A. Schmal

Histamine release in dogs by Cremophor El® and its derivatives: Oxethylated oleic acid is the most effective constituent

Several preparations of Cremophor El®, several of other non-ionic detergents and several components of Cremophor El were tested for their histamine-releasing capacity in dogs. Lutensol AP 10 and a derivative of 1,2-propylenglycol were ineffective, but showed excellent properties as detergents. Thus the histamine-releasing capacity was not necessarily combined with the tenside effect of the surfactants.Oleic acid found in Tween 80 as well as in Cremophor El seems to be the most effective constituent, but the alcohol seems also to be important for the histamine-releasing capacity. The development of a non-toxic solubilizer for lipophilic drugs seems of considerable clinical interest.

A phylogenetic study on the occurrence and distribution of histamine in the gastro-intestinal tract and other tissues of man and various animals

Abstract Using a specific fluorimetric and biological method, the occurrence and distribution of histamine was investigated in man, various mammals, birds, reptiles, amphibians, bony and cartilaginous fishes, lancelets, tunicates, echinoderms, molluscs, and crustaceans. The amine was identified by the fluorescence spectrum, by specific antihistaminics in the bioassay, by the comparison of the fluorimetric histamine values following three different isolation procedures, and in some tissues also by thin-layer chromatography. Histamine was found in all chordates in considerable concentrations with the exception of the stomachless carp. The distribution of histamine in the body, however, varied largely from species to species. Only the gastric mucosa of all vertebratesinvestigated was relatively rich in histamine. The amine was nearly uniformly distributed in amphibians and fishes, in which only the stomach and partly the intestinum showed higher histamine concentrations than all the numerous other tissues investigated. The distribution of histamine, however, in mammals, birds, and reptiles showed great variations from tissue.to tissue. Organs free from histamine were first found in fishes going backward in the phylogeny. Because of the great variabilities in the distribution of histamine in the body of numerous species which were studied in this investigation, only one hypothesis can be developed with respect to a common physiological significance of histamine: there is a selective accumulation of histamine in the gastric mucosa of all chordates possessing acid-secreting cells and a low concentration of histamine in the gastro-intestinal tract of stomachless fishes. The gastric acid secretion is stimulated by histamine in all vertebrates investigated, whereas in many fishes histamine has no effects on the circulation or on smooth muscles of the gastro-intestinal tract or on the uterus. Thus, stored histamine probably has a specific function in the gastric mucosa, but not a general function, such as the regulation of ubiquitous metabolic processes or the regulation of microcirculation.

Elevated plasma histamine concentrations in surgery: causes and clinical significance

SummaryHistamine concentrations in plasma, whole blood and various tissues of human subjects, monkeys, pigs and dogs were determined by fluorometric methods before, during and after surgical operations. Following intraabdominal surgery in 6 of 22 patients elevated plasma histamine levels were found several hours after the end of operation. Some of the causes of histamine release in surgery were found to be premedication by atropine, intravenously administered anaesthetics, infusion of plasma substitutes and manipulation on the gut. Acute blood losses were without effect on the plasma histamine levels. Clinical symptoms and pathophysiological reactions, such as tachycardia, hypotension, increased gastric secretion and anaphylactoid reactions could be related to the release of histamine in some circumstances.ZusammenfassungHistaminkonzentrationen in Plasma, Vollblut und verschiedenen Geweben von Mensch. Affe, Schwein und Hund wurden vor, während und nach Operationen mit fluorometrischen Methoden gemessen. nach intraabdominellen eingriffen wurden bei 6 von 22 Patienten erhöhte Plasmahistaminspiegel noch Stunden nach der Operation gefunden.Als Ursachen der Histaminfreisetzung bei Operationen wurden nachgewiesen: Prämedikation durch Atropin, Anästhesieeinleitung mit intravenös verabreichten Kurznarkotika, Infusion von Plasmasubstituten und Manipulationen am Darm. Akuter Blutverlust war ohne Einfluß auf die Plasmahistaminspiegel. Klinische Symptome und pathophysiologische Reaktionen, wie Tachykardie, arterielle Hypotension, erhöhte Magensekretion und anaphylaktoide Reaktionen konnten auf Histaminfreisetzung unter bestimmten Umständen zurückgeführt werden.

Evaluation of histamine elimination curves in plasma and whole blood of several circulatory regions: A method for studying kinetics of histamine release in the whole animal

Histamine concentrations in canine whole blood and plasma were determined under several pharmacological, pathophysiological, and clinical conditions, using fluorometric methods.The specificity of the assay for whole-blood histamine was investigated by comparing 3 purification procedures for the isolation of histamine from whole blood including butanol extraction (Shore), ion-exchange chromatography on Dowex 50 W-X 8, and the combination of these 2 methods (Lorenz). Histamine in whole blood was identified in analytical and preparative samples by fluorescence spectra, thin-layer chromatography, degradation by diamine oxidase from pig kidney and inactivation by histamine methyltransferase from guinea-pig brain as well as by biological tests on the isolated guinea-pig ileum. Since butanol extraction resulted in significantly higher ‘histamine’ values than the other two purification procedures, ion-exchange chromatography on Dowex 50 was recommended as the method of choice for the specific determination of histamine in dogs whole blood.Normal values of histamine concentrations in canine plasma were tentatively estimated. They depended on the time between pretreatment of the animals (anaesthesia, operation) and the collection of blood and showed an approximately logarithmic normal distribution. The median, the lower/upper quartiles and the range of the plasma histamine levels obtained 30 minutes after the end of pretreatment were 0.2, 0–0.4 and 0–1.2 ng/ml, respectively. Nearly 50% of the values were zero (below 0.1 ng according to the sensitivity of the method), only 1% of them exceeded slightly 1 ng/ml. Thus histamine release by drugs or by other medical treatments was only stated, when plasma histamine levels exceeded 1 ng/ml and decreased in a way to give an elimination curve of approximately first-order kinetics (Bateman function).Histamine concentrations in dogs whole blood showed approximately a logarithmic normal distribution. The median, lower/upper quartiles and range were 47, 34/75 and 13–209 ng/ml respectively.The histamine levels in the whole blood of four circulatory regions did not show any significant differences. The plasma histamine concentrations in the portal vein were slightly higher than in the hepatic veins.The injection of exogenous histamine and the concomitant determination of plasma and whole-blood histamine levels in four circulatory regions showed that the plasma histamine determination was the more sensitive method for measuring histamine elimination curves than the whole-blood histamine assay.The elimination of exogenous histamine administered intravenously was influenced by several drugs including inhibitors of histamine inactivation and histamine receptor antagonists. Aminoguanidine and the H2-receptor antagonist burimamide slowed down the disappearance of histamine from the plasma, the H1-receptor antagonist dimethpyrindene enhanced it, but amodiaquine had no significant effects. Dimethpyrindene and burimamide were capable of releasing histamine in dogs, in some cases to a considerable extent.The plasma substitute Haemaccel®, a chemically modified gelatin, released histamine in dogs. Using batch 3000, from 27 animals investigated, 15 animals showed elevated plasma histamine levels and a hypotensive blood pressure response, whereas in 12 of the dogs it did not show an effect on these parameters. The plasma histamine levels at the time of maximum hypotension showed an approximately logarithmic normal distribution. This frequency distribution in combination with the varying incidence of anaphylactoid reactions depending on the batches used seemed very important for the interpretation of clinical reactions to Haemaccel in human test persons and patients.By histamine determinations in plasma and whole blood of several circulatory regions and in various tissues before and after infusion of Haemaccel it could be demonstrated that the sites of histamine release by Haemaccel in dogs were especially the skin of the upper hemisphere of the body and the liver, whereas the gastro-intestinal tract took up histamine from the circulation.These numerous results under various experimental conditions may be considered as an evidence for the high quality and reliability of the method to study histamine release in the whole animal or in human subjects by evaluating histamine elimination curves in plasma.

Problems in the assay of histamine release by gelatin: o-Phthaldialdehyde-induced fluorescence, inhibition of histamine methyltransferase and H1-receptor antagonism by Haemaccel

When 3 fluorometric techniques for the determination of histamine were compared following histamine release by plasma substitutes, 2 o-phthaldialdehyde-reactive substances were detected in Haemaccel. By ionexchange chromatography and subsequent solvent partition they could not be separated sufficiently from histamine. They interfered considerably with the histamine assay when the incubation was carried out with 1% o-phthaldialdehyde at 21°C for 4 minutes (Shore) or with 0.05% o-phthaldialdehyde at 0–2°C for 40 minutes (Håkanson). But following the incubation of histamine with 0.05% o-phthaldialdehyde at 21°C for 4 minutes the determination of histamine release by Haemaccel in dogs and human subjects was no longer impaired.The o-phthaldialdehyde-reactive substances in Haemaccel showed fluorescence excitation/emission maxima of 370/460 nm. Using 0.05% o-phthaldialdehyde at 21°C the maximum luminiscence was achieved after an incubation period of 50 minutes, at 0–2°C after about 2 hours. In contrast to histamine the Haemaccel-induced fluorescence was very stabil. By thin-layer chromatography on cellulose the 2 substances in Haemaccel could be differentiated from histamine by their Rf-values. Their fluorescence remained constant after incubation of the extracts with histamine methyltransferase.The original solution of Haemaccel as well as Haemaccel extracts after chromatography on Dowex 50 and solvent partition showed both an inhibitory and a pseudoactivating effect on histamine methyltransferase as well as a H1-receptor antagonist activity on the isolated guineapig ileum. These studies on Haemaccel may be considered as an example of the problems, which occur in the biochemical demonstration and evaluation of histamine release by macromolecular substances.

Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol.

After an i.v. application of 100 mg tramadol in 13 healthy volunteers (1) no change in plasma histamine concentration could be detected, (2) systemic anaphylactoid reactions did not occur, (3) cutaneous reactions were not rated as anaphylactoid since itching and erythema were seen only once after tramadol whereas erythema was also observed twice after saline, (4) blood pressure and heart rate were only very slightly and transiently elevated without any abnormalities in ECG-readings and (5) only side effects typical for opioid therapy were observed.

Augmentation of pentagastrin stimulated gastric secretion in the Heidenhain pouch dog by amodiaquine: inhibition of histamine methyltransferase in vivo?

In 9 dogs, whose maximum gastric acid response to pentagastrin was evoked by 6 μg/kg, the total gastric secretion as well as the peak gastric secretion was enhanced by amodiaquine. The optimum dose of this antimalarial drug was 2 mg/kg, whereas 0.25 mg/kg were without effect and 3 mg/kg reduced already the augmentation of gastric secretion by this substance. The increase in acid output by amodiaquine was greater than that in volume. The total secretion was more enhanced than the peak secretion, which means a longer duration of the amodiaquine potentiated gastric secretion elicited by pentagastrin, than that without application of amodiaquine contrary to that stimulated by exogenous histamine.Amodiaquine itself did not stimulate gastric acid secretion, in contrast to prostigmine and carbachol. Thus amodiaquine seemed not to enhance gastric secretion by a direct or indirect parasympathomimetic action. The question whether amodiaquine acted on gastric secretion in a specific way and not by parasympathomimetic effects, led to investigations in several exocrine glands. In salivary glands, amodiaquine did neither stimulate the secretion in all doses investigated nor did it enhance the pilocarpine and acetylcholine induced salivation with any significance and regularity. Also the pancreatic and biliary secretion was neither stimulated by amodiaquine nor was the secretin induced secretion of the pancreas and liver augmented by amodiaquine. Thus the enhancing effect of this drug on the histamine and pentagastrin stimulated gastric secretion was very likely specific for the gastric mucosa and not due to a parasympathomimetic action of the drug.In contrast to the findings in various exocrine glands of the gastrointestinal tract, the arterial hypotension following the i.v. injection of acetylcholine was increased specifically by a preceeding i.v. injection of amodiaquine, whereas the equi-effective actions of histamine, serotonin and bradykinin as well as the hypertension by epinephrine and norepinephrine were not influenced by amodiaquine. This specific effect of the antimalarial drug very probably was not caused by an inhibition of the unspecific choline esterase in the blood.Since in exocrine glands no evidence could be found for a parasympathomimetic action or other modes of action of amodiaquine, it seemed probable that amodiaquine potentiated the histamine and pentagastrin stimulated gastric secretion by an inhibition of histamine methyltransferase in vivo.

Über die Kallikreinausscheidung im Harn des Menschen nach Nierentransplantation

ZusammenfassungNach Nierentransplantation war die Kallikreinausscheidung im Harn sehr gering, öfter gleich Null. Wurde die implantierte Niere toleriert, so stiegen die Werte langsam wieder an, in einem Fall, der über 20 Monate verfolgt werden konnte, bis in den Normbereich. Beim Eintreten von Abstoßungsreaktionen sank die Kallikreinausscheidung stark ab, meist bevor das Allgemeinbefinden der Patienten sich auffällig verschlechterte, oder die Harnstoffwerte stärker angestiegen waren. Bei einer Reihe von Patienten war vorübergehend Renin, bei anderen Histamin in sehr hohen Mengen im Harn nachweisbar.SummaryAfter kidney transplantation the urinary excretion of kallikrein is extremely small, often zero. If the transplant is tolerated it rises slowly again, in a patient which could be controlled over 20 month up to normal values. In cases of rejection reactions the kallikrein excretion diminished greatly, in most cases before the patients turned in a bad condition or the urea concentration in blood rose heavily. In some cases renin could be demonstrated in urine, in others very high amounts of histamine.

o-Phthaldialdehyde reactive substances in dog's plasma and gelatin (Haemaccel®) complicating the determination of histamine

ConclusionThese results indicate that even small alterations of the incubation procedure witho-phthaldialdehyde may considerably influence the specificity of the fluorometric histamine assay. Tests for identification of this amine are always necessary in studies on histamine in body fluids or following the administration of drugs.

Zum Mechanismus der Sekretionsstimulierung und Blutdrucksenkung durch Histalog (Betazol®): Histaminliberierung und Potenzierung der Wirkung von Kininen und Serotonin

ZusammenfassungIn der beim maximalen Histalogtest üblichen Dosis von 2 mg/kg, zeigt Histalog bei verschiedenen Tierspezies neben dirketen histaminartigen Wirkungen auch noch eine Steigerung der Serotonin- und Kininwirkung. Wahrscheinlich sind deshalb Antihistaminica ohne Antikinin- und Antiserotoninwirkung gegenüber Nebenerscheinungen des maximalen Histalogtestes wirkungslos. 13fach höhere Histaminspiegel im Magensaft als im Blutplasma des Menschen sprechen für eine Histaminliberierung durch Histalog.SummaryHistalog in a dose of 2 mg/kg which is used for maximal stimulation of the human gastric acid secretion, showed not only directly histamine-like actions, but also an enhancement of the action of kinins and seotonin in different species. This seems to be the reason why antihistaminic drugs without antikinin and antiserotonin action do not prevent the side effects of histalog during the test. 13-fold higher histamine levels in human gastric juice than in plasma support the hypothesis, that histalog stimulates gastric secretion by a release of histamine.