Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development

AbstractCardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data.
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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Discussion The pericardium is a bi-layered membrane that envelops the heart and provides a barrier to prevent disease and also decreases friction as the heart moves. Pericarditis is the inflammation of pericardium. The incidence is underreported as asymptomatic or mild disease may go unrecognized. From hospitalized patient data, 0.2-5% of patients with various cardiac disease had pericarditis. An incidence rate for hospitalizations of 3.32 per 100,000 person years has been cited. Percarditis occurs more often in adolescent males. Treatment of the underlying cause or suspected cause is important, along with close monitorin...
Source: PediatricEducation.org - Category: Pediatrics Authors: Tags: Uncategorized Source Type: news
CONCLUSIONS: There is an association between dose-weight interaction and adverse events. The odds of any adverse event occurring were higher when low-weight patients (<50 kg) received high-dose CFZ (≥200 mg). Gastrointestinal and skin-related adverse events were more common when high-dose CFZ was used in patients weighing <50 kg. Chest pain was reported in patients receiving high- and low-dose CFZ, irrespective of weight, and may be a symptom of cardiac toxicity. Plasma concentrations of CFZ may be affected by drug-drug interactions, so active drug safety monitoring including electrocardiograms is recommended rout...
Source: South African Medical Journal - Category: African Health Tags: S Afr Med J Source Type: research
ConclusionsDelamanid is a relatively safe drug with few side effects. However, some patients could not continue it because of difficulty of use in combination, therefore delamanid should be prescribed considering the side effects of all therapies in the regimen.
Source: Respiratory Investigation - Category: Respiratory Medicine Source Type: research
Conclusions: Use of the shorter MDR-TB regimen was constrained by patient eligibility. Poor tolerability and drug adverse effects were universal in our patients.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Tuberculosis Source Type: research
The objective of the study was to evaluate the clinical impact of QTc prolongation and the number of cardiac events in patients receiving Bdq/Dlm treatment for MDR-TB in treatment centres of the Tuberculosis Network European Trialsgroup (TBnet), a clinical research collaboration of the European Respiratory Society, within the World Health Organization (WHO) Europe region.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Original Articles: Research letters Source Type: research
A 79-year-old asymptomatic man was referred to our clinic for routine immigration screening. His past medical history was significant only for remote treated pulmonary tuberculosis and heavy tobacco use. Examination revealed oxygen saturations of 90%, blood pressure of 150/90mmHg, and a prominent right ventricular heave. There was no digital clubbing. Chest X-ray demonstrated an enlarged cardiothoracic ratio with a prominent right heart border and left hilar enlargement (Figure 1A ). His electrocardiograph (ECG) showed atrial fibrillation, right axis deviation and anterior T-wave inversion consistent with right ventricular strain (Figure 1B).
Source: Heart, Lung and Circulation - Category: Cardiology Authors: Tags: Image Source Type: research
Patient Presentation A 9-year-old male came to clinic with a 1 month history of painful joint swelling. One month ago he started having right ankle pain that was intermittent but consistent. One day ago his right wrist, right ankle and bilateral knees had some swelling but no erythema or warmth. He says that he has pain in them when he moves but not when he is resting and he denies any joint stiffness or gelling. He also had 1-2 days of multiple red skin lesions on his extremities and trunk, not overlying the affected joints. The skin lesions do not come and go and do not itch. They are mainly discrete circular lesions wi...
Source: PediatricEducation.org - Category: Pediatrics Authors: Tags: Uncategorized Source Type: news
Authors: Anggorowati N, Sulistyaningsih RC, Ghozali A, Subronto YW Abstract A 30-year-old Javanese-Indonesian man was admitted with complaints of 3 months persistent fever, weight loss, and fatigue. He had never known his past history of unprotected HIV until the admission. His only risk factor is unsafe sex. The patient seemed well nourished. Physical examination revealed blood pressure 100/60 mmHg, pulse 100 beats per minute, respiratory rate 20 times per minute, and temperature 38.8°C. Multiple cervical and inguinal lymphadenopathies were also found. Electrocardiogram showed anterolateral ischemic finding, w...
Source: Acta medica Indonesiana - Category: Internal Medicine Tags: Acta Med Indones Source Type: research
This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively). Sputum smear and cul...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Respiratory infections and tuberculosis Original Articles: Tuberculosis Source Type: research
Conclusions: Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appear to carry a sizeable risk of QT prolongation in patients with newly-diagnosed pulmonary tuberculosis. This is to-date the largest dataset studying the effects of anti-tuberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen. PMID: 28438924 [PubMed - as supplied by publisher]
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
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