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Role of Plant-Based Bioflavonoids in Combating Tuberculosis
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Alka Pawar, Yatendra Kumar Satija
Pyrazinamide (PZA) is an analogue of nicotinamide. It is a prodrug, which requires conversion to pyrazinoic acid by enzyme MTB pyrazinamidase.85 It possesses an in vivo-enhanced lesion cleansing action and interferes in the production of virulence factors that highlight powerful antibacterial activity. PZA mainly attacks the cell membrane of mycobacteria. Ribosomal protein SA (RpsA), which encodes for ribosomal protein S1 (an essential protein implicated in protein translation as well as in the ribosome-sparing process of trans-translation), has been reported as the cellular target of PZA.67 Over-expression of RpsA has been correlated with PZA resistance in MTB.
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Pyrazinamide (PZA) is a synthetic nicotinamide analog which is a pro-drug activated by human and mycobacterial amidases to form pyrazinoic acid (POA). It is a highly water-soluble weak acid (log P −1.88, pKa 0.5, MW 123.11). The mechanism of action remains disputed but it appears that accumulation of protonated POA due to defective efflux mechanisms specific to Mycobacterium tuberculosis damages many important cellular processes including fatty acid synthesis, trans-translation, and energy metabolism.55In vitro MIC99s for wild-type strains range from <8 to 64 μg/mL.56 The spontaneous rate of mutations conferring resistance is approximately 1 in 105.57 Resistance is associated with mutations in the pncA gene and less commonly in the rpsA gene encoding the ribosomal S1 protein.5
High-Performance Liquid Chromatography
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Joel J. Kirschbaum, Adorjan Aszalos
After oral administration, pyrazinamide is hydrolyzed to pyrazinoic acid, which was determined at concentrations of 1–10 μg/ml in 300 μl of serum with its metabolite, 5-hydroxypyrazinoic acid [80]. An amino column and precolumn, 40 × 4.6 mm, were used with a mobile phase of 0.01 M ammonium phosphate buffer, pH 4.2-acetonitrile (30:70) flowing at 2 ml/min through a 254 nm detector.
Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs
Published in Expert Review of Anti-infective Therapy, 2020
Liliana Rodrigues, Pedro Cravo, Miguel Viveiros
In the last years, several efflux inhibitors of plant origin have been described. Reserpine, piperine, farnesol, luteolin and biochanin A are among the most used in M. tuberculosis. The alkaloid reserpine was used for many years as an antihypertensive, but its toxicity limited its clinical use [56,86]. Nevertheless, this compound has been widely used in the in vitro evaluation of the activity of antimicrobial agents, namely in mycobacteria. For example, reserpine reduced ciprofloxacin resistance mediated by Rv2686 and decreased the MIC of isoniazid in M. smegmatis expressing mmpL7 [22,39]. In addition, reserpine increased susceptibility to isoniazid in M. bovis BCG and in M. tuberculosis susceptible and resistant strains [88,89]. This compound has also been shown to inhibit the pyrazinoic acid efflux pump, thus, increasing susceptibility to pyrazinamide in M. tuberculosis [90].
Berberis aristata Ameliorates Testicular Toxicity Induced by Combination of First-Line Tuberculosis Drugs (Rifampicin + Isoniazid + Pyrazinamide) in Normal Wistar Rats
Published in Journal of Dietary Supplements, 2019
Radhika Sharma, Neha Goyal, Mandakini Singla, Vijay Lakshmi Sharma
As a result of cellular metabolism, reactive oxygen species (ROS) are produced in the body; at low concentration, they do not cause any harm, but at higher concentration they can cause adverse modifications to the cells and their components such as DNA, lipids, and proteins. Increase in production of ROS is a primary factor responsible for testicular toxicity. In our body, isoniazid is metabolized as isoniazid hydrazide or acetyl isoniazid by action of enzyme n-acetyl transferase (NAT-2) that further gets converted into hydrazine, which is a harmful metabolite leading to formation of free radicals (Ebrahimzadeh et al., 2009). Rifampicin in combination with isoniazid catalyzes the hydrolysis of isoniazid with the help of enzyme isoniazid hydrolase. Pyrazinamide metabolizes into 5-hydroxy pyrazinoic acid; the mechanism of action of pyrazinamide is not known, but it is thought to enhance the toxicity.
Non-tuberculous mycobacteria: a disease beyond TB and preparedness in India
Published in Expert Review of Respiratory Medicine, 2021
Surendra K Sharma, Vishwanath Upadhyay
Only a few Indian studies have reported treatment details and outcome in NTM-PD and this can be attributed to the following reasons: (i) NTM-PD patients were probably treated empirically as TB patients; (ii) most of the Indian studies have reported NTM data generated in the laboratories; (iii) clinical correlation of isolated NTM species was not done. None of the studies has provided information on lung surgery and non-pharmacological treatment such as pulmonary rehabilitation including chest physiotherapy and breathing exercises. Likewise, there is a lack of information on drug susceptibility testing (DST), treatment details including number of drugs, intermittent versus daily treatment and occurrence of adverse and serious adverse events. However, in patients with NTM-PD, a macrolide based 3–4 drug regimen should be administered on the basis of the severity of disease [7]. Although, there are limited clinical trials defining optimal number of drugs used for NTM-PD treatment [4,74]. DST as such is controversial in the management of NTM disease. It is recommended for MAC against macrolides and amikacin when there is a lack of clinical, microbiological and radiological response [7]. Similarly, in M. abscessus, testing of mutations in erm41 and 23S rRNA genes conferring resistance to macrolide should be considered and phenotypic DST for macrolides (on day 3rd and 14th) and amikacin is suggested [7,9]. In the case of M. kansasii pulmonary disease, clinical presentation is similar to pulmonary TB and the treatment outcome with anti-TB drugs (rifampicin, isoniazid and ethambutol) is uniformly good and therefore, DST for rifampicin is suggested only when there is no response to treatment [7]. Pyrazinamide is not effective in its treatment because of the absence of pyrazinamidase in NTM, which is essential for its conversion into its active compound pyrazinoic acid [75].