RESUMEN
INTRODUCTION: During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN. METHODS: CSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk. RESULTS: BMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05). CONCLUSION: Our study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.
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Astrocitos , Proteína Morfogenética Ósea 4 , Hiperalgesia , Microglía , Neuralgia Posherpética , Animales , Microglía/metabolismo , Astrocitos/metabolismo , Proteína Morfogenética Ósea 4/metabolismo , Masculino , Ratas , Humanos , Anciano , Neuralgia Posherpética/líquido cefalorraquídeo , Neuralgia Posherpética/metabolismo , Femenino , Hiperalgesia/metabolismo , Persona de Mediana Edad , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Proteínas Portadoras/metabolismoRESUMEN
Stattic, a commercial inhibitor of STAT3, can drive the development of neuropathic pain. Exploring the connection between Stattic and JAK1/STAT3 signaling may facilitate the understanding of neuropathic pain caused by postherpetic neuralgia (PHN). In the current study, as crucial regulators of inflammation, STAT3 and its associated JAK1/STAT3 pathway were found to be upregulated and activated in the L4-L6 dorsal root ganglion (DRG) of mice in response to resiniferatoxin (RTX)-induced PHN, while subcutaneous administration of Stattic was found to downregulate STAT3 expression and phosphorylation in a PHN model. Stattic administration further attenuated hypersensitivity to mechanical and thermal stimuli in PHN mice, and alleviated inflammation and cell death in the L4-L6 DRG of mice. Overexpression of STAT3 via microinjection of a lentiviral-STAT3 overexpression vector reversed the abnormal decrease of STAT3 at both the mRNA and protein levels in the L4-6 DRGs of PHN mice and significantly promoted hypersensitivity to mechanical stimuli in the mice. Collectively, we found that subcutaneous static administration alleviated RTX-induced neuropathic pain by deactivating JAK1/STAT3 in mice.
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Modelos Animales de Enfermedad , Ganglios Espinales , Neuralgia Posherpética , Factor de Transcripción STAT3 , Animales , Neuralgia Posherpética/metabolismo , Ratones , Factor de Transcripción STAT3/metabolismo , Ganglios Espinales/metabolismo , Masculino , Neuralgia/metabolismo , Inflamación/metabolismo , Janus Quinasa 1/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Ratones Endogámicos C57BL , Inyecciones Subcutáneas , Transducción de Señal , Óxidos S-Cíclicos , DiterpenosRESUMEN
Accumulating evidence strongly supports that PINK1 mutation can mediate mitochondrial autophagy dysfunction in dopaminergic neurons. This study was conducted to determine the role of PINK1 in the pathogenesis of postherpetic neuralgia (PHN) and find new targets for its treatment. A rigorous literature review was conducted to identify 2801 compounds from more than 200 plants in Asia. Virtual screening was used to shortlist the compounds into 20 groups based on their binding energies. MM/PBSA was used to further screen the compound dataset, and vitexin, luteoloside, and 2'-deoxyadenosine-5'-monophosphate were found to have a score of - 59.439, - 52.421, and - 47.544 kcal/mol, respectively. Pain behavioral quantification, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, western blotting, and transmission electron microscopy were used to confirm the effective mechanism. Vitexin had the most significant therapeutic effect on rats with PHN followed by luteoloside; 2'-deoxyadenosine-5'-monophosphate had no significant effect. Our findings suggested that vitexin could alleviate PHN by regulating mitochondrial autophagy through PINK1.
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Neuralgia Posherpética , Proteínas Quinasas , Animales , Masculino , Ratas , Apigenina/farmacología , Apigenina/uso terapéutico , Autofagia/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Simulación del Acoplamiento Molecular , Neuralgia Posherpética/tratamiento farmacológico , Neuralgia Posherpética/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteínas Quinasas/metabolismo , Ratas Sprague-DawleyRESUMEN
Postherpetic neuralgia (PHN) is a notorious neuropathic pain featuring persistent profound mechanical hyperalgesia with significant negative impact on patients' life quality. CDDO can regulate inflammatory response and programmed cell death. Its derivative also protects neurons from damages by modulating microglia activities. As a consequence of central and peripheral sensitization, applying neural blocks may benefit to minimize the risk of PHN. This study aimed to explore whether CDDO could generate analgesic action in a PHN-rats' model. The behavioural test was determined by calibrated forceps testing. The number of apoptotic neurons and degree of glial cell reaction were assessed by immunofluorescence assay. Activation of PKC-δ and the phosphorylation of Akt were measured by western blots. CDDO improved PHN by decreasing TRPV1-positive nociceptive neurons, the apoptotic neurons, and reversed glial cell reaction in adult rats. It also suppressed the enhanced PKC-δ and p-Akt signalling in the sciatic nerve, dorsal root ganglia (DRG) and spinal dorsal horn. Our research is the promising report demonstrating the analgesic and neuroprotective action of CDDO in a PHN-rat's model by regulating central and peripheral sensitization targeting TRPV1, PKC-δ and p-Akt. It also is the first study to elucidate the role of oligodendrocyte in PHN.
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Neuralgia Posherpética , Neuralgia , Ácido Oleanólico/análogos & derivados , Humanos , Adulto , Ratas , Animales , Neuralgia Posherpética/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neuralgia/metabolismo , Analgésicos , Ganglios Espinales/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.
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Herpesvirus Humano 1 , Proteínas de la Membrana , Neuralgia Posherpética , Nucleotidiltransferasas , Proteína-Arginina N-Metiltransferasas , Regulación hacia Arriba , Animales , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Neuralgia Posherpética/metabolismo , Neuralgia Posherpética/inmunología , Ratones Endogámicos C57BL , Inmunidad Innata , Humanos , Ratones Noqueados , Masculino , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Herpes Simple/inmunología , Microglía/metabolismo , Microglía/inmunología , Proteínas Serina-Treonina QuinasasRESUMEN
Botulinum toxin type A (BoNT/A) has exhibited efficacy in postherpetic neuralgia (PHN) treatment, and this study aims to uncover its underlying mechanisms. Resiniferatoxin (RTX)-induced PHN rats were given BoNT/A. Rat postoperative pain behaviors were assessed by Von Frey test. Cleaved-synaptosomal protein 25 kDa (cl-SNAP-25) or cathelicidin antimicrobial peptide (CAMP) expression in rat dorsal root ganglia (DRG) was detected by immunofluorescence or immunohistochemistry. Healthy rat-derived DRG neurons were transfected, incubated with lipopolysaccharides (LPS)/adenosine 5'-triphosphate (ATP) to stimulate pyroptosis and treated with BoNT/A. The CCK-8, Western blot, ELISA, and qRT-PCR were used to assess the viability, levels of pyroptosis-related proteins proinflammatory cytokine levels, as well as CAMP and ELANE mRNA levels. BoNT/A (30 U/kg) promoted cl-SNAP-25 expression in rat DRG and reversed RTX-induced decrease of rat paw withdrawal thresholds and CAMP expression and increase of pyroptosis-associated protein and inflammatory factor expression in rat DRG. CAMP interacted with ELANE in rat DRG neurons. BoNT/A attenuated LPS/ATP-stimulated inhibition of viability and CAMP expression and upregulation of inflammatory mediators, pyroptosis-related proteins, and ELANE expression in rat DRG neurons, which was counteracted by CAMP silencing. However, ELANE knockdown offset the effect of CAMP silencing in LPS/ATP/BoNT/A-treated rat DRG neurons. On the whole, BoNT/A alleviates rat DRG neuron pyroptosis during PHN by upregulating CAMP to inhibit ELANE.
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Toxinas Botulínicas Tipo A , Neuralgia Posherpética , Ratas , Animales , Toxinas Botulínicas Tipo A/farmacología , Toxinas Botulínicas Tipo A/metabolismo , Neuralgia Posherpética/metabolismo , Catelicidinas/metabolismo , Catelicidinas/farmacología , Elastasa de Leucocito/metabolismo , Elastasa de Leucocito/farmacología , Ganglios Espinales/metabolismo , Lipopolisacáridos/farmacología , Piroptosis , Neuronas , Adenosina Trifosfato/metabolismoRESUMEN
Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. The present study investigated the P2X7 receptor antagonist brilliant blue G (BBG) whether inhibits endoplasmic reticulum stress and pyroptosis (a necrotic form of cell death) and alleviates PHN. Varicella zoster virus (VZV)-infected CV-1 cells were used to induce PHN model. Mechanical paw withdrawal thresholds were measured using an ascending series of von Frey filaments. Immunohistochemistry was used to detect the expression of P2X7R in nerve tissues. Western blot was used to determine the expression of endoplasmic reticulum (ER) stress and pyroptosis-related molecules. The expression of IL-1ß and IL-18 in tissue homogenate was detected by ELISA. The PHN rat has the lower paw withdrawal threshold, but higher expression of P2X7 in nerve tissues. And, endoplasmic reticulum stress was activated and pyroptosis was increased in PHN rats. BBG can decrease pain thresholds and reduce ER stress and pyroptosis in PHN rats. In addition, ER stress activator tunicamycin (TM) can reverse the effect of BBG on the paw withdrawal thresholds, endoplasmic reticulum stress, and pyroptosis. Therefore, P2X7 receptor antagonist BBG alleviates PHN by activating ER stress and reducing pyroptosis.
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Estrés del Retículo Endoplásmico , Herpes Zóster/complicaciones , Neuralgia Posherpética/prevención & control , Antagonistas del Receptor Purinérgico P2X/farmacología , Piroptosis , Receptores Purinérgicos P2X7/química , Colorantes de Rosanilina/farmacología , Animales , Herpes Zóster/virología , Herpesvirus Humano 3/patogenicidad , Indicadores y Reactivos/farmacología , Neuralgia Posherpética/metabolismo , Neuralgia Posherpética/patología , Neuralgia Posherpética/virología , Ratas , Ratas WistarRESUMEN
BACKGROUND: Postherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs). METHODS: Resiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells. RESULTS: RTX injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level, and enhanced IL-6, IL-1ß, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection. CONCLUSION: These findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.
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Canales Iónicos Sensibles al Ácido/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diterpenos/farmacología , Ganglios Espinales/efectos de los fármacos , Neuralgia Posherpética/metabolismo , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Ganglios Espinales/metabolismo , Hiperalgesia , Masculino , Neuralgia Posherpética/patología , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
OBJECTIVES: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster, but the mechanism of PHN is still unclear. Activation of spinal astrocytes is involved in PHN. Our study aims to explore whether lncRNA KCNA2 antisense RNA (KCNA2-AS) regulates spinal astrocytes in PHN through signal transducers and activators of transcription 3 (STAT3). METHODS: Varicella zoster virus (VZV)-infected CV-1 cells were injected into rats to construct a PHN model. Primary spinal cord astrocytes were activated using S-Nitrosoglutathione (GSNO). Glial fibrillary acidic protein (GFAP; marker of astrocyte activation), phosphorylated STAT3 (pSTAT3), and KCNA2-AS were analyzed by immunofluorescence and RNA fluorescence in situ hybridization. RNA pull-down and RNA immunoprecipitation were used to detect binding of KCNA2-AS to pSTAT3. RESULTS: KCNA2-AS was highly expressed in the spinal cord tissue of PHN model rats, and was positively correlated with GFAP expression. GFAP was significantly increased in GSNO-induced cells, but the knockdown of KCNA2-AS reversed this result. Meanwhile, pSTAT3 was significantly increased in GSNO-induced cells, but knockdown of KCNA2-AS reduced pSTAT3 within the nucleus while the total pSTAT3 did not change significantly. pSTAT3 bound to KCNA2-AS and this binding increased with GSNO treatment. Furthermore, knockdown of KCNA2-AS in PHN model rats relieved mechanical allodynia. CONCLUSION: Down-regulation of KCNA2-AS alleviates PHN partly by reducing the translocation of pSTAT3 cytoplasm to the nucleus and then inhibiting the activation of spinal astrocytes.
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Astrocitos/metabolismo , Canal de Potasio Kv.1.2/genética , Neuralgia Posherpética/genética , Neuralgia Posherpética/metabolismo , ARN Largo no Codificante , Factor de Transcripción STAT3/metabolismo , Médula Espinal/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Óxido Nítrico/metabolismo , Interferencia de ARN , Ratas , Médula Espinal/fisiologíaRESUMEN
Varicella zoster virus (VZV) results in chicken pox and herpes zoster. Female rats show a higher level of herpes zoster associated pain than males, consistent with human studies. In this study, we addressed the novel hypothesis that sex difference in herpes zoster associated pain is due, in part, to estradiol modulating activity in the thalamus. To test this hypothesis a high and low physiological dose of estradiol was administered to castrated and ovariectomized rats and the affective pain response was measured after injection of VZV into the whisker pad. Thalamic infusion of the estrogen receptor antagonist ICI 182,780 concomitant with a high dose of estradiol addressed the role of estradiol binding to its receptor to effect pain. Phosphorylated extracellular signal-regulated protein kinase (pERK) positive cells were measured in excitatory (glutaminase positive) and inhibitory (glutamate decarboxylase 67 positive) cells of the lateral thalamic region. Our results show that a high dose of estradiol significantly reduced the pain response in both males and females. pERK significantly increased in excitatory cells after treatment with a low dose of estradiol and increased in inhibitory cells after treatment with a high dose of estradiol. Administration of ICI 182,780 significantly increased the pain response, reduced expression of GABA related genes in the thalamic region and significantly reduced the number of inhibitory cells expressing pERK. The results suggest that estradiol attenuates herpes zoster pain by increasing the activity of inhibitory neurons within the thalamus and that this reduction includes an estrogen receptor dependent mechanism.
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Estradiol/uso terapéutico , Núcleos Talámicos Laterales/efectos de los fármacos , Neuralgia Posherpética/tratamiento farmacológico , Dolor/tratamiento farmacológico , Infección por el Virus de la Varicela-Zóster/complicaciones , Animales , Estradiol/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Fulvestrant/farmacología , Herpesvirus Humano 3 , Núcleos Talámicos Laterales/metabolismo , Masculino , Ratones , Neuralgia Posherpética/metabolismo , Dolor/etiología , Dolor/metabolismo , FosforilaciónRESUMEN
Herpes zoster (HZ) is an infectious dermatosis with high incidence worldwide. Age is a key risk factor for HZ, and postherpetic neuralgia (PHN) is the main sequelae. Until now, no index has been available to predict the pathogenesis of PHN, and rare reports have focused on the immune response during aging and PHN. In this study, we selected immunoglobulin and complement proteins as markers for humoral immunity, while T lymphocyte subsets and natural killer (NK) cells were selected as markers for cell immunity, to systematically study the characteristics of immune responses in the peripheral blood of HZ patients. Our data showed that the absolute number of CD3+ T cells and CD8+ T cells decreased during aging and PHN. This implies that more attention should be paid to prevent the occurrence of PHN, especially in the aged population.
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Envejecimiento/inmunología , Complejo CD3/inmunología , Linfocitos T CD8-positivos/inmunología , Herpes Zóster/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Complejo CD3/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteínas del Sistema Complemento/metabolismo , Femenino , Herpes Zóster/sangre , Herpes Zóster/virología , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Humanos , Inmunoglobulinas/sangre , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neuralgia Posherpética/sangre , Neuralgia Posherpética/inmunología , Neuralgia Posherpética/metabolismo , Factores de Riesgo , Subgrupos de Linfocitos T/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Lidocaine 5% medicated plaster is the first lidocaine containing product for chronic use. As no previous investigations have been conducted to evaluate the population pharmacokinetics of long-term exposure to lidocaine 5% medicated plasters, further insights into the evaluation of the pharmacokinetic properties of lidocaine and its metabolites were needed for the assessment of its safety. METHODS: The population pharmacokinetic properties of lidocaine and its metabolites were evaluated after multiple applications of lidocaine 5% medicated plasters based on data collected for up to 14.5 months from two phase III clinical trials (up to 2.5 months in the first trial, and up to 12 months in a follow-up trial) in post-herpetic neuralgia patients. Modeling was performed using nonlinear mixed effects as implemented in NONMEM® (nonlinear mixed-effect modeling) v.5. A stepwise forward inclusion and backward elimination procedure were used for covariate model building. RESULTS: The model provides reliable estimates of the pharmacokinetic behavior of lidocaine after medicated plaster application. It was validated using simulations and showed adequate predictive properties. Apparent Clearance was estimated to be 48 L/h after application of two or fewer plasters, whereas its value increased to 67 L/h after application of three plasters. Model-based simulations predicted no accumulation of lidocaine or any of its metabolites after long-term exposure of three simultaneous plasters up to 1 year. The variability explained by adding covariates into the model for the long-term exposures of lidocaine following one plaster or three simultaneous plaster applications was found to be very small with respect to the overall between-subject variability. CONCLUSIONS: In conclusion, exposure to lidocaine after the application of the lidocaine medicated plaster was found to be primarily affected by the number of plasters simultaneously applied, i.e., it increased with the number of applied patches, but less than proportionally. No clinically relevant effect of other covariates was found to affect the exposure to lidocaine or its metabolites. As no accumulation was predicted by the model, long-term exposure to lidocaine and its metabolites is not expected to lead to any safety concerns in post-herpetic neuralgia patients.
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Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Lidocaína/administración & dosificación , Lidocaína/farmacocinética , Neuralgia Posherpética/tratamiento farmacológico , Neuralgia Posherpética/metabolismo , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Postherpetic neuralgia is spontaneous pain and allodynia that persist long after the disappearance of the cutaneous lesions caused by herpes zoster. Inoculation of mice with herpes simplex virus-1 causes herpes zoster-like skin lesions and herpetic and postherpetic pain. Although NMDA receptors have been suggested to be involved in postherpetic pain as in other types of neuropathic pain, the neural mechanism remains unclear. NMDA receptor NR2B subunit is the most tyrosine-phosphorylated protein in the brain, and Tyr1472 is the major phosphorylation site of this subunit. RESULTS: To elucidate the role of Tyr1472 phosphorylation of the NR2B subunit in herpetic and postherpetic allodynia, we inoculated herpes simplex virus-1 into the unilateral hind paw of knock-in mice with a mutation of Tyr1472 of the NR2B subunit to Phe (Y1472F-KI). On day 7 post-inoculation, acute herpetic allodynia was observed in more than 80% of the inoculated wild-type and Y1472F-KI mice. Y1472F-KI mice showed significantly reduced intensity and incidence of postherpetic allodynia on days 45-50 post-inoculation as compared with wild-type mice. The innervation in the skin at the postherpetic neuralgia phase was retained to a greater extent in the Y1472F-KI mice. The level of activating transcription factor-3 mRNA, a marker of axonal damage, increased much less in the dorsal root ganglia (DRGs) of Y1472F-KI mice than in those of wild-type mice; and the level of nerve growth factor mRNA significantly increased in wild-type mice, but not at all in Y1472F-KI mice on day 7 post-inoculation. Production of nerve growth factor was at the basal level in the skin of both groups of mice on day 50 post-inoculation. Nerve growth factor and glial cell-derived neurotrophic factor stimulated neurite outgrowth of cultured DRG neurons from Y1472F-KI mice, similarly or less so as they did the outgrowth of those from wild-type mice. Wild-type DRG neurons were more susceptible to glutamate neurotoxicity than Y1472F-KI ones. CONCLUSIONS: Taken together, the present data suggest that phosphorylation of the NR2B subunit at its Tyr1472 is involved in the development of postherpetic allodynia due to nerve damage and that the nerve damage at the acute herpetic phase is correlated with the incidence of postherpetic pain.
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Neuralgia Posherpética/metabolismo , Fosfotirosina/metabolismo , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Modelos Animales de Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Ganglios Espinales/virología , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Sustitución del Gen , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Herpes Simple/metabolismo , Herpes Simple/patología , Herpesvirus Humano 1/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Mutantes/metabolismo , N-Metilaspartato/farmacología , Neuralgia Posherpética/patología , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neurotoxinas/toxicidad , Fosforilación/efectos de los fármacos , Piel/inervación , Piel/patología , Relación Estructura-Actividad , Sustancia P/metabolismoRESUMEN
The article is devoted to modern views of the pathogenesis of postherpetic neuralgia, the risks of its occurrence in patients with herpetic ganglionitis and treatment in the acute period to prevent the development of chronic pain, as well as in the treatment of already developed postherpetic neuralgia with the use of glutamate receptors antagonists.
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Amantadina/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Herpes Zóster Ótico/rehabilitación , Neuralgia Posherpética/rehabilitación , Administración Oral , Amantadina/administración & dosificación , Esquema de Medicación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Herpes Zóster Ótico/metabolismo , Humanos , Inyecciones Intravenosas , Neuralgia Posherpética/metabolismoRESUMEN
INTRODUCTION: In early 2011, the FDA gave approval to a new preparation of gabapentin, licensed for the treatment of post-herpetic neuralgia (PHN). Gabapentin is commonly used worldwide for multiple indications, which include neuropathic pain. The new drug combines generic gabapentin with a polymeric delivery system allowing for extended release and is licensed to be given only as a once-daily dosing regimen. AREAS COVERED: The article aims to review the available evidence relating to the pharmacokinetics, tolerability and efficacy of extended-release gabapentin (GpER). It addresses the current state of the drug's progress through regulation and the intention of its manufacturer for the market. EXPERT OPINION: Although GpER has been approved by the FDA for once-daily use in PHN, there is a relative paucity of data for both its efficacy and the optimum dosing schedule (once or twice a day). There are no data directly comparing GpER with the immediate-release preparation or other first-line treatments for PHN. Therefore, the true status of GpER as a treatment option needs to be enhanced with additional experimental evidence for its efficacy and favourable side-effect profile.
Asunto(s)
Aminas/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Neuralgia Posherpética/tratamiento farmacológico , Ácido gamma-Aminobutírico/uso terapéutico , Aminas/farmacocinética , Analgésicos no Narcóticos/farmacocinética , Ácidos Ciclohexanocarboxílicos/farmacocinética , Preparaciones de Acción Retardada , Gabapentina , Humanos , Neuralgia Posherpética/metabolismo , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
AIM: Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters. METHODS: This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM. RESULTS: A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL(cr) ). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy. CONCLUSION: The developed model identified CL(cr) and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.
Asunto(s)
Analgésicos/farmacocinética , Neuropatías Diabéticas/metabolismo , Neuralgia Posherpética/metabolismo , Ácido gamma-Aminobutírico/análogos & derivados , Adulto , Anciano , Analgésicos/administración & dosificación , Ensayos Clínicos como Asunto , Humanos , Persona de Mediana Edad , Modelos Teóricos , Pregabalina , Adulto Joven , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
Varicella-zoster virus (VZV) is a ubiquitous human herpes virus typically acquired in childhood when it causes varicella (chickenpox), following which the virus establishes a latent infection in trigeminal and dorsal root ganglia that lasts for the life of the individual. VZV subsequently reactivates, spontaneously or after specific triggering factors, to cause herpes zoster (shingles), which may be complicated by postherpetic neuralgia and several other neurological complications including vasculopathy. Our understanding of VZV latency lags behind our knowledge of herpes simplex virus type 1 (HSV-1) latency primarily due to the difficulty in propagating the virus to high titers in a cell-free state, and the lack of a suitable small-animal model for studying virus latency and reactivation. It is now established beyond doubt that latent VZV is predominantly located in human ganglionic neurons. Virus gene transcription during latency is epigenetically regulated, and appears to be restricted to expression of at least six genes, with expression of gene 63 being the hallmark of latency. However, viral gene transcription may be more extensive than previously thought. There is also evidence for several VZV genes being expressed at the protein level, including VZV gene 63-encoded protein, but recent evidence suggests that this may not be a common event. The nature and extent of the chronic inflammatory response in latently infected ganglia is also of current interest. There remain several questions concerning the VZV latency process that still need to be resolved unambiguously and it is likely that this will require the use of newly developed molecular technologies, such as GeXPS multiplex polymerase chain reaction (PCR) for virus transcriptional analysis and ChIP-seq to study the epigenetic of latent virus genome ( Liu et al, 2010 , BMC Biol 8: 56).
Asunto(s)
Epigenómica , Ganglios Espinales/virología , Herpes Zóster/patología , Herpesvirus Humano 3/patogenicidad , Latencia del Virus/genética , Varicela/virología , ADN Viral/análisis , ADN Viral/genética , Ganglios Espinales/metabolismo , Regulación Viral de la Expresión Génica , Genes Virales , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/crecimiento & desarrollo , Humanos , Neuralgia Posherpética/metabolismo , Neuralgia Posherpética/virología , Neuronas/metabolismo , Neuronas/virología , Análisis de Secuencia de ADNRESUMEN
The electroporation mediated transdermal delivery (Protocol - 120 V, 10 ms, 30 pulses at 1 Hz with post pulse waiting period of 20 min) of doxepin using pure drug solution (PDS) and doxepin-hydroxypropyl-beta-cyclodextrin (HPCD) complex solution (CDS) was studied using porcine epidermis model. The stoichiometry of drug-HPCD inclusion complex was determined by differential scanning calorimetry (DSC). The amount of doxepin retained in the epidermis following electroporation did not differ significantly between PDS and CDS. When the drug loaded epidermis was subjected to "Release studies", doxepin release attained a plateau within approximately 2.5 days in case of PDS, whereas in case of CDS, doxepin release was prolonged up to 5 days. Mechanistic studies across the nonbiological barriers demonstrated that the slow dissociation of complex was responsible for sustained release of drug from the epidermis. Pharmacodynamic studies were carried out by electroporation mediated delivery of CDS and PDS in hairless rats. The analgesic effect of doxepin was prolonged in case of CDS as compared to PDS.