A novel codrug made of the combination of ethionamide and its potentiating booster: synthesis, self-assembly into nanoparticles and antimycobacterial evaluation

Pastor, Alexandra; Machelart, Arnaud; Li, Xue; Willand, Nicolas; Baulard, Alain R.; Brodin, Priscille; Desmaële, Didier

doi:10.1039/c9ob00680j

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…Interestingly, (29) was found able to self-assemble into nanoparticles in a very stable way, which displayed a drug loading of about 80%. Moreover, a suspension of these nanoparticles was found very active in a mouse model, upon direct intranasal administration into the lung [86]. This compound represents a further example of the flexibility and effectiveness of the multitargeting approach.…”

Section: Ethionamide and Ethionamide Booster Co-administrationmentioning

confidence: 92%

“…However, these nanoparticles displayed drug loading only of 5%. A great improvement was achieved by the synthesis of a co-drug (29), able to self-associate into nanoparticles (Figure 10) [86]. The new compound was obtained by tethering N-hydroxymethyl derivatives of both (27) and (28) through a glutaric linker, potentially cleavable intracellularly by esterase.…”

Section: Ethionamide and Ethionamide Booster Co-administrationmentioning

confidence: 99%

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Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis

2020

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Tuberculosis is still an urgent global health problem, mainly due to the spread of multi-drug resistant M. tuberculosis strains, which lead to the need of new more efficient drugs. A strategy to overcome the problem of the resistance insurgence could be the polypharmacology approach, to develop single molecules that act on different targets. Polypharmacology could have features that make it an approach more effective than the classical polypharmacy, in which different drugs with high affinity for one target are taken together. Firstly, for a compound that has multiple targets, the probability of development of resistance should be considerably reduced. Moreover, such compounds should have higher efficacy, and could show synergic effects. Lastly, the use of a single molecule should be conceivably associated with a lower risk of side effects, and problems of drug–drug interaction. Indeed, the multitargeting approach for the development of novel antitubercular drugs have gained great interest in recent years. This review article aims to provide an overview of the most recent and promising multitargeting antitubercular drug candidates.

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Section: Ethionamide and Ethionamide Booster Co-administrationmentioning

confidence: 92%

Section: Ethionamide and Ethionamide Booster Co-administrationmentioning

confidence: 99%

Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis

2020

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“…Therefore, our results provide informed PK/PD support for the most recent guidelines, which suggest using other, more-potent drugs while deprioritizing ETA (2). Of interest, however, companion drugs consisting of inhalable ETA and a booster are being investigated for an improved antimycobacterial activity and toxicity profile, which could reintroduce ETA as a desirable agent for MDR-TB patients (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Al‐Shaer

Märtson

Alghamdi

et al. 2020

Antimicrob Agents Chemother

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Ethionamide (ETA), an isonicotinic acid derivative, is part of multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines deprioritized ETA due to potential less effectiveness compared to other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens to assess target attainment. This study included subjects from four different sites, including both healthy volunteers and patients with MDR-TB. The TB centers included were two in the US and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, 1,000-2,250 mg total daily regimens were simulated, and target attainment using published minimum inhibitory concentrations (MICs) and 1.0-log kill and resistance suppression targets were assessed using Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag-time. The mean (SD) final population parameter estimates were: absorption rate constant 1.02 hr-1 (1.11), elimination rate constant 0.69 hr-1 (0.46), volume of distribution 104.16 L (59.87), and lag-time 0.43 hr (0.32). Total daily dose of 1,500 mg or more was needed to achieve ≥90% 1.0-log kill target attainment at MIC 1 mg/L, and 2,250 mg/day achieved 80% resistance suppression target attainment at MIC 0.5 mg/L. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting current recommendations for ETA deprioritization.

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“…Firstly, ETH and its booster BDM43266 were chemically linked to produce a co-drug [ 128 ]. Remarkably, the co-drug was capable of self-assembling into NPs of approximately 200 nm.…”

Section: The Potential Of Nanoparticles Regarding the Treatment Of Tu...mentioning

confidence: 99%

Nanosized Drug Delivery Systems to Fight Tuberculosis

2023

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Tuberculosis (TB) is currently the second deadliest infectious disease. Existing antitubercular therapies are long, complex, and have severe side effects that result in low patient compliance. In this context, nanosized drug delivery systems (DDSs) have the potential to optimize the treatment’s efficiency while reducing its toxicity. Hundreds of publications illustrate the growing interest in this field. In this review, the main challenges related to the use of drug nanocarriers to fight TB are overviewed. Relevant publications regarding DDSs for the treatment of TB are classified according to the encapsulated drugs, from first-line to second-line drugs. The physicochemical and biological properties of the investigated formulations are listed. DDSs could simultaneously (i) optimize the therapy’s antibacterial effects; (ii) reduce the doses; (iii) reduce the posology; (iv) diminish the toxicity; and as a global result, (v) mitigate the emergence of resistant strains. Moreover, we highlight that host-directed therapy using nanoparticles (NPs) is a recent promising trend. Although the research on nanosized DDSs for TB treatment is expanding, clinical applications have yet to be developed. Most studies are only dedicated to the development of new formulations, without the in vivo proof of concept. In the near future, it is expected that NPs prepared by “green” scalable methods, with intrinsic antibacterial properties and capable of co-encapsulating synergistic drugs, may find applications to fight TB.

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A novel codrug made of the combination of ethionamide and its potentiating booster: synthesis, self-assembly into nanoparticles and antimycobacterial evaluation

Abstract: A self-assembling codrug of ethionamide with its booster induced reduction of the bacterial load in mycobacterium-infected mice upon intranasal administration.

Cited by 10 publications

References 32 publications

Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis

Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Nanosized Drug Delivery Systems to Fight Tuberculosis

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