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Khan_Md._Saifur_R_201605_PhD.pdf
Khan_Md_Saifur_R_201605_PhD.pdf
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THE NOVEL PHARMACOLOGICAL ACTIONS OF ISONIAZID: A PROPOSAL FOR ITS MODE OF ACTION

  • Author / Creator
    Khan, Md. Saifur R
  • Isoniazid (INH) is one of the first-line anti-tuberculosis (TB) drugs against both active and latent TB, which is caused mainly by Mycobacterium tuberculosis (Mtb). The inhibition of bacterial cell wall synthesis has been previously proposed as the mode of action of INH. However, it cannot explain a number of queries such as: (a) how does INH kill waxy granuloma-residing Mtb (since INH cannot penetrate into granuloma due to very low lipophilicity); (b) how does INH kill latent TB bacteria which do not a possess typical cell wall, and (c) why being an antibiotic, INH treatment time is remarkably long (6 to 9 months). These limitations suggest INH may have another mode of action(s) which can be deciphered by comprehending the role of INH on the host immune system. To do so, a number of in vitro studies were conducted here. In the first study, human neutrophil myeloperoxidase was found capable of forming the INH-NAD+ adduct, which inhibits cell wall synthesis (as does bacterial KatG). This suggests neutrophils could play a very important role against active TB during INH treatment. In the second study, INH showed a significant cytoprotective effect against oxidative stress-induced phagocytic cell necrosis which is the decisive cause of the granuloma degradation followed by active TB infection. This study suggests that INH ensures latency by defending necrotic degradation. In the third study, INH showed significant capacity to stimulate monocytic differentiation. Since monocyte-derived macrophages are considered as the major immune defense within granuloma due to their nitric oxide, INH-induced monocytic differentiation most likely has a contribution to both latent and active TB eradication. These three novel pharmacological actions of INH together have been presented in order to propose other modes of action of INH, which explain the previously mentioned limitations.

  • Subjects / Keywords
  • Graduation date
    2017-06:Spring 2017
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3PC2TN21
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Siraki, Arno (Pharmacy and Pharmaceutical Sciences, University of Alberta)
  • Examining committee members and their departments
    • Willmore, Bill (Biology, Carleton University)
    • Lacy, Page (Medicine, University of Alberta)
    • Ussher, John (Pharmacy and Pharmaceutical Sciences, University of Alberta)
    • Fahlman, Richard (Biochemistry, University of Alberta)