Basic & Clinical Pharmacology & Toxicology最新文献

Gamma-hydroxybutyric acid (GHB), a potential agent in drug-facilitated sexual assault, is difficult to detect due to rapid elimination, endogenous presence, and possible postsampling formation. We conducted a randomised, placebo-controlled trial in 30 healthy volunteers, administering 50-mg/kg sodium oxybate or placebo, to investigate symptoms, pharmacokinetics and endogenous concentrations. Blood was collected in fluoride-oxalate (FX) tubes, and urine and oral fluid in additive-free tubes, at baseline, 1, 2, 3, 4, 6, 12, and 24 (urine only) hours post-administration. Samples were immediately cooled, stored at −70°C, and analysed using LC–MS/MS. Maximal endogenous GHB concentrations were 0.050 μg/mL in blood, 0.41 μg/mL in urine, and 0.93 μg/mL in oral fluid. GHB-treated participants reported vertigo and fatigue, with no significant memory impairment. Median peak GHB concentrations post-administration were 50, 440, and 29 μg/mL in blood, urine, and oral fluid, respectively. Oral fluid appeared unsuitable for GHB detection. As endogenous concentrations in blood did not exceed 0.050 μg/mL, a theoretical cut-off with a safety margin (0.25 μg/mL) would yield a negligible risk of false positives in samples collected in FX tubes and cooled immediately. Applying this cut-off extended the blood detection window ≥ 2 h in all GHB-treated participants, surpassing that in urine at a 6-μg/mL cut-off.

Reversible cholinesterase inhibitors have been investigated to address prophylactic and therapeutic outcomes against organophosphorus nerve poisoning, and procyclidine is concomitantly used to compensate for their adverse effects. We designed double-layer patches with microneedles composed of a cream layer for immediate release and a hyaluronic acid–based thin solid layer for sustained release. Rivastigmine and procyclidine were added to the two layers with different doses, and their transdermal absorption was explored in guinea pigs for the first time. The contents of hyaluronic acid and the number of microneedles were also examined to determine the optimal patches, which would achieve the mean target plasma concentrations of the two drugs for 72 h. Plasma concentrations of rivastigmine and procyclidine were determined using a validated HPLC–MS/MS method, and acetylcholinesterase (AChE) activity was monitored and correlated with plasma rivastigmine concentrations. The systemic exposure of both drugs was successfully characterised in guinea pigs, and the change was relevant in terms of different patches with microneedles. The inhibitory effect on AChE was prolonged despite the decay of rivastigmine concentrations. Finally, the preparation of a double-layer patch with microneedles was suggested, and the present results would help explain the prophylactic and therapeutic effects of rivastigmine and procyclidine against biochemical weapons.

Rapid serum paracetamol (acetaminophen) concentration measurement is essential in suspected intoxication, but centralized laboratory analyses often delay initiation of antidotal therapy. We studied the feasibility of a novel electrochemical single-walled carbon nanotube/Nafion-based point-of-care (POC) method in detecting paracetamol in 99 suspected overdose patient serum samples. POC was compared with the standard photoelectric enzymatic method (PEM) and ultra-high performance liquid chromatography–photodiode array and corona-charged aerosol detector (UHPLC-DAD-CAD). We also analysed for 900 concomitant pharmaceuticals, drugs and chemicals in 197 samples with time-of-flight mass spectrometry to assess interference with paracetamol concentration measurements. Paracetamol concentrations measured with UHPLC-DAD-CAD ranged between 0 and 2100 μmol/L, with 19% above the therapeutic level (≥ 200 μmol/L). Comparing POC with UHPLC-DAD-CAD, the false positives and negatives were 10% and 15%, respectively, at concentrations ≥ 30 μmol/L. All POC method false negatives occurred at concentrations < 45 μmol/L. PEM showed 8% false positives and negatives compared with UHPLC-DAD-CAD. Other substances detected included caffeine (78%), antidepressants (41%), benzodiazepines (34%) and antipsychotics (28%). They did not interfere with POC concentration measurement. The novel POC method is promising for measuring serum paracetamol at relevant concentrations.

Immune mediated inflammatory diseases (IMIDs) are common, chronic, inflammatory diseases. There has been an expansion of monoclonal antibodies to treat the disease. However, the response is not universal; reasons for non-response may include suboptimal drug concentrations for which therapeutic drug monitoring (TDM) may lead to improved outcomes. Several laboratory assays are available to measure biologic drug concentrations, but variation in assay accuracy may introduce bias. External quality assessments (EQA) provide assurance of the performance of a laboratory test. The aim of this work was to survey current quality assessment procedures that are in place in laboratories undertaking TDM of therapeutic antibodies for the treatment of IMIDs to guide clinical decision making across Europe. A survey was sent out to institutions undertaking TDM across Europe. In total, 26 institutions responded; the vast majority (96.2%) of institutions utilize an internal quality control, with 42% of institutions not reporting participation in a national EQA scheme. Barriers to EQA participation included insufficient information about relevant organizations and financial constraints. These results demonstrate that, although TDM assay performance is well controlled locally, better access to EQA and standards may further aid the translatability of results between laboratories and aid the adoption of published reference values.