RESUMO
How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.
Assuntos
Lateralidade Funcional , Doenças do Labirinto/complicações , Atividade Motora/fisiologia , Animais , Comportamento Animal , Humanos , Camundongos , Transmissão Sináptica/fisiologia , Vestíbulo do Labirinto/fisiologia , Vestíbulo do Labirinto/fisiopatologiaRESUMO
The peripheral nervous system (PNS) is subject to a wide range of structural and functional insults including direct damage to axons, loss of myelin, and progressive deficits in saltatory conduction. Drugs that damage the PNS often result in neuropathies that impact the structure and function of targeted nerves. In most cases, both sensory and motor neurons are affected with damage initially evident in the distal extremities. Drug-induced neuropathies are potentially reversible following cessation of treatment, but early stages of neuropathy can be subclinical and asymptomatic making diagnosis difficult. Nerve biopsy is highly validated and provides definitive evidence of nerve injury and corresponding severity; however, it is limited in some respects and electrophysiological measures can complement histopathological assessments and provide a functional measure of potential toxicity. In a drug development setting, nerve conduction assessments are valuable to monitor nerve function longitudinally if nerve damage is suspected or confirmed, and importantly, can be used to monitor progression and/or recovery of a drug-induced neuropathy. This review will summarize the methodology used in nerve conduction assessments as well as discuss data interpretation and considerations for use in nonclinical species. Finally, the use of nerve conduction assessments in nonclinical drug development is discussed.
Assuntos
Condução Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Humanos , Modelos Animais , Preparações FarmacêuticasRESUMO
The nonclinical safety profile of GS-8873, a hepatitis B virus RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3, and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at weeks 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose-responsive NCV reductions and latency increases worsened across all dose groups compared with controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared with controls. No monkey nervous system microscopic findings were observed. No-observed-adverse-effect-levels could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of no-observed-adverse-effect-levels. The best-fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 and 0.1 mg/kg/day, respectively.
Assuntos
Antivirais , Vírus da Hepatite B , Administração Oral , Animais , Antivirais/farmacologia , Antivirais/toxicidade , Haplorrinos , Vírus da Hepatite B/efeitos dos fármacos , Ratos , Ratos Wistar , Estudos RetrospectivosRESUMO
BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.
Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacocinética , Animais , Cães , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias da Próstata/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13-18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long-standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease-but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small-fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre-specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject- and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN.
Assuntos
Neuropatias Diabéticas/diagnóstico , Condução Nervosa/fisiologia , Neuropatias Diabéticas/classificação , Neuropatias Diabéticas/fisiopatologia , Eletrodiagnóstico , Humanos , Pesquisa , Índice de Gravidade de DoençaRESUMO
The evaluation of neurotoxic damage involves a unique set of challenges. Vulnerable structures, such as neocortex, hippocampus, spinal cord, and peripheral nerve are complex and sharply differentiated; deficits can result from insults to one or more element(s) in the system (e.g., myelin, axon, soma, synapse, or glia). In-life assessment of neurotoxic damage is complicated by the relative inaccessibility of structures in the brain and spinal cord, and recovery is severely limited. Histopathology and electrophysiology represent two of the most commonly used and valuable techniques in this field. This review outlines the strengths and limitations of these procedures and focuses on circumstances in which findings from these measures are dissociated. Electrophysiology is noninvasive and affords a longitudinal view of onset and progression of deficits; however, measures are generally weighted to large-diameter myelinated axons and to regions of primary sensory and motor processing. Histology is a highly validated biomarker, but it is restricted by sampling issues and is insensitive to some elements of neurotoxicity (e.g., altered channel function) associated with profound functional consequences. The central tenet of the discussion is that histology and electrophysiology offer complementary views of neurotoxic damage and, whenever possible, they should be used in concert.
Assuntos
Eletrofisiologia/métodos , Síndromes Neurotóxicas/patologia , Doenças do Sistema Nervoso Periférico/patologia , Medula Espinal/patologia , Animais , Axônios/patologia , Biomarcadores , Fenômenos Eletrofisiológicos , Modelos Animais , Bainha de Mielina/patologia , Condução Nervosa , Nervos Periféricos/patologiaRESUMO
Electroencephalography is increasingly being used to probe the functional organization of auditory cortex. Modulation of the electroencephalographic (EEG) signal by tones was examined in primary auditory cortex (A1) of awake monkeys. EEG data were measured at 4 laminar depths defined by current source density profiles evoked by best frequency (BF) tones. Midlaminar multiunit activity was used to define the tuning characteristics of A1 sites. Presentation of BF tones increased EEG power across the range of frequencies examined (4-290 Hz), with maximal effects evident within the first 100 ms after stimulus onset. The largest relative increases in EEG power generally occurred at very high gamma frequency bands (130-210 Hz). Increases in EEG power for frequencies less than 70 Hz primarily represented changes in phase-locked activity, whereas increases at higher frequencies primarily represented changes in non-phase-locked activity. Power increases in higher gamma bands were better correlated with the A1 tonotopic organization than power increases in lower frequency bands. Results were similar across the 4 laminar depths examined. These findings highlight the value of examining high-frequency EEG components in exploring the functional organization of auditory cortex and may enhance interpretation of related studies in humans.
Assuntos
Estimulação Acústica/métodos , Córtex Auditivo/fisiologia , Eletroencefalografia/métodos , Potenciais Evocados Auditivos/fisiologia , Vigília/fisiologia , Animais , Haplorrinos , Macaca fascicularis , Masculino , Fatores de TempoRESUMO
BACKGROUND: Recent consensus guidelines recommend pregabalin as a first-tier treatment for painful diabetic peripheral neuropathy (DPN). We evaluated the efficacy of pregabalin 600 mg/d (300 mg dosed BID) versus placebo for relieving DPN-associated neuropathic pain, and assessed its safety using objective measures of nerve conduction (NC). METHODS: In this randomized, double-blind, placebo-controlled trial, the primary efficacy measure was endpoint mean pain score (MPS) from daily pain diaries (11-point scale). NC velocity and sensory and motor amplitudes were assessed at baseline, endpoint, and end of follow-up (2 weeks post-treatment). At each timepoint, the median-motor, median-sensory, ulnar-sensory, and peroneal-motor nerves were evaluated. Secondary efficacy measures included weekly MPS and proportion of responders (patients achieving >or=50% reduction in MPS from baseline to endpoint). After 1-weeks' dosage escalation, pregabalin-treated patients received 300 mg BID for 12 weeks. RESULTS: Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and approximately 5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001). For all four nerves, 95% CIs for median differences in amplitude and velocity from baseline to endpoint and baseline to follow-up included 0 (ie, no significant difference vs. placebo). Significant pain improvement among pregabalin-treated patients was evident at week 1 and sustained at every weekly timepoint. More pregabalin-treated patients (49%) than controls (23%) were responders (p <.001). CONCLUSION: Pregabalin 600 mg/d (300 mg BID) effectively reduced pain, was well tolerated, and had no statistically significant or clinically meaningful effect on NC in patients with painful DPN.
Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Dor/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Analgésicos/uso terapêutico , Neuropatias Diabéticas/fisiopatologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Nervo Mediano/efeitos dos fármacos , Nervo Mediano/fisiopatologia , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Dor/fisiopatologia , Medição da Dor/métodos , Nervo Fibular/efeitos dos fármacos , Nervo Fibular/fisiopatologia , Placebos , Pregabalina , Resultado do Tratamento , Nervo Ulnar/efeitos dos fármacos , Nervo Ulnar/fisiopatologia , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Zoniporide, an inhibitor of the Na+-H+ exchanger-1, was administered by continuous intravenous infusion to rats and dogs for up to 1 month. In 1-month studies, histological and functional changes were observed in select portions of the peripheral nervous system; however, these findings were not detected in 2-week studies at similar or higher doses. In the 1-month rat study, there was dose-dependent, minimal, focal, or multifocal nerve fiber (axonal) degeneration in the spinal cord and/or sciatic nerve. In a follow-up rat study, findings included slowing of caudal nerve conduction velocity and axonal degeneration in the spinal cord (dorsal funiculus), dorsal roots, dorsal root ganglia (DRG), radial, sciatic, and tibial nerves. In the 1-month dog study, there was impairment of the patellar reflex and associated postural reaction changes, minimal to marked proximal nerve fiber degeneration in the DRG, and minimal nerve fiber degeneration in the dorsal roots and funiculi of the spinal cord. Minimal nerve fiber degeneration of equivocal significance was noted in various peripheral nerves. Taken together, these findings were consistent with a specific effect on peripheral sensory nerve fibers. These studies demonstrated that zoniporide produces clinical, electrophysiologic, and microscopic evidence of peripheral sensory axonopathy and establishes the importance of careful preclinical evaluation of neurological function.
Assuntos
Guanidinas/toxicidade , Degeneração Neural/etiologia , Fibras Nervosas , Síndromes Neurotóxicas/etiologia , Pirazóis/toxicidade , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Animais , Cães , Eletrofisiologia , Feminino , Guanidinas/sangue , Guanidinas/química , Guanidinas/farmacocinética , Infusões Intravenosas , Masculino , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Fibras Nervosas/ultraestrutura , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Pirazóis/sangue , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Microtubule inhibitor (MTI)-based chemotherapies used in the treatment of breast cancer--including vinca alkaloids, taxanes, and epothilones--are known to be associated with peripheral neuropathy. The incidence and severity of neuropathy, most frequently sensory in nature, depend on the agent used, absolute and cumulative drug dose, administration schedule, and presence of comorbidities. Although some first-generation vinca alkaloids, such as vincristine, were associated with severe mixed sensory/motor neuropathy, the deficits associated with newer agents in this class (eg, vinflunine) are generally milder and limited to distal sensory signs and symptoms. Among the taxanes, sensory neuropathy is reported more often with administration of paclitaxel and albumin-bound paclitaxel and less frequently with docetaxel. Epothilones, a new class of MTI, may be associated with grade 3/4 peripheral neuropathy; however, the neuropathy associated with ixabepilone, a novel epothilone B analog, is generally mild to moderate and reversible to baseline or grade 1 levels. The neuropathy induced by MTI therapy is best managed with dose adjustments and/or treatment delay. This article provides an overview of the incidence, characteristics, and management of MTI-associated neurotoxicities for known vinca alkaloids and taxanes, as well as newer agents, such as vinflunine and ixabepilone.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Polineuropatias/etiologia , Moduladores de Tubulina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Moduladores de Tubulina/classificaçãoRESUMO
The effects of fidarestat, an aldose reductase inhibitor (ARI), were assessed on nerve conduction velocity (NCV) in somatic nerves and on multiple measures of bladder function in rats made hyperglycemic with streptozotocin (STZ) and in age-matched controls. Nerve conduction velocity was recorded at baseline and at 10, 20, 30, and 50 days after confirmation of the STZ-induced hyperglycemia in all rats (N=47); bladder function was assessed in a representative subset of rats (N=20) at Day 50. Caudal NCV was markedly slowed by STZ, and this effect was significantly reversed by fidarestat. The initial deficit and treatment-related improvement were especially evident for responses driven by high-frequency repetitive stimulation. Of the 11 parameters of bladder activity assessed, four measures-bladder capacity, micturition volume, micturition frequency, and bladder weight-were significantly different in the control and STZ-treated groups. These deficits were not affected by fidarestat. At Day 50, the induced deficits in bladder function were highly correlated with caudal NCV (r values ranging from 0.70 to 0.96; P values ranging from .02 to <.0001). These results suggested that fidarestat improved the slowing of somatic nerve NCV in hyperglycemic rats, but it was not effective in reversing associated bladder dysfunction, in spite of the highly significant correlation between these two diabetes-induced deficits. Possible explanations for this dissociation are discussed.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Diabetes Mellitus Experimental/fisiopatologia , Condução Nervosa/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Análise de Variância , Animais , Feminino , Hiperglicemia/induzido quimicamente , Imidazolidinas , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Micção/fisiologiaRESUMO
OBJECTIVE: Lack of C-peptide in type 1 diabetes may be an important contributing factor in the development of microvascular complications. Replacement of native C-peptide has been shown to exert a beneficial influence on peripheral nerve function in type 1 diabetes. The aim of this study was to evaluate the efficacy and safety of a long-acting C-peptide in subjects with type 1 diabetes and mild to moderate peripheral neuropathy. RESEARCH DESIGN AND METHODS: A total of 250 patients with type 1 diabetes and peripheral neuropathy received long-acting (pegylated) C-peptide in weekly dosages of 0.8 mg (n = 71) or 2.4 mg (n = 73) or placebo (n = 106) for 52 weeks. Bilateral sural nerve conduction velocity (SNCV) and vibration perception threshold (VPT) on the great toe were measured on two occasions at baseline, at 26 weeks, and at 52 weeks. The modified Toronto Clinical Neuropathy Score (mTCNS) was used to grade the peripheral neuropathy. RESULTS: Plasma C-peptide rose during the study to 1.8-2.2 nmol/L (low dose) and to 5.6-6.8 nmol/L (high dose). After 52 weeks, SNCV had increased by 1.0 ± 0.24 m/s (P < 0.001 within group) in patients receiving C-peptide (combined groups), but the corresponding value for the placebo group was 1.2 ± 0.29 m/s. Compared with basal, VPT had improved by 25% after 52 weeks of C-peptide therapy (Δ for combined C-peptide groups: -4.5 ± 1.0 µm, placebo group: -0.1 ± 0.9 µm; P < 0.001). mTCNS was unchanged during the study. CONCLUSIONS: Once-weekly subcutaneous administration of long-acting C-peptide for 52 weeks did not improve SNCV, other electrophysiological variables, or mTCNS but resulted in marked improvement of VPT compared with placebo.
Assuntos
Peptídeo C/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Neuropatias Diabéticas/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nervos Periféricos/metabolismo , Análise de Regressão , Adulto JovemRESUMO
Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.
Assuntos
Antineoplásicos/farmacologia , Lactamas Macrocíclicas/farmacologia , Microtúbulos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxazóis/farmacologia , Alcaloides de Vinca/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Dimerização , Genômica , Humanos , Lactamas Macrocíclicas/química , Camundongos , Microscopia Eletrônica , Mitose , Transplante de Neoplasias , Oxazóis/química , Tubulina (Proteína)/química , Vimblastina/análogos & derivados , Vimblastina/química , Vimblastina/farmacologia , Alcaloides de Vinca/química , VinorelbinaRESUMO
Concerns regarding the safety of silver-mercury amalgam fillings continue to be raised in the absence of any direct evidence of harm. The widespread population exposure to amalgam mandated that a thorough investigation be conducted of its potential effects on the nervous system. The National Institute of Dental and Craniofacial Research and U.S. Air Force investigators collaborated in the ongoing Air Force Health Study (AFHS) of Vietnam era veterans. The primary study question involved adverse health effects associated with exposure to herbicides or dioxin. An assessment of exposure to dental amalgam fillings was added to the 1997-1998 health examination to investigate possible associations between amalgam exposure and neurological abnormalities. Our study population consisted of 1663 dentate AFHS participants, comprised of 986 AFHS controls and 677 Ranch Hand veterans who were exposed to dioxin in Vietnam. Two hundred and fifty-two of the participants had confirmed diabetes mellitus. Study outcomes included clinical neurological signs, vibrotactile thresholds, and summary variables for different levels of peripheral neuropathy. A limitation of our study is that our database did not include more sensitive continuous measures such as nerve conduction studies. No significant associations were found between amalgam exposure and clinical neurological signs of abnormal tremor, coordination, station or gait, strength, sensation, or muscle stretch reflexes or for any level of peripheral neuropathy among our study participants. A statistically significant association was detected between amalgam exposure and the continuous vibrotactile sensation response for the combined non-diabetic participants and separately for non-diabetic AFHS controls. No significant association in this measure was detectable for non-diabetic Ranch Hand veterans or among the combined diabetic participants. The association is a sub-clinical finding that was not associated with symptoms, clinically evident signs of neuropathy, or any functional impairment. Overall, we found no association between amalgam exposure and neurological signs or clinically evident peripheral neuropathy. Our findings do not support the hypothesis that exposure to amalgam produces adverse, clinically evident neurological effects.
Assuntos
Amálgama Dentário/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Veteranos , Técnicas de Diagnóstico Neurológico , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estados UnidosRESUMO
The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats. ZD6126 was administered i.v. at up to maximum tolerated doses using subacute (0 to 20 mg/kg/d for 5 days) and chronic (0 to 10 mg/kg/d for 5 days, repeated monthly for 6 months) dosing regimens. A separate study examined a combination of ZD6126 (three cycles of ZD6126 given as in the chronic dosing regimen) and paclitaxel (12 mg/kg/wk for 9 weeks) to assess whether coadministration of ZD6126 altered the time course or magnitude of a paclitaxel-induced neuropathy. Neurotoxic potential was examined using a comprehensive series of tests including a functional observation battery, measurements of muscle strength (forelimb and hind limb grip strength), nociception (tail flick test), locomotor activity, neuropathology, and whole nerve electrophysiology. There was no evidence that ZD6126 induced neurotoxicity in the rat following either subacute or chronic i.v. dosing. In a chronic electrophysiology study, ZD6126 produced a slight slowing of the maturational increase of caudal nerve amplitude, with some evidence of reversibility. However, this was not associated with any changes in caudal nerve conduction velocity, motor nerve conduction velocity or amplitude, functional observation battery behavioral and function parameters (including no effects on tail flick latency), and neuropathology. As expected, paclitaxel administration was associated with a significant decrease in caudal nerve conduction velocity (P = 0.0001). Coadministration of ZD6126 did not increase the neurotoxicity of paclitaxel. These studies suggest that ZD6126 should not induce the peripheral neuropathy associated with other antitubulin chemotherapeutic agents and that ZD6126 may not exacerbate the neurotoxicity of other agents with dose-limiting neuropathies.
Assuntos
Doenças do Sistema Nervoso/induzido quimicamente , Compostos Organofosforados/toxicidade , Animais , Injeções Intravenosas , Masculino , Atividade Motora/efeitos dos fármacos , Tecido Nervoso/efeitos dos fármacos , Tecido Nervoso/patologia , Doenças do Sistema Nervoso/patologia , Condução Nervosa/efeitos dos fármacos , Compostos Organofosforados/administração & dosagem , Ratos , Ratos WistarRESUMO
The therapeutic effects of botulinum toxin are principally, if not exclusively, derived from an alteration in the release of acetylcholine (ACh) at pre-synaptic neurons. The rationale for how these effects could be beneficial in conditions characterized by excessive muscle contraction is clear, but the hypotheses regarding botulinum toxin-induced effects on pain are highly speculative. We explore five possible mechanisms by which botulinum toxin could directly or indirectly alter pain, including: 1) changes in the sensitivity and response patterns of group III and IV muscle nociceptors, 2) diminished activity in the gamma-motor neurons and consequent changes in muscle spindle afferents, 3) alterations in cholinergic control of vascular and autonomic functions, including neurogenic inflammation, 4) induced neuroplastic changes in the processing of afferent somatosensory activity at multiple levels of the neuroaxis, and 5) direct non-cholinergic effects on pain afferents.
Assuntos
Toxinas Botulínicas/metabolismo , Toxinas Botulínicas/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Dor/tratamento farmacológico , Dor/fisiopatologia , Acetilcolina/antagonistas & inibidores , Acetilcolina/metabolismo , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Toxinas Botulínicas/farmacologia , Humanos , Fusos Musculares/efeitos dos fármacos , Fusos Musculares/fisiopatologia , Músculo Esquelético/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Produced by Clostridium botulinum, botulinum toxins are high molecular weight protein complexes consisting of the neurotoxin and additional nontoxic proteins that function to protect the toxin molecule. The neurotoxin acts to inhibit the release of acetylcholine at the neuromuscular junction, causing muscle paralysis. Purified toxin complexes have found a niche in the treatment of clinical disorders involving muscle hyperactivity. The different serotypes are structurally and functionally similar; however, specific differences in neuronal acceptor binding sites, intracellular enzymatic sites, and species sensitivities suggest that each serotype is its own unique pharmacologic entity. Recently, botulinum toxin type B has been developed as a liquid formulation to avoid the lyophilization (vacuum-drying) and reconstitution processes associated with decreasing the potency and stability of current type A toxin preparations. Biochemical tests were conducted to evaluate the quality of toxin in this formulation. In 3 consecutive manufacturing lots, the botulinum toxin type B complex was found to be highly purified, intact, uniform, and consistent from lot to lot. Also, it showed long-term stability at refrigerator and room temperatures (2 to 25 degrees C). Electrophysiologic studies in cynomolgus monkeys showed that botulinum toxin type B is effective in paralyzing injected muscle groups, with minimal spread to relatively distant noninjected muscles.
Assuntos
Antidiscinéticos/metabolismo , Antidiscinéticos/farmacologia , Toxinas Botulínicas/metabolismo , Toxinas Botulínicas/farmacologia , Animais , Toxinas Botulínicas Tipo A , Estabilidade de Medicamentos , Haplorrinos , Modelos Animais , Doenças Musculares/tratamento farmacológicoRESUMO
UNLABELLED: Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as ≥30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials. PERSPECTIVE: This article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Distrofia Simpática Reflexa/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Analgésicos não Narcóticos/efeitos adversos , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Distrofia Simpática Reflexa/fisiopatologia , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
A novel non-invasive technique was applied to measure velocity within slow conducting axons in the distal extreme of the sciatic nerve (i.e., digital nerve) in a rat model. The technique is based on the extraction of rectified multiple unit activity (MUA) from in vivo whole nerve compound responses. This method reliably identifies compound action potentials in thinly myelinated fibers conducting at a range of 9-18 m/s (Aδ axons), as well as in a subgroup of unmylinated C fibers conducting at approximately 1-2 m/s. The sensitivity of the method to C-fiber conduction was confirmed by the progressive decrement of the responses in the 1-2 m/s range over a 20-day period following the topical application of capsaicin (ANOVA p<0.03). Increasing the frequency of applied repetitive stimulation over a range of 0.75 Hz to 6.0 Hz produced slowing of conduction and a significant decrease in the magnitude of the compound C-fiber response (ANOVA p<0.01). This technique offers a unique opportunity for the non-invasive, repeatable, and quantitative assessment of velocity in the subsets of Aδ and C fibers in parallel with evaluation of fast nerve conduction.
RESUMO
The assessment of changes in sensory-motor function in clinical research presents a unique set of difficulties. Clinimetrics is the science of measurement as related to the identification of a clinical disorder, the tracing of the progression of the condition under study, and calculation of its impact. The selection of appropriate measures for clinical studies of sensory-motor function must consider validity, sensitivity, specificity, responsiveness, reliability, and feasibility. Reasonable measures of motor function in clinical research include manual examination of muscle strength, electrophysiology, functional scales, patient-reported outcomes (e.g., quality of life), and for severe conditions such as ALS, survival. The assessment of sensory function includes targeted electrophysiology and QOL, as well as more focused measures such as quantitative sensory testing and the scoring of positive symptoms. Each individual measure and each combination of endpoints has its strengths and limitations.