Augmentation of allergic histamine release from human leukocytes by nonsteroidal anti-inflammatory-analgesic agents

Augmentation of allergic histamine release in vitro with human leukocytes was produced by numerous nonsteroidal anti-inflammatory--analgesic agents, primarily the arylalkanoic and anthranilic acids. Augmentation occurred without release of histamine by the agents in the absence of the allergen (ragweed) and only under conditions of an accompanying release by the allergen. As a consequence of augmentation, less allergen was necessary to produce a given response in the presence of these agents. It is suggested that some of these agents might enhance mediator release in immediate-type hypersensitivity reactions. The same agents reported to exacerbate chronic urticaria, i.e., indomethacin, mefenamic acid, sodium salicylate, aspirin, sodium benzoate, and tartrazine, also augmented allergic histamine release. Pharmacologically mediated augmentation of mediator release from stimulated cells is suggested to be involved in the exacerbation of existing chronic urticaria by the acidic nonsteroidal anti-inflammatory-analgesic agents.     

Migraine and non-steroidal anti-inflammatory agents]

Controlled studies of nonsteroidal antiinflammatory drugs (NSAIDs) for the management of migraine attacks or for the prophylactic long-term treatment of migraine are reviewed herein. A large number of NSAIDs have been tested against a placebo or reference drug, including aspirin, indomethacin, mefenamic acid, tolfenamic acid, flufenamic acid, ibuprofen, flurbiprofen, fenoprofen, naproxen and sodium naproxen, diclofenac and lornoxicam. For the treatment of acute attacks, published studies found that the NSAIDs were significantly more effective than the placebo and at least as effective as the reference drugs. Adverse effects were absent or mild in this indication. Studies of NSAIDs as prophylactic treatment of migraine attacks are less numerous but also point to the value of this approach. However, long-term use of NSAIDs is associated with side-effects, mainly involving the gastrointestinal tract.     

Helicobacter pylori and non-steroidal anti-inflammatory agents

Observations on the interactions between the two main causes of gastroduodenal lesions--treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori(H.p.)-infection--remain controversial. However, H.p.-infection does not need to be harmful additively or synergistically, but could also be protective against the toxic effects of NSAIDs on the mucosa. Therefore, specific therapeutic strategies are needed for different clinical situations.     

Effect of non-steroidal anti-inflammatory drugs (NSAID) on the histamine release induced by compound 48/80 and cardiac anaphylaxis in guinea-pig isolated heart

Histamine release from guinea pig heart treated with compound 48/80 was potentiated by the cyclooxygenase inhibitors indomethacin and piroxicam but not by aspirin or phenylbutazone. This differential effect suggests that the potentiation is not merely due to an inhibition of prostaglandin synthesis. Piroxicam potentiated the histamine release induced by cardiac anaphylaxis whereas indomethacin reduced this effect. The SRS-A antagonist FPL 55712 inhibited histamine release induced by cardiac anaphylaxis, but not that evoked by compound 48/80, and also prevented the potentiation due to indomethacin and piroxicam. In total, these data suggest that the potentiation of histamine release by piroxicam and indomethacin is probably due to a diversion of arachidonic acid metabolism from the cyclooxygenase to the lipoxygenase pathways. The resulting lipoxygenase products may then regulate histamine release, with the secretion due to antigen being more sensitive to such modulation than that evoked by compound 48/80.     

A rapid and highly predictive in vitro assay for non-steroidal anti-inflammatory agents

The inhibition of the production of malonyldialdehyde (MDA) in guinea-pig lung homogenates, incubated in the presence of 50 microM arachidonic acid and 1.4 mM adrenaline, has been exploited as a simple and reliable assay to test in vitro non-steroidal anti-inflammatory agents (NSAIA). The inhibitory potencies of a series of reference NSAIA, which correlated fairly well with in vivo anti-inflammatory activity as determined by carrageenin oedema, are herewith reported. The specificity of the assay was also evaluated by testing up to forty miscellaneous drugs: none of these significantly reduced the MDA production.     

Management of rhinitis: allergic and non-allergic

RHINITIS IS A GLOBAL PROBLEM AND IS DEFINED AS THE PRESENCE OF AT LEAST ONE OF THE FOLLOWING: congestion, rhinorrhea, sneezing, nasal itching, and nasal obstruction. The two major classifications are allergic and nonallergic rhinitis (NAR). Allergic rhinitis occurs when an allergen is the trigger for the nasal symptoms. NAR is when obstruction and rhinorrhea occurs in relation to nonallergic, noninfectious triggers such as change in the weather, exposure to caustic odors or cigarette smoke, barometric pressure differences, etc. There is a lack of concomitant allergic disease, determined by negative skin prick test for relevant allergens and/or negative allergen-specific antibody tests. Both are highly prevalent diseases that have a significant economic burden on society and negative impact on patient quality of life. Treatment of allergic rhinitis includes allergen avoidance, antihistamines (oral and intranasal), intranasal corticosteroids, intranasal cromones, leukotriene receptor antagonists, and immunotherapy. Occasional systemic corticosteroids and decongestants (oral and topical) are also used. NAR has 8 major subtypes which includes nonallergic rhinopathy (previously known as vasomotor rhinitis), nonallergic rhinitis with eosinophilia, atrophic rhinitis, senile rhinitis, gustatory rhinitis, drug-induced rhinitis, hormonal-induced rhinitis, and cerebral spinal fluid leak. The mainstay of treatment for NAR are intranasal corticosteroids. Topical antihistamines have also been found to be efficacious. Topical anticholinergics such as ipratropium bromide (0.03%) nasal spray are effective in treating rhinorrhea symptoms. Adjunct therapy includes decongestants and nasal saline. Investigational therapies in the treatment of NAR discussed include capsaicin, silver nitrate, and acupuncture.     

Pharmacological studies of antigen-induced arthritis in BALB/c mice I. Characterization of the arthritis and the effects of steroidal and non-steroidal anti-inflammatory agents

Chronic monoarticular allergic arthritis was induced in BALB/c mice using methylated BSA as antigen and Freund's complete adjuvant, together with Bordetella pertussis as a secondary adjuvant. The optimum conditions for induction of chronic persistent arthritis and the histological characteristics of the arthritic lesion are described.Both the synovitis and erosive progression of the arthritis could be suppressed by daily treatment with prednisolone (1–10 mg/kg) or dexamethasone (0.5–2.5 mg/kg) for 4 weeks commencing 2 weeks after the induction of arthritis. In contrast, daily treatment with the non-steroidal anti-inflammatory agents ibuprofen (50–100 mg/kg), flurbiprofen (1–9 mg/kg) or indomethacin (0.1–3 mg/kg) had no significant effect on either the synovitis or erosions as judged histologically. Synovial fluid differential leukocyte counts were altered by treatment with ibuprofen and indomethacin but not by flurbiprofen or the corticosteroids.The suppressive effect of the corticosteroids was not due to either suppression of antibody synthesis or alteration of the number of leukocytes in the peripheral circulation.     

Glycogenolysis and control of anaphylactic histamine release by cyclic adenosine monophosphate-related agents. II. Modification of histamine release by glycogenolytic metabolites.

D-glucose-6-phosphate (less than or equal to 5 x 10(-3) M), pyruvate, lactate (less than or equal to 1 X 10(-2) M), and dibutyryl cyclic AMP (less than 5 X 10(-3) M) were capable of inhibiting anapylactic histamine release in vitro from chopped guinea pig lung. In lower concentrations, pyruvic acid and lactate, as well as dibutyryl cyclic AMP, enhanced the release. Significant synergism was observed betweenpyruvate (5 X 10(-3) M) and isoproterenol (1 X 10(-8) M) in the inhibition of histamine release. The inhibitory actions of isoproterenol, glucose-6-phosphate, and pyruvate were influenced by calcium ion concentration. However, beta blockade, which diminished the isoproterenol effect, was without efect on pyruvate (1 X 10(-2) M) to the release system. Glucose-6-phosphate and isoproterenol did not have this effect. The results, together with a prevouus study, suggest that glycogenolysis may possess a role in the anaphylactic istamine release in vitro from sensitized lung fragments...     

Platelet augmentation of IgE-dependent histamine release from human basophils and mast cells

A factor(s) from human platelets enhances IgE-mediated histamine release from human basophils and mast cells. This effect is directly related to the platelet number; at physiological platelet/leukocyte ratios (40:1), the enhancement was 66 +/- 11%. Platelet stimulation by thrombin more than doubled the enhancement, to 172 +/- 10% at 40:1. Mast cell release was also enhanced by platelets although the magnitude was more limited (86 +/- 13% at 40:1 with thrombin). Direct basophil/platelet contact was unnecessary in that platelet supernatants were fully active; a direct platelet factor/basophil interaction is suggested, however, by the fact that basophils purified 100-fold with respect to other leukocytes were enhanced by the platelet factors. The appearance of platelet-enhancing activity is associated with the release of an alpha-granule marker (PF4) rather than with products of arachidonic acid metabolism (thromboxane B2). The platelet factor(s) responsible for these effects are not dialyzable, are heat stable and do not appear to be identical to PF4 or platelet-derived growth factor (PDGF). Since anti-IgE-stimulated basophils cause PF4 release and this correlates with the release of enhancing factor, we suggest that a pro-inflammatory feed forward relationship exists. Together with our previous data showing that platelets are activated in vivo during antigen challenge of allergic asthmatic subjects, these results suggest that platelets may be important in modulating IgE-mediated allergic reactions in man.     

Inhibition of allergic histamine release by azelastine and selected antiallergic drugs from rabbit leukocytes

The ability of azelastine to inhibit allergic histamine release from rabbit mixed leukocytes was studied and compared with selected antiallergic drugs. Azelastine, ketotifen, diphenhydramine, theophylline and disodium cromoglycate (DSCG) produced concentration-dependent inhibition of allergic histamine release from rabbit basophils. The concentrations inhibiting histamine release by 50% (IC50; microM) were as follows: azelastine = 4.5; ketotifen = 9.5; diphenhydramine = 18.9; theophylline = 56.9; DSCG = greater than 1,000. DSCG was added to the cells immediately prior to antigen challenge. All other drugs were preincubated for a period of 10 min prior to antigen challenge. At the IC50 level, azelastine is about 2, 4, 13 and greater than 200 times as effective as ketotifen, diphenhydramine, theophylline and DSCG, respectively. The IC50 of azelastine following 0, 10 and 30 min preincubation were 2.4, 1.9 and 3.5 microM, respectively. These observations showed: (1) azelastine is capable of acting rapidly on basophils and of inhibiting allergic histamine secretion, and (2) the prolongation of the preincubation time of azelastine up to 30 min with rabbit leukocytes did not exhibit any sign of tachyphylaxis (loss of activity). In conclusion, azelastine is a potent inhibitor of allergic histamine secretion from the leukocytes of ragweed-sensitized rabbits.     

Glycogenolysis and control of anaphylactic histamine release by cyclic adenosine monophosphate--related agents.

The relationship of glycogen and glucose to anaphylactic histamine release from chopped sensitized guinea pig lung in vitro was studied. A parallelism was observed between the total amount of glycogen in the sensitized lung and the total amount of histamine released from the lung by antigen-antibody reactions. Removal of glucose from the medium for tissue suspension resulted in reduction in histamine release. Depletion of glycogen and/or glucose from the system was associated with (1) abolition of the inhibition of histamine release by isoproterenol and high concentrations of dibutyryl cyclic adenosine monophosphate (AMP) and (2) increase in the rate of enhancement of histamine release by lower concentrations of dibutyryl cyclic AMP. The results indicate that (1) glycogen may be one of the ultimate energy sources for anaphylactic histamine release, and (2) the presence of adequate amounts of glycogen and/or glucose in the sensitized tissue is necessary for the normal beta adrenergic effects on the histamine release in vitro from sensitized lung fragments.     

Endotoxins release histamine by complement activation and potentiate bacteria-induced histamine release

The histamine-releasing capability of bacterial lipopolysaccharides (LPS) was examined in human leukocyte suspensions. LPS alone did not release histamine, but it was found to enhance the histamine release caused by bacteria in basophils from persons sensitized to these bacteria. In the presence of serum, LPS was able to release histamine through complement activation. It is speculated that endotoxins reinforce release of histamine caused by bacteria in persons sensitized to these microorganisms, and a direct mediator release via complement activation might play a role in septic conditions.     

Inhibition of arachidonic acid induced mortality in rabbits with several non-steroidal anti-inflammatory agents

The intravenous administration of arachidonic acid to rabbits is an effective in vivo model for evaluating potential anti-thrombotic drugs. Most of the non-steroidal antiinflammatory agents (NSAIFA) inhibit this arachidonic acid induced mortality (except sodium salicylate and acetaminophen). However, there is a lack of correlation between the relative potencies from various assays (rabbit antithrombotic, anti-inflammatory, alalgesic, ulcerogenic and inhibition of prostaglandin synthetase evaluations). These studies imply other actions with NSAIFA than an effect solely on the prostaglandin biosynthetic pathway.     

Characterization of mononuclear cell-derived histamine release enhancing factor

Histamine release enhancing factor (HREF) is a product of phytohemagglutinin-stimulated mononuclear cells that substantially augments in vitro IgE-mediated basophil histamine release. The factor is stable at 56 degrees C and has a molecular weight in the 10,000 to 30,000 dalton range. The magnitude of HREF activity produced is dependent on the concentration of mononuclear cells cultured and the final concentration of HREF during basophil challenge. The HREF phenomenon could not be attributed to phytohemagglutinin, alpha- or gamma-interferon, arachidonic acid metabolites, or interleukin-1 or 2. HREF appears to be a unique cytokine of potential importance in the immunology of inflammatory and atopic processes.     

Modulation of antigen-induced histamine release from bovine granulocytes by several anti-allergic agents.

Sensitised bovine granulocytes release histamine when exposed to antigen. Several anti-allergic agents, some previously shown to be active in cattle, were tested to investigate their modulation of this histamine release process. Diethylcarbamazine citrate potentiated release at low concentrations and inhibited at high concentrations. Sodium meclofenamate and PR-D-92-EA were potent inhibitors. Acetylsalicylic acid and ICI 74,917 inhibited at high concentrations. Disodium cromoglycate was relatively ineffective, although it potentiated histamine release at low concentrations.     

Inhibition of rheumatoid factor production by non-steroidal anti-inflammatory drugs

The effects of NSAIDs on IgM rheumatoid factor production in vitro and on serum rheumatoid factor concentration in vivo were investigated using indomethacin (5.0μg/ml), carprofen (10μg/ml) and piroxicam (10μg/ml). IgM rheumatoid factor was isolated from lymphocytes of patients suffering from rheumatoid arthritis. NSAIDs inhibited IgM rheumatoid factor production in vitro. Furthermore, serum IgM rheumatoid factor was reduced when NSAIDs were administered in vivo. It is thought that NSAIDs effectively remove suppressor T-cells from the tonic inhibitory action of PGE₂. This previously unrecognized action of NSAIDs may be a factor in their efficacy in rheumatoid arthritis.     

In vivo modulation of leukotaxis by non-steroidal anti-inflammatory drugs

Since non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for inhibition of inflammation, anin vivo assay for leukotaxis would be of use in comparing the biological activity effects of the agents. Here, the effects of 4 different NSAIDs onin vivo leukocyte accumulation was determined by quantitatingN-formyl-methionyl-leucylphenylalanine induced leukotaxis in the rabbit anterior eye chamber. New Zealand white female rabbits were treated for three days with the following regimens: ibuprofen or aspirin, 0.1, 1.0, 10.0 or 100.0 mg/kg/day, indomethacin or flurbiprofen, 0.01, 0.1, 1.0, or 10.0 mg/kg/day. Indomethacin and flurbiprofen significantly reduced leukotaxis in a dose of 10.0 mg/kg/day. Aspirin was associated with a weak inhibition of leukotaxis. Ibuprofen had biphasic effects, 1.0 mg/kg/day potentiated and 10 mg/kg/day inhibited leukotaxis, whereas leukocyte accumulation was uneffected by a high dose (100.0 mg/kg/day). These results suggest that modulation of leukotaxis by NSAIDs may reflect a differential dose-response sensitivity of lipoxygenase and cycloxygenase pathways.