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The interaction between antihistaminic drug oxatomide (OXT) and calf-thymus DNA (CT-DNA) has been investigated in a physiological buffer (pH 7.4) using UV–Vis, fluorescence, 1H NMR and circular dichroism spectral techniques coupled with viscosity measurements, KI quenching, voltammetry and in silico molecular modeling studies. OXT binds with CT-DNA in a concentration-dependent manner. At a lower [Drug]/[CT-DNA] molar ratio (0.6–0.1), OXT intercalates into the base pairs of CT-DNA, while at a higher [Drug]/[CT-DNA] molar ratio (13–6), the drug binds in the minor grooves of CT-DNA. The binding constants for the interaction are found to be in the order of 103–105 M−1, and the groove binding mode of interaction exhibits a slightly higher binding constant than that of intercalative mode. Thermodynamic analysis of binding constants at three different temperatures suggests that both these modes of binding are mainly driven by hydrophobic interactions (ΔHo > 0 and ΔSo > 0). Voltammetric investigations indicate that the electro-reduction of OXT is an adsorption controlled process and shifts in reduction peak potentials reiterate the concentration-dependent mode of binding of the drug with CT-DNA. The free energy landscape obtained at the all-atom level, using metadynamics simulation studies, revealed two major binding forces: partial intercalation and minor groove binding, which corroborate well with the experimental results. Communicated by Ramaswamy H. Sarma

Vaccination is a well-known trigger for mast cell degranulation in subjects affected by mastocytosis. Nevertheless, there is no exact standardized protocol to prevent a possible reaction after a vaccine injection, especially for patients who have already presented a previous vaccine-related adverse event, considering that these patients frequently tolerate future vaccine doses. For this reason, we aim to share our experience at Meyer Children’s University Hospital in Florence to raise awareness on the potential risk for future vaccinations and to discuss the valuable therapeutic strategies intended to prevent them, taking into account what is proposed by experts in literature. We describe the case of an 18-month-old female affected by a polymorphic variant of maculopapular cutaneous mastocytosis that presented an extensive bullous cutaneous reaction 24 hours after the second dose (booster dose) of inactivated-tetravalent influenza vaccine, treated with a single dose of oral corticosteroid therapy with betamethasone (0.1 mg/kg) and an oral antihistamine therapy with oxatomide (1 mg/kg/daily) for a week, until resolution. To the best of our knowledge, in the literature, no documented case of reaction to influenza vaccine in maculopapular cutaneous mastocytosis is described. Subsequently, the patient started a background therapy with ketotifen daily (0.05 mg/kg twice daily), a non-competitive H1-antihistamine, and a mast cell stabilizer (dual activity). A non-standardized pharmacological premedication protocol with an H1-receptor antagonist (oxatomide, 0.5 mg/kg) administered 12 hours before the immunizations, and a single dose of betamethasone (0.05 mg/kg) together with another dose of oxatomide (0.5 mg/kg) administered 2 hours before the injections was followed to make it possible for the patient to continue with the scheduled vaccinations. Indeed, no reactions were subsequently reported. Thus, in our experience, a background therapy with ketotifen associated with a premedication protocol made by two doses of oxatomide and a single dose of betamethasone was helpful to make possible the execution of the other vaccines. We suggest how in these children, it could be considered the idea of taking precaution when vaccination is planned, regardless of the kind of vaccine and if a dose of the same vaccine was previously received. However, international consensus needs to be reached to manage vaccinations in children with mastocytosis and previous adverse reactions to vaccines.

Background: Oxatomide, a H1-receptor antagonist, exerts besides its well-known anti-allergic potential an array of anti-inflammatory activities. We wondered whether oxatomide might influence the release of IL-8 from human epithelial cells activated with agonists of TLR2, which mainly expresses on airway epithelial cells. Methodology: We used the human lung epithelial cell line A549 and primary Human nasal epithelial cell line for our in vitro studies. IL-8 releases from these cell lines were determined by IL-8 enzyme immunoassay. NF-kB was analysed by Luciferase reporter assay. Confluent epithelial cell monolayer were pre-incubated with oxatomide for 30 min and afterwards activated with lipoprotein as a TLR2 agonist for 24 h. Results: Epithelial cells stimulated with lipoprotein showed a significantly increased release of IL-8. Pre-incubation with oxatomide diminished the IL-8 release from cells activated with lipoprotein in a significant manner. Furthermore, activity of the NF-kB was determined by luciferase reporter assy. Besides, oxatomide inhibits expression of MIP2, a homologue of human IL-8, and neutrophilic infiltration in nasal membrane of mice intranasally exposed with lipoprotein. These results suggest that oxatomide reduced the release of IL-8 from respiratory epithelial cells stimulated with lipoprotein. Conclusion: Therefore, oxatomide might exert anti-inflammatory effects beyond its H1-receptor antagonistic activity in the course of inflammatory respiratory tract disorders such as acute bacterial rhinitis.

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

Summary In Japan, loratadine, fexofenadine, cetirizine and epinastine are currently approved for paediatric use. However, none of these drugs is officially approved for use in children aged under 2 years, and therefore older second-generation antihistamines such as ketotifen and oxatomide are sometimes prescribed for these patients. Because ketotifen and oxatomide have relatively strong sedative effects, one should be cautious when using these antihistamines in young children. In fact, there are reports describing the development of West syndrome, an intractable epilepsy, in 4-month-old infants taking these drugs. Recent clinical trials in Japanese children with allergic rhinitis have shown no serious adverse effects associated with several new second-generation antihistamines, supporting previous overseas reports. New second-generation antihistamines should be approved in the near future for young children in Japan.

Histamine H1 receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity. Keywords:: constitutive activity, histamine H1 receptor gene transcription, inverse agonist

A rapid, sensitive and specific high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method has been developed and validated for the determination of oxatomide in human plasma. Flunarizine hydrochloride was employed as the internal standard (IS). The analytes were chromatographically separated on a Shimadzu Shim-pack VP-ODS C18 column (250 x 2.0 mm i.d.) with a mobile phase consisting of methanol and aqueous ammonium acetate solution (10 mm, pH 4.0; 85:15, v/v). Detection was performed on a single quadrupole mass spectrometer using an electrospray ionization interface with the selected-ion monitoring (SIM) mode. The method showed excellent linearity (r = 0.9995) over the concentration range of 0.5-500 ng/mL with good accuracy and precision. The intra- and inter-batch precisions were within 10% relative standard deviation. The recoveries were more than 90%. The validated method was successfully applied to a preliminary pharmacokinetic study of oxatomide in Chinese healthy male volunteers.

The authors report a pilot open-label two-center therapeutic trial of oxatomide in 14 steroid-naive DMD boys aged 5–10 years. Comparison of linear evolutions between 3 months medication-free lead-in periods and 6 months treatment periods showed no significant differences in quantitative (QMT) and manual (MMT) measurements of muscle strength and timed functional tests. A modest mitigation of strength deterioration over time cannot be excluded.

Activation of the P2X7 receptor by extracellular ATP is associated with various immune responses including allergic inflammation. Anti-allergic agents, such as H1-antihistamines, are known to inhibit the effects of different chemical mediators such as acetylcholine and platelet-activating factor. Therefore, we hypothesized that some anti-allergic agents might affect P2X7 receptor function. Using N18TG2 and J774 cells, which express functional P2X7 receptors, the effects of several anti-allergic agents on P2X7 receptor function were investigated by monitoring the ATP-induced increase in intracellular Ca(2+) concentrations ([Ca(2+)]i). Among the various agents tested, oxatomide significantly inhibited P2X7 receptor-mediated [Ca(2+)]i elevation in a concentration-dependent manner without affecting the P2Y2 receptor-mediated response in both N18TG2 and J774 cells. Consistently, oxatomide inhibited P2X7 receptor-mediated membrane current and downstream responses such as mitogen-activated protein kinase activation, inflammation-related gene induction, and cell death. In addition, oxatomide inhibited P2X7 receptor-mediated degranulation in mouse bone marrow-derived mast cells. Whole cell patch clamp analyses in HEK293 cells expressing human, mouse, and rat P2X7 receptors revealed that the inhibitory effect of oxatomide on ATP-induced current was most prominent for the human P2X7 receptor and almost non-existent for the rat P2X7 receptor. The potent inhibitory effects of oxatomide on human P2X7 receptor-mediated function were confirmed in RPMI8226 human B cell-like myeloma cells, which endogenously express the P2X7 receptor. Our results demonstrated that the antihistamine oxatomide also acts as a P2X7 receptor antagonist. Future studies should thus evaluate whether P2X7 receptor antagonism contributes to the anti-allergic effects of oxatomide.

The charge transfer complex (CT-complex) between oxatomide drug and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) was studied spectrophotometrically in 10 solvents at different temperatures. The donor oxatomide is found to form stable 1:1 stoichiometric complex with DDQ and the stoichiometry was unaffected by change in polarity of the solvent studied. The DeltaH degrees, DeltaS degrees and DeltaG degrees values are all negative, so the studied complex is reasonably stable and exothermic in nature. The ionization potential of the drug was determined using the CT-absorption bands of the complex in all the solvents. The dissociation energy of the charge transfer excited state for the CT-complex in different solvents was also determined and is found to be constant. The spectroscopic and thermodynamic properties were observed to be sensitive to the nature of the solvent.

Objective: Inflammatory mediators (IMs) play a major role in the production of middle ear effusion (MEE). Tumor necrosis factor (TNF)-α and leukotrienes (LTs) appear to be important in the pathogenesis of otitis media with effusion (OME). The purpose of this study is to determine the effect of TNF-α and LT antagonist on the outcome of experimental immune-mediated OME. Study Design: Prospective. Methods: Otitis media was induced in rats by injecting keyhole limpet hemocyanin (KLH) transtympanically 7 days after systemic immunization. Experimental groups were treated with soluble TNF receptor type I (sTNF RI) or oxatomide simultaneously. Seventy-two hours after transtympanic injection, MEE was aspirated, and temporal bone was taken. Vascular permeability (VP) of the middle ear mucosa was measured using the Evans blue dye technique. Hematoxylin-eosin stain and immunohistochemical stain for leukocyte common antigen was performed. Results: In KLH, sTNF RI, and oxatomide groups, MEE was developed in 83%, 0%, and 66% of the ears, respectively. The sTNF RI group showed significant decrease in effusion production, inflammation, mucosal thickening, and VP compared with the KLH group. These parameters were less significant in the oxatomide group than in the sTNF RI group. Conclusion: Transtympanic administration of sTNF RI and oxatomide appears to suppress the development of immune-mediated MEE.

Oxatomide is an antiallergic drug with a double mechanism of action: it possesses antagonistic activity on the H1 histaminergic receptor and it inhibits the production and release of flogistic and allergic mediators by effector cells, presumably acting as a selective calcium channel blocker on these cellular types. The efficacy and safety of oxatomide have been evaluated in many studies conducted on patients affected by different clinical conditions, demonstrating remarkable flexibility. It proved to be safe and effective also in extreme ages, i.e. children under 3 months of age and elderly over 80 years. Approved indications include rhinitis, asthma, conjunctivitis, urticaria, atopic and allergic dermatitis and food allergy and intolerance. In direct comparisons, oxatomide consistently proved superior than placebo and equally or more effective than other consolidated antiallergics. The drug tolerability is good, its main side effects are drowsiness and weight gain, usually transient. Cardiac and hepatic safety data are very reassuring, as is the case for drug interaction potential. Form an economical point of view, the drug acquisition cost is acceptable, being among the lowest in its class, at equally effective doses. Overall, the efficacy in several clinical conditions, the good tolerability in most patients and the reasonable purchase cost suggest that oxatomide is characterized by excellent risk-to-benefit and cost-to-benefit ratios in the treatment of allergic pathologies.

Intercellular adhesion molecules (ICAMs), in particular ICAM-1, appear to play a crucial role in the recruitment and migration of inflammatory cells to the site of an allergic reaction. Glucocorticoids and allergen-specific immunotherapy have been shown to exert effects on selected components of this system, both in vitro and in vivo, but further research is required to better understand the effects of these therapies. Nasal and conjunctival challenge models (including natural and experimental allergen exposure) represent useful and safe tools for studying the activity of antiallergy drugs in vivo. These tests allow the investigation of a wide variety of parameters including inflammatory infiltrate, ICAM-1 expression, and changes in the concentration of soluble inflammatory mediators. With these tools, anti-inflammatory activity related to the modulation of epithelial cell adhesion molecules has been demonstrated in vivo for several H(1)-receptor antagonists (azelastine, cetirizine, loratadine, levocabastine, oxatomide, and terfenadine). Fexofenadine is a nonsedating, long-acting antihistamine with highly selective H(1)-receptor antagonist activity and a particularly favorable safety profile. In addition, fexofenadine has proven anti-inflammatory activity and has been shown to inhibit a number of mediators at clinically relevant concentrations, including in vitro inhibition of ICAM-1 expression on conjunctival and nasal epithelial cells.

The effects of anti-pruritic drugs on scratching behavior associated with passive cutaneous anaphylaxis in histamine H(1) receptor-deficient and wild-type mice were studied. Passive sensitization with mouse monoclonal anti-dinitrophenyl-immunoglobulin E (IgE) resulted in an increase in the incidence of scratching behavior induced by intravenous injection of dinitrophenyl-ovalbumin in both wild-type and histamine H(1) receptor-deficient mice. The histamine H(1) receptor antagonist diphenhydramine inhibited scratching behavior induced by antigen in passively sensitized wild-type mice, whereas no effect was observed in histamine H(1) receptor-deficient mice. On the other hand, oxatomide inhibited scratching behavior in both mice, although the effect in wild-type mice was more potent than that in histamine H(1) receptor-deficient mice. Tranilast inhibited scratching behavior with the same potency in both mice. We concluded that the scratching behavior associated with passive cutaneous anaphylaxis involves not only histamine H(1) receptors but also other chemical mediators. Furthermore, the results of the present study indicated that oxatomide has an antagonistic effect on histamine H(1) receptors as well as anti-pruritic effect in vivo.

We report two cases of cheilitis granulomatosa. A 38-year-old female and a 45-year-old male presented with swelling of the lower lip. Neither case included the three symptoms of Melkerson-Rosenthal syndrome, which is characterized by swelling of lip, facial paralysis and plicated tongue. Both patients were treated successfully with oxatomide. Sarcoidosis, Crohn's disease, angioedema had to be considered in the differential diagnosis.

A rapid liquid chromatographic method was developed for the determination of oxatomide in its finished active pharmaceutical ingredient form and in the presence of its process impurities. The method was developed on a sub 2 mm Hypersil Zorbax XDB C18 column (30 3 4.6 mm, i.d., 1.8 mm). The rapid method employed a gradient mobile phase consisting of solvent A: 0.01 M tetrabutylammonium hydrogen sulfate and 0.5% (w/v) ammonium acetate in water and solvent B: acetonitrile. A flow rate of 2 mL/min was employed with the diode-array detector set at 230 nm. The original method supplied by Janssen Pharmaceuticals Ltd was run on a Thermo Scientific octadecylsilyl silica gel C18 column (100 3 4.6 mm, i.d., 5 mm) with an analysis time of 20 min. The main aim was to substantially reduce the analysis time while maintaining good efficiency. Run-time was reduced to 6.5 min with a total loss in analysis time of 68%. Solvent consumption was also reduced by 68%. Validation according to the International Conference of Harmonization guidelines was undertaken. The parameters examined were accuracy, precision, linearity, selectivity, robustness, limit of detection and limit of quantification; all criteria were met. Sample stability testing was also carried out. Oxatomide proved stable under ambient and 48C temperatures and in the presence of light for up to 24 h.

Experimental and epidemiological studies have indicated that central histaminergic neuron system plays an important role in inhibition of convulsive disorders through histamine H(1)-receptors, especially in developing period. Histamine H(1) antagonists increase the duration of electrically induced convulsions in 21-day-old mice, but not in 42-day-old mice. Epidemiological studies suggested that histamine H(1) antagonist may be one of the risk factors in febrile convulsions. In histidinemic patients who were considered to have high brain histamine content, the incidence of convulsions was lower than that of ordinary population.The centrally acting histamine H(1) antagonists including pyrilamine and ketotifen facilitate the development of amygdaloid kindling in rats, an experimental model of epileptogenic process. On the contrary, epinastine, a histamine H(1) antagonist which scarcely enters the brain, shows no facilitation. These findings suggest that the central histaminergic neuron system plays an inhibitory role on the seizure development through central histamine H(1)-receptors.Recently, three cases has been reported in which West syndrome developed 8-10 days after ketotifen or oxatomide administration. Considering experimental and clinical studies, histamine H(1) antagonists may be associated with West syndrome and may be hazardous to infants. Further careful experimental and clinical studies will be required to elucidate the relationships between West syndrome and central histaminergic neuron system.

The present study was performed to compare the properties of ebastine--the long duration of antiallergic effect and less penetration to the CNS--with those of other H1-antihistamines. Passive cutaneous anaphylactic reaction was induced and the dye leakage from the skin measured after oral administration of the various H1-antihistamines in guinea pigs. The H1-antihistamines examined inhibited passive cutaneous anaphylactic reactions, with ED50 values of 1.55-5.77 mg/kg administered orally. Evaluation at doses close to the ED50 values determined that the rank order of the various H1-antihistamines for the duration of antiallergic effects, calculated from the AUC, was as follows: ebastine>cetirizine> or =oxatomide=loratadine=epinastine. The inhibition of [3H]-mepyramine binding to the cortical membrane was examined ex vivo after oral administration of the drugs in rats. Ketotifen as a positive control of sedative antihistamine, oxatomide, cetirizine, ebastine and epinastine dose-dependently inhibited the [3H]-mepyramine binding to rat cortical membranes. However, ebastine and epinastine did not show 50% [3H]-mepyramine binding inhibition even at 100 mg/kg orally In conclusion, ebastine was shown to be a potent and long-lasting H1-antihistamine with less effect to the CNS. Consequently, in conjunction the two experimental models used in this study--passive cutaneous anaphylactic reaction in guinea pigs and ex vivo [3H]-mepyramine binding to rat cortical membrane--may be important to estimate the duration of antiallergic effects of drugs and to detect their sedative effects, which are important indicators in the development of new antiallergic drugs.

Oxatomide and phenylephrine have been simultaneously determined in pharmaceutical tablets containing a large excess of paracetamol (ca. 20:1 and 100:1 in weight, respectively) by two spectrofluorometric methods. The strong absorbance of paracetamol at the excitation maxima of the analytes and the severe overlapping between the emission and excitation spectra of the latter gives rise to a highly interfering system. Conventional standard addition was applied to the first-derivative of the emission spectra at two appropriate zero-crossing wavelengths. This method involves adding oxatomide or phenylephrine to an acid aqueous solution (pH=2) of the tablet components, in the ranges 0–6.40 and 0–1.00 mg l−1, respectively. Generalized standard addition was also applied to emission spectra of mixtures obtained by adding both analytes to the unknown samples, and processing the obtained spectral data with a suitable computational program. Both techniques were satisfactorily employed for assaying commercial pharmaceutical tablets. Critical examination of the spectra for the studied analytes as a function of the concentration of paracetamol provides an explanation as to why multivariate calibration methods such as partial least-squares (PLS) cannot be applied to the present system.

The tissue kallikrein level in the nasal wash was measured before and after 4-week administration of oxatomide (30 mg per day) in 9 patients with perennial allergy. It was found that tissue kallikrein level in the nasal wash obtained following provocation tests significantly decreased from 6.05 ± 4.43 (10-10 mol/hour/L)to 1.84 ± 0.93 (10-10 mol/hour/L) after the administration of oxatomide. Improvement in subjective symptoms was also observed in all patients after the administration. These results would indicate that kinin in the system is actively involved in the pathogenesis of nasal allergy.

Background: Lipid mediators play a pivotal role in the pathogenesis of allergic and inflammatory reactions. These molecules include metabolites of arachidonic acid (AA) and the group of platelet-activating factor (PAF)-related phospholipids. The initial step in the synthetic pathway of both classes of lipid mediators is catalyzed by members of the phospholipase A2 (PLA2) family. Oxatomide is a histamine H1 receptor antagonist currently used in the treatment of allergic disorders. Preliminary evidence indicates that oxatomide may exert anti-inflammatory activities unrelated to H1 receptor antagonism. Methods: We investigated the effect of oxatomide on lipid mediator production by human neutrophils. Results: Preincubation (15 min, 37°C) of neutrophils with oxatomide (10–100 µM) concentration-dependently inhibited (10–70%) the release of AA induced by the Ca2+ ionophore A23187 (0.5 µM). Oxatomide also comparably inhibited the release of the four major metabolites of AA induced by A23187 (LTB4, 20-OH-LTB4, 20-COOH-LTB4 and 5-HETE). In addition, oxatomide reduced by 60% the production of PAF induced by A23187. The simultaneous inhibition of the production of AA metabolites and PAF suggested that oxatomide could influence the activity of cytosolic PLA2 (cPLA2). To test this hypothesis, we evaluated the functional activity of cPLA2 in neutrophils preincubated with oxatomide. This preincubation inhibited (72 ± 24%) the increase in cPLA2 activity induced by A23187. Conclusions: These results indicate that oxatomide reduces the biosynthesis of lipid mediators in human neutrophils by inhibiting cPLA2. This inhibitory effect of oxatomide may contribute to the anti-inflammatory activity of this drug in allergic diseases.

Anti-scratch effects of oxatomide and epinastine were examined in mice. Scratching behavior and cutaneous reactions were induced in BALB/c, ICR and ddY mice by dinitrofluorobenzene painting, passive cutaneous anaphylaxis and substance P injection, respectively. Although oxatomide and epinastine failed to inhibit scratching behavior in BALB/c mice, they inhibited the cutaneous reaction significantly. The drugs potently inhibited both scratching behavior and cutaneous reaction in ICR mice. They also inhibited scratching behavior and cutaneous reaction in ddY mice, although cetirizine and terfenadine failed to affect them. Histamine did not induce frequent scratching behavior in BALB/c and ddY mice. These results indicate that oxatomide and epinastine inhibit the scratching behavior in ICR mice associated with passive cutaneous anaphylaxis mainly through an antagonistic action on histamine H 1 receptors. The results also indicate that these drugs inhibit substance P-induced scratching behavior in ddY mice through an action independent of the antagonistic action on histamine H 1 receptors.

Oxatomide is an H 1 antihistaminic drug that also inhibits mediator release from mast cells. From previous studies, it appeared that inhibition of the influx of extracellular calcium is the major cause of this inhibition of exocytosis. Here, we explored the role of drug–membrane interactions in the inhibition of mediator release. We investigated the effects on phase transition and fluidity of artificial membranes. All compounds studied distorted the phase transition in l -α-dipalmitoylphosphatidylcholine liposomes, which correlated with the drug-induced increase in membrane fluidity measured by fluorescence anisotropy of the bilayer interacting probe 1-[4-(trimethylamino)-phenyl]-6-phenylhexa-1,3,5-triene. Erythrocytes were used to study membrane effects on a cellular level. The hypotonic-induced haemolysis of erythrocytes was inhibited by the drugs. Compounds which increased membrane fluidity of liposomes to a greater extent were also more active in decreasing haemolysis. Drug-induced disturbance of the membranes is related to their effect on the activity of store-operated Ca 2+ channels. The activity of these channels in rat basophilic leukemia cells, assayed as 45 Ca 2+ influx, was most effectively inhibited by oxatomide derivatives, thereby inducing a more rigid membrane structure. Small changes in molecular structure affect the activity of the drugs and these structure–activity relations are discussed.

A randomized, controlled, single blind study was carried out to compare the efficacy and safety of oxatomide and disodium chromoglycate in the treatment of adverse reactions to food. Twenty-three patients (16F and 7M) with urticaria (16 patients), respiratory (5 patients), intestinal (15 patients) and/or neurological symptoms (3 patients) were treated for 60 days: 14 (9F and 5M; mean ± SD age 36.3 ± 13.8 years) with oxatomide, 60 mg every evening and 9 (7F and 2M; 31.5 ± 15.1 years) with disodium chromoglycate, 500 mg three times a day. Both therapies lasted two months. On admission and after 15,30 and 60 days skin (wheals, itching, vesicular blisters, scratching lesions), respiratory (rhinorrhea, sneezing, coughing, wheezing), intestinal (constipation, diarrhea, bloating, abdominal pain and/or cramps) and neurological (headache, irritability) symptoms were assessed. Wheals decreased in number and size in both groups (p Both treatments were effective as regards cutaneous, intestinal and respiratory symptoms, with a significant reduction of itching, wheals and vesicular blisters and the complete relies of intestinal disorders. The drugs were well tolerated.

The antiallergic drug oxatomide and analogs inhibit mediator release from a rat basophilic leukemia (RBL-2H3) cell line, which is frequently used as a mast cell model. By investigating a series of derivatives of oxatomide with different inhibiting activities on exocytosis, we aimed to evaluate the role of their effects on the early steps of the signal transduction cascade in the inhibition of exocytosis. The active compounds induced hyperphosphorylation of tyrosine residues both in stimulated as well as in resting cells. Furthermore, some elevation of the inositol 1,4,5-trisphosphate (IP3) formation upon antigen activation was observed for the active derivatives. Ca2+ fluxes were also studied. The inhibition of the antigen-induced 45Ca2+ influx correlated with the effects of the drugs on exocytosis. Furthermore, the inhibitory activity on antigen- and thapsigargin-mediated exocytosis correlated well. Adherence of the cells to fibronectin, stimulating cellular integrin receptors, was synergistic to antigen activation of the RBL cells. However, oxatomide did lack any effect on integrin-mediated processes, as the IC50 value for exocytosis was identical for fibronectin-adhered cells and standard cultured cells. We conclude that oxatomide and its analogs inhibit exocytosis, mainly by inhibiting Ca2+ influx over store-operated Ca2+ (SOC) channels. The drugs have a direct effect on the store-operated Ca2+ channels or affect the direct regulation of these channels.

The priming activity on polymorphonuclear leukocytes (PMLs) of nasal lavage fluid obtained from children with seasonal allergic rhinitis after specific allergic challenge, before and after a 14-day treatment period with orally administered oxatomide 12.5 mg twice daily, was investigated by means of chemiluminescence. Luminol-amplified chemiluminescence of PMLs activated with N-formylmethionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate (PMA) was evaluated in the presence or absence of nasal lavage fluid. A significant increase in the chemiluminescence response of fMLP-stimulated PMLs was induced by nasal lavage fluid. No significant change was observed in PMA-stimulated PMLs. Oxatomide treatment significantly reduced the effect of nasal lavage fluid on PMLs. These data suggest a priming potency on PMLs of nasal lavage fluid obtained from patients with seasonal allergic rhinitis after specific challenge, probably because of the presence of various inflammatory mediators. Oxatomide treatment significantly reduced this priming capacity. This effect may be attributed to the inhibition of cellular recruitment or to the reduction of mediator release at the inflammation site.

The effects of 10 antiallergic drugs (astemizole, azelastine, ebastine, emedastine, epinastine, ketotifen, oxatomide, terfenadine, pemirolast and tranilast) on neuronal dopamine uptake were examined. Some drugs examined showed a concentration-dependent inhibition of [ 3 H]dopamine uptake into synaptosomal preparations of the rat striatum. The inhibition constant (Ki) values were 231–876 nM for ebastine, terfenadine, oxatomide and astemizole. The specific binding of [ 3 H ] (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) (GBR12935) to the rat striatal membranes was also inhibited by these antiallergic drugs. There was a good correlation between the degrees of inhibition of [ 3 H]dopamine uptake and [ 3 H]GBR 12935 binding. Then, the behavioral excitement induced by l -DOPA (100 mg/kg, s.c.) plus pargyline hydrochloride (80 mg/kg, i.p.) in mice was significantly enhanced by i.p. treatment with ebastine (10 mg/kg) and astemizole (5 mg/kg). These results suggest that the neuronal dopamine uptake is inhibited by some antiallergic drugs, especially ebastine.

Our previous study revealed that passive cutaneous anaphylaxis (PCA) can be produced in congenitally mast cell-deficient WBB6F1-W/Wv (abbreviated as W/Wv) mice on sensitization with undiluted or slightly diluted allogeneic and xenogeneic antisera but not on sensitization with allogeneic monoclonal immunoglobulin (Ig)E and IgG1 antibodies regardless of the antibody concentration [1]. In view of these findings, the present study was conducted to characterize PCA in this strain from its drug susceptibilities using mast cell-bearing WBB6F1-(+)/+ (abbreviated as +/+) and B6D2F1 mice as references. PCA in W/Wv mice mediated by a low dilution (1:4) of hyperimmune serum to bovine serum albumin of the B6D2F1 mouse origin was markedly suppressed by CV-6209, an antagonist of platelet-activating factor (PAF), but not by antihistamines such as cyproheptadine and oxatomide. In contrast, PCA in +/+ and B6D2F1 mice mediated by a high dilution (1:128) of the anti-serum (virtually by IgG1 antibody) was nearly completely suppressed by antihistamines but not by CV-6209. A remarkable difference between PCA in W/Wv and reference mice was also observed in the susceptibility to monoclonal anti-mouse granulocyte (Gr-1) antibody: PCA in W/Wv mice was potently suppressed by the 1- to 3-day pretreatment with this antibody but that in references was not at all. Putting these present results together with the previous finding that anti-granulocyte antibody greatly reduces circulatory Gr-1+ leukocytes, 1 to 3 days after the treatment [2], it is highly probable that PCA in W/Wv mice mediated by some antibody isotypes other than IgE and IgG1 is produced by PAF mainly released from Gr-1+ cells, while IgG1 antibody-mediated PCA in mast cell-bearing reference mice is evoked by histamine derived from mast cells. PCA homologous to that in W/Wv mice could also be produced in the reference mice on sensitization with undiluted or slightly diluted antiserum, when generalized blueing due to excess IgG1 antibody was removed by the oxatomide treatment before the antigen challenge.

While it is clear that the clinical expression of IgE-mediated diseases depends upon the actions of multiple mediators, histamine, the earliest recognized mediator of allergy, remains a prominent contributor. Histamine released from mast cells binds to specific receptors (H1, H2, H3) to produce its clinical effects. The cardinal features of asthma include smooth muscle spasm, mucosal edema, inflammation and mucus secretion. It has been demonstrated that two of these features, bronchospasm and mucosal edema, can be caused by H1-receptor stimulation, while H2- and possibly H1-activation are probably minor causes of mucus secretion. Histamine interacts directly with the endothelial cells (EC) and induces permeability, a transient expression of P-selectin and the secretion of lipid mediators (e.g. PGI2, PAF and LTB4). Moreover, histamine induces a significant increase of IL-6 and IL-8 secretion by EC. Since IL-8 exerts a chemotactic activity for neutrophils, eosinophils and basophils, and IL-6 is involved in endothelium permeability, the secretion of cytokines may be involved in the late phase reaction. Some antihistamines (i.e., levocabastine, terfenadine, loratadine, azelastine and oxatomide) can reduce ICAM-1 expression. The participation of histamine in the allergic inflammation, including asthma, must be re-examined, since the effects of histamine are more widespread.

1. 1. The present study was carried out to investigate the effect of 3,5-bis-(acetoxyacetylamino)-4-chloro-benzonitrile (TYB-2285) on the accumulation of eosinophils in the peritoneal cavity of Wistar rats sensitized with Ascaris suum extract (Asc). 2. 2. Rats were sensitized by IP injection of Asc on day 0 and were challenged by IP injection of Asc on day 7. Antigen challenge caused a specific, delayed infiltration of eosinophils into the peritoneal cavity that was inhibited by PO administration of TYB-2285, but not by ketotifen fumarate, in a dose-dependent manner (3–30 mg/kg). 3. 3. TYB-2285 inhibited the infiltration of eosinophils when during the induction phase, but not during the effector phase. The inhibitory effect of TYB-2285 when during the induction phase was stronger than any other antiallergic drugs, such as tranilast, azelastine, ibudilast, repirinast, tazanolast, oxatomide, or pemirolast. 4. 4. Transfer of lymphocytes, but not serum, from sensitized rats to intact rats provoked a remarkable infiltration of eosinophils after the antigen challenge. In the experiment of adoptive transfer in rats, TYB-2285 was effective when given to donor rats. 5. 5. These results demonstrate that TYB-2285 inhibits the accumulation of eosinophils presumably by inhibiting antigen recognition.

The effects of a newly synthesized compound, SWR-00151 (4-[2-[4-(1H-indol-3-yl)-1-piperidinyl)ethyl]-2(1H)-quinolinone), on experimental Type I allergic models were investigated. Results obtained were as follows: The compound (3 approximately 30 mg/kg, p.o.) dose-dependently inhibited 48-hr passive cutaneous anaphylaxis (PCA) in the rat. From the strong antagonism against the histamine-induced contraction of the isolated guinea pig ileum and the lack of suppressive effect on anaphylactic histamine release from rat peritoneal exudate cells, it is deduced that the compound's inhibitory action against PCA is due to antihistaminic action. Both gamma 1-rich serum- and IgE-rich serum-mediated experimental asthmas in the guinea pig were also considerably inhibited by a small dose (1 mg/kg, p.o.) of the compound. The inhibitory mechanism seems to be almost the same as that of the PCA because the compound did not show any effect on the experimental asthma in guinea pigs pretreated with H1- and H2-antihistaminics. In addition to that, it is well known that the model is largely mediated by anaphylactically released histamine. On the other hand, while ketotifen and oxatomide, which possess potent antihistaminic activity, modestly suppressed a rat experimental asthma SWR-00151 still demonstrated a substantial inhibitory activity, strongly suggesting that histamine does not play an important role in this asthma model. Serotonin was revealed to be partly responsible for the early phase of the reaction by the assessment with methysergide, an antiserotonergic, and SWR-00151 as well as oxatomide and ketotifen showed slight antagonism against serotonin in high concentrations (10(-6) and 10(-5) M) in vitro. When thromboxane (TX) B2 in the plasma was measured during the reaction, significant increased levels of the chemical mediator were found, which were obviously prevented by the treatment with SRW-00151. From these results, SWR-00151 is expected to be a drug effective for the treatment of asthma through mechanisms not only of antihistaminic action but also through inhibition of anaphylactic formation/release of other mediators like TXA2.

This study was designed to compare the efficacy and safety of cetirizine and oxatomide in young children who have perennial allergic rhinitis. During this 10-day multicenter, doubleblinded, randomi...

The patients with Japanese Cedar Pollinosis registered in 1993 were divided to either the preventive dosing group or the therapeutic dosing group. Various migrated cells in nasal lavage fluid collected during the season were measured, and the clinical symptoms and onset dates were compared between the two groups. The preventive dosing group started to take Oxatomide more than 4 weeks before the beginning of pollen scattering, whereas the therapeutic dosing group started to take this drug in a similar manner after pollen began to scatter and after symptoms developed. The preventive dosing group showed a significant inhibition of total subjective symptoms early in the season as compared with the therapeutic dosing group. At the same time, the preventive treatment significantly delayed the onset of clinical symptoms. There were no remarkable changes in eosinophils and CD68 positive cells in nasal lavage early in the season in the preventive dosing group, whereas neutrophils and eosinophil cationic protein (ECP) showed a significant decrease. From these result, we conclude that starting to take anti-allergic drugs more than 4 weeks before the beginning of pollen scattering can inhibit clinical symptoms early in the season and also delay the onset of symptoms in a year predicted to have a great quantity of cedar pollen scattering.

Summary Background TMK688 is being developed as ati anti-allergic drug having both 5-lipoxygenasc inhibitory activity atid anti-histaminc activity. Method We compared the inhibition ol the late asthmatic rcsponses by TMK688 with that by other anti-allergic agents in actively sensitized guinea pigs, and examined the relationship between 5-lipoxygetiase inhibition and the late asthmatic responses Results At 1–3.2 mg/kg, TMK688 inhibited the increases in respiratory resistance, leukotriene (LT) B4 and C4 production in the lungs and eosinophil infiltralion into the alveoli during the late asthmatic response, whereas the eliects tended to lessen at the dose of 10mg/kg. These effects are thought to be caused by the 5-lipoxygenase inhibitory activity of TMK688 because Azelastine. an anti-allergic drug having potent antihistamine activity, exhibited no effect. ONO-1078. a peptide LT antagonist. inhibited the late-phase bronchoconstriction at a dose of 100mg/kg p.o., but not the increase in the infiltration of inflammatory cells into the alveoli, suggesting that the late-phase bronchoconstriction is induced, in part, by peptide LTs, i.e. LT C4, D4 and E4 atid that the inflammatory cell infiltration may be caused by LTB4, TMK688 inhibited the immediate bronchoconstriction dose-dependently, and the effect was significant at a dose of 10mg/kg orally. Since Azelastine, Ketotifen and Oxatomide suppressed the bronchoconstriction at far lower doses than did TMK688, the inhibitory effect was mainly caused by its antihistamine activity. Conclusions TMK688 appears to be a novel anti-allergic drug having inhibitory effects on both the bronchoconstriction and the infiltration of inflatnmutory cells during late asthmatic responses.

The objective of this study was to evaluate the influence of oxatomide β-cyclodextrin inclusion complex on the physicochemical properties and bioavailability of the drug. Oxatomide β-cyclodextrin solid complex was prepared with equimolar ratio of both oxatomide and β-cyclodextrin in presence or absence of water soluble polymers using different techniques. The coevaporated complex prepared in presence of PVP-K15 showed a prompt drug release and significantly increased % dissolution efficiency compared to the pure oxatomide. Moreover, the results of bioavailability evaluation of this complex in rabbits compared to commercial drug product indicated a 73.15% increase in the oral bioavailability of oxatomide. In conclusion, inclusion complex of oxatomide with β-cyclodextrin prepared by coevaporation in presence of PVP-K15 not only results in an enhancement of the oxatomide dissolution rate but also improves the bioavailability of oxatomide.

慢性のそう痒性皮膚疾患を対象に常用量のオキサトミド(セルテクト®)を投与し軽快の後, 半量1日1回投与による維持療法の検討をおこなった。回収症例89例中1例を除く88例について解析した。皮膚症状は痒疹群を除く蕁麻疹群, 湿疹·皮膚炎群および皮膚そう痒症群において不変あるいは軽快を示した。疾患群別再燃率は痒疹群で85.7%, 湿疹·皮膚炎群で33.3%, 蕁麻疹群で16.7%, 皮膚そう痒症群で15.3%, 全症例では30.7%であった。有効率は蕁麻疹群が79.2%, 皮膚そう痒症群が76.9%, 湿疹·皮膚炎群が55.6%, 痒疹群が14.3%, 全症例では62.5%であった。副作用としては88例中1例にのみ浮腫と肝機能異常が認められた。有用度は極めて有用が44.3%, 有用が39.8%であった。以上の結果からオキサトミドの1日1回減量維持療法は痒疹群を除く慢性のそう痒性皮膚疾患に対し試みる価値のある方法であると考えられた。

Oxatomide (OXA), a histamine H1 receptor antagonist, is effective in the treatment of patients with allergic rhinitis, some allergic skin disorders, and bronchial asthma. We have characterized the effect of OXA on the immunologic release of preformed (histamine and tryptase) and de novo synthesized mediators (leukotriene C4:LTC4 and prostaglandin D2:PGD2) from human basophils and mast cells purified (from 10 to 82%) from human lung parenchyma (HLMC) and skin tissue (HSMC). Preincubation (15 min, 37 degrees C) of basophils with OXA (10(-7)-10(-5) M) before Der p I antigen or anti-IgE challenge concentration-dependently (10-40%) inhibited the immunologic release of histamine and LTC4. OXA (10(-7)-10(-5) M) also inhibited (10-40%) histamine, tryptase and LTC4 release from HLMC activated by anti-IgE. In addition, OXA caused a concentration-dependent inhibition of histamine, tryptase and PGD2 release from HSMC immunologically challenged with a monoclonal antibody against the alpha chain of the high affinity receptor for IgE (anti-Fc epsilon RI) or anti-IgE. These results demonstrate that OXA exerts anti-inflammatory activities by inhibiting the release of preformed and de novo synthesized mediators from human basophils and mast cells.

The therapeutic effect of oxatomide on experimental otitis media with effusion (OME) induced by secondary immune response was investigated in chinchillas. Oxatomide was administered daily in three different doses (5, 10, 30 mg/kg b.w.t.) for a period of 2 weeks, starting 2 days after the instillation of keyhole limpet hemocyanin (KLH) into the tympanic cavity. The severity of OME was assessed by observing the eardrum under a surgical microscope, by tympanography, and by histological findings. The concentrations of leukotriene C4 and LTD4 in middle ear effusion (MEE) were also measured, 7 days after the KLH instillation. It was found that oral administration of oxatomide in dosages of 10 and 30 mg/kg alleviated the experimental OME. The mean LTD4 concentration measured in MEE from chinchillas given 30 mg oxatomide was significantly lower than that measured in the control group. The radioactivity of 14C-labelled oxatomide in MEE and the autoradiographic findings revealed that orally administered oxatomide was rapidly absorbed from the digestive tract and transported to the middle ear via blood circulation. The findings suggest that the effect of oxatomide can be anticipated in patients with OME.

We studied the effects of antiallergic drugs, epinastine, ketotifen, oxatomide, mequitazine and cromolyn sodium on superoxide anion (O 2 - ) generation from rat neutrophils. Epinastine, ketotifen, oxatomide and mequitazine dose-dependently prevented the N-formyl-Met-Leu-Phe- and phorbol 12-myristate 13-acetate-induced O 2 - generation, but cromolyn sodium did not prevent it. When membrane and cytosol fractions were incubated with each drug, epinastine, ketotifen and mequitazine prevented O 2 - generation. On the other hand, when only the membrane fraction was incubated with each drug, ketotifen and mequitazine prevented O 2 - generation, but epinastine did not. Epinastine may inhibit the NADPH oxidase system through the obstruction of NADPH oxidase-associated cytosol components.

Oxatomide at therapeutic doses generates occasionally drowsiness in children. When administered at toxic doses, however oxatomide may induce long lasting impaired consciousness. We now report a case of severe long lasting impaired consciousness induced by therapeutic doses of oxatomide occurring in a child affected by acute gastroenteritis. The clinical symptoms, the pharmacogenetic tests of polymorphisms in cytochrome P450 metabolizing enzymes (CYPs) and the clinical and laboratory analyses indicate that the enhanced drug sedative effect is likely due to an acute, yet mild, inflammatory state of the patient. These findings highlight the importance of assessing common, not serious inflammatory states when oxatomide is prescribed in paediatric patients.

The effect of topically applied sodium cromoglycate solution in moderate to severe atopic dermatitis (AD) in children aged 4-14 years was studied in a double-blind, placebo-controlled, randomized group-comparative trial. One group of patients was treated with topical sodium cromoglycate solution and oral oxatomide whereas the other group was treated with topical placebo solution and oral oxatomide. After 4 weeks, AD improved significantly in the group treated with the sodium cromoglycate solution and oxatomide combination while marginal improvement was noted in the placebo. In addition, spontaneous IgE production from peripheral blood mononuclear cells decreased significantly in the sodium cromoglycate group but not in the placebo group. These results suggest that sodium cromoglycate solution may be very effective in combination with anti-allergic medication in the treatment of moderate to severe AD in children.

そう痒性皮膚疾患に対するオキサトミドの1日1回(計60mg)投与群と, 1日2回(計60mg)投与群の止痒効果と安全性につき比較検討する目的で封筒法にて調査を行った。解析対象例は511例〔A群(1日2回投与): 275例, B群(1日1回投与): 236例〕で, 成人には60mg/日, 小児には1mg/kg/日の経口投与を行った。そう痒については, 両群とも投与後には有意に減少が認められた。さらに, 投与後のそう痒の重症度はB群の方がA群に比べて有意に軽症化していることが認められた。最終有効性については, 改善以上を示したのはA群で85.8%, B群で89.4%であり, 安全性については, A群93.8%, B群93.6%を示したことより, 両群間には差はなく同等の有用性を示すものと考えられた。副作用はA群で17例(6.2%), B群で15例(6.4%)の発現が認められ, そのうち眠気の訴えが最も多く, A群は16例(5.8%)でB群は12例(5.1%)で差は認められなかった。以上より, そう痒を伴う皮膚疾患に対し, オキサトミドの1日1回投与は1日2回投与と比較して有用な投与方法と考えられた。

慢性皮膚そう痒性疾患である蕁麻疹, 湿疹, 皮膚炎, 皮膚そう痒症の190例を対象とし, オキサトミド1日60mg分2投与を行い, 自覚症状(そう痒)の程度が0(なし)あるいは1(軽度)に寛解した時点で1日1回30mg半量投与による維持療法を行い, その有用性を検討した。維持療法期間における再燃は解析対象例155例中22例にみられ, 再燃率は14.2%であった。疾患別の再燃率は蕁麻疹群—15.0%, 湿疹·皮膚炎群—14.0%, 痒疹群—25.0%, 皮膚そう痒症—14.3%であり, 再燃期間については一定の傾向はみられなかった。副作用は全例においてみられなかった。全症例を含む有用度は85.8%であった。以上のことからそう痒を伴う慢性皮膚疾患における自覚症状(そう痒)寛解時の維持療法としてのオキサトミドの半量投与は治療の過程の上で有用な投与法と考えられた。

In this objective evaluation of the efficacy of prophylactic treatment for Japanese cedar pollinosis during natural allergen exposure, oxatomide (60mg/day, per os) was administered during the spring of 1993. The prophylactic treatment group (n=10) received the medication from Jan. 11. The no treatment group (n=10) did not receive the medication. Total subjective symptom scores, blood eosinophil counts and the level of albumin in nasal secretions were examined and compared in two groups on Mar 12.Three parameters in the prophylactic treatment group were lower than those in the no treatment group. The differences in subjective symptoms and blood eosinophil counts were significant. The effect of prophylactic treatment can be evaluated objectively.

According to the previous concepts of antiallergic drugs, it was difficult to select the essential antiallergic drugs which was necessary for treatment of patients with allergy. We, therefore, attempted to discover that antiallergic drugs have the any pharmacologic actions on the process of allergic response. We divided into three stages on the process of allergic response in this animal experiment. Antiallergic drugs used in this study were azelastine hydrochloride, ketotifen fumarate, tranilast and oxatomide. First, we observed the suppression of IgE production in rats on the administration of azelastine hydrochloride. Secondly, we observed that azelastine hydrochloride and ketotifen fumarate inhibited the interaction between anti-DNP-As and DNP-As on ELISA. Thirdly, we observed that tranilast and azelastine hydrochloride reduced, more effectively than any other antiallergic drug, the release of histamine from rabbit washed platelets by PAF.In addition, it was observed that azelastine hydrochloride and ketotifen inhibited dose-dependently the increase of permeability induced by PAF or histamine in rats. From these results, we could propose the new concepts that some of antiallergic drug inhibited the IgE production.

1. Guinea-pig tracheal contractions by histamine and by the cholinoceptor agonist, arecoline, are significantly enhanced (30% and 20%, respectively), 96 h after intra-tracheal inoculation with Parainfluenza-3 (PI-3) virus. 2. The airway hyperresponsiveness in animals inoculated with virus coincides with a significant increase in the number of broncho-alveolar cells (82%), and in the albumin concentration (121%) in lung lavage fluid, relative to values obtained in guinea-pigs challenged with control solution. 3. The chemiluminescence production by isolated broncho-alveolar cells, obtained from virus-infected guinea-pigs 96 h after inoculation stimulated with PI-3 virus in vitro, is significantly reduced by 42% relative to broncho-alveolar cells obtained from animals inoculated with control solution. This diminution was not specific for stimulation by PI-3 virus since the chemiluminescence production was also significantly reduced by 30% in response to zymosan. 4. Pretreatment of the guinea-pigs with the anti-allergic drugs, oxatomide (2.5 mg kg-1) or nedocromil (2.5 mg kg-1), or the specific H1-histamine receptor antagonist, levocabastine (0.25 mg kg-1), administered intra-peritoneally twice a day for five successive days, inhibits the virus-induced airway hyperresponsiveness, suppresses the influx of broncho-alveolar cells and increase in albumin content, and corrects the reduced chemiluminescence production by broncho-alveolar cells in response to zymosan. 5. In contrast, the cyclo-oxygenase inhibitor, suprofen (5.0 mg kg-1), the 5-HT2 receptor antagonist, ketanserin (0.63 mg kg-1), or the Ca2+ overload blocker, flunarizine (2.5 mg kg-1) do not modify the above mentioned processes. 6. The platelet-activating factor receptor antagonist, WEB 2170 (10 mg kg-1), reduces virus-induced airway hyperresponsiveness and influx of broncho-alveolar cells into the lungs but does not attenuate the increase of albumin in the bronchial lavage fluid. 7. Guinea-pigs nebulized with histamine, twice a day (30 min) during 4 successive days, do not demonstrate an increased airway responsiveness, but instead show tachyphylaxis in response to histamine in vitro. In addition, no influx of inflammatory cells is found in these animals. 8. These results suggest that histamine does not directly increase the responsiveness of the guinea-pig trachea; however, histamine may be involved in a cascade of events leading to airway hyperresponsiveness after a viral infection, a process that could be related to an influx and/or an activation of broncho-alveolar cells after PI-3 virus stimulation.