Leukotriene antagonists and synthesis inhibitors: New directions in asthma therapy

Holgate, Stephen T.; Bradding, Peter; Sampson, Anthony P.

doi:10.1016/s0091-6749(96)70220-8

Cited by 191 publications

(95 citation statements)

References 63 publications

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“…As the LAR is accompanied by inflammatory cell recruitment and often by an associated increase in BHR, it is considered to be a useful model of airway inflammation [39]. Corticosteroids, sodium cromoglycate, nedocromil sodium, theophylline and leukotriene antagonists are all successful in attenuating the LAR and the accompanying BHR [6,[39][40][41]. Treatment with theophylline, as well as attenuating the LAR, is associated with a decrease in activated eosinophils in bronchial biopsies 24 h after allergen exposure [8].…”

Section: Discussionmentioning

confidence: 99%

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

Harbinson

MacLeod²,

Hawksworth³

et al. 1997

Eur Respir J

115

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Recent studies have suggested that theophylline, a nonspecific phospho-diesterase inhibitor, has useful anti-inflammatory actions in asthma. Phosphodiesterase 4 (PDE4) represents the predominant PDE isoenzyme present in inflammatory cells. PDE4 inhibitors might, therefore, have beneficial effects in asthma. Sideeffects, specifically nausea, have limited the use of existing agents. CDP840 is an orally active, potent and selective PDE4 inhibitor. We have examined the effect of CDP840 on the allergen-induced asthmatic response, its possible modes of action, and its tolerability at therapeutic doses.A total of 54 patients were recruited to three double-blind, placebo-controlled studies. The first study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on the allergen-induced asthmatic response in patients with known dual response to allergen. A second study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on airway responsiveness to histamine. A third study examined whether single dose CDP840 (15 and 30 mg) had significant bronchodilatory effects.In all studies, CDP840 was well-tolerated, with no patients reporting nausea. CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. The late asthmatic response (LAR) to allergen, expressed as area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.016), an effect which persisted to the end of the observation period. The early asthmatic response (EAR) was unaffected, and there was no bronchodilatory effect at the doses used. Treatment with CDP840 did not affect bronchial hyperresponsiveness to histamine.In conclusion, CDP840 significantly attenuated the late asthmatic response to allergen challenge in the absence of any bronchodilatory or histamine antagonist effect. This suggests that CDP840 may exert its effects via an anti-inflammatory mechanism.

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Section: Discussionmentioning

confidence: 99%

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

Harbinson

MacLeod²,

Hawksworth³

et al. 1997

Eur Respir J

115

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“…Among the human disease conditions thought to result from excess availability of the cysteinyl leukotrienes is asthma. 64,73 Inhibition of ALOX5 activity or blockade of the CysLT 1 receptor by cLI is associated with clinically significant improvements in asthma outcome. 74 The regulation of ALOX5 is multifaceted; known mechanisms include regulation of action of the mature protein and regulation of ALOX5 gene transcription and translation.…”

Section: Pharmacogenetics Of Leukotrienes In Asthmamentioning

confidence: 99%

The pharmacogenetics of asthma: a candidate gene approach

et al. 2001

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“…O LTB4 é um potente agente quimiotático para neutrófilos. Os LTC4, LTD4 e LTE4 agem contraindo a musculatura lisa das vias aéreas, aumentam a permeabilidade vascular, promovem vasodilatação, hipersecreção de muco, edema de mucosa e redução do transporte mucociliar 73 .…”

Section: Antileucotrienosunclassified

Asthma in children: classification and treatment

Solé

Ic²,

Mc³

et al. 1998

J Pediatr (Rio J)

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ResumoObjetivos: Rever conceitos, gravidade e planos de tratamento a longo prazo da asma na criança.Método: Identificar os agentes desencadeantes e/ou agravantes dos quadros agudos de asma e classificá-la para permitir-se o estabelecimento de um plano de tratamento a longo prazo.Resultado: Classificada como leve, moderada e grave, a asma terá planos distintos de manejo, ficando a abordagem com agentes antiinflamatórios reservada às formas moderada e grave.Conclusões: No tratamento do paciente asmático, a identificação e o controle dos agentes etiológicos e dos possíveis agravantes é parte fundamental. A via inalatória é a mais adequada para a administração de fármacos a pacientes asmáticos. As principais drogas habitualmente utilizadas no tratamento da asma são revistas e o emprego precoce de glicocorticosteróides inalados tem sido recomendado pela maioria dos autores.J. pediatr. (Rio J.). 1998; 74 (Supl.1): S48-S58: asma, alérge-nos, criança, tratamento, terapia inalatória, imunoterapia. AbstractObjectives: To review concepts, classification based on severity, and long term treatment for children with asthma.Methods: To identify precipitating factors of acute asthma attacks and classify the disease in order to establish long term treatment.Results: Different plans of management according to its classification: mild, moderate and severe asthma. Antiinflammatory therapy is reserved to moderate and severe asthma.Conclusions: The identification and control of the etiologic and precipitating factors are important tasks in the management of asthma. The inhalatory route is the most appropriate to treat patients suffering from asthma. The usual drugs indicated in asthma treatment are reviewed. Precocious treatment with inhaled glucocorticosteroids is recommended by several authors. J. pediatr. (Rio J. IntroduçãoA asma é definida pelo II Consenso Brasileiro no Manejo da Asma como uma doença crônica das vias aéreas caraterizada por a) obstrução ao fluxo aéreo reversível (embora não completamente em alguns pacientes) espontaneamente ou com tratamento; b) inflamação em que muitas células têm um papel importante, em particular mastócitos e eosinófilos; c) aumento da reatividade das vias aéreas a uma variedade de estímulos (hiper-responsividade brônquica = HRB); d) episódios recidivantes de sibilância, dispnéia, aperto no peito e tosse, particularmente à noite e pela manhã ao acordar 1 .A análise de fragmentos de mucosa brônquica obtidos por endoscopia, mesmo de indivíduos com asma leve e de início recente, ou por autópsia de indivíduos asmáticos falecidos durante episódio agudo, revela alterações características que variam de intensidade segundo a gravidade da asma. Estas alterações incluem: a) infiltração da mucosa e submucosa com células inflamatórias (especialmente eosinófilos e linfócitos T), b) descamação irregular do epitélio, c) espessamento da musculatura lisa da via aérea, d) fibrose subepitelial, e) hiperplasia de glândulas mucosas e de células caliciformes e f) tampões mucosos disseminados na asma fatal 2,3 .O p...

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Leukotriene antagonists and synthesis inhibitors: New directions in asthma therapy

Cited by 191 publications

References 63 publications

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

The pharmacogenetics of asthma: a candidate gene approach

Asthma in children: classification and treatment

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