48/80, Histamine liberator

After an intravenous injection of Compound 48/80 (1 mg/kg body weight) the phagocytic function of the reticuloendothehal system (India ink clearance) of female albino rats remained xmchanged (LAzAr et al. 1968). Carbon granules could not be seen in the lungs or kidneys. 

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Boiling an acidified cotton extract does not lower its anaphylatoxin activity whereas endotoxins lose their activity by this procedure. Furthermore, it is argued that the endotoxin hypothesis is not compatible with the fact that different parts of the cotton plant contain different amoxmts of histamine liberating factor, particularly as plant parts which are more contaminated by handling, i.e. cotton hairs, have no histamine liberating activity. 

Histamine Liberation. Histamine liberation is not caused by fungal extracts, fungal cultures. Bacillus cultures, or their extracts, but is caused by cotton dust extracts and by known endotoxins when a sensitive method is used. 

Histamine, an important mediator (local signaling substance) and neurotransmitter, is mainly stored in tissue mast cells and basophilic granulocytes in the blood. It is involved in inflammatory and allergic reactions. Histamine liberators such as tissue hormones, type E immunoglobulins (see p. 300), and drugs can release it. Histamine acts via various types of receptor. Binding to Hi receptors promotes contraction of smooth muscle in the bronchia, and dilates the capillary vessels and increases their permeability. Via H2 receptors, histamine slows down the heart rate and promotes the formation of HCl in the gastric mucosa. In the brain, histamine acts as a neurotransmitter. 

Besides such antigen-antibody reactions, which play a critical role in the pathogenesis of many allergic, anaphylactic, and hypersensitivity reactions, histamine also can be released from tissue stores in response to physical stimuli, effects of the so-called histamine liberators, a number of chemical substances, various drugs, and toxins. 

Can precipitate asthma, as these drugs are histamine liberators. 

Mivacurium is a potent histamine liberator even in clinically useful doses of 0.15-0.2 mg-kg-1 this can result in a significant reduction in arterial pressure. 

These are adverse reactions resembling the effects of histamine liberation Chistaminoid ) and unrelated to the mode of action of the drug itself. Histamine release appears to be the main factor involved in all types of hypersensitivity reactions and its release explains most of the manifestations. The term anaphylactoid may equally be used to describe these reactions, meaning simply that they resemble anaphylactic reactions, while the term anaphylactic is used specifically for immune-mediated phenomena involving previous sensitisation of the patient. It is often difficult to determine the true nature and cause of the reaction. 

Similar local effects may be produced by injecting histamine liberators (compound 48/80, morphine, etc) intradermally or by applying the appropriate antigens to the skin of a sensitized person. Although most of these local effects can be prevented by adequate doses of an H -receptor-blocking agent, H2 and H3 receptors may also be involved. 

The first detailed paper in the field of the pharmacology of the pyrido-[l,2-o]pyrimidines was a study on the histamine-liberating and nonspecific spacmolytic activity of 2-(2-dimethylaminoethyl)-3-(4-methoxyphenyl-methyl)-4-oxo-4//-py rido [ 1,2-a] pyrimidine.383... 

Severe systemic reactions after atracurium administration may be due to antibody-mediated anaphylaxis (38) rather than non-specific histamine liberation. It has been suggested that systemic effects from non-specific histamine release are dose-dependent. 

Boileau S, Hummer-Sigiel M, Moeller R, Drouet N. Reevaluation des risques respectifs d anaphylaxie et d his-taminobliteration avec les substances anesthesiologiques. [Reassessment of the respective risks of anaphylaxis and histamine liberation with anesthetic substances.] Ann Fr Anesth Reanim 1985 4(2) 195-204. 

Heparin-liberators. Peptone and specific antigen in the sensitized animal are the most effective liberators of heparin from mast cells. Many histamine liberators also liberate heparin but since many are strongly basic amines, they may combine with and mask the liberated heparin. Commercial heparin may have some action as a heparin-liberator - . 

Within seconds of the intravenous injection of a histamine liberator, human subjects experience a burning, itching sensation. This effect, most marked in the pcdms of the hand and in the face, scalp, and ears, is soon followed by a feeling of intense warmth. The skin reddens, and the color rapidly spreads aver the trunk. Blood pressure falls, the heart rate accelerates, and the subject usually complains of headache. After a few minutes, blood pressure recovers, and crops of hives usually appear on the skin. Colic, nausea, hypersecretion of acid, and moderate bron-chospasm also occur frequently... 

Its depolarizing neuromuscular blocking effect is very transient because of its rapid hydrolysis by cholinesterases. It does not cause histamine liberation and hence it is well tolerated. Single-dose therapy of suxamethonium chloride is generally used to relax the skeletal muscle for orthopedic manipulation, endotracheal intubation, in laryngospasm and also to check the intensity of convulsions in patients receiving electroshock treatment (electroconvulsive therapy). 

Feldberg, W. and Raton, W.D.M., 1951, Release of histamine from skin and muscle in the cat by opium alkaloids and other histamine liberators, J. Physiol, 114 490-509. 

Brasch RC, Rockoff SD, Kuhn C, Chaplyvy M (1970) Contrast media as histamine liberators. II. Histamine release into venous plasma during intravenous urography in man. Invest Radiol 5 510... 

RAST (radioallergosorbent test) or enzyme assay (IgE, IgG) Histamine liberation from granulocytes Basophil degranulation test Passive hemagglutination Lymphocyte transformation test Macrophage inhibition test Rosette test... 

Histamine liberation from basophil leukocytes from the peripheral blood has as yet seldom been applied for the detection of allergies of type I. 

The halide complex salts of platinum, chloroplatinites and chloroplatinates, are highly reactive with proteins, with particular affinity for sulphydryl bonds. They can also be histamine liberators (Parrot et al. 1967,1969). These salts thus represent a polar example of a chemical molecule with most of the features which complicate study as allergens. Many of the problems have been resolved and the findings will be given in extenso . Examples of the relevant platinum salts (molecular weight 444 daltons) are ammonium hexachloroplatinate (NH4)2 [Pt Cl ] and te-trachloroplatinate (NH4)2 [PtCm. 

Ozeki S, Tejima K (1974) Drug interaction. II. Binding of some pyrazolone and pyrazolidine derivates to bovine serum albumin. Chem Pharm Bull (Tokyo) 22 1297 Perelmutter L, Khera K (1969) Rat mast cells in human reagin detection. Lancet 1 1269 Rocklin RE, MacDermott RP, Chess L, Schlossman SF, David JP (1974) Studies on mediators production by highly purified human T and B lymphocytes. J Exp Med 140 1303 Rockoff ID, Brash R, Kuhn C (1970) Contrast media as histamine liberators. Invest Radiol 5 503... 

The possible cause of the symptoms seen in immediate reactions may be direct release of vasoactive mediators by the emulsifier. Histamine liberation has been suggested by Schubert and Wretlind (1961). It is known that certain synthetic emulsifiers like Tweens are so-called macromolecular histamine releasers in dogs (Halpern 1956). Similar action of other emulsifiers is therefore feasible in a few predisposed individuals. Among other potential mechanisms for elicitation of early reactions, liberation of ATP from blood cells (Schubert and Wretlind 1961) and formation of flocculates inducing ischemic changes (Wadell et al. 1957) have been proposed. Formation of circulating flocculates could also lead to activation of the plasma enzyme systems. 

The complement system can also be activated without a preceding inunune reaction, and activated complement components (C3a, C5a) can induce histamine liberation and allergoid reactions. Accordingly, the clinical pictures described as allergic reactions to vitamins, and especially the anaphylactoid reactions after administration of vitamin B, should be attributed to an allergoid reaction until the presence of vitamin-specific antibodies has been unequivocally demonstrated. There have been no detailed investigations, so far, of the direct mast cell degranulating ability of vitamins. Therefore, it is not yet possible to come to any definite conclusion on this point. Reactions can also be caused by the vehicles used as well as by possible decomposition products. 

Jaques R, Brugger M (1969) Synthetic polypeptides related to corticotrophin acting as histamine liberators. Pharmacology 2 361... 

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