Telangiectasia macularis eruptive perstans (TMEP) in childhood: A case report and literature review

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Leukotriene generation and clinical implications.

Since the elucidation of the structure of the cysteinyl leukotrienes (LTs) > 20 years ago, considerable progress has been made in our understanding of the role of these molecules in health and disease, particularly regarding bronchial asthma. This study will review the biochemistry of the 5-lipoxygenase pathway for LT generation. It will discuss the early evidence that LTs, the cysteinyl LTs in particular, have the biological properties expected for molecules that participate in the pathogenesis of bronchial asthma and the evidence for their formation in the airways of asthmatic individuals. It will briefly review tile evidence that LT-modifying drugs are effective in the management of bronchial asthma and will discuss novel developments in our understanding of the proinflammatory properties of the LTs including their role as autocrine mediators of leukocyte responses. The pharmacogenomics of 5-lipoxgenase and LTC4 synthase in bronchial asthma will be discussed.

Long-acting beta2-agonists or leukotriene receptor antagonists as add-on therapy to inhaled corticosteroids for the treatment of persistent asthma.

It is well accepted that the combination of inhaled corticosteroids (ICSs) and long-acting beta2-agonists (LABAs) is effective in achieving asthma control, as it treats both components of asthma pathophysiology, namely inflammation and smooth muscle dysfunction of the airways. Leukotriene receptor antagonists (LTRAs) can also be used as add-ons to ICS therapy in patients whose asthma is not controlled by ICSs alone. The purpose of this review is to compare the effectiveness of ICSs plus LABAs with that of ICSs plus LTRAs for the treatment of persistent asthma that is not controlled by ICSs alone. Several studies have shown that, in comparison with an ICS plus an LTRA, the addition of an LABA to ICS therapy provides greater improvements in pulmonary function and overall control of asthma as measured by use of rescue medication and the number of exacerbations of the asthma, symptom-free days and symptom-free nights. The greater improvements in pulmonary function observed with an ICS plus the LABA, salmeterol, occurred within the first week of treatment (at first treatment assessment), and remained significantly greater than those achieved with an ICS plus an LTRA over the duration of the treatment. Moreover, the salmeterol-fluticasone propionate combination (SFC) produces consistently greater improvements in pulmonary lung function and control of asthma than does the addition of an LTRA to fluticasone propionate. In addition, SFC is a more cost-effective treatment option than fluticasone propionate plus montelukast for patients with asthma that is uncontrolled by ICSs alone. Important cost savings can be made with SFC in clinical practice compared with other combinations of ICSs plus salmeterol or ICSs plus LTRAs.

Treatment of asthmatic patients with a cysteinyl leukotriene receptor-1 antagonist montelukast (Singulair), decreases the eosinophil survival-enhancing activity produced by peripheral blood mononuclear leukocytes in vitro.

BACKGROUND: Montelukast (Singulair, MSD) has been shown to have a beneficial effect on the clinical symptoms of asthma. We aimed to investigate the effect of montelukast treatment on the production of eosinophil survival-enhancing cytokines by peripheral blood mononuclear cells (PBMNC). METHODS: PBMNC obtained from 15 grass-allergic patients (7 treated with montelukast and 8 with a placebo) were cultured for 72 h. Eosinophils from allergic patients were cultured with MNC supernatants alone or with addition of neutralizing antibodies, and the proportion of living cells was assessed by flow cytometry. In another experiment PBMNC from 6 allergic patients were cultured in vitro in the presence of montelukast or vehicle. Following stimulation the production of GM-CSF in monocytes was assessed. RESULTS: Eosinophil survival in the MNC supernatants from the placebo-treated patients was significantly (P < 0.05) higher than in supernatants from montelukast-treated patients. GM-CSF was the predominant cytokine responsible for the eosinophil survival-enhancing activity (ESEA). In vitro production of GM-CSF by allergen-stimulated monocytes was significantly suppressed by addition of montelukast. CONCLUSION: Treatment of patients with montelukast decreased the production of MNC-derived cytokines, particularly GM-CSF. We suggest that cysteinyl leukotriene receptor-1 (CysLT-R1) antagonists may act, at least partially, by diminishing the production of GM-CSF from PBMNCs.

The use of leukotriene receptor antagonists (LTRAs) as complementary therapy in asthma.

The cysteinyl-leukotrienes (cysLTs: LTC4, LTD4 and LTE4) have an important pathophysiological role in asthma. They are not only extremely potent bronchoconstrictors, but are also involved in the central mechanisms of the asthmatic inflammation and the subsequent remodelling of the airways. Allergen-induced bronchoconstriction as well as spontaneous exacerbations of asthma are associated with increased secretion of LTE4 in urine. This increase does not seem to be affected by high doses of inhaled or systemic corticosteroids. On the contrary, both in vivo and in vitro experiments indicate that corticosteroids to a certain degree may even upregulate the cysLTs synthesis. Moreover, inhaled medication may not get as far as the small airways, which are affected by inflammatory changes in asthma. Hence, the combination of an oral leukotriene receptor antagonist (LTRA) with an inhaled corticosteroid (ICS) seems a rational therapeutic approach to achieve a more complete control of the inflammatory mechanisms in asthma. The additive effects by combining an LTRA with an ICS have been investigated in adults as well as in children from 6-14 years of age. The addition of LTRA improves lung function, and reduces day and night time symptoms in all age groups. More importantly, the combination has also been found to decrease the exacerbation rates in all age groups. More recently, a few studies have compared the effect of additive therapy with LTRA and ICS versus long-acting beta 2-agonists (LABAs) and ICS in asthmatics. Depending on the patient and outcome parameters preselection, some studies found that addition of LABA to ICS resulted in a better lung function and a better overall disease control. Yet one--unsponsored-study, comparing the protective effects of LABA versus LTRA on inflammatory outcome parameters in asthma, found a significant protection against airway hyperresponsiveness to adenosine monophosphate (AMP), together with significant decreases in exhaled nitric oxide (NO) and sputum eosinophils following one week treatment with LTRA, whereas the initial protection by LABA on the AMP responsiveness was lost after one week, and no anti-inflammatory effects could be observed. Similar beneficial effects from LTRA therapy are expected in patients with nocturnal asthma, in whom a decreased responsiveness to corticosteroids has been demonstrated. The choice of either combination therapy has clinical implications. It seems that especially patients with a suboptimal lung function and a significant beta 2-agonist reversibility will benefit from the addition of a LABA, whereas asthmatics with mainly exercise-induced asthma, nocturnal symptoms, or a frequent worsening due to low tolerance to provocative stimuli, may mostly benefit by adding an LTRA to ICS. However, it remains to be determined which combination has the most profound effect on the inflammatory process and the structural changes in asthma.