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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

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.

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 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.

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.

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.

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.

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 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.

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.

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.

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.

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 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.

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.

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.

A series of 6 new N -(pyridin-2-yl)-3-(piperazin-1-yl)propanamides were synthesized from the corresponding N -pyridinylpropenamides to determine potential antiallergic activity as assayed in vivo by the passive cutaneous anaphylaxis test. The IC 50 of compound 12 after oral administration was comparable to that of oxatomide.

A number of N-[4-[4-(1H-indol-3-yl)piperidinoalkyl]-2- thiazolyl]alkanesulfonamides (8--21) were synthesized and evaluated for their preventive effects on systemic anaphylaxis in guinea pigs. Structure-activity analysis revealed that methane- and ethanesulfonamide derivatives having a one to three methylene tether between the piperidine and thiazole rings exhibited potent activity but the introduction of a substituent on the indole part reduced the activity. Administration (100 mg/kg p.o.) of the four compounds 8, 9, 12, 13, together with ketotifen, oxatomide, terfenadine and azelastine as reference compounds, to mice revealed that only compound 8 caused no significant increase of the sleeping time induced by hexobarbital. In addition, compound 8 (10 mg/kg i.v.) did not change the electroencephalogram in conscious rabbits. These results led to the selection of N-[4-[4-(1H-indol-3-yl)piperidinomethyl]-2-thiazolyl]methanesulfon amide (8, FK613) for further development as a novel antiallergic agent. Clinical evaluation of FK613 is now in progress.

The molecular complexes of the donors ketaconazole (KTZ) and oxatomide (OXA) drugs with 2,3,5,6-tetrachloro-1,4-benzoquinone (p-chloranil, p-CHL) have been investigated spectroscopically (UV–vis, FT-IR and 1H NMR) and spectrofluorimetrically in different solvents and temperatures. The stoichiometry of the complexes was found to be 1:1. The data are discussed in terms of formation constant, molar extinction coefficient, oscillator strength, dipole moment, ionization potential, dissociation energy and thermodynamic parameters. The results indicated that the formation of molecular complex is spontaneous and endothermic. The fluorescence quenching studies indicated that the interaction of the donors is spontaneous and the fluorescence quenching increased with an increase in the intensity of complexation with the acceptor.

The crystal structure of the monohydrate of oxatomide, 1-{ 3- [4-(diphenylmethyl)- 1-piperazinyl]propyl }- 1,3-dihydro-2H-benzimidazol-2-one, has been determined at 100 K. The oxatomide molecule adopts an extended conformation with a planar benzimidazolone fragment. The water molecule has a cohesive function, connecting three oxatomide molecules by intermolecular hydrogen bonds.

A number of N-[4-[4-(1H-indol-3-yl)piperidinoalkyl]-2-thiazolyl]alkanesulfonamides (8-21) were synthesized and evaluated for their preventive effects on systemic anaphylaxis in guinea pigs. Structure-activity analysis revealed that methane- and ethanesulfonamide derivatives having a one to three methylene tether between the piperidine and thiazole rings exhibited potent activity but the introduction of a substituent on the indole part reduced the activity. Administration (100mg/kg p.o.) of the four compounds 8, 9, 12, 13, together with ketotifen, oxatomide, terfenadine and azelastine as reference compounds, to mice revealed that only compound 8 caused no significant increase of the sleeping time induced by hexobarbital. In addition, compound 8 (10mg/kg i.v.) did not change the electroencephalogram in conscious rabbits. These results led to the selection of N-[4-[4-(1H-indol-3-yl)piperidinomethyl]-2-thiazolyl]methanesulfonamide (8, FK613) for further development as a novel antiallergic agent. Clinical evaluation of FK613 is now in progress.

A series of 6 new N -(pyridin-2-yl)-3-(piperazin-1-yl)propanamides were synthesized from the corresponding N -pyridinylpropenamides to determine potential antiallergic activity as assayed in vivo by the passive cutaneous anaphylaxis test. The IC 50 of compound 12 after oral administration was comparable to that of oxatomide.

A new series of piperidineacrylate derivatives was prepared and evaluated for antiallergic activity. Most of the compounds showed potent activities in the rat passive cutaneous anaphylaxis (PCA) assay. In particular, ethyl 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidimeacrylate (1a) was more potent than oxatomide and terfenadine in this assay, and was selected for further study. Some pharmacological properties of 1a are presented.

At 1-week intervals, 12 healthy volunteers received oral cetirizine 10mg, oxatomide 30mg, ketotifen 1mg or placebo under randomised double-blind crossover conditions. Wheal and flare were induced by skin prick tests using histamine 100 and 500 g/L before, and 4, 8 and 24 hours after, drug ingestion. At each session volunteers recorded levels of pruritus and sedation on two 10cm visual analogue scales. Cetirizine was significantly more potent than oxatomide (p = 0.0001), ketotifen (p = 0.0002) or placebo (p = 0.0001) in the inhibition of wheals, with similar results for flare (p = 0.0007, 0.0001 and 0.0002, respectively). Relief from pruritus was significantly better with cetirizine than with oxatomide (p = 0.003) or ketotifen (p = 0.002). Cetirizine was slightly better than placebo in relieving pruritus, but this was not statistically significant. Oxatomide and ketotifen were clearly more sedative than cetirizine (p = 0.05 and p = 0.0006, respectively), which was not significantly different from placebo. In conclusion, cetirizine appeared to be better in reducing histamine-induced wheal, flare and pruritus compared with ketotifen and oxatomide, and had less sedative effect.

Inhibitory effects of various histamine receptor-blocking agents including antiallergic agents on metabolic activations of neutrophils were examined by measuring leukotrienes (C4, D4 and E4) formation, arachidonic acid release and superoxide generation. The stimulation of neutrophils by calcium ionophore (A23187) causes the production of leukotrienes concomitantly with the release of arachidonic acid from the cells and these were effectively diminished with a variety of antihistaminic agents. Almost all the histamine H1 receptor-blocking drugs studied here showed as inhibitors of the metabolic activations of neutrophils, although the degree was dependent on the drug concentrations. The order of potency of the inhibitory effects on the arachidonic acid release were: homochlorcyclizine, clemastine, and azelastine (IC50 less than 20 microM) greater than oxatomide (IC50 less than 60 microM) and diphenylpyraline greater than triprolidine, meclizine, diphenhydramine (IC50 greater than 100 microM). The superoxide generation from neutrophils activated by phorbol 12-myristate 13-acetate was also effectively inhibited by these agents, but generally lower concentrations were required to obtain the same degrees of effects. These results indicated that some of the histamine H1 receptor-blocking drugs, such as clemastine and homochlorcyclizine, may act as inhibitors of formation of leukotrienes at the locus of inflammation.

A simple method for preparing mouse eosinophils was established, and the characteristics of the eosinophils were assessed including their responses to anti-allergic drugs.Mouse eosinophils were prepared from peritoneal exudate cells of BALB/c mice primed and boosted with antigen ovalbumin (OVA).Surface phenotypes, migration activities and leukotriene C(4) (LTC(4)) production abilities of these eosinophils were examined. In addition, the effects of anti-allergic drugs, oxatomide and tranilast, on generation of LTC(4) from mouse eosinophils were examined.Eosinophils of mice boosted with OVA were phenotypically and functionally identical with human eosinophils. Around 1 x 10(7) eosinophils were obtained from mouse peritoneal exudate. It was found that these mouse eosinophils enabled to migrate in response to eotaxin as well as platelet-activating factor (PAF), and generated LTC(4) by IL-5 stimulation. Moreover, it was revealed that clinically used anti-allergic drugs inhibited LTC(4)-production dose-dependently.The present study provides a convenient method to obtain fully functional mouse eosinophils that are useful for drug screening and for evaluating implications of eosinophils in allergic responses.

A 32-year-old epileptic patient with a lengthy history of multiple-drug abuse and psychotic disorders was found to have an elevated serum carbamazepine concentration of 40.5 mg/L (therapeutic range 4-12 mg/L) using particle-enhanced turbidimetric inhibition immunoassay (PETINIA). Serum reanalysis by LC-DAD revealed only high hydroxyzine (HDZ) concentration (HDZ = 0.55 mg/L; therapeutic range

We report a 4-month-old female infant who developed West syndrome eleven days after administration of a histamine H1 antagonist, oxatomide, for atopic dermatitis. It has been reported that some histamine H1 antagonists induce seizures in epileptic patients. The age, the interval between oxatomide administration, and the onset of West syndrome and its clinical course were similar to two previously reported 3-month-old infants with West syndrome associated with ketotifen administration. We should be cautious in using the histamine H1 antagonists, oxatomide and ketotifen, in young infants because such agents could potentially disturb the anticonvulsive central histaminergic system.

The single peroral administration of the ethyl acetate extract or essential oil of German chamomile (Matricaria recutita L.) showed remarkable antipruritic effects in the compound 48/80-induced itch-scratching test in ddY mice, if suitable vehicle was used. The ethyl acetate extract or essential oil of German chamomile dissolved in the vehicle of 10% ethanol, 10% Tween 80 and 80% physiological saline was orally administrated 2 h before pruritus provocation by compound 48/80 subcutaneous injection. The ethyl acetate extract or essential oil of German chamomile showed significant dose-dependent inhibition of the compound 48/80-induced scratching without affecting spontaneous motor activity. The antipruritic effects of antihistamine H1 antagonists, oxatomide (10 mg/kg) and fexofenadine (10 mg/kg), were only partial in this test. However, the antipruritic effects of these agents were remarkably enhanced by the combined administration of the ethyl acetate extract of German chamomile (300 mg/kg). Thus, the co-medication with the ethyl acetate extract, or essential oil of German chamomile and antihistamines might be effective for the pruritus which could not be perfectly resolved alone by conventional antihistamines.

Oxatomide is an antiallergic drug used for the treatment of diseases mediated by type I allergy. Recently, terfenadine and astemizole, which have antiallergic actions similar to those of oxatomide, showed side effects on the cardiovascular system. This might be because concomitant drugs such as itraconazole inhibit cytochrome P450 3A4 (CYP3A4), the enzyme responsible for the degradation of terfenadine and astemizole, and thus the blood concentrations of the drugs are abnormally increased. In another article of this issue, we have reported that oxatomide is metabolized by CYP2D6-Val and CYP3A4, and simultaneously inhibits the metabolism of the model substrates for these enzymes. In this study, we performed the kinetic analysis of oxatomide metabolism using microsomes prepared from human liver, and found that the Km and Vmax values were 26.1 microM and 1254.4 pmol/mg protein/min, respectively. Ketoconazole, one of the representative inhibitors for CYP3A4, potently inhibited the metabolism of oxatomide, but other well-known CYP inhibitors did not show significant inhibition. These results suggest that the metabolism of oxatomide is principally catalyzed by CYP3A4. Furthermore, oxatomide inhibited the metabolism of (+/-) bufuralol and testosterone, model substrates for CYP2D6 and CYP3A4, respectively, in a dose-dependent manner with the Ki values of 57.4 and 24.3 microM, respectively. These observations, together with the finding that the putative highest concentration of oxatomide in blood was congruent with 40 ng/ml ( congruent with 93 nM) at 4 h after each dosage during consecutive 6-d administration, encouraged us to conclude that oxatomide won't inhibit CYP2D6 or CYP3A4 at clinical doses.

Oxatomide (CAS 60607-34-3) is an antiallergic agent effective against allergic rhinitis, urticaria, pruritus dermatitis, eczema dermatitis and bronchial asthma. The aim of this study was to establish the method for simultaneously determining oxatomide and its major metabolite M-11 in human serum, human plasma and rat plasma by high-performance liquid chromatography (HPLC). The method was applied to study the influences of alimentation on pharmacokinetics of oxatomide in rats. After extracting oxatomide and its metabolite M-11 from human serum, human plasma or rat plasma with diethyl ether under alkaline condition, sulfuric acid was added to the organic layer and oxatomide and M-11 were back-extracted. The aqueous layers were analysed by HPLC equipped with a fluorimetric detector. The method was highly sensitive and precise for quantitation of oxatomide and M-11 in human serum, human plasma and rat plasma in the concentration range of 1 to 125 ng/ml. Plasma concentration of oxatomide decreased biphasically with an elimination half-life (T1/2) of 1.59 h after intravenous administration of oxatomide (1 mg/kg) to non-fasting male rats. After oral administration of oxatomide (30 mg/kg) to fasting male rats, plasma concentration of oxatomide increased rapidly, and reached the maximum concentration of 188 ng/ml (Cmax) at 1.0 h. Plasma concentration of oxatomide decreased monophasically. The T1/2 was 2.58 h. The bioavailability was 6.74%. Plasma concentration of M-11 increased rapidly, and reached Cmax of 64.3 ng/ml at 0.7 h, and decreased monophasically with T1/2 of 3.79 h. After oral administration of oxatomide to non-fasting male rats, plasma concentration of oxatomide reached Cmax of 378 ng/ml at 3.3 h. The T1/2 was 3.27 h and the bioavailability was 17.5%. The Cmax and AUC0-infinity of M-11 were larger than those after oral administration of oxatomide to fasting male rats. These results demonstrated the usefulness of this method for monitoring and basic examination of biological samples and the influence of alimentation on absorption of oxatomide. Determination of plasma oxatomide concentrations would provide a useful indication of therapeutic efficacy.

We previously reported that the histamine H1 receptor antagonist terfenadine enhances the excitotoxic response to N-methyl-D-aspartate (NMDA) receptor agonists in cerebellar neurons. Here we investigated whether this unexpected action of terfenadine relates to its antihistamine activity, and which specific events in the signal cascade coupled to NMDA receptors are affected by terfenadine. Low concentrations of NMDA (100 microM) or glutamate (15 microM) that were only slightly (

The effects of Fujibitol, a preparation of crude drugs in wide clinical use for treatment of chronic rhinitis and empyema, on experimental allergic rhinitis in rats were studied. Fujibitol inhibited nasal allergic symptoms, i.e. sneezing and nasal rubbing, induced by antigen in sensitized animals. An increase in dye leakage into the nasal cavity induced by antigen was also inhibited by Fujibitol. On the other hand, no inhibitory effects were observed on either the nasal allergic symptoms or increase in dye leakage into the nasal cavity induced by histamine. However, Fujibitol was effective in inhibiting histamine release from the nasal cavity induced by antigen. Oxatomide used as positive control drug showed potent inhibitory effects on nasal symptoms and dye leakage into the nasal cavity induced by histamine and antigen. These results suggested that Fujibitol showed a remarkable protective effect against experimental rhinitis induced by antigen via inhibition of histamine release from the nasal cavity.

For the immunopharmacological characterization of murine passive anaphylactic shock, the effects of antihistaminics and/or anti-platelet-activating factor (anti-PAF) agents were studied on the shock mediated by allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum. IgE antibody-mediated shock was strongly suppressed by cyproheptadine (10 mg/kg, ip) in every strain regardless of the age and sex of the mice and the presence or absence of a shock potentiator. As far as tested with CTS, DS, and B6D2F1 mice, IgE antibody-mediated shock was also suppressed by the other two antihistamines, triprolidine (10 mg/kg, ip) and oxatomide (100 mg/kg, po). This type of shock was not suppressed by an anti-PAF agent, CV-6209 (3.3 mg/kg, iv), when tested on aged CTS mice given no shock potentiator and young DS mice given a potentiator such as Bordetella pertussis organisms or DL-propranolol. IgG1 antibody-mediated shock was also suppressed by cyproheptadine in general except for CTS mice. Suppression in the DL-propranolol-treated DS and C3H/He mice was not very marked on sensitization with undiluted or slightly diluted IgG1 ascites but quite striking on sensitization with properly diluted ascites. In contrast with the effect of cyproheptadine, suppression by CV-6209 was obvious in aged CTS mice but not in young DL-propranolol-treated DS mice. The shock in DL-propranolol-treated DS mice sensitized with undiluted or slightly diluted ascites was completely abolished by the combined use of these two agents. These results suggest that histamine and/or PAF play a major role in IgE antibody- and IgG1 antibody-mediated shock. However, so far as tested in young DS mice, the shock mediated by hyperimmune serum differed in drug susceptibility from that mediated by the monoclonal antibodies. In the absence of shock potentiators, prevention was produced by cyproheptadine in the males which had been sensitized with the 1:4 or 1:8 dilution of the immune serum. In the presence of DL-propranolol, prevention was not produced even by the combined treatment with cyproheptadine and CV-6209. Therefore, it is likely that some mediators other than histamine and PAF, whose release is triggered by antibody isotypes other than IgE and IgG1, play a greater role for the shock mediated by hyperimmune serum than for the shock mediated by IgE or IgG1 antibody, especially in the presence of shock potentiators.

The effects of 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL-79), a newly developed antiallergic drug, on various chemical mediators and on chemical mediator release were investigated. Orally administered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B4, LTC4, histamine and prostaglandin (PG) D2 from the chopped lung tissues of actively sensitized guinea pigs. On the other hand, release of PGE2, one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chronic administration of HQL-79 clearly reduced PGD2 contents and enhanced PGE2 contents in the lungs of repeatedly antigen-exposed guinea pigs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such as epinastine, terfenadine, oxatomide and cetirizine inhibited the PGD synthase. HQL-79 did not affect PGE synthase in sheep vesicular gland microsomes. These results suggest that antiallergic and antiasthmatic effects of HQL-79 could be ascribed to antihistaminic- and anti-5-HT effects, chemical mediator release inhibition, PGE2-release enhancement and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD2 and PGE2 production is a conspicuous pharmacological feature of HQL-79.

Effects of 11 histamine H 1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined. The immediate phase reaction (IPR) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines' examined. The inhibition of IPR by cetirizine and mequitazine were potent, but those by cyproheptadine and diphenhydramine were weak. The later phase reaction (LPR) assessed at 24 hours after antigen application was inhibited by chlorphemramine, oxatomide, ketotifen, mequitazine, emedastine, terfenadine and azelastine. The inhibition of LPR by emedastine was potent, but those by ketotifen and terfenadine were only partial. Emedastine inhibited both IPR and LPR comparably. Present results indicate that H 1 receptor activation is involved in the IPR of the biphasic cutaneous reaction, and that the blockade of H 1 receptors at IPR does not contribute to the attenuation of following LPR. Histamine H 1 receptor antagonists inhibiting the LPR have a property distinct from H 1 receptor antagonism, which may have an additional benefit for the treatment of allergic diseases.

The effects of histamine H 1 receptor antagonists on compound 48/80-induced scratching behavior were studied in mice. Classical histamine H 1 receptor antagonists such as diphenhydramine and chlorpheniramine caused a potent depressant effect on compound 48/80-induced scratching behavior. Histamine H 1 receptor antagonists having antiallergic activity (an inhibition of mast cell degranulation), such as azelastine and oxatomide and nonsedative histamine H 1 receptor antagonists such as terfenadine, epinastine and astemizole, also showed a relatively potent effect. On the other hand, the effects of tranilast and cromolyn sodium—antiallergic drugs without histamine H 1 receptor antagonistic activity—were extremely weak. Diazepam had weak or no depressant effects on compound 48/80-induced scratching behavior. These results suggest that inhibition of compound 48/80-induced scratching behavior is mainly due to histamine H 1 receptor antagonistic activity and not to the sedative action of the drugs.

To clarify the effects of anti-allergic drugs on substance P (SP) and vasoactive intestinal peptide (VIP) levels in nasal secretions, we employed competitive enzyme-linked immunoassays to measure concentrations of those neuropeptides in nasal secretions from 40 patients with house dust nasal allergy before and after administration of azelastine and oxatomide. One mg of azelastine and 30 mg of oxatomide were administrated twice a day for 4 weeks. Mean values of SP concentrations and ratios of SP to total protein of the nasal allergy group were significantly higher than those of the control group (p < 0.002). The VIP/total protein ratio of the allergy group was also significantly higher than that of the control group, although the VIP concentration alone was not. Mean levels of SP and VIP from patients with severe symptoms were significantly higher than those of the control group (p < 0.05), although those values were not significantly different between patients with moderate symptoms and control subjects. Azelastine and oxatomide effectively reduced SP levels in nasal secretions (p < 0.005), but they did not significantly decrease VIP levels. The reduction of SP levels was significant in patients with excellent responses to those drugs (p < 0.005), but not in patients with poor responses. These findings suggest that SP and VIP levels in nasal secretions may reflect the clinical state of nasal allergy and be one of the better parameters available for evaluating the clinical efficacy of anti-allergic drugs against nasal allergy.

In a mast cell model, oxatomide displays inhibition of mediator release which is not related to its histamine H1 receptor antagonistic activity. From a previous study it appeared that especially early steps in the signal transduction leading to exocytosis were influenced by oxatomide. We now studied effects of oxatomide on those early steps in more detail. The antigen- and thapsigargin-mediated exocytosis in rat basophilic leukemia (RBL-2H3) cells were both inhibited by oxatomide. After aggregation of high affinity receptors for immunoglobulin E (Fc epsilon RI), protein tyrosine phosphorylation is induced. Oxatomide caused remarkable changes in the tyrosine phosphorylation pattern in resting cells. Also after antigen and thapsigargin activation, changes in the tyrosine phosphorylation of cellular proteins are observed. In addition, Ca2+ fluxes were studied by means of the net influx of 45Ca2+ and by measuring intracellular free Ca2+ concentrations ([Ca2+]) with the fluorescent probe fura-2. Oxatomide inhibited the 45Ca2+ influx and the increase in [Ca2+]i upon antigen and thapsigargin activation of the cells. Neither the release of Ca2+ from internal stores nor the efflux of Ca2+ over the plasma membrane seems to be affected. The effect of oxatomide on Ca2+ influx was further characterized by studying Ba2+ influx in the absence of extracellular free Ca2+. We conclude that inhibition of mediator release is mainly caused by inhibition of influx of extracellular Ca2+, via plasma membrane Ca2+ channels that are activated by depletion of intracellular Ca2+ stores. The molecular mechanism with which oxatomide might interfere with these channels is discussed.