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

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

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

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

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

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

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

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

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

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

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

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

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

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

The efficacy of oxatomide (Celtect®), an antiallergic agent, in the treatment of Japanese cedar pollinosis was evaluated in this study of 138 patients, 90 of whom received it prophylactically and 48 therapeutically.There were good clinical results in 51 of the former and in 21 of the latter. Thus, treatment with oxatomide, either prophylactically or therapeutically appears to be beneficial in the clinical control of pollinosis. The prophylactic and therapeutic effects could not be compared adequately, since the criteria for their evaluation differed. The prophylactic effectiveness was evident throughout the pollen season, while the therapeutic effectiveness was greatest during the middle and late periods of the season.

Oxatomide was administered to 78 patients (total 86 ears) with otitis media with effusion for four weeks after myringotomy, and its effectiveness and safety were evaluated. The rate of clinical efficacy was 47.7% (marked effect, 15.1%; moderate effect, 23.3%; slight effect, 9.3%). The appearance of the tympanic membrane was improved in 40.7% of the ears. There was improvement in 34.2% of the ears on the pure tone audiogram and in 36.9% on the tympanogram. A side effect was observed in 1 patient (1.3%), but it was mild and no treatment was required. On the basis of these results, oxatomide was judged to be effective in the treatment of otitis media with effusion.

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.

抗アレルギー剤オキサトミド1日60mg 1回投与(以下60mg分1)の可能性と安全性について, 健常成人男子による単回投与およびその14日間連続投与による血中濃度, アレルギー性皮膚疾患の患者に対する分1·分2投与クロスオーバー試験による臨床効果の検討を行った。 1. オキサトミド60mg分1連続投与では, 投与後6日目付近より未変化体の血中濃度は定常状態となった。また, 定常時の血中濃度は, 単回投与時パラメーターからのシミュレーションよりもやや高い値を示し, また消失相の半減期も延長した。 2. 活性代謝物M-11の血中濃度も未変化体と同様の変化を示し, ヒトにおいてM-11がオキサトミドの臨床効果発現に関与しているものと考えられた。 3. オキサトミドの60mg分1と分2投与(以下60mg分2)でのアレルギー性皮膚疾患に対する臨床効果はほぼ同等であり, 安全性の面で60mg分1に問題はなかった。 以上の結果から, オキサトミドの60mg分1は, 60mg分2と同等の効果と安全性が期待され, 患者の状況によって試みても良い投与法と考えられた。

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.

オキサトミド60mg/日投与とステロイド外用にて, 皮膚症状が軽快しているアトピー性皮膚炎患者において, ステロイド外用状況を変えることなくオキサトミドを減量し, 皮膚症状の推移を観察した。その結果, 4週後の観察でオキサトミド60mg/日を継続投与した群では, その悪化率は2.9%にすぎなかったが, オキサトミド30mg/日に減量した群では, 悪化率は18.5%であり, 無投与群のそれは48.0%であった。その悪化傾向は, オキサトミド減量後1週目にすでにみられはじめ, 期間の経過にしたがって増加する傾向がみられた。悪化した皮膚症状のうち, そう痒の悪化がとくに顕著であった。これらの結果は, 抗アレルギー薬であるオキサトミドがアトピー性皮膚炎の抑制に有効であることを示唆している。

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.

高齢者では老化に伴う薬物代謝の遅延があり, 副作用の発現抑制という観点からも, 一般成人に比べより慎重な薬剤投与が必要である。今回, 老人性皮膚そう痒症に対するオキサトミド(セルテクト®)の有効性とより有用な使用法を知る目的で, 本剤の成人常用量である60mg投与群と, その半量である30mg投与群で, 封筒法による群間比較を行った。その結果, 60mg投与群にそう痒の重症度に有意な偏りがあったが, 両群ともに全般改善度で66.7%, 75.9%の改善度(改善以上)が得られ, また安全度, 有用度にも両群間に有意差は認められなかった。したがって老人性皮膚そう痒症では, セルテクト®1日30mgの投与から開始しても十分な止痒効果が得られ, 症状に応じて増量する投与法がより有用性の高い使用法であると考えられた。

Many anti-allergic drugs for the treatment of allergic rhinitis are manufactured or available for sale in Japan. These include topical steroids, cromolyn sodium-like compounds (mast cell stabilizing agents), and non-sedative antihistamines. However, the mode of action and classification of these drugs are still contraversial. No definitive evidence has yet been presented supporting the assertion that mast cell stabilizing agents inhibit allergen induced chemical mediator release from the human nasal mucosal mast cell. Some mast cell stabilizing agents also have the antihistaminic effect that antihistamines do, and some anti-histamines inhibit chemical mediator release like mast cell stabilizing agents do. Further studies using human nasal mast cells are required to clarify the mode of action of each drug.We have performed clinical trials of many anti-allergic drugs using a standardized double blind intergroup comparative method in patients with perennial allergic rhinitis. For general improvement of allergic symptoms, mast cell stabilizing agents such as tranilast, traxanox, and azelastine were superior to inactive placebo; ketotifen, oxatomide and tranilast were also superior to clemastine fumarate ; and, tranilast was comparable to amlexanox, tazanolast, traxanox and repirinast; topical amlexanox and ketotifen were also comparable to cromolyn sodium.New anti-histamines such as terfenadine and astemizole were comparable to ketotifen, and loratazine was comparable to mequitazine for general improvement of allergic symptoms.

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.

Background: Eosinophils accumulated in sites of allergic inflammation are thought to play a crucial role in the pathogenesis of allergic disorders including asthma, allergic rhinitis, and atopic dermatitis, and tissue eosinophilia is attributable to increased eosinophil survival or decreased eosinophil apoptosis. Objective: Effects of the antiallergic, histamine H 1 blocker oxatomide on viability and apoptosis of eosinophils isolated from the peripheral blood of atopic subjects were studied. Methods: Eosinophil viability and apoptosis were evaluated by using a colorimetric assay and annexin V-labeling, caspase-3 activity, and DNA fragmentation assay. Results: The viability of eosinophils increased in the presence of IL-5 (10 ng/mL), confirming that IL-5 prolongs eosinophil survival in vitro. Application of oxatomide at concentrations over 20 μmol/L for 24 hours decreased the IL-5-induced enhancement of eosinophil viability. Double staining of the cells with annexin V and propidium iodide showed that deprivation of IL-5 promoted spontaneous eosinophil apoptosis and that oxatomide facilitated apoptosis and suppressed the prolongation of eosinophil survival stimulated by IL-5. In the absence of IL-5, approximately 71% and 96% of eosinophils after 24 and 48 hours, respectively, underwent spontaneous apoptosis. IL-5 decreased the rate of eosinophil apoptosis to 38% and 52% after 24 and 48 hours, respectively. Oxatomide increased eosinophil apoptosis in a concentration-dependent manner in the presence of IL-5. Furthermore, oxatomide increased caspase-3 activity and DNA fragmentation. Conclusion: We demonstrated that oxatomide possesses a novel therapeutic effect of apoptosis promotion on eosinophils and prevents the antiapoptotic effects of IL-5, suggesting that oxatomide may contribute to resolution of tissue eosinophilia in allergic inflammation. (J Allergy Clin Immunol 2003;111:567-72.)

There has been no study comparing the long-term effects of ketotifen, oxatomide, and cetirizine for the treatment of perennial allergic rhinitis among children.We conducted a study to compare the efficacy of the three agents for the treatment of perennial allergic rhinitis among children.The study consisted of a double-blind, placebo-controlled, randomized design, comprising 69 perennial allergic rhinitis patients with mite allergy, aged 6 to 12 years, randomly assigned to 1 of 4 test treatment groups for 3 months: 19 in the cetirizine group (10 mg daily), 18 in the ketotifen group (1 mg, twice daily), 16 in the oxatomide group (1 mg/kg, twice daily), and 16 in the placebo group. We used the nasal symptom score of diary card and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire and eosinophil cation protein peripheral blood total eosinophil count and immunoglobulin E level, eosinophil proportion from a nasal smear, and nasal peak expiratory flow rate to evaluate the effect of the four agents.Cetirizine was significantly more effective at reducing the mean rhinorrhea score compared with oxatomide for both weeks 8 and 12 (P0.01). Before the end of week 12, cetirizine was significantly more effective than ketotifen (P0.01). Cetirizine and oxatomide significantly decreased the mean Pediatric Rhinoconjunctivitis Quality of Life Questionnaire score compared with the placebo for week 12 (P0.05).Cetirizine was more effective than oxatomide and ketotifen for the relief of nasal congestion and rhinorrhea, and was responsible for significantly decreasing the eosinophil representation of a posttreatment nasal smear.

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.

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.

Background There are no studies on the use of cetirizine in children under the age of 6. Objective We compared the efficacy and tolerability of cetirizine in patients with idiopathic chronic urticaria to the more widely used antihistamine, oxatomide. Methods This double-blind study was performed on 62 patients (38 male and 24 female) with idiopathic chronic urticaria, recruited from four different medical centers of the national territory (Ancona, Cagliari, Catania, and Messina). The children's ages ranged from 2 to 6 years (mean 3.85). The patients were randomly assigned to two treatment groups: one group treated 31 children with cetirizine at a dosage of 5 mg q.d., and a second group treated 31 children for the same amount of time with oxatomide, at a dosage of 25 mg q.d. Sixty-two children began the treatment, but five did not finish the study (three in the cetirizine and two in the oxatomide group). Thus, the clinical study and the statistical evaluation were conducted on 57 children (28 cetirizine and 29 oxatomide). The Student's t test was used to compare severity of the illness and changes in the hematochemical tests. Results Overall, the effectiveness of the two medications in treating erythema, papules, edema, and itching showed comparable therapeutic activity ( P 0.001). Neither medication produced significant side effects. Conclusions The results of the present study suggest that cetirizine may represent an effective and safe pharmacologic therapy for chronic urticaria in preschool children. There was no evidence for changes in hematochemical and urinary values, demonstrating the safety and the tolerability of the two antihistamines, even when given to young children.