Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). ...Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach.
•Strategies to load therapeutics into polysaccharide nanogels have been highlighted.•The formulation of polysaccharide-based vaccines has been described.•Microfluidics for facilitating the scalability of nanogel formulations has been discussed.
Intracellular pathogens are a critical challenge for antimicrobial therapies. Staphylococcus aureus (S. aureus) causes approximately 85% of all skin and soft tissue infections in humans worldwide and ...more than 30% of patients develop chronic or recurrent infections within three months, even after appropriate antibacterial therapies. S. aureus is also one of the most common bacteria found in chronic wounds. Recent evidences suggest that S. aureus is able to persist within phagolysosomes of skin cells (i.e. keratinocytes, phagocytic cells), being protected from both the immune system and a number of antimicrobials. To overcome these limits, nano-formulations that enable targeted therapies against intracellular S. aureus might be developed. Herein, the biodistribution and intracellular localisation of hyaluronan (HA) and HA-based nanoparticles (nanogels, NHs) are investigated, both after intravenous (i.v.) injections (in mice) and topical administrations (in ex vivo human skin). Results indicate HA and NHs accumulate especially in skin and liver of mice after i.v. injection. After topical application on human skin explants, no penetration of both HA and NHs was detected in skin with intact stratum corneum. By contrast, in barrier-disrupted human skin (with partial removal and loosening of stratum corneum), HA and NHs penetrate to the viable epidermis and are taken up by keratinocytes. In mechanically produced wounds (skin without epidermis) they accumulate in wound tissue and are taken up by dermis cells, e.g. fibroblasts and phagocytic cells. Interestingly, in all cases, the cellular uptake is CD44-mediated. In vitro studies confirmed that after CD44-mediated uptake, both HA and NHs accumulate in lysosomes of dermal fibroblasts and macrophages, as previously reported for keratinocytes. Finally, the colocalisation between intracellular S. aureus and HA or NHs is demonstrated, in macrophages. Altogether, for the first time, these results strongly suggest that HA and HA-based NHs can provide a targeted therapy to intracellular S. aureus, in persistent skin or wound infections.
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•Hyaluronan (HA) and its self-assembled nanogels (NHs) mainly accumulate in skin and liver of mice after i.v. injection•HA and NHs do not penetrate human skin with intact stratum corneum•In barrier-disrupted human skin HA and NHs penetrate to the viable epidermis and are mostly taken up by keratinocytes•In wounds HA and NHs are taken up by dermis cells. In all cases, the cellular uptake is CD44-mediated•HA and NHs accumulate within lysosomes of skin cells and colocalise with intracellular S. aureus
The adulteration of drugs of abuse is a well-known practice with alarming public health implications. In fact, the presence of other substances than those declared by the drug dealers may expose the ...consumers to unexpected adverse effects, even potentially fatal ones depending on the adulterant. Various adulterants are often added during the manufacturing process as cutting agent for deliberate underdosing, such as in case of levamisole for cocaine, or to strengthen the drug ef-fect, as in case of fentanyl for heroin. The authors aimed to elaborate on such unfolding dynamics and concluded that continuous development of effective analytical tools, along with a closely focused evaluation of each case by the medical doctor is essential to clarify the origin of the intoxications, so as to undertake the best therapeutic pathway.
Purpose
To prospectively evaluate the efficacy and safety of RIRS, SWL and PCNL for lower calyceal stones sized 1–2 cm.
Materials and methods
Patients with a single lower calyceal stone with an ...evidence of a CT diameter between 1 and 2 cm were enrolled in this multicenter, randomized, unblinded, clinical trial study. Patients were randomized into three groups: group A: SWL (194 pts); group B: RIRS (207 pts); group C: PCNL (181 pts). Patients were evaluated with KUB radiography (US for uric acid stones) at day 10 and a CT scan after 3 months. The CONSORT 2010 statement was adhered to where possible. The collected data were analyzed.
Results
The mean stone size was 13.78 mm in group A, 14.82 mm in group B and 15.23 mm in group C (
p
= 0.34). Group C compared to group B showed longer operative time 72.3 vs. 55.8 min (
p
= 0.082), fluoroscopic time 175.6 vs. 31.8 min (
p
= 0.004) and hospital stay 3.7 vs. 1.3 days (
p
= 0.039). The overall stone-free rate (SFR) was 61.8% for group A, 82.1% for group B and 87.3% for group C. The re-treatment rate was significantly higher in group A compared to the other two groups, 61.3% (
p
< 0.05). The auxiliary procedure rate was comparable for groups A and B and lower for group C (
p
< 0.05). The complication rate was 6.7, 14.5 and 19.3% for groups A, B and C, respectively.
Conclusions
RIRS and PCNL were more effective than SWL to obtain a better SFR and less auxiliary and re-treatment rate in single lower calyceal stone with a CT diameter between 1 and 2 cm. RIRS compared to PCNL offers the best outcome in terms of procedure length, radiation exposure and hospital stay.
ISRCTN 55546280.
Cervical cord damage is likely to contribute to the accumulation of disability in multiple sclerosis (MS) and can be quantified in vivo using MRI. We used conventional and diffusion tensor (DT) MRI ...to: (a) define the temporal evolution of intrinsic tissue injury and atrophy in the cervical cord from MS patients, (b) investigate how these two aspects of cord damage are interrelated and (c) assess the correlation of cord MRI metrics with concomitant brain damage and disability. Conventional and DT MRI of the brain and cervical cord were obtained from 42 MS patients and 9 healthy controls at baseline and after a mean follow-up of 2.4 years. At each time-point, we measured: cervical cord lesion number, cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA). Brain T2 lesion volume, grey matter MD, normal appearing white matter (NAWM) MD and FA, as well as longitudinal normalized percentage brain volume changes were also measured. In MS patients, cervical cord cross-sectional area (P < 0.001) and FA (P = 0.01) decreased, and cervical cord MD increased (P < 0.001) during follow-up. Cord FA decrease, but not cord cross-sectional area and MD, was significantly higher (P = 0.05) in primary progressive MS patients than in those with either relapsing–remitting or secondary progressive MS. At baseline and follow-up, moderate correlations were found between intrinsic cord diffusivity abnormalities and cord cross-sectional area (r values ranging from 0.34 to 0.58), but not between their changes over time. No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of cord T2-visible lesions. Brain NAWM MD (P = 0.03) and brain volume (P < 0.001) also changed in patients. There was no significant correlation between cord and brain MRI metrics at both time-points, as well as between their changes occurred over the follow-up. Baseline cord cross-sectional area (r = −0.40, P = 0.01) and FA (r = −0.40, P = 0.03) correlated with increase in disability at follow-up. This study shows that both progressive tissue loss and injury to the remaining tissue occur in the cervical cord of MS patients, and that these two components of cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage. MS cord pathology also seems to be independent of concomitant brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual.
Purpose
We evaluated if, during lithotripsy, bacteria may be detected in the irrigation fluid of percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS). The concordance between ...urine culture from stone fragmentation (SFUC), bladder (BUC), renal pelvic (RPUC) and stone (SC) was analyzed. We also assessed the correlation between variables and cultures and their association with systemic inflammatory response syndrome (SIRS) and of a positive SC.
Methods
We included 107 patients who underwent PCNL (
n
= 53) and RIRS (
n
= 54) from January 2017 to May 2018. Samples for RPUC were obtained by renal catheterization. Stone fragments and irrigation fluid sample were sent for culture.
Results
SFUC was positive in 17 (15.9%), BUC in 22 (20.6%), RPUC in 26 (24.3%) and SC in 30 patients (28%). The concordance between SFUC and SC was the highest among all cultures: 94.1%. SFUC and SC grew identical microorganisms in 15/17 (88.2%) patients. Out of 17 (15.9%) patients with SIRS, 8 (7.5%) had sepsis. SFUC had the highest PPV and specificity to detect positive SC and SIRS. Previous urinary tract infection, a preoperative nephrostomy, stone diameter and composition, staghorn calculi, PCNL, positive BUC, RPUC and SFUC were predictors of infected stone. Variables that indicate complex stones, complex PCNL and an infection of the upper tract were associated with SIRS.
Conclusion
SFUC is technically feasible, easy to retrieve and to analyze. The spectrum of SFUC potential application in clinical practice is when is not possible to perform a SC, e.g. complete dusting or during micro-PCNL.
The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for ...many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.
We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.
A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).
Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.
•Hyaluronic acid-cholesterol nanohydrogels (NHs) were loaded with levofloxacine (LVF).•LVF-NHs were active against P. aeruginosa and S. aureus.•LVF-NHs eradicated bacteria in intracellular ...infections.
In the present work, an innovative approach based on the delivery of levofloxacin (LVF) from polysaccharide nanohydrogels for the treatment of bacterial intracellular infections is described. The nanohydrogels (NHs) were obtained by self-assembling of the hyaluronic acid-cholesterol amphiphilic chains in aqueous environment. LVF, a fluoroquinolone antibiotic scarcely efficient in intracellular infections, was entrapped within such NHs by nanoprecipitation, thus forming a drug delivery system (LVF-NHs) that was tested for its activity on different bacteria strains. The MIC values of levofloxacin-loaded nanohydrogels were determined for Staphylococcus aureus and Pseudomonas aeruginosa strains and compared to those obtained using free LVF. The intracellular antimicrobial activity of LVF-NHs and free LVF was compared on HeLa epithelial cell line infected by the above mentioned bacteria, and the increase in antibacterial efficacy of LVF-NHs with respect to that of free LVF was evidenced. The obtained results allow to conclude that this new approach can be considered as really promising method for intracellular infection treatments.
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