Oedema, histamine

The median histamine oedema, 10 min after the injection of 50 jug of histamine, was 16 units (=1.6 mm). The paw diameter increase followed an approximately normal distribution. values higher than 21 or lower than 10 units being very rare (less than 5 %). Inhibition of the histamine oedema in animals after oral administration of a test compound was therefore considered significant for all values below 10 units. ED5Q-values were calculated on the number of guinea-pigs with significantly inhibited histamine oedema (19). 

The results obtained in the guinea-pig anaphylaxis test after oral oxatomide administration are presented in Fig. 1. A dose-dependent increase in the number of animals protected from the acute anaphylactic shock was observed and the histamine-induced paw oedema was similarly reduced by increasing doses of oxatomide. As previously found with cinnarizine, protection from anaphylactic shock was a more sensitive measure of the activity of oxatomide than was the reduction of paw oedema. In comparison with cinnarizine, however, oxatomide was considerably more potent. The calculated ED5o s, 2 h after oral administration, were 0. 16(0. 081 - 0. 31) mg/kg for protection from anaphylactic shock and 0. 30(0. 18 - 0. 50) mg/kg for inhibition of histamine oedema. 

For the oxatomide-analogues the results of histamine antagonism in vitro, together with the EDsq s for protection from anaphylactic shock and the values of histamine oedema at a standard dose of 2. 5 mg/k.g are summarized in Table III a and b. 

Figure 1. Individual survival time and histamine oedema after oral oxatomide administration (t 2 hr) in the guinea pig anaphylaxis test...

Histamine antagonism in vitro (A q), protection from anaphylactic schock (EDjo) histamine oedema values. 

Compound to challenge (h) Protection from Anaphylactic shock hihibition of Histamine Oedema... 

In Table VI a and b the results of 56 oxatomide analogues (36 benzimidazolones and 20 benzimidazoles) are summarized. All compounds were tested at a standard dose of 10 mg/kg. In particular those compounds are active which showed the highest activity in guinea-pig anaphylaxis and histamine oedema, e. g. the benzimidazolones 8, 9, 10, 13, 14, 23, 24 and 25 and the benzimidazoles 48, 61 and 62. However, no linear correlation was found. 

Oxatomide has been selected from a new chemical series of benzimidazolones and benzimidazoles on the basis of its activity on hypersensitivity and histamine-induced reactions in three species, the guinea-pig, the rat and the dog. In a well-known model, the guinea-pig anaphylaxis, oxatomide was at least as effective on the anaphylactic shock as on the histamine oedema induced in the same animals. In the rat, the new compound was an orally active inhibitor of PCA-reactions. Compound 48/80-induced lethal shock was prevented at doses of the same order as those required to inhibit histamine skin reactions. In the dog inhibition of allergic reactions, induced by Ascaris allergens in the skin of hypersensitive dogs, inhibition of histamine skin reactions and reduction of circulating histamine released by Cremophor EL were obtained by virtually the same oral doses. 

The classical skin response to local release of histamine that results from contact with an allergen, irritant or following an insect bite. A central wheal develops as a direct result of local inflammation and the the oedema the follows the increased capillary permeability caused by histamine acting on HI-receptors on vascular-endothelial cells. 

Invasion of the tissues by an infective agent initiates an inflammatory response in the animal. This is non-specific and is mediated primarily by substances released from tissues that are damaged as a result of either trauma or the toxic effects of the infective agent. The major mediator is the vasoactive amine histamine, which causes an increased local blood flow and capillary permeability, resulting in local oedema. A major aspect of the inflammatory response is the involvement of large numbers of phagocytic cells, particularly the polymorphonuclear leucocytes. These are chemotactically attracted to the inflamed tissues and are mainly responsible for the elimination of particulate material. This often results in the destruction of many of these cells and the formation of pus. 

The majority of clinically definite and immunologically confirmed reactions have erythema as a main feature. Erythema is, however, a common accompaniment to the administration of many drugs, often as a result of directly mediated histamine release, and it should not be regarded as part of a life-threatening reaction unless there are changes in other systems of the body. In addition, most reactors have oedema, particularly of the eyelids. 

In the ovary the ovulatory surge of LH increases blood flow [98]. This is accompanied by an increase in vascular permeability in the follicles resulting in oedema which persists through the time of follicle rupture and ovulation. The effect of LH can be mimicked by histamine but not by FSH or serotonin. Leukocytes accumulate in Graafian follicles near the time of ovulation and fibroblasts migrate from the theca layer to the stratum granulosum. 

Q3 A type 1 hypersensitivity reaction is responsible for the development of the allergy. The symptoms are due to the effects of mast cell degranulation with the release of histamine. Mast cells are located in the nasal passages and the nasal mucosa is sensitive to the effects of histamine released from these cells, leading to inflammation of the mucous membranes of the nose. The inflammation is associated with oedema and swelling, vasodilation and an increase in the secretion of mucus. The mucous membrane of other sections of the respiratory tract (accessory sinuses, nasopharynx, and upper and lower respiratory tract) will also be affected by the allergic reaction. 

Hj-receptor mediates the oedema and vascular effects of histamine (see above)... 

The allergen, whether it is a drug, pollen or dust mite, causes production of immunoglobulin E (IgE) antibodies on first exposure. These antibodies attach themselves to mast cells. On subsequent exposure to the same allergen the combination of IgE and allergen causes the mast cells to release a variety of chemicals including histamine. The effects of this can be local, for example hay fever, asthma and urticaria, or systemic causing whole body oedema and anaphylactic shock. 

The concept of an endogenous mediator of increased permeability was supported by the classical studies of Lewis on histamine. The increase in vascular permeability is a biphasic process, the earlier transient stage, in some species at least, resulting from the release of histamine. After suitable mild inflammatory stimuli, the tissue oedema may often be inhibited by anti-histaminic drugs. In a limited sense, therefore, antihistaminic drugs may be regarded as having anti-inflammatory activity, but they are not discussed in detail in this review. 

In the rat, which is relatively insensitive to histamine, and possibly also in the mouse, 5-hydroxytryptamine (serotonin) may be an important factor in the production of vascular permeability " . Thus, inflammatory oedema in these species may often be prevented by the administration of serotonin inhibitors such as bromolysergic acid diethylamide . It is generally accepted, however, that histamine and 5-hydroxytryptamine cannot account for all the manifestations of vascular permeability in inflammation. Attention has been focused on possible mediators of higher molecular weight, especially peptides and proteins. 

Table 2.8. Approximate effectiveness of some derivatives of phenothiazine in inhibiting oedema-production by 5-hydroxytryptamine (5-HT) histamine, dextran, egg-white and compound 48/80...

The effect of phenothiazines on formalin oedema, however, seems to be the result of a different pharmacological activity, since Parratt and West demonstrated that neither histamine nor 5-hydroxytryptamine plays a major role in the reaction . Lish, Albert, Peters and Allen concluded that there is no relationship between the antihistamine and anti-5-hydroxytryptamine actions of phenothiazines and their ability to reduce formalin oedema. This belief is further substantiated by the work of Winter, Risley and Nuss , who showed that cyproheptadine, a non-phenothiazine inhibitor of both... 

An a,p-unsaturated, y-lactone linear sesterterpene (21) was isolated from the Caribbean sponge Thorecta korridus that exhibited inflammatory activity both in vivo inducing paw oedema and in vitro inducing release of histamine [46]. 

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