antiallergy activity in vitro. At micromolar concentrations, loratadine inhibits the release of histamine from Con A and A23187‐stimulated rat peritoneal mast cells and the release of histamine and leukotrine C4 from a Con A‐stimulated cloned murine mast cell line

Bronchodilator and antiallergy activity of forskolin.

Forskolin is a diterpene from the roots of Coleus forskohli which directly activates the adenylate cyclase and raises cyclic AMP levels in a variety of tissues. Forskolin was studied for its effects on the tone of airway smooth muscle and the immunologic release of leukotrienes and histamine. The bronchospasm induced by inhaled antigen in sensitized guinea pigs was prevented in a dose-related fashion by the intravenous (i.v.) or intratracheal administration of forskolin. Forskolin was more potent than aminophylline and less potent than salbutamol. There was no evidence that forskolin would potentiate the in vivo bronchodilator effects of either salbutamol or aminophylline. Forskolin was approximately 100 times more potent than aminophylline by the i.v. and intratracheal routes to reverse an established allergic bronchospasm. Forskolin given intratracheally also inhibited the bronchospasm to i.v. histamine, with a short duration of action. In vitro forskolin (less than 1 microM) inhibited contractions of lung parenchyma provoked by histamine, LTC4 or antigen. Forskolin (1 microM) also inhibited the immunologically stimulated release of LTD4 and histamine from sensitized guinea pig lung. These studies show that forskolin shares with other agents that elevate cyclic AMP levels the ability to relax airway smooth muscle and inhibit mediator release in vitro and elicit a bronchodilation in vivo.

The hyperglycemic activity of benzothiadiazine and other diuretics

Abstract Considerable evidence is available which demontrates the tendency of certain benzothiadiazine diuretics to elevate blood glucose values in seemingly normal, as well as diabetic or pre-diabetic, individuals (1–5). A recent review (5) concerning the benzothiadiazine diuretics suggest that the hyperglycemic potential of all members of this chemical class is equivalent to their diuretic potency. The paucity of data encouraged us to determine systematically the degree of hyperglycemia elicited in rats by eleven benzothiadiazine diuretics. Chlorthalidone (an isoindoline), quinethazone (a quinazoline), and ethacrnic acid were included in this investigation as examples of diuretics of other chemical types.

Adrenergic changes due to pertussis: Insulin, glucose and free fatty acids ☆

Abstract Pertussis sensitization increases plasma insulin (IRI) levels and also facilitates insulin release by isoproterenol, norepinephrine, phenylephrine, and theophylline. Further, pertussis reverses epinephrine-induced insulin suppression. The elevated IRI levels are attenuated generally by a β-adrenergic receptor blocker, MJ-1999, and in some instances an α-adrenergic receptor blocker, phenoxybenzamine. Thus, pertussis appears to enhance the β-agonist responsiveness insofar as insulin is concerned. Pertussis Glucose Adrenergic Insulin Free fatty acids

The effect of altered carbohydrate metabolism in pertussis-sensitized mice on anaphylaxis

Abstract An attenuated reponse to epinephrine-induced hyperglycemia has been demonstrated in rats injected with Bordetella pertussis alone and in mice sensitized with horse serum or in combination with B. pertussis . This response is not a reflection of reduced liver glycogen. In the mice sensitized with horse serum only, protection against anaphylaxis is afforded by some but not all hyperglycemia-inducing agents tested. Alloxan and epinephrine protect, whereas diazoxide does not. Alloxan was considerably less protective in the horse serum-pertussis-sensitized mouse. Diazoxide, glucose, and epinephrine did not protect. Prednisolone and betamethasone, at doses that protect against lethal anaphylaxis in the horse serum-pertussis-sensitized mouse, also restore epinephrine hyperglycemia in the pertussis rat. Possible mechanisms of protection of these compounds are discussed. No definite link between the carbohydrate abnormality of the pertussis animal and anaphylactic sensitivity has been established.

Effect of epinephrine on hepatic glycogen phosphorylase and synthetase activities in normal and pertussis-sensitized rats.

Abstract To investigate the nature of the diminished hyperglycemic response to epinephrine in pertussis-sensitized rats, we compared the response to epinephrine of the hepatic enzymes, glycogen phosphorylase and glycogen synthetase, and of peripheral lactate release in normal and sensitized rats. The epinephrine-induced activation of hepatic phosphorylase was markedly diminished in pertussis rats. Pertussis sensitization did not alter either the decrease in hepatic glycogen synthetase activity or the elevation of plasma lactate produced by epinephrine administration. The findings indicate that a diminished activation of hepatic phosphorylase, associated with and possibly dependent upon a relative hyperinsulinism, can account for the attenuated hyperglycemic response to epinephrine in pertussis rats.

Synthesis of 7,8-acetylenic analogs of hexahydro leukotriene-E4 with agonist and antagonist activities: convenient stereoselective routes to E- and Z-enynes

Abstract E- and Z-enynes available by stereoselective dehydrations of Co 2 (CO) 6 completed and uncomplexed propargyl alcohols 13 and 5 produced acetylenic LT-E 4 analogs with contractile activity similar to leukotrienes. Their 5-desoxy analogs were found to have antagonist activity against LT-C 4 induced contractions on isolated guinea pig lung parenchyma.

Synthesis of butanoic acid 4,4′-[(4E, 6Z, 9Z-pentadecatrien-2-ynylidene)-bis with leukotriene- like activity: Novel acetylenic acetals and dithioacetals as antagonists of leukotriene-C4

Abstract A selective exchange reaction of the symmetrical acetal 5a with protected cysteine readily provided the hemi-thioacetals 9a and 11a related to leukotriene-E 4 . Use of acetylene-bis-(diethyl acetal) 12 led to a facile synthesis of the title compound 17a. Its corresponding hexahydro analogs displayed marked antagonist activity against LT-C 4 induced contractions on isolated guinea pig lung parenchyma.

The role of a Ca2+/calmodulin dependent plasma membrane Ca2+ channel during concanavalin A activation of MC9 mast cells

The effects of Con A on free cytoplasmic calcium concentrations in the cloned murine mast cell, MC9, have been measured using the fluorescent calcium indicator quin 2. Con A causes a rapid, small yet sustained rise in free cytosolic calcium (up to 245 nM) followed closely by increased45calcium uptake and more slowly by histamine release. The increases in45calcium uptake and histamine release require extracellular calcium. However, the Ca2+ influx blockers, nifedipine and verapamil inhibit these responses only at concentrations significantly higher than those used in smooth muscle to oppose potential-dependent events, and diltiazem is inactive. These observations suggest that, in these mast cells, other types of channels control Ca2+ entry.In contrast, the intracellular Ca2+ blocker, TMB-8, inhibits both the Con A-induced histamine release and the Ca2+ changes. The calmodulin antagonists calmidazolium, trifluoperazine and W-7 are also highly effective inhibitors of both the Ca2+ changes and histamine release in direct proportion to their potency against calmodulin-dependent phosphodiesterase, implicating calmodulin in the regulation of stimulus-secretion in MC9 cells. These data imply that histamine release follows increases in intracellular Ca2+ concentration. Free intracellular Ca2+ results from rapid release from internal stores and is followed by a slower but more sustained influx of extracellular Ca2+.