RESUMEN
INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.
Asunto(s)
Ácidos Aminoisobutíricos/uso terapéutico , Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Ciclopropanos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Lactamas Macrocíclicas/uso terapéutico , Leucina/análogos & derivados , Cumplimiento de la Medicación , Prolina/análogos & derivados , Pirrolidinas/uso terapéutico , Quinoxalinas/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Femenino , Humanos , Leucina/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/uso terapéutico , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Background/Aims: Glecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection. Methods: The study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments. Results: The analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12: one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%). Conclusions: G/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.
Asunto(s)
Hepatitis C Crónica , Ácidos Aminoisobutíricos , Antivirales/efectos adversos , Bencimidazoles , Ensayos Clínicos Fase III como Asunto , Ciclopropanos , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas , República de Corea , Sulfonamidas , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Glecaprevir/pibrentasvir is approved for treating adults infected with HCV genotypes 1-6. In clinical trials, glecaprevir/pibrentasvir was associated with high rates of sustained virologic response at post-treatment week 12 (SVR12) and was well tolerated. A systematic review and meta-analysis of the real-world effectiveness and safety of glecaprevir/pibrentasvir were undertaken. METHODS: Real-world studies reporting SVR12 in adults with HCV infection (n ≥20) treated with glecaprevir/pibrentasvir were identified in journal publications from January 1, 2017, to February 25, 2019, and congress presentations through April 14, 2019. Random-effects meta-analysis was used to determine SVR12 rates using data from ≥2 cohorts; intention-to-treat (ITT) analyses included patients treated with glecaprevir/pibrentasvir who had SVR12 data available, discontinued early, or were lost to follow-up; modified ITT (mITT) analyses excluded those with non-virologic failure. Naïve pooling was used to calculate adverse event (AE) rates. RESULTS: Overall, 12,531 adults were treated with glecaprevir/pibrentasvir (18 cohorts). Of patients with post-treatment week 12 data, SVR12 rates were 96.7% (95% CI 95.4-98.1) in the ITT population (n = 8,583, 15 cohorts) and 98.1% (95% CI 97.1-99.2) in the mITT population (n = 7,001, 14 cohorts). SVR12 rates were ≥95% across subgroups (HCV genotype, cirrhosis status, treatment history, treatment duration, on-label treatment, and subgroups of interest). AEs were reported in 17.7% (1,271/7,199) of patients (8 cohorts). Serious AEs were reported in 1.0% (55/5,522) of patients (6 cohorts). The most frequent AEs were pruritus, fatigue, and headache. AE-related treatment discontinuations were reported in 0.6% (33/5,595) of patients (6 cohorts). CONCLUSIONS: Consistent with clinical trials, real-world evidence indicates that glecaprevir/pibrentasvir is a well-tolerated and highly effective pangenotypic treatment for a broad range of HCV-infected patients. LAY SUMMARY: It is important to assess treatments for hepatitis C virus (HCV) in the real world, as patient populations tend to be more diverse and potentially less adherent to treatment compared to those in clinical trials. Results from 18 studies performed in real-world clinics were pooled and analyzed to investigate the effectiveness and safety of a direct-acting antiviral combination (glecaprevir/pibrentasvir) in routine clinical practice. This analysis showed that glecaprevir/pibrentasvir is highly effective and well tolerated across all HCV genotypes and patient groups studied. It also showed that results seen in the real world are similar to the results seen in clinical trials, even in patients historically considered more challenging to treat.
Asunto(s)
Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/efectos adversos , Quinoxalinas/efectos adversos , Sulfonamidas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Combinación de Medicamentos , Fatiga/inducido químicamente , Fatiga/etiología , Femenino , Cefalea/inducido químicamente , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Prurito/inducido químicamente , Respuesta Virológica Sostenida , Adulto JovenRESUMEN
Although direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection are highly efficacious and safe, treatment initiation is often limited in patients with neuropsychiatric disorders due to concerns over reduced treatment adherence and drug-drug interactions. Here, we report adherence, efficacy, safety and patient-reported outcomes (PROs) from an integrated analysis of registrational studies using the pangenotypic DAA regimen of glecaprevir and pibrentasvir (G/P). Patients with chronic HCV genotypes 1-6 infection with compensated liver disease (with or without cirrhosis) receiving G/P for 8, 12 or 16 weeks were included in this analysis. Patients were classified as having a psychiatric disorder based on medical history and/or co-medications. Primary analyses assessed treatment adherence, efficacy (sustained virologic response at post-treatment week 12; SVR12), safety and PROs. Among 2522 patients receiving G/P, 789 (31%) had a psychiatric disorder with the most common diagnoses being depression (64%; 506/789) and anxiety disorders (27%; 216/789). Treatment adherence was comparably high (>95%) in patients with and without psychiatric disorders. SVR12 rates were 97.3% (768/789; 95% CI = 96.2-98.5) and 97.5% (1689/1733; 95% CI = 96.7-98.2) in patients with and without psychiatric disorders, respectively. Among patients with psychiatric disorders, SVR12 rates remained >96% by individual psychiatric diagnoses and co-medication classes. Overall, most adverse events (AEs) were mild-to-moderate in severity with serious AEs and AEs leading to G/P discontinuation occurring at similarly low rates in both patient populations. In conclusion, G/P treatment was highly efficacious, well-tolerated and demonstrated high adherence rates in patients with chronic HCV infection and psychiatric disorders.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Quinoxalinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Aminoisobutíricos , Antidepresivos/uso terapéutico , Ciclopropanos , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Masculino , Trastornos Mentales/complicaciones , Persona de Mediana Edad , Prolina/análogos & derivados , Pirrolidinas , Respuesta Virológica Sostenida , Cumplimiento y Adherencia al Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Chronic hepatitis C virus (HCV) infection with genotypes (GT) 1 and 2 accounts for over 50% of HCV infections globally, including over 97% of all HCV infections in Japan. Here, we report an integrated analysis of efficacy and safety of 8-week treatment with the all-oral, fixed-dose combination of the direct acting antivirals (DAA), glecaprevir and pibrentasvir (G/P), in DAA-naïve Japanese and overseas patients without cirrhosis and with HCV GT1 or GT2 infection. METHODS: Data from 899 DAA-naïve patients without cirrhosis and with HCV GT1 or GT2 infection treated with G/P (300/120 mg) for 8 weeks in the six Phase 2 or 3 overseas or Japan-only clinical trials were included. All patients who received ≥ 1 dose of G/P were included in an intent-to-treat (ITT) analysis. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and safety of the 8-week regimen in the ITT population. RESULTS: Overall, SVR12 was achieved by 98.9% (889/899) of DAA-naïve patients without cirrhosis, including 99.2% (597/602) of GT1-infected and 98.3% (292/297) of GT2-infected patients. Less than 1% (2/899) of patients overall and no Japanese patients experienced virologic failure. SVR12 rate was > 97% for patients regardless of baseline characteristics, and common comorbidities or co-medications. Overall, < 1% (2/899) discontinued G/P due to an adverse event (AE) and 1.6% (14/899) of patients experienced a serious AE. CONCLUSIONS: 8-week G/P treatment is safe and efficacious in DAA-naive patients without cirrhosis and with HCV GT1 or GT2 infection, demonstrating high SVR12 rates regardless of baseline patient and disease characteristics. CLINICALTRIALS. GOV IDENTIFIERS: The trials discussed in this paper were registered with ClinicalTrials.gov as follows: NCT02707952 (CERTAIN-1), NCT02723084 (CERTAIN-2), NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02738138 (EXPEDITION-2).
Asunto(s)
Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Combinación de Medicamentos , Femenino , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Japón , Masculino , Persona de Mediana Edad , Pirrolidinas/efectos adversos , Quinoxalinas/efectos adversos , Estudios Retrospectivos , Sulfonamidas/efectos adversos , Respuesta Virológica Sostenida , Adulto JovenRESUMEN
Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment-naïve or -experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post-treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off-label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow-up data at post-treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2-96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b-infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro-esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post-baseline Grade 3-4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real-world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real-world setting.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/uso terapéutico , Carbamatos/uso terapéutico , Ciclopropanos , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/epidemiología , Humanos , Internacionalidad , Lactamas Macrocíclicas , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Estudios Prospectivos , Ribavirina/uso terapéutico , Ritonavir/uso terapéutico , Sulfonamidas/uso terapéutico , Respuesta Virológica Sostenida , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Valina , Adulto JovenRESUMEN
The spinal cord demonstrates several forms of plasticity that resemble brain-dependent learning and memory. Among the most studied form of spinal plasticity is spinal memory for noxious (nociceptive) stimulation. Numerous papers have described central pain as a spinally-stored memory that enhances future responses to cutaneous stimulation. This phenomenon, known as central sensitization, has broad relevance to a range of pathological conditions. Work from the spinal cord injury (SCI) field indicates that the lumbar spinal cord demonstrates several other forms of plasticity, including formal learning and memory. After complete thoracic SCI, the lumbar spinal cord can be trained by delivering stimulation to the hindleg when the leg is extended. In the presence of this response-contingent stimulation the spinal cord rapidly learns to hold the leg in a flexed position, a centrally mediated effect that meets the formal criteria for instrumental (response-outcome) learning. Instrumental flexion training produces a central change in spinal plasticity that enables future spinal learning on both the ipsilateral and contralateral leg. However, if stimulation is given in a response-independent manner, the spinal cord develops central maladaptive plasticity that undermines future spinal learning on both legs. The present paper tests for interactions between spinal cord training and central nociceptive sensitization after complete spinal cord transection. We found that spinal training alters future central sensitization by intradermal formalin (24 h post-training). Conversely intradermal formalin impaired future spinal learning (24 h post-injection). Because formalin-induced central sensitization has been shown to involve NMDA receptor activation, we tested whether pre-treatment with NMDA would also affect spinal learning in manner similar to formalin. We found intrathecal NMDA impaired learning in a dose-dependent fashion, and that this effect endures for at least 24 h. These data provide strong evidence for an opposing relationship between nociceptive plasticity and use-dependent learning in the spinal cord. The present work has clinical implications given recent findings that adaptive spinal training improves recovery in humans with SCI. Nociception below the SCI may undermine this rehabilitation potential.
RESUMEN
Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity-dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI.
RESUMEN
How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain.
RESUMEN
Chronic central neuropathic pain after central nervous system injuries remains refractory to therapeutic interventions. A novel approach would be to target key intracellular signaling proteins that are known to contribute to continued activation by phosphorylation of kinases, transcription factors, and/or receptors that contribute to changes in membrane excitability. We demonstrate that one signaling kinase, calcium/calmodulin-dependent kinase II (CaMKII), is critical in maintaining aberrant dorsal horn neuron hyperexcitability in the neuropathic pain condition after spinal cord injury (SCI). After contusion SCI at spinal level T10, activated CaMKII (phosphorylated, pCaMKII) expression is significantly upregulated in the T7/8 spinal dorsal horn in neurons, but not glial cells, and in oligodendrocytes in the dorsal column in the same rats that displayed at-level mechanical allodynia. Furthermore, identified spinothalamic neurons demonstrated significant increases of pCaMKII after SCI compared to sham-treated control animals. However, neither astrocytes nor microglia showed pCaMKII expression in either sham-treated or SCI rats. To demonstrate causality, treatment of SCI rats with KN-93, which prevents CaMKII activation, significantly attenuated at-level mechanical allodynia and aberrant wide dynamic range neuronal activity evoked by brush, pressure, and pinch stimuli and a graded series of von Frey stimuli, respectively. Persistent CaMKII activation contributes to chronic central neuropathic pain by mechanisms that involve maintained hyperexcitability of wide dynamic range dorsal horn neurons. Furthermore, targeting key signaling proteins is a novel, useful therapeutic strategy for treating chronic central neuropathic pain.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Neuralgia/enzimología , Neuralgia/etiología , Traumatismos de la Médula Espinal/complicaciones , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Antígeno CD11b/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Masculino , Dimensión del Dolor , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/fisiología , Ratas , Ratas Sprague-Dawley , Médula Espinal/patología , Estilbamidinas , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Factores de TiempoRESUMEN
Effective treatments for patients suffering from chronic pain remain an area of intense focus within the pharmaceutical industry, as the development of novel therapies would help to treat an area of significant unmet medical need. The successful development of pharmacological agents to treat inflammatory and neuropathic pain conditions relies on a thorough understanding of the mechanisms that underlie the development and maintenance of chronic pain states. The goal of this review is to highlight recent discoveries regarding the intracellular signaling mechanisms that appear to play a critical role in persistent inflammatory and neuropathic pain. The review will focus on the mitogen activated protein kinase family of enzymes and the data suggesting that treatments designed to inhibit the activation of these enzymes may lead to significant advancements in the treatment of chronic pain. The review will also highlight the important interplay between neurons and non-neuronal cells (i.e., microglia and astrocytes) within the dorsal horn of the spinal cord in the generation and maintenance of chronic inflammatory and neuropathic pain.
Asunto(s)
Dolor Crónico/enzimología , Sistema de Señalización de MAP Quinasas/fisiología , Microglía/enzimología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuronas/enzimología , Animales , Neuropatías Diabéticas/enzimología , Humanos , Osteoartritis/enzimologíaRESUMEN
Not all spinal contusions result in mechanical allodynia, in which non-noxious stimuli become noxious. The studies presented use the NYU impactor at 12.5 mm drop or the Infinite Horizons Impactor (150 kdyn, 1 s dwell) devices to model spinal cord injury (SCI). Both of these devices and injury parameters, if done correctly, will result in animals with above level (forelimb), at level (trunk) and below level (hindlimb) mechanical allodynia that model the changes in evoked somatosensation experienced by the majority of people with SCI. The sections are as follows: 1) Mechanisms of remote microglial activation and pain signaling in "below-level" central pain 2) Intracellular signaling mechanisms in central sensitization in "at-level" pain 3) Peripheral sensitization contributes to "above level" injury pain following spinal cord injury and 4) Role of reactive oxygen species in central sensitization in regional neuropathic pain following SCI. To summarize, differential regional mechanisms contribute to the regional chronic pain states. We propose the importance of understanding the mechanisms in the differential regional pain syndromes after SCI in the chronic condition. Targeting regional mechanisms will be of enormous benefit to the SCI population that suffer chronic pain, and will contribute to better treatment strategies for other chronic pain syndromes.
Asunto(s)
Hiperalgesia/fisiopatología , Dolor Intratable/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/fisiopatología , Quimiocina CCL21/metabolismo , Gliosis/etiología , Gliosis/fisiopatología , Hiperalgesia/etiología , Inflamación/etiología , Inflamación/fisiopatología , Microglía/metabolismo , Estrés Oxidativo/fisiología , Dolor Intratable/etiología , Especies Reactivas de Oxígeno/metabolismo , Traumatismos de la Médula Espinal/complicacionesRESUMEN
BACKGROUND: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain. RESULTS: The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain. CONCLUSION: Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.
Asunto(s)
Acetanilidas/farmacología , Analgésicos/farmacología , Canales de Calcio/fisiología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/fisiología , Neuralgia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Purinas/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Ancirinas , Línea Celular , Modelos Animales de Enfermedad , Humanos , Inflamación , Masculino , Neuralgia/etiología , Neuralgia/patología , Dolor/etiología , Dolor/patología , Ratas , Ratas Sprague-Dawley , Canal Catiónico TRPA1 , Canales Catiónicos TRPCRESUMEN
Recent work regarding chronic central neuropathic pain (CNP) following spinal cord injury (SCI) suggests that activation of key signaling molecules such as members of the mitogen activated protein kinase (MAPK) family play a role in the expression of at-level mechanical allodynia. Previously, we have shown that the development of at-level CNP following moderate spinal cord injury is correlated with increased expression of the activated (and thus phosphorylated) forms of the MAPKs extracellular signal related kinase and p38 MAPK. The current study extends this work by directly examining the role of p38 MAPK in the maintenance of at-level CNP following spinal cord injury. Using a combination of behavioral, immunocytochemical, and electrophysiological measures we demonstrate that increased activation of p38 MAPK occurs in the spinal cord just rostral to the site of injury in rats that develop at-level mechanical allodynia after moderate SCI. Immunocytochemical analyses indicate that the increases in p38 MAPK activation occurred in astrocytes, microglia, and dorsal horn neurons in the spinal cord rostral to the site of injury. Inhibiting the enzymatic activity of p38 MAPK dose dependently reverses the behavioral expression of at-level mechanical allodynia and also decreases the hyperexcitability seen in thoracic dorsal horn neurons after moderate SCI. Taken together, these novel data are the first to demonstrate causality that increased activation of p38 MAPK in multiple cell types play an important role in the maintenance of at-level CNP following spinal cord injury.
Asunto(s)
Neuralgia/enzimología , Traumatismos de la Médula Espinal/enzimología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Enfermedades del Sistema Nervioso Central/enzimología , Enfermedades del Sistema Nervioso Central/etiología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Imidazoles/farmacología , Masculino , Neuralgia/etiología , Dolor/enzimología , Dolor/etiología , Dimensión del Dolor/métodos , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/complicaciones , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
In this study, we evaluated whether propentofylline, a methylxanthine derivative, modulates spinal glial activation and GABAergic inhibitory tone by modulation of glutamic acid decarboxylase (GAD)(65), the GABA synthase enzyme, in the spinal dorsal horn following spinal cord injury (SCI). Sprague-Dawley rats (225-250 g) were given a unilateral spinal transverse injury, from dorsal to ventral, at the T13 spinal segment. Unilateral spinal injured rats developed robust bilateral hindlimb mechanical allodynia and hyperexcitability of spinal wide dynamic range (WDR) neurons in the lumbar enlargement (L4-L5) compared to sham controls, which was attenuated by intrathecal (i.t.) administration of GABA, dose-dependently (0.01, 0.1, 0.5 microg). Western blotting and immunohistochemical data demonstrated that the expression level of GAD(65) protein significantly decreased on both sides of the lumbar dorsal horn (L4/5) after SCI (p<0.05). In addition, astrocytes and microglia showed soma hypertrophy as determined by increased soma area and increased GFAP and CD11b on both sides of the lumbar dorsal horn compared to sham controls, respectively (p<0.05). Intrathecal treatment with propentofylline (PPF 10 mM) significantly attenuated the astrocytic and microglial soma hypertrophy and mechanical allodynia (p<0.05). Additionally, the Western blotting and immunohistochemistry data demonstrated that i.t. treatment of PPF significantly prevented the decrease of GAD(65) expression in both sides of the lumbar dorsal horn following SCI (p<0.05). In conclusion, our present data demonstrate that propentofylline modulates glia activation and GABAergic inhibitory tone by modulation of GAD(65) protein expression following spinal cord injury.
Asunto(s)
Neuroglía/metabolismo , Dolor/prevención & control , Traumatismos de la Médula Espinal/prevención & control , Xantinas/uso terapéutico , Ácido gamma-Aminobutírico/fisiología , Animales , Masculino , Neuroglía/efectos de los fármacos , Dolor/complicaciones , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/metabolismo , Factores de Tiempo , Xantinas/farmacologíaRESUMEN
Spinal cord fMRI is a useful tool for studying spinal mechanisms of pain, hence for analgesic drug development. Its technical feasibility in both humans and rats has been demonstrated. This study investigates the reproducibility, robustness, and spatial accuracy of fMRI of lumbar spinal cord activation due to transcutaneous noxious and non-noxious electrical stimulation of the hindpaw in alpha-chloralose-anesthetized rats. Blood oxygenation level-dependent (BOLD) and blood volume-weighted fMRI data were acquired without and with intravenous injection of ultra small superparamagnetic iron oxide particles (USPIO), respectively, using a gradient echo (GE) echo planar imaging (EPI) technique at 4.7 T. Neuronal activation in the spinal cord induced by noxious stimulation to the hindpaw (2 ms wide, 5 mA amplitude, known to activate C-fibers) can be robustly detected by both fMRI techniques with excellent reproducibility and peaked at the stimulus frequency of 40 Hz. However, both fMRI techniques were not sensitive to neuronal activation in spinal cord induced by non-noxious stimulation (0.3 ms, 1.5 mA, known only to activate A-fibers). Spatially, the fMRI signal extended approximately 5 mm in the longitudinal direction, covering L(3)-L(5) segments. In the cross-sectional direction, the highest signal change of blood volume-weighted fMRI was in the middle of the ipsilateral dorsal horn, which roughly corresponds to laminae V and VI, while the highest signal change of BOLD fMRI was in the ipsilateral dorsal surface. This study demonstrates that spinal cord fMRI can be performed in anesthetized rats reliably and reproducibly offering it as a potential tool for analgesic drug discovery.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Oxígeno/sangre , Dolor/patología , Médula Espinal/patología , Animales , Medios de Contraste , Interpretación Estadística de Datos , Imagen Eco-Planar , Estimulación Eléctrica , Compuestos Férricos , Pie , Miembro Posterior , Magnetismo , Masculino , Ratas , Ratas WistarRESUMEN
The effect of two chronic motor training paradigms on the ability of the lumbar spinal cord to perform an acute instrumental learning task was examined in neonatally (postnatal day 5; P5) spinal cord transected (i.e., spinal) rats. At approximately P30, rats began either unipedal hindlimb stand training (Stand-Tr; 20-25min/day, 5days/week), or bipedal hindlimb step training (Step-Tr; 20min/day; 5days/week) for 7 weeks. Non-trained spinal rats (Non-Tr) served as controls. After 7 weeks all groups were tested on the flexor-biased instrumental learning paradigm. We hypothesized that (1) Step-Tr rats would exhibit an increased capacity to learn the flexor-biased task relative to Non-Tr subjects, as locomotion involves repetitive training of the tibialis anterior (TA), the ankle flexor whose activation is important for successful instrumental learning, and (2) Stand-Tr rats would exhibit a deficit in acute motor learning, as unipedal training activates the ipsilateral ankle extensors, but not flexors. Results showed no differences in acute learning potential between Non-Tr and Step-Tr rats, while the Stand-Tr group showed a reduced capacity to learn the acute task. Further investigation of the Stand-Tr group showed that, while both the ipsilateral and contralateral hindlimbs were significantly impaired in their acute learning potential, the contralateral, untrained hindlimbs exhibited significantly greater learning deficits. These results suggest that different types of chronic peripheral input may have a significant impact on the ability to learn a novel motor task, and demonstrate the potential for experience-dependent plasticity in the spinal cord in the absence of supraspinal connectivity.
Asunto(s)
Condicionamiento Operante/fisiología , Terapia por Ejercicio/métodos , Destreza Motora/fisiología , Plasticidad Neuronal/fisiología , Traumatismos de la Médula Espinal/rehabilitación , Análisis de Varianza , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Vértebras Lumbares , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/patología , Vértebras TorácicasRESUMEN
Although recovery from spinal cord injury is generally meager, evidence suggests that step training can improve stepping performance, particularly after neonatal spinal injury. The location and nature of the changes in neural substrates underlying the behavioral improvements are not well understood. We examined the kinematics of stepping performance and cellular and synaptic electrophysiological parameters in ankle extensor motoneurons in nontrained and treadmill-trained rats, all receiving a complete spinal transection as neonates. For comparison, electrophysiological experiments included animals injured as young adults, which are far less responsive to training. Recovery of treadmill stepping was associated with significant changes in the cellular properties of motoneurons and their synaptic input from spinal white matter [ipsilateral ventrolateral funiculus (VLF)] and muscle spindle afferents. A strong correlation was found between the effectiveness of step training and the amplitude of both the action potential afterhyperpolarization and synaptic inputs to motoneurons (from peripheral nerve and VLF). These changes were absent if step training was unsuccessful, but other spinal projections, apparently inhibitory to step training, became evident. Greater plasticity of axonal projections after neonatal than after adult injury was suggested by anatomical demonstration of denser VLF projections to hindlimb motoneurons after neonatal injury. This finding confirmed electrophysiological measurements and provides a possible mechanism underlying the greater training susceptibility of animals injured as neonates. Thus, we have demonstrated an "age-at-injury"-related difference that may influence training effectiveness, that successful treadmill step training can alter electrophysiological parameters in the transected spinal cord, and that activation of different pathways may prevent functional improvement.
Asunto(s)
Actividad Motora , Neuronas Motoras , Plasticidad Neuronal , Traumatismos de la Médula Espinal/fisiopatología , Transmisión Sináptica , Animales , Animales Recién Nacidos , Fenómenos Biomecánicos , Femenino , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción , Vértebras TorácicasRESUMEN
Using spinally transected rats, research has shown that neurons within the L4-S2 spinal cord are sensitive to response-outcome (instrumental) relations. This learning depends on a form of N-methyl-D-aspartate (NMDA)-mediated plasticity. Instrumental training enables subsequent learning, and this effect has been linked to the expression of brain-derived neurotrophic factor. Rats given uncontrollable stimulation later exhibit impaired instrumental learning, and this deficit lasts up to 48 hr. The induction of the deficit can be blocked by prior training with controllable shock, the concurrent presentation of a tonic stimulus that induces antinociception, or pretreatment with an NMDA or gamma-aminobutyric acid-A antagonist. The expression of the deficit depends on a kappa opioid. Uncontrollable stimulation enhances mechanical reactivity (allodynia), and treatments that induce allodynia (e.g., inflammation) inhibit learning. In intact animals, descending serotonergic neurons exert a protective effect that blocks the adverse consequences of uncontrollable stimulation. Uncontrollable, but not controllable, stimulation impairs the recovery of function after a contusion injury.
Asunto(s)
Condicionamiento Operante/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/fisiología , Humanos , N-Metilaspartato/fisiología , Receptores de GABA/fisiología , Médula Espinal/citología , Traumatismos de la Médula Espinal/rehabilitaciónRESUMEN
Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated form of the transcription factor cyclic AMP responsive element binding protein (CREB) in spinal segments of dermatomes corresponding to permanent mechanical allodynia, a model of chronic central neuropathic pain (CNP; (Crown, E.D., Ye, Z., Johnson, K.M., Xu, G.Y., McAdoo, D.J., Westlund, K.N., Hulsebosch, C.E., 2005. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci. Lett. 384, 139-144)). Given that not all rats that receive moderate SCI develop CNP, the current study was designed to further analyze changes in persistent CREB activation and in the activation state of upstream intracellular signaling cascades (e.g., mitogen-activated protein kinases [MAPKs]) in populations of rats that receive SCI and weeks later develop CNP and rats that receive SCI but do not develop CNP. The results indicate that activated kinases such as pERK 1/2, p-p38 MAPK, but not pJNK, are upregulated in injured rats that develop CNP as compared to injured rats that fail to develop CNP. In addition, the current results replicated our previous finding that activated CREB is upregulated following SCI, however, only in SCI rats that developed CNP. Taken together, these results indicate that activation of intracellular signaling cascades traditionally associated with long-term potentiation and memory is associated with the expression of chronic CNP following SCI.