Food-induced histaminosis under diamine oxidase (DAO) blockade in pigs: further evidence of the key role of elevated plasma histamine levels as demonstrated by successful prophylaxis with antihistamines.

Using a recently established porcine model, it was clearly shown that oral histamine administration is extremely dangerous in the presence of diamine oxidase (DAO) blockade. Due to the severity of the symptoms (20% death) and the clinical relevance, further interest has been focussed on strategies to prevent or alleviate food induced histaminosis. In a randomized controlled trial, 10 pigs under DAO blockade were challenged with oral histamine (60 mg). Half of these animals received a prophylactic premedication with a combination of H1- and H2-receptor antagonists. As expected, all animals developed a massive increase in plasma histamine levels, with significantly higher values in the control group (median: 123 ng/ml) compared to the antihistamine group (median: 32 ng/ml). In contrast, clinical symptoms were only observed in the control group. The maximum fall in mean arterial pressure (hypotension) was 60 mmHg (median for control group) but only 15 mmHg (median) under antihistamine pretreatment. These results firstly provide further evidence for the causal role of histamine in the new disease concept and secondly enable us to investigate appropriate therapeutic measures for patients at risk.

Comparison of the histamine-releasing activity of cremophor E1 and some of its derivatives in two experimental models: the in vivo anaesthetized dog and in vitro rat peritoneal mast cells.

Histamine release caused by drugs and/or their solvents in clinical conditions is a well documented observation but the mechanism of this reaction is poorly understood. Hence in this study, the histamine releasing ability of cremophor E1 and six derivatives of 12-hydroxystearic acid (12-HSA) were compared in two models: the in vivo anaesthetized dog and the in vitro isolated rat peritoneal mast cells. The results obtained in both systems differed markedly. Only one compound DH (the diester of 12-HSA with polyethylene glycol) released histamine in both systems. The two substances, which exhibited the weakest histamine releasing ability in the dog model (almost inactive at the doses given) were powerful releasers of histamine from rat peritoneal mast cells (TN, 12-HSA polymerized with ethylene oxide; and ME, the monoester of 12-HSA esterified with polyethylene glycol). The release of histamine from rat peritoneal mast cells was potentiated as the temperature was elevated above 37 degrees C. Due to the heterogeneity of mast cells from both different species and different tissues in the same animal, it is important to choose the appropriate predictive model for clinically important adverse reactions to drugs and/or their solvents. Agents which release histamine by non-specific mechanisms are not uninteresting for the clinical situation.

Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: analysis of various components in cremophor El and development of a compound with reduced toxicity.

Anaphylactoid reactions in man following administration of drugs solubilized with cremophor El (polyethylenglycolglycerol riconoleate) are a considerable clinical problem. Since these reactions occur in dogs on first exposure and in pigs on second exposure, the 'dog model' was used in this communication to analyse components and chemical modifications of cremophor El and its components for their clinical effects, their hypotensive actions and their histamine-releasing capacity. Two series of experiments in 1978 and 1980 were performed in 144 adult mongrel dogs of both sexes. In these studies histamine release was not related to the effect of the solubilizing agents as tensides and was elicited by rather low doses (about 10--100 mg/kg i.v.). The effect of these substances on blood pressure and on blood histamine levels was connected with distinct chemical features: the most potent compounds were oxethylated and additionally esterified unsaturated or hydroxylated fatty acids. Several phases in hypotensive reactions were observed, including an immediate response, a delayed blood pressure response and a late response about 15--20 min after injection. Only the delayed response was associated with histamine release. The combination of cardiovascular effects and histamine release was fatal on some occasions indicating that histamine release can be dangerous. Compared to cremophor El, the tenside effect was equal, but the toxicity was reduced in oxethylated 12-hydroxystearic acid. It is recommended that this solubilizer should be used in further extended studies in animals and - if these are successful - in clinical trials.

[Role of histamine in acute pancreatitis]. / Zur Rolle des Histamins bei der akuten Pankreatitis.

Elevated histamine concentrations of pathophysiological significance could be determined in plasma of dogs suffering from acute pancreatitis according to Pfeffer. This result was also obtained in dogs treated with aminoguanidine, a very effective diamine oxidase blocker, in addition to the duodenal blind loop preparation. Elevated histamine concentrations were found in nine out of ten dogs.

[Penalization in microtropia (author's transl)]. / Penalisation bei der kleinen Esotropie

Near penalization was carried out in 113 children, from which 35 were younger than 5 1/2, and 78 older than 5 1/2 years. We were especially interested in the older group with small angles of squint from zero to five degrees. The treatment with regard to amblyopia in this group is difficult, but we saw also in cases with non-foveal fixation a rapid increase of the near visual acuity because of spherical overcorrection. The distant visual acuity was increased mainly to 0.6. There was no influence upon the angle of squint and the correspondence. In the younger group (below 5 1/2 years) the results with regard to visual acuity, fixation and angle of squint were more favourable. We think, that we will get these results only by occlusion and prism over- and full-correction, if there are no external reasons, such as schoolage, which prevent this treatment.