Low discovery rates for new antibiotics, commercial disincentives to invest, and inappropriate use of existing drugs have created a perfect storm of antimicrobial resistance (AMR). This "silent pandemic" of AMR looms as an immense, global threat to human health. In tandem, many potential novel drug candidates are not progressed due to elevated hydrophobicity, which may result in poor intracellular internalization and undesirable serum protein binding. With a reducing arsenal of effective antibiotics, enabling technology platforms that improve the outcome of treatments, such as repurposing existing bioactive agents, is a prospective option. Nanocarrier (NC) mediated drug delivery is one avenue for amplifying the therapeutic outcome. Here, the performance of several antibiotic classes encapsulated within the lipid-based cubosomes is examined. The findings demonstrate that encapsulation affords significant improvements in drug concentration:inhibition outcomes and assists in other therapeutic challenges associated with internalization, enzyme degradation, and protein binding. We emphasize that a currently sidelined compound, novobiocin, became active and revealed a significant increase in inhibition against the pathogenic Gram-negative strain, Pseudomonas aeruginosa. Encapsulation affords co-delivery of multiple bioactives as a strategy for mitigating failure of monotherapies and tackling resistance. The rationale in optimized drug selection and nanocarrier choice is examined by transport modeling which agrees with experimental inhibition results. The results demonstrate that lipid nanocarrier encapsulation may alleviate a range of challenges faced by antibiotic therapies and increase the range of antibiotics available to treat bacterial infections.
Therapeutic delivery of neuropeptides including oxytocin and somatostatin is associated with numerous difficulties including low stability, low oral bioavailability, and a short half-life in vivo. For delivery to the brain, these issues are exacerbated by difficulties in crossing the blood–brain barrier. Lipid-based nanomaterials may offer specific advantages for the delivery of therapeutic peptides including good biocompatibility, retention of peptide activity, and controlled release properties. Herein we have investigated the use of the lipid bicontinuous cubic phase as a depot formulation for the controlled release of the neuropeptides oxytocin and somatostatin. Retention of the cubic architecture was confirmed up to high peptide concentrations of at least 30 mg mL−1 for both peptides. Encapsulation had only minimal effect on the peptide secondary structure in both cases. Controlled release of the peptides from the cubic phase was diffusion controlled over the first 24 h. The time-dependent self-assembly of somatostatin into nanofibrils within the bicontinuous cubic phase led to a unique two-stage release mechanism, with diffusion-controlled release of the peptide monomer over the first 24 h followed by a much slower linear release of the peptide from the nanofibrils. Results suggest that the lipid bicontinuous cubic phase is a highly prospective nanomaterial for the encapsulation and controlled release of neuropeptide therapeutics.
Background: Our HEGITO liver unit provides the in- and out-patient (pt) tertiary referral services including liver transplantation (LT) Since 2014, HEGITO has kept registry (RH7) of patients hospitalized with cirrhosis / advanced chronic liver disease (ACLD) The social distancing policy restrictions were introduced in Slovakia on March 16, 2020 and they have substantially changed the usual provision of HEGITO services: We 1 deferred or diverted to telemedicine most of planned and on-demand outpatient services, 2 deferred planned and delimited to region-proper lower-rank institutions acute hospitalizations and, 3 deferred LT except for urgent indications In this study, we aimed to analyze the registrations to and mortality in RH7 pre- and during the COVID-19 era Methods: Using a sample of pt registered to RH7 anytime from its start in 2014 and passing away before March 16, 2020 (PRE-COVID COHORT), we conducted a survival analysis using a Cox proportional hazard model with following factors: gender, age, BMI, CTP, MELD, LFI, ACLF, TSF, DYNAMO, CRP, LEU We used this model to predict individual median residual lifetime for remaining 563 pt from RH7 who were alive at March 16 (COVID COHORT) We compared actual cumulative number of deaths between March 16 and June 6, with predictions based on the Cox PH model Deaths were ascertained by the weekly reports from the Healthcare Surveillance Authority with the special query for COVID 19 code Results: We identified 1091 pt in PRECOVID COHORT with median age 56 8, MELD 16, 60 8% male, and 563 pt in COVID COHORT with median age 55 7, MELD 14, 57 2% male, respectively Registry data shows a significant drop in weekly new registrations to RH7: four in March 2020 vs 17 8 average in March 2014-2019, followed by a sharp increase after these policies were lifted (Figure) Registered mortality in COVID COHORT was higher than mortality predicted by the Cox PH model using PRE-COVID COHORT (28 vs 22) Of note, there was no death related to COVID 19 in the COVID COHORT Conclusion: Analysis of our cirrhosis registry has revealed significantly decreased regsitrations and increased mortality during COVID 19 era We speculate that they are causally related to the impact of the pandemic on the quality of cirrhosis care (Tapper, J Hep 20;73: 441)
Antibiotic-resistant bacteria pose a significant threat to humanity. Gram-negative strains have demonstrated resistance to last resort antibiotics, partially due to their outer membrane, which hinders transport of antimicrobials into the bacterium. Nanocarrier (NC)-mediated drug delivery is one proposed strategy for combating this emerging issue. Here, the uptake of self-assembled lipid nanocarriers of cubic symmetry (cubosomes) into bacteria revealed fundamental differences in the uptake mechanism between Gram-positive and Gram-negative bacteria. For Gram-positive bacteria, the NCs adhere to the outer peptidoglycan layers and slowly internalize to the bacterium. For Gram-negative bacteria, the NCs interact in two stages, fusion with the outer lipid membrane and then diffusion through the inner wall. The self-assembled nature of the cubosomes imparts a unique ability to transfer payloads via membrane fusion. Remarkably, the fusion uptake mechanism allowed rapid NC internalization by the Gram-negative bacteria, overcoming the outer membrane responsible for their heightened resilience. Here this is demonstrated by the marked reduction in the minimal inhibition concentration required for antibiotics against a pathogenic strain of Gram-negative bacteria, Escherichia coli. These results provide mechanistic insight for the development of lipid NCs as a new tool to combat bacteria.
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