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The number of airway epithelial cells (AEC) in bronchus lumen after various types of anaphylactic shock of similar intensity was determined in guinea pigs. Aerosol-induced anaphylactic shocks were studied after four types of active sensitization: sensitization by IM injection of 30 mg/kg ovalbumin mixed with Freund's complete adjuvant; sensitization by IM injection of 30 mg/kg ovalbumin; sensitization by IP injection of 1 μg ovalbumin and 50 mg A1 (OH)3 by animal; sensitization by 2 exposures to 1%-ovalbumin aerosol at a 7-day interval. One, 3,6,24 and 48 h after the anaphylactic reaction the number of AEC in bronchoalveolar lavage fluid (BALF) was counted in comparison to guinea pigs sensitized but exposed to 0.9% NaCl aerosol. The number of AEC was significantly increased only 24–48 h after the shock in animals sensitized with ovalbumin in Freund's complete adjuvant. In animals passively sensitized by antiserum obtained with sensitization by ovalbumin in Freund's complete adjuvant and challenged by IV or aerosol administration of antigen, non rise in the number of AEC was obtained 24–48 h after the shock. The higher amount of AEC 24–48 h after the anaphylactic reaction in animals actively sensitized by ovalbumin in Freund's complete adjuvant could be related to the higher increase in the number of neutrophils and of mononuclears obtained in the BALF at these times in comparison to other types of active sensitization. The rise in the number of AEC only after the active reaction seems to show the part played by T-lymphocytes in the induction of this effect. The increase in the number of eosinophils in BALF and the appearance of the hyperreactivity cannot be related to the rise in the AEC in bronchus lumen.

Tioxamast (F 1865) is an antiallergic drug that, administered systemically, reduces anaphylaxis in various models in rats. This action is due mainly to the inhibition ofthe synthesis and release of certain mediators. Orally or intraduodenally administered tioxamast inhibits IgE-dependent passive cutaneous anaphylaxis (ED50 = 0.8 mg/kg), IgE-dependent passive pulmonary anaphylaxis (ED50 = 0.5 mg/kg), and IgG-dependent passive cutaneous anaphylaxis (ED50 = 0.6 mg/kg). It has little or no effect on the increase of cutaneous capillary permeability induced by various mediators. In IgE-dependent passive peritoneal anaphylaxis in rats, tioxamast reduces the release of histamine (IC50 = 0.024 µg/ml) and of β-glucuronidase (IC50 = 0.102 µg/ml). Also, histamine release is inhibited in IgG-dependent peritoneal anaphylaxis (IC50 = 0.103 µg/ml). The antiallergic compound has less effect on the release of histamine induced by the compound 48/80 in the peritoneal cavity of rats (IC50 = 1.67 µg/ml). Tioxamast inhibits the synthesis in vitro of leukotriene B4 (LTB4) by peritoneal neutrophils from rats stimulated by A23187 (IC50 = 8.88 µg/ml). At higher tioxamast concentrations, metabolites ofthe cyclo-oxygenase pathway are inhibited at concentrations ofthe same order of magnitude as those that inhibit Naja naja phospholipase A2 (IC50 = 144 µg/ml). Tioxamast also reduces the production of free radicals by leukocytes from the pleural cavity of rats which had phagocytosed opsonized zymosan (IC50 = 5.21 µg/ml).

We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.

The action of theophylline was studied on the inflammatory reaction obtained in bronchoalveolar lavage fluid 24 h after an active anaphylactic shock had been induced by ovalbumin inhalation in conscious sensitized guinea-pigs. The compound was administered twice by intraperitoneal administration after the anaphylactic reaction at a dose of 50 mg kg−1. When the guinea-pigs were sensitized by intramuscular injection of 30 mg kg−1 ovalbumin or by ovalbumin aerosol, theophylline reduced the number of eosinophils and mononuclear cells in the fluid. When animals were sensitized by intramuscular injection of 30 mg kg−1 ovalbumin mixed with Freund's complete adjuvant, treatment with the xanthine derivative decreased only the number of eosinophils. In the three models theophylline did not modify significantly the number of neutrophils. Thus theophylline always reduced pulmonary eosinophilia irrespective of the mode of sensitization used to induce anaphylactic shock.

Twenty-four hours after an active anaphylactic shock induced by inhalation of antigen in conscious guinea pigs sensitized by a large dose of ovalbumin in complete Freund's adjuvant, a noteworthy bronchial inflammation, characterized by increased numbers of neutrophils, mononuclear cells and eosinophils in the bronchoalveolar lavage fluid, was observed. Some drugs administered after the anaphylactic shock were investigated using this model. Disodium cromoglycate primarily reduced the number of mononuclear cells and eosinophils. Dexamethasone and theophylline decreased the number of eosinophils. Salbutamol and mepyramine increased neutrophils. Indomethacin did not give rise to any significant effect. This test appears to be of use for the investigation of anti-inflammatory compounds in the prophylactic treatment of asthma.

A model of bronchial hyperreactivity at various times after an active anaphylactic shock in conscious guinea pigs is described. The bronchial inflammation was quantified in parallel by determination of the number of mononuclear cells, neutrophils, and eosinophils in bronchoalveolar lavage (BAL) fluids. The guinea pigs were sensitized by an intramuscular (i.m.) injection of a large dose of ovalbumin in Freund's complete adjuvant. The administration of ovalbumin (to induce anaphylactic shock) and of histamine to investigate bronchial hyperreactivity was by aerosol. The bronchial hyperreactivity to histamine was observed 3-6 hr after the anaphylactic shock. In the BAL fluid a decrease (1-3 hr) and then an increase (24-48 hr) in the number of mononuclear cells was found as well as an increase in neutrophils (3-48 hr) and in eosinophils (6-48 hr). The hyperreactivity was not correlated with changes in one category of cell in the BAL fluid. This model constitutes one simple test for investigating bronchial hyperreactivity in conscious guinea pigs. Further work is needed to try to determine the possible inflammatory parameters responsible for the hyperreactivity.

Injection of zymosan in rat pleural cavity provokes an exudate which is already detectable at 15 min and which is maximum at 24 h. The leucocyte count (mostly neutrophils) increases at 2-4 h and is maximum at 48 h. In this paper the reaction has been studied up to 6 h. Evidence of histamine release, of mast cell degranulation and of reduction of the exudate by anti-H1 compounds, as well as by sodium cromoglycate, proves the active role played by histamine in the early stage of pleurisy. Serotonin (whose role was studied exclusively using antagonists) seems to have only a minor part in the early phase of the reaction. Some metabolites of arachidonic acid were determined in the pleural exudate at 1 h and 6 h. The concentration of leukotriene B4 was high at 1 h and decreased at 6 h. The thromboxane B2 level was already high at 1 h and was neatly augmented at 6 h while the amount of prostaglandin F1 alpha was high at both times. The non-steroidal anti-inflammatory substances studied all reduced the pleural exudate at 1 h but their activity then varied from each other at 6 h. Cyclooxygenase and lipoxygenase inhibitors (phenidone, BW755C) induced a reduction of the exudate at both times. Zymosan-induced pleurisy seemed thus to be an excellent model for the investigation of antiallergic and anti-inflammatory compounds active on histamine and cyclooxygenase and lipoxygenase pathways.

Injections of zymosan in mouse and rat paws provoke inflammatory reactions, the kinetics of which are different. In both models, inflammation occurs at an early stage but oedema is maximal at 30 min in rat paw and 6 h in mouse paw. In this study the two reactions have been studied up to 6 h. The reduction of oedema by anti-H 1 compounds, as well as by disodium cromoglycate, proves the active role played by histamine in rat paw oedema. In mouse its role appears to be minor or non-existent. Serotonin seems to be clearly implicated in the early stages of the oedema in mouse, somewhat less in rat. In the two species, non-steroidal anti-inflammatory compounds only reduce the 4–6 h phase. BW755C and phenidone reduce the early and late phase of paw oedema in both species, with the exception of phenidone which is inactive on the 4–6 h phase in the mouse. We can hypothesize that in the two species some leukotrienes seem to be implicated principally in the early phases, while derivatives of cyclooxygenase play a more important role in the late phases. Theophylline reduces inflammation in the two models, hydrocortisone acetate, however, is only active on the late phases. These results indicate that there are important differences in the participation of the various mediators studied in the two models.

Cantharidin applied to the Swiss mouse ear induced a clearly observable inflammatory reaction after 6 hr, maximal after 24 hr, and persisting several days. Desonide and hydrocortisone strongly inhibited the acute (6 hr) and delayed (24 hr) phases after their local application, while, after oral treatment, a reduction in the acute edema was obtained only when using high doses. The cutaneous application of high doses of mepyramine, disodium cromoglycate, methysergide, and (at a quite lower level) cimetidine reduced the 6-hr inflammation. Phenylbutazone and acetylsalicylic acid showed little activity on the same phase after their cutaneous administration. All the nonsteroid compounds produced little or no effect on the 24-hr inflammation after their cutaneous application and were quite inactive on both phases after their systemic treatment. The cantharidin-induced inflammatory reaction in Swiss mouse seems thus to be characterized by two phases. The chronic delayed phase is an example of chronic inflammation without the involvement of immunological processes. Histamine and serotonin might be involved in the acute inflammation.

Injection of platelet-activating factor (PAF-acether) into the pleural cavity of rats induced the accumulation of a moderately intense exudate within 30 to 60 minutes. By comparison with animals given injections of the vehicle alone, the animals given this mediator had elevated levels of leukotriene C 4 -immunoreactive material (LTC 4 im) in the exudate and decreased quantities of thromboxane B 2 (TxB 2 ) and of 6-KetoF 1α -prostaglandin (6-Keto PGF 1α ). Nifedipine, verapamil, and diltiazem reduced the pleural exudate with no major effect on the mediators. Both salbutamol and theophylline reduced the exudate and the levels of LTC 4 im. Acetylsalicylic acid, phenylbutazone and indomethacin significantly inhibited the exudate, greatly lowered the quantities of cyclooxygenase derivatives and tended to increase LTC 4 im. Phenidone, which inhibits the cyclooxygenase and lipoxygenase pathways, decreased the exudate and the three mediators. The phospholipase A 2 inhibitor, chloroquine, decreased both the amount of exudate and moderately the concentration of LTC 4 im. The glucocorticoids studied had no effect on the exudate or on the mediators. These results suggest that the role of the increased LTC 4 im in the induction of the pleurisy is not clear

Lotifazole (F 1686) — 4-phenyl-2-(2′, 2′, 2-trichloroethoxycarboxamido) thiazole — has a range of antiinflammatory activities in animals that differs from the activities of classic non-steroidal drugs. It reduces carrageenin-induced oedema in rats, UV-induced erythema in guinea pigs, and Arthus pleurisies in rats only at high doses. It does not affect Freund's-adjuvant polyarthritis, and it only slightly affects passive skin anaphylaxis in rats and anaphylactic shock in guinea pigs. Lotifazole does not greatly inhibit prostaglandin synthesis. However, at low doses and after various conditions of treatment, F 1686 reduces PPD- andBordetella- pertussis-induced delayed-hypersensitivity pleurisy in guinea pigs and rats, respectively, and contact hypersensitivity reactions to picryl chloride and oxazolone in mice. Its action on the two models of delayed-hypersensitivity pleurisy is reflected in a decrease of the pleural exudate and of the number of mononuclear cells in the focus of inflammation. At active doses, Lotifazole does not cause changes in the differential leukocyte count in normal animals. It appears, furthermore, to be a T-lymphocyte stimulant.

The injection of PAF-acether into the pleural cavity of the rat induced a maximal exudate after 30-60 min which then decreased and disappeared after 24 hours. In addition, the mediator produced a decrease in the number of leukocytes in the pleural cavity 30 min after injection and an increase in the number of cells after 6 hours.