Drug-in-cyclodextrin-in-polymeric nanoparticles: A promising strategy for rifampicin administration.

The aim of this work was to develop novel chitosan (CH) based nanoparticles (NPs) for rifampicin (RIF) delivery. RIF, a lipophilic molecule, was incorporated inside NPs as a complex with an anionic cyclodextrin, sulphobutyl-ether-ß-cyclodextrin (SBE-ß-CD). NPs were then prepared through the ionic gelation method by exploiting the interaction between CH and SBE-ß-CD-RIF complex (CH/SBE-ß-CD-RIF NPs), possibly in the presence of other crosslinkers, like carboxymethylcellulose (CH/SBE-ß-CD-RIF/CMC NPs) and pentasodium tripolyphosphate (CH/SBE-ß-CD-RIF/TPP NPs). NPs were then characterized for their size, ζ-potential, morphology, yield, drug loading, stability, mucoadhesion, in vitro drug release and antimicrobial activity. Results demonstrated that the functional properties of loaded NPs, like their size, ζ-potential, and stability, varied on the basis of the CH/crosslinker weight ratio. Interestingly, all the developed NPs had a round shape and were characterized by high yield values and mucoadhesive properties. Among them, NPs based on CH/SBE-ß-CD-RIF and CH/SBE-ß-CD-RIF/CMC have gained high drug loading, provided a sustained release of RIF and showed the best antimicrobial activity. Thus, both types of NPs may be considered as promising nanocarriers for the release of RIF.

Drug delivery to the brain: In situ gelling formulation enhances carbamazepine diffusion through nasal mucosa models with mucin.

The objective of this work was to optimize a thermosensitive in situ gelling formulation to improve intranasal and nose-to-brain delivery of the antiepileptic drug carbamazepine (CBZ). A preliminary procedure of vehicles obtained just mixing different fractions of poloxamer 407 (P407) and poloxamer 188 (P188) revealed preparations with phase transition temperatures, times to gelation and pH values suitable for nasal delivery. Subsequently, the mucoadhesive properties of the most promising formulations were tuned by adding hydroxypropylmethylcellulose types of different viscosity grades, and the effect of the adhesive polymers was evaluated by testing in vitro time and strength of mucoadhesion on specimens of sheep nasal mucosa. The formulation that showed the greatest mucoadhesive potential in vitro, with a time and force of mucoadhesion equal to 1746,75 s and 3.66 × 10-4 N, respectively, was that composed of 22% P407, 5% P188 and 0.8% HPMC low-viscous and it was further investigated for its ability to increase drug solubility and to control the release of the drug. Lastly, the capability of the candidate vehicle to ensure drug permeation across the biomimetic membrane Permeapad®, an artificial phospholipid-based barrier with a stratified architecture, and the same barrier enriched with a mucin layer was verified. The final formulation was characterized by a pH value of 6.0, underwent gelation at 32.33°C in 37.85 s, thus showing all the features required by in situ gelling thermosensitive preparations designed for nasal delivery and, more notably, it conserved the ability to favor drug permeation in the presence of mucin. These findings suggest that the optimized gelling system could be a promising and easy to realize strategy to improve CBZ delivery to the brain exploiting both a direct and indirect pathway.

Human Lactobacillus Biosurfactants as Natural Excipients for Nasal Drug Delivery of Hydrocortisone.

The inclusion of a chemical permeation enhancer in a dosage form is considered an effective approach to improve absorption across the nasal mucosa. Herein we evaluated the possibility of exploiting biosurfactants (BS) produced by Lactobacillus gasseri BC9 as innovative natural excipients to improve nasal delivery of hydrocortisone (HC). BC9-BS ability to improve HC solubility and the BS mucoadhesive potential were investigated using the surfactant at a concentration below and above the critical micelle concentration (CMC). In vitro diffusion studies through the biomimetic membrane PermeaPad® and the same synthetic barrier functionalized with a mucin layer were assessed to determine BC9-BS absorption enhancing properties in the absence and presence of the mucus layer. Lastly, the diffusion study was performed across the sheep nasal mucosa using BC9-BS at a concentration below the CMC. Results showed that BC9-BS was able to interact with the main component of the nasal mucosa, and that it allowed for a greater solubilization and also permeation of the drug when it was employed at a low concentration. Overall, it seems that BC9-BS could be a promising alternative to chemical surfactants in the nasal drug delivery field.

Influence of Lactobacillus Biosurfactants on Skin Permeation of Hydrocortisone.

One of the most widely used strategies to improve drug diffusion through the skin is the use of permeation enhancers. The aim of this work was to investigate the effect of two biosurfactants (BS), produced by Lactobacillus crispatus BC1 and Lactobacillus gasseri BC9, on the skin permeation profile of hydrocortisone (HC, model drug). HC aqueous solubility and in vitro diffusion studies through porcine skin were performed in the presence of BC1-BS and BC9-BS at concentrations below and above critical micellar concentrations (CMC). Moreover, skin hydration tests and differential scanning calorimetry (DSC) analysis were performed to further investigate BS interaction with the outermost layer of the skin. Both BS increased HC solubility, especially at concentrations above their CMC. At concentrations below the CMC, drug permeation through the skin was improved, as the result of a dual effect: a) the formation of a superficial lipophilic environment, as confirmed by the reduction in skin hydration and b) the interaction between BS and the stratum corneum (SC), as demonstrated by the DSC curves. From the obtained data, it appears that BC1-BS and BC9-BS could represent new promising green excipients for drug permeation enhancement through the skin.

Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.

Epidemiology of paraneoplastic neurological syndromes: a population-based study.

BACKGROUND: The epidemiology of paraneoplastic neurological syndromes (PNS) remains to be defined. We present here the first population-based incidence study and report the clinical spectrum and antibody profile of PNS in a large area in Northeastern Italy. METHODS: We performed a 9-year (2009-2017) population-based epidemiological study of PNS in the provinces of Udine, Pordenone and Gorizia, in the Friuli-Venezia Giulia region (983,190 people as of January 1, 2017). PNS diagnosis and subgroups were defined by the 2004 diagnostic criteria. Age- and sex-adjusted incidence rates were calculated. RESULTS: We identified 89 patients with a diagnosis of definite PNS. Median age was 68 years (range 26-90), 52% were female. The incidence of PNS was 0.89/100,000 person-years. PNS incidence rates increased over time from 0.62/100,000 person-years (2009-2011), 0.81/100,000 person-years (2012-2014) to 1.22/100,000 person-years (2015-2017). The prevalence of PNS was 4.37 per 100,000. Most common PNS were limbic encephalitis (31%), cerebellar degeneration (28%) and encephalomyelitis (20%). Among antibody (Ab)-positive cases, most frequent specificities included: Yo (30%), Hu (26%), and Ma2 (22%), while the most frequent associated tumors were lung (17%) and breast cancer (16%), followed by lymphoma (12%). PNS developed in 1 in every 334 cancers in our region. Statistically significant associations were observed between cancer type and Ab-specificity (P < 0.001), and between neurological syndrome and Ab-specificity (P < 0.001). CONCLUSIONS: This first population-based study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.

Status epilepticus mimicking stroke recurrence.

AIM OF THE STUDY: The aim of the study was to evaluate the clinical characteristics of patients with previous stroke (either ischemic or hemorrhagic), who developed status epilepticus (SE) mimicking a stroke relapse. MATERIALS AND METHODS: We performed a retrospective cohort study of patients brought to hospital by the emergency service between December 2016 and January 2018 with a stroke code as possible candidates for intravenous thrombolysis and who had already have a previous stroke. Among them, patients admitted for negative symptoms and finally discharged with a diagnosis of SE mimicking stroke were selected and their clinical characteristics collected. All patients underwent routine blood sample analysis, head computed tomography (CT) scan and, when indicated, CT angiography and CT-perfusion imaging of the head. After admission in our stroke unit, an Electroencephalogram (EEG) was performed within 3 h in patients suspected with SE, then classified according to International League Against Epilepsy (ILAE) classification (2015). Outcome measures were SE duration, antiepileptic drugs (AEDs) administered, mortality at 12 months, Engel scale, and modified Rankin scale (m-RS) at 6 months. A second cohort included those consecutive patients discharged with a true stroke relapse in the same considered time span. Clinical characteristics of these two cohorts were compared using Mann-Whitney test or Student t-test (Confidence Interval (C.I.) 95%, p < 0.05) for continuous variable and Fisher exact test or Pearson-Chi test for dichotomic variables (p < 0.05). Survival rates were calculated, and a Log-Rank test was performed to evaluate differences in survival distribution. Only in the group with SE, m-RS at 6 months and recurrence of SE were also evaluated. RESULTS: Eleven patients were discharged with a diagnosis of SE mimicking stroke and 65 patients with stroke relapse. Temporal lobe localization was significantly more represented in group with SE (p = 0.036) while there was no difference regarding age, sex, and National Institutes of Health Stroke Scale (NIHSS). The m-RS was significantly higher in patients with hemorrhage relapse, mainly due to the high incidence of amyloid angiopathy in this subgroup. Status epilepticus recurred in 36.4% of patients, presenting with the same clinical features, and most patients (62.5%) achieved a good seizure control at 6 months (Engel scale = 1). A difference in mortality at 12 months (all cause considered) appeared only when distinguishing strokes between ischemic and hemorrhagic (Chi-Square: 10.711, p < 0.005). DISCUSSION AND CONCLUSION: Status epilepticus is not infrequent in patients with previous stroke and may present with negative neurological symptoms, thus mimicking a stroke recurrence. EEG should be considered as a potential diagnostic tool in the acute stroke setting, at least in patients with previous stroke. This article is part of the Special Issue "Seizures & Stroke".

Seizures Do Not Affect Disability and Mortality Outcomes of Stroke: A Population-Based Study.

Although seizures are frequently seen after cerebrovascular accidents, their effects on long-term outcome in stroke patients are still unknown. Therefore, the aim of this study was to investigate the relationship between post-stroke seizures and the risk of long-term disability and mortality in stroke patients. This study is part of a larger population-based study. All patients were prospectively followed up by a face-to-face interview or a structured telephone interview. We enrolled 635 patients with first-ever stroke and without a history of seizures. Prevalence of ischemic stroke (IS) was 85.2%, while the remaining 14.8% of patients were affected by intracerebral hemorrhage (ICH). During the study period, 51 subjects (8%) developed post-stroke seizures. Patients with post-stroke seizures were younger, had a higher prevalence of ICH, had a more severe stroke at admission, were more likely to have an IS involving the total anterior circulation, and were more likely to have a lobar ICH than patients without seizures. Moreover, subjects with seizures had more frequently hemorrhagic transformation after IS and cortical strokes. At 24 months, the risk of disability in patients with seizures was almost twice than in those without seizures. However, the negative effect of seizures disappeared in multivariate analysis. Kaplan-Meier survival curves at 12 years were not significantly different between patients with and without post-stroke seizures. Using the Cox multivariate analysis, age, NIHSS at admission, and pre-stroke mRS were independently associated with all-cause long-term mortality. In our sample, seizures did not impair long-term outcome in patients affected by cerebrovascular accidents. The not significant, slight difference in favor of a better survival for patients with seizures may be attributed to the slight age difference between the two groups.

When Nothing Goes Right: An Unexpected Tongue Deviation in Internal Carotid Artery Dissection.

Internal carotid artery dissection is a frequent cause of stroke in young people. The artery dissection and the formation of an intramural hematoma could also cause mass effect on surrounding structures, causing disorders such as cranial nerve palsies (about 12% of the cases), including XII cranial nerve. In the setting of an ischemic stroke, lower cranial nerve palsy could also be due to infratentorial ischemic lesions; however, there have been also rare reports of lower cranial nerve palsy due to supratentorial cerebral ischemic lesions. We describe a case of a 55-year-old man who presented with right internal carotid artery dissection and deviation to the left of the protruded tongue. The direction of the deviation of the protruded tongue was unexpected in this patient, because if the XII nerve palsy was due to mass effect related to the intramural hematoma of the dissected artery, a deviation to the right should have happened. Anyway, a subsequent magnetic resonance revealed also an acute ischemic lesion in the right tongue area in the primary motor cortex of the patient, providing a rare, but a fitting neuroanatomical explanation of the deviation and also providing clinical evidence of functional dominance of the crossed projections of the cortico-lingual tracts.

Stroke-Like Presentation of Paraneoplastic Cerebellar Degeneration: a Single-Center Experience and Review of the Literature.

Paraneoplastic cerebellar degeneration (PCD) is usually thought to have a subacute progression over several weeks. We report herein incidence and clinical features of hyperacute onset PCD, a vertebrobasilar stroke mimic. We performed a retrospective analysis of all suspected PCD cases referred to the Udine University Hospital between 2009 and 2017. Our center provides the only neuroimmunology laboratory for three provinces of the Friuli-Venezia Giulia region, Italy (983,190 people as of January 1, 2017). Inclusion criteria were (1) abrupt onset of neurological symptoms; (2) initial consideration of a vascular etiology; (3) final diagnosis of "definite PCD." We also carried out a systematic review of the literature in order to identify previous stroke-like PCD cases. Between 2009 and 2017, 24 patients received a final diagnosis of PCD. The age-standardized incidence rate of PCD was 0.22/100,000 person-years. Two cases (8.3%) had a stroke-like onset, with an incidence of 0.02/100,000 person-years. Additionally, 10 previously reported stroke-like PCD cases were identified. Among all cases (n = 12), 67% were female; median age was 51 years (range, 22-69). An associated cancer was discovered in all cases. Brain imaging was normal in most (75%) of the patients. Cerebrospinal fluid (CSF) analysis showed inflammatory alterations in 73% of the cases. Cancer treatment was more effective than immunotherapy in improving the neurological syndrome. Typical patients with hyperacute PCD are middle-aged women with normal brain imaging, inflammatory markers in CSF, and cancer. Surgery of the underlying cancer is probably the best treatment. PCD must be considered in the differential diagnosis of acute-onset ataxia and/or vertigo.

Efficacy and Safety of Intravenous Thrombolysis in Patients with Acute Ischemic Stroke and Pre⁻Existing Disability.

Little is known about intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients with pre-existing disability. Disabled patients are often excluded from IVT treatment. Previous studies investigated the role of pre-existing disability on outcomes in AIS patients after IVT. However, no studies have been conducted to date to determine whether IVT may improve clinical outcomes in AIS patients with pre-existing disability. The aim of our study was to evaluate efficacy and safety of IVT in patients with pre-existing moderate and moderately severe disability (pre-stroke modified Rankin Scale score = 3 or 4) affected by AIS. This study was based on a retrospective analysis of a prospectively collected database of consecutive patients admitted to the Udine University Hospital with AIS from January 2015 to May 2018. The efficacy endpoints were the rate of favorable outcome and rate of major neurological improvement. The safety endpoints were the rate of mortality at three months, presence of intracranial hemorrhage (ICH), and presence of symptomatic intracranial hemorrhage (sICH). The study population included 110 AIS patients with pre-existing moderate and moderately severe disability, 36 of which received (IVT+) and 74 did not receive IVT (IVT-). AIS disabled patients treated with IVT had higher rates of favorable outcome (66.7% vs. 36.5%, p = 0.003) and major neurological improvement (39.4% vs. 17.4%, p = 0.01) compared to non-treated ones. Two in three disabled patients returned to their pre-stroke functional status when treated with IVT. Prevalence of three-month mortality, ICH, and sICH did not differ in the two groups. Disabled patients affected by AIS significantly improved after IVT. Moderate and moderately severe disability alone should not be considered, per se, as a contraindication to IVT treatment.