Background: Rituximab is commonly used to treat patients with primary glomerular diseases; however, its pharmacokinetics in this population have not been fully described yet. Materials and methods: This single-center, open-label, uncontrolled clinical trial included adult patients with glomerular diseases who required rituximab treatment (NEFRTX; EudraCT: 2020-000484-23). Patients received 1 or 0.5 g of rituximab on day 1 (and d14 in some cases). Blood and urine samples were collected at days 1, 7, 14, 28, and 45 to measure biochemical parameters (proteinuria, albuminemia, plasma immunoglobulin, and urine immunoglobulin), rituximab, and antidrug antibody concentrations. The gene encoding the neonatal fragment-crystallizable receptor was also characterized. Linear regression and Win-Nonlin 1.1 were used for pharmacokinetic analysis. Results: Thirty-five cases (30 patients) were included in this study. Pharmacokinetic parameters were expressed as mean (SD): maximum plasma concentration, 179.4 (71.8) mcg/mL; volume of distribution, 78.9 (31.4) mL/kg; clearance, 0.30 (0.27) mL/h/kg; half-life (t _1/2 ), 11.6 (5.8) d; elimination rate constant, 0.0036 (0.0030) hour ⁻¹ ; and area under the curve, 117,756.1 (88,228.1) mcg·h/mL. Antidrug antibody was detected on d1 in 3 cases (8.6%) and was negative by d28. Rituximab t _1/2 was represented by the formula: t _1/2 = A-B·Log (Proteinuria)+C·Albuminemia, where A = 515.1 (128.8–901.3), B = 182.1 (−108.6 to −35.4), and C = 39.5 (−10.9 to 89.9). There were significant differences in rituximab t _1/2 based on diagnosis ( P = 0.025), early treatment ( P = 0.008), proteinuria >2.4 g /24h ( P < 0.001), plasma immunoglobulin 2.4 g /24h may require higher frequent dosing for adequate rituximab exposure. Establishing an optimal dosing regimen in this population remains warranted.

Background: The clinical outcomes of patients with Acute Myeloid Leukemia (AML) remain unsatisfactory. Therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate antileukemic activity of the lead compound in vitro and a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationships of several rationally designed BiQ analogues with amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

Pulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. This is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. The pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, 9 adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 h. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. Voriconazole nebulization is well-tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

Background: This study evaluated the long-term effectiveness and safety of a multidisciplinary early proactive therapeutic drug monitoring (TDM) program combined with Bayesian forecasting for infliximab (IFX) dose adjustment in a real-world dataset of paediatric patients with inflammatory bowel disease (IBD). Methods: A descriptive, ambispective, single-centre study of paediatric patients with IBD who underwent IFX serum concentration measurements between September 2015 and September 2023. The patients received reactive TDM before September 2019 (n = 17) and proactive TDM thereafter (n = 21). We analysed for clinical, biological, and endoscopic remission; treatment failure; hospitalisations; emergency visits; and adverse drug reactions. The IFX doses were adjusted to maintain trough concentrations ≥ 5 µg/mL, with specific targets for proactive TDM. Results: Of the 38 patients, 21 had Crohn’s disease (CD), 16 ulcerative colitis (UC), and 1 undetermined IBD. The mean (standard deviation) IFX trough concentrations were 6.83 (5.66) µg/mL (reactive) and 12.38 (9.24) µg/mL (proactive) (p = 0.08). No statistically significant differences between groups were found in remission rates or treatment failure. The proactive group had fewer hospitalisations (14.29% vs. 23.53%; p = 0.47) and shorter median hospitalisation days (6 vs. 19; p = 0.50), although the difference was not statistically significant. The number of patients with adverse reactions (infusion related reactions and infections) was higher in the proactive group (38.10% vs. 23.53%; p = 0.34) but the difference was not significantly different. Conclusions: Proactive TDM showed no significant differences in treatment outcomes compared to reactive TDM. However, the results in both the reactive and proactive TDM groups were not worse than those reported in other studies. Further studies with larger samples are needed to optimize the treatment strategies for pediatric IBD patients.

Pulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. This is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. The pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, nine adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 hours. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. Voriconazole nebulization is well tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

A few months ago, we presented the results from a case-control study evaluating solid organ transplantation (SOT) recipients’ outcomes after COVID-19 requiring hospitalization, which showed a trend towards higher mortality among SOT patients compared to controls¹. Other authors reported similar results regarding mortality², whereas Chavarto et al. found no increased risk of death among kidney recipients compared to controls³. We hypothesize that COVID-19 might affect long-term survival of SOT recipients, drug-drug interactions (DDI) might contribute to graft rejection and COVID-19 unknown long-term effects might specially affect immunosuppressed patients⁴; here, we aim to evaluate the long-term outcomes of SOT patients affected by COVID-19.