Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin : a study protocol of a phase II clinical trial (HighShort-RP)

Introduction: Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen. Methods and analysis: Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C-max) and area under the concentration-time curve (AUC(0-24h)) are estimated by non-compartmental analysis. Conditions for early model-informed precision dosing of high-dose pyrazinamide-rifampicin are pharmacometrically explored. Adverse drug effects are monitored throughout the study and graded according to Common Terminology Criteria for Adverse Events V.5.0. Early bactericidal activity is assessed by time to positivity in BACTEC MGIT 960 of induced sputum collected at day 0, 5, 8, 15 and week 8. Minimum inhibitory concentrations of first-line drugs are determined using broth microdilution. Disease severity is assessed with X-ray grading and a validated clinical scoring tool (TBscore II). Clinical outcome is registered according to WHO definitions (2020) in addition to occurrence of relapse after end of treatment. Primary endpoint is pyrazinamide AUC(0-24h) and main secondary endpoint is safety. Ethics and dissemination: The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal

Metal allergy : Gold

Gold is today a well-known but still controversial contact sensitizer. The patch test reaction to gold is sometimes difficult to read, and positive reactions typically appear late; therefore, two readings are of utmost importance. Gold is not generally within the baseline series but is recommended in any dental and metal series. Gold can give rise not only to local eczematous reactions, chronic papular reactions, or generalized dermatitis, but also to lichenoid reactions, especially when in contact with the oral mucosa. The sensitizer can also give rise to systemic allergic contact dermatitis when exposure is systemic. Female sex, dental gold restorations and age are factors that are associated with contact allergy to gold

Hypersensitivity to cardiovascular implants : Stents

Percutaneous coronary interventions and stenting have existed since the 1970s. Stents can be made of different materials and have different designs. A complication to the intervention and especially to bare metal stents is in-stent restenosis with neointimal proliferation and chronic inflammation, which has several causes briefly discussed below. A possible association between stents and metal allergy has been investigated. With regard to stents, studies have been mainly retrospective, in itself a limitation, and show somewhat disparate results. This chapter will focus on some of these findings but also on general knowledge of stents and what happens in the vessel. This insight is meant to assist those who advise patients and cardiologists and who investigate patients with stents where question of metal allergy is raised