Targeting immunoliposomes to EGFR-positive glioblastoma.

BACKGROUND: We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients. PATIENTS AND METHODS: Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained. RESULTS: There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood-brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome. CONCLUSIONS: We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo-in this case doxorubicin-can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers.

The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation containing the absorption-enhancer chitosan were studied in 12 healthy volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the ß2 band (18-25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum-effect (E(max)) model indicated disequilibrium between plasma and effect-site concentrations, with equilibration half-lives of 2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out-of-hospital emergency settings with no immediate i.v. access.

Implementation of treatment guidelines to support judicious use of antibiotic therapy.

BACKGROUND AND OBJECTIVE: Judicious use of antibiotics is essential considering the growth of antimicrobial resistance and escalating costs in health care. This intervention study used treatment guidelines to improve antibiotic therapy by changing prescribing practice. METHODS: A before-after intervention study was performed in a 550-bed tertiary care teaching hospital in Switzerland, with an additional follow-up analysis 1 year later. The pre-intervention phase included chart analysis of current antibiotic use in 100 consecutive patients from the representative medical and surgical wards included in the study. Treatment guidelines were defined, taking into account published guidelines, the local antibacterial sensitivity of the pathogens, and the hospital antibiotic formulary defined by the drug and therapeutics committee. The guidelines were presented to the medical residents on a pocket card. They were informed and educated by the pharmacist (intervention). In the post-intervention phase immediately after the instruction, and in the follow-up phase 1 year later, a prospective analysis of antibiotic prescription was performed by chart review of 100 antibacterial treatments in consecutive patients to detect changes in antibiotic prescribing (treatment) and to determine whether these changes were sustained. RESULTS: The pre-intervention review of antibiotic use showed the need for therapy improvements in urinary tract infections (UTI) and hospital-acquired pneumonia (HAP). In the post-intervention phase 100% of UTI were treated as recommended, compared to 30% before the intervention (P < 0.001). The follow-up analysis showed a decrease in guideline adherence to 39% in patients with UTI. Before implementation of the clinical guidelines, HAP was inappropriately treated like community-acquired pneumonia (CAP). Immediately after the intervention, 50% of HAP patients were treated as recommended, and 1 year later (follow-up phase) 56% of HAP patients received the recommended antibiotic medication. This change in prescription practice was significant (P < 0.05). CONCLUSION: Antibiotic treatment guidelines for the infections most commonly occurring in hospitalized patients resulted in a significant increase in appropriate antibiotic use. The program was successful in changing prescription practice and achieved a sustained optimization of HAP therapy. Implementing, teaching and monitoring treatment guidelines can have a major impact on patient care.