FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis.

Vitamin B12 (B12) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P1. Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B12 pathways. Genetic and pharmacological S1P1 inhibition upregulates a transcobalamin 2 (TCN2)-B12 receptor, CD320, in immediate-early astrocytes (ieAstrocytes; a c-Fos-activated astrocyte subset that tracks with experimental autoimmune encephalomyelitis [EAE] severity). CD320 is also reduced in MS plaques. Deficiency of CD320 or dietary B12 restriction worsens EAE and eliminates FTY720's efficacy while concomitantly downregulating type I interferon signaling. TCN2 functions as a chaperone for FTY720 and sphingosine, whose complex induces astrocytic CD320 internalization, suggesting a delivery mechanism of FTY720/sphingosine via the TCN2-CD320 pathway. Taken together, the B12-TCN2-CD320 pathway is essential for the mechanism of action of FTY720.

A Preliminary Study of Pharmacokinetics and Pharmacodynamics of Oral Fingolimod in Dogs.

BACKGROUND/AIM: Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes egress from lymphoid organs. It has been used as a disease-modifying drug for human multiple sclerosis and has shown better therapeutic effects than other conventional therapies. Therefore, this study was performed to obtain preclinical data of fingolimod in dogs. MATERIALS AND METHODS: Nine laboratory Beagle dogs were used and randomized into three groups for pharmacokinetics (PK) and pharmacodynamics (PD). The dogs were administered once with a low-dose (0.01 mg/kg, n=3), medium-dose (0.05 mg/kg, n=3), and high-dose (0.1 mg/kg, n=3) of fingolimod, orally. Samples were collected serially at predetermined time points, and whole blood fingolimod concentrations were measured using high-performance liquid chromatography-mass spectrometry. Differential counts of leukocytes over time were determined to identify immune cells' response to fingolimod. RESULTS: Regarding PK, the concentration of fingolimod in the blood increased in a dose-dependent manner, but it was not proportional. Regarding PD, the number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). Eosinophils were significantly reduced in low- (p=0.0006) and medium- (p=0.0006) doses, and neutrophils were also significantly reduced in medium-(p=0.0345) and high- (p=0.0016) doses. CONCLUSION: This study provides the basis for future clinical applications of fingolimod in dogs with immune-mediated diseases, such as meningoencephalitis of unknown etiology.

Symptomatic Diethylene Glycol Ingestion Successfully Treated with Fomepizole Monotherapy.

BACKGROUND: Diethylene glycol (DEG) is an industrial solvent with many uses, including brake fluids. It has also caused mass poisonings after use as an inappropriate substitute for propylene glycol or glycerin, though individual ingestions are rare. Like other toxic alcohols, DEG is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase, with toxicity likely mediated by the resulting metabolites. Fomepizole, an alcohol dehydrogenase inhibitor, is used to prevent metabolite formation with other toxic alcohol exposures. Fomepizole is recommended for DEG poisoning, though supporting clinical evidence is limited. CASE REPORT: A 31-year-old man presented after ingestion of DEG-containing brake fluid and hydrocarbon-containing "octane booster." He was noted to be clinically intoxicated, with a mildly elevated anion gap metabolic acidosis and no osmolar gap. DEG level was later found to be elevated, consistent with his ingestion. He was treated with fomepizole alone, with resolution of metabolic acidosis and clinical findings over the next 2 days. No delayed neurologic sequelae were present at 52-day follow-up. Our case provides additional evidence supporting the use of fomepizole for DEG poisoning. Consistent with other toxic alcohols, DEG poisoning, especially early presentations, may benefit from empiric fomepizole administration. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: DEG poisoning is potentially life threatening, but treatable if identified early. An ingestion can be toxic despite a normal osmolar gap, leading to false reassurance. Finally, it is rare, so emergency physicians must be made aware of its potential dangers.

The protective role of FTY720 in promoting survival of allograft fat in mice.

Fat transplantation is widely used for soft-tissue filling and wound repair. Owing to the biological changes in adipocytes in some metabolic diseases, allograft fat can provide a better source of donor fat than autologous fat. Fingolimod (FTY720) possesses a powerful immunomodulatory function. This study aimed to investigate the protective effect of FTY720 in allogeneic fat transplantation. C57BL/6J mice that received allografts were randomly divided into two groups and treated with saline and FTY720, respectively. Fat graft samples were obtained at 1, 6, and 20 weeks posttransplantation. Graft volumes, graft structure, and immune cells were estimated using histological examination, immunohistochemistry, staining immunofluorescence (IF), and quantitative real-time polymerase chain reaction (qRT-PCR). Inflammatory cytokine mRNA expression in grafts was detected by qRT-PCR. FTY720 treatment significantly enhanced allograft retention, structural integrity, and neovascularization, thereby demonstrating the potential of FTY720 in improving graft survival. Further IF staining showed that FTY720 increased regulatory T cell infiltration and reduced macrophage infiltration to some extent. FTY720 treatment also enhanced the expression of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 and weakened the expression of the pro-inflammatory cytokines TNF-α and IL-6. Furthermore, FTY720 treatment upregulated the expression of CD31 positive cells. This study demonstrated the potential efficacy of FTY720 in improving the graft survival rate of syngeneic fat allograft models, possibly by suppressing immune rejection and promoting angiogenesis. Therefore, this study offers key insights into the potential application of a drug-assisted strategy to prolong allograft fat survival.

Acute cough in children and adolescents: A systematic review and a practical algorithm by the Italian Society of Pediatric Allergy and Immunology.

The current systematic review presented and discussed the most recent studies on acute cough in pediatric age. After that, the Italian Society of Pediatric Allergy and Immunology elaborated a comprehensive algorithm to guide the primary care approach to pediatric patients, such as infants, children, and adolescents, with acute cough. An acute cough is usually consequent to upper respiratory tract infections and is self-resolving within a few weeks. However, an acute cough may be bothersome, and therefore remedies are requested, mainly by the parents. An acute cough may significantly affect the quality of life of patients and their family.Several algorithms for the management of acute cough have been adopted and validated in clinical practice; however, unlike the latter, we developed an algorithm focused on pediatric age, and, also, in accordance to the Italian National Health System, which regularly follows the child from birth to all lifelong. Based on our findings, infants from 6 months, children, and adolescents with acute cough without cough pointers can be safely managed using well-known medications, preferably non-sedative agents, such as levodropropizine and/or natural compounds, including honey, glycerol, and herb-derived components.

Drug Delivery: Hydrophobic Drug Encapsulation into Amphiphilic Block Copolymer Micelles.

Drug encapsulation into amphiphilic block copolymer micelles aims to increase drug solubility and minimize drug degradation upon administration, avoid undesirable side effects and ameliorate drug bioavailability. Drug encapsulation methodologies including thin-film hydration method and organic cosolvent method are described in this chapter. Often, it is desirable to determine the most efficient solubilization protocol leading to functional drug delivery nanovehicles in each case. The encapsulation of curcumin into PEO-b-PPO-b-PEO (Pluronic F-127) polymeric micelles through thin-film hydration method presents the most promising results. Indomethacin can be loaded successfully into the hydrophobic cores of PEO-b-PCL amphiphilic block copolymer micelles following both encapsulation protocols.

Characteristics, Properties and Analytical Methods for Determination of Dropropizine and Levodropropizine: A Review.

Dropropizine is a peripheral antitussive drug that acts by inhibiting cough reflex through its action on the peripheral receptors and their afferent conductors. It is marketed in a racemic form or its pure enantiomer called levodropropizine and both are available worldwide in various drug dosage formulations such as tablets, sirup and oral solution. Due to the widespread use of antitussives in the clinic it is necessary to develop efficient analytical methodologies for quality control and also for pharmacokinetic, bioavailability and bioequivalence studies. This review presents a survey of the characteristics, properties and analytical methods used for drug determination, being carried out through scientific articles as well as in official compendia. From the analyzed studies, the majority reports the use of HPLC/UV techniques for drug determination, but also spectrophotometric UV/Vis methods as well as gas chromatography, and voltammetric, potentiometric and conductometric titration methods. In addition, the methodologies addressed the determination of dropropizine or levodropropizine in different types of matrices such as raw material, pharmaceutical formulations, plasma and urine. Despite the extensive clinical use of dropropizine, data from this review evidenced a still limited number of studies dealing with analytical methods for its determination in different matrices, which may be of concern since the applicability of these methods is important for quality assurance, efficacy and safety of the medicine.

Fingolimod (FTY720) prevents chronic rejection of rodent cardiac allografts through inhibition of the RhoA pathway.

The Fingolimod (FTY720, Gilenya) is clinically approved for the treatment of multiple sclerosis (MS). Its therapeutic effect on MS is based on the ability to bind sphingosine 1-phosphate (S1P) receptors and block the exit of immune cells from the lymphoid organs, thus preventing immune cell-dependent injury to the central nervous system (CNS). We showed recently that, besides the S1P-related activity, the FTY720 also down-regulates RhoA, which is a master regulator of the actin cytoskeleton. Our previous studies showed that FTY720 also down-regulates Rictor, which is a signature molecule of mTORC2 complex, which regulates RhoA and dictates actin cytoskeleton specificity. Because, our previous studies showed that chronic rejection correlates with the upregulation of RhoA and mTORC2 components and that the inhibition of RhoA pathway prevents chronic rejection, here we studied the effect of FTY720 on the chronic rejection of rat and mouse cardiac allografts. We show that FTY720 in conjunction with the inhibitors of early T cell response, (CTA4-Ig in mice and Everolimus in rats) blocks macrophage infiltration into the grafts and prevents chronic rejection of rat and mouse cardiac transplants. This indicates that FTY720 may be repurposed from the MS application to the clinical transplantation as an anti-chronic rejection drug.

Randomized clinical trial of an elastomeric sealant for hemostasis in thoracic aortic surgery.

OBJECTIVES: This study aimed to demonstrate the efficacy and safety of a newly developed elastomeric sealant, which does not require any blood coagulation system to exert its effect, during thoracic aortic surgery. METHODS: This is a multicenter, randomized study conducted in six hospitals in Japan. A total of 81 patients undergoing replacement surgery of a thoracic aortic aneurysm using cardiopulmonary bypass were randomized with a ratio of 2-:1 for those patients designated to receive the sealant (Group S, 54 patients) or those without the usage of the sealant (Group C, 27 patients). The primary endpoints were bleeding from each anastomosis at two time points: (1) immediately before applying protamine and (2) 15 min after applying protamine. The patients were followed for 6 months. RESULTS: The number of anastomoses checked for bleeding was 196 in Group S and 117 in Group C. Before protamine sulfate administration, complete hemostasis was obtained in 155 anastomoses (79%) in Group S compared to 45 anastomoses (38%) in Group C (p < 0.001). Fifteen minutes after the administration of protamine sulfate infusion, bleeding stopped completely in 173 anastomoses (88%) in Group S and in 71 anastomoses (61%, p < 0.001) in Group C. Between the two groups, there were no marked differences in the patient background or in the incidence of major adverse events. CONCLUSIONS: The sealant is effective in achieving hemostasis, even under fully heparinized conditions. The novel sealant is safe and effective in thoracic aortic surgery, one of the most demanding surgical situations for hemostasis.

Felbamate add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Levodropropizine suppresses seizure activity in rats with pentylenetetrazol-induced epilepsy.

BACKGROUND: Millions of individuals worldwide suffer from epilepsy, and up to 25% of patients have seizures that are resistant to currently available antiepileptic drugs. Hence, there continues to be a need for more seizure medications that are effective yet tolerable. Levodropropizine (LVDP) is an established antitussive drug that, based on preclinical data, may also have antiepileptic activity. METHODS: We treated rats with either intraperitoneal (IP) LVDP at two different doses or placebo in randomized fashion and then exposed them to IP pentylenetetrazol (PTZ), a potent seizure-inducing compound. We measured the rats' subsequent seizure activity with electroencephalography (EEG), Racine's convulsion scale (RCS) and time to first myoclonic jerk (TFMJ) to determine whether LVDP has antiepileptic properties in our murine model for epilepsy. RESULTS: When compared to placebo, LVDP at both doses significantly suppressed seizure activity. Mean EEG spike wave percentage score decreased from 76.8% (placebo) to 13.1% (lower dose) and 7.6% (higher dose, bothp < 0.0001). RCS decreased from a mean of 5.8 (placebo) to 1.83 (lower dose) and 1.16 (higher dose, both p < 0.05). TFMJ had increased from a mean of 65.1 s (placebo), to 247.3 s (lower dose) and 295.5 s (higher dose, both p < 0.0001). CONCLUSIONS: Levodropropizine, a common antitussive drug, suppresses seizure activity in rats with PTZ-induced status epilepticus. Given the ongoing need to find effective therapies for refractory epilepsy, the possibility of using levodropropizine as an antiepilepticshould be further explored.

Felbamate as an add-on therapy for refractory partial epilepsy.

BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

A Randomized Clinical Trial Comparing the Effects of Antitussive Agents on Respiratory Center Output in Patients With Chronic Cough.

BACKGROUND: Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO2 rebreathing test in patients with chronic cough of any origin. METHODS: Twenty-four outpatients (aged 39-70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg levodropropizine, 15 mg dihydrocodeine, or a matching placebo. Subsequently, patients breathed a mixture of 93% oxygen and 7% CO2 for 5 min. Fractional end-tidal CO2 (Fetco2) and inspiratory minute ventilation (V˙i) were continuously monitored. Changes in breathing pattern variables were also assessed. RESULTS: At variance with dihydrocodeine, levodropropizine and placebo did not affect respiratory responses to hypercapnia (P < .01). The ventilatory increases by hypercapnia were mainly accounted for by a rise in the volume components of the breathing pattern. CONCLUSIONS: The results are consistent with a peripheral action by levodropropizine; the assessment of ventilatory responses to CO2 may represent a useful tool to investigate the central respiratory effects of antitussive agents. TRIAL REGISTRY: European Union Clinical Trials Register (EudraCT No.: 2013-004735-68); URL: https://www.clinicaltrialsregister.eu/.

Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma.

OSU-2S is a FTY720 (Fingolimod) derivative that lacks immunosuppressive properties but exhibits strong anti-tumour activity in several haematological and solid tumour models. We have recently shown OSU-2S to mediate potent cytotoxicity in human mantle cell lymphoma cell lines and primary cells. We report here the pre-clinical activity of OSU-2S in spontaneous B-cell lymphoma of dogs which shares many characteristics of human lymphoma. OSU-2S mediated apoptosis in canine B-cell lines and primary B-cell lymphoma cells obtained from spontaneous lymphoma bearing dogs. OSU-2S induced reactive oxygen species (ROS) in canine lymphoma cells and inhibition of ROS partially rescued OSU-2S-mediated cell death. These studies provide a rational basis for the use of spontaneous lymphoma in pet dogs as a preclinical large animal model for the development of OSU-2S as small molecule for treating people and dogs with lymphoma.

Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance.

New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

Evaluating the safety and efficacy of felbamate in the context of a black box warning: A single center experience.

INTRODUCTION: Felbamate was approved in 1993 to treat partial seizures with and without secondary generalization in adults and in Lennox-Gastaut Syndrome in children. Its use was later restricted when rare but fatal cases of aplastic anemia and hepatic failure were identified. METHODS: This single center analysis retrospectively evaluated the safety and efficacy of felbamate in a cohort of children, adolescents, and adults with epilepsy. RESULTS: A chart review identified 103 patients taking felbamate. The range of felbamate dose was 300-4500 mg (mean: 1800 ± 900 mg). The duration of therapy ranged from 1 month to 20 years (mean duration: 35 ± 45 months). Eighteen (17.5%) subjects experienced adverse events including insomnia, nausea, vomiting, decreased appetite, weight loss, gastric discomfort, diarrhea, mood and behavioral problems, high blood pressure, headache, and elevated liver enzymes. Out of these, 6 (5.9%) patients discontinued the therapy. No hepatic failure or agranulocytosis was observed. Fifty-nine (57.72%) patients achieved ≥ 50% reduction in seizure frequency, and 30 (29.12%) patients achieved seizure freedom. CONCLUSIONS: These findings suggest that felbamate is safe, well tolerated, and effective in treatment of various types of epilepsy syndromes.

Aneurysmal bone cyst: A 19-case series managed by percutaneous sclerotherapy.

INTRODUCTION: Sclerotherapy offers an alternative to surgery for the treatment of aneurysmal bone cyst (ABC). The main objective of the present study was to assess the radiological efficacy of sclerotherapy in terms of ossification on MRI. Secondary objectives were to assess clinical efficacy on pain evaluation and to analyze recurrence and complications according to type of sclerosing agent and intraoperative imaging technique. MATERIALS AND METHODS: Between 2006 and 2014, 19 patients (7 females, 12 males, aged 3 to 17 years) with ABC treated by sclerotherapy were included. Six received Ethibloc(®), 9 Aetoxisclerol(®), 2 liquid absolute alcohol, and 2 absolute alcohol gel. Assessment used fluoroscopy in 17 cases and CT in 2. Ossification was assessed on MRI and pain on a visual analog scale and HEDEN score. RESULTS: Ossification was complete in 11 cases (84.6%) and partial in 2 (15.4%). Eighteen patients (94.7%) were pain-free at 3 months. There was no recurrence, at a minimum 2 years' follow-up. One case of skin necrosis was observed, associated with use of liquid absolute alcohol; there was 1 case of arterial reflux of Ethibloc(®) under CT control. DISCUSSION: Sclerotherapy enables minimally invasive treatment of lesions that are deep, difficult of access to surgery and potentially damaging. Use of absolute alcohol gel and fluoroscopic control seems to improve the risk/benefit ratio, limiting complications by vascular extravasation of the sclerosing agent, thanks to real-time visualization of diffusion. Its clinical and radiological efficacy makes sclerotherapy and alternative primary treatment choice in ABC. LEVEL OF EVIDENCE: IV, retrospective study.

Antioxidant impregnated ultra-high molecular weight polyethylene wear debris particles display increased bone remodeling and a superior osteogenic:osteolytic profile vs. conventional UHMWPE particles in a murine calvaria model.

Periprosthetic osteolysis remains a major limitation of long-term successful total hip replacements with ultra-high molecular weight polyethylene (UHMWPE) bearings. As intra and extracellular reactive oxygen species are know to contribute to wear debris-induced osteoclastic bone resorption and decreased osteoblastic bone formation, antioxidant doped UHMWPE has emerged as an approach to reduce the osteolytic potential of wear debris and maintain coupled bone remodeling. To test this hypothesis in vivo, we evaluated the effects of crosslinked UHMWPE wear debris particles (AltrX(™) ), versus similar wear particles made from COVERNOX(™) containing UHMWPE (AOX(™) ), in an established murine calvaria model. Eight-week-old female C57B/6 mice (n = 10/Group) received a pre-op micro-CT scan prior to surgical implantation of the UHMWPE particles (2mg), or surgery without particles (sham). Dynamic labeling was performed by intraperitoneal injection of calcein on day 7 and alizarin on day 9, and the calvaria were harvested for micro-CT and histology on day 10. Surprisingly, we found that AOX particles induced significantly more bone resorption (1.72-fold) and osteoclast numbers (1.99-fold) vs. AltrX (p < 0.001). However, AOX also significantly induced 1.64-fold more new bone formation vs. AltrX (p < 0.01). Moreover, while the osteolytic:osteogenic ratio of both particles was very close to 1.0, which is indicative of coupled remodeling, AOX was more osteogenic (Slope = 1.13 ± 0.10 vs. 0.97 ± 0.10). Histomorphometry of the metabolically labeled undecalcified calvaria revealed a consistent trend of greater MAR in AOX vs. AltrX. Collectively, these results demonstrate that anti-oxidant impregnated UHMWPE particles have decreased osteolytic potential due to their increased osteogenic properties that support coupled bone remodeling. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:845-851, 2016.

The rise and fall of felbamate as a treatment for partial epilepsy--aplastic anemia and hepatic failure to blame?

Felbamate has been approved for refractory partial seizures since the early nineties. Due to safety concerns regarding its use, namely, in aplastic anemia and hepatic failure, felbamate's use has been restricted and a 'Black Box' warning has been inserted. Nonetheless, it is a useful drug in refractory cases of partial epilepsy. There are certain precautions which can prevent and minimize the serious idiosyncratic reactions associated with felbamate, thereby providing an option in refractory cases where no other drug works.

Fingolimod does not enhance cerebellar remyelination in the cuprizone model.

Fingolimod (FTY720) is approved for treatment of relapsing-remitting multiple sclerosis. In vitro studies have found that fingolimod stimulates remyelination in cerebellar slices, but in vivo animal studies have not detected any positive effect on cerebral remyelination. The discrepant findings could be a result of different mechanisms underlying cerebral and cerebellar remyelination. The cuprizone model for de- and remyelination was used to evaluate whether fingolimod had an impact on cerebellar remyelination in vivo. We found that fingolimod did not have any effect on cerebellar remyelination, number of mature oligodendrocytes, microglia or astrocytes when fed after cuprizone exposure.