Transnasal targeted delivery of therapeutics in central nervous system diseases: a narrative review.

Currently, neurointervention, surgery, medication, and central nervous system (CNS) stimulation are the main treatments used in CNS diseases. These approaches are used to overcome the blood brain barrier (BBB), but they have limitations that necessitate the development of targeted delivery methods. Thus, recent research has focused on spatiotemporally direct and indirect targeted delivery methods because they decrease the effect on nontarget cells, thus minimizing side effects and increasing the patient's quality of life. Methods that enable therapeutics to be directly passed through the BBB to facilitate delivery to target cells include the use of nanomedicine (nanoparticles and extracellular vesicles), and magnetic field-mediated delivery. Nanoparticles are divided into organic, inorganic types depending on their outer shell composition. Extracellular vesicles consist of apoptotic bodies, microvesicles, and exosomes. Magnetic field-mediated delivery methods include magnetic field-mediated passive/actively-assisted navigation, magnetotactic bacteria, magnetic resonance navigation, and magnetic nanobots-in developmental chronological order of when they were developed. Indirect methods increase the BBB permeability, allowing therapeutics to reach the CNS, and include chemical delivery and mechanical delivery (focused ultrasound and LASER therapy). Chemical methods (chemical permeation enhancers) include mannitol, a prevalent BBB permeabilizer, and other chemicals-bradykinin and 1-O-pentylglycerol-to resolve the limitations of mannitol. Focused ultrasound is in either high intensity or low intensity. LASER therapies includes three types: laser interstitial therapy, photodynamic therapy, and photobiomodulation therapy. The combination of direct and indirect methods is not as common as their individual use but represents an area for further research in the field. This review aims to analyze the advantages and disadvantages of these methods, describe the combined use of direct and indirect deliveries, and provide the future prospects of each targeted delivery method. We conclude that the most promising method is the nose-to-CNS delivery of hybrid nanomedicine, multiple combination of organic, inorganic nanoparticles and exosomes, via magnetic resonance navigation following preconditioning treatment with photobiomodulation therapy or focused ultrasound in low intensity as a strategy for differentiating this review from others on targeted CNS delivery; however, additional studies are needed to demonstrate the application of this approach in more complex in vivo pathways.

Targeted Delivery of Erythropoietin Hybridized with Magnetic Nanocarriers for the Treatment of Central Nervous System Injury: A Literature Review.

Although the incidence of central nervous system injuries has continued to rise, no promising treatments have been elucidated. Erythropoietin plays an important role in neuroprotection and neuroregeneration as well as in erythropoiesis. Moreover, the current worldwide use of erythropoietin in the treatment of hematologic diseases allows for its ready application in patients with central nervous system injuries. However, erythropoietin has a very short therapeutic time window (within 6-8 hours) after injury, and it has both hematopoietic and nonhematopoietic receptors, which exhibit heterogenic and phylogenetic differences. These differences lead to limited amounts of erythropoietin binding to in situ erythropoietin receptors. The lack of high-quality evidence for clinical use and the promising results of in vitro/in vivo models necessitate fast targeted delivery agents such as nanocarriers. Among current nanocarriers, noncovalent polymer-entrapping or polymer-adsorbing erythropoietin obtained by nanospray drying may be the most promising. With the incorporation of magnetic nanocarriers into an erythropoietin polymer, spatiotemporal external magnetic navigation is another area of great interest for targeted delivery within the therapeutic time window. Intravenous administration is the most readily used route. Manufactured erythropoietin nanocarriers should be clearly characterized using bioengineering analyses of the in vivo size distribution and the quality of entrapment or adsorption. Further preclinical trials are required to increase the therapeutic bioavailability (in vivo biological identity alteration, passage through the lung capillaries or the blood brain barrier, and timely degradation followed by removal of the nanocarriers from the body) and decrease the adverse effects (hematological complications, neurotoxicity, and cytotoxicity), especially of the nanocarrier.

Comparison of a novel algorithm quantitatively estimating epifascial fibrosis in three-dimensional computed tomography images to other clinical lymphedema grading methods.

No method has yet been approved for detecting lymphedema fibrosis before its progression. This study assessed the feasibility of computed tomography-based estimation of fibrosis. This observational, cross-sectional study included patients with lymphedema affecting one limb. Three types (maximum, mean, minimum) of computed tomography reticulation indexes were digitally calculated from trans-axial images using absorptive values, and the computed tomography reticulation indexes compared with clinical scales and measurements. Of 326 patients evaluated by at least one of lymphoscintigraphy, bio-electrical impedance, and computed tomography, 24 were evaluated by all three. The mean number of computed tomography scans in these patients was 109. Sixteen patients had breast cancer, seven had gynecologic cancers, and one had primary lymphedema. Mean computed tomography reticulation index (r = 0.52, p < 0.01) and maximal computed tomography reticulation index (r = 0.45, p < 0.05) were significantly associated with time from initial limb swelling to computed tomography. Mean computed tomography reticulation index (r = 0.86, p < 0.01), minimal computed tomography reticulation index (r = 0.79, p < 0.01), and maximal computed tomography reticulation index (r = 0.68, p < 0.01) were significantly associated with International Society of Lymphedema substage. Minimal computed tomography reticulation index correlated with 1-kHz-based bio-electrical impedance ratio (r = -0.46, p < 0.05) and with standardized proximal limb circumference difference ratio (r = 0.45, p < 0.05) of both limbs. Maximal computed tomography reticulation index had a sensitivity of 0.78, specificity of 0.60, and areas under the curve of 0.66 in detecting lymphoscintigraphic stage IV. The algorithm utilizing three-dimensional computed tomography images of epifascial fibrosis may be used as a marker for lymphedema duration, limb swelling, International Society of Lymphedema substage, and interstitial lymphatic fluids of lymphedema. The current approach shows promise in providing an additional method to assist in characterizing and monitoring lymphedema patients.

Therapeutic time window for the effects of erythropoietin on astrogliosis and neurite outgrowth in an in vitro model of spinal cord injury.

BACKGROUND: The objective of this study was to investigate the underlying molecular mechanisms and the therapeutic time window for preventing astrogliosis with erythropoietin (EPO) treatment after in vitro modeled spinal cord injury (SCI). METHODS: Cultured rat spinal cord astrocytes were treated with kainate and scratching to generate an in vitro model of SCI. EPO (100U/mL or 300U/mL) was added immediately or 2, 4, or 8 hours after injury. Some cultures were also treated with AG490, an inhibitor of the EPO-EPO receptor (EpoR) pathway mediator Janus kinase 2 (JAK2). To evaluate neurite extension, rat embryonic spinal cord neurons were seeded onto astrocyte cultures and treated with EPO immediately after injury in the presence or absence of anti-EpoR antibody. RESULTS: EPO treatment at up to 8 hours after injury reduced the expression of axonal growth inhibiting molecules (glial fibrillary acidic protein, vimentin, and chondroitin sulfate proteoglycan), cytoskeletal regulatory proteins (Rho-associated protein kinase and ephephrin A4), and proinflammatory cytokines (tumor necrosis factor-alpha, transforming growth factor-beta, and phosphorylated-Smad3) in a dosedependent manner (P < .001). Most effects peaked with EPO treatment 2-4hours after injury. Additionally, EPO treatment up to 4 hours after injury promoted expression of the EpoR (>2-fold) and JAK2 (>3-fold) in a dose-dependent manner (P < .001), whereas co-treatment with AG490 precluded these effects (P < .001). EPO treatment up to 4hours after injury also enhanced axonal b-III tubulin-immunoreactivity (>12-fold), and this effect was precluded by co-treatment with an anti-EpoR antibody (P < .001). CONCLUSIONS: EPO treatment within 8 hours after injury reduced astrogliosis, and EPO treatment within 4 hours promoted neurite outgrowth. EPO therapy immediately after spinal cord injury may regulate glia to generate an environment permissive of axonal regeneration.

Enhanced Reality Showing Long-Lasting Analgesia after Total Knee Arthroplasty: Prospective, Randomized Clinical Trial.

To overcome the limitation of short-term efficacy of virtual reality (VR), an enhanced reality (ER) analgesia, (combination of the VR, real-time motion capture, mirror therapy [MT]) involving a high degree of patients' presence or embodiment was explored. Patients, who underwent unilateral total knee arthroplasty (TKA), received ER analgesia. The duration was 5 times a week, for 2 weeks for one group and 5 times a week, for 1 week in the other. Visual Analogue Scale (VAS) at rest and during movement, active knee range of motion (ROM) for flexion and extension were measured repeatedly. After screening 157 patients, 60 were included. Pre-interventional evaluation was performed at 6.7 days and ER was initiated at 12.4 days after surgery. Evaluation was performed at 5, 12, 33 days after the initiation of ER. Analgesia in the 2 week therapy group was effective until the third evaluation (p = 0.000), whereas in the other group, it was effective only until the second evaluation (p = 0.010). Improvement in ROM in the 2 week group was also maintained until the third evaluation (p = 0.037, p = 0.009). It could lay the foundations for the development of safe and long-lasting analgesic tools.

Velopharyngeal Incoordination Caused by Phenytoin-Induced Toxicity.

Phenytoin induces lymphoid proliferation, resulting in complications that can range from tissue hyperplasia to lymphoma. Some of the complications resolve spontaneously after drug discontinuation. This report describes for the first time a case of dysphagia with lack of velopharyngeal coordination and nasopharyngeal reflux combined with massive palatine tonsillar hypertrophy. The condition did not develop before phenytoin administration, was induced by phenytoin, and spontaneously resolved upon drug discontinuation. The patient was referred for a video-fluoroscopic swallowing study owing to a recurring nasal reflux of foods that had developed since phenytoin administration. The video-fluoroscopic swallowing study revealed incidentally that the large bilateral elongated masses extended downward into the larynx and disturbed velar elevation. This finding was confirmed by computed tomography of the neck, which showed that palatine tonsillar hypertrophy disturbed the laryngopharynx on both sides. The symptoms (sleep apnea and nasal reflux) and the abnormal imaging findings disappeared without surgery approximately 1 month after drug discontinuation. This case suggests that dysphagia related to phenytoin-induced lymphoid hypertrophy may be treated by phenytoin discontinuation followed by a sufficient amount of time to allow symptom resolution rather than by prompt surgery.

Ataxic gait following total gastrectomy for gastric cancer.

A 58-year-old woman, who had undergone total gastrectomy for early gastric cancer 9 years previously, visited the outpatient clinic complaining of progressive difficulty in walking for 15 d. Laboratory examinations showed macrocytic anemia and a decreased serum vitamin B12 concentration and increased serum concentrations of folate, vitamin E and copper. Magnetic resonance imaging showed multifocal high signal intensities along the posterior column of the cervical and thoracic spinal cord. Treatment consisted of intramuscular injections of vitamin B12 for 7 d, which increased her serum level of vitamin B12 to normal. This was followed by weekly intramuscular injections of vitamin B12 for another 2 wk and oral administration of vitamin B12 three times per day. After comprehensive rehabilitation for 4 wk, she showed sufficient improvements in strength and ataxic gait, enabling her to return to her normal daily activities.

Preemptive Femoral Nerve Block Could Reduce the Rebound Pain After Periarticular Injection in Total Knee Arthroplasty.

BACKGROUND: We evaluated the effectiveness of postoperative pain management using intraoperative periarticular injection (PAI) and/or electromyography-guided preoperative femoral nerve block (FNB) in knees undergoing total knee arthroplasty (TKA). METHODS: This study included 90 patients (90 knees) who underwent primary TKA. Thirty patients received a single injection of electromyography-guided FNB, 30 received intraoperative PAI, and 30 received both. Pain at rest and while moving was evaluated by a visual analog scale (VAS) at 0, 4, 8, 24, and 48 hours. Postoperative range of motion, time to walking, amount of opioid consumption, and complications were analyzed. RESULTS: VAS immediately after surgery was significantly higher in the FNB group than in the PAI and combined groups, but did not differ significantly in the latter 2 groups. VAS after 4 and 8 hours showed similar results. VAS after 24 hours was significantly higher in the PAI than in the FNB and combined groups. After 48 hours, there were no differences among the 3 groups. Total opioid consumption was lower in the combined than in the FNB and PAI groups. Postoperative range of motion and time to walking were similar in the 3 groups. CONCLUSION: PAI was more effective than FNB during the early (0-8 hours) postoperative period after TKA. Patients treated with PAI, however, experienced rebound pain at 24 hours. The combination of PAI and FNB may provide greater postoperative pain management than either alone for the first 24 hours after TKA.

Ultrasonography- or electrophysiology-guided suprascapular nerve block in arthroscopic acromioplasty: a prospective, double-blind, parallel-group, randomized controlled study of efficacy.

PURPOSE: To evaluate the efficacy of ultrasonography-guided (UG) and electrophysiology-guided (EG) suprascapular nerve block (SNB) for arthroscopic acromioplasty with regard to pain relief. METHODS: A prospective, double-blind, randomized controlled clinical trial was performed from June 2007 to April 2010. Patients who were scheduled for elective arthroscopic acromioplasty and who met the inclusion criteria were assigned to 1 of 2 experimental groups (UG or EG SNB) or to 1 blind group (using anatomic landmarks). Before surgery, an SNB was performed with either ultrasonographic or electrophysiologic guidance or with no assistive devices (blind). Variables were collected at 4, 24, 48, and 72 hours postoperatively. RESULTS: Sixty-three patients were initially enrolled in the study, but 11 dropped out for various reasons. In the UG group at 4 hours, the visual analog scale score at rest (30 ± 12.0 v 39 ± 9.9 for EG group and 41 ± 11.8 for blind group) and when the patient was moving (42 ± 15.2 v 52 ± 11.5 for EG group and 53 ± 12.6 for blind group) was significantly decreased compared with the EG and blind groups (P < .05). Opioid consumption during the first 24 hours was significantly reduced in the UG and EG groups (4.3 ± 1.9 mg and 3.8 ± 2.3 mg, respectively) compared with the blind group (5.1 ± 2.2 mg) (P < .05). The visual analog scale score at rest and when the patient was moving; the pain score on the University of California, Los Angeles questionnaire; and the activities of daily living score on the American Shoulder and Elbow Surgeons questionnaire in the EG and UG groups improved more than the values in the blind group over the follow-up intervals (P < .05). Morphine consumption in the EG and UG groups by the first, second, and third days was significantly smaller than that in the blind control group (P < .05). CONCLUSIONS: UG and EG SNB can reduce pain and painkiller consumption for up to 72 hours postoperatively. Ultrasonographic or electrophysiologic guidance is more effective than the blind method of SNB. LEVEL OF EVIDENCE: Level I, randomized controlled trial with significant difference.

Improved single-limb balance after total knee arthroplasty.

PURPOSE: Unsteady ambulation shortly after total knee arthroplasty (TKA) may cause falling. Postural sway may predict the risk of falling. This prospective single-blinded observational study therefore evaluated the effects of TKA on single-limb standing balance (SLSB) and factors related to change in SLSB. METHODS: Patients with varus deformity and medial compartment degeneration were evaluated between September and December 2010. The Western Ontario and McMaster Universities Osteoarthritis Index and Kellgren/Lawrence scale were assessed, as were varus angle, number of painful knees, isometric peak torque of the quadriceps femoris, balance index of double limbs, and postural sway of single limbs. RESULTS: Twelve patients were enrolled and 11 were analysed. The mean ± SD postural sway of single limbs (i.e., SLSB) was reduced significantly after TKA, from 30.3 ± 20.8 cm to 18.5 ± 9.3 cm (p = 0.02). Amelioration was in proportion to pre-operative postural sway (ß = 0.92). CONCLUSIONS: SLSB in patients with varus knees with osteoarthritis was improved significantly 11 days after TKA. Poorer pre-operative SLSB was associated with better post-operative SLSB. TKA may be useful for the immediate reduction of falling in patients with osteoarthritis.

Excessive gastrocnemius fibrosis developed after radiofrequency-induced cosmetic volume reduction.

Cosmetic shaping of the lower leg is becoming increasingly popular. The use of radiofrequency therapy in cosmetic medicine also is growing. To date, no serious complications have been reported after the use of cosmetic radiofrequency therapy. This report describes a patient who presented at the author's clinic with a disabling ankle plantarflexion contracture in both calves that developed during a period of 18 months after cosmetic radiofrequency volume reduction. This reduction, performed at another clinic, involved applying a bipolar electrode with a mean power of 35 W at each of approximately 100 spots for 2 to 4 s. On each calf, 15 kJ was applied in a crisscross fashion. Magnetic resonance imaging and muscle biopsy indicated excessive gastrocnemius fibrosis. The patient was treated using botulinum toxin injections followed by serial castings and intensive physiotherapy. After treatment, the patient was able to walk with less difficulty and showed no tiptoeing. This appears to be the first report of serious muscle contracture after cosmetic radiofrequency volume reduction requiring extensive rehabilitation management.