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Pharmaceutical Chemistry Journal 2022The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole...
The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole derivatives. ETH and PTH were reacted with coumarin intermediates () to provide the target compounds ( and , respectively). Spectral studies confirmed the assigned structures of . The Microplate Alamar Blue Assay was utilized to evaluate the anti-TB activity of compounds against H37Rv strain in comparison to ETH, PTH, isoniazid (INH), and pyrazinamide (PYZ) as standard drugs. The cytotoxicity studies were carried out versus HepG2 and Vero cell lines. In addition. molecular docking studies of concerning the DprE1 enzyme and the evaluation of physicochemical and pharmacokinetic parameters were performed. Compounds and displayed equal minimum inhibitory concentration (MIC) values in comparison to INH (3.125 μg/ml) and PYZ (3.125 μg/ml), whereas and displayed better MIC values (1.562 μg/mL) than INH and PYZ. All compounds presented better anti-TB potential than ETH (6.25 μg/mL) and PTH (6.25 μg/mL). The studies of toxicity revealed that were safe up to 300 μg/mL concentration versus Vero and HepG2 cell lines. The molecular docking studies suggested that could possess anti-TB activity through the inhibition of the DprE1 enzyme. The studies showed that followed Lipinski's rule (drug-likeliness) and exhibited better gastrointestinal absorption than BTZ043 and macozinone. In conclusion, the ETH and PTH-based coumarinyl-thiazole template can help developing selective DprE1 enzyme inhibitors as potent anti-TB agents.
PubMed: 36531826
DOI: 10.1007/s11094-022-02782-0 -
Infection & Chemotherapy Dec 2013Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration required... (Review)
Review
Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared with drug-susceptible TB. The efficacy of treatment for MDR-TB is poorer than that for drug-susceptible TB. The selection of drugs in MDR-TB is based on previous treatment history, drug susceptibility results, and TB drug resistance patterns in the each region. Recent World Health Organization guidelines recommend the use of least 4 second-line drugs (a newer fluoroquinolone, an injectable agent, prothionamide, and cycloserine or para-aminosalicylic acid) in addition to pyrazinamide. The kanamycin is the initial choice of injectable durgs, and newer fluoroquinolones include levofloxacin and moxifloxacin. For MDR-TB, especially cases that are extensively drug-resistant, group 5 drugs such as linezolid, clofazimine, and amoxicillin/clavulanate need to be included. New agents with novel mechanisms of action that can be given for shorter durations (9-12 months) for MDR-TB are under investigation.
PubMed: 24475350
DOI: 10.3947/ic.2013.45.4.367 -
SAGE Open Medical Case Reports 2022Among drug-related complications, drug-related nephrotoxicity is the commonest. It is the cause for 7% of all drug-related toxicities among inpatients and accounts for...
Among drug-related complications, drug-related nephrotoxicity is the commonest. It is the cause for 7% of all drug-related toxicities among inpatients and accounts for 20% to 30% of acute renal failure. Acute interstitial nephritis is one of the drug-related adverse reactions and occurs due to a drug-related type 4 hypersensitivity reaction. In this case report, we reported acute interstitial nephritis that causes acute renal failure (acute kidney injury) in a patient taking Prothionamide therapy. This drug-related side effect had not been reported. In this case report, we report a patient who develops fatigability, rash, and intermittent fever after 14 days of taking the drug Prothionamide. The main aims of this case report are to use it as a pharmacovigilance report for drug-producing companies and to consider a further study on this side effect. It is also an alert for clinicians to consider this side effect when patients develop acute interstitial nephritis while taking Prothionamide.
PubMed: 35585853
DOI: 10.1177/2050313X221094076 -
Antimicrobial Agents and Chemotherapy Sep 2022Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains...
Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight <50 kg and 750 mg/day for weight >50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values <0.4 μg/mL in 1.0-log kill target. However, a fixed dose of 750 mg/day was the only regimen that achieved the target resistance suppression of ≥90% for MIC values of <0.2 μg/mL. In conclusion, fixed-dose prothionamide (750 mg/day), regardless of weight-band, was appropriate for adult MDR-TB patients with weights of 40 to 67 kg.
Topics: Adult; Antitubercular Agents; Humans; Prothionamide; Tuberculosis, Multidrug-Resistant
PubMed: 35938799
DOI: 10.1128/aac.01893-21 -
The World Allergy Organization Journal May 2023To evaluate drug resıstant tuberculosis patients who developed drug hypersensitivity to antituberculosis drug.
OBJECTIVE
To evaluate drug resıstant tuberculosis patients who developed drug hypersensitivity to antituberculosis drug.
METHODS
This was a retrospective study. The primary aim of the study is to determine the demographic and clinical characteristics of patients who develop drug hypersensitivity in drug resistant tuberculosis patients. The secondary aim of the study is to examine the treatment results. Demographic features, tuberculosis diagnostic indicator, clinical signs of developing hypersensitivity reaction, reaction time, and treatment were evaluated.
RESULTS
A total of 25 patients were included in the study. The prevalence of hypersensitivity in drug resistance patients was 11.9%. Twelve (48%) of the cases were women. Mean age (mean ± SD) was 37.24 ± 14.44 years; early type hypersensitivity reaction in 13 (52%). Three patients were isoniazid resistant; 19 patients were multidrug-resistant (MDR); 2 patients were pre-extensive drug resistant (Pre-XDR), 1 patient was extensive drug resistance (XDR) tuberculosis. The most common skin findings were maculopapular eruption and urticaria. But also we had seen ısole angıodema, urtıcarıa and angıoedema, erythema multıforme, lıchenoıd drug eruptıon and drug rash with eosinophilia and systemic symptoms. In patients who developed a hypersensitivity reaction, the responsible agent was identified in 14 cases in total. Among the drugs, pyrazinamide, ethambutol, moxifloxacin, amikacin, para amino salicylic, prothionamide, and cycloserine are the responsible agents. When evaluated in terms of treatment results, 15 (60%) patients successfully completed the treatment.
CONCLUSION
Our study is the first study in the literature that evaluated the drug hypersensitivity in drug resıstance tuberculosis patients. Drug hypersensitivity that develops with tuberculosis treatment may lead to discontinuation or change in treatment. İt can cause treatment failure, drug resistance, relapse, and even death. In resistant tuberculosis, the already existing resistance pattern may become more difficult to treat. Success can be achieved with the right management in these patients who have few treatment options, more drug side effects, and high treatment failure rates. The established regimen should be curative and prevent recurrence.
PubMed: 37251814
DOI: 10.1016/j.waojou.2023.100778 -
The European Respiratory Journal Sep 2016
Comparative Study Review
Topics: Antitubercular Agents; Ethionamide; Humans; Prothionamide; Tuberculosis, Multidrug-Resistant
PubMed: 27288034
DOI: 10.1183/13993003.00438-2016 -
Clinical Microbiology and Infection :... Aug 2019Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrug-resistant tuberculosis (MDR-TB). Both drugs have a common target InhA, so...
OBJECTIVES
Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrug-resistant tuberculosis (MDR-TB). Both drugs have a common target InhA, so prothionamide can be ineffective against isoniazid-resistant (INH) Mycobacterium tuberculosis. We aimed to investigate the prevalence of mutations in katG, ethA, ndh, ethR, mshA, inhA and/or its promoter associated with independent resistance and cross-resistance to INH and/or prothionamide-resistant (PTO) M. tuberculosis isolates.
METHODS
We sequenced the above genes in 206 M. tuberculosis isolates with susceptibility testing against ten drugs.
RESULTS
Of the 173 INH PTO isolates, 170 (98.3%) harboured mutations in katG, 111 (64.2%) in ethA, 58 (33.5%) in inhA or its promoter, 5 (2.9%) in ndh, 3 (1.7 %) in ethR and 2 (1.2%) in mshA. Among the 18 INH PTO isolates, mutations in katG were found in all of them; one had a mutation in the inhA promoter and another in ndh. Of the five INH PTO isolates, four showed mutations in ethA and two in the inhA promoter. Notably, 55 novel non-synonymous mutations were found in them and 20.2% of the PTOM. tuberculosis isolates harboured no known mutations.
CONCLUSIONS
This is the first report to investigate cross-resistance between INH and/or PTO isolates. Among INH (94.4% MDR-TB) M. tuberculosis isolates, the high diversity of mutations for independent resistance and cross-resistance with prothionamide highlight the importance of both phenotypic susceptibility and genotypic diagnosis when using it to treat patients with INH-TB. The high proportion (one-fifth) of PTOM. tuberculosis isolates showed no known mutation related to PTO genes, so uncovered resistance mechanism(s) of prothionamide exist.
Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Promoter Regions, Genetic; Prothionamide; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant
PubMed: 30583053
DOI: 10.1016/j.cmi.2018.12.008 -
Oman Medical Journal Jan 2022This systematic review explores the effectiveness and safety of a short-term regimen (STR) in treating multidrug-resistant tuberculosis (MDR-TB). We use several cohort... (Review)
Review
This systematic review explores the effectiveness and safety of a short-term regimen (STR) in treating multidrug-resistant tuberculosis (MDR-TB). We use several cohort studies which were searched using standardized Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The keywords were used based on problem, intervention, comparison, and outcome consisted of MDR-TB and STR. Seven cohort studies were selected from 314 studies. The result showed that STR has better therapeutic efficacy and shorter duration than the 2011 World Health Organization regimen for MDR-TB with success rates above 50% in respective studies. The most effective regimen was kanamycin-high-dose isoniazid-clofazimine-ethambutol-prothionamide-pyrazinamide-gatifloxacin in the intensive phase for four months and clofazimine-ethambutol-pyrazinamide-gatifloxacin-prothionamide in the continuation phase for eight months. Gastrointestinal problems, ototoxicity, dysglycemia, and liver problems were the most reported side effects. STR provides good effectiveness in MDR-TB treatment in terms of treatment success rate and short therapy duration.
PubMed: 35211341
DOI: 10.5001/omj.2021.64 -
International Journal of Infectious... Feb 2022The shorter treatment regimen (STR) for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) has achieved successful outcomes in many countries. However, there... (Observational Study)
Observational Study
SETTING
The shorter treatment regimen (STR) for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) has achieved successful outcomes in many countries. However, there are few studies on high-dose gatifloxacin-based STR with adverse drug reactions (ADRs) and management.
DESIGN
A prospective observational study was conducted with MDR/RR-TB patients who were treated with a standardized 9 or 12 - month regimen: including gatifloxacin (Gfx), clofazimine (Cfz), ethambutol (EMB), and pyrazinamide (PZA), and supplemented by amikacin (Am), isoniazid (INH), and prothionamide (Pto) during an intensive phase of 4 or 6 - month. Monitored ADRs monthly until treatment completion and then followed up every three months for one year.
RESULTS
Among the 42 eligible patients, 35 (83.3%) completed treatment successfully, 1 (2.4%) lost to follow-up (LTFU), and 6 (14.3%) failed due to ADRs, with no death. The most important ADR was drug-induced liver damage, which occurred in 24 out of 42 (57.1%) patients and resulted in 4 (9.5%) failed treatments and 4 (9.5%) adjusted treatments. QT interval prolongation occurred in 17 out of 42 (40.5%) patients, 9 (21.4%) of them with the corrected QT interval according to Fridericia (QTcF) > 500 ms resulting in 7 (16.7%) adjusted treatments.
CONCLUSIONS
This study confirmed the effectiveness of the high-dose gatifloxacin-based STR but severe ADRs, especially hepatotoxicity and QT interval prolongation should never be ignored.
Topics: Antitubercular Agents; Gatifloxacin; Humans; Isoniazid; Pyrazinamide; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 34861398
DOI: 10.1016/j.ijid.2021.11.037 -
Biological & Pharmaceutical Bulletin 2015The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo...
The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs. The [I]max/Ki values were 0.20 or less for rifampicin, rifabutin, and thioacetazone; 0.15-2.0 for isoniazid; 0.14-1.5 for rifapentine; 0.29-1.4 for ethionamide; 0.41-2.2 for prothionamide; and 0.12-6.3 for clofazimine. The highest [I]max/Ki values were 2.0 for isoniazid on CYP3A4 [testosterone (T)]; 1.5 for rifapentine on CYP3A4 [midazolam (M)]; 1.4 for ethionamide on CYP2C8; 2.2, 1.8, and 1.3 for prothionamide on CYP2B6, CYP2C19, and CYP2C8, respectively; and 6.3 and 5.7 for clofazimine on CYP3A4 (M) and CYP3A4 (T), respectively. These drugs with high [I]max/Ki values lead to clinical DDIs. Considering the drug regimens for tuberculosis (TB) and co-infection with TB and human immunodeficiency virus, the inhibitory potential for CYP3A4 and CYP2B6 is particularly important. These results suggest that clofazimine and prothionamide are likely to cause clinically relevant DDIs when co-administered with products metabolized by CYP3A4 and CYP2B6, respectively. Isoniazid and rifapentine may cause DDIs with drugs metabolized by CYP3A4.
Topics: Antitubercular Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Microsomes, Liver
PubMed: 26094899
DOI: 10.1248/bpb.b15-00313