Neurotoxic Drugs Research Articles

Neurofunctional test batteries in safety pharmacology – Current and emerging considerations for the drug development process

Regulatory guidelines recommend specialised safety pharmacology assessments in animals to characterise drug-induced effects on the central nervous system (CNS) prior to first-in-human trials, including the functional observational battery or Irwin test (here collectively termed neurofunctional assessments). These assessments effectively detect overtly neurotoxic drugs; however, the suitability of the in vivo assessments to readily detect more subtle drug effects on the nervous system has been questioned.A survey was formulated by an international expert working group convened by the (NC3Rs) to capture practice in CNS neurofunctional assessment tests and opinions on the perceived impact of in vivo test battery endpoints. Impact was defined as “the impact of measures alone/in combination on decision making in drug development or candidate selection when using the neurofunctional assessment”.The results demonstrate that rodents are predominantly used for small molecule assessments, whereas non-rodents are frequently used to test biotherapeutics. Practice varied between respondents in terms of experimental design. Subsets of test battery endpoints were consistently considered highly impactful (e.g. convulsions, stereotypic behaviors); however, the perceived impact level of other endpoints varied depending whether drugs were designed for CNS targets. Many endpoints were considered to have no or minimal impact, whereas a subset of endpoints in CNS test batteries appears more impactful than others.A critical evaluation is required to assess whether the translational value of CNS in vivo safety pharmacology assessments could be increased by modifying or augmenting standard CNS test batteries. A revised approach to CNS safety assessment has the potential to reduce animal numbers without compromising patient safety.

PB2162 INCIDENCE & SEVERITY OF BORTEZOMIB‐INDUCED PERIPHERAL NEUROPATHY WITH THE USE OF GENERIC BORTEZOMIB IN MONOCLONAL GAMMOPATHIES: A PROSPECTIVE STUDY FROM INDIA

Background:The proteasome inhibitor Bortezomib is one of the most effective frontline drugs in the therapeutic armamentarium against monoclonal gammopathies. However, drug‐induced peripheral neuropathy is the major dose‐limiting toxicity and adversely affects quality of life. Generic preparations of bortezomib are mainstay of therapy in resource‐poor countries due to significantly higher cost of original brand of bortezomib.Aims:The present study aims to analyze the incidence & severity of bortezomib‐induced peripheral neuropathy (BIPN) in patients of monoclonal gammopathies receiving generic bortezomib in a resource‐poor setting.MethodsThis non‐randomized, prospective study enrolled total 73 bortezomib‐naïve patients of monoclonal gammopathies between July 2016 & February 2019. Both newly diagnosed & relapsed patients of symptomatic multiple myeloma (MM), Waldenstrom macroglobulinemia (WM) & primary amyloidosis, who had no baseline evidence of peripheral neuropathy were included. Patients having disease‐related neuropathy & patients who had earlier received thalidomide or other neurotoxic drugs were excluded. All study patients received one of the generic bortezomib brands available in India. Bortezomib was initially administered at 1.3 mg/m2 dose, by subcutaneous injection, on days 1,8,15,22 of each 28 days’ cycle. Patients were clinically evaluated for BIPN before each cycle, & at onset of BIPN symptoms. Bortezomib dose was modified according to grade of BIPN (Table 1). Bortezomib was discontinued in grade 3‐4 neuropathy, & restarted after BIPN symptoms improved to < grade 3.Results:Median patient age was 58 years (32‐76 years). Majority (62/73 patients, 85%) had MM, eight patients had WM & three patients had Primary Amyloidosis. Twenty‐seven patients in the study (37%) developed BIPN during treatment. Severity of BIPN in study is shown in Table 2. BIPN symptoms were reversible in 90% patients after discontinuation of bortezomib. Median follow up was 7 months (2‐18 months).imageSummary/Conclusion:In our study, approximately one‐third of patients with monoclonal gammopathies treated with subcutaneously administered generic bortezomib developed bortezomib‐induced peripheral neuropathy. The incidence of severe (grade 3‐4) BIPN was about 12%, leading to temporary/permanent discontinuation of bortezomib and also interfering with quality of life.image

Functional loss among patients receiving neurotoxic chemotherapeutic drugs

Functional loss among patients receiving neurotoxic chemotherapeutic drugs

MON-142 Neuropathy in a Patient with Diabetes Mellitus: Not Always a Diabetic Disease

Diabetic neuropathy (DN) is the most common form of neuropathy in patients with diabetes mellitus (DM). Although DN is very common, other etiologies for neuropathy can exist or co-exist in patients with DM. DN might be nonspecific and mimic neuropathies seen in other diseases. Therefore, its proper diagnosis requires a thorough history and exclusion of secondary causes such as leprosy. Due to increase in world-wide travel and migration, and because the transmission pathways of Mycobacterium leprae are not fully understood, it is now crucial to be aware of tropical diseases, such as leprosy, not generally seen or recognized in non-endemic countries. We report a case of 74-year old man with a 5-year history of DM who complained of feet paresthesia over the last four years, more pronounced on the left foot and progressively worse. Good glycemic control was achieved since diagnosis with Metformin. Microvascular complications were absent. Renal and thyroid function were normal as well as vitamin B12 levels. The patient denied alcohol or drug abuse, and did not have peripheral arterial disease, cancer, or use any neurotoxic drug. On examination of the lower limbs, deep tendon reflexes diminished. A mildly decreased vibration perception and numbness on the lower left limb were also observed. No other finding was present (normal pin-prick, normal gait and proprioception), nor did he present with muscle weakness. Amitriptyline and thioctic acid were prescribed with no clinical response. During the last year, multiple hyperpigmented anesthetic cutaneous lesions emerged in his legs and back. He subsequently developed a left foot drop and autonomic dysfunction. A diagnosis of borderline tuberculoid leprosy and type 1 reaction were established and a planned 12-month multidrug therapy (MDT) initiated. After six months of MDT, at last follow-up, the patient’s sensory neuropathy showed mild improvement. Resolution of autonomic symptoms was seen and nearly complete clearing of the skin lesions. In conclusion, leprosy and DM can cause progressive and irreversible nerve damage with similar clinical patterns. But, in cases of asymmetric neuropathy in a patient with DM, leprosy must be ruled out first before ascribing DM as the cause of the neuropathy. A thorough epidemiological history is mandatory to avoid misdiagnosis. If leprosy is not recognized and consequently left untreated, patients are at risk for permanent nerve damage. Leprosy is a potentially curable disease, contrary to DM. Other etiologies for neuropathy can exist in patients with DM.

Effect of methamphetamine on rat primary midbrain cells; mitochondrial biogenesis as a compensatory response

Methamphetamine (MA), neurotoxic drug of abuse, causes cell death in vitro and in vivo via several mechanisms such as mitochondrial dysfunction. In this study we evaluated the effect of MA on cell viability and mitochondrial biogenesis in primary midbrain culture. Primary mesencephalon cells prepared from E14.5 rat embryo were treated with 0.2–5 mM MA concentrations for 24, 48, and 72 h. Morphological changes of the cells were observed under light microscope. Cell viability and cell death following MA were assessed using MTT assay and immunocytochemistry. Gene expressions of mitochondrial biogenesis-involved factors (PGC1α, NRF1 and TFAM), and neuronal and glial markers were measured by qPCR. Low to moderate MA concentrations elevated cell viability in all time points, while higher concentrations and longer incubation times (48 and 72 h) decreased it. Sphered cell bodies and neurites degeneration were observed following exposure to high MA concentrations. MA at 5 mM concentration decreased the number of β3-tubulin-, TH-, GFAP- and Iba1-positive cells, and their corresponding mRNA levels; however, 1 mM MA reduced α-synuclein mRNA. Unexpectedly, gene expression of PGC1α, NRF1 and TFAM was increased in response to 5 mM MA, with no changes following 1 mM MA. The results indicated that MA effect on cell viability occurs in a dose-dependent manner. While moderate concentrations increased cell viability, the higher ones reduced it and caused cell death. Mitochondrial biogenesis activation, as a compensatory mechanism, did not prevent neuronal and glial cell death following high MA concentration.

Differential expression of cyclin-dependent kinases in the adult human retina in relation to CDK inhibitor retinotoxicity

Cyclin-dependent kinases (CDKs) are a family of kinases associated predominantly with cell cycle control, making CDK inhibitors interesting candidates for anti-cancer therapeutics. However, retinal toxicity (loss of photoreceptors) has been associated with CDK inhibitors, including the pan-CDK inhibitor AG-012896. The purpose of this research was to use a novel planar sectioning technique to determine CDK expression profiles in the ex vivo human retina with the aim of identifying isoforms responsible for CDK retinotoxicity. Four CDK isoforms (CDK11, 16, 17 and 18) were selected as a result of IC50 data comparing neurotoxic (AG-012986 and NVP-1) and non-neurotoxic (dinaciclib and NVP-2) CDK inhibitors, with IC50s at CDK11 showing a clear difference between the neurotoxic and non-neurotoxic drugs. CDK11 was maximally expressed in the photoreceptor layer, whereas CDK16, 17 and 18 showed maximal expression in the inner nuclear layer. CDK5 (an isoform associated with retinal homeostasis) was maximally expressed in the retinal ganglion cell layer. Apart from CDK18, each isoform showed expression in the photoreceptor layer. The human Müller cell line MIO-M1 expressed CDK5, 11, 16 and 17 and AG-01298 (0.02–60 µM) caused a dose-dependent increase in MIO-M1 cell death. In conclusion, CDK11 appears the most likely candidate for mediation of photoreceptor toxicity. RNA profiling can be used to determine the distribution of genes of interest in relation to retinal toxicity in the human retina.

Machine Learning Models for the Prediction of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of cancer chemotherapy that can be life debilitating and cause extreme pain. The multifactorial and poorly understood mechanisms of toxicity have impeded the identification of novel treatment strategies. Computational models of drug neurotoxicity could be implemented in early drug discovery to screen for high-risk compounds and select safer drug candidates for further development. Quantitative-structure toxicity relationship (QSTR) models were developed to predict the incidence of PN. A manually curated library of 95 approved drugs were used to develop the model. Molecular descriptors sensitive to the incidence of PN were identified to provide insights into structural modifications to reduce neurotoxicity. The incidence of PN was predicted for 60 antineoplastic drug candidates currently under clinical investigation. The number of aromatic nitrogens was identified as the most important molecular descriptor. The chemical transformation of aromatic nitrogens to carbons reduced the predicted PN incidence of bortezomib from 32.3% to 21.1%. Antineoplastic drug candidates were categorized into three groups (high, medium, low) based on their predicted PN incidence. QSTR models were developed to link physicochemical descriptors of compounds with PN incidence, which can be utilized during drug candidate selection to reduce neurotoxicity.

Neurological Disorders among the Outpatients Living with Human Immuno Deficiency Virus (HIV) Following at the Parakou Hospital in 2014

Objective: To study the frequency of neurological disorders associated to HIV infection. Methods: This cross-sectional study was carried out from 16th June to 16th September 2014 and included all 289 HIV-outpatients admitted to the Parakou University hospital. All data were recorded, physical examination was performed and the medical sheet of each patient was assessed. The diagnosis of neurological disorder (central and peripheral) was based on clinical features, past medical history, biological test and CT-scan data after multidisciplinary staff. Epi-data and Epi-Info 6.04C were used to perform analysis. Results: They were 73 (25.3%) male with a mean age of 38.0 years +/− 10.1 years. The mean duration of disease was 48.5 months +/− 37.1 months. 150 (51.9%) of them were at Stage 3 of the disease. All patients (99.7%) were infected by HIV1, 188 (76.1%) had CD4 cells at the onset of the follow-up less than 350 cells/mm3 and 260 (90.0%) were on ART. Among the 289 patients, 110 had at least one neurological disorder, the frequency of neurological disorders was 38.1%. The main neurological disorders were peripheral neuropathy (34.3%), isolated headache (5.2%), stroke (0.7%), cerebral toxoplasmosis (0.7%) and one case of dementia (0.7%). The main associated factors were the age of patient and exposure on neurotoxic drug, especially ART. Conclusion: The neurological disorders were more frequent among HIV patients with a high frequency of peripheral neuropathy probably due to ART.

Neuroimaging of reward mechanisms in Gambling disorder: an integrative review.

Gambling disorder (GD) was reclassified as a behavioral addiction in the DSM-5 and shares clinical and behavioral features with substance use disorders (SUDs). Neuroimaging studies of GD hold promise in isolating core features of the addiction syndrome, avoiding confounding effects of drug neurotoxicity. At the same time, a neurobiologically-grounded theory of how behaviors like gambling can become addictive remains lacking, posing a significant hurdle for ongoing decisions in addiction nosology. This article integrates research on reward-related brain activity (functional MRI) and neurotransmitter function (PET) in GD, alongside the consideration of structural MRI data as to whether these signals more likely reflect pre-existing vulnerability or neuroadaptive change. Where possible, we point to qualitative similarities and differences with established markers for SUDs. Structural MRI studies indicate modest changes in regional gray matter volume and diffuse reductions in white matter integrity in GD, contrasting with clear structural deterioration in SUDs. Functional MRI studies consistently identify dysregulation in reward-related circuitry (primarily ventral striatum and medial prefrontal cortex), but evidence is mixed as to the direction of these effects. The need for further parsing of reward sub-processes is emphasized, including anticipation vs outcome, gains vs. losses, and disorder-relevant cues vs natural rewards. Neurotransmitter PET studies indicate amplified dopamine (DA) release in GD, in the context of minimal differences in baseline DA D2 receptor binding, highlighting a distinct profile from SUDs. Preliminary work has investigated further contributions of opioids, GABA and serotonin. Neuroimaging data increasingly highlight divergent profiles in GD vs. SUDs. The ability of gambling to perpetually activate DA (via maximal uncertainty) may contribute to neuroimaging similarities between GD and SUDs, whereas the supra-physiological DA effects of drugs may partly explain differences in the neuroimaging profile of the two syndromes. Coupled with consistent observations of correlations with gambling severity and related clinical variables within GD samples, the overall pattern of effects is interpreted as a likely combination of shared vulnerability markers across GD and SUDs, but with further experience-dependent neuroadaptive processes in GD.

The interactive effects of ketamine and ethanol on dopamine expression in the ventral tegmental area of rats

BackgroundA number of studies have demonstrated the significant and rapid antidepressant effects of ketamine, which is also known as a neurotoxic and illicit drug. Ketamine and alcohol are increasingly used together in clubs by teenagers and young adults. Previous studies have proven that chronic ketamine consumption induces a delayed and persistent activation of the dopamine (DA) system. However, the rewarding properties of recreational ketamine abuse remain unclear, and the underlying mechanisms of the effects on the DA system after administration of ketamine with ethanol are yet to be explored.MethodsHere, we evaluated the effects of two different doses of ketamine (30 mg/kg and 60 mg/kg) with and without ethanol (0.3156 g/kg) on DA concentration in the rat’s ventral tegmental area (VTA), a vital region in the reward and motivation system. We explored the effects of the combined drug treatment on the expression profiling of the DA metabolism genes, tyrosine hydroxylase, dopa decarboxylase, vesicular monoamine transporter 2, and synaptosomal-associated protein 25, as well as protein expression level of brain-derived neurotrophic factor in the rat’s VTA.ResultsWe found that administration of ketamine with ethanol led to a significant increase of DA in the VTA associated with differential regulation of mRNA levels of the four DA metabolism genes and protein levels of brain-derived neurotrophic factor. Moreover, the rewarding properties of coadministration of ketamine and ethanol were related to dopaminergic neuron activation in the VTA.ConclusionThese results indicated the possibility that combined drug treatment might positively affect the mesencephalic DA reward system.

Evaluation of the effects of sensorimotor exercise on physical and psychological parameters in breast cancer patients undergoing neurotoxic chemotherapy.

Breast cancer is the most common cancer disease of women in industrialized countries. Neurotoxic chemotherapy drugs are known to harm peripheral nerves and cause a chemotherapy-induced peripheral neuropathy (CIPN). CIPN is one of the most common adverse events associated with Paclitaxel chemotherapy and may remain present long after the termination of chemotherapy. Thus, it reduces the patients' quality of life (QoL) both during chemotherapy and onwards, and can impose a danger on breast cancer survivors due to an increased risk of falling and fall-related injuries. The aim of this randomized-controlled trial (RCT) (n = 36) (IG: intervention group, n = 17) (CG: control group, n = 19) was to determine whether sensorimotor exercises have a positive effect on physical and psychological parameters in breast cancer patients undergoing neurotoxic chemotherapy (Paclitaxel). As a result, we were able to show significant improvements in postural stability in monopedal stance [left leg 16.17 ± 3.67 vs. 21.55 ± 5.33 (p < 0.001) and right leg 15.14 ± 2.30 vs. 20.85 ± 5.05 (p < 0.001)] and in bipedal stance [T1 vs. T0, - 0.49 (IG) vs. + 1.14 (CG) p = 0.039]. These results in posturography correlate with the clinical presentation with intervention group patients scoring significantly better on the Fullerton Advanced Balance Scale [37.71 ± 2.73 vs. 34.47 ± 3.98 (p = 0.004)]. Moderate strength training successfully prevented a strength loss in the IG that was remarkable in the CG (- 1.60 vs. 0.60, p = 0.029). Concerning the psychological parameters assessed via EORTC- and MFI-questionnaires, no significant improvements were found. Future studies should focus on the correlation of clinical and posturometry findings and subjective QOL such as the long-term-development of CIPN.

Neurofilament light chain as disease biomarker in a rodent model of chemotherapy induced peripheral neuropathy

The objective of this study is to test the feasibility of using serum neurofilament light chain (NfL) as a disease biomarker in Chemotherapy Induced Peripheral Neuropathy (CIPN) since this easy accessible biological test may have a large impact on clinical management and safety of cancer patients.We performed this preclinical study using a well-characterized rat model based on repeated administration of the cytostatic drug vincristine (VCR, 0.2 mg/kg intravenously via the tail vein once/week for 4 times). Serial NfL serum concentration was measured using the in-house Simoa NfL assay and peripheral neuropathy onset was measured by sensory and motor nerve conduction studies.Serum NfL measure in untreated and VCR-treated rats demonstrated a steady, and significant increase during the course of VCR administration, with a final 4-fold increase with respect to controls (p < .001) when sign of axonopathy and loss of intraepidermal nerve fibers were clearly evident and verified by behavioral, neurophysiological and pathological examination.This simple monitoring approach based on serum NfL concentration measures may be easily translated to clinical practice and should be considered as a putative marker of CIPN severity in a typical oncology outpatient setting. Further studies are needed to validate its utility in cancer patients treated with different neurotoxic drugs.

Mitoxantrone is More Toxic than Doxorubicin in SH-SY5Y Human Cells: A 'Chemobrain' In Vitro Study.

The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro neurotoxicity of two commonly used chemotherapeutic drugs, DOX and MTX, and study their underlying mechanisms in the SH-SY5Y human neuronal cell model. Undifferentiated human SH-SY5Y cells were exposed to DOX or MTX (0.13, 0.2 and 0.5 μM) for 48 h and two cytotoxicity assays were performed, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction and the neutral red (NR) incorporation assays. Phase contrast microphotographs, Hoechst, and acridine orange/ethidium bromide stains were performed. Mitochondrial membrane potential was also assessed. Moreover, putative protective drugs, namely the antioxidants N-acetyl-l-cysteine (NAC; 1 mM) and 100 μM tiron, the inhibitor of caspase-3/7, Ac-DEVD-CHO (100 μM), and a protein synthesis inhibitor, cycloheximide (CHX; 10 nM), were tested to prevent DOX- or MTX-induced toxicity. The MTT reduction assay was also done in differentiated SH-SY5Y cells following exposure to 0.2 μM DOX or MTX. MTX was more toxic than DOX in both cytotoxicity assays and according to the morphological analyses. MTX also evoked a higher number of apoptotic nuclei than DOX. Both drugs, at the 0.13 μM concentration, caused mitochondrial membrane potential depolarization after a 48-h exposure. Regarding the putative neuroprotectors, 1 mM NAC was not able to prevent the cytotoxicity caused by either drug. Notwithstanding, 100 μM tiron was capable of partially reverting MTX-induced cytotoxicity in the NR uptake assay. One hundred μM Ac-DEVD-CHO and 10 nM cycloheximide (CHX) also partially prevented the toxicity induced by DOX in the NR uptake assay. MTX was more toxic than DOX in differentiated SH-SY5Y cells, while MTX had similar toxicity in differentiated and undifferentiated SH-SY5Y cells. In fact, MTX was the most neurotoxic drug tested and the mechanisms involved seem dissimilar among drugs. Thus, its toxicity mechanisms need to be further investigated as to determine the putative neurotoxicity for multiple sclerosis and cancer patients.

Ex-vivo expression of chemokine receptors on cells surrounding cutaneous nerves in patients with HIV-associated sensory neuropathy.

HIV-associated sensory neuropathy (HIV-SN) remains common in HIV+ individuals receiving antiretroviral therapy (ART), even though neurotoxic antiretroviral drugs (e.g. stavudine) have been phased out of use. Accumulating evidence indicates that the neuropathy is immune-mediated. We hypothesize that chemokines produced locally in the skin promote migration of macrophages and T cells into the tissue, damaging cutaneous nerves causing HIV-SN. We assessed chemokine receptor expression on infiltrating CD14 and CD3 cells around cutaneous nerves in standardized skin biopsies from HIV-SN+ patients (n = 5), HIV-SN- patients (n = 9) and healthy controls (n = 4). The AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen was used to assess Indonesian HIV+ patients receiving ART without stavudine (case definition: bilateral presence of at least one symptom and at least one sign of neuropathy). Distal leg skin biopsies were stained to visualize chemokine receptors (CCR2, CCR5, CXCR3, CXCR4, CX3CR1), infiltrating CD3 and CD14 cells, and protein-gene-product 9.5 on nerves, using immunohistochemistry and 4-colour confocal microscopy. Intraepidermal nerve fibre density was variable in patients without HIV-SN and generally lower in those with HIV-SN. CX3CR1 was more evident on CD14 cells whereas CCR2, CCR5, CXCR3 and CXCR4 were more common on CD3 cells. Expression of CX3CR1, CCR2 and CCR5 was more common in HIV-SN+ patients than those without HIV-SN. CXCR3 and CXCR4 were upregulated in all HIV+ patients, compared with healthy controls. Inflammatory macrophages expressing CX3CR1 and T cells expressing CCR2 and CCR5 may participate in peripheral nerve damage leading to HIV-SN in HIV+ patients treated without stavudine. Further characterization of these cells is warranted.

Change in Anticancer Drug Sensitivity During Neuronal Differentiation of PC12 Cells.

Although there are many reports of anticancer drug-induced neurotoxicity, most previous data have been derived from neuronal cell models grown in a variety of culture conditions. This has prevented accurate assessment of the potency of their neurotoxicity and of changes in drug sensitivity of neuronal cells during differentiation. In this study, a simple neuronal differentiation induction system was established and the relative potency of neurotoxicity of eight anticancer drugs was compared during neuronal cell differentiation. Rat PC12 cells were induced to differentiate into neuronal cells by 50 ng/ml nerve growth factor in serum-free Dulbecco's modified Eagle's medium, followed by overlay of fresh nutrients at day 3, without medium change. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. During differentiation, PC12 cells became 1.1-to more than 10,000-fold resistant to anticancer drugs. Topoisomerase inhibitors (doxorubicin, SN-38, etoposide) were the most toxic to differentiated PC12 cells, followed by docetaxel, gefitinib, melphalan, 5-fluorouracil and methotrexate. Docetaxel showed the highest cytotoxicity against undifferentiated PC12 cells, but its cytotoxicity was dramatically reduced during differentiation. The present study demonstrated considerable variation in the neurotoxicity of anticancer drugs during the cell differentiation process. The present simple assay system may be useful to search for neuroprotective substances.

In Search of a Gold Standard Patient-Reported Outcome Measure for Use in Chemotherapy- Induced Peripheral Neuropathy Clinical Trials.

Purpose:To test a reduced version—CIPN15—of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy scale (QLQ-CIPN20) to establish a possible gold-standard patient-reported outcome measure for chemotherapy-induced peripheral neuropathy (CIPN).Methods:Using a prospective, longitudinal, case–control design, patients (n = 121) receiving neurotoxic chemotherapy completed the CIPN15 at baseline and 12 weeks and underwent objective neurological assessment using the 5-item Total Neuropathy Score-Clinical (TNSc). Healthy controls (n = 30) completed the CIPN15 once. Structural validity was evaluated using factor analysis. Because a stable factor structure was not found, a sum score was used to evaluate measures of the CIPN15’s psychometric properties—reliability, validity, sensitivity, and responsiveness—as follows: internal consistency via Cronbach’s α and item–item correlations; test–retest reliability via correlation between 2 CIPN15 scores from each patient; concurrent validity via correlation between CIPN15 and 5-item TNSc scores; contrasting group validity via comparison of CIPN15 scores from patients and healthy controls; sensitivity via descriptive statistics (means, standard deviation, ranges); and responsiveness via Cohen’s d effect size.Results:Most patients received single agent oxaliplatin (33.7%), paclitaxel (21.2%), or more than 1 neurotoxic drug concurrently (29.8%). Factor analysis revealed no stable factor structure. Cronbach’s α for the CIPN15 sum score was 0.91 (confidence interval [CI] = 0.89-0.93). Test–retest reliability was demonstrated based on strong correlations between the 2 scores obtained at the 12-week time point (r = 0.86; CI = 0.80-0.90). The CIPN15 and 5-item TNSc items reflecting symptoms (not signs) were moderately correlated (r range 0.57-0.72): concurrent validity. Statistically significant differences were found between patient and healthy control CIPN15 mean scores (P < .0001): contrasting group validity. All items encompassed the full score range but the CIPN15 linearly converted sum score did not: sensitivity. The CIPN15 was responsive based on a Cohen’s d of 0.52 (CI = 0.25-0.79).Conclusion:The sum-scored CIPN15 is reliable, valid, sensitive, and responsive when used to assess taxane- and platinum-induced CIPN.

Neurotoxicity of anesthetic drugs: an update.

This article reviews the most recently published evidence that investigated anesthesia-induced neurotoxicity in both animals and humans, especially as it pertains to the perinatal period. Several recent studies have focused on better understanding the complex mechanisms that underlie intravenous and volatile anesthesia-induced neurotoxicity in animals. Adjuvant agents that target these pathways have been investigated for their effectiveness in attenuating the neuroapoptosis and neurocognitive deficits that result from anesthesia exposure, including dexmedetomidine, rutin, vitamin C, tumor necrosis factor α, lithium, apocynin, carreic acid phenethyl ester. Five clinical studies, including one randomized control trial, provided inconsistent evidence on anesthesia-induced neurotoxicity in humans. Despite a growing body of preclinical studies that have demonstrated anesthesia-induced neurotoxic effects in the developing and aging brain, their effects on the human brain remains to be determined. The performance of large-scale human studies is limited by several important factors, and noninvasive biomarkers and neuroimaging modalities should be employed to define the injury phenotypes that reflect anesthesia-induced neurotoxicity. Ultimately, the use of these modalities may provide new insights into whether the concerns of anesthetics are justified in humans.

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

Safeguarding Infant Brains: A Multidisciplinary Challenge-Results of a Survey, Update on Current Scientific Evidence, and Recommendations on How to Deal with Possible Anesthetic Drug Neurotoxicity.

Potential neurotoxicity of anesthetic drugs has been among the most intensively discussed issue in pediatric anesthesia for more than 10 years. It remains unclear how far this discussion has reached the European pediatric surgical community. Our aim was to investigate the thoughts of pediatric surgeons regarding this topic. In addition, we provide an update on the current scientific evidence regarding neurotoxicity together with recommendations for clinical practice. A web-based survey to assess the thoughts of practicing European pediatric surgeons regarding neurotoxicity and how it may have influenced their daily practice of pediatric surgery was launched via the European Pediatric Surgeons' Association Web site. A total of 72 responses could be analyzed. A majority of the respondents were interested in the topic but felt a need to further explore it. Thirty-one respondents have changed their daily practice of pediatric surgery due to potential anesthetic drug toxicity. Eighteen respondents reported to be concerned about neurotoxicity, 29 held a neutral position, and 8 were not concerned. Twenty-seven respondents found it a shared responsibility of the surgeon and the anesthesiologist to deal with the neurotoxicity issue. The majority of respondents found a necessity for further research on anesthetic drug neurotoxicity, assigning the highest priority to prospective longitudinal human studies and the lowest to animal studies. The neurotoxicity question has reached the pediatric surgical community. Currently available scientific data do not support the theory of anesthetic drug-induced neurotoxicity in young children. Recent interdisciplinary clinical research focuses on neurodevelopmental outcome after surgery in neonates and infants. The European Safe Anesthesia For Every Tot initiative suggests focusing on proper conduct of anesthesia in children rather than on possible anesthetic drug neurotoxicity.

A serious nightmare: psychiatric and neurologic adverse reactions to mefloquine are serious adverse reactions.

Mefloquine (originally marketed as Lariam) is a neurotoxic quinoline derivative antimalarial drug that is known to cause serious and potentially lasting neuropsychiatric adverse reactions. Since 2013, drug regulators in several jurisdictions, including the United States, the United Kingdom, Ireland, and Canada, have required their mefloquine labels be updated to warn that when used for malaria prophylaxis the drug should be discontinued at the onset of neurologic or psychiatric symptoms. These recent changes to the international labeling serve to imply that psychiatric and neurologic reactions to mefloquine prophylaxis may be an early warning of an impending more serious reaction that may further jeopardize the patient with continued use of the drug. To prevent these more serious effects, these drug labels now warn that mefloquine should be discontinued and that patients seek immediate medical intervention to obtain an alternative antimalarial drug when psychiatric or neurologic symptoms occur. When used correctly for malaria prophylaxis as the updated labeling now directs, it is reasonable to expect that mefloquine will be discontinued, and an alternative drug substituted, in each patient who develops psychiatric or neurologic symptoms. This opinion discusses the implications of this updated labeling for the reporting of adverse reactions and for the continued use of the drug in malaria prophylaxis.