Tags

Type your tag names separated by a space and hit enter

Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis.
Pharm Res. 2016 10; 33(10):2495-505.PR

Abstract

PURPOSE

Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models.

METHODS

PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs.

RESULTS

PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment.

CONCLUSION

The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.

Authors+Show Affiliations

Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, North Carolina, 27709, USA.Department of Chemistry, University of Albany, State University of New York, Albany, New York, 12222, USA.Department of Chemistry, University of Albany, State University of New York, Albany, New York, 12222, USA.Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA. miriam_braunstein@med.unc.edu. School of Medicine, University of North Carolina at Chapel Hill, 6211 Marsico Hall, Chapel Hill, North Carolina, 27599-7290, USA. miriam_braunstein@med.unc.edu.RTI International, 3040 Cornwallis Road, Research Triangle Park, North Carolina, 27709, USA. ahickey@rti.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27351427

Citation

Young, E F., et al. "Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis." Pharmaceutical Research, vol. 33, no. 10, 2016, pp. 2495-505.
Young EF, Perkowski E, Malik S, et al. Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis. Pharm Res. 2016;33(10):2495-505.
Young, E. F., Perkowski, E., Malik, S., Hayden, J. D., Durham, P. G., Zhong, L., Welch, J. T., Braunstein, M. S., & Hickey, A. J. (2016). Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis. Pharmaceutical Research, 33(10), 2495-505. https://doi.org/10.1007/s11095-016-1974-5
Young EF, et al. Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis. Pharm Res. 2016;33(10):2495-505. PubMed PMID: 27351427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis. AU - Young,E F, AU - Perkowski,E, AU - Malik,S, AU - Hayden,J D, AU - Durham,P G, AU - Zhong,L, AU - Welch,J T, AU - Braunstein,Miriam S, AU - Hickey,Anthony J, Y1 - 2016/06/28/ PY - 2016/05/06/received PY - 2016/06/15/accepted PY - 2016/6/29/entrez PY - 2016/6/29/pubmed PY - 2017/12/6/medline KW - TB drugs KW - inhaled therapy KW - pyrazinoic acid KW - pyrazinoic acid esters KW - tuberculosis SP - 2495 EP - 505 JF - Pharmaceutical research JO - Pharm. Res. VL - 33 IS - 10 N2 - PURPOSE: Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models. METHODS: PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs. RESULTS: PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment. CONCLUSION: The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB. SN - 1573-904X UR - https://www.unboundmedicine.com/medline/citation/27351427/Inhaled_Pyrazinoic_Acid_Esters_for_the_Treatment_of_Tuberculosis_ L2 - https://doi.org/10.1007/s11095-016-1974-5 DB - PRIME DP - Unbound Medicine ER -