Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.

Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.

New findings on the incidence and management of CNS adverse reactions in ALK-positive NSCLC with lorlatinib treatment.

To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency.

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine.

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with a novel nucleoside derivative including a 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, in vitro and in vivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. In vitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. In vivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

The Designer Drug αPHP Affected Cell Proliferation and Triggered Deathly Mechanisms in Murine Neural Stem/Progenitor Cells.

Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25-2000 µM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.

Long-term toxicity of fluoroquinolones: a comprehensive review.

Fluoroquinolones (FQs) are highly potent bactericidal antibiotics with broad-spectrum activity against Gram-negative/positive bacteria. The Food and Drug Administration (FDA) anticipated the presence of a long-lasting incapacity of Fluoroquinolone Associated Toxicity (FQAT), which is not officially documented yet. This review aimed to précis the existing information on FQA long-term toxicity, such as cardiotoxicity, aortic aneurysm, tendon rupture, nephrotoxicity, hepatotoxicity, peripheral neuropathy, vagus nervous dysfunction, reactive oxygen species (ROS), phototoxicity, glucose hemostasis, and central nervous system (CNS) toxicity. We are focused on the CNS toxicity of FQs, either due to the direct action of the FQs on CNS receptors or by other drug co-administration, including nonsteroidal anti-inflammatory disease (NSAIDs) and theophylline. Due to the nature of the R7 side chain, FQs containing unsubstituted 7-piperazine and 7-pyrrolidine have the most significant effect. The gamma-aminobutyric acid-A (GABAA) receptor and CNS effects are inhibited through at least three possible mechanisms. Firstly, by the pharmacological action of the quinolone directly. Secondly, FQ-NSAIDs interact pharmacodynamically in which the interaction between the FQ and a receptor is significantly altered by the presence of another drug that interacts with the same receptor. An example may be the interaction between NSAIDs and some FQs. Thirdly, a pharmacokinetic drug-drug interaction leads to a higher concentration of quinolone or the other drug. An example may be the interaction between theophylline and benzodiazepines with some FQs.

Imidacloprid poisoning in a young female: a case report.

BACKGROUND: Imidacloprid, a neonicotinoid insecticide, is widely used in agricultural settings. Consequently, cases of accidental and suicidal poisoning are increasingly seen in clinical practice. Although cases with varied clinical presentations and toxicological profiles have been reported, standard management principles are lacking. CASE PRESENTATION: We present a case of Imidacloprid poisoning in a 25-year-old previously healthy indigenous Tamang female without a classic toxidrome requiring ventilatory support, complicated by a prolonged neuropsychiatric sequela. CONCLUSIONS: Although uncommonly reported, imidacloprid toxicity may lead to life-threatening complications and hence should be suspected in cases of unidentified poisoning with a relevant toxidrome. Vigilance on the part of treating physicians plays a crucial role in appropriate management.

Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS.

There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1-30 µM) and exposure times (24-48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs.

Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold - A Retrospective Cohort Study.

Purpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C min threshold for CNS toxicity. Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2-19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C min significantly affects the occurrence of CNS toxicity and the threshold of C min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C min >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Conclusion: Voriconazole trough concentration of C min is an independent risk factor for CNS toxicity, and the threshold of C min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.

Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain.

There is a dearth of studies focused on understanding pharmacokinetics, pharmacodynamics and toxicodynamics of polymyxins following direct administration to the central nervous system (CNS). In this study, for the first time, untargeted metabolomics were employed to ascertain the perturbations of brain metabolism in the rat cerebral cortex following direct brain injection of 0.75 mg/kg polymyxin B (1 and 4 h) through the right lateral ventricle. In the right cortex metabolome, ICV polymyxin B induced a greater perturbation at 1 h compared to negligible effect at 4 h. Pathway enrichment analysis showed that sphingolipid, arginine, and histidine metabolism, together with aminoacyl-tRNA biosynthesis were significantly affected in the right cortex metabolome. Furthermore, intracerebroventricular (ICV) polymyxin B dysregulated the two arms (CDP-choline and CDP-ethanolamine) of the Kennedy pathway that governs the de novo biosynthesis of neuronal phospholipids. Importantly, the key intermediates of metabolic pathways that maintain cellular redox balance (e.g., glutathione metabolism) and mitochondrial function (e.g., electron transport chain) were markedly depleted. The abundance of key metabolites (e.g., N-acetyl-l-glutamate) associated with diverse CNS disorders (e.g., neurodegenerative disease) were also significantly perturbed. The biological significance of these metabolic perturbations on the CNS includes impaired oxidant-antioxidant balance, impaired neuronal lipid homeostasis and mitochondrial dysfunction. Furthermore, ICV polymyxin B caused a significant alteration in the abundance of several metabolic biomarkers associated with cerebral ischemia, oxidative stress as well as certain neurological disorders. These findings may facilitate the development of new pharmacokinetic/pharmacodynamic strategies to attenuate polymyxins ICV related CNS toxicities and stimulate the discovery of safer next-generation polymyxin-like lipopeptide antibiotics.

Does minimal central nervous system involvement in childhood acute lymphoblastic leukemia increase the risk for central nervous system toxicity?

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003).

Toxicokinetic evaluation during intoxication of psychotropic drugs using brain microdialysis in mice.

In the event of an overdose, the pharmacokinetics of the drug may be altered, resulting in an unexpectedly rapid increase in blood and tissue drug concentrations. Because central nervous system (CNS)-acting drugs are the major cause of hospitalization for overdose, brain concentrations, which are closely related to the development of acute psychotropic symptoms, would be important. However, due to the lack of an appropriate model for overdose, it is difficult to predict the CNS symptoms of patients with acute poisoning. To clarify the toxicokinetics during intoxication with CNS-acting drugs, we investigated the relationship between the dose and concentrations in the blood and brain in mice. Therapeutic or toxic doses of phenobarbital, flunitrazepam, imipramine, and amoxapine were administered intraperitoneally to mice. Serum and extracellular fluid of the brain were collected up to 24 hr after administration and analyzed using LC-MS/MS to determine the pharmacokinetic parameters in the serum and brain. A comparison of the four psychotropic drugs showed that the toxicokinetics of amoxapine in the blood and brain are clearly different from others, with the brain concentrations being specifically highly susceptible to increase during dose escalation. These results are consistent with the CNS-related symptoms observed in amoxapine overdose. Therefore, the methodology of the current study could be useful for predicting CNS toxicity during psychotropic drug poisoning.

Pharmacogenetics of the Central Nervous System-Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia.

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations' matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

Local Anesthetic-Induced Central Nervous System Toxicity during Interscalene Brachial Plexus Block: A Case Series Study of Three Patients.

Local anesthetics are commonly administered by nuchal infiltration to provide a temporary interscalene brachial plexus block (ISB) in a surgical setting. Although less commonly reported, local anesthetics can induce central nervous system toxicity. In this case study, we present three patients with acute central nervous system toxicity induced by local anesthetics applied during ISB with emphasis on neurological symptoms, key neuroradiological findings and functional outcome. Medical history, clinical and imaging findings, and outcome of three patients with local anesthetic-induced toxic left hemisphere syndrome during left ISB were analyzed. All patients were admitted to our neurological intensive care unit between November 2016 and September 2019. All three patients presented in poor clinical condition with impaired consciousness and left hemisphere syndrome. Electroencephalography revealed slow wave activity in the affected hemisphere of all patients. Seizure activity with progression to status epilepticus was observed in one patient. In two out of three patients, cortical FLAIR hyperintensities and restricted diffusion in the territory of the left internal carotid artery were observed in magnetic resonance imaging. Assessment of neurological severity scores revealed spontaneous partial reversibility of neurological symptoms. Local anesthetic-induced CNS toxicity during ISB can lead to severe neurological impairment and anatomically variable cerebral lesions.

The clinical toxicity of imidacloprid self-poisoning following the introduction of newer formulations.

BACKGROUND: Self-poisoning with imidacloprid has been previously shown to have low toxicity in humans. Since 2007 newer formulations of Imidacloprid with unknown solvents have been introduced and the potential clinical consequences of these products have not been described. METHODS: Clinical and demographic data were prospectively collected from admissions following oral ingestion of imidacloprid from seven hospitals in Sri Lanka. Data was collected from 2002 to 2007 in an already published study. We compared this data on poisonings collected from 2010 to 2016 following the introduction of new formulations of imidacloprid. RESULTS: From 2002-2007, there were 56 patients with ingestion to imidacloprid compared to 67 patients post 2010 The median time to presentation prior to 2007 was 4 h (IQR 2.3-6.0 hrs) and post 2010 was only 2.0 hr (IQR 1.5 to 3.1 hrs). The median amount ingested was 15 ml (IQR 10.0-50.0mls) prior to 2007 and 27.5mls (IQR 5.0-71.8mls) post 2010. In both studies most patients developed non-specific symptoms including nausea, vomiting, epigastric pain and headache. However, prior to 2007 only 1.9% of the cohort required mechanical ventilation due to respiratory failure and there were no reported deaths. In contrast, post 2010; deaths occurred in 3.0% of the cohort and 6.0% required mechanical ventilation for respiratory failure. The cause of mortality was due to one case of cardiorespiratory failure and the other due to a prolonged admission complicated with lobar pneumonia leading to decompensated liver failure on the background of undiagnosed liver cirrhosis. CONCLUSION: Although acute exposure to imidacloprid is usually associated with mild non-specific symptoms, since the introduction of new formulations of imidacloprid, the toxic profile has changed with reported cases of death as well as an increase in cases requiring mechanical ventilation. The change in toxicity could be due to the solvents used in the newer formulations but also due to higher dose of imidacloprid described in our latter cohort. Further research into these solvents needs to be done and continued toxicovigilance is required.

Antibiotic-induced epileptic seizures: mechanisms of action and clinical considerations.

In recent years, there has been growing interest in the development of epileptic seizures as an adverse effect of antibiotic therapy. The most commonly accepted mechanisms underlying the development of antibiotic-induced seizures include direct- and indirect gamma-aminobutyric acid (GABA) antagonism, inhibition of GABA synthesis, and glutaminergic N-methyl-D-Aspartate (NMDA) receptor agonistic activity. Inhibitory pathway inhibition leads to increased neuronal excitability and lowered seizure threshold. Blockage of myoneural presynaptic acetylcholine release, mitochondrial dysfunction, interference of neural protein synthesis, and oxidative stress caused by the generation of neurotoxic radicals also contributes to the development of neurotoxicity. Patients with pre-existing risk factors such as renal or hepatic insufficiency, central nervous system pathology, neurological diseases, history of epilepsy or seizures, critical illness, and increased age are more susceptible to seizure development as a consequence of antibiotic therapy. Administration of antibiotics, together with antiseizure drugs, may also lead to enhanced seizure risk due to drug interactions, which predisposes to alterations in drug metabolism and therapeutic efficacy.

Hyperbaric medicine simulation education curriculum: CNS toxicity during Treatment Table 6 and intubated ICU patient with mucous plugging.

INTRODUCTION/BACKGROUND: The incidence of complications and number of critically ill patients in hyperbaric medicine is relatively low [1]. This poses a challenge to those tasked with educating trainees as well as maintaining the skills of staff. Hyperbaric medicine fellows may not be exposed to critical patient scenarios or complications of hyperbaric medicine during a one-year fellowship. Additional staff may be unfamiliar with these situations as well. The purpose of hyperbaric simulation curriculum is to train health care providers for rare situations. To our knowledge, this hyperbaric simulation curriculum is the first published use of simulation education in the specialty of undersea and hyperbaric medicine. MATERIALS AND METHODS: Two simulation cases have been developed that involve a patient with oxygen toxicity during hyperbaric treatment as well as an ICU patient with mucous plugging. RESULTS: Medical training simulations are an effective method of teaching content and training multiple roles in Undersea and Hyperbaric Medicine. SUMMARY/CONCLUSIONS: A hyperbaric simulation curriculum is an achievable educational initiative that is able to train multiple team members simultaneously in situations that they may not encounter on a regular basis. We believe that this could be easily exported to otherinstitutions for further education.

Pharmacokinetics and brain distribution of amitraz and its metabolites in rats.

Amitraz is an acaricide and insecticide widely used in agriculture and veterinary medicine. Although central nervous system (CNS) toxicity is one of major toxicities following oral ingestion of amitraz, the understanding of the cause of the toxicity is limited. This study evaluated the systemic and brain exposure of amitraz and its major metabolites, BTS27271, 2',4'-formoxylidide, and 2,4-dimethylaniline following administration of amitraz in male Sprague-Dawley rats. Significant metabolism of amitraz was observed following the intravenous and oral administration. Amitraz related metabolites were majority of the total exposure observed, especially following oral administration. BTS27271 had higher brain exposure than amitraz and its other metabolites, which was due to low plasma protein binding but high brain tissue binding of BTS27271. Since BTS27271 has similar or higher toxicity and α2-adrenoreceptor agonist potency than amitraz, its exposure in brain tissues may be the major cause of CNS toxicity of amitraz in animals and humans.

Large volume re-irradiation for recurrent meningioma with pulsed reduced dose rate radiotherapy.

PURPOSE: Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether pulsed reduced dose rate radiotherapy (PRDR) was well tolerated in a small cohort of patients with recurrent meningioma. METHODS: We retrospectively identified eight patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Acute and late toxicities were graded based on CTCAE 4.0. RESULTS: Of eight patients, six had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667 Gy/min. Median time between radiation courses was 7.7 years. Median PRDR dose was 54 Gy in 27 fractions to a median volume of 261.6 cm3. Two patients (25%) had in field failure with a median follow up of 23.3 months. PFS at 6 months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥ 2 acute or late toxicities. CONCLUSIONS: PRDR re-irradiation was well tolerated and appeared effective for a small cohort of patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.