ABSTRACT
BACKGROUND/AIM: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database. PATIENTS AND METHODS: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month. CONCLUSION: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.
Subject(s)
Amantadine , Humans , Amantadine/adverse effects , Male , Adverse Drug Reaction Reporting Systems , Pharmacovigilance , Central Nervous System/drug effects , Central Nervous System/pathology , Female , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/diagnosis , Japan , Middle Aged , Aged , Drug-Related Side Effects and Adverse Reactions/diagnosisABSTRACT
PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) may trigger immune-related adverse events which rarely affect the central nervous system (CNS-irAEs). Over the past few years, cumulative data have led to the characterization of well defined syndromes with distinct cancer and antibody associations as well as different outcomes. RECENT FINDINGS: The most frequent CNS-irAE is encephalitis, which includes three main groups: meningoencephalitis, a nonfocal syndrome usually responsive to corticosteroids; limbic encephalitis, associated with high-risk paraneoplastic neurological syndromes (PNS) antibodies (e.g. anti-Hu, anti-Ma2) and neuroendocrine cancers, characterized by poor treatment response and outcomes; and cerebellar ataxia, with variable outcomes (worse when high-risk PNS antibodies are detected). Additionally, a diffuse encephalopathy without inflammatory findings, with poor response to corticosteroids and high mortality has been described. The spectrum of CNS-irAEs also includes meningitis, myelitis, and rarer presentations. A subset of CNS-irAEs (i.e. limbic encephalitis and/or rapidly progressive cerebellar ataxia) is undistinguishable from ICI-naïve PNS. SUMMARY: The clinical and outcomes diversity of CNS-irAEs suggests different pathogenic mechanisms, which need to be understood to establish more effective and specific treatment modalities. It is crucial to identify biomarkers able to predict which patients will experience severe CNS-irAEs, to anticipate their diagnosis, and to predict long-term outcomes.
Subject(s)
Immune Checkpoint Inhibitors , Humans , Immune Checkpoint Inhibitors/adverse effects , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/immunology , Neoplasms/drug therapy , Neoplasms/immunologyABSTRACT
BACKGROUND AND PURPOSE: Although rare, neurological adverse events have been reported post-COVID-19 vaccination. This study reports 16 patients diagnosed with CNS inflammatory demyelinating diseases (CNS-IDD) within 6 weeks of COVID-19 vaccine administration. METHODOLOGY: A prospective observational study was conducted from June 2021 to May 2022. All patients were diagnosed according to the latest international guidelines with CNS-IDD within 6 weeks of COVID-19 vaccine exposure. Data regarding the demographic profile, clinical features, type of COVID-19 vaccination, radiological findings and occurrence of symptoms were noted and further analysed using descriptive statistics. RESULTS: We reported 16 cases (median age 40 years) of CNS demyelination: fourteen occurred in temporal association with ChAdOx1-S vaccine and two in association with BBV152 vaccine. Median time duration of presenting symptoms after vaccination was 19 days (3-40 days). The most common presentation was myelitis (7/16 patients), followed by optic neuritis (6/16 patients). Demyelination events were reported after first and second dose in thirteen and five patients respectively, although two patients reported such events after both vaccine dosages. Myelin oligodendrocyte glycoprotein (MOG) IgG antibodies were positive in eight patients. Tumefactive demyelination was seen in four patients. Management included high-dose methylprednisolone, PLEX, IVIG or a combination of those, with a favourable outcome in the majority of cases. CONCLUSION: Although a rare event, awareness regarding potential demyelinating episodes post-COVID-19 vaccination can help in early diagnosis. The presence of increased MOG-IgG antibodies with temporal association in post-COVID vaccine patients raises a possibility of an immunogenic phenomenon leading to demyelinating disorders.
Subject(s)
COVID-19 , Central Nervous System Diseases , Demyelinating Diseases , Humans , Adult , COVID-19 Vaccines/adverse effects , Myelin-Oligodendrocyte Glycoprotein , Autoantibodies , COVID-19/prevention & control , Demyelinating Diseases/chemically induced , Central Nervous System Diseases/chemically induced , Vaccination/adverse effects , Immunoglobulin GABSTRACT
Central nervous system (CNS) complications are considered adverse events during the treatment of pediatric acute lymphoblastic leukemia (ALL). This study aimed to assess the incidence, types, clinical and radiologic patterns, risk factors, and the fate of different CNS complications during the treatment of pediatric ALL. A retrospective study included 390 patients with pediatric ALL, treated according to St. Jude total XV protocol at the National Cancer Institute, Cairo University, from January 2012 to December 2017. Thirty-nine (10%) patients developed different types of CNS complications. Nineteen (4.9%) patients had cerebrovascular complications, 12 (3.1%) patients had posterior reversible encephalopathy syndrome (PRES), and 6 (1.5%) patients had leukoencephalopathy; both CNS infections and leukemic infiltrates were diagnosed in one patient each. CNS complications were significantly higher in patients older than 10 years old, patients with high-risk disease, and patients who were classified as CNS III status with a statistically significant P value of 0.040, 0.020, and 0.002, respectively. There were 31 (79.5%) cases that achieved complete recovery, 6 (15.4%) patients who died, and 2 (5.1%) patients who developed residual neurological deficits. In conclusion, pediatric patients with ALL, who presented with older age, high-risk disease initially, and had initial CNS III status, were at higher risk of developing acute CNS complications during their treatment period. Patients who developed visual disturbances were associated with unfavorable outcomes. Despite that, around 80% of patients showed complete recovery, but still, 15% of them died from these complications.
Subject(s)
Central Nervous System Diseases , Posterior Leukoencephalopathy Syndrome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Retrospective Studies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/epidemiology , Central Nervous SystemABSTRACT
Objective: To investigate the clinical characteristics of patients with acute phosphine poisoning, and to follow up and evaluate the prognosis of patients. Methods: In May 2022, 12 patients with phosphine poisoning by respiratory inhalation in Beijing Chao-Yang Hospital of Capital Medical University were analyzed. The patients were treated with symptomatic support therapy. Three months later, patients were re-evaluated the symptoms of poisoning, pulmonary function and magnetic resonance imaging (MRI) of the brain to understand the prognosis of the phosphine poisoning. Results: The main symptoms of 12 patients were respiratory and central nervous system symptoms with hypoxia. The symptoms of poisoning improved after treatment. Follow-up found that the patients had different degrees of residual symptoms. Pulmonary function showed increased airway resistance. Airway challenge test was positive in some patients. MRI of the head of some patients showed small ischemic focus in bilateral frontal lobes. Conclusion: Acute phosphine poisoning may cause persistent damage to the respiratory system and central system, and residual symptoms after 3 months.
Subject(s)
Central Nervous System Diseases , Phosphines , Poisoning , Respiratory Tract Diseases , Humans , Follow-Up Studies , Lung , Phosphines/poisoning , Poisoning/diagnosis , Central Nervous System Diseases/chemically induced , Respiratory Tract Diseases/chemically inducedABSTRACT
Cyclophosphamide (CYC) may be an effective treatment in patients who fail first line therapy for severe central nervous system (CNS) inflammatory disorders including CNS vasculitis, neuromyelitis optica, autoimmune encephalitis, tumefactive and aggressive multiple sclerosis (MS). We performed a retrospective analysis of 46 patients treated with CYC after failing first line therapy for severe CNS inflammatory conditions. Primary outcomes included modified Rankin Scale (mRS) for patients classified into a non-MS group, Expanded Disability Status Score (EDSS) for MS patients, and Targeted Neurological Deficit score (TND) for all patients. Secondary outcome included neuroimaging studies following CYC treatment. By the second follow up period (average of 7 months) mRS in the non-MS group improved from 3.7 to 2.2 and EDSS in the MS group improved from 5.6 to 3.8. Average TND score at 7 months was 2.8 (mild-marked improvement). At first follow up (average 5.6 months), 76.2% (32/42) patients had either stable or improving imaging, and 83.3% (30/36) patients had stable or improving imaging at second follow up (average 13.6 months). Adverse events were reported by 31.9% of patients with most common being nausea and vomiting, headache, alopecia, and hyponatremia. Treatment with CYC can result in disease stabilization of severe CNS inflammatory diseases and is generally well tolerated.
Subject(s)
Central Nervous System Diseases , Multiple Sclerosis , Humans , Retrospective Studies , Cyclophosphamide/therapeutic use , Cyclophosphamide/adverse effects , Multiple Sclerosis/drug therapy , Treatment Outcome , Central Nervous System Diseases/diagnostic imaging , Central Nervous System Diseases/drug therapy , Central Nervous System Diseases/chemically induced , Central Nervous SystemABSTRACT
PURPOSE OF REVIEW: The treatment of acute lymphoblastic leukemia (ALL) is one of the success stories of pediatric oncology, but challenges and questions remain, including the optimal approach to the treatment of central nervous system (CNS) leukemia. It is unclear why some children with ALL develop CNS leukemia and others do not, and there remains debate regarding optimal regimens for prophylaxis, upfront treatment, and the treatment of CNS relapses. These topics are especially important since both cranial radiation therapy (CRT) and intensive intrathecal therapy carry risks of both short- and long-term adverse effects. In this review, we aim to identify areas of ongoing debate on this topic, review the biology of CNS leukemia, and summarize clinical trial data that address some of these questions. RECENT FINDINGS: Both retrospective and meta-analyses have demonstrated that few patients with ALL benefit from CRT as a component of CNS-directed treatment for de novo disease, allowing cooperative groups to greatly limit the number of patients undergoing CRT as part of their initial ALL regimens. More recent efforts are focusing on how best to assay for low levels of CNS disease at the time of diagnosis, as well as the biological drivers that may result in CNS leukemia in certain patients. Progress remains to be made in the identification and treatment of CNS leukemia in pediatric ALL. Advancements have occurred to limit the number of children undergoing CRT, but much has yet to be learned to better understand the biology of and risk factors for CNS leukemia, and novel approaches are required to approach CNS relapse of ALL.
Subject(s)
Central Nervous System Diseases , Central Nervous System Neoplasms , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/drug therapy , Central Nervous System Neoplasms/etiology , Central Nervous System Neoplasms/therapy , Child , Humans , Injections, Spinal , Methotrexate/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Recurrence , Retrospective StudiesABSTRACT
Although many neurotoxicity prediction studies of food additives have been developed, they are applicable in a qualitative way. We aimed to develop a novel prediction score that is described quantitatively and precisely. We examined cell viability, reactive oxygen species activity, intracellular calcium and RNA transcription level of potential prediction related genes to develop a high-throughput neurotoxicity test method in vitro to screen the neurotoxicity of hazardous factors in food using AI-based machine learning. We trained artificial intelligence models (random forest and neural network) to predict neurotoxicity precisely, establishing a universal classification assessment score (CA-Score) that relies on the expression status of only 13 of prediction related genes. The CA-Score system is almost universally applicable to food risk factors (p<0.05) in a manner independent of platform (microarray or RNA sequencing) by being compared with cut-off value 23.487 to judge whether it's neurotoxic or not. We finally validated our prediction with the external validation of CA-Score on neural precursor cells derived from embryonic stem cells. Therefore, we draw a conclusion that the AI-based machine learning including neural network and random forest is likely to provide a useful tool for large-scale screening of neurotoxicity in food risk factors.
Subject(s)
Central Nervous System Diseases/chemically induced , Food Additives/toxicity , Gene Expression Regulation/drug effects , Machine Learning , Neural Stem Cells/drug effects , Calcium , Cell Line, Tumor , Cell Survival/drug effects , Food Contamination , Humans , Neural Networks, Computer , Reactive Oxygen Species , Reproducibility of Results , Risk FactorsABSTRACT
BACKGROUND: Neuron-specific enolase (NSE) is released into serum when nerve cells are damaged, and the levels thereof are used to determine neurological prognosis in patients who have suffered cardiac arrest or stroke. Delayed neuropsychiatric sequelae (DNS), a major complication of carbon monoxide poisoning (COP), can be caused by inflammatory response which is a mechanism of neuronal injury in cardiac arrest and stroke. NSE is known as a predictor of neurological prognosis in ischemic brain injury after cardiac arrest, and it is also reported as a predictor of DNS in acute COP. When serum NSE is measured serially in cardiac arrest patients, the best time to predict neurological prognosis is known at 48-72 h, but there are no studies analyzing serial serum NSE in acute COP. Thus, we explored whether serum NSE levels measured three times at 24 h intervals after COP predicted the development of DNS. METHODS: This prospective observational study was conducted on patients treated for COP from May 2018 to April 2020 in a tertiary care hospital in Korea. Neuron-specific enolase levels were assessed 24, 48, and 72 h after presentation at hospital. We used logistic regression to explore the association between NSE levels and DNS development. RESULTS: The NSE level was highest at 48 h, and the difference between the DNS group and the non-DNS group was greatest on the same time point. On multivariable logistic regression analysis, the NSE level at 48 h of >20.98 ng/mL (odds ratio [OR], 3.570; 95% confidence interval [CI], 1.412-9.026; P = .007) and the initial Glasgow Coma Scale (GCS) score of <9 (OR, 4.559; 95% CI, 1.658-0.12.540; P = .003) was statistically significant for DNS development. CONCLUSION: Early identification of those who will experience DNS in acute COP patients is clinically important for deciding treatment. In this study, we revealed that NSE level of >20.98 ng/mL at 48 h time point can be used as an independent predictor of DNS (OR, 3.570; 95% CI, 1.412-9.026; P = .007; AUC, 0.648).
Subject(s)
Carbon Monoxide Poisoning/blood , Central Nervous System Diseases/chemically induced , Phosphopyruvate Hydratase/blood , Adult , Carbon Monoxide Poisoning/pathology , Central Nervous System Diseases/blood , Central Nervous System Diseases/pathology , Female , Humans , Male , Middle Aged , Phosphopyruvate Hydratase/genetics , Phosphopyruvate Hydratase/metabolismABSTRACT
Multiple sclerosis (MS) is a neurodegenerative disorder characterized by periodic neuronal demyelination, which leads to a range of symptoms and eventually to disability. The goal of this research was to use UPLC-Orbitrap/MS to identify validated biomarkers and explore the metabolic mechanisms of MS in mice. Thirty-two C57BL/6 male mice were randomized into two groups that were fed either normal food or 0.2% CPZ for 11 weeks. The mouse demyelination model was assessed by LFB and the expression of MBP by immunofluorescence and immunohistochemistry. The metabolites of the corpus callosum were quantified using UPLC-Orbitrap/MS. The mouse pole climbing experiment was used to assess coordination ability. Multivariate statistical analysis was adopted for screening differential metabolites, and the ingenuity pathway analysis (IPA) was used to reveal the metabolite interaction network. We successfully established the demyelination model. The CPZ group slowly lost weight and showed an increased pole climbing time during feeding compared to the CON group. A total of 81 metabolites (VIP > 1 and P < 0.05) were determined to be enriched in 24 metabolic pathways; 41 metabolites were markedly increased, while 40 metabolites were markedly decreased in the CPZ group. The IPA results revealed that these 81 biomarker metabolites were associated with neuregulin signaling, PI3K-AKT signaling, mTOR signaling, and ERK/MAPK signaling. KEGG pathway analysis showed that two significantly different metabolic pathways were enriched, namely, the glycerophospholipid and sphingolipid metabolic pathways, comprising a total of nine biomarkers. Receiver operating characteristic analysis showed that the metabolites (e.g., PE (16 : 0/22 : 6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), PC (18 : 0/22 : 4(7Z, 10Z, 13Z, 16Z)), cytidine 5'-diphosphocholine, PS (18 : 0/22 : 6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), glycerol 3-phosphate, SM (d18 : 0/16 : 1(9Z)), Cer (d18:1/18 : 0), galabiosylceramide (d18:1/18 : 0), and GlcCer (d18:1/18 : 0)) have good discrimination ability for the CPZ group. In conclusion, the differential metabolites have great potential to serve as biomarkers of demyelinating diseases. In addition, we identified metabolic pathways associated with CPZ-induced demyelination pathogenesis, which provided a new perspective for understanding the relationship between metabolites and CNS demyelination pathogenesis.
Subject(s)
Central Nervous System Diseases/metabolism , Corpus Callosum/metabolism , Cuprizone/toxicity , Demyelinating Diseases/metabolism , Animals , Biomarkers/metabolism , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/pathology , Chromatography, Liquid , Corpus Callosum/drug effects , Corpus Callosum/pathology , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Male , Mass Spectrometry , Metabolome , Mice , Mice, Inbred C57BL , Monoamine Oxidase Inhibitors/toxicityABSTRACT
Organophosphate (OP) pesticides are commonly known for their neurotoxicity. In the current experiments, two OPs used agriculturally, chlorpyrifos and dimethoate, were separately adminis- tered with centrally acting caffeine that is known to affect the pharmacological action of other substances. The aim of this study was to determine whether the combination of OP and caffeine may influence their neurotoxic potential. For this purpose, some neurobehavioral effects of this concomitant exposure were assessed in adult Swiss mice. All substances were given intra- peritoneally (i.p.) as single injections. In the passive avoidance task, chlorpyrifos (100 mg/kg) administered together with caffeine (40 mg/kg) significantly impaired acquisition. In the rota-rod test, the addition of caffeine at doses of 20 and 40 mg/kg, induced motor coordination impairment in chlorpyrifos (100 mg/kg)-treated mice. Neurobehavioral impairments were not observed for caffeine, chlorpyrifos and dimethoate (50 mg/kg) given separately as well as for the combina- tion of dimethoate and caffeine. Chlorpyrifos (100 mg/kg) alone and in combination with caffeine (40 mg/kg) significantly reduced acetylcholinesterase (AChE) activity. The current study shows that concomitant exposure to caffeine and chlorpyrifos can cause neurotoxic effects in mice despite the absence of these effects when caffeine and chlorpyrifos are administered alone. How- ever, the possible mechanisms involved need further investigations.
Subject(s)
Caffeine/toxicity , Central Nervous System Diseases/chemically induced , Chlorpyrifos/toxicity , Dimethoate/toxicity , Animals , Caffeine/administration & dosage , Chlorpyrifos/administration & dosage , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/toxicity , Dimethoate/administration & dosage , Drug Interactions , Drug Therapy, Combination , Male , MiceABSTRACT
BACKGROUND: Exposure to heavy metals has been considered harmful and can cause cognitive deficits in preschool children. OBJECTIVE: To investigate the possible mediation effect of neurotransmitters on the relationship of heavy metal exposure with neurobehaviour. METHODS: The levels of blood heavy metals and neurotransmitters, along with the neurobehavioural scores, were determined in preschool children. Multiple linear regression was used to assess the relationship between heavy metals, neurotransmitters, and neurobehavioural scores. Furthermore, the mediating role of neurotransmitters was investigated. RESULTS: An interquartile range (IQR) increase in lead (6.10 µg/L) was associated with a decrease of 8.52%, 30.06%, and 20.10% for Glutamic acid (Glu), Glycine (Gly), and gamma-aminobutyric acid (GABA), respectively. An IQR increase in arsenic (19.37 µg/L) was associated with an increase of 6.32% and 2.09% for Gly and GABA, respectively. Further, an IQR increase in zinc (15.58 µg/L) was associated with an increase of 1.44% for Ser, whereas the IQR increase was associated with a decrease of 2.14%, 2.24%, and 1.89% for Glu, Gly, and GABA, respectively. An IQR increase in selenium (38.75 µg/L) was associated with an increase of 1.88% for GABA. Moreover, both Glu and Gly decreased by 2.87% for an IQR increase in manganese (16.92 µg/L). An IQR increase in mercury (15.22 µg/L) was associated with a decrease of 2.43% for Ser, but the IQR increase was associated with an increase of 4.99% and 3.09% for Gly and GABA, respectively. It was found that Glu and Serine (Ser) have a significant linear relationship with conduct score and impulsivity-hyperactivity index, and that there was a significant linear relationship between Ser and the learning disability index. GABA and conduct score and attention-deficit hyperactivity disorder (ADHD) index have a significant linear relationship. There is a significant linear relationship between Gly and conduct, anxiety, ADHD, and impulsivity-hyperactivity index. The results of the mediating effect analysis indicated that Ser, Glu, Gly, and GABA have a specific mediating effect between blood heavy metals and neurobehaviour. CONCLUSION: We showed the mediating effect of neurotransmitters. The current study may provide valuable information regarding the prevention and management of metal-related neurological disorders in preschool children.
Subject(s)
Central Nervous System Diseases/chemically induced , Environmental Pollutants/toxicity , Metals, Heavy/toxicity , Neurotransmitter Agents/metabolism , Child Development/drug effects , Child, Preschool , Cross-Sectional Studies , Humans , MaleABSTRACT
BACKGROUND: Harmine is a ß-carboline alkaloid that displays antidepressant, antitumor and other pharmacological effects. However, the strong toxic effects limit its clinical application, and should be first considered. PURPOSE: To evaluate the in vivo toxicity of harmine and explore intervention strategies against its toxicity. METHODS: The in vivo toxicity of harmine was assessed from the symptoms, biochemical indices, and cardiovascular effects in mice. The intervention experiments were performed by using anesthetics, central drugs, and peripheral anticholinergics. RESULTS: The acute toxicity of harmine is significantly dose-dependent and the median lethal dose is 26.9 mg/kg in vivo. The typical symptoms include convulsion, tremor, jumping, restlessness, ataxia, opisthotonos, and death; it also changes cardiovascular function. The anesthetics improved the survival rate and abolished the symptoms after harmine poisoning. Two central inhibitors, benzhexol and phenytoin sodium, uniformly improved the survival rates of mice poisoned with harmine. The peripheral anticholinergics didn't show any effects. CONCLUSION: Harmine exposure leads to central neurological symptoms, cardiovascular effects and even death through direct inhibition of the central AChE activity, where the death primarily comes from central neurological symptoms and is cooperated by the secondary cardiovascular collapse. Central inhibition prevents the acute toxicity of harmine, and especially rapid gaseous anesthetics such as isoflurane, might have potential application in the treatment of harmine poisoning.
Subject(s)
Anesthetics/therapeutic use , Cardiovascular Diseases/prevention & control , Central Nervous System Diseases/prevention & control , Harmine/toxicity , Isoflurane/therapeutic use , Phenytoin/therapeutic use , Trihexyphenidyl/therapeutic use , Acetylcholinesterase/metabolism , Anesthetics/pharmacology , Animals , Cardiovascular Diseases/chemically induced , Central Nervous System Diseases/chemically induced , Cholinergic Antagonists , Dose-Response Relationship, Drug , Harmine/poisoning , Isoflurane/pharmacology , Lethal Dose 50 , Male , Mice, Inbred ICR , Phenytoin/pharmacology , Trihexyphenidyl/pharmacologyABSTRACT
The developmental neurotoxicity of calcium cyclamate was evaluated in Sprague Dawley [Crl:CD(SD)] rats, administered in drinking water, in comparison to a concurrent control group (water) and a positive control group given propylthiouracil (PTU). Calcium cyclamate was administered to F0 females for 4 weeks prior to pairing, throughout mating, gestation and lactation and to F1 offspring from weaning to 12 weeks of age, PTU was administered by gavage to F0 females from Day 6 of gestation up to Day 20 of lactation. Target calcium cyclamate doses were 0, 250, 500 and 1,000 mg/kg bw/day, while the PTU dose was 0.5 mg/kg bw/day. No treatment-related effects of cyclamate were observed in either the F0 or F1 generations on reproductive performance or neurobehavioral development. In comparison, PTU exposure resulted in developmental delays, memory impairment and a number of neuropathological and morphometric outcomes. The results from the unique developmental neurotoxicity study design, corroborate the absence of hyperactivity and any other neurotoxic effects following cyclamate administration at levels up to 878 mg/kg bw/day in F0 females and 784 mg/kg bw/day in F1 animals. This demonstrates the suitability of PTU as a positive control and confirms the safe use of cyclamate as a no-calorie sweetener.
Subject(s)
Central Nervous System Diseases/chemically induced , Cyclamates/toxicity , Memory Disorders/chemically induced , Prenatal Exposure Delayed Effects , Sweetening Agents/toxicity , Animals , Animals, Newborn , Cyclamates/administration & dosage , Dose-Response Relationship, Drug , Female , Male , Pregnancy , Rats , Rats, Sprague-Dawley , Sweetening Agents/administration & dosageABSTRACT
Lead is a heavy metal pollutant that is widely present in the environment. It affects every organ system, yet the nervous system appears to be the most sensitive and primary target. Although many countries have made significant strides in controlling Pb pollution, Pb poisoning continuous to be a major public health concern. Exposure to Pb causes neurotoxicity that ranges from neurodevelopmental disorders to severe neurodegenerative lesions, leading to impairments in learning, memory, and cognitive function. Studies on the mechanisms of Pb-induced nervous system injury have convincingly shown that this metal can affect a plethora of cellular pathways affecting on cell survival, altering calcium dyshomeostasis, and inducing apoptosis, inflammation, energy metabolism disorders, oxidative stress, autophagy and glial stress. This review summarizes recent knowledge on multiple signaling pathways associated with Pb-induced neurological disorders in vivo and in vitro.
Subject(s)
Central Nervous System Diseases/chemically induced , Environmental Pollutants/toxicity , Lead/toxicity , Animals , Calcium/metabolism , Gene Expression Regulation/drug effects , HumansABSTRACT
OBJECTIVE: To explore the predictive value of neutrophil-lymphocyte ratio (NLR) at presentation for delayed neurological sequelae (DNS) in carbon monoxide (CO) poisoning. METHODS: This single-center retrospective observational study included a total of 253 consecutive patients who visited the emergency department (ED) due to acute CO intoxication between 7 October 2015 and 31 December 2019. The included patients had a history of coma and their blood routine was measured within one hour of ED admission. They were divided into two groups according to the presence of DNS, including those who developed DNS (DNS group) and those who did not (non-DNS group). RESULTS: A total of 171 patients were included in this research, and 49 (28.7%) developed DNS. The median NLR at ED admission was obviously higher in the DNS group (10.60 [9.69-15.34]) than in the non-DNS group (7.53 [5.86-8.56]) (p < 0.001). Multivariate analysis indicated that a high NLR (adjusted odds ratio (AOR): 1.78, 95% confidence interval (CI): 1.46-2.18) and the occurrence of acute brain lesions (AOR: 7.50, 95%CI: 2.86-19.68) on diffusion-weighted imaging were independent predictors of DNS. The NLR was more than 8.97. The prediction of occurrence of DNS had a sensitivity of 93.88% and a specificity of 84.43%. Kappa value was 0.713. The predicted results showed good authenticity and consistency. CONCLUSION: The level of NLR at presentation had good predictive value for the development of DNS, showing the superior value for clinical application.
Subject(s)
Carbon Monoxide Poisoning/pathology , Central Nervous System Diseases/chemically induced , Lymphocyte Count , Lymphocytes , Neutrophils , Adult , Aged , Central Nervous System Diseases/pathology , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective StudiesSubject(s)
3,4-Methylenedioxyamphetamine/toxicity , Alkaloids/toxicity , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/therapy , Central Nervous System Stimulants/toxicity , Emergency Service, Hospital/statistics & numerical data , Illicit Drugs/toxicity , Adolescent , Adult , Female , Humans , Male , Retrospective Studies , Taiwan , Treatment Outcome , Young AdultABSTRACT
Accidental intoxications from environmental pollutants, as well as intentional self- and chemical warfare-related poisonings affect millions of people worldwide each year. While many toxic agents can readily enter the central nervous system (CNS), the blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. Consequently, poisoning antidotes usually cannot reach their site of action in the CNS in therapeutically relevant concentrations, and thus only provide effective protection to the peripheral nervous system. This limitation can be overcome by encapsulating the antidotes in nanoparticles (NP), which can enhance their CNS accumulation without damaging the integrity of the BBB. Among nanocarriers, polymer-based drug delivery systems exhibit remarkable benefits, such as bioavailability, cell uptake and tissue retention. Furthermore, due to their capacity to mask unfavorable physicochemical properties of cargo drugs, polymeric NPs were able to improve BBB transport of various pharmaceuticals. However, while polymer NP-mediated treatment of various pathological brain conditions, such as glioma and Alzheimer's disease were exhaustively studied, the application of polymeric nanocarriers for brain-targeted delivery of antidote molecules has not been adequately examined. To display its therapeutic potential, we review the state of the art of polymer NP-assisted CNS delivery of antidotes for various poisonings, including heavy metal and organophosphorus intoxications.
Subject(s)
Antidotes/therapeutic use , Biological Transport/drug effects , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/drug therapy , Metals, Heavy/toxicity , Nanoparticle Drug Delivery System , Polymers , Blood-Brain Barrier/drug effectsABSTRACT
Neuropsychiatric disorders and central nervous system-related symptoms are very common in people with HIV and can have a very negative impact on their quality of life and worsen the prognosis of the disease. These disorders are multifactorial in origin, but may be triggered or worsened by the use of certain antiretroviral treatments. This paper reviews the epidemiology of neuropsychiatric disorders and symptoms in people with HIV, the recommendations and tools available for their early assessment, as well as the neurotoxicity of the main families of antiretroviral (ARV) drugs. It is important to focus on improvement towards the detection of these disorders during the first evaluation or patient follow-up, aimed at improving quality of life. Because of the central nervous system neurotoxicity profile of different antiretroviral drugs, proactive assessment of neuropsychiatric disorders and symptoms prior to treatment start and during follow-up is necessary.
Subject(s)
Anti-HIV Agents , Central Nervous System Diseases , HIV Infections , Pharmaceutical Preparations , Anti-HIV Agents/adverse effects , Anti-Retroviral Agents/adverse effects , Central Nervous System Diseases/chemically induced , Central Nervous System Diseases/epidemiology , HIV Infections/complications , HIV Infections/drug therapy , Humans , Quality of LifeABSTRACT
The development of novel antiretroviral treatments has led to a significant turning point in the fight against HIV. Although therapy leads to virologic suppression and prolonged life expectancies, HIV-associated neurocognitive disorder (HAND) remains prevalent. While various hypotheses have been proposed to explain this phenomenon, a growing body of literature explores the neurotoxic effects of antiretroviral therapy. Research to date brings into question the potential role of such medications in neurocognitive and neuropsychiatric impairment seen in HIV-positive patients. This review highlights recent findings and controversies in cellular, molecular, and clinical neurotoxicity of antiretrovirals. It explores the pathogenesis of such toxicity and relates it to clinical manifestations in each medication class. The concept of accelerated aging in persons living with HIV (PLWH) as well as potential treatments for HAND are also discussed. Ultimately, this article hopes to educate clinicians and basic scientists about the neurotoxic effects of antiretrovirals and spur future scientific investigation into this important topic. Graphical Abstract.