Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial

Padmapriyadarsini, Chandrasekaran; Bhavani, Perumal Kannabiran; Natrajan, Mohan; Ponnuraja, C; Kumar, Hemanth; S, Gomathy; Guleria, Randeep; Jawahar, Shaheed M; Singh, Manjula; Balganesh, Tanjore S.; Swaminathan, Soumya

doi:10.1136/bmjopen-2018-024363

Cited by 33 publications

(29 citation statements)

References 20 publications

(22 reference statements)

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“…In parallel, the portfolio is sure to see 'adjunct therapy' compounds that modulate the host response [92][93][94][95]. Repurposed candidate drugs offer faster development options and are also expected to enrich the TB portfolio [97][98][99][100][101][102][103]. These could also be weapons against the 'persister' population.…”

Section: Phenotypic-screening Efforts At Astrazeneca Indiamentioning

confidence: 99%

Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Bandodkar¹,

Shandil

Bhat³

et al. 2020

Applied Sciences

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After several years of limited success, an effective regimen for the treatment of both drug-sensitive and multiple-drug-resistant tuberculosis is in place. However, this success is still incomplete, as we need several more novel combinations to treat extensively drug-resistant tuberculosis, as well newer emerging resistance. Additionally, the goal of a shortened therapy continues to evade us. A systematic analysis of the tuberculosis drug discovery approaches employed over the last two decades shows that the lead identification path has been largely influenced by the improved understanding of the biology of the pathogen Mycobacterium tuberculosis. Interestingly, the drug discovery efforts can be grouped into a few defined approaches that predominated over a period of time. This review delineates the key drivers during each of these periods. While doing so, the author’s experiences at AstraZeneca R&D, Bangalore, India, on the discovery of new antimycobacterial candidate drugs are used to exemplify the concept. Finally, the review also discusses the value of validated targets, promiscuous targets, the current anti-TB pipeline, the gaps in it, and the possible way forward.

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Section: Phenotypic-screening Efforts At Astrazeneca Indiamentioning

confidence: 99%

Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Bandodkar¹,

Shandil

Bhat³

et al. 2020

Applied Sciences

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“…The treatment of TB mainly depends on the special anti-TB regimen involving multiple medications. Notably, the regimen is well known for a long duration and inevitable drug side effects, which results in poor adherence to medication, and further leads to the emergence of drug resistance [3]. Given the current situation, alternative anti-TB drugs with minimal drug toxicity are needed to drive the anti-TB regimen more safe and effective.…”

Section: Introductionmentioning

confidence: 99%

“…Metformin, a first-line medication for the treatment of type 2 diabetes, showed the potential for an anti-TB treatment in recent studies [3–8]. The drug was a widely used therapy among diabetics with limited adverse events.…”

Section: Introductionmentioning

confidence: 99%

Impact of metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic review

Xia

et al. 2019

BMC Infect Dis

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Background Tuberculosis (TB) remains one of the infectious diseases with a leading cause of death among adults worldwide. Metformin, a first-line medication for the treatment of type 2 diabetes, may have potential for treating TB. The aims of the present systematic review were to evaluate the impact of metformin prescription on the risk of tuberculosis diseases, the risk of latent TB infection (LTBI) and treatment outcomes of tuberculosis among patients with diabetic mellitus. Methods Databases were searched through March 2019. Observational studies reporting the effect of metformin prescription on the risk and treatment outcomes of TB were included in the systematic review. We qualitatively analyzed results of included studies, and then pooled estimate effects with 95% confidence intervals (CIs) of different outcome using random-effect meta-analyses. Results This systematic review included 6980 cases from 12 observational studies. The meta-analysis suggested that metformin prescription could decrease the risk of TB among diabetics (pooled odds ratio [OR], 0.38; 95%CI, 0.21 to 0.66). Metformin prescription was not related to a lower risk of LTBI (OR, 0.73; 95%CI, 0.30 to 1.79) in patients with diabetes. Metformin medication during the anti-tuberculosis treatment is significantly associated with a smaller TB mortality (OR, 0.47; 95%CI, 0.27 to 0.83), and a higher probability of sputum culture conversion at 2 months of TB disease (OR, 2.72; 95%CI, 1.11 to 6.69) among patients with diabetes. The relapse of TB was not statistically reduced by metformin prescription (OR, 0.55; 95%CI, 0.04 to 8.25) in diabetics. Conclusions According to current observational evidence, metformin prescription significantly reduced the risk of TB in patients with diabetes mellitus. Treatment outcomes of TB disease could also be improved by the metformin medication among diabetics.

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“…Novita et al showed that metformin enhances the bactericidal effect of anti-tuberculosis treatment via autophagy in patients with tuberculosis and diabetes (Novita et al, 2019). Another study was designed to assess the effect of metformin by means of a detailed autophagy biomarker panel in tuberculosis (Padmapriyadarsini et al, 2019). Chloroquine significantly decreased HCV-RNA in Hepatitis C in a quadruple-blind, randomized Phase IV study (Peymani et al, 2016).…”

Section: Infectious Diseasesmentioning

confidence: 99%

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

2020

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Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e. protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/ mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second-and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy in vitro and in vivo. mTOR is a downstream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.

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Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial

Cited by 33 publications

References 20 publications

Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Impact of metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic review

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

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