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    • We have demonstrated that a direct inhibitor

    2018-10-23

    We have demonstrated that a direct inhibitor on InhA can retain the outstanding profile of isoniazid and considering the DMPK parameters of both compounds the antitubercular effect is achieved at similar exposures of free drug proving our initial orexin antagonist and overcoming resistances mediated by KatG. GSK693 has demonstrated in vivo efficacy comparable to the marketed drug isoniazid without being a pro-drug, thus overcoming most of INH associated liabilities. Besides, its improved property profile should translate into a safer treatment. Overall, this achievement opens the door to the development of a direct inhibitor of the enoyl-ACP reductase (InhA) as an attractive drug candidate for the therapy of Tuberculosis.
    Author contributions
    In memoriam statement
    Funding sources
    Conflict of interest
    Introduction Sarcoidosis, a chronic inflammatory disorder of unknown cause, is the most frequently observed interstitial lung disease of unknown origin in Europe (Baughman and Grutters, 2015). It usually affects the lung and lymphatic system, but its clinical features are varied and non-specific, and it shows variable radiographic presentation, all of which makes accurate diagnosis a challenge. Typically, sarcoidosis is diagnosed when clinical and/or radiographic findings are supported by histological evidence of non-caseating granulomatous inflammation, and when other causes of granulomas and local reactions can be reasonably excluded (Iannuzzi et al., 2007; Costabel et al., 2008; Am J Respir Crit Care Med, 1999). Another problem with diagnosing sarcoidosis is that, unless patients show typical manifestations of Löfgren syndrome, biopsy is recommended, making diagnosis invasive (Iannuzzi et al., 2007; Costabel et al., 2008; Am J Respir Crit Care Med, 1999). As a result, investigators continue to search for reliable, less invasive methods to diagnose sarcoidosis. Growing evidence points to the possibility of analyzing the bronchoalveolar lavage fluid (BALF) to aid in diagnosis. In sarcoidosis, TH1 hyperimmune response to an unknown agent causes CD4+ T lymphocytes to accumulate in affected tissues and leads to the formation of non-caseating granulomas (Baughman et al., 2003). As a result, many patients with sarcoidosis show elevated lymphocytosis and CD4/CD8 ratio in BALF, and this elevated ratio has been associated with a diagnosis of sarcoidosis (Baughman et al., 2003; Costabel, 1997). Indeed, clinicians may opt not to perform diagnostic biopsy in patients who present both a clinical picture typical of sarcoidosis and an elevated BALF CD4/CD8 ratio (Kvale, 2003; Kantrow et al., 1997). Several studies have suggested that the BALF CD4/CD8 ratio can supplement the results of other tests when diagnosing sarcoidosis (Wells and Hirani, 2008; Chretien et al., 1985; Stoller et al., 1987). However, whether the BALF CD4/CD8 ratio can reliably perform as a diagnostic tool remains controversial. The ratio shows high variability (Kantrow et al., 1997), and studies of its diagnostic performance suggest variable sensitivity and specificity. To gain a clearer picture of the diagnostic usefulness of this ratio, we performed a meta-analysis to summarize its overall diagnostic performance based on the available literature.
    Methods This study was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews, as well as the Meta-analysis Statement and methods recommended by the Cochrane Diagnostic Test Accuracy Working Group (Leeflang et al., 2008). Institutional review board approval was not required for this retrospective meta-analysis.
    Results
    Discussion Numerous studies have focused on the potential value of BALF CD4/CD8 ratio for diagnosis of sarcoidosis. This is based on the fact that CD4+ T cells interacting with antigen-presenting cells appear to trigger formation of sarcoid granulomas and help maintain them (Iannuzzi et al., 2007; Baughman et al., 2003). In addition, activated alveolar macrophages and CD4+ T cells participate in the influx of mononuclear cells into the alveoli that often precedes sarcoid granuloma formation in the lung (Baughman et al., 2011; Jones, 2002). Diagnostic studies have reported highly variable sensitivity and specificity when using the CD4/CD8 ratio, prompting us to perform what we believe to be the first meta-analysis to assess the available evidence on the diagnostic usefulness of this ratio in sarcoidosis.