Thioridazine: resurrection as an antimicrobial agent?

Thanacoody, H K Ruben

doi:10.1111/j.1365-2125.2007.03021.x

Cited by 69 publications

(60 citation statements)

References 69 publications

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“…This resulted in 20 M test compounds (6.7 M final in 15 l). Compounds were added to 320 wells (columns [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Column 2 was used for the negative control (no VLA-4 ligand added).…”

Section: Methodsmentioning

confidence: 99%

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Discovery of Very Late Antigen-4 (VLA-4, α4β1 Integrin) Allosteric Antagonists

Chigaev

Williams

et al. 2011

Journal of Biological Chemistry

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Integrins are cell adhesion receptors that mediate cell-tocell, or cell-to-extracellular matrix adhesion. They represent an attractive target for treatment of multiple diseases. Two classes of small molecule integrin inhibitors have been developed. Competitive antagonists bind directly to the integrin ligand binding pocket and thus disrupt the ligand-receptor interaction. Allosteric antagonists have been developed primarily for ␣ L ␤ 2 -integrin (LFA-1, lymphocyte function-associated antigen-1). Here we present the results of screening the Prestwick Chemical Library using a recently developed assay for the detection of ␣ 4 ␤ 1 -integrin allosteric antagonists. Secondary assays confirmed that the compounds identified: 1) do not behave like competitive (direct) antagonists; 2) decrease ligand binding affinity for VLA-4 ϳ2 orders of magnitude; 3) exhibit antagonistic properties at low temperature. In a cell based adhesion assay in vitro, the compounds rapidly disrupted cellular aggregates. In accord with reports that VLA-4 antagonists in vivo induce mobilization of hematopoietic progenitors into the peripheral blood, we found that administration of one of the compounds significantly increased the number of colony-forming units in mice. This effect was comparable to AMD3100, a well known progenitor mobilizing agent. Because all the identified compounds are structurally related, previously used, or currently marketed drugs, this result opens a range of therapeutic possibilities for VLA-4-related pathologies.

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Section: Methodsmentioning

confidence: 99%

“…Because these compounds are previously used or currently marketed drugs (17)(18)(19), which are known to possess immunosuppressive properties (20), this effect on VLA-4 ligand binding provides a plausible explanation for the mechanism of immunosuppression (21).…”

mentioning

confidence: 99%

Discovery of Very Late Antigen-4 (VLA-4, α4β1 Integrin) Allosteric Antagonists

Chigaev

Williams

et al. 2011

Journal of Biological Chemistry

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“…When thioridazine is administered orally it is rapidly absorbed, with peak plasma concentrations occurring within 2-3 h. Thioridazine is widely distributed in tissues like the liver, blood and kidney [19,20], yet it is distributed less favourably to the brain [45]. It is not useful for treatment of cavitary pulmonary M. tuberculosis because the concentration of thioridazine required for killing or inhibiting M. tuberculosis outside the macrophage exceeded the concentration that could be achieved in patients receiving standard dosages [43].…”

Section: Clinical Studiesmentioning

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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“…It is, however, debatable whether the QTc pro longation issue would have sunk thioridazine quite so conclusively had the safety profiles of the second-generation antipsychotics with which it was in competition been as comprehensively under stood then as they are now (see Owens 2012, this issue). Thioridazine and its metabolites do continue to stimulate interest as potentially cheap and safe antituberculous and anti malarial agents for poorer countries (Amaral 2001;Thanacoody 2007).…”

Section: Pericyazine (Periciazine) (Table 3)mentioning

confidence: 99%

Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1)

Owens

2012

Adv. psychiatr. treat

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SummaryA number of pragmatic trials have cast doubt on the concept of ‘atypicality’ in relation to antipsychotic drugs, and some commentators have argued that the dichotomy between ‘typical’ (‘first-generation’) and ‘atypical’ ('second-generation’) compounds is artificial and should be abandoned, leaving the entire class of antipsychotics available for consideration in more individualised treatment planning. However, younger psychiatrists now gain little or no experience in the use of older antipsychotics. This is the first of two articles addressing practical issues for consideration in prescribing the older antipsychotics available in the UK. It covers background, including the fundamental clinical action of antipsychotics, the nature of drug licensing and identification of pharmacological parameters that may be of value in prescribing decisions, and discusses the phenothiazines: chlorpromazine, promazine, levomepromazine, pericyazine, perphenazine, trifluoperazine and prochlorperazine.

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Thioridazine: resurrection as an antimicrobial agent?

Cited by 69 publications

References 69 publications

Discovery of Very Late Antigen-4 (VLA-4, α4β1 Integrin) Allosteric Antagonists

Discovery of Very Late Antigen-4 (VLA-4, α4β1 Integrin) Allosteric Antagonists

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1)

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