Robinson, John C.

Abstract Background Posaconazole immediate release (IR) suspension is the standard product for enteral feeding tube (EFT) administration but has erratic pharmacokinetic behaviour, often resulting in subtherapeutic concentrations. Limited evidence suggests that posaconazole oral delayed-release (DR) tablets may be crushed. Methods This was a retrospective cohort study of hospitalized adults who received EFT administration of posaconazole IR suspension or crushed DR tablets between 2018 and 2024. Patients were eligible if they had at least one serum drug concentration drawn ≥5 days after posaconazole initiation. The primary outcome was attainment of therapeutic drug concentrations. Secondary outcomes included time to therapeutic serum concentration, adverse drug events, and frequency of occluded EFT. Results Of the included patients, 48 received IR suspension and 100 received DR tablets. Baseline characteristics and severity of illnesses were well balanced. Among IR suspension and crushed DR tablet recipients, 39% and 80% achieved therapeutic concentrations, respectively (P = 0.002). After adjusting for age, sex, BMI, drug interactions, posaconazole indication and malabsorptive conditions, crushed DR tablets were significantly more likely than IR suspension to achieve therapeutic posaconazole concentrations within 30 days (HR 5.22, 95% CI 2.35–11.61). Occluded EFTs were more frequent among crushed DR tablet recipients (27% versus 10%, P = 0.022), while no differences were observed in the occurrence of hepatotoxicity or hypokalaemia. Conclusions With EFT administration, crushed posaconazole DR tablets were associated with a greater likelihood of achieving therapeutic concentrations compared with IR suspension. The optimal technique for administering crushed DR tablets to prevent EFT complications warrants investigation.

Ischemic preconditioning is characterized by resistance to ischemia reperfusion injury in response to previous short ischemic episodes, a protective effect that can be mimicked pharmacologically. The underlying mechanism of protection remains controversial and requires greater understanding before it can be fully exploited therapeutically. To investigate the overall effect of preconditioning on the myocardial proteome, isolated rabbit ventricular myocytes were treated with drugs known to induce preconditioning, adenosine or diazoxide (each at 100 μmol/L for 60 minutes). Their protein profiles were then compared with vehicle-treated controls (n=4 animals per treatment) using a multitiered 2D gel electrophoresis approach. Of 28 significantly altered protein spots, 19 nonredundant proteins were identified (5 spots remained unidentified). The majority of these proteins are involved in mitochondrial energetics, including subunits of tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. These changes were not indiscriminate, with only a small number of enzymes or complex subunits altered, indicating a very specific and targeted affect of these 2 preconditioning mimetics. Among the changes were shifts in the extent of posttranslational modification of 4 proteins. One of these, the adenosine-induced phosphorylation of the ATP synthase β subunit, was fully characterized with the identification of 5 novel phosphorylation sites. This proteomics approach provides an overall assessment of the cellular response to pharmacological treatment with adenosine and diazoxide and identifies a distinct subset of enzymes and protein complex subunit that may underlie the preconditioned phenotype.