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Role of Plant-Based Bioflavonoids in Combating Tuberculosis
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Alka Pawar, Yatendra Kumar Satija
Delamanid (OPC67683) and pretomanid–moxifloxacin–pyrazin-amide (PA-824) are two latest drugs in combination, which belong to imidazooxazoles. Both drugs are presently in phase III clinical trial. Activation of these pro-drugs depends upon the MTB F420-deazaflavin-dependent nitroreductase (Ddn). The Ddn enzymatically reduces PA-824, which results in intracellular discharge of detrimental reactive nitrogen species that attacks mycobacterial respiration process.42 The PA-824 drug is active against both active and latent TB, therefore it helps in reducing the TB treatment time.21 Delamanid drug is used mainly in the cure of multidrug resistant TB and it attacks the biosynthesis of mycolic acid, a component of cell wall. When pooled with other anti-TB drugs, it shows maximum efficiency with tolerable toxicity.28
Delamanid and Pretomanid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Eric Nuermberger, Emily Kendall
Efficacy of delamanid for tuberculosis has been evaluated in phase II trials, and phase III trial results are forthcoming. A 2-week study of early bactericidal activity first showed that delamanid lowered sputum bacterial counts in smear-positive non–MDR-TB subjects (Diacon et al., 2011). Delamanid was then evaluated in combination with a clinician-selected optimized background regimen in a randomized, placebo-controlled trial (Study 204) of 481 adult pulmonary MDR-TB patients (Gler et al., 2012). The proportion of patients who achieved the primary outcome—namely sputum culture conversion by day 57—was significantly higher in the subjects treated with delamanid plus optimized background regimen (45% and 42% with sputum culture conversion for doses of 100 mg twice daily and 200 mg twice daily, respectively) than in those receiving placebo plus optimized background regimen (30% sputum culture conversion). Delamanid also increased 2-month culture conversion among the subset of subjects who had XDR-TB at baseline (7/16 subjects with delamanid vs. 1/10 subjects who received placebo) (Gupta et al., 2015b).
The Renewal of Interest in Nitroaromatic Drugs
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Nicolas Primas, Caroline Ducros, Patrice Vanelle, Pierre Verhaeghe
A similar study on the antitubercular bicyclic nitroimidazole delamanid (14) showed that it was a potent inhibitor of L. donovani both in vitro and in vivo (Patterson et al. 2016). Delamanid (14) (EC50 = 0.087 μM) was found to be more active than the standard drug miltefosine (19) (EC50 = 3.3 μM) and the active fexinidazole metabolite (13) (EC50 = 5.3 μM) when assessed against intracellular L. donovani amastigotes. The (S)-enantiomer of delamanid was less potent, in line with its enantiomeric specificity in M. tuberculosis (Sasaki et al. 2006). Twice-daily oral dosing of delamanid (14) at 30 mg.kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Despite this favorable in vivo activity called for preclinical evaluation, the recent identification of DNDI-VL-2098 (22) (Figure 8) as a preclinical candidate by the DNDi stopped the development of delamanid (14). It was recently showed that bicyclic nitroaromatics delamanid (14), DNDI-VL-2098 (22) and (R)-PA-824 (21) were activated by a type 2 nitroreductase (Wyllie et al. 2016b). Structures of new antileishmanials leads DNDI-0690 (24) and DNDI-8219 (25) DNDI-VL-2001 (23), DNDI-VL-2098 (22) and related analogs (22, 23, 26–28).
The pharmacotherapeutic management of pulmonary tuberculosis: an update of the state-of-the-art
Published in Expert Opinion on Pharmacotherapy, 2022
Ginenus Fekadu, Dilys Yan-wing Chow, Joyce H.S. You
Delamanid, a nitroimidazole derivate that inhibits the cell wall of mycobacteria, was the second approved novel oral anti-TB agent since the approval of bedaquiline [44]. Despite the earlier reporting of favorable treatment outcomes [45], a phase 3 randomized, placebo-controlled, clinical trial of the treatment containing delamanid for TB patients with multi-drug resistance (n = 511) later reported no significant difference in the reduction in time for sputum culture to convert over a period of 24 weeks [46]. There were theoretical safety concerns of combining delamanid with bedaquiline because QT interval prolongation is a common side effect of both agents. The safety of combining delamanid and bedaquiline had been evaluated in a retrospective cohort study (n = 28) and found no additive or synergistic QT-prolonging effects [47]. The 2018 meta-analysis of individual patient data for longer MDR-TB regimens revealed no statistically significant risk reduction for unfavorable outcomes (treatment failure/relapse and death) associated with delamanid. In the 2020 WHO guidelines, delamanid was categorized as a group C medicine [10].
Prevention and treatment of tuberculosis in solid organ transplant recipients
Published in Expert Review of Anti-infective Therapy, 2020
Cybele L. Abad, Raymund R. Razonable
Classically represented by metronidazole, nitroimidazoles are currently being re-investigated for their anti-TB properties. They are thought to act on TB through anaerobiosis. Delamanid (OPC67683) is a nitro‐dihydro‐imidazooxazole that was first shown to be active against M. tuberculosis in vitro and then in the experimental mice model [102]. Its mechanism of action is probably through inhibition of mycolic acid biosynthesis [102]. Delamanid requires nitroreduction by an F420‐deazaflavin‐dependent nitroreductase (Ddn) for activation. It seems probable that delamanid also kills by producing NO or an as yet unidentified radical, and that this acts randomly within M. tuberculosis. Delamanid is currently in Phase III clinical trials for the treatment of MDR‐TB. In a landmark study [103], delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with MDR-TB. Another closely related nitroimidazole, PA‐824, is currently in Phase II trials [95].
Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children
Published in Expert Review of Clinical Pharmacology, 2018
H. Simon Schaaf, Anthony J. Garcia-Prats, Lindsay McKenna, James A. Seddon
The nitroimidazo-oxazole, delamanid (Deltyba, Otsuka Novel Products GmbH, Munich, Germany), previously known as OPC-67683 is another new drug shown to be effective when added to an MDR-TB regimen in a randomized, placebo-controlled phase 2b trial [67]. Delamanid is the first compound from a new drug class (nitro-dihydro-imidazooxazoles) that is bactericidal and specific to M. tuberculosis, including MDR strains. Following bioreduction within M. tuberculosis by the mycobacterial F420 system (as it is thought to be a prodrug), it inhibits mycolic acid biosynthesis. It has activity against both growing and dormant mycobacteria. A phase 3 randomized controlled trial of delamanid vs. placebo with an OBR for MDR-TB has recently been completed (NCT01424670) [41]; provisional results presented at the 48th Union World Conference on Lung Health in Guadalajara, Mexico, showed similar outcomes with or without delamanid under strict trial conditions, though shorter times to culture conversion were observed among those treated with delamanid. In April 2014, delamanid received conditional approval by the EMA based on phase 2b data – since then it has also been approved in Hong Kong, Japan, South Korea, Turkey, The Philippines, China, Indonesia, and India and filed in Peru and South Africa; dossiers are also reportedly being prepared for registration in Vietnam and Russia. It is also included in the complimentary list (with age restriction >6 years) of the WHO Model List of Essential Medicines (March 2017), the most effective and safe medicines needed in a health system.