677 The therapeutic effects of MK-571, a potent and selective leukotriene (LT) D receptor antagonist, in patients with chronic asthma

Margolskee, Dorothy J.; Bodman, Stephen F.; Dockhorn, Robert J.; Israel, E.; Kemp, James P.; Mansmann, Herbert C.; Minotti, Dominick A.; Spector, Sheldon; Stricker, William E.; Tinkelman, D.; Townley, R. C.; Winder, John; Williams, Vanessa C.

doi:10.1016/0091-6749(91)91959-w

Cited by 44 publications

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“…Consistent with prior studies, we were unable to correlate circulating mediator levels of leukotrienes, FEV 1 measurement or airway reactivity to histamine [32]. At altitude, the concentration of house dust mite allergen is reduced [27,30], and it has been suggested that it is the decreased exposure to house dust mite which accounts for the improvement of lung function in allergic asthmatic subjects after a stay at altitude. All our subjects were sensitive to house dust mite allergen on skin-prick testing, and it is possible that increased allergen exposure to house dust mite after return to sea level resulted in the deterioration of lung function.…”

Section: Discussionsupporting

confidence: 73%

“…Antigen-induced bronchoconstriction is attenuated by prior treatment with leukotriene receptor antagonist [24,25], supporting a role for the cysteinyl leukotrienes in acute allergic bronchoconstriction. The improvement in basal lung function after ingestion of an oral active LTD 4 receptor antagonist [26], and improvement of pulmonary lung function following long-term administration of leukotriene receptor antagonists [27], supports a role for the cysteinyl leukotrienes in influencing basal bronchial tone.…”

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confidence: 92%

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Effect of altitude on urinary leukotriene (LT) E4 excretion and airway responsiveness to histamine in children with atopic asthma

Christie¹,

Yntema²,

Tagari³

et al. 1995

Eur Respir J

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E Ef ff fe ec ct t o of f a al lt ti it tu ud de e o on n u ur ri in na ar ry y l le eu uk ko ot tr ri ie en ne e ( (L LT T) ) E E 4 4e ex xc cr re et ti io on n a an nd d a ai ir rw wa ay y r re es sp po on ns si iv ve en ne es ss s t to o h hi is st ta am mi in ne e i in n c ch hi il ld dr re en n w wi it th h a at to op pi ic c a as st th hm ma a Subjects were randomly divided into two groups. Measurements of baseline forced expiratory volume in one second (FEV 1 ), the concentration of histamine producing a 20% decrease in FEV 1 , (PC20 FEV 1 ), serum total immunoglobulin E (IgE), eosinophil count, and urinary LTE 4 concentration were determined prior to and following a 2 week stay in The Netherlands (sea level) in eight subjects (4 males and 4 females, aged 14±0.5 yrs) (mean±SEM) and over a similar time period in six subjects (4 males and 2 females, aged 15±0.3 yrs) resident in Davos, Switzerland.There was no significant difference in total IgE and eosinophil count, and no significant correlation between urinary LTE 4 and PC20FEV 1 histamine, FEV 1 , total IgE, and eosinophil count. In subjects returning to Davos from The Netherlands there was a significant increase in urinary LTE 4 from a baseline value of 16.9 pg·mg -1 creatinine (GM, range 0.3-101.7 pg·mg -1 creatinine) to 52.3 pg·mg -1 creatinine (GM, range 8.8-301.6 pg·mg -1 creatinine), a significant decrease in PC20FEV 1 from 1.7 mg·ml -1 (GM, range 0.3-16.4 mg·ml -1 ) to 0.9 mg·ml -1 (GM, range 0.1->32 mg·ml -1 ), and a significant fall in FEV 1 from 3.0±0.3 to 2.8±0.3 l (mean±SEM). There was no significant change in urinary LTE 4 , FEV 1 or PC20FEV 1 histamine during a similar period of time in subjects resident in Davos.Thus, following a visit to sea level, children with atopic asthma who are usually resident at altitude exhibit a fall in FEV 1 and an increase in airway responsiveness to histamine, which is associated with a threefold increase in urinary LTE 4 excretion. Eur Respir J., 1995, 8, 357-363 The cysteinyl leukotrienes (LTC 4 , LTD 4 and LTE 4 ) are derived from arachidonic acid by the action of 5-lipoxygenase, which generates 5-hydroperoxyeicosatetraenoic acid and then leukotriene A 4 (LTA 4 ) [1][2][3]. LTA 4 is metabolized by the addition of glutathione to form LTC 4 . LTC 4 may be converted by γ-glutamyltranspeptidase to generate LTD 4 , which is converted by a dipeptidase to yield LTE 4 [4,5]. In vitro the cysteinyl leukotrienes, LTC 4 , LTD 4 and LTE 4 , contract smooth muscle and enhance microvascular permeability [6][7][8]. In humans they are potent bronchoconstrictor agents when inhaled, and increase nonspecific bronchial hyperresponsiveness [9][10][11][12].In man, there is rapid metabolism of LTC 4 to LTD 4 and then to LTE 4 . LTE 4 may be further metabolized to oxidation products, which are excreted into bile and urine [13][14][15][16]. Combined reversed-phase high performance liquid chromatography (RP-HPLC) and radioimmunoassay (RIA) enables urinary LTE 4 to be measured [17], and the values have been used as an estimate of th...

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Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 92%

Effect of altitude on urinary leukotriene (LT) E4 excretion and airway responsiveness to histamine in children with atopic asthma

Christie¹,

Yntema²,

Tagari³

et al. 1995

Eur Respir J

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“…154 At the end of the trial, FEV 1 was improved 8-14%, morning and evening asthma symptoms were reduced 30%, and -agonist use was also reduced 30%. These results were comparable to those found for inhibitor 1 and further confirm the therapeutic benefit of LT modulation in patients with chronic asthma.…”

Section: Peptidyl Leukotriene Antagonists That Have Progressed To CLImentioning

confidence: 97%

Modulators of Leukotriene Biosynthesis and Receptor Activation

1996

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IntroductionThe history of leukotriene (LT) research has been documented in numerous articles and reviews since the discovery of the LT biosynthetic pathway 1 and the delineation of the various chemical structures involved in the pathway and their total synthesis. 2 Three previous Perspective articles have provided periodic updates, the first in 1981, 3 the second 1 decade later covering LT receptor antagonists, 4 and the third in 1992 covering LT biosynthesis inhibitors. 5 With this background, the task of this Perspective is to update the status of LT intervention research by providing an overview of the leading enzyme inhibitors and receptor antagonists as well as the status of clinical trials with these agents and how the latter are influencing the development of new therapeutic modalities for the treatment of inflammation and allergy.The clinical proof-of-concept for LT intervention has taken longer than expected considering that the biosynthesis and chemical composition of LTs were delineated by 1979. It is now clear that LT intervention therapy represents a promising new modality for the treatment of asthma. Several compounds including the 5-lipoxygenase (5-LO) inhibitor zileuton (1) and the cysteinyl LT antagonist zafirlukast (2) have completed pivotal clinical trials, while several other LT modulators are progressing to this stage. Within a few years the therapeutic potential of these new agents in asthma and other inflammatory and allergic disorders will be evident. Leukotriene Intervention StrategiesLeukotriene Biosynthesis. Leukotrienes are biosynthesized via the 5-LO (arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34) pathway of arachidonic acid (AA) metabolism ( Figure 1). The 5-LO product LTA 4 is a pivotal reactive epoxide intermediate in an important branch in the biosynthetic pathway that is further metabolized by either (i) stereoselective hydration by LTA 4 hydrolase to LTB 4 or (ii) glutathione addition by LTC 4 synthase to LTC 4 . Successive amino acid cleavage steps convert LTC 4 to LTD 4 and then to LTE 4 . The cysteinyl LTs (LTC 4 , LTD 4 , LTE 4 ) are the constituents of the biological substance previously known as slowreacting substance of anaphlyaxis (SRS-A). 6 LTB 4 is a very potent neutrophil chemotactic agent, inducing neutrophil adherence to endothelial cells, degranulation, and modulation of cytokine production. The biosynthesis, release, and recovery of LTs from specific cells involved in inflammatory disorders together with the observed ability of these products to mimic aspects of disease support their involvement as mediators of inflammatory and allergic disorders. 7,8 Despite such circumstantial evidence, confirmation of the pathophysiological role of these mediators requires selective blockade of their actions.At the outset of research efforts in the LT area, it was not entirely clear which LTs or subsequent metabolites were the predominant mediators of a particular human disorder. LTs are short-lived, being rapidly converted to inactive metabolites, and prolonged expressi...

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“…Studies using more potent and specific antagonists have recently been completed. MK-571 administered orally for 6 weeks resulted in a mean increase in FEV1 of 8-14%, a decrease in daytime symptom scores by 30%, a decrease in bagonist inhaler use by 30% and improved diurnal variation in peak expiratory flow rate [112]. Development of MK-571 has been suspended, in favour of the (R)-enantiomer, MK-679.…”

Section: Studies In Clinical Asthma (Table 3)mentioning

confidence: 99%

Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy

Chung¹

1995

Eur Respir J

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677 The therapeutic effects of MK-571, a potent and selective leukotriene (LT) D receptor antagonist, in patients with chronic asthma

Cited by 44 publications

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Effect of altitude on urinary leukotriene (LT) E4 excretion and airway responsiveness to histamine in children with atopic asthma

Effect of altitude on urinary leukotriene (LT) E4 excretion and airway responsiveness to histamine in children with atopic asthma

Modulators of Leukotriene Biosynthesis and Receptor Activation

Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy

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