Risk of gout flare after medication: prescription symmetry sequence analysis.

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Molecular and cellular remodeling of HepG2 cells upon treatment with antitubercular drugs.

Drug-induced liver injury (DILI) is an adverse outcome of the currently used tuberculosis treatment regimen, which results in patient noncompliance, poor treatment outcomes, and the emergence of drug-resistant tuberculosis. DILI is primarily caused by the toxicity of the drugs and their metabolites, which affect liver cells, biliary epithelial cells, and liver vasculature. However, the precise mechanism behind the cellular damage attributable to first-line antitubercular drugs (ATDs), as well as the effect of toxicity on the cell survival strategies, is yet to be elucidated. In the current study, HepG2 cells upon treatment with a high concentration of ATDs showed increased perforation within the cell, cuboidal shape, and membrane blebbing as compared with control/untreated cells. It was observed that ATD-induced toxicity in HepG2 cells leads to altered mitochondrial membrane permeability, which was depicted by the decreased fluorescence intensity of the MitoRed tracker dye at higher drug concentrations. In addition, high doses of ATDs caused cell damage through an increase in reactive oxygen species production in HepG2 cells and a simultaneous reduction in glutathione levels. Further, high dose of isoniazid (50-200 mM), pyrazinamide (50-200 mM), and rifampicin (20-100 µM) causes cell apoptosis and affects cell survival during toxic conditions by decreasing the expression of potent autophagy markers Atg5, Atg7, and LC3B. Thus, ATD-mediated toxicity contributes to the reduced ability of hepatocytes to tolerate cellular damage caused by altered mitochondrial membrane permeability, increased apoptosis, and decreased autophagy. These findings further emphasize the need to develop adjuvant therapies that can mitigate ATD-induced toxicity for the effective treatment of tuberculosis.

Anti-tubercular therapy (ATT) induced exfoliative dermatitis-A case series.

Tuberculosis is a serious contagious disease mainly affecting the lungs and is common in the developing countries. The essential component of all antitubercular regimens include Isoniazid, pyrazinamide as first-line drugs. A serious cutaneous adverse drug reaction namely exfoliative dermatitis (erythroderma) is associated with isoniazid use though uncommon but is common among pyrazinamide users. Here we report 3 cases of tuberculosis patients on antitubercular therapy (ATT) for 8 weeks, came to hospital OP (outpatient) with severe generalized redness and scaling with itching distributed all over the body and trunk. Immediately ATT was discontinued and all the three patients were administered antihistaminic and corticosteroid. The patients recovered within 3 weeks. To confirm ATT induced erythroderma and narrow down the offending agents, sequential rechallenge with ATT was done and again these patients had similar lesions erupt all over the body only with isoniazid and pyrazinamide. Antihistamine, steroids were started and the symptoms resolved and completely recovered within 3 weeks. Prompt withdrawal of the culprit drug along with appropriate medications and supportive measures is necessary for good prognosis. Physicians must be judicious while prescribing ATT especially, isoniazid and pyrazinamide as these can precipitate fatal cutaneous adverse reactions. Strict vigilance may help in early detection of this type ADR and timely management.

Efficacy and safety of an innovative short-course regimen containing clofazimine for treatment of drug-susceptible tuberculosis: a clinical trial.

In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

Treatment Strategy for Rifampin-Susceptible Tuberculosis.

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

Pyrazinamide related prolonged drug-induced liver injury: A case report.

RATIONALE: Drug induced liver injury (DILI) is a common side effect causing treatment discontinuation during tuberculosis (TB) treatment, and pyrazinamide (PZA) usually leads to a delayed and prolonged abnormal liver function of the 4 standard anti-tuberculosis regimens. However, a prolonged hepatitis lasting more than 4 months is rarely reported. PATIENT CONCERNS: A 78-year-old man presented with general weakness and poor appetite on his seventh week of anti-TB treatment for tuberculosis lymphadenitis. DIAGNOSIS: Drug induced liver injury, PZA-related. NAT2 slow acetylator phenotype was accidentally found during workup of DILI. INTERVENTION: A liver biopsy was performed and PZA-related DILI was suspected. All anti-TB medications were therefore discontinued. OUTCOME: After withholding all anti-TB medications for 4 months, the elevations of aminotransferases and hyperbilirubinemia completely resolved. Anti-TB therapy was switched to ethambutol and levofloxacin for 15 months without adverse events. Long-term ultrasound follow-up was performed and cervical lymphadenopathy completely resolved. CONCLUSION: Our patient presents with PZA related prolonged DILI resolved after drug discontinuation for 4 months. NAT2 slow acetylator phenotype may be related to this condition through unknown mechanisms.

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial.

BACKGROUND: The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. METHODS: This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. DISCUSSION: This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. TRIAL REGISTRATION: ClinicalTrials.gov NCT04485156 . Registered on July 24, 2020.

Bioequivalence and Pharmacokinetic Evaluation of 2 Pyrazinamide Formulations in Healthy Chinese Adults: A Single-Dose, Open-Label, Randomized-Sequence, 2×2 Crossover Study.

A single-dose, open-label, randomized-sequence, 2×2 crossover study was conducted in healthy Chinese adults, after fasting and postprandial, to evaluate the bioequivalence of 2 pyrazinamide (PZA) formulations. Fasting and postprandial tests were conducted in 24 cases. Test-reference and reference-test were randomly divided into 2 sequence groups, with 12 cases in each group. The concentration of PZA in plasma was determined after 0.5 g single oral PZA test and reference formulations by the high-performance liquid chromatography-tandem mass spectrometry method. In the fasting group, the 90% confidence intervals (CIs) of the 2 formulations maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC) from time 0 to last detectable plasma concentration, and AUC from time 0 to infinity after logarithmic conversion were 104.8% to 121.9%, 97.7% to 101.6%, and 97.7% to 101.6%, respectively. In the postprandial group, the 90%CIs of the 2 formulations' Cmax , AUC from time 0 to last detectable plasma concentration, and AUC from time 0 to infinity after logarithmic conversion were 86.4% to 100.2%, 96% to 102%, 95.8% to 102.3%, respectively. The 90%CIs of the test/reference Cmax ratio and AUC ratio were within the acceptable range of 80.00% to 125.00% for bioequivalence under both fasting and postprandial conditions. No serious adverse events occurred during treatment with the test formulation or the reference formulation.

Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China.

BACKGROUND: Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment. METHODS: Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens. RESULTS: Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% versus 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% versus 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC0-24h/MIC) of 231 and linezolid AUC0-24h/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis. CONCLUSIONS: Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome.

High-dose gatifloxacin-based shorter treatment regimens for MDR/RR-TB.

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.

Efficacy and safety of combined isoniazid-rifampicin-pyrazinamide-levofloxacin dry powder inhaler in treatment of pulmonary tuberculosis: A randomized controlled trial.

OBJECTIVE: To determine the efficacy and safety of add-on dry powder for inhalation (DPI) of combined anti-TB agents prepared as a particulate system (study group) compared with placebo DPI (control group) in patients diagnosed with pulmonary TB. METHODS: This study was a randomized, placebo-controlled, double-blinded parallel design. Subjects were pulmonary TB patients, new or re-treatment, aged 18 years or older. The eligible patients were randomly allocated (1:1) to either the study group or the control group using stratified blocked randomization. The add-on DPI of combined anti-TB therapy (each capsule contained isoniazid 5 mg, rifampicin 2 mg, pyrazinamide 16 mg, and levofloxacin 2 mg) was used throughout the course of the standard oral anti-TB treatment. The primary outcome was Mycobacterium tuberculosis (MTB) sputum culture conversion measured after receiving treatment for eight weeks. Secondary outcomes were clinical signs and symptoms of pulmonary TB and adverse drug reactions (ADRs) related to anti-TB agents. The percentages of patients who achieved the primary outcome were compared (95% confidence interval). All analyses were performed using the modified intention-to-treat principle. RESULTS: 91 patients were randomly allocated: 44 to the study group and 47 to the control group. Important baseline data (%peak expiratory flow rate, chest X-ray findings, resistance to anti-TB agents, renal and liver function tests) were similar between the two groups. Although the percentages of patients who achieved the primary outcome were similar in both groups (34/44 [77.3%] in the study group and (34/47 [72.3%] in the control group; relative risk [RR] 1.07, 95% CI 0.84-1.36; p = 0.589), the study group patients seemed to achieve the primary outcome earlier than the control group (22/44 [50.0%] vs 15/47 [31.9%]; RR 1.57, 95% CI 0.94-2.61; p = 0.079) at the end of week 4. Cough was significantly lower in the study group than in the control group (23/44 [52.3%] vs 43/47 [91.5%]; RR 0.57, 95% CI 0.43-0.77; p < 0.001) at week 4 of treatment. Hemoptysis was found in approximately half of each group at baseline. The percentage of patients having hemoptysis was substantially reduced at week 2 of treatment (5 [11.4%] in the study group and 11 [23.0%] in the control group, p = 0.132). Regarding safety outcomes, no dyspnea or severe ADRs were reported. Adverse events (AEs) related to oral anti-TB agents, (e.g. liver function tests) were in normal ranges in most patients in both groups during the treatment. The incidences of common AEs reported (e.g. anorexia, dizziness, numbness, arthralgia, rash, and itching) were similar between the two groups, while the incidences of nausea and vomiting were significantly lower in the study group than the control group (38.6% vs 74.5%, p = 0.001, and 43.2% vs 66.0%, p = 0.029, respectively). CONCLUSIONS: Add-on combined anti-TB DPI therapy to the standard oral anti-TB treatment did not increase MTB sputum culture conversion at two months of treatment. However, the percentage of patients having cough in the study group was significantly lower than in the control group at two months after treatment. A reduction in cough might represent adequate response to treatment, and result in a decreased risk of spread of infection. Combined anti-TB DPI therapy was safe. Further study investigated in a larger sample using higher strengths of DPI therapy is required.

Refining MDR-TB treatment regimens for ultra short therapy (TB-TRUST): study protocol for a randomized controlled trial.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients' treatment outcome individually and minimize resistance amplification. METHODS: TB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36-44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24-32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36-44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177(354 in total). DISCUSSION: Rapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It's foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs. TRAIL REGISTRATION: ClinicalTrial.gov, NCT03867136 . Registered on March 7, 2019.

Ameliorative potential of Adhatoda vasica against anti-tubercular drugs induced hepatic impairments in female Wistar rats in relation to oxidative stress and xeno-metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Adhatoda vasica Nees is widely used herb of indigenous system to treat various ailments especially upper respiratory tract infections. Not only, anti-tubercular efficacy of crude extract and phytoconstituents of A. vasica has been documented but its hepatoprotective role against various drugs mediated hepatic alterations in different animal models has also been observed. BACKGROUND AND PURPOSE: Isoniazid, rifampicin and pyrazinamide (H-R-Z) are anti-tubercular drugs normally prescribed by health professionals for the treatment of tuberculosis, however along with their medical effectiveness these drugs also exhibit hepatotoxicity among TB patients. Unexpectedly, substantial toxicological data on the metabolism of anti-TB drugs are available but the mystery behind these xenobiotics is too complex and partly implicit. In this study, we further explored the hepatotoxic effects of these xeno-metabolic products and their amelioration by Adhatoda vasica Nees by elucidating its mechanistic action. METHODS: We generated a hepatotoxic rodent model by oral administration of H, R and Z (30.85, 61.7 and 132.65 mg/kg body weight) drugs for 25 days in Wistar rats. Additionally, to achieve hepatoprotection two different doses of Adhatoda vasica Nees ethanolic leaf extract (200 and 300 mg/kg body weight) were used along with H-R-Z dosage, orally and once daily for 25 days and tried to ascertain their mechanistic action. For this, initially phytoconstituents of the extract were evaluated followed by extract standardization using RP-HPLC and FTIR methods. Furthermore, antioxidant activity of the extract was analyzed by DPPH assay. Finally, different treated groups were analyzed for hepatic oxidative stress markers, antioxidant markers, histopathological changes and gene expression study including CYP2E1, CYP7A1, NAT, NR1I2 and UGT1A1 genes involved in phase I and phase II xeno-metabolism. RESULTS: Estimated content of vasicine in RP-HPLC method and free-radical scavenging activity in DPPH assay was found to be 134.519 ± 0.00269µg/10mg of leaf extract and 47.81 µg/mL respectively. In H-R-Z treated group, a significant increase in the levels of thiobarbituric acid, significant reduction in the levels of GSH, and enzymatic markers and marked changes in hepatic histological architecture were observed. In addition, there was significance up-regulation of CYP7A and NAT genes, down-regulation of CYP2E1 gene and insignificant expression levels of NR1I2 and UGT1A1 genes were observed in H-R-Z group. Conversely, high dose of A. vasica extract effectively diminished these alterations by declining oxidative stress and boosting of antioxidant levels. In addition, it acted as bi-functional inducer of both phase I (CYP2E1) and phase II (NAT and UGT1A1) enzyme systems. CONCLUSION: Hence, we concluded that anti-TB drugs exposure has potential to generate reactive metabolites that eventually cause hepatotoxicity by altering oxidant-antioxidant levels and their own metabolism. This study not only emphasized on xeno-metabolism mediated hepatic alterations but also explore the benefit of A. vasica on these toxic insults.

Safety of Pyrazinamide for the Treatment of Tuberculosis in Older Patients Over 75 Years of Age: A Retrospective Monocentric Cohort Study.

OBJECTIVES: Pyrazinamide (PZA) has a controversial safety profile in older patients. We aimed to assess the frequency and risk factors for adverse drug reactions (ADRs) in patients over 75 years of age treated for tuberculosis with or without PZA. METHODS: We conducted a retrospective monocentric study including patients aged over 75 years treated for active tuberculosis between 2008 and 2018. The frequency, type, seriousness, and causality assessment of ADRs to anti-tuberculosis treatment were compared between patients receiving PZA or not. Risk factors for ADRs were investigated using univariable and multivariable analyses by logistic regression. RESULTS: Among the 110 patients included, 54 (49.1%) received PZA (group 1) and 56 (50.9%) did not (group 2). ADRs to anti-tuberculosis drugs occurred in 31 patients (57.4%) in groups 1 and 15 (26.8%) in group 2 (p = 0.003). PZA-related ADRs occurred in 40.7% of exposed patients. Frequency of renal ADRs was higher in group 1 (9.3% vs 0%; p = 0.026). Rates of hepatic (18.5% vs 12.5%; p = 0.38), digestive (22.2% vs 8.9%; p = 0.054), and allergic (14.8% vs 5.4%; p = 0.12) ADRs were numerically higher in group 1 although the differences were not statistically significant. Serious ADRs occurred more frequently in group 1 (24.1% vs 8.9%; p = 0.03). The use of PZA was the only independent risk factor for ADRs to anti-tuberculosis drugs (odds ratio 3.75, 95% CI 1.5-9.6; p = 0.0056). No risk factors for PZA-related ADRs were identified. CONCLUSION: In older French patients, the use of PZA was associated with more frequent ADRs to anti-tuberculosis drugs.

Clinical characteristics of pyrazinamide-associated hepatotoxicity in patients at a hospital in Lima, Peru. / Características clínicas de la hepatotoxicidad asociada a la pirazinamida en pacientes de un hospital de Lima, Perú.

In order to determine the characteristics of drug-induced liver injury (DILI), adult patients diagnosed with tuberculosis and with an anti-tuberculosis treatment scheme including pyrazinamide were studied. The re-exposure process was used for the cause-effect analysis of the DILI. A total of 10 patients were found with pyrazinamide-associated DILI; the median age and hospital stay were 40.5 years (from 22 to 76 years) and 41 days (from 11 to 130 days), respectively. The median time in which the events appeared was 14 days (from 3 to 46 days); jaundice was observed in 4 patients and radiological patterns such as hepatocellular, mixed and cholestatic were found in 5, 3 and 2 patients, respectively. Mild presentation of DILI was observed in 6 cases (60%) and moderate in 3 (30%). In conclusion, pyrazinamide-associated DILI required prolonged hospital stay, presented jaundice in little more than a third of the cases, and radiologically, the hepatocellular pattern predominated.

Con el objetivo de determinar las características de la enfermedad hepática inducida por el medicamento (DILI) se realizó un estudio de pacientes adultos con diagnóstico de tuberculosis y esquema de tratamiento antituberculoso con pirazinamida. El análisis de causa efecto de la DILI fue mediante el proceso de reexposición. Se encontraron 10 pacientes con DILI asociada a pirazinamida, la mediana de edad y de estancia hospitalaria fue de 40,5 años (rango 22-76) y 41 días (rango 11-130), respectivamente. La mediana de presentación del evento fue de 14 días (rango 3-46), 4 pacientes presentaron ictericia, 5 tuvieron patrón hepatocelular, 3 mixtas y 2 colestásicos. La presentación de la DILI fue leve en 6 casos (60%) y moderados en 3 (30%). En conclusión, la DILI asociada a la pirazinamida requiere estancia hospitalaria prolongada, se presenta con ictericia en un poco más de un tercio de los casos siendo el patrón predominante el hepatocelular.

Optimal Design, Characterization and Preliminary Safety Evaluation of an Edible Orodispersible Formulation for Pediatric Tuberculosis Pharmacotherapy.

The severity of tuberculosis (TB) in children is considered a global crisis compounded by the scarcity of pharmaceutical formulations suitable for pediatric use. The purpose of this study was to optimally develop and evaluate a pyrazinamide containing edible orodispersible film formulation potentially suitable for use in pediatrics actively infected with TB. The formulation was prepared employing aqueous-particulate blending and solvent casting methods facilitated by a high performance Box Behnken experimental design template. The optimized orodispersible formulation was mechanically robust, flexible, easy to handle, exhibited rapid disintegration with initial matrix collapse occurring under 60 s (0.58 ± 0.05 min ≡ 34.98 ± 3.00 s) and pyrazinamide release was controlled by anomalous diffusion coupled with matrix disintegration and erosion mechanisms. It was microporous in nature, light weight (57.5 ± 0.5 mg) with an average diameter of 10.5 mm and uniformly distributed pyrazinamide load of 101.13 ± 2.03 %w/w. The formulation was physicochemically stable with no evidence of destructive drug-excipient interactions founded on outcomes of characterization and environmental stability investigations. Preliminary inquiries revealed that the orodispersible formulation was cytobiocompatible, palatable and remained intact under specific storage conditions. Summarily, an edible pyrazinamide containing orodispersible film formulation was optimally designed to potentially improve TB pharmacotherapy in children, particularly the under 5 year olds.

The high incidence of severe adverse events due to pyrazinamide in elderly patients with tuberculosis.

BACKGROUND: Pyrazinamide (PZA) is a common drug that causes serious adverse events (SAEs). The aim of this study was to determine the incidence of and risk factors for SAEs due to PZA during first-line anti-tuberculosis treatment. METHODS: The medical records of patients with tuberculosis (TB) treated with PZA-containing regimens including first-line drugs-ethambutol, rifampicin, and isoniazid-from January 2003 to June 2016 were reviewed. SAEs were defined as side effects that led to drug discontinuation. The causative drug was determined based on the disappearance of the SAEs upon drug withdrawal and/or the recurrence of the same SAEs with re-challenge. RESULTS: Of 2,478 patients with TB, 16.4% experienced SAEs. The incidence of SAEs increased significantly as age increased, except with rifampin. PZA accounted for most SAEs (55.8%). Hepatotoxicity was the most common SAE due to PZA (44.5%), followed by gastrointestinal (GI) intolerance (23.8%). The risk of SAEs due to PZA increased significantly as age increased, when sex and comorbidities were adjusted (odds ratio, 1.013; 95% confidence interval, 1.004-1.023; P = 0.007). In the subgroup analysis, older age was an independent risk factor for GI intolerance but not for hepatotoxicity. CONCLUSION: PZA was the most common drug associated with SAEs among the first-line anti-TB drugs, and old age was an independent factor for SAE occurrence. This study suggests that the early recognition of whether the causative agent is PZA may improve effective treatment compliance, particularly in elderly patients.

Ocular adverse events in drug sensitive TB patients on daily fixed dose combination anti-TB drugs: A record review study from Kerala, India.

BACKGROUND: Government of India's Revised National TB Control Programme (RNTCP) has begun implementing daily fixed dose combination (FDC) anti-TB treatment regimen for drug sensitive TB patients in which ethambutol is given for six months. Prolonged ethambutol use is known to cause ocular adverse drug events (ADE). OBJECTIVES: To assess the magnitude of ocular ADEs in adult drug sensitive TB patients initiated on daily FDCs and to describe the demographic and clinical profile of patients with ocular ADEs. METHODS: We conducted a retrospective cohort study involving review of RNTCP records of all adult (age >14 years) drug sensitive TB patients initiated on daily FDCs between1st January 2018 and 31st July 2018 in Thiruvananthapuram district, Kerala State, India. RESULTS: 714 patients were initiated on daily FDCs during the study period. It was unknown whether all patients had undergone assessment for ocular ADEs. However, of these 714 patients, 8 patients (1.1%) were documented to have had ocular ADEs. Seven of these 8 patients had received ethambutol more than 15 mg/kg body weight and had developed ocular symptoms (decreased/blurring of vision) 3 months after TB treatment initiation. Ethambutol was stopped in all these 8 patients. In 5 patients it was recorded that ocular ADEs had resolved following stoppage of ethambutol and in the remaining it was unknown. CONCLUSION: The study confirms the occurrence of ocular ADEs among drug sensitive TB patients on daily FDCs and recommends strengthening of systems for assessing, documenting and managing ocular ADE.