Hyperosmolar triggering of histamine release from human basophils.

Idiopathic reactions occurring during the infusion of hyperosmolar solutions, such as radiocontrast dyes, cause a significant number of deaths each year. These reactions are similar to those which follow mediator release during allergen-induced anaphylaxis. In attempting to explain these nonimmunologic reactions, we examined the direct effect of hyperosmolarity on normal human basophils with emphasis on release induced by mannitol. The cells of all donors released histamine in vitro in response to hyperosmolar (0.2-0.7 M) solutions of a number of solutes including mannitol. That this was not a toxic process was supported by a number of criteria, including inhibition of release by excess stimulus at 37 degrees C and a lack of release at 4 degrees C. Furthermore, electron microscopic studies revealed that hyperosmolar stimulation did not disrupt the cell membrane or lead to any signs of cytotoxicity. In contrast to antigen-stimulated release, where granules fuse only with the cell membrane, granules in mannitol-stimulated cells, in addition to fusing with the cell membrane, may also be extruded into a common intracellular sac before exteriorization. Characteristics similar to antigen-induced histamine release included the time-course for release, inhibition by drugs that modify phospholipid metabolism, p-bromophenacyl bromide, and eicosa-5,8,11,14-tetraynoic acid, and augmentation of release by deuterium oxide (D(2)O). The release process differed from antigen-induced release by a number of criteria, including independence from immunoglobulin (Ig)E-related mechanisms, insensitivity to agonists that elevate intracellular cyclic AMP, minimal dependence on extracellular calcium, lack of inhibition by 2-deoxyglucose and theophylline, and a temperature optimum of 32 degrees C. We conclude that this noncytotoxic hyperosmolar release process is different from IgE-mediated secretory events and may well play a role in the idiopathic reactions which occur secondary to the infusion of hyperosmolar solutions in man.

Intranasal fluticasone propionate is more effective than terfenadine tablets for seasonal allergic rhinitis.

BACKGROUND: We compared the efficacy and tolerability of the intranasal corticosteroid fluticasone propionate with that of the antihistamine terfenadine in patients with seasonal allergic rhinitis. METHODS: Two hundred thirty-two adults and adolescents with seasonal allergic rhinitis received intranasal fluticasone propionate (200 micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 2 weeks in a double-blind, randomized, parallel-group study. Main outcome measures were clinician- and patient-rated individual and total nasal symptom scores (based on ratings of nasal obstruction, sneezing, nasal itching, and rhinorrhea); clinician-rated overall response to therapy; changes in nasal inflammatory cell counts; adverse events; and morning plasma cortisol concentrations. RESULTS: Both clinician- and patient-rated total and individual nasal symptom scores were significantly lower in the fluticasone group than in either the terfenadine group or the placebo group at nearly every measured time point throughout the treatment period. After 2 weeks of therapy, clinician-rated total nasal symptom scores decreased by 49% in the fluticasone group compared with 27% in the terfenadine group and 19% in the placebo group. In general, therapy with terfenadine was not statistically distinguishable from that with placebo based on patient-rated total or individual nasal symptom scores. According to clinician ratings, 64% of fluticasone-treated patients compared with 49% and 44% of patients treated with terfenadine and placebo, respectively, experienced significant or moderate improvement. A greater percentage of fluticasone-treated patients compared with either terfenadine- or placebo-treated patients experienced reductions in intranasal eosinophil and basophil counts after 2 weeks of therapy. No unusual or serious drug-related adverse events were reported. Morning plasma cortisol concentrations after 2 weeks of therapy did not differ among groups. CONCLUSION: Fluticasone aqueous nasal spray, a well-tolerated corticosteroid preparation that can be administered once daily, is more effective than terfenadine tablets or placebo in controlling symptoms of seasonal allergic rhinitis.

Neuropathy presenting as prolonged dyspnea. Case report and review of literature.

Polyneuropathy presented as isolated respiratory muscular paralysis. Transdiaphragmatic pressure measurements, nerve conduction studies, electromyography, and biopsy of intercostal muscle confirmed the nature of the process. Patients with unexplained respiratory insufficiency must be carefully evaulated for underlying neuromuscular disease.

Purification of human basophils by negative selection.

Enriched populations of human basophils were prepared using a combination of negative selection techniques. First, a 2-step discontinuous gradient was made using 65% and 55% isotonic Percoll. Purification of plasma basophils by centrifugation through the gradient increased basophils from 0.96 +/- 0.55% to 14.6 +/- 7.9% (n = 9). In 5 other experiments a second step was added in which contaminating mononuclear cells were removed using a panning technique. In this technique, Percoll separated cells were treated with anti-T-cell antibodies. Contaminating T-cells were selectively removed by adherence to a petri dish coated with affinity purified goat anti-mouse IgG. Basophil purity was increased to 34 +/- 15% using this step. These experiments demonstrated that negative selection techniques can yield an increase in basophil purity 50-100-fold. The purified basophils contained the expected quantity of histamine (1.36-1.54 pg/basophil) and released the same amount of histamine in response response to different concentrations of goat anti-human IgE Fc as did unpurified cells.

Comparison of histamine release effects of ionic and non-ionic radiographic contrast media.

Histamine release may underline the side effects (particularly anaphylactoid) of radiographic contrast media. To study the histamine-releasing properties of radiographic contrast media, this study measured the in vitro release of histamine from human basophils incubated with diatrizoate, a standard ionic radiographic contrast agent, and with iopamidol, a newly developed non-ionic contrast agent. The basophils were separated from blood obtained from 16 patients scheduled for coronary angiography. For both diatrizoate and iopamidol, the concentration of histamine released varied as the concentration of radiographic contrast agent was increased from 0.075 M to 0.50 M. At the higher concentrations tested, the percent of histamine released by iopamidol was about half that released by diatrizoate (p less than 0.05). These data suggest that the use of non-ionic contrast media may involve less patient risk from the histamine-mediated allergic and/or hemodynamic side effects associated with radiographic contrast procedures.

Fluticasone propionate aqueous nasal spray is safe and effective for children with seasonal allergic rhinitis.

INTRODUCTION: Fluticasone propionate aqueous nasal spray, a new topical corticosteroid preparation, is effective when given as 200 micrograms once daily in patients (> 12 years of age) with seasonal allergic rhinitis. STUDY OBJECTIVE: To evaluate the efficacy and safety of fluticasone proprionate aqueous nasal spray in children aged 4 to 11 years with seasonal allergic rhinitis. STUDY DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group. PATIENTS: Two hundred fifty children aged 4 to 11 years with moderate-to-severe nasal symptoms, a positive skin test reaction to a late-summer or autumn allergen, a history of seasonal allergic rhinitis, and documentation of an unsatisfactory response to conventional treatment. INTERVENTIONS: Children were randomly assigned to receive fluticasone propionate, either 100 micrograms or 200 micrograms, or placebo, given by intranasal spray once daily in the morning for 14 days. MEASUREMENTS AND RESULTS: Severity of nasal symptoms (obstruction, rhinorrhea, itching, and sneezing) was recorded on visual analog scales by investigators at weekly visits and by patients (or adult guardian) daily in the evening. According to investigator and patient ratings, both fluticasone propionate 100 micrograms/d and 200 micrograms/d lowered total nasal symptom scores when compared with placebo. Both dosages of fluticasone propionate were more effective than placebo on the basis of investigator-rated overall clinical evaluation of efficacy at the end of treatment, with significant improvement (as opposed to moderate or mild improvement, no change or worsening) noted in 21% to 29% of the active-treatment groups vs 9% in the placebo group. There were no significant differences between the two fluticasone propionate dosages in any efficacy measurement. Morning plasma cortisol concentrations and frequency of drug-related adverse events were similar in the fluticasone propionate and placebo groups. CONCLUSION: In children as young as 4 years, 100 micrograms of fluticasone propionate aqueous nasal spray given once daily is as effective as 200 micrograms given once daily, the usual adult dose for the treatment of seasonal allergic rhinitis. Both fluticasone propionate dosages were well tolerated and neither dosage appears to interfere with the hypothalamic-pituitary-adrenal axis in children.

Anti-immunoglobulin induced histamine release from naturally abundant basophils in the snapping turtle, Chelydra serpentina.

The dose response, temperature sensitivity, time course and calcium dependency of histamine release from snapping turtle basophils treated with rabbit anti-turtle immunoglobulin (RATIg) sera was explored. This investigation indicated that the level of histamine release induced by RATIg was dependent upon the concentration of RATIg with concentrations of 350 mcg/ml inducing optimal release. In addition, release was temperature dependent with release increasing over a temperature range of 10 degrees C to maximal at 27 degrees C. Release was also dependent on the length of exposure to RATIg. Release increased steadily over a time period of 0 to 30 minutes with the higher concentrations of RATIg inducing the most rapid release. Basophil-histamine release was also found to be calcium dependent. This study indicates that the snapping turtle basophil possesses similar characteristics to that of its mammalian counterparts. It is proposed that the very wide temperature range over which turtle basophils release histamine is an important feature in he immune resistance of this ectothermic animal.

Adrenal function in adult asthmatics during long-term daily treatment with 800, 1,200, and 1,600 micrograms triamcinolone acetonide. Multicenter study.

A study to assess the effect of the long-term use of triamcinolone acetonide (TA) on adrenal function was conducted with 143 male and female patients with asthma who were randomly assigned to receive 800, 1200, or 1,600 micrograms of TA daily for six months. Adrenal function was assessed prior to treatment and after two weeks and one, three, and six months of TA use. The effect of TA was evaluated by measuring plasma cortisol levels just prior to and 30 min after a bolus IV injection of 0.25 mg cosyntropin. Adrenal suppression was assumed if the plasma concentration of cortisol did not increase by at least 7 micrograms/dl from the prestimulation value, and remained below 18 micrograms/dl 30 min after the cosyntropin injection. Urine collected for 24 h prior to each cosyntropin stimulation was assayed for free cortisol and related metabolites to confirm suppression. Although all treatment regimens caused some reduction in the 24-h excretion of corticosteroid products, none of the mean values was below the normal ranges. The mean data indicate that TA had no significant effect on adrenal function at any dose or at any time for the patients overall. Individually, three patients exhibited some reduction in adrenal function.

Fluticasone propionate: an effective alternative treatment for seasonal allergic rhinitis in adults and adolescents.

BACKGROUND: Topical corticosteroids are widely regarded as the reference standard in allergic rhinitis therapy because they are well tolerated and effective against all rhinitis symptoms. We evaluated the efficacy, onset of action, and safety of two dosing regimens of the new corticosteroid fluticasone propionate compared with that of beclomethasone dipropionate in patients with moderate to severe seasonal allergic rhinitis. METHODS: In this double-blind, randomized multicenter trial, 110 adolescents and 128 adults were treated for 4 weeks with one of the following regimens: fluticasone aqueous nasal spray 100 micrograms twice daily or 200 micrograms once daily, beclomethasone aqueous nasal spray 168 micrograms twice daily, or placebo. RESULTS: Patient-rated scores for nasal obstruction, rhinorrhea, and combined nasal symptoms indicated that the two fluticasone regimens were equally effective and that both were superior to beclomethasone during most of the study (P < or = .05) and to placebo throughout the study (P < or = .01). Both fluticasone regimens also demonstrated significant clinical efficacy by 24 hours after the first dose. Clinician-rated mean total nasal symptoms scores for all three active treatments were superior to placebo at most time points but were not significantly different from each other. All treatments were well tolerated, with similar incidence and type of adverse events in all treatment groups and no apparent effects on hypothalamic-pituitary-adrenal (HPA) axis function. CONCLUSIONS: Fluticasone aqueous nasal spray was effective in relieving nasal symptoms in adolescents and adults with seasonal allergic rhinitis. Fluticasone administered once or twice daily was superior to beclomethasone administered twice daily in relieving nasal obstruction and rhinorrhea and in reducing nasal symptoms more quickly.

Basophil "releasability" in patients with asthma.

This study was based on the premise that mediator release plays a role in the pathogenesis of allergen-induced as well as nonallergen-induced asthma. We studied histamine release from human basophils obtained from patients with asthma and from control subjects. These cells were challenged with several different stimuli: goat anti-human IgE-Fc, C5-peptide, N-formyl-methionyl-leucyl-phenylalanine (f-met peptide), Ca++ ionophore A23187, hyperosmolar mannitol, and D2O. Release induced by any one stimulus was unrelated to the response to any other stimulus. The basophils of patients with asthma and control subjects responded similarly to most stimuli: they were significantly less responsive to C5-peptide and f-met peptide, and significantly more responsive to D2O. The results suggest that there is a parameter of releasibility that must be defined for each separate stimulus, and that patients with asthma can be differentiated from normal persons by the response of their basophils to selected stimuli.

Naturally abundant basophils in the snapping turtle, Chelydra serpentina, possess cytophilic surface antibody with reaginic function.

Basophils constitute 50 to 63% of the blood leukocytes in Chelydra serpentina, the snapping turtle. Immunoglobulin (Ig) on the surface of the turtle basophil was detected by indirect immunofluorescence by using an IgG fraction from rabbit anti-turtle Ig serum (RATIg) and a fluoresceinated goat anti-rabbit antibody incubated at 4 degrees C. However, when the cells were incubated with RATIg at 22 degrees C, the basophil number, as determined by Wright's stain and neutral red counts, decreased dramatically. This morphologic evidence of degranulation was directly proportional to the antiserum concentration. Degranulation also correlated with cell histamine release (r = 0.73). In other experiments, turtle basophils were found to express antigen-specific surface Ig after immunization with sheep red blood cells (SRBC). Washed basophils from immunized turtles formed basophil-SRBC rosettes in vitro. Basophils from control turtles did not. Basophil-SRBC rosettes could also be induced by in vitro passive sensitization by preincubation of normal turtle basophils in the SRBC immune turtle sera. This study shows clearly that the turtle basophil has an immune capacity analogous to the mammalian basophil/mast cell. This study also contains the first direct evidence for the existence of reaginic antibody (or antibodies) in an ectothermic vertebrate. Finally, C. serpentina is proposed as a unique animal model for the study of basophil function.

Augmentation of antigen-stimulated histamine release from human basophils by serum-treated zymosan particles. II. Dependence on IgE-mediated release.

It was observed previously that serum-treated zymosan particles (Zx) augmented antigen and anti-IgE stimulated histamine release. With most of the enhancement attributed to an increased rate of release, this suggested that Zx was active only during the course of IgE-mediated release. This association between IgE-mediated histamine release and responsiveness to Zx was examined further in the present report. Addition of Zx at various time intervals after release had been initiated indicated that the basophil responsiveness to Zx was limited in duration; maximum responsiveness to Zx correlated closely with the period in which the rate of IgE-mediated histamine release was maximum. The time-dependent decline in sensitivity to Zx paralleled the kinetics for desensitization to antigen. Addition of Zx failed to cause release from basophils desensitized in vitro or from basophils of a donor who failed to release histamine upon challenge with anti-IgE. In contrast to the enhancement of IgE-mediated release, Zx did not augment histamine release caused by C5a or the synthetic peptide f-Met-Leu-Phe. It is concluded that an obligatory link exists between ongoing IgE-mediated histamine release and enhancement by Zx.

Adenosine receptor on human basophils: modulation of histamine release.

Adenosine, at physiologic concentrations, inhibits in vitro IgE-mediated human basophil histamine release in a dose-dependent fashion. The inhibition dose-response curve is paralleled by an adenosine-induced increase in cAMP levels of human leukocyte preparations. Further evidence that the adenosine effect is related to changes in cAMP levels is that the nucleoside inhibits only in the first stage of antigen-induced histamine release and fails to inhibit the release caused by ionophore A23187. A poorly metabolized derivative of adenosine, 2-chloroadenosine inhibits as effectively as adenosine; dipyridamole, which blocks adenosine uptake, does not impair the inhibition caused by adenosine. Finally, theophylline, which is a competitive antagonist of adenosine in human lymphocytes also blocks the inhibition of release caused by adenosine. These data suggest that adenosine acts via a specific cell-surface receptor linked to adenylate cyclase. It appears that the human basophil has a specific receptor for adenosine and that this nucleoside may modulate the in vivo release of the mediators of immediate hypersensitivity reactions.

Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses.

The efficacy of immunotherapy in cat-induced asthma was studied by use of a purified fraction of cat-pelt extract and a double-blind protocol. Nine active-treatment subjects who received a mean cumulative dose of cat allergen, 1 of 10.9 units, and eight placebo-treatment subjects completed the study. Active treatment resulted in significant reductions in bronchial sensitivity (p less than 0.05) and prick test titer (p less than 0.01). In addition, active treatment resulted in a significant delay in the onset of ocular (p less than 0.05) and pulmonary (p less than 0.02) symptoms on exposure to living cats. Significant increases in IgG antibody to cat allergen 1 (p less than 0.001) and cat albumin (p less than 0.01) also occurred with active treatment. There was no significant change in bronchial reactivity to methacholine or in the sensitivity of circulating basophils. These results confirm the validity of immunotherapy in allergic asthma where there is careful patient selection and well defined treatment preparations.

Radiographic contrast media-induced noncardiogenic pulmonary edema: case report and review of the literature.

Adverse reactions are a frequent complication of exposure to radiographic contrast media (RCM). These reactions are most often anaphylactoid in nature and are characterized by the occurrence of urticaria, angioedema, bronchospasm, and shock. In patients who have had an anaphylactoid reaction to RCM and in whom reexposure is indicated, various pretreatment protocols have been developed to mitigate the risk for recurrence. We report the case of a 46-year-old man who, while undergoing cardiac catheterization, developed noncardiogenic pulmonary edema. This is the first reported case of the occurrence of noncardiogenic pulmonary edema secondary to RCM documented with Swan-Ganz data. In addition, our patient developed noncardiogenic pulmonary edema despite pretreatment with prednisone and diphenhydramine, administered because of a past history of a similar reaction. Potential mechanisms for such a reaction are discussed.

In vitro basophil histamine release induced by mannitol in a patient with a mannitol-induced anaphylactoid reaction.

Anaphylactoid reactions in man are associated with the infusion of diagnostic and therapeutic agents. The etiology of such reactions remains unknown, but clinically they have the signs and symptoms that mimic those associated with in vivo histamine release. We report that the leukocytes of a patient who suffered an anaphylactoid reaction associated with the infusion of mannitol repeatedly released histamine in vitro when the leukocytes were challenged with low concentrations of mannitol (less than 0.1 M). In 44% deuterium oxide buffer, the patient's cells were tenfold more reactive to mannitol as compared to normal leukocytes and were pharmacologically modulated in a fashion similar to IgE-dependent release. The temperature optimum for this nonhyperosmolar (less than 0.1M) mannitol-induced, deuterium oxide-dependent release was the same as that for IgE-dependent release. Desensitization of the patient's cells with anti-IgE completely suppressed release induced by low concentrations of mannitol but did not affect the hyperosmolar (greater than 0.1M) mannitol-induced release of basophil histamine. These studies suggest that patients experiencing anaphylactoid reactions may be identified by use of in vitro basophil histamine release.

Modulation of histamine release from human basophils in vitro by physiological concentrations of zinc.

Zinc, at physiologic concentrations, inhibits in vitro histamine release from human basophils induced by several immunologic (i.e., antigen and anti-immunoglobulin E (IgE) and nonimmunologic [Ca++ ionophore A23187 and formylated tripeptide formyl-methionyl-leucyl-phenylalanine (f-met peptide)] stimuli in a dose-dependent manner. Inhibition begins at about 10(-6) (ionophore A23187, anti-IgE and antigen) or 10(-5) M (f-met peptide) and is maximum at 10(-4) M (80--100% inhibition of histamine release). The activity of zinc is about 25-fold greater with respect to ionophore A23187 (ID50 = 1.1 x 10(-6) M) than to f-met peptide-induced (ID50 = 4 x 10(-5) M) histamine release. Its activity on IgE-mediated histamine release is intermediate between these two extremes (ID50 = 9.7 x 10(-6) M). Zinc does not affect the first stage of histamine release but acts on the calcium-dependent second stage. It is a competitive antagonist of the action of Ca++ in histamine secretion induced by antigen, anti-IgE and f-met peptide (but not by A23187) with a dissociation constant of about 1.2 x 10(-5) M. The addition of colchicine with zinc fails to increase the inhibition caused by the ion alone, suggesting the two compounds work via a common mechanism of action. Deuterium oxide reversed, in a dose-dependent manner, the inhibition of histamine release caused by zinc. These results suggest that the effect of zinc on histamine release from human basophils may be related to its influence on the microtubule system, directly or via its interaction with calcium.

Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma.

We studied the effect of a single oral dose of ICI 204,219 on subject response to bronchoprovocation and quantitative skin testing with standardized allergen (cat dander). Cat-allergic male subjects with asthma entered the double-blind, randomized, placebo-controlled, crossover study. Each subject received a 40 mg dose of ICI 204,219 or placebo on study days separated by at least 10 days. After dosing, each subject underwent bronchoprovocation with cat allergen until a provocative dose of allergen caused a 20% decrease in FEV1 or a maximum dose of 30,000 AU/ml was reached. Fifteen subjects entered and 13 completed the study. No significant shift in the dose-response curve of the quantitative skin test occurred in any subject. A mean tenfold increase in the interpolated provocative concentration causing a 20% decrease in FEV1 was observed between ICI 204,219 (6996 +/- 3204 AU/ml) and placebo (460 +/- 98 AU/ml). Eight of 12 subjects required more antigen to provoke a bronchoprovocation response after dosing with ICI 204,219 than that required with placebo (range, threefold to 30-fold), three demonstrated no difference (less than twofold), and one subject required less antigen after ICI 204,219 (sevenfold less). Area under the curve measurements were significantly different (p less than 0.05) between ICI 204,219 and placebo for the fixed time from the end point of the allergen bronchoprovocation to 5 hours after provocation. In conclusion, this trial demonstrates that a single oral dose of ICI 204,219 antagonizes the bronchoconstriction induced by inhaled cat allergen.

Effect of solvent on the histamine-releasing, enzyme-releasing, and mitogenic properties of the calcium ionophore A23187.

The potency of the calcium ionophore A23187 in inducing three activities of human leukocytes (histamine secretion from basophils, enzyme secretion from PMNs, and proliferation of lymphocytes) was markedly dependent on the solvent (DMSO versus ethanol versus aqueous buffer) used for its initial sonication. While 0.1 micrograms/ml of DMSO- and ethanol-solubilized A23187 induced maximal histamine release from basophils and histaminase release from PMNs, concentrations of aqueous buffer-sonicated ionophore of greater than or equal to 1 microgram/ml were required for an equivalent response. Ionophore sonicated in organic solvents caused a maximum release of 40% of PMN beta-glucuronidase, at an optimal concentration tenfold higher than that required for maximal histaminase release; ionophore sonicated in aqueous buffers, even at high concentrations, effected a release of less than 5% of cellular beta-glucuronidase. A23187 also induced lymphocyte proliferation over a narrow concentration range; 0.05 micrograms/l of DMSO-sonicated ionophore induced optimal proliferation and concentrations greater than or equal to 0.2 micrograms/ml were toxic. Twofold higher concentrations of ethanol-sonicated ionophore and fourfold higher concentrations of aqueous-sonicated ionophore were necessary for maximal proliferation, and the magnitude of the maximal response with aqueous-sonicated A23187 was only one-half that of DMSO-solubilized agent. Ionophore-induced release of histamine from basophils and enzymes from PMNs was not cytotoxic, since ionophore induced neither LDH nor histamine release from heat-treated (47 degrees C) cells. These results explain several previous, discordant reports on the presence or absence of an effect of A23187 on cellular secretory events, on differing dose-response relationships, and on cytotoxic versus noncytotoxic mechanisms of action.

Mechanisms of contraction induced by partially purified slow reacting substance from human polymorphonuclear leukocytes and leukotriene D in guinea pig ileal smooth muscle.

On the basis of the experiments described here, we suggest that the mechanism of action of SRS in guinea pig ileal longitudinal muscle is very similar to that used by other agonists in this preparation, namely interactions at a specific receptor to activate Ca++ channels leading to Ca++ influx and mechanical response. SRS responses differ in 1 important respect from those produced by other agonists. SRS and leukotriene D cause the generation of a slower contraction, which has a greater resistance to reversal by washing. The basis for this unique and prolonged duration of action is unknown but may represent an exceptionally tight, or even irreversible, association with a membrane component. Current studies on the structure of SRS may be helpful in this regard. Although not definitive, this report clearly indicates that a SRS "receptor" is, in fact, present on smooth muscle and that it utilizes a pool of calcium channels common to all smooth muscle agonists.