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Background Objectives Methods Results Conclusion Oxatomide, an antihistamine drug of the diphenylmethylpiperazine family, has anti‐inflammatory effects in airway disease. Because oxatomide was shown to cause diverse physiological responses in several cell models, the impact of oxatomide on Ca2+ signaling and its related physiological effects has not been explored in IMR‐90 human fetal lung fibroblasts.This study assessed the effect of oxatomide on cell viability and intracellular free Ca2+ concentrations ([Ca2+]i) and examined whether oxatomide‐induced cytotoxicity through Ca2+ signaling in IMR‐90 cells.Cell viability was measured by the cell proliferation reagent (WST‐1). [Ca2+]i was measured by the Ca2+‐sensitive fluorescent dye fura‐2.Oxatomide (10–40 μM) concentration dependently reduced cell viability and induced [Ca2+]i rises in IMR‐90 cells. This cytotoxic effect was reversed by chelation of cytosolic Ca2+ with BAPTA‐AM. In terms of Ca2+ signaling, oxatomide‐caused Ca2+ entry was inhibited by modulators of store‐operated Ca2+ channels (2‐APB and SKF96365) and protein kinase C (PKC) inhibitor (GF109203X). Furthermore, oxatomide‐induced Ca2+ influx was confirmed by Mn2+‐induced quench of fura‐2 fluorescence. In a Ca2+‐free medium, preincubation with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin inhibited oxatomide‐evoked [Ca2+]i rises. Conversely, treatment with oxatomide abolished thapsigargin‐induced [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 also inhibited oxatomide‐caused [Ca2+]i rises.In IMR‐90 cells, oxatomide‐induced cytotoxicity by preceding [Ca2+]i rises involving PKC‐sensitive store‐operated Ca2+ entry and PLC‐dependent Ca2+ release from the endoplasmic reticulum. BAPTA‐AM, with its Ca2+ chelating effects, may be a potential compound for preventing oxatomide‐induced cytotoxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] Various oxatomide derivatives were designed and synthesized to develop novel P2X 7 receptor (P2X 7 R) antagonists. Evaluation for in-vitro P2X 7 R antagonist assay showed that DPM-piperazine moiety of oxatomide was required to maintain an inhibitory activity. The structure of both alkyl chains and aromatic head groups strongly affected P2X 7 R inhibitory activity, and the analogue, with C4-type saturated alkyl chain and a non-substituted or fluorine-substituted indole, was 7.3 to 6.4 times more potent as a P2X 7 R antagonist than oxatomide. [ABSTRACT FROM AUTHOR]

Background: Plasma membrane fluidity of polymorphonuclear leukocytes (PMN) was investigated in 10 allergic asthmatic children before and after oxato-mide treatment. Methods: Membrane fluidity was studied by measuring the steady state fluorescence anisotropy of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) incorporated into polymorphonuclear leukocyte (PMN) plasma membranes. Results: There was an increase in membrane fluidity at the surface of PMN from asthmatic children. Oxatomide treatment significantly decreased PMN membrane fluidity. Conclusions: These data suggest that oxatomide may induce changes in the physicochemical properties of the PMN plasma membrane in asthmatic subjects. These changes may modify the functional activities of PMN.

Activation of the P2X7 receptor by extracellular ATP is associated with various immune responses including allergic inflammation. Anti-allergic agents, such as H 1 -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 P2Y 2 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. [ABSTRACT FROM AUTHOR]

The interaction of oxatomide (OXA), azacyclonol (AZA) and chloropheniramine (ClPA) antihistamine drugs with iodine was studied spectrophotometrically in different solvents and at three different temperatures. The electronic, FT-IR, far-IR, and mass spectra of the resulting charge-transfer (CT) complexes were recorded, in addition to thermal analysis. The results obtained show that the stoichiometries of the reactions are all 1:1. The observed time dependence of the CT band and subsequent formation of $$ {\text{I}}_{3}^{ - } $$ in solution were related to the slow transformation of the initially formed 1:1 (donor: I) outer complex to an inner complex (electron donor-acceptor), followed by a fast reaction of the inner complex with iodine to form a triiodide ion. The characteristic strong absorptions of $$ {\text{I}}_{3}^{ - } $$ are observed around 360 nm. The CT-complexes have the formulae [(OXA)I] $$ {\text{I}}_{3}^{ - } $$, [(AZA)I] $$ {\text{I}}_{3}^{ - } $$ and [(ClPA)I] $$ {\text{I}}_{3}^{ - } $$. The formation constants ( K), molar absorption coefficients ( ε), and thermodynamic parameters Δ H, Δ S and Δ G of these interaction have been determined and discussed. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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

Abstract: 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 ΔH°, ΔS° and ΔG° 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. [Copyright &y& Elsevier]

Abstract: 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 2h 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 (10mg/kg) and fexofenadine (10mg/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 (300mg/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. [Copyright &y& Elsevier]

ABSTRACT Background: Plasma membrane fluidity of polymorphonuclear leukocytes (PMN) was investigated in 10 allergic asthmatic children before and after oxatomide treatment. Methods: Membrane fluidity was studied by measuring the steady state fluorescence anisotropy of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) incorporated into polymorphonuclear leukocyte (PMN) plasma membranes. Results: There was an increase in membrane fluidity at the surface of PMN from asthmatic children. Oxatomide treatment significantly decreased PMN membrane fluidity. Conclusions: These data suggest that oxatomide may induce changes in the physicochemical properties of the PMN plasma membrane in asthmatic subjects. These changes may modify the functional activities of PMN. [ABSTRACT FROM AUTHOR]

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 A[sub 2] (PLA[sub 2] ) family. Oxatomide is a histamine H[sub 1] receptor antagonist currently used in the treatment of allergic disorders. Preliminary evidence indicates that oxatomide may exert anti-inflammatory activities unrelated to H[sub 1] 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 Ca[sup 2+] ionophore A23187 (0.5 μM). Oxatomide also comparably inhibited the release of the four major metabolites of AA induced by A23187 (LTB[sub 4] , 20-OH-LTB[sub 4] , 20-COOH-LTB[sub 4] 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 PLA[sub 2] (cPLA[sub 2] ). To test this hypothesis, we evaluated the functional activity of cPLA[sub 2] in neutrophils preincubated with oxatomide. This preincubation inhibited (72 ± 24%) the increase in cPLA[sub 2] activity induced by A23187. Conclusions: These results indicate that oxatomide reduces the biosynthesis of lipid mediators in human neutrophils by inhibiting cPLA[sub 2] . This inhibitory effect of oxatomide may contribute to the anti-inflammatory activity of this drug in allergic diseases.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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

The new antiallergic drug oxatomide was evaluated in 40 schoolchildren suffering from severe allergic seasonal rhinoconjunctivitis. Antihistamine drugs had earlier given insufficient symptomatic relief. Double-blind technique was used. There was no significant difference in effect between oxatomide, the antihistamine cinnarizine in combination with phenylpropanolamine and placebo. The results do not support the hypothesis that oxatomide is superior to antihistamine drugs in the treatment of severe seasonal rhinoconjunctivitis. [ABSTRACT FROM AUTHOR]