Central nervous system (CNS) disorders especially neurodegenerative disorders are the major challenge for public health and demand the great attention of researchers to protect people against them. ...In past few decades, different treatment strategies have been adopted, but their therapeutic efficacy are insufficient and have only shown partial mitigation of symptoms and are further associated with severe adverse effects. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BSCFB) guard the CNS from harmful substances and pose as the major challenges in delivering drugs into CNS for treatment of CNS complications such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke, epilepsy, brain tumors, multiple sclerosis, encephalitis, and many more. Nanotechnology has come out as an exciting and promising new platform of treating neurological disorders and has shown great potential to overcome problems related to the conventional treatment approaches. Molecules can be nanoengineered to carry out multiple specific functions such as to cross the blood-brain barrier, target specific cell or signaling pathway, respond to endogenous stimuli, and act as a vehicle for gene delivery, support nerve regeneration and cell survival. In present review, the role of nanocarrier systems such as liposomes, micelles, solid lipid nanoparticles, dendrimers, and nanoemulsions for delivery of various neurotherapeutic agents has been discussed, besides this, their mechanism of action, and nanoformulation of different neuroprotective agents like curcumin, edaravone, nerve growth factors in CNS disorders like Alzheimer’s, Parkinsonism, epilepsy, stroke and brain tumors has been reviewed.
Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein ...tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT.
In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST.
Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28:26, median age 56 years (range 20–82 years), ECOG performance status 0:1:2 = 24:28:2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3–14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1–7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2.
Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.
We evaluated the neuro-, immuno-, and male reproductive toxicity of zinc oxide nanoparticles (ZnO NPs) alone and in combination with lead acetate. We also studied the therapeutic role of α-lipoic ...acid postexposure. Lead (10 mg/kg, body weight), ZnO NPs (100 mg/kg, bwt) alone, and their combination were administered orally in Wistar rats for 28 days, followed by the administration of α-lipoic acid (15 mg/kg, bwt) for the next 15 days. Our results demonstrated protective effects of α-lipoic acid on lead and ZnO NP–induced biochemical alterations in neurological, immunological, and male reproductive organs in rats. The altered levels of blood δ-aminolevulinic acid dehydratase (ALAD), immunoglobulins (IgA, IgG, IgM, and IgE), interleukins (IL-1β, IL-4, and IL-6), caspase-3, and tumor necrosis factor (TNF-α) were attenuated by lipoic acid treatment. Lead and ZnO NP–induced oxidative stress was decreased by lipoic acid treatment, while a moderate recovery in the normal histoarchitecture of the brain section (cortex and hippocampus) and testes further confirmed the neuro- and male reproductive toxicity of lead and ZnO NPs. We also observed a significant decrease in the blood metal content in the animals treated with lipoic acid compared to the lead-administered group, indicating the moderate chelating property of lipoic acid. It may thus be concluded that lipoic acid might be a promising protective agent against lead and ZnO NP–induced alterations in the neurological, immunological, and reproductive parameters.
Display omitted
•Solid Lipid nanoparticles were loaded with MiADMSA.•Nano MiADMSA and bulk MiADMSA were tested against arsenic toxicity.•More pronounced efficacy of Nano-MiADMSA against arsenic ...neurotoxicity.•Reduced Oxidative stress, neurobehavioral changes and arsenic concentration.
Chelation therapy is considered as a safe and effective strategy to combat metal poisoning. Arsenic is known to cause neurological dysfunctions such as impaired memory, encephalopathy, and peripheral neuropathy as it easily crosses the blood-brain barrier. Oxidative stress is one of the mechanisms suggested for arsenic-induced neurotoxicity. We prepared Solid Lipid nanoparticles loaded with Monoisoamyl 2, 3-dimercaptosuccinic acid (Nano-MiADMSA), and compared their efficacy with bulk MiADMSA for treating arsenic-induced neurological and other biochemical effects. Solid lipid nanoparticles entrapping MiADMSA were synthesized and particle characterization was carried out by transmission electron microscopy (TEM) and dynamic light scattering (DLS). An in vivo study was planned to investigate the therapeutic efficacy of MiADMSA-encapsulated solid lipid nanoparticles (Nano-MiADMSA; 50 mg/kg orally for 5 days) and compared it with bulk MiADMSA against sodium meta-arsenite exposed rats (25 ppm in drinking water, for 12 weeks) in male rats. The results suggested the size of Nano-MiADMSA was between 100−120 nm ranges. We noted enhanced chelating properties of Nano-MiADMSA compared with bulk MiADMSA as evident by the reversal of oxidative stress variables like blood δ-aminolevulinic acid dehydratase (δ-ALAD), Reactive Oxygen Species (ROS), Catalase activity, Superoxide Dismutase (SOD), Thiobarbituric Acid Reactive Substances (TBARS), Reduced Glutathione (GSH) and Oxidized Glutathione (GSSG), Glutathione Peroxidase (GPx), Glutathione-S-transferase (GST) and efficient removal of arsenic from the blood and tissues. Recoveries in neurobehavioral parameters further confirmed nano-MiADMSA to be more effective than bulk MiADMSA. We conclude that treatment with Nano-MiADMSA is a better therapeutic strategy than bulk MiADMSA in reducing the effects of arsenic-induced oxidative stress and associated neurobehavioral changes.
The presence of IPH is considered the most dangerous feature because it is significantly associated with clinical ipsilateral cerebrovascular events. Our aim was to explore the characterization of ...plaque with CT in symptomatic subjects with bilateral intraplaque hemorrhage.
Three-hundred-forty-three consecutive patients with recent anterior circulation ischemic events (<2 weeks) and CT of the carotid arteries (performed within 14 days of the cerebrovascular event) evaluated between June 2012 and September 2017 were analyzed for plaque volume composition to identify all subjects with bilateral intraplaque hemorrhage. Plaque volume was semiautomatically measured, and tissue components were classified according to the attenuation values such as the following: calcified (for values of ≥130 HU), mixed (for values of ≥60 and <130 HU), lipid (for values of ≥25 and <60 HU), and intraplaque hemorrhage (for values of <25 HU). Twenty-one subjects (15 men; mean age, 70 ± 11 years; range, 44-87 years) had bilateral intraplaque hemorrhage and were included in the analysis.
Volume measurement revealed significantly larger plaques on the symptomatic side compared with the asymptomatic one (mean, 28 ± 9 versus 22 ± 8 mm,
= .007). Intraplaque hemorrhage volume and percentage were also significantly higher in the plaque ipsilateral to the cerebrovascular event (
< .001 and < .001, respectively). The volume of other plaque components did not show a statically significant association except for lipid and lipid + intraplaque hemorrhage percentages (23% versus 18% and 11% versus 15%), which were significantly different between the symptomatic and the asymptomatic sides (.016 and .011, respectively). The intraplaque hemorrhage/lipid ratio was higher on the symptomatic side (0.596 versus 0.171,
= .001).
In patients with bilateral intraplaque hemorrhage and recent ischemic symptoms, the plaque ipsilateral to the symptomatic side has significantly larger volume and a higher percentage of intraplaque hemorrhage compared with the contralateral, asymptomatic side.
Our aim was to assess the relationship between volume and percentage of intraplaque hemorrhage measured using CT and the occurrence of cerebrovascular events at the time of CT.
...One-hundred-twenty-three consecutive subjects (246 carotid arteries) with a mean age of 69 years who underwent CTA were included in this retrospective study. Plaque volume of components and subcomponents (including intraplaque hemorrhage volume) was quantified with dedicated software.
Forty-six arteries were excluded because no plaque was identified. In the remaining 200 carotid arteries, a statistically significant difference was found between presentation with cerebrovascular events and lipid volume (
= .002), intraplaque hemorrhage volume (
= .002), percentage of lipid (
= .002), percentage of calcium (
= .001), percentage of intraplaque hemorrhage (
= .001), percentage of lipid-intraplaque hemorrhage (
= .001), and intraplaque hemorrhage/lipid ratio (
= .001). The highest receiver operating characteristic area under the curve was obtained with the intraplaque hemorrhage volume with a value of 0.793 (
= .001), percentage of intraplaque hemorrhage with an area under the curve of 0.812 (
= .001), and the intraplaque hemorrhage/lipid ratio with an area under the curve value of 0.811 (
= .001).
Results of our study suggest that Hounsfield unit values <25 have a statistically significant association with the presence of cerebrovascular events and that the ratio intraplaque hemorrhage/lipid volume represents a strong parameter for the association of cerebrovascular events.
Intraplaque hemorrhage is considered a leading parameter of carotid plaque vulnerability. Our purpose was to assess the CT characteristics of intraplaque hemorrhage with histopathologic correlation ...to identify features that allow for confirming or ruling out the intraplaque hemorrhage.
This retrospective study included 91 patients (67 men; median age, 65 ± 7 years; age range, 41-83 years) who underwent CT angiography and carotid endarterectomy from March 2010 to May 2013. Histopathologic analysis was performed for the tissue characterization and identification of intraplaque hemorrhage. Two observers assessed the plaque's attenuation values by using an ROI (≥ 1 and ≤2 mm
). Receiver operating characteristic curve, Mann-Whitney, and Wilcoxon analyses were performed.
A total of 169 slices were assessed (59 intraplaque hemorrhage, 63 lipid-rich necrotic core, and 47 fibrous); the average values of the intraplaque hemorrhage, lipid-rich necrotic core, and fibrous tissue were 17.475 Hounsfield units (HU) and 18.407 HU, 39.476 HU and 48.048 HU, and 91.66 HU and 93.128 HU, respectively, before and after the administration of contrast medium. The Mann-Whitney test showed a statistically significant difference of HU values both in basal and after the administration of contrast material phase. Receiver operating characteristic analysis showed a statistical association between intraplaque hemorrhage and low HU values, and a threshold of 25 HU demonstrated the presence of intraplaque hemorrhage with a sensitivity and specificity of 93.22% and 92.73%, respectively. The Wilcoxon test showed that the attenuation of the plaque before and after administration of contrast material is different (intraplaque hemorrhage, lipid-rich necrotic core, and fibrous tissue had
values of .006, .0001, and .018, respectively).
The results of this preliminary study suggest that CT can be used to identify the presence of intraplaque hemorrhage according to the attenuation. A threshold of 25 HU in the volume acquired after the administration of contrast medium is associated with an optimal sensitivity and specificity. Special care should be given to the correct identification of the ROI.
CT is considered the standard reference both for quantification and characterization of carotid artery calcifications. Our aim was to investigate the relationship among different types of calcium ...configurations detected with CT within the plaque with a novel classification and to investigate the prevalence of cerebrovascular events.
Seven hundred ninety patients (men = 332; mean age, 69.7 SD, 13 years; 508 symptomatic for cerebrovascular symptoms and 282 asymptomatic) who underwent computed tomography of the carotid arteries were retrospectively included in this institutional review board-approved study. The plaque was classified into 6 types according to the different types of calcium configurations as the following: type 1, complete absence of calcification within the plaque; type 2, intimal or superficial calcifications; type 3, deep or bulky calcifications; type 4, adventitial calcifications with internal soft plaque of <2 mm thickness; type 5, mixed patterns with intimal and bulky calcifications; and type 6, positive rim sign.
The highest prevalence of cerebrovascular events was observed for type 6, for which 89 of the 99 cases were symptomatic. Type 6 plaque had the highest degree of correlation with TIA, stroke, symptoms, and ipsilateral infarct for both sides with a higher prevalence in younger patients. The frequency of symptoms observed by configuration type significantly differed between right and left plaques, with symptoms observed more frequently in type 6 calcification on the right side (50/53; 94%) than on the left side (39/46; 85%,
< .001).
We propose a novel carotid artery plaque configuration classification that is associated with the prevalence of cerebrovascular events. If confirmed in longitudinal analysis, this classification could be used to stratify the risk of occurrence of ischemic events.
Inflammatory changes in the fat tissue surrounding the coronary arteries have been associated with coronary artery disease and high-risk vulnerable plaques. Our aim was to investigate possible ...correlations between the presence and degree of perivascular fat density and a marker of vulnerable carotid plaque, namely contrast plaque enhancement on CTA.
One-hundred patients (76 men, 24 women; mean age, 69 years) who underwent CT angiography for investigation of carotid artery stenosis were retrospectively analyzed. Contrast plaque enhancement and perivascular fat density were measured in 100 carotid arteries, and values were stratified according to symptomatic (ipsilateral-to-cerebrovascular symptoms)/asymptomatic status (carotid artery with the most severe degree of stenosis). Correlation coefficients (Pearson ρ product moment) were calculated between the contrast plaque enhancement and perivascular fat density. The differences among the correlation ρ values were calculated using the Fisher r-to-z transformation. Mann-Whitney analysis was also calculated to test differences between the groups.
There was a statistically significant positive correlation between contrast plaque enhancement and perivascular fat density (ρ value = 0.6582,
value = .001). The correlation was stronger for symptomatic rather than asymptomatic patients (ρ value = 0.7052,
value = .001 versus ρ value = 0.4092,
value = .001).
There was a positive association between perivascular fat density and contrast plaque enhancement on CTA. This correlation was stronger for symptomatic rather than asymptomatic patients. Our results suggest that perivascular fat density could be used as an indirect marker of plaque instability.
To evaluate the pulmonary transit time (PTT) and its derived parameters using cardiac magnetic resonance imaging (CMRI) as markers of diastolic dysfunction in Takotsubo syndrome (TS) and its ...relationship with transthoracic echocardiography and CMRI parameters.
Twenty-two patients with TS, who exhibited diastolic dysfunction as assessed by transthoracic echocardiography, were enrolled retrospectively and the PTT, pulmonary transit time index (PTTI), and pulmonary blood volume index (PBVI) were evaluated using first-pass CMRI. PTT was calculated as the number of cardiac cycles required for a bolus of contrast agent to move from the right ventricle (RV) to the left ventricle (LV), whereas PTTI represents the PTT interval corrected for the heart rate. Finally, PBVI was calculated as the product of PTTI, and RV stroke volume indexed for body surface area. Normal references of PTT, PTTI, and PBVI were evaluated in a cohort of 20 age- and sex-matched healthy controls.
Compared with healthy subjects, TS patients showed significantly higher PTT, PTTI, and PBVI (p=0.0001, p=0.0001, and p=0.002, respectively). Using multivariable logistic regression, PBVI provided the best differentiation between TS and controls (AUC 0.84). PBVI was significantly associated with the index of diastolic dysfunction and left atrial strain parameters. In addition, PBVI demonstrated a significant correlation with global T2 mapping (r=0,520, p=0,019).
PTT and the derived parameters, as assessed using first-pass CMRI, are potential tools for assessing LV diastolic dysfunction in patients with TS.
•PTT was suggested as a feasible CMR tool to assess diastolic dysfunction.•TS patients showed higher PTT, PTTI, and PBVI values in comparison with healthy controls.•PTT and its derived parameters may be new tools in evaluating the diastolic function in TS patients.
PDF
