Severe Central Nervous System Toxicity Research Articles

BDNF-TrkB/proBDNF-p75NTR pathway regulation by lipid emulsion rescues bupivacaine-induced central neurotoxicity in rats

Bupivacaine (BPV) can cause severe central nervous system toxicity when absorbed into the blood circulation system. Rapid intravenous administration of lipid emulsion (LE) could be used to treat local anaesthetic toxicity. This study aimed to investigate the mechanism by which the BDNF-TrkB/proBDNF-p75NTR pathway regulation by LE rescues BPV induced neurotoxicity in hippocampal neurons in rats. Seven- to nine-day-old primary cultured hippocampal neurons were randomly divided into 6 groups: the blank control group (Ctrl), the bupivacaine group (BPV), the lipid emulsion group (LE), the bupivacaine + lipid emulsion group (BPV + LE), the bupivacaine + lipid emulsion + tyrosine kinase receptor B (TrkB) inhibitor group (BPV + LE + K252a), the bupivacaine + lipid emulsion + p75 neurotrophic factor receptor (p75NTR) inhibitor group (BPV + LE + TAT-Pep5). All hippocampal neurons were incubated for 24 h, and their growth state was observed by light microscopy. The relative TrkB and p75NTR mRNA levels were detected by real-time PCR. The protein expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, TrkB, p75NTR and cleaved caspase-3 were detected by western blotting. The results showed that primary hippocampal neuron activity was reduced by BPV. As administration of LE elevated hippocampal neuronal activity, morphology was also somewhat improved. The protein expression and mRNA levels of TrkB and p75NTR were decreased when BPV induced hippocampal neuronal toxicity, while the expression of BDNF was increased. At the same time, BPV increased the original generation of cleaved caspase-3 protein content by hippocampal neurons, while the content of cleaved caspase-3 protein in hippocampal neurons cotreated with LE and BPV was decreased. Thus, this study has revealed LE may reduce apoptosis and promote survival of hippocampal neurons by regulating the BDNF-TrkB pathway and the proBDNF-p75NTR pathway to rescue BPV induced central neurotoxicity in rats.

Use of anti-TNFs for difficult-to-treat urticaria: response to Cooke et al.

Dear editor We read with interest the recent paper by Cooke et al about the use of biologic agents for intractable urticaria.1 Particularly, the authors reckon that the evidence supporting the use of anti-TNFs is limited by the small numbers of patients in non-controlled studies, often with urticarial disorders not typical of chronic urticaria such as vasculitis and delayed pressure urticaria. However, we want to draw the authors’ and readers’ attention to our report from 2013 about the use of adalimumab and etanercept in 20 patients with chronic urticaria with or without angioedema2 (updated in 2015 with an additional five patients).3 This report is to date the largest series of patients published and adds substantially to the small body of evidence supporting the use of anti-TNFs in subgroups of patients with chronic urticaria unresponsive to conventional therapy or omalizumab. Notably, 60% of our patients obtained complete or almost complete resolution of urticaria and angioedema after onset of therapy with either adalimumab or etanercept, whereas another 15% of our patients experienced partial response to therapy. Some of our patients were previously unresponsive to or experienced side effects from omalizumab. Duration of treatment ranged between 2 and 39 months. We observed side effects in 30% of our patients, particularly mild recurrent upper respiratory infections, whereas one patient experienced severe central nervous system toxicity. We propose that adalimumab and etanercept may be effective in some patients with chronic urticaria who do not respond sufficiently to high-dose antihistamines or in whom other immunosuppressive drugs or omalizumab are ineffective or associated with unacceptable side effects. However, patients should be monitored closely due to the possibility of severe side effects of anti-TNF treatment. We agree that larger ran-domized controlled trials are needed before a definite recommendation can be made in regards to the use of anti-TNFs for chronic urticaria.

Optimization of methylene blue using Ca2+ and Zn2+ bio-polymer hydrogel beads: A comparative study

Recently noted that the methylene blue cause severe central nervous system toxicity. It is essential to optimize the methylene blue from aqueous environment. In this study, a comparison of an optimization of methylene blue was investigated by using modified Ca2+ and Zn2+ bio-polymer hydrogel beads. A batch mode study was conducted using various parameters like time, dye concentration, bio-polymer dose, pH and process temperature. The isotherms, kinetics, diffusion and thermodynamic studies were performed for feasibility of the optimization process. Freundlich and Langmuir isotherm equations were used for the prediction of isotherm parameters and correlated with dimensionless separation factor (RL). Pseudo-first order and pseudo-second order Lagegren's kinetic equations were used for the correlation of kinetic parameters. Intraparticle diffusion model was employed for diffusion of the optimization process. The Fourier Transform Infrared Spectroscopy (FTIR) shows different absorbent peaks of Ca2+ and Zn2+ beads and the morphology of the bio-polymer material analyzed with Scanning Electron Microscope (SEM). The TG & DTA studies show that good thermal stability with less humidity without production of any non-degraded products.

Flecainide-Induced Myoclonus

Flecainide is a class 1c antiarrhythmic that acts by blocking sodium channels to reduce intracardiac conduction and is used mainly in the treatment of supraventricular arrhythmias. Dizziness, visual disturbances, headache, and nausea are commonly associated with flecainide, but severe central nervous system toxicity is rare. Here, we report the case of a 71-year-old woman with a history of renal transplantation who developed severe myoclonus 24 hours after being started on flecainide, 100 mg 2 times a day, because of atrial fibrillation. This symptom completely disappeared once the drug was removed. Only 2 patients presenting with flecainide-induced myoclonus have been previously reported. Although the exact pathophysiologic explanation of this phenomenon remains unclear, it is well known that the susceptibility to severe flecainide toxicity is increased in patients with chronic kidney disease.

Use of Intravenous Lipid Emulsion to Reverse Central Nervous System Toxicity of an Iatrogenic Local Anesthetic Overdose in a Patient on Peritoneal Dialysis

To describe a case of severe central nervous system toxicity after an overdose of lidocaine by local infiltration in a peritoneal dialysis patient and subsequent treatment of the toxicity with lipid emulsion. A 31-year-old male received an iatrogenic overdose of 1600 mg of lidocaine 2% by infiltration during an attempt to remove and replace a peritoneal dialysis catheter. Within 10 minutes after the last lidocaine injection, the patient exhibited features of local anesthetic toxicity, which included tachycardia, hypertension, shortness of breath, dizziness, and a choking sensation that progressed to hallucinations, dysarthria, and uncoordinated, weak limb movement. Within 10 minutes after administration of a single 1.5-mg/kg intravenous bolus of 1.5 mL/kg [corrected], the patient improved dramatically. After observation overnight in a monitored care setting, the patient was discharged home with no apparent neurologic sequelae. Systemic toxicity due to regional anesthesia with local anesthetic agents such as lidocaine has been well described in the medical literature. The use of lipid emulsion as an antidote to the toxicity of local anesthetics and other lipophilic drugs has been suggested as a valuable intervention in both early, rapidly progressive toxicity, as well as toxicity that is refractory to standard treatment. Patients with advanced chronic kidney disease may be more susceptible to systemic effects of lidocaine due to decreased drug elimination. Central nervous system toxicity due to an overdose of lidocaine was quickly reversed by intravenous lipid emulsion in our patient.

Levofloxacin-Induced Delirium: Is It a Dangerous Drug in Patients with Renal Dysfunction?

The central nervous system (CNS) toxicity of fluoroquinolones is well known but usually occurs benign. In the literature, there are a few number of severe CNS toxicity cases related to fluoroquinolones. Levofloxacin is a third-generation fluorinated quinolone antibiotic, is the active levo stereoisomer of ofloxacin, and has one of the most favorable adverse reaction profiles. We describe a case of delirium associated with levofloxacin in a 55-year-old man who was hospitalized in our medical clinic for pneumonia.

Preparation, characterization and tissue distribution of brucine stealth liposomes with different lipid composition

Objective: To improve the therapeutic index of brucine, the novel stealth liposomes (SLS-n), composed of naturally unsaturated and hydrogenated soy phosphatidylcholines, with significant difference of phase transition temperature, were developed to encapsulate brucine.Methods: Brucine-loaded stealth liposomes with different lipid compositions were prepared and characterized for their entrapment efficiency (EE), particle size, zeta potential and in vitro drug release profile. Tissue distribution after intravenous administration of different brucine formulations was further compared in tumor-bearing mice.Results: Compared with the conventional stealth liposomes composed of SPC (SLS-s) or HSPC (SLS-h), EE and zeta potential of SLS-n were increased slightly, and the size was decreased slightly. The results of drug release showed that SLS-n were more stable than SLS-s. After intravenous administration, tumor AUC in SLS-s, SLS-n and SLS-h treated animals were 1.33, 1.72 and 2.59-fold higher than in mice treated with the same dose of free brucine, respectively. Compared with brucine solution, administration of SLS-s and SLS-n could significantly decrease brucine concentration in brain, but administration of SLS-h resulting in significantly increased (2.75-fold) concentration in 10 min.Conclusion: Since brucine has severe central nervous system toxicity, our study indicated that SLS-n could considerably improve the therapeutic index of brucine.

CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity

Methylene blue has only recently been noted to cause severe central nervous system toxicity. Methylene blue is used for various conditions, including, intravenously, in methemoglobinemia, vasoplegia and as an aid to parathyroidectomy (at doses of 1-7.5 mg kg(-1)). This review of the current evidence concludes that 13 of 14 of the reported cases of CNS toxicity were serotonin toxicity that met the Hunter Serotonin Toxicity Criteria. That has important preventative and treatment implications. Serotonin toxicity is precipitated by the monoamine oxidase inhibitor (MAOI) property of methylene blue interacting with serotonin reuptake inhibitors. Serotonin toxicity is reviewed, using the lessons inherent in the methylene blue story and experience, to illustrate how the mechanisms and potency of serotonergic drugs interact to determine severity. Recent human data showed that an intravenous dose of only 0.75 mg kg(-1) of methylene blue produced a peak plasma concentration of 500 ng ml(-1) (1.6 µM), indicating that the concentration in the central nervous system reaches a level that inhibits monoamine oxidase A. That is consonant with the actual occurrence of severe serotonin toxicity in humans at the dose of only 1 mg kg(-1). It seems that all proposed uses of methylene blue entail levels that block monoamine oxidase, so cessation of serotonin reuptake inhibitors should be very carefully considered before using methylene blue.

Novel Nanoliposomal CPT-11 Infused by Convection-Enhanced Delivery in Intracranial Tumors: Pharmacology and Efficacy

We hypothesized that combining convection-enhanced delivery (CED) with a novel, highly stable nanoparticle/liposome containing CPT-11 (nanoliposomal CPT-11) would provide a dual drug delivery strategy for brain tumor treatment. Following CED in rat brains, tissue retention of nanoliposomal CPT-11 was greatly prolonged, with >20% injected dose remaining at 12 days for all doses. Tissue residence was dose dependent, with doses of 60 microg (3 mg/mL), 0.8 mg (40 mg/mL), and 1.6 mg (80 mg/mL) resulting in tissue half-life (t(1/2)) of 6.7, 10.7, and 19.7 days, respectively. In contrast, CED of free CPT-11 resulted in rapid drug clearance (tissue t(1/2) = 0.3 day). At equivalent CED doses, nanoliposomal CPT-11 increased area under the time-concentration curve by 25-fold and tissue t(1/2) by 22-fold over free CPT-11; CED in intracranial U87 glioma xenografts showed even longer tumor retention (tissue t(1/2) = 43 days). Plasma levels were undetectable following CED of nanoliposomal CPT-11. Importantly, prolonged exposure to nanoliposomal CPT-11 resulted in no measurable central nervous system (CNS) toxicity at any dose tested (0.06-1.6 mg/rat), whereas CED of free CPT-11 induced severe CNS toxicity at 0.4 mg/rat. In the intracranial U87 glioma xenograft model, a single CED infusion of nanoliposomal CPT-11 at 1.6 mg resulted in significantly improved median survival (>100 days) compared with CED of control liposomes (19.5 days; P = 4.9 x 10(-5)) or free drug (28.5 days; P = 0.011). We conclude that CED of nanoliposomal CPT-11 greatly prolonged tissue residence while also substantially reducing toxicity, resulting in a highly effective treatment strategy in preclinical brain tumor models.

Myeloablation by intravenous busulfan and hematopoietic reconstitution with autologous marrow in a canine model

We have previously described pharmacokinetic studies with a dimethylsulfoxide-based intravenous busulfan preparation in a canine model and in preliminary clinical trials. Using the same intravenous busulfan preparation, we carried out a dose escalation study to determine a marrow-ablative dose and to test the ability of autologous marrow to reconstitute hematopoiesis in dogs so treated. Busulfan was given intravenously at doses of 3.75 to 40 mg/kg. Marrow ablation was achieved at 20 mg/kg given either as a single dose or in four daily increments of 5 mg/kg each. There was a relative sparing of lymphocytes. A busulfan dose of 40 mg/kg resulted in severe central nervous system toxicity. Otherwise, nonhematopoietic toxicity was minimal and restricted to mild hepatic abnormalities. Four dogs were given busulfan at 20 mg/kg followed 30 hours later by infusion of autologous marrow, and all showed prompt and complete hematopoietic reconstitution. The area under the curve (AUC) determined by busulfan concentration in plasma over time was dose dependent, ranging from 12 to 100 microg x h/mL for busulfan doses of 3.75-20 mg/kg. There was a suggestion that the plasma half-life increased at the highest busulfan doses used. Intravenous administration of busulfan circumvented differences in bioavailability; nevertheless, considerable variations in the pharmacokinetic parameters were observed between individual animals. Thus, intravenous busulfan can be given safely and is effective in ablating hematopoiesis. However, factors other than absorption influence the AUC, and individualization of dosing may be required even with intravenous administration of the drug. Biol Blood Marrow Transplant 1999;5(5):316-21.

Rocket Propellant Inhalation in the Apollo-Soyuz Astronauts

Acute exposure to monomethylhydrazine and dinitrogen tetroxide, the principal toxic irritants in rocket fuels, is described with particular attention to the development of pulmonary edema as a herbinger of more severe central nervous system toxicity. An acute respiratory embarrassment is documented and possible means of therapy based on animal experimental models is suggested. Early clinical and radiographic examination as a baseline for further evaluation is essential, with follow-up radiographs recommended for assessment of possible developing chronic lung disease.