Tranexamic acid: Preoperative prophylactic therapy for patients with hereditary angioneurotic edema

Short-term therapy of 96-hr duration with tranexamic acid was prophylactically effective as defined by the absence of attacks of angioedema in 14 patients with hereditary angioedema undergoing 10 dental and 4 general surgical procedures. Eight of the 14 patients had previously undergone dental extractions without prophylactic therapy with antifibrinolytic agents and each had experienced one or more attacks of angioedema. Seven of these 8 patients had a cumulative experience of 13 episodes of laryngeal edema after dental extractions and the eighth had a bout of cutaneous angioedema. Although the number of dental extractions conducted without prophylactic antifibrinolytic therapy cannot be accurately defined in retrospect, the prominence of laryngeal edema in this circumstance is striking when compared with the absence of attacks in the presence of prophylaxis with tranexamic acid. Methyltestosterone and impeded androgens are now known to be effective prophylaxis for spontaneous and, presumably, postoperative attacks when employed chronically because their administration is associated with correction of the biochemical defect of hereditary angioneurotic edema, but their chronic administration to children and women of childbearing age requires further definition because of their potential pituitary suppressive action. Tranexamic acid prophylaxis makes it possible to offer to untreated patients with hereditary angioneurotic edema dental work and other operative procedures that in the past were withheld or conducted with considerable risk.     

Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema.

Daily therapy and alternate-day therapy with the attenuated androgen oxymetholone were compared in patients with hereditary angioedema (HAE). Fifteen of 16 patients who experienced at least monthly attacks of HAE without treatment were asymptomatic on administration of 5 mg oxymetholene daily. When 13 of the patients who had been maintained asymptomatically on 5 mg oxymetholone daily were advanced to a treatment schedule of 5 mg every other day, seven attacks occurred during a cummulative 50 mo of therapy. The adverse effects that occurred with daily oxymetholone therapy largely subsided when the patients received alternate-day therapy, while a significant mean rise in C4 protein and function occurred only on daily therapy. Statistically significant mean increases in serum levels of C1INH occurred with daily therapy and were maintained with alternate-day therapy. Clinical benefit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise C1INH to the lower limit of normal. The finding that alternate-day therapy diminished the side effects of the drug while affording a substantial reduction in the incidence and severity of attacks indicates the feasibility of this therapeutic approach.     

Exercise-induced anaphylaxis

Sixteen patients were seen because of possibly life-threatening exercise-associated symptoms similar to anaphylactic reactions. Asthma attacks, cholinergic urticaria and angioedema, and cardiac arrythmias are recognized as exertion-related phenomena in predisposed patients but are distinct from the syndrome described here. A syndrome characterized by the exertion-related onset of cutaneous pruritus and warmth, the development of generalized urticaria, and the appearance of such additional manifestations as collapse in 12 patients, gastrointestinal tract symptoms in five patients, and upper respiratory distress in 10 patients has been designated exercise-induced anaphylaxis, because of the striking similarity of this symptom complex to the anaphylactic syndrome elicited by ingestion or injection of a foreign antigenic substance. There is a family history of atopic disease for 11 patients and cold urticaria for two others and a personal history of atopy in six. The size of the wheals, the failure to develop an attack with a warm bath or shower or a fever, and the prominence of syncope rule against the diagnosis of conventional cholinergic urticaria. There is no history or evidence of an encounter with an environmental source of antigen during the exercise period.     

Acute anaphylaxis associated with serum complement depletion.

A 45-year-old woman with rheumatoid arthritis developed anaphylaxis 6 min after receiving a subcutaneous injection of lidocaine, followed by an intra-articular injection of lidocaine mixed with methprednisolone acetate. One hour after the onset of anaphylaxis, serum complement component levels were markedly depressed and remained so far 18 hr. Circulating immune complexes and antibodies to lidocaine could not be demonstrated. Neither lidocaine nor methylprednisolone acetate activated the patient's complement system in vitro. Subsequently, total hemolytic activity (CH50) levels were variable, complement component protein concentrations of C1q, C1s, C4, C2, C3, C5, C6, C9, and Factor B were normal, but hemolytic activity of C4 and C2 was diminished. Serum C1 inhibitor concentrations were normal or slightly depressed. The patient has never had any symptoms suggestive of angiodema. It is postulated that the endogenous complement abnormality present in this patient may have contributed to the anaphylactic reaction.     

Delayed cold-induced urticaria: a dominantly inherited disorder.

A delayed cutaneous response to cold, characterized by areas of erythematous, edematous deep swelling at 9 to 18 hr after experimental ice challenge, was recognized in a 10-yr-old boy and several members of his family. Biopsy of the cold-induced lesion showed edema and an infiltrate of mononuclear cells; mast cells were normal, and immunoglobulins, complement factors, and fibrin were not detected by immunofluorescence techniques. Local cold challenge did not release histamine or induce alterations in the complement system or the enzymes, histaminase, and histamine methyl transferase. The delayed cutaneous response to cold could not be passively transferred with serum or tissue extracts to monkey skin. Family studies suggested an autosomal-dominant mode of inheritance.     

Clinical and biochemical effects of stanozolol therapy for hereditary angioedema

Stanozolol, an inexpensive anabolic steroid with a 30:1 anabolic:androgenic ratio, was administered to 12 male and 15 female patients with biochemically proven hereditary angioedema over a 2-yr period to obtain a systematic assessment of the relationship between drug dosage and clinical response, incidence of side effects, and amelioration of complement abnormalities. All 27 patients attained the minimal effective dose, ranging from 0.5 to 2 mg daily, which controlled the frequency and intensity of symptoms with minimal side effects. At daily maintenance doses of 2, 1, and 0.5 mg the frequencies of attacks per weeks of therapy were 1/14.6, 1/7.2, and 1/8.2 wk, respectively. Side effects with maintenance therapy included menstrual abnormalities and virilization in four females and elevation of serum creatinine phosphokinase (CPK) in five males. In six patients on maintenance doses of stanozolol, serum levels of testosterone, free thyroxin (T4), and thyroxin binding globulin (TBG) (four males), and of estradiol, progesterone, T4, and TBG (two females) were normal. Slightly low serum levels of progesterone and TBG were found in two females who had normal menstrual cycles. Statistically significant elevations above pretherapy levels of serum inhibitor to the activated first component of complement function and C4 protein and function occurred when patients were on maintenance therapy, but these measurements remained below the lower limit of normal range. Higher doses of stanozolol (4 mg/day), which caused greater immunochemical responses, were unnecessary for control of clinical disease and were unjustified for chronic therapy because of more frequent side effects.     

Effects of beta adrenergic blockade on histamine and prostaglandin-F2 alpha responsiveness in the dog

To examine whether either the degree of existing beta adrenergic tone or the magnitude of beta adrenergic response during bronchoconstriction might account for the differences that exist between dogs in their pulmonary responsiveness to aerosol challenge with bronchoconstrictor agents, dose-response curves were performed in a group of dogs to either histamine or prostaglandin-F2 alpha, both before beta blockade with propranolol. Beta blocked had no significant effect on control values of dynamic compliance (Cdyn) or resistance of the lung (RL) or on pulmonary responsiveness to prostaglandin f2 alpha. Although propranolol did not have a significant effect on aerosol responsiveness to histamine for the group of dogs taken together, those dogs initially least responsive to aerosol histamine did become more responsive after beta blockade. This effect of beta blockade was statistically significant only for Cdyn and not for RL, suggesting enhancement of peripheral airway effects. We conclude that a beta adrenergic mechanism may contribute to the range of responsiveness found among dogs in their pulmonary responsiveness to histamine but that other as yet undefined factors must also contribute to the differences that exist among dogs in their pulmonary responsiveness to bronchoconstrictor agents.     

In vivo effect of cimetidine on canine pulmonary responsiveness to aerosol histamine

A series of experiments were designed to discover whether pulmonary histamine H₂ receptors might be of physiologic importance in vivo in the dog. Dose-response curves were performed to aerosol histamine in 11 dogs both before and 1 hr after H₂ receptor blockade with cimetidine (1 mg/kg as a rapid intravenous infusion). Cimetidine had no significant effect on control values of dynamic compliance or resistance of the lung. In the 11 dogs tested H₂ receptor antagonism significantly potentiated (p < 0.05) the animals' pulmonary responsiveness to aerosol histamine. The potentiation of histamine constrictor effects produced by cimetidine were more marked on those dogs initially least responsive to aerosol histamine (p < 0.01). We have found evidence for the presence of inhibitory H₂ receptors in canine airways and for the distribution of these receptors among dogs, explaining in part the previously described differences among dogs in the pulmonary responsiveness to aerosol histamine.     

Effect of ragweed hyperimmune human gamma globulin on in vivo and in vitro parameters of ragweed sensitivity.

The effect of ragweed hyperimmune human gamma globulin upon in vitro and in vivo parameters of ragweed sensitivity was examined. In a double-blind study, 40 ragweed sensitive patients were divided into 2 groups and received either ragweed hyperimmune human gamma globulin (treated) or normal pooled globulin (control). Parameters of ragweed sensitivity studied before and following injections of the gamma globulin included skin test and nasal provocation end point titration, specific IgE antibody as measured by the RAST, leukocyte histamine release, total serum ragweed antibody level, and total serum IgE. Changes in measured parameters varied in both groups of patients. In the "treated" patient group, 1 wk later nasal sensitivity decreased significantly, and there was a trend toward decreased histamine release from leukocytes. No discernable effect was noted upon the other parameters. Thus, with the dosage used, the parenterally administered hyperimmune gamma globulin did not influence most measurements of ragweed hypersensitivity. The concept of this therapeutic approach might warrant further investigation.     

Magnitude and site of airway response to exercise in asthmatics in relation to arterial histamine levels

In order to determine if there is a relationship among arterial histamine levels, state of disease activity, and the magnitude and site of obstruction in exercise-induced asthma, we recorded airway resistance, lung volumes, spirometry, and density dependence of maximum expiratory flow before and after an exercise challenge in 17 asymptomatic individuals. These observations were then related to the concentration of histamine in systemic arterial blood. This study demonstrates that those individuals whose disease process was the most active at the time of investigation had more depressed lung function and higher baseline histamine levels, and responded to the challenge with severe obstruction that involved the airways in the periphery of the lung. In contrast, those subjects whose underlying disease was more quiescent had lower histamine values and the response to provocation was less severe and predominated in the larger airways. In neither group did the postchallenge values for histamine increase. It is suggested that the factor that determines these patterns of response is the state of inflammation of the airways, for which histamine may serve as a marker.     

Hypersensitivity to pancreatic extracts in parents of patients with cystic fibrosis.

Because immediate hypersensitivity reactions can occur in individuals exposed to powdered pancreatic extracts, 36 patients with cystic fibrosis and 51 patents of such patients wwer studied for evidence of sensitization. Sensitivity to the extracts as evidence by history and skin testing was infrequent in the children with cystic fibrosis. However, skin testing for immediate hypersensitivity with either crude pancreatic extracts or inactivated trypsin correlated well in their patents with a history of clinical symptoms. IgE mediation of these reactions in sensitized individuals was demonstrated by antigen-induced histamine release from leukocytes, passive transfer studies, and immediate response to inhalation challenge.     

Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of bronchial responses to cat allergen and histamine.

Ten asymptomatic patients with normal pulmonary function were selected for a double-blind trial of immunotherapy in cat-induced asthma. Each patient had a positive prick test to cat pelt extract and also a positive bronchial challenge response to the same extract. Patients were randomly assigned to active treatment or placebo groups and received weekly or biweekly injections over a 3 to 4-month period. The 5 patients who received the active treatment received a cumulative dose of cat pelt extract that ranged from 16.4 to 44.8 mg of total solid containing 1.7 to 4.7 mg of cat allergen 1. Apparent systemic reactions were observed in 3 patients who received the placebo and 3 patients who received the active treatment. The 5 patients who received the active treatment showed a reduction in skin reactivity to cat pelt extract as well as a significant mean reduction in bronchial sensitivity to the same extract. The 5 patients who received the placebo showed no significant changes in skin reactivity or bronchial sensitivity to cat pelt extract. Bronchial response to histamine did not change significantly in either the active treatment of the placebo group.     

The chronicity of acute attacks of asthma--mechanical and therapeutic implications.

Defects in ventilatory function can persist for considerable periods of time following the amelicoration of the signs and symptoms of acute episodes of asthma. Serial spirographic and lung volume determinations in such patients demonstrate that the pattern of resolution of these abnormalities is such that their subtlest manifestations are depressed flow rates in the mid vital capacity range and/or elevations in residual volumes. These changes are believed to represent the effects of residual obstruction that is located in the airways in the periphery of the lung. Recent studies suggest that this residua is capable of influencing the lung's response to asthmogenic stimulis, and imply that it may be beneficial to place asthmatics on continuous therapy for as long as they have alterations in lung function.     

Effects of experimental rhinovirus 16 infection on airways and leukocyte function in normal subjects

We infected 7 normal volunteers with rhinovirus 16. In general, the symptoms and alterations in airways were minimal although all subjects had upper respiratory symptoms. Three subjects developed in addition lower respiratory and systemic symptoms accompanied by either an increase in the volume of isoflow or a positive methacholine response. Furthermore, these three had a decrease in beta adrenergic and Hz histamine receptor responses of their granulocytes. Since the peripheral airway obstruction and decreased beta adrenergic and H2 histamine responses occurred together, these two phenomenon may have a common cause. All seven subjects had a decrease in number of circulating E rosette forming lymphocytes, and in 6 of 7, there was a decrease in the antibody-dependent cellular cytotoxicity capacity of mononuclear cell preparations. It is not clear whether these changes reflect redistribution of mononuclear cells or alteration of their function.     

Inuction of immunological tolerance in immunoglobulin E B lymphocytes in rats.

Immunological tolerance has been induced in 2,4-dinitrophenyl (DNP)-specific bone marrow-derived or B lymphocytes of the IgE AND IgG antibody classes by treatment of rats with the DNP derivative of D-amino acid copolymer, D-glutamic acid, D-lysine (D-GL). The tolerant state is manifested as an inability of treated rats to produce serum anti-DNP antibodies and the failure of peritoneal cells from tolerant animals to release histamine following in vitro antigen challenge. The implications of these and related observations for potential therapeutic measures in clinical hypersensitivity states are discussed.     

Mediator release in local heat urticaria: protection with combined H1 and H2 antagonists

Two patients with local heat urticaria were examined for evidence of histamine release and for changes in mast cell morphology after local heat challenge. Both patients demonstrated significant release of histamine into the draining venous blood in the challenged arm. Biopsy specimens revealed mucosal edema after 30 min, followed by a mononuclear, perivascular infiltrate by 6 hr, and increasing in intensity by 24 hr. Degranulated mast cells were observed by electron microscopy. Heat challenge was repeated after treatment with hydroxyzine, cimetidine, or a combination of both drugs. Neither hydroxyzine nor cimetidine alone affected the clinical response to challenge, but both drugs together completely abolished the clinical response. In addition, the combination of both drugs taken regularly completely prevented symptoms. This observation suggests that histamine is one of the major mediators of this disorder and that both H1 and H2 receptors are operative.