Pyrazinoic Acid Amide-An Agent Active Against Experimental Murine Tuberculosis

Solotorovsky, Morris; Gregory, Francis J.; Ironson, Elliott J.; Bugie, Elizabeth; O'Neill, Richard; Pfister, rd K.

doi:10.3181/00379727-79-19447

Cited by 39 publications

(24 citation statements)

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“…Following a small clinical study on its use in treating patients, 11,12 it was then studied at Cornell University using the long-term mouse model. 12 Mice were infected and treated with a combination of PZA with INH, to prevent rapid emergence of PZA resistance.…”

Section: ■ Introductionmentioning

confidence: 99%

Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy

et al. 2015

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Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 μm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 μm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ∼180 °C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy.

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Section: ■ Introductionmentioning

confidence: 99%

Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy

et al. 2015

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“…Its discovery as a TB drug was based on a serendipitous observation that nicotinamide had certain activity against mycobacteria in animal models (3). Subsequent synthesis of nicotinamide analogs and direct testing in the mouse model of tuberculosis (TB) infection without in vitro testing led to the identification of PZA as a most active agent (4, 5). Before 1970s, PZA was mainly used as a second-line TB drug for the treatment of drug resistant TB or in treatment of relapsed TB because of the hepatic toxicity caused by higher PZA dosage (3.0 g) and longer treatment used in earlier clinical studies.…”

Section: The History: the Unusual Discovery And The Roller Coaster Ofmentioning

confidence: 99%

Mechanisms of Pyrazinamide Action and Resistance

et al. 2014

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PZA is a unique anti-tuberculosis drug that plays a key role in shortening the TB therapy. PZA kills non-replicating persisters that other TB drugs fail to kill, and thus making it an essential drug for inclusion in any drug combinations for treating drug susceptible and drug-resistant TB such as MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation and perhaps pantothenate /coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase involved in conversion of the prodrug PZA to the active form POA. Mutations in the drug target RpsA are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype based PZA susceptibility testing is not reliable due to false resistance, and sequencing of the pncA gene represents a more rapid, cost-effective and more reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a ‘tipping point’ that inspires new efforts at developing a new type of antibiotics or drugs that target non-replicating persisters for improved treatment of not only TB but also other persistent bacterial infections.

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“…For instance, isoniazid (INH) was discovered serendipitously after observing the growth inhibiting property of its precursor molecule, nicotinamide. Similarly, pyrazinamide would not have been discovered had it not been tested directly in animals, an approach that would be highly unusual today [15]. Prior to the determination of the sequence of the Mtb genome [16], most of the screening activities in TB research relied on a small number of existing targets and whole cell screening.…”

Section: Different Targets Available For Tb Therapy: Old and Newmentioning

confidence: 99%

Biopharmaceutics, Pharmacokinetics and Pharmacodynamics of Antituberculosis Drugs

Budha¹,

Lee²,

Meibohm³

2008

CMC

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Tuberculosis (TB) is the leading cause of mortality due to a single infectious agent. The currently used combination drug regimens produce cure rates that exceed 95%, given good patient adherence during the multiple months treatment period. However the recent surge in HIV infections and the synergy between HIV and TB as well as the emergence of resistance resulted in an unforeseen increase in the number of TB cases, including multi-drug resistant (MDR) and extensively-drug resistant (XDR) forms of TB. Consequently, there is an urgent need to develop novel, fast acting antituberculosis drugs with high potency that can provide treatment options for all forms of TB. It is well known that the current TB drugs exhibit differences in their in vivo activity profile and these differences are largely determined by their pharmacodynamics (PD), i.e. intrinsic antibacterial activity, biopharmaceutical properties such as solubility and permeability, and pharmacokinetic (PK) properties such as drug exposure, tissue distribution, and protein binding. An understanding of the relationships among these properties is considered key for a rational use of antituberculosis therapeutics. The current review provides a comprehensive summary of physicochemical/biopharmaceutical, PK, and PD properties of currently used antituberculosis drugs and novel agents under development. Also, a brief review of PK/PD parameters of current TB drugs is given and properties of a desirable TB drug target and drug molecule are outlined. The information provided herewith may be useful in the optimization of biopharmaceutical and PK/PD characteristics in the development of novel TB therapeutics and in the design of optimal treatment regimens.

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Pyrazinoic Acid Amide-An Agent Active Against Experimental Murine Tuberculosis

Cited by 39 publications

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Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy

Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy

Mechanisms of Pyrazinamide Action and Resistance

Biopharmaceutics, Pharmacokinetics and Pharmacodynamics of Antituberculosis Drugs

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