Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections

Amaral, Leonard; Viveiros, Miguel

doi:10.1016/j.ijantimicag.2012.01.012

Cited by 73 publications

(60 citation statements)

References 70 publications

(93 reference statements)

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“…Reduction of the dose of both revealed a synergistic activity between the antibiotic and the non-antibiotic [53]. Similar synergistic effects have been observed between thioridazine in combination with antibiotics for treating extensively drug-resistant infections of pulmonary tuberculosis [54,55].…”

Section: Consequences Of the Two-sided Effect Of Psychotherapeutic Drsupporting

confidence: 71%

“…Yes [62][63][64][65][66] Can the synergy between psychotherapeutics and "classical" antibiotics/chemotherapeutics be expoited (for example to reduce the dose)? Yes [53,56,[67][68][69] Can new antibiotics be developed from the already known non-antibiotics Yes [19,54,55,64,[70][71][72][73][74] Can "purer" drugs be developed by utilizing stereo-specificity? Up until 1985, 85% of all drugs were mixtures Yes [71,72,75,[76][77][78] Will this polypharmacy have any influence on the pharmacokinetics or pharmacodynamics of clinical treatment for the patient/host Yes [60,75,[79][80][81][82][83][84][85][86] up until now, have not been able to treat.…”

Section: Perspective Expectation Referencesmentioning

confidence: 99%

See 1 more Smart Citation

The Accepted “Clinical Interaction Model”: A Special Case of Reality

Jeh¹,

Fey²

2017

J Bioequiv Availab

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Section: Consequences Of the Two-sided Effect Of Psychotherapeutic Drsupporting

confidence: 71%

Section: Perspective Expectation Referencesmentioning

confidence: 99%

The Accepted “Clinical Interaction Model”: A Special Case of Reality

Jeh¹,

Fey²

2017

J Bioequiv Availab

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“…Phenothiazines have the ability to inhibit the bacterial efflux pump that protects the bacterial cell against harmful substances [59]. Thioridazine not only inhibits specific efflux pump systems but also the expression of genes that code for efflux pumps of M. tuberculosis [61].…”

Section: Phenothiazines: Thiorizadinementioning

confidence: 99%

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

Alsaad

Wilffert

Altena

et al. 2013

European Respiratory Journal

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Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis.A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012.We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, cotrimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.@ERSpublications Six antimicrobial drugs are not listed in WHO guidelines on MDR-TB treatment but could offer potential for TB treatment

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“…After the discovery of chlorpromazine (2) in 1952, more than 5000 phenothiazine derivatives were synthesized and evaluated biological activity, and many substances had been used clinically as anticonvulsant, antipsychotic, antiemetic, antimicrobial, antihistamine, antitumor agent 4 . Several phenothiazine derivatives such as chlorpromazine, thioridazine (3) had showed antituberculosis activity which able to circumvent the MDR resistance [5][6][7][8] . So this tricyclic basic core had been chosen as a part of new antituberculosis structure.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and bioevaluation of new pyranophenothiazine derivatives

Nguyen¹,

Dufat²,

Michel³

et al. 2017

Pharm Sci Asia

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Until now, tuberculosis is always a dangerous infectious disease. Because of the enlargement of multidrug-resistant strains (MDR-TB), the need of new drugs becomes more important. Fusing of 2 pharmacophores (phenothiazine and benzopyran), we intend to synthesize some new pyranophenothiazine derivatives, and evaluate their antituberculosis activities. The designed compounds were prepared using conventional synthetic methods with all PA chemical agents (from Merk, TCI, Sigma). The structure of all synthesized compounds had been confirmed by analysis of NMR and MS spectra. Antimycobacterial activity of the synthesized compounds on Mycobacterium bovis BCG (or on the virulent strain Mycobacterium tuberculosis H37Rv for the most promising compounds) had been determined using the Microdilution resazurin assay. 2 compounds 8 and 9 were obtained by Claisen rearrangement of intermediate dimethylpropargyl ether. The sulfoxide and (+)cis-diol sulfoxide derivatives were obtained by oxydation, and the dihydro-derivatives -by reduction of the leader compounds. The anti-tuberculosis activities of 12 synthesized compounds were evaluated. Only the leading compound of linear structure (pyrano[b]phenothiazine) and 2 non-sulfoxide derivatives of angular structure (pyrano[a]phenothiazine) exhibited a mild inhibiting activity on the tested tuberculosis source. 12 new pyrano-phenothiazine compounds have been prepared and bioevaluated. The results showed that 3 compounds exhibited a mild inhibiting activity on the tested tuberculosis source. These structural requirements will be taken into account for the design of further analogues in pyranophenothiazine series.

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Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections

Cited by 73 publications

References 70 publications

The Accepted “Clinical Interaction Model”: A Special Case of Reality

The Accepted “Clinical Interaction Model”: A Special Case of Reality

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

Synthesis and bioevaluation of new pyranophenothiazine derivatives

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