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Gastrointestinal Tract
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Judit E. Markovits, Graham R. Betton, Donald N. McMartin, Theresa Boulineau
Erosion/ulceration of the gastric mucosa can result from chemical, pH, mechanical, hypoxia, hypovolemia, or vasoconstriction challenges. The unstirred layer of the gastric mucus provides a pH gradient between the acidic lumen and bicarbonate secreting surface cells. In oral toxicology studies, direct exposure, especially to gavage formulations, activates uptake into acidic compartments for compounds with low pKas. This direct exposure as well as systemic plasma exposure can lead to gastric mucosal erosion or ulceration. Macroscopically, erosions/ulcers are more common in the antral mucosa and pylorus, commencing as brown pinhead foci (Figure 11.14d). Histologically, erosions/ulcers that show partial mucosal deficit and an inflammatory cell infiltrate usually are centered above an arteriole (Figure 11.14e). Cytoprotection requires prostaglandins and mucosal blood flow, and NSAIDs block prostacyclin production required to maintain local perfusion. Inhibitors of the cyclooxygenase (COX-1) enzyme prevent eicosanoid synthesis, reducing production of prostaglandins, prostacyclins, and thromboxanes. 5-Lipoxygenase inhibitors and pranlukast, a leukotriene antagonist, can negate NSAID-induced ulceration (Nakamori et al. 2010). The hypergastrinemia seen after antisecretory drug treatment upregulated COX-2 and prostaglandin E2 conferred cytoprotection against ethanol-induced gastric injury (Tsuji et al. 2002). Trefoil factor family 2 (TFF2) produced by mucous neck cells is also cytoprotective against NSAID-induced ulceration in mice (Farrell et al. 2002).
Management of Asthma in Older Adults
Published in Jonathan A. Bernstein, Mark L. Levy, Clinical Asthma, 2014
LTRAs, such as montelukast, are considered an appropriate add-on therapy in combination with ICS for asthmatics of all ages, and may be considered as a monotherapy in mild asthmatics.22,24 The efficacy of antileukotrienes for older asthmatics has not been extensively studied. A recent study of 513 asthmatics over 60 years of age found that montelukast decreased exacerbations and the need for rescue inhaler use among severe asthmatics who were taking ICS and a LABA.48 In addition, a study of 41 asthmatics over 65 years of age found that pranlukast was equivalent to an ICS as a monotherapy for mild asthma.49 LTRAs thus appear to be useful for some older asthmatics. In particular, a trial of these medications for older asthmatics with nasal polyposis and/or aspirin-exacerbated respiratory disease (AERD) is reasonable, given that AERD patients have been shown to incur greater improvements in asthma control with LTRAs than can be achieved with ICS alone. In addition, because they are in pill form, LTRAs are easier to use for older patients who have difficulties with inhalers. While they are generally well tolerated, a potential increased risk of Churg–Strauss vasculitis has been reported among patients taking leukotriene antagonists. In addition, concerns have been raised regarding psychological side effects, including a potentially increased risk of suicide.50 Physicians prescribing these medications in older asthmatics, who are at increased risk of depression and cognitive impairment, must be aware of these risks.
Vasculitis induced by drugs
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Michiel De Vries, Marjolein Drent, Jan-Wil Cohen Tervaert
Vaccinations and desensitization have been implicated as precipitating factors.11,12 In addition, CSS is associated with use of drugs such as leukotriene receptor antagonists (LRAs). LRAs have an anti-inflammatory and a bronchodilatator effect. LRAs are zafirlukast, pranlukast and montelukast. Furthermore, a 5-lipoxygenase inhibitor (zileuton) is available which is also associated with the occurrence of CSS. A number of explanations may account for the association between LRAs and CSS:13–18There is coincidental development of a full-blown CSS with the introduction of a leukotriene receptor antagonist.LRAs prevent airway obstruction by blocking the bronchoconstrictor effects of leukotrienes and therefore decrease the need for corticosteroids which allow the manifestations of CSS to develop. Also CSS has been reported in several asthmatic patients not on LRAs while tapering corticosteroids.There is an imbalance in leukotriene receptor stimulation. The LRAs block the effect of cysteinyl leukotrienes LTC4, LTD4 and LTE4, but do not block the effect of LTB4 which is a chemoattractant for eosinophils and neutrophils. Since reports of LTB4 inhibition by zileuton, a strong 5-lipoxyoxigenase inhibitor, and CSS are also described, this hypothesis seems unlikely.CSS is a hypersensitivity reaction to LRA treatment.
Asthma pharmacotherapy: an update on leukotriene treatments
Published in Expert Review of Respiratory Medicine, 2019
Hoang Kim Tu Trinh, So-Hee Lee, Thi Bich Tra Cao, Hae-Sim Park
The potency to inhibit CysLTR1 is lower in pranlukast than in montelukast and zafirlukast [24]; however, the potency to suppress PGE2 synthesis is similar. Pranlukast is well tolerated in both adults and children with asthma [28,29]. The current in vivo study demonstrates that pranlukast interferes transforming growth factor-β1 (TGF-β1)/Smad signaling in asthma mice, thus suppressing airway inflammation and remodeling [30]. Nevertheless, there are rare cases of pranlukast-induced immediate hypersensitivity reactions or severe anaphylactic shock, with cross-reactivity with montelukast [31]. An improved formulation of pranlukast is suggested to effectively control persistent asthma, with lower doses and similar adverse events profiles [32].
Prostaglandin D2 receptor antagonists in allergic disorders: safety, efficacy, and future perspectives
Published in Expert Opinion on Investigational Drugs, 2019
Giancarlo Marone, Maria Rosaria Galdiero, Antonio Pecoraro, Valentina Pucino, Gjada Criscuolo, Maria Triassi, Gilda Varricchi
In a recent multicenter, randomized, double-blind, parallel-group study of patients with SAR ONO-4053 (Ono Pharmaceutical Co.), a specific DP1 antagonist, and pranlukast, a leukotriene receptor antagonist, or placebo were compared in patients with SAR [101]. Both ONO-4053 and pranlukast were safe and had higher efficacy than placebo on all nasal and eye symptoms. The authors suggested that the efficacy of ONO-4053 derived from both its DP1 antagonism and its inhibitory effect on mast cell degranulation at high concentrations. The safety and efficacy of selective DP1 antagonists should be verified in larger and longer-term trials on allergic rhinitis.