Oxatomide,a new orally active drug which inhibits both the release and the effects of allergic mediators

Summary Oxatomide is a new potent inhibitor of anaphylactic and allergic reactions. After oral administration, the compound both inhibits the release of endogenous histamine and prevents the effects of exogenous histamine, at comparable doses. The combination of these effects appears to be the basis of the effectiveness of oxatomide in allergic reactions and may lead to clinical applications different from classical antihistaminics and from cromoglycate.     

Allergic reactions,cyclic AMP and histamine release

Summary Both isobutylmethylxantine and theophylline increased the level of cyclic AMP in the mast cell. Theophylline reduced the allergic histamine release, whereas isobutylmethylxynthine caused a pronounced potentiation of the histamine release. This indicates that the hypothesis of an inverse relationship between the level of cyclic AMP in mast cells and histamine release is too simple.This work was supported by grants from the Danish Medical Research Council (Grant No. 512-5270) and from Lundbeckfonden.     

Allergic reactions, cyclic AMP and histamine release.

Both isobutylmethylxanthine and theophylline increased the level cyclic AMP in the mast cell. Theophylline reduced the allergic histamine release, whereas isobutylmethylxynthine caused a pronounced potentiation of the histamine release. This indicates that the hypothesis of an inverse relationship between the level of cyclic AMP in mast cells and histamine release is too simple.     

Type III (Arthus) allergic reactions and endotoxin toxicity in guinea-pigs.

Lipoplysaccharide (endotoxin) from E. coli cells produced lethal effects in guinea-pigs. Endotoxin caused no visible dermal change in normal animals, but produced skin reactions characterized by specific Arthus-type (Type III immune hypersensitivity) vascular inflammation in immunized animals. It is concluded that Arthus allergic reactions were evoked by endotoxin, however, endotoxin lethal toxicity appears independent of this process.     

Biological implications of preformed mast cell mediators

Mast cells store an impressive array of preformed compounds (mediators) in their secretory granules. When mast cells degranulate, these are released and have a profound impact on any condition in which mast cell degranulation occurs. The preformed mast cell mediators include well-known substances such as histamine, proteoglycans, proteases, and preformed cytokines, as well as several recently identified compounds. Mast cells have recently been implicated in a large number of novel pathological settings in addition to their well-established contribution to allergic reactions, and there is consequently a large current interest in the molecular mechanisms by which mast cells act in the context of a given condition. In many cases, preformed mast cell mediators have been shown to account for functions ascribed to mast cells, and these compounds are hence emerging as major players in numerous pathologies. In this review we summarize the current knowledge of preformed mast cell mediators.     

Type III (Arthus) allergic reactions and endotoxin toxicity in guinea-pigs

Summary Lipopolysaccharide (endotoxin) fromE. coli cells produced lethal effects in guinea-pigs. Endotoxin caused no visible dermal change in normal animals, but produced skin reactions characterized by specific Arthus-type (Type III immune hypersensitivity) vascular inflammation in immunized animals. It is concluded that Arthus allergic reactions were evoked by endotoxin, however, endotoxin lethal toxicity appears independent of this process.Acknowledgment. Supported by a grant from the National Health and Medical Research Council of Australia.     

Gastrin: Obligatory intermediate in the postprandial mobilization of gastric histamine in the rat

Summary In unoperated fasted rats, feeding raised the serum gastrin concentration, reduced the gastric mucosal histamine content and activated the gastric histidine decarboxylase. The reduction of gastric histamine and activation of histidine decarboxylase was induced also by the injection of pentagastrin. In antrectomized rats, feeding failed to produce these effects. Injection of pentagastrin, however, still lowered gastric histamine and activated gastric histidine decarboxylase. Thus, antral gastrin seems to be an obligatory mediator of the postprandial activation of histidine decarboxylase and mobilization of histamine.Acknowledgments. Grant support from the Swedish and Danish Medical Research Councils (14P-4822, 04X-1007, 17X-4144 and 512-2540).     

A novel strategy for development of glucocorticoids through non-genomic mechanism

Glucocorticoids (GCs) are routinely believed to take effect through genomic mechanisms, which are also largely responsible for GCs’ side effects. Beneficial non-genomic effects of GCs have been reported as being independent of the genomic pathway. Here, we synthesized a new type of GCs, which took effect mainly via non-genomic mechanisms. Hydrocortisone was conjugated with glycine, lysine and phenylalanine to get a bigger molecular structure, which could hardly go through the cell membrane. Evaluation of the anti-inflammatory efficacy showed that hydrocortisone-conjugated glycine (HG) and lysine could inhibit neutrophil degranulation within 15 min. HG could inhibit IgE-mediated histamine release from mast cells via a non-genomic pathway, and rapidly alleviate allergic reaction. Luciferase reporter assay showed that HG would not activate the glucocorticoid response element within 30 min, which verified the rapid effects independent of the genomic pathway. The work proposes a novel insight into the development of novel GCs, and provides new tools for experimental study on non-genomic mechanisms.     

Gastrin: obligatory intermediate in the postprandial mobilization of gastric histamine in the rat.

In unoperated fasted rats, feeding raised the serum gastrin concentration, reduced the gastric mucosal histamine content and activated the gastric histidine decarboxylase. The reduction of gastric histamine and activation of histidine decarboxylase was induced also by the injection of pentagastrin. In antrectomized rats, feeding failed to produce these effects. Injection of pentagastrin, however, still lowered gastric histamine and activated gastric histidine decarboxylase. Thus, antral gastrin seems to be an obligatory mediator of the postprandial activation of histidine decarboxylase and mobilization of histamine.     

Histamine receptor-mediated signaling during development and brain function in adulthood

Histamine might have an important role in brain development. However, most studies have focused on short-term effects of histamine receptor-mediated signaling on brain function in adulthood. Little is known about the potential long-term effects of histamine receptor-mediated signaling during development on brain function in adulthood. We hypothesize that increased postsynaptic histamine receptor-mediated signaling during development has detrimental effects on brain function in adulthood. Our data support this hypothesis. In the developing mouse brain, histamine H3 receptor blockade, which increases histamine release, has detrimental sex-dependent effects on object recognition, spatial learning in the water maze, and pre-pulse inhibition in adulthood. Our data also support the hypothesis that histamine mediates the detrimental long-term sex-dependent effects of methamphetamine exposure early in life on these brain functions in adulthood. Therefore, increased efforts are warranted to carefully evaluate the effects of drugs that directly or indirectly affect histamine receptor-mediated signaling during development on cognitive function later in life.     

The effects of histamine dihydrochloride on blastocyst implantation in the laboratory rat

Summary This investigation studied the effects of intrauterine injections of histamine dihydrochloride on blastocyst implantation in the laboratory rat. Results of this study lend support to the idea that histamine is the initiator of implantation through the induction of decidualization in this species.     

Action of histamine and vasoactive intestinal peptide (VIP) on cyclic AMP in gastric glands isolated from human fetal stomach

Histamine and VIP produce an elevation of cAMP production in gastric glands isolated from the human fetal stomach at 15 weeks gestation. These effects were attributed to the activation of 2 distinct receptor-cAMP systems, one being sensitive to histamine in parietal cells, and the other being sensitive to VIP in muco-peptic cell populations. The results suggest that histamine and VIP may play a role in inducing gastric secretion during fetal life in man.     

Action of histamine and vasoactive intestinal peptide (VIP), on cyclic AMP in gastric glands isolated from human fetal stomach

Summary Histamine and VIP produce an elevation of cAMP production in gastric glands isolated from the human fetal stomach at 15 weeks of gestation. These effects were attributed to the activation of 2 distinct receptor-cAMP systems, one being sensitive to histamine in parietal cells, and the other being sensitive to VIP in muco-peptic cell populations. The results suggest that histamine and VIP may play a role in inducing gastric secretion during fetal life in man.     

Zur Spezifität des durch Bradykinin,Kallidin und Met-Kallidin ausgelösten Blutdruckreflexes an der Katze

Summary Synthetic kinins (bradykinin, kallidin and met-kallidin) administered via the femoral artery in the isolated hindlimb of the cat elicits vasoconstriction, a reflex on the systemic blood pressure, a stimulation of respiration, and contraction of nictitating membrane. Acetylcholine elicits these reflex reactions in the body too. Atropine blocks this reflex, but not the reactions of kinins. Phenylbutazone administered via the femoral artery blocks the reflex reactions of acetylcholine and kinins as well as the vasoconstriction of histamine and the kinins in the isolated hindlimb. Phenylbutazone elicits by itself a reflex reaction. Of all the synthetic substances, the kinins are the most specific drugs inducing reflex reactions.     

Antiallergische Wirkung bakterieller Polysaccharide

Summary It is shown that certain bacterial polysaccharides possess marked antianaphylactic properties. These hitherto unknown effects, which are not due to a change in sensitivity to histamine, result from a complex and peculiar mechanism of action.     

Stimulation of pyruvate carboxylation by gastric secretagogues

Pyruvate carboxylation was stimulated by 2 gastric secretagogues, histamine and dibutyryl cyclic AMP, and by butyrate. Thiocyanate, an inhibitor of acid secretion, produced a slight decrease. Avidin significantly reduced acid secretion and this effect was overcome by biotin and oxalacetate. The results suggest that carboxylation of pyruvate is one of the reactions controlling oxidative metabolism and acid secretion in toad gastric mucosa.     

Histamine as an extremely potent releaser of vasopressin in the rat

Summary Intraperitoneal and intraventricular injection of histamine induces a very fast and high elevation of vasopressin in rat plasma as determined by radioimmunoassay. The effects are dose and time related. The intraventricular injection is more effective with regard to time and dose than the intraperitoneal injection.     

Radiation-released histamine in the rhesus monkey as modified by mast-cell depletion and antihistamine

Summary 4000 rads of mixed gamma neutron radiation administered to rhesus monkeys released a significant amount of histamine into their circulation. When the monkeys were treated with a mast-cell histamine depleter (compound 48/80) for 4 days and then irradiated, no increase in circulating histamine was seen. When 48/80 was given 20 min after irradiation, only a slight increase in histamine was seen, indicating that 4000 rads had released most of the mast-cell histamine.     

Histamine as an extremely potent releaser of vasopressin in the rat.

Intraperitoneal and intraventricualr injection of histamine induces a very fast and high elevation of vasopressin in rat plasma as determined by radioimmunoassay. The effects are dose and time related. The intraventricular injection is more effective with regard to time and dose than the intraperitoneal injection.