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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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

The inhibitory effects of some newly developed H1-blockers on the step-through active avoidance response in rats were studied in comparison with those of classical H1-blockers. Single administration of diphenhydramine, pyrilamine, promethazine and chlorpheniramine caused dose-related depressant effects on the active avoidance response. Ketotifen and azelastine caused less potent inhibition than the classical H1-blockers, while the effects of astemizole and oxatomide were almost negligible in suppressing the response. Following chronic administration of pyrilamine and promethazine, the acquisition of active avoidance response was significantly retarded compared with the control group, where-as new H1-blockers caused a somewhat but not significantly slower acquisition than the control group. Chronic administration of astemizole and oxatomide caused only transient suppression of the response. However, classical H1-blockers such as pyrilamine and promethazine caused sustained inhibition for as long as drug administration was continued.

共同研究により, そう痒性皮膚疾患に対するオキサトミド(セルテクト)の臨床的有用性を検討する目的で, 本剤の単独治療と抗ヒスタミン剤の併用治療の比較試験を封筒法により行つた。その結果セルテクトの単独治療および併用治療ともに早期より効果が発現し, 両群ともに各観察日での全般改善度で70∼80%の改善度(改善以上)が得られた。また, 止そう効果についても両群ともに満足な効果が得られたが, そう痒の程度の強い症例については併用治療が単独治療に比し早期(1週後)の改善度で有意に優れた結果が得られ, この様な症例に対しては併用治療の有用性が示唆された。安全性についても特に問題はなかつた。したがつてそう痒性皮膚疾患に対するセルテクトを基本にした治療法は臨床的に有用であると考えられた。

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 is an antiallergic drug used for the treatment of diseases mediated by type I allergy. Recently, it has been reported that terfenadine and astemizole, which have antiallergic actions similar to those of oxatomide, show side effects on the cardiovascular system, such as QT prolongation, ventricular arrhythmia and cardiac arrest. This might be because concomitant drugs such as itraconazole inhibit cytochrome P450 3A4 (CYP3A4), the enzyme responsible for degradation of terfenadine and astemizole, and thus the blood concentrations of the drugs are abnormally increased. On the other hand, isoforms of P450 involved in the metabolism of oxatomide have not been clarified. Therefore, we attempted to identify these isoforms using microsome preparations of in vitro expression systems derived from a human lymphoblastoid cell line. Oxatomide was metabolized by CYP2D6-Val and CYP3A4, but not by CYP1A2, CYP2C9-Arg, CYP2C9-Cys or CYP2C19. We also examined whether oxatomide showed inhibitory effects on metabolic activity of individual P450 isozymes using model substrates for each isozyme. Oxatomide did not inhibit the metabolism of the model substrates for CYP1A2, CYP2C9-Arg, CYP2C9-Cys and CYP2C19, but inhibited the degradation of those for CYP2D6-Val and CYP3A4. It was found that oxatomide is metabolized by CYP2D6 and CYP3A4 in human liver microsomes, and simultaneously acts as an inhibitor for these isoforms, responsible for the metabolism of the drug itself.

Oxatomide (CAS 60607-34-3, KW-4354) is an effective antiallergic agent for allergic rhinitis, urticaria, pruritus cutaneous, and eczema/dermatitis, etc. Terfenadine (CAS 50679-08-8) and astemizole (CAS 68844-77-9), antiallergic agents, have been reported to induce QT prolongation leading to serious ventricular arrhythmia (torsades de pointes) as cardiovascular adverse effects. The present study was carried out to determine whether oxatomide and terfenadine have effects on QT interval as a single drug or in combination with itraconazole (CAS 84625-61-6), an antifungal agent with a CYP3A4 inhibitory effect, in conscious dogs. Terfenadine alone induced QT prolongation at the dose of 30 mglkg p.o. When itraconazole was administered at the dose of 100 mg/ kg p.o. I h before terfenadine administration, terfenadine induced QT prolongation at the dose of 10 mglkg p.o. On the other hand, oxatomide did not induce QT prolongation either as a single agent at the dose of 30 mglkg p.o. or In combination with itraconazole at the dose of 10 mglkg p.o. The results present no evidence that oxatomide has the potential to provoke ventricular arrhythmia.

We studied the effect of oxatomide, an antiallergic drug, on the resistance of K562 cells to doxorubicin. Oxatomide synergistically potentiated the cytotoxicity of doxorubicin in doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 1-10 microM, but had hardly any synergistic effect on the parental cell line (K562) at the same concentration. Oxatomide inhibit P-glycoprotein pump-efflux activity and the binding of [3H]-azidopine to the cell-surface protein P-glycoprotein, in a dose-related manner. These results indicate that oxatomide reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

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.

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.

Interleukin-2 responsiveness of lymphocytes induced by Dermatophagoides farinae antigen was suppressed upon exposure to 20 to 2000 ng/ml of oxatomide for 24 h in a dose-related manner in children with mite-sensitive bronchial asthma. Suppression was greater in the plastic-adherent antigen-presenting cells than in the T-cells. Oxatomide suppressed the production of interleukin-1alpha induced by Dermatophagoides farinae antigen in plastic-adherent cells. These results indicate that the target cells of oxatomide are antigen-presenting cells and not T-cells. Oxatomide also suppressed interleukin-2 responsiveness in lymphocytes exposed to purified protein derivative, but not in those exposed to concanavalin A. Unlike its effect on cell proliferation, oxatomide potentiated the Dermatophagoides farinae-induced production of interferon-gamma, which was suppressed by stimulation with Dermatophagoides farinae antigen in lymphocytes from the patients. In contrast, production of interferon-gamma induced by concanavalin A was not affected by this drug. These results indicate that oxatomide suppresses interleukin-2 responsiveness of allergen-activated helper T-cells and increases the production of interferon-gamma induced by Dermatophagoides farinae antigen, without causing cell proliferation.

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.

Background Azelastine, oxatomide, and ketotifen are used for patients with allergic diseases. These drugs inhibit the release of chemical mediators including the Leukocyteendothelial; however, the mechanism involved is unclear. Objective To clarify the mechanism of inhibition, we investigated the effects of three drugs on the function of phospholipase A 2 , 5-lipoxygenase, leukotriene C 4 synthase, and leukotriene A 4 hydrolase, which are all catabolic enzymes involved in synthesizing leukotriene C 4 and leukotriene B 4 in rat basophilic leukemia (RBL)-1 cells. Methods and results The production of leukotriene C 4 and leukotriene B 4 was measured by high performance liquid chromatography (HPLC). All three drugs inhibited the production of leukotriene C 4 and leukotriene B 4 when cells were stimulated with A23187. All three drugs also inhibited the A23187-stimulated release of 3 Harachidonic acid from membrane phospholipids. Azelastine inhibited the production of leukotriene C 4 , but not leukotriene B 4 , when either arachidonic acid or leukotriene A 4 free acid was used as the substrate in our cell free system. Oxatomide and ketotifen did not inhibit the synthesis of either leukotriene C 4 or leukotriene B 4 in the same cell free study. Conclusion Results indicated that oxatomide and ketotifen inhibit the production of leukotriene C 4 and leukotriene B 4 by inhibiting phospholipase A 2 activity, whereas, azelastine inhibits the leukotriene C 4 production by inhibiting phospholipase A 2 and leukotriene C 4 synthase.

In a model for mucosal mast cells (RBL-2H3 cells) a set H1-antagonist derived anti-allergic drugs containing a diphenylmethyl piperazinyl moiety was examined for their ability to inhibit release of the mediator beta-hexosaminidase. Cells were activated with antigen or the calcium ionophore A23187, whether or not in combination with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Oxatomide, hydroxyzine and cetirizine inhibit the antigen induced beta-hexosaminidase release. The release triggered by A23187, whether or not in combination with TPA is hardly influenced by the compounds. A biphasic dependence of the inhibition of exocytosis in RBL cells on lipophilicity is observed with the optimum at log P is 5-6. The extremely lipophilic compounds meclozine and buclizine are not active in this model. pH dependence of the effect of the drugs shows that especially the uncharged species are active in inhibiting exocytosis. The investigated compounds show an effect on phase transitions in L-alpha-phosphatidylcholine dipalmitoyl liposomes as assayed with differential scanning calorimetry (DSC). For the less extremely lipophilic compounds the induced changes in the phospholipid membranes increased with lipophilicity. The relation between structural features of the drug and the interaction with phospholipids is discussed in view of the DSC results. We conclude that location of the active drugs at the membrane or the membrane/protein interface is important for the inhibiting activity on exocytosis. This could affect several membrane related processes, which are abundant in the early phases of the IgE-mediated signal transduction process.

The influence of anti-allergic drugs on lymphocyte function was investigated by examining the blastic activity and cytokine production of human peripheral blood leukocytes in response to concanavalin A stimulation in vitro. Addition of ketotifen, disodium cromoglycate and oxatomide did not influence peripheral blood leukocyte blastic activity even when high concentrations (10.0 micrograms/ml) of these drugs were added to cell cultures. However, azelastine and terfenadine caused inhibition of peripheral blood leukocyte activation. Interleukin-2, interleukin-3, interleukin-4 and interleukin-5 production from peripheral blood leukocytes was strongly suppressed when the cells were cultured in the presence of these agents. This suppression was observed even when lower concentrations (1.0 and 0.5 micrograms/ml) of these agents were added to the cultures.

The present study was performed to investigate the putative suppressive effects of H1-receptor antagonists (HRA) of the second generation (astemizole (AS), cetirizine (CT), loratadine (LO), oxatomide (OX) and terfenadine (TF)) on the mediator release from human basophils activated by two classical stimuli. Anti-IgE-mediated histamine release was inhibited in a dose-dependent fashion by TF (maximum inhibitory value: 33.8 +/- 7.6%, 100 microM, n = 7), whereas the other HRA exhibited weaker activity. The anti-IgE-induced LTC4 production was strongly suppressed by TF, LO and OX (92.4 +/- 6.3%, 90.8 +/- 6.0% and 88.5 +/- 5.6%, 100 microM, n = 4-5), while AS was less active (56.4 +/- 4.1%, 100 microM, n = 5). Histamine release induced by incubation with grass pollen antigen (0.01%) was inhibited by TF (40.7 +/- 4.1%, 50 microM, n = 4), but the other HRA showed only low activity. The present findings suggest that some HRA might exhibit direct inhibitory effects on activation of IgE-receptor bearing cells.

This study was designed to analyse prostaglandins (PGs) in human nasal lavage fluid using the combination of microcolumn high performance liquid chromatography and a He/Cd laser induced fluorescence detection system. Forty-seven patients with allergic rhinitis and 12 healthy volunteers were investigated. Four species of PG, i.e. PGD2, PGE2, PGF2 alpha, and 6-keto-PGF1 alpha were detected in the nasal lavage fluid. Concentrations of PGD2 (1.33 +/- 0.17 nmol/ml) and PGE2 (0.87 +/- 0.11 nmol/ml) in nasal lavage fluid from patients with allergic rhinitis (the allergy group) were significantly increased compared with those of volunteers (the control group, 0.23 +/- 0.16 nmol/ml, 0.29 +/- 0.19 nmol/ml, respectively). On the other hand, no significant differences were observed in concentrations of either PGF2 alpha or 6-keto-PGF1 alpha between the control group and the allergy group. Histamine concentration in nasal lavage fluid was significantly increased in the allergy group (53 +/- 7.6 nmol/l) compared with the control group (3.4 +/- 1.0 nmol/l). No significant correlation was observed between PGD2 and histamine concentration (r = 0.24), or between PGE2 and histamine concentration (r = 0.08) in nasal lavage fluid from patients with allergic rhinitis. Treatment with oxatomide, an anti-histamine and anti-allergic drug, significantly improved symptom scores, but did not alleviate them completely. Concentrations of each PG detected in nasal lavage fluid did not change significantly after oxatomide treatment. It is concluded that, not only histamine but also PGs, particularly PGD2 and PGE2, might be involved in the genesis of allergic rhinitis.