Symptoms Of Anaphylaxis Research Articles

Pathomechanisms of dextran-induced anaphylactoid/anaphylactic reactions in man.

Immune complex-mediated (type III) anaphylaxis is shown to be the pathomechanism of severe dextran-induced anaphylactic reactions in man. Mild reactions may be either antibody-dependent or not. Patients with severe reactions have regularly high titers of preformed, circulating dextran-reactive antibodies and represent a small subpopulation of high responders to dextran. Upon infusion of clinical dextran, noxious immune complexes are formed, leading to mediator release and symptoms of anaphylaxis. Consequently, application of the hapten inhibition principle is recommended for prevention of such reactions.

Circulating antibodies and blood histamine in cattle after treatment against hypodermosis

Studies have been made of the effect of treatment with an organophosphorus insecticide on calves with or without Hypoderma infestation. A close relationship has been demonstrated between variations of circulating antibodies and blood histamine levels. It is suggested that histamine is released following an immunological reaction due to the formation of complexes between antigenic proteins of the dying larvae and circulating antibodies. Other etiologic agents such as intrinsic larval toxicity were also examined. The small variations of histamine levels suggest that histamine plays only a minor part in the mediation of symptoms of anaphylaxis often observed in parasitised cattle after preventive treatment against hypodermosis.

DRUG-INDUCED ANAPHYLAXIS, CONVULSIONS, DEAFNESS, AND EXTRAPYRAMIDAL SYMPTOMS

DRUG-INDUCED ANAPHYLAXIS, CONVULSIONS, DEAFNESS, AND EXTRAPYRAMIDAL SYMPTOMS

Reduced Symptoms of Anaphylaxis in Chickens by ACTH or Heat

Exogenous ACTH, when administered intramuscularly in four equal doses of 2 I.U./100 gm. of body weight at 24, 23, 22, and 21 hours prior to challenge with BSA, reduced the severity of anaphylaxis in BSA sensitized juvenile chickens. Additionally, a single heat exposure (45° C.) of 30 minutes at 24 hours prior to challenge consistently reduced the severity of anaphylaxis. Single heating exposures at 24 hours prior to sensitization or at 48 hours prior to challenge did not influence the anaphylactic response. In one of two experiments single heat exposures at one hour prior to challenge reduced the severity of anaphylaxis. The levels of anti-BSA antibody which existed immediately prior to challenge were not affected by the heat treatments. These data demonstrate clearly that exogenous ACTH and a single, non-lethal heating episode, when applied 24 hours prior to the induction of anaphylaxis, reduced the severity of the symptoms associated with this particular hypersensitive reaction in the domestic chicken.

Determination of heparin in small tissue samples.

The association of heparin and mast cells is on the basis of the metachromatic color change produced in toluidine blue. Among agents from biologic sources, heparin is the most effective in producing this change in a test tube. The mast cells are the most prominent components that show the changes in histologic sections. Many reports have been published on the amine components of mast cells-histamine and 5-hydroxytryptamine (5-HT). Although our studies in 1939 (1) showed that the symptoms of anaphylaxis in dogs were due to the release of both histamine and heparin from liver mast cells, biologic studies of heparin have not been as extensive as those of histamine and 5-HT after the original observation. That is because, although there have been methods for identifying and measuring both histamine and 5-HT in small tissue samples, there have been no corresponding procedures for heparin. A great deal of my research for the last 35 years has been directed at remedying this deficiency, and this I believe we have accomplished by microelectrophoresis (Fig. 1) (2, 4).

LOCAL AND SYSTEMIC ANAPHYLAXIS IN THE PERTUSSIS-INOCULATED MOUSE.

IT is now well known that mice injected with Bordetella pertussis vaccine plus an antigen will produce more antibodies to that antigen than mice injected with antigen alone1,2. Such mice also develop an enhanced susceptibility to anaphylactic shock1–3. However, the level of circulating antibodies in an animal as measured by agglutination, haemagglutination, or precipitin techniques appears to be unrelated to the susceptibility of that animal to systemic anaphylaxis1,2,4. The following experiment indicates that the incidence of active cutaneous anaphylaxis in the pertussis-inoculated mouse parallels the incidence of systemic anaphylaxis. Mice were sensitized with 5 billion B. pertussis organisms and 1 mg of bovine serum albumin. On the seventh day after sensitization, 10 µg bovine serum albumin in 0.05 ml. of saline and 0.05 ml. of saline were injected into separate areas of the skin of the back. Fifteen min later, 0.25 ml. of 0.5 per cent Evans blue dye was injected into a lateral tail vein. Thirty min after the dye, the animals were challenged intraperitoneally with 2 mg of bovine serum albumin. Of 50 mice challenged in this manner, 32 died of anaphylaxis within 30 min. The survivors were classified as having symptoms of anaphylaxis or as having no symptoms and were killed 30 min after challenge. All animals were then tested for active cutaneous anaphylaxis by inspecting the inner side of the skin of the back for accumulation of dye at the site of antigen injection.

Problems of drug reactions ∗

I N GENERAL, reactions from drugs are usually classified as (1) allergic causing symptoms of anaphylaxis, (2) side actions causing undesirable responses apart from the main therapeutic goal, and (3) delayed toxicity causing varied pathologic syndromes usually associated with the peculiar metabolism of the drug. In addition, it is recognized that when multiple drugs are utilized, the chances of additive, synergistic and potentiating effects, usually undesirable, are increased.

Studies on the Role of Serotonin and Mast Cells in Anaphylaxis of the Mouse Produced with Soluble Antigen-Antibody Complexes

Summary The influence of various treatments on the anaphylactic response of the Swiss-Webster mouse to challenge with a soluble antigen-antibody complex composed of bovine serum albumin-antibovine serum albumin was studied. Protection against anaphylaxis was afforded by prechallenge treatment with either reserpine, epinephrine, norepinephrine, dopamine, histamine and sodium salicylate or with the “serotonin antagonists” lysergic acid diethylamide, its bromine analogue and chlorpromazine. The antihistamine agent, pyrilamine maleate, was without effect. The protective effect of reserpine can be abolished with 5-hydroxytryptophan but not with 3,4-dihydroxyphenylalanine. Histamine or sodium salicylate did not affect the response to intravenous challenge with serotonin or histamine. Prechallenge treatment with 5-hydroxytryptamine or 5-hydroxytryptophan increased the susceptibility of the animals to anaphylaxis. The highly sensitive pertussis-vaccinated mouse was protected against anaphylaxis by prechallenge treatment with epinephrine but not by prechallenge treatment with reserpine, the bromine analogue of lysergic acid diethylamide or dopamine. The refractory state induced by prior sublethal doses of antigen-antibody complex was not reversed by the administration of mouse complement or 5-hydroxytryptophan or a combination of both substances. Mice of the DBA/2 strain show only mild symptoms of anaphylaxis following doses of antigen-antibody complex three times those necessary to produce fatal anaphylaxis in a high percentage of Swiss-Webster mice. Examination of various tissues following anaphylactic death produced with the complex gave no indication that morphologic changes in mast cells accompany anaphylaxis.

Passive anaphylaxis in the dog; a quantitative study.

Summary(1) Dogs have been passively sensitized by administration of antiserum to bovine serum albumin developed in the rabbit. 21 mg of antibody nitrogen sensitized each of 2 5 dogs. All manifested symptoms of anaphylaxis and 13 of these died; 6 (of 8) following a dose of 17.3 mg of antigen nitrogen, 1 (of 4) after 10.88 mg, 6 (of 12) after 5.4 mg, and 1 following a dose of 4.33 mg of bovine serum albumin nitrogen. (2) Latent periods varied from 3% to 36 hours. No correlation could be shown between latent period and shocking dose. (3) Sensitizing doses of 10.5-16.8 mg antibody nitrogen followed by antigen in amounts of 4.33-13.0 mg of nitrogen produced symptoms of anaphylaxis in 7 dogs but all recovered, (4) An immediate and rapid fall in blood pressure was the one symptom exhibited by all 32 animals.

The Antigenicity of Collagen

Summary In rabbits receiving rabbit collagen coupled to diazotized sulfanilic acid and in others receiving commercial gelatin similarly treated, there were formed no precipitating or complement-fixing antibodies to the homologous antigens after intravenous or intraperitoneal injection. Normal human collagen, alone or coupled through benzidine with human serum globulin, did not give rise to demonstrable antibody formation in rabbits after intramuscular or intraperitoneal injection, even in the presence of the adjuvants of Freund and McDermott. In guinea pigs, following a single sensitizing injection, the same materials did not give rise to the symptoms of anaphylaxis upon intravenous injection. Rabbits injected with these materials showed no consistent, significant pathologic change. Complement fixation and precipitin tests of 19 sera of patients with lupus erythematosus, dermatomyositis, scleroderma, rheumatoid arthritis, and acute rheumatic fever failed to demonstrate the presence of antibodies against normal human collagen. For purposes of purification, the collagen employed in these experiments was subjected to chemical and physical manipulations which may have affected adversely the demonstration of antigenicity.

The effect of inhalation of antigens by the guinea pig on the production of anaphylaxis

1. 1. A method for delivering an anigen by the inhalant route is described. 2. 2. Experiments using ragweed pollen powder and fluid antigen, and horse dander powder and fluid antigen by the inhalant route failed to produce satisfactory symptoms of anaphylaxis in guinea pigs. 3. 3. The injection of thyroxin did not lower the threshold of susceptibility to anaphylaxis of guinea pigs to inhalant exposure. 4. 4. Although primary intravenous injection of guinea pigs with fluid antigen was performed, inhalant exposure after a suitable incubation period failed to give rise to symptoms of anaphylaxis.

An evaluation of Benadryl, Pyribenzamine, and otherso-called antihistaminic drugs in the treatment of allergy

T HERE is more than one school of thought with respect to the genesis of hypersensitive phenomena. The toxic or anaphylatoxin theory was based on the assumption that an antigen to which an animal is sensitized, when reinjected, is split by proteolytic ferments into toxic degradation products which produce the now well-known symptoms characteristic of the hypersensitive state. This early concept was later modified by a substantial amount of evidence favoring the hypothesis that histamine is liberated from the tissues during the antigen-antibody inter-reaction, and that the symptoms of anaphylaxis and allergy are, therefore, directly attributable to the action of the released histamine. In recent years, the advocacy of this hypothesis by several staunch proponents has awakened a renewed interest in the search for chemical or biologic substances capable of abolishing or diminishing some or all of the effects of the released histamine. 1-6 Hill and Mart in / in 1932, critically reviewed 165 substances or methods that might serve to inhibit anaphylaxis nonspecifically, and they came to the conclusion that none were ideal for the purpose. In the succeeding years, considerable additional experimentation was done, but the interpretation of results in most instances is open to question according to Feinberg s who reviewed much of it in 1944. One of the first of this series was the enzyme, histaminase, which destroys histamine in vitro. I t was recommended for oral and parenteral use. Although it was received with great ~elat and was enthusiastically advocated for the relief of all forms of allergy (under the trade name of Torantil), it soon found its resting place as another of the many ineffectual remedies. 1~ 11 Fell and his co-workers 2, 18 offered still another approach to the problem by developing a substance which became known as hapamine. It is a histaminehapten combination with despeciated, normal, horse serum globulin: The underlying concept was that injections of this substance would produce antibodies against histamine and thus fort ify the individual against the allergic symptoms induced by liberated histamine. The procedure proved unsound not only because it did not produce any immunity but because it induced sensitivity to the new hapten antigen in a number of instances. We are now in the throes of experimenting with a new series of so-called antihistaminic drugs. The two drugs most widely advocated are Benadryl, a Parke, Davis product which was studied by Loew and associates, 14~6 and Wells and associates, ~, xs and Pyribenzamine, a Ciba product reported upon by

Histamine-Protein Complexes: Synthesis and Immunologic Investigation

Summary A synthetic antigen was prepared by coupling the isocyanate derivative of histamine with despeciated horse serum globulin. The immunologic properties of the antigen were studied. The antiserum gave cross-reactions with histamine-azo-proteins, and the precipitative reaction was inhibited by histamine and by β-(5-Imidazolyl) ethyl isocyanate. Protection against symptoms of anaphylaxis in guinea-pigs after immunization with the complex was demonstrated by both in vivo and in vitro experiments.

Inhalant sensitization and shock in guinea pigs under controlled atmospheric conditions: II. Histamine, histaminase, and acetylcholine as possible preventives

1. 1. The air-conditioned chamber has proved a valuable method of studying the preventive or modifying effect of various pharmacologic agents on inhalation sensitization. 2. 2. Histamine injected before, during, and after sensitization, under the conditions of our experiments, did not prevent clinical or lethal anaphylactic shock. 3. 3. Histamine injections in large doses, given just prior to each exposure of the animals to the sensitizing allergen and just before subsequent shock exposure, seemed to delay the appearance and reduced the violence of clinical symptoms of anaphylaxis in a small group of animals. 4. 4. Acetylcholine injections given before, during, and after sensitization did not appear to modify the course of anaphylactic responses. There is slight suggestive evidence that acetylcholine and histamine injected within a short period of one another, at the same time intervals during sensitization as the acetylcholine group, delayed the appearance of clinical anaphylaxis. 5. 5. Histaminase solution given intranasally during inhalation sensitization and shock not only did not protect animals against clinical anaphylaxis but actually augmented their symptoms. Histaminase here also acted as a sensitizing allergen. It was observed that the application of a watery solution to the nasal membranes may lower the threshold of sensitization to a dry allergen. 6. 6. Histaminase injected intravenously in animals sensitized either by inhalation or peritoneal injection did not protect them against anaphylactic symptoms following the in halationof horse dander.

Studies on the Histamine-Content of the Blood and Tissues of the Rabbit During Anaphylactic Shock

Summary During acute anaphylactic shock in the rabbit, there occurs a marked decrease in the blood-histamine, a lesser decrease in the plasma-histamine and a leucopenia. There does not appear to be any correlation between these changes and the symptoms of anaphylaxis. There is a decrease in the histamine-content of the lung and spleen of the rabbit following the production of anaphylactic shock. In non-sensitized rabbits, there is little or no change in the histamine-content of the blood following the intravenous injection of horse serum. A leucopenia may occur. When egg albumin is injected intravenously, however, a decrease in both the blood-histamine and the white blood count occurs. Histamine-shock in the rabbit is characterized by a moderate decrease in the histamine-content of the blood and a marked increase in the histamine-content of the plasma. A moderate leucopenia also occurs. These findings then differ from those which occur in anaphylactic shock in this species. By superimposing anaphylaxis on histamine-shock in the rabbit, it may be shown that not only is the histamine-content of the blood diminished, but that there is also some mechanism for the removal of large amounts of histamine from the plasma. It is also shown that a sudden increase in the plasma-histamine may occur under these circumstances.

Anaphylaxis in the Pregnant Rat

Attempts have been made to elucidate the rôle of the endocrine glands in determining the susceptibility of animals to anaphylactic shock. Kepinow and Lanzenberg found that thyroidectomy protected the guinea pig and rabbit against anaphylactic shock by inhibiting active sensitization with antigen. This, however, could not be repeated by Applemans nor Yun; and Fleisher and Wilhelmj thought the protection was much less complete than the former authors believed. Blom demonstrated the converse, that injection of thyroid preparations to sensitized guinea-pigs during the period of sensitization or shortly before the shocking dose, markedly increased the severity of anaphylactic shock; his method of injecting the shocking dose of antigen directly into the heart is, however, open to question. Adrenalectomy was shown by Kepinow, in guinea pigs, and Flashman, and Wyman, in rats, to increase the susceptibility of these animals to anaphylactic shock. Epinephrin has long been known to protect against the symptoms of anaphylaxis. Wolfram and Zwemer showed that cortin administered from 2 to 6 hours before a shocking dose protected a large proportion of guinea pigs against anaphylaxis; and Dragstedt, Mills and Mead noted that cortical extract administered to dogs 48 hours to 5 minutes before diminished the severity of, but did not prevent anaphylactic shock. Administration of parathyroid extract has led to contradictory results. Levinson and Matthews claimed that amounts sufficient to raise the blood calcium of dogs to 15 mg % was without influence on the frequency of anaphylactic shock. Hajós, on the other hand, found that the injection of parathyroid extract (Collip) decreased the sensitivity of guinea pigs to anaphylaxis. Hajós also reported that, while anterior pituitary extracts were without influence on anaphylaxis in the guinea pig, posterior lobe extract caused a decrease in sensitivity.

Kubiczek, M. Pain-relieving effect of cobra venom (Polska gaz. Jek. 3-5. 1936)

Material a. is 23 sl .; in order to avoid the toxic effect of the poison, the dose during the first injection should not exceed 2.5 IU. Further dosage depends on the case and the nature of the action; the pause between individual injections should be at least 3 days, and the maximum dose should not exceed 20 IU. Cobra venom has no effect on pain caused by pressure on nerve endings and trunks; a good result can be expected with trigeminal neuralgia, sciatica, etc. It must be assumed that in such cases, cobra venom is not only an analgesic, but also a means of irritating therapy. If after the first injection, symptoms of anaphylaxis, edema, urticaria and itching develop, then further treatment is contraindicated; the same applies to the first symptoms of poisoning (nausea, vomiting and general weakness). Treatment with cobra venom is contraindicated in severe patients with uncompensated heart defects, lung diseases, acute kidney disease and advanced neoplasms.

Studies in Anaphylaxis in the Rabbit

Summary Of 53 rabbits treated with the Grove series of injections with egg white (described in the text), 70 per cent were made maximally sensitive to intravenous test, 5.6 per cent exhibited slight symptoms of anaphylaxis and 24.4 per cent failed to show any symptoms. Similar results were obtained with horse serum. Variations in the number or the selected routes of the injections lessened the effectiveness of the treatment in establishing anaphylactic sensitiveness in the animals. The established sensitiveness persists for at least two or three weeks. An additional subcutaneous injection given one week after the period of highest sensitiveness usually causes no diminution in the concentration of the blood-borne antibodies; nevertheless the sensitiveness of the animals is always greatly diminished or entirely extinguished. Active sensitization of rabbits does not depend entirely upon the degree of antibody productivity because animals showing a high power of antibody production may be wholly insensitive and vice versa.

Studies in Anaphylaxis

Abstract Recent investigations on the inhibition of anaphylactic shock by use of a blood anti-coagulant indicate a close relationship between the gross symptoms of shock and changes in the dispersion of the blood colloids. Kyes and Strauser (1), by rendering the blood incoagulable with heparin, have prevented the symptoms of anaphylaxis in sensitized pigeons. In confirmatory papers (2) (3), we have reported observations which indicate that no symptoms of anaphylaxis may be recorded in the majority of cases, in guinea pigs hypersensitive to horse serum, provided the clotting time of the blood is changed with heparin. There were, however, some instances in which the animals reacted typically to the critical dose of antigen, although the blood had previously been rendered incoagulable. It is the purpose of this paper to offer a possible explanation for these observations, and to present certain findings that tend to support the theory on the physico-chemical nature of anaphylaxis, in particular the nature of the symptoms observed in guinea pigs.

Further Studies on the Influence of Heparin on Anaphylactic Shock in the Guinea Pig

Abstract In an earlier paper (1) we confirmed the observations of Kyes and Strauser (2) with regard to the inhibitory effect of heparin on the anaphylactic syndrome. In our studies guinea pigs hypersensitive to horse serum, instead of pigeons hypersensitive to sheep serum, as used by Kyes and Strauser, were employed. In view of the failure of Hanzlik, Butt and Stockton (3), of Hyde (4), and of Reed and Lamson (5) to support our findings, we present additional data which substantiate our previous findings, using as a criterion of shock the classical symptoms of anaphylaxis. We have checked the reaction by the Dale and by the bronchospasm method of Koessler and Lewis (6). In a limited number of animals we controlled the coagulation time of the blood by means of the capillary tube method prior to the injection of the shocking dose of the antigen and also at the height of shock.