In vitro evaluation of novel inhalable dry powders consisting of thioridazine and rifapentine for rapid tuberculosis treatment

Parumasivam, Thaigarajan; Chan, John Gar Yan; Pang, Angel; Quan, Diana; Triccas, James A.; Britton, Warwick J.; Chan, Hak‐Kim

doi:10.1016/j.ejpb.2016.07.014

Cited by 11 publications

(3 citation statements)

References 41 publications

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“…Promising examples of the future use of thioridazine in new short term therapeutic regimens against any form of antibiotic resistance of Mtb come from the recent studies that demonstrated the possibility of effectively using nanoparticles containing thioridazine and rifampicin for rapid tuberculosis treatment in vitro and in a zebrafish model [101,102]. The use of TZ as a therapeutic adjuvant for anti-TB therapy is currently being expanded in Argentina and India.…”

Section: Discussionmentioning

confidence: 99%

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

Amaral

Viveiros

2017

Antibiotics

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This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against all encountered Mycobacterium tuberculosis (Mtb) regardless of its antibiotic resistance phenotype, as well as in vivo as a therapy for mice infected with multi-drug resistant strains of Mtb, or for human subjects infected with extensively drug resistant (XDR) Mtb. The mechanisms of action by which TZ brings about successful therapeutic outcomes are presented in detail.

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Section: Discussionmentioning

confidence: 99%

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

Amaral

Viveiros

2017

Antibiotics

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“…In our previous studies, we have established that solubilized rifapentine was tolerated by human airway epithelial (Calu-3), human alveolar basal epithelial (A549), and human THP-1 monocyte-derived macrophage cell lines up to a concentration of 60 μg/mL. ,,, In contrast, tobramycin, a currently FDA-approved drug for treatment of cystic fibrosis via the inhalation route, is nontoxic to lung epithelial cells up to a concentration of 1.0 g/mL . However, the cytotoxicity of rifapentine could be overestimated in the in vitro assays as the drug was dissolved in an organic solvent (i.e., DMSO) prior to use in the assays, while a gradual dissolution is expected after it is deposited in the lungs.…”

Section: Discussionmentioning

confidence: 99%

Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation

et al. 2016

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Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.

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“…In addition to first-line antituberculosis drugs, the adjuvant treatment with efflux transporters inhibitors [11], such as verapamil or thioridazine [11,12,13] has demonstrated to be beneficial in increasing the intracellular concentrations of antibacterials [11,12,13,14,15,16] shortening the duration of treatment [12,17], and reducing the onset of drug resistance. Resistance to rifampicin and isoniazid acquired by mutation establishes MDR strains.…”

Section: Introductionmentioning

confidence: 99%

Sodium Hyaluronate Nanocomposite Respirable Microparticles to Tackle Antibiotic Resistance with Potential Application in Treatment of Mycobacterial Pulmonary Infections

et al. 2019

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Tuberculosis resistant cases have been estimated to grow every year. Besides Mycobacterium tuberculosis, other mycobacterial species are responsible for an increasing number of difficult-to-treat infections. To increase efficacy of pulmonary treatment of mycobacterial infections an inhalable antibiotic powder targeting infected alveolar macrophages (AMs) and including an efflux pump inhibitor was developed. Low molecular weight sodium hyaluronate sub-micron particles were efficiently loaded with rifampicin, isoniazid and verapamil, and transformed in highly respirable microparticles (mean volume diameter: 1 μm) by spray drying. These particles were able to regenerate their original size upon contact with aqueous environment with mechanical stirring or sonication. The in vitro drugs release profile from the powder was characterized by a slow release rate, favorable to maintain a high drug level inside AMs. In vitro antimicrobial activity and ex vivo macrophage infection assays employing susceptible and drug resistant strains were carried out. No significant differences were observed when the powder, which did not compromise the AMs viability after a five-day exposure, was compared to the same formulation without verapamil. However, both preparations achieved more than 80% reduction in bacterial viability irrespective of the drug resistance profile. This approach can be considered appropriate to treat mycobacterial respiratory infections, regardless the level of drug resistance.

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In vitro evaluation of novel inhalable dry powders consisting of thioridazine and rifapentine for rapid tuberculosis treatment

Cited by 11 publications

References 41 publications

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation

Sodium Hyaluronate Nanocomposite Respirable Microparticles to Tackle Antibiotic Resistance with Potential Application in Treatment of Mycobacterial Pulmonary Infections

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