RESUMO
BACKGROUND: For chronic pain after thoracic surgery, optimal timing of its diagnosis and effective treatment remains unresolved, although several treatment options are currently available. We examined the efficacy and safety of mirogabalin, in combination with conventional pain therapy (nonsteroidal anti-inflammatory drugs and/or acetaminophen), for treating peripheral neuropathic pain (NeP) after thoracic surgery. METHODS: In this multicenter, randomized, open-label, parallel-group study, patients with peripheral NeP were randomly assigned 1:1 to mirogabalin as add-on to conventional therapy or conventional treatment alone. RESULTS: Of 131 patients of consent obtained, 128 were randomized (mirogabalin add-on group, 63 patients; conventional treatment group, 65 patients). The least squares mean changes (95% confidence interval [CI]) in Visual Analogue Scale (VAS) score for pain intensity at rest from baseline to Week 8 (primary endpoint) were - 51.3 (- 54.9, - 47.7) mm in the mirogabalin add-on group and - 47.7 (- 51.2, - 44.2) mm in the conventional group (between-group difference: - 3.6 [95% CI: - 8.7, 1.5], P = 0.161). However, in patients with Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) score (used for the screening of NeP) ≥ 12 at baseline, the greater the S-LANSS score at baseline, the greater the decrease in VAS score in the mirogabalin add-on group, while no such trend was observed in the conventional treatment group (post hoc analysis). This between-group difference in trends was statistically significant (interaction P value = 0.014). Chronic pain was recorded in 7.9% vs. 16.9% of patients (P = 0.171) at Week 12 in the mirogabalin add-on vs. conventional treatment groups, respectively. Regarding activities of daily living (ADL) and quality of life (QOL), changes in Pain Disability Assessment Scale score and the EQ-5D-5L index value from baseline to Week 8 showed significant improvement in the mirogabalin add-on group vs. conventional treatment group (P < 0.001). The most common adverse events (AEs) in the mirogabalin add-on group were dizziness (12.7%), somnolence (7.9%), and urticaria (3.2%). Most AEs were mild or moderate in severity. CONCLUSIONS: Addition of mirogabalin to conventional therapy did not result in significant improvement in pain intensity based on VAS scores, but did result in significant improvement in ADL and QOL in patients with peripheral NeP after thoracic surgery. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071200053 (registered 17/11/2020).
Assuntos
Compostos Bicíclicos com Pontes , Dor Crônica , Neuralgia , Cirurgia Torácica , Humanos , Qualidade de Vida , Atividades Cotidianas , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Resultado do TratamentoRESUMO
We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.
Assuntos
Modelos Animais de Doenças , Hiperalgesia , Neuralgia , Ratos Wistar , Nervos Espinhais , Tramadol , Animais , Tramadol/administração & dosagem , Tramadol/farmacologia , Masculino , Neuralgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Nervos Espinhais/efeitos dos fármacos , Ligadura/efeitos adversos , Quimioterapia Combinada , Relação Dose-Resposta a Droga , Ratos , Trânsito Gastrointestinal/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Compostos Bicíclicos com Pontes , PolissacarídeosRESUMO
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks' intervention on chemotherapy completion and CIPN severity. METHODS: Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events. RESULTS: Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), - 1.7 (- 2.4 to - 1.0) (p < 0.001). Patients with baseline NRS of ≥ 6 experienced a 44.0% reduction in score from baseline to week 12 (LOCF): mean change (95% CI), - 3.3 (- 5.0 to - 1.5) (p = 0.002). Chemotherapy was discontinued in 18 (34.6%) patients; CIPN led to discontinuation in only 2 (3.8%). There was no notable worsening of CIPN severity in terms of Common Terminology Criteria for Adverse Events grade or Modified Total Neuropathy Score-reduced, although use of pain medications during chemotherapy might cause worsening of CIPN due to underestimation of subjective symptoms. QOL score based on the EuroQol five-dimensional descriptive system did not worsen during the 12 weeks. Thirty-one percent of patients experienced adverse drug reactions, and the most common event was somnolence (13.5%). Serious adverse events and death occurred in 3 patients and 1 patient, respectively; however, they were unrelated to mirogabalin treatment. CONCLUSIONS: Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021).
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Doenças do Sistema Nervoso Periférico , Humanos , Antineoplásicos/efeitos adversos , Neoplasias Pulmonares/induzido quimicamente , Dor , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/terapia , Estudos Prospectivos , Qualidade de VidaRESUMO
Cimetidine at a clinical dosage decreased the renal clearance (CLr) of mirogabalin in humans by inhibition of renal secretion. Mirogabalin is a substrate of human OAT1/3, OCT2, MATE1 and/or MATE2-K. To clarify the mechanism behind the above interaction, it was investigated whether cimetidine inhibits the process of mirogabalin uptake at the basolateral side or the process of its efflux at the apical side in rat kidney in vivo.Cimetidine was administered to rats by a constant infusion to achieve an unbound plasma concentration of 7.0 µM and examine its effect on the renal disposition of [14C]metformin, [3H]p-aminohippuric acid (PAH), and [14C]mirogabalin.Cimetidine significantly induced the intrarenal accumulation of radioactivity (Kp, kidney) and decreased the renal clearance (CLr) of [14C]mirogabalin. These effects resulted in significantly decreased total clearance (CLt). Kp, kidney, and CLr of [14C]metformin, except CLt, were also affected, but no parameters of [3H]PAH were affected by cimetidine.These findings clarified that an unbound plasma concentration of cimetidine of 7.0 µM inhibited the apical efflux not the basolateral uptake of [14C]mirogabalin in rat kidney, suggesting that mirogabalin/cimetidine interaction was caused by inhibiting the apical efflux transporter, human MATE1 and/or MATE2-K, not the basolateral uptake transporter, human OCT2, in the kidney.
Assuntos
Cimetidina , Metformina , Ratos , Humanos , Animais , Cimetidina/farmacologia , Proteínas de Transporte de Cátions Orgânicos , Transportador 2 de Cátion Orgânico , Rim , Metformina/farmacologiaRESUMO
BACKGROUND: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. METHODS: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. RESULTS: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. CONCLUSIONS: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics.
Assuntos
Neuralgia , Nociceptividade , Camundongos , Humanos , Animais , Oxaliplatina/uso terapêutico , Estreptozocina , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Paclitaxel/farmacologia , Paclitaxel/uso terapêuticoRESUMO
The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys.Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study, and metabolite identification were also conducted after the oral administration of [14C]mirogabalin.Plasma exposure (Cmax and AUCinf) increased dose-proportionally after the oral administration of mirogabalin at 1, 3, and 10 mg/kg to rats and monkeys. Mean total body clearance (CLtot) after intravenous administration at 3 mg/kg was 13.5 mL/min/kg in rats and 9.02 mL/min/kg in monkeys, and absolute bioavailability at 3 mg/kg was 97.6% in rats and 85.2% in monkeys. There was a greater recovery of radioactivity in urine than that in faeces after the oral administration of [14C]mirogabalin. The main radioactive component in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), an oxidised metabolite of mirogabalin, mirogabalin N-glucuronide and O-glucuronide of oxidised A204-4455 were detected as minor components in monkeys and rats.Mirogabalin administered orally was almost completely eliminated via urinary excretion. A small part of the orally administered dose of mirogabalin was metabolised via glucuronidation at the amine and carboxylic acid moiety and oxidation as the primary metabolic pathway.
Assuntos
Compostos Bicíclicos com Pontes , Administração Oral , Animais , Haplorrinos , Ligantes , RatosRESUMO
Mirogabalin is a α2δ ligand as well as pregabalin. The aim of this study was to clarify whether mirogabalin is a substrate of human LAT1, which involved in absorption and disposition of pregabalin, and to investigate transporters involved in renal secretion and absorption of mirogabalin using transporter-expressing cells and fresh human kidney slices.We employed uptake assay of [3H]mirogabalin by HEK293T or HEK293 cells transiently overexpress human OAT1, OAT3, OCT2, LAT1/4F2hc, LAT2/4F2hc, PEPT1, and PEPT2 proteins. Transport assay of MDCKII cells transiently overexpress OCT2/MATE1, and OCT2/MATE2-K proteins was conducted. Contribution of transporters to renal secretion was investigated by uptake assay using human kidney slices.Uptake clearances of [3H]mirogabalin by OAT1-, OAT3-, OCT2-, PEPT1-, and PEPT2-expressing cells were higher than that by vector cells, but by LAT1/4F2hc and LAT2/4F2hc-expressing cells were not. In transport assay using OCT2/MATE1 and OCT2/MATE2-K cells, [3H]mirogabalin showed directional transport from basolateral to apical side. Contribution of OAT1, OAT3, and OCT2 was observed by uptake of [3H]mirogabalin into the kidney slices.These results indicate that mirogabalin is not a substrate of LAT1, but of PEPT1 and PEPT2 involved in absorption and of OAT1, OAT3, OCT2, MATE1 and/or MATE2-K involved in its urinary secretion.
Assuntos
Proteínas de Transporte de Cátions Orgânicos , Humanos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Células HEK293 , Ligantes , Pregabalina , Transportador 2 de Cátion Orgânico/metabolismoRESUMO
Mirogabalin (MGB, Tarlige®), an inhibitor of the α2δ-1 subunit of voltage-gated Ca2+ (CaV) channels, is used as a way to alleviate peripheral neuropathic pain and diabetic neuropathy. However, to what extent MGB modifies the magnitude, gating, and/or hysteresis of various types of plasmalemmal ionic currents remains largely unexplored. In pituitary tumor (GH3) cells, we found that MGB was effective at suppressing the peak (transient, INa(T)) and sustained (late, INa(L)) components of the voltage-gated Na+ current (INa) in a concentration-dependent manner, with an effective IC50 of 19.5 and 7.3 µM, respectively, while the KD value calculated on the basis of minimum reaction scheme was 8.2 µM. The recovery of INa(T) inactivation slowed in the presence of MGB, although the overall current-voltage relation of INa(T) was unaltered; however, there was a leftward shift in the inactivation curve of the current. The magnitude of the window (INa(W)) or resurgent INa (INa(R)) evoked by the respective ascending or descending ramp pulse (Vramp) was reduced during cell exposure to MGB. MGB-induced attenuation in INa(W) or INa(R) was reversed by the further addition of tefluthrin, a pyrethroid insecticide known to stimulate INa. MGB also effectively lessened the strength of voltage-dependent hysteresis of persistent INa in response to the isosceles triangular Vramp. The cumulative inhibition of INa(T), evoked by pulse train stimulation, was enhanced in its presence. Taken together, in addition to the inhibition of CaV channels, the NaV channel attenuation produced by MGB might have an impact in its analgesic effects occurring in vivo.
Assuntos
Ácido Acético , Neoplasias Hipofisárias , Compostos Bicíclicos com Pontes , Humanos , Neoplasias Hipofisárias/patologia , SódioRESUMO
Mirogabalin is a novel α2δ ligand approved in Japan for the treatment of peripheral neuropathic pain. However, the sites of action of α2δ ligands to produce analgesic effects on inflammatory pain remain unclear. In this study, we investigated the analgesic effect and site of action of mirogabalin using the rat formalin test, an acute inflammatory pain model. Mirogabalin was administered orally, intrathecally, and intracerebroventricularly. Open field tests were performed to evaluate the effect of oral-, intrathecally, and intracerebroventricularly administered mirogabalin on locomotor activity and orientation ability. Oral mirogabalin produced an analgesic effect when the formalin test was performed 4 h, but not 1 or 2 h, after oral administration. Intrathecal, but not intracerebroventricular, administration of mirogabalin produced analgesic effects when mirogabalin was administered 10 min before formalin injection. These analgesic effects were not antagonized by idazoxan, an α2 adrenergic antagonist; WAY100135, a 5-HT1A antagonist; or naloxone, an opioid receptor antagonist. Mirogabalin attenuated moving distances 1 and 2 h after oral administration and 10 min after intracerebroventricular administration, but not 10 min after intrathecal administration. In the oral administration group, the time course of the analgesic effect was different from that of moving distance. In the intracerebroventricular group, mirogabalin attenuated moving distances but did not produce an analgesic effect. In the intrathecal group, mirogabalin produced an analgesic effect but did not affect moving distances. These findings suggest that the analgesic effect of mirogabalin on the rat formalin test is mediated by spinal action and not by the activation of α2, 5-HT1A, or opioid receptors, and that the inhibitory effect of mirogabalin on moving distances is mediated by the supraspinal brain.
Assuntos
Analgésicos , Neuralgia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Compostos Bicíclicos com Pontes , Ligantes , RatosRESUMO
BACKGROUND: The prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN. METHODS: A total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups. RESULTS: In both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001). CONCLUSIONS: Although both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients. TRIAL REGISTRATION: Not applicable.
Assuntos
Analgésicos/uso terapêutico , Compostos Bicíclicos com Pontes/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Neoplasias Pancreáticas , Doenças do Sistema Nervoso Periférico , Pregabalina/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Gabapentinoids such as gabapentin and pregabalin, which bind specifically to the α2δ subunit of voltage-gated Ca2+ channels, are used for first-line treatment of neuropathic pain. Here, we examined the analgesic effect of mirogabalin besilate (referred to simply as mirogabalin), a novel gabapentinoid, focusing on its action on the spinal cord and the descending noradrenergic pain inhibitory system. When administered systemically (10 and 30 mg/kg, intraperitoneally (i.p.)) and locally (10 and 30 µg, intracerebroventricularly (i.c.v.) or intrathecally (i.t.)) to mice, mirogabalin was found to exert analgesic effects on thermal (plantar test) and mechanical (von Frey test) hypersensitivity developing after partial sciatic nerve ligation. Notably, its analgesic effects (30 mg/kg, i.p. and 30 µg, i.c.v.) disappeared in mice pretreated with yohimbine hydrochloride (3 µg, i.t.). Moreover, in mice harboring a mutation in the α2δ-1 subunit resulting in substitution of arginine at position 217 with alanine to prevent gabapentinoid binding (R217A mutant mice), the analgesic effects of pregabalin and mirogabalin (30 µg, i.c.v., respectively) on mechanical hypersensitivity were almost completely suppressed. These results clearly demonstrate that mirogabalin also operates via the descending noradrenergic system, and that binding to the α2δ-1 subunit supraspinally is essential for the pain relief effect of gabapentinoids.
Assuntos
Analgésicos , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacologia , Canais de Cálcio/metabolismo , Neuralgia/tratamento farmacológico , Norepinefrina/metabolismo , Animais , Compostos Bicíclicos com Pontes/metabolismo , Canais de Cálcio/genética , Vias de Administração de Medicamentos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Mutantes , Mutação , Ligação Proteica/efeitos dos fármacosRESUMO
The metabolism, excretion, and pharmacokinetics of mirogabalin were investigated following a single oral administration of [14C]mirogabalin at 30 mg/5.55 MBq to six healthy male subjects.The mean recovery values of radioactivity in urine and faeces were 96.85 and 1.21%, respectively. The main component of radioactivity in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), mirogabalin N-glucuronide, and glucuronide of oxidized A204-4455 were detected as minor components in the specimens. Renal clearance of mirogabalin was higher than the glomerular filtration rate of the human kidneys, indicating renal secretion is involved in the clearance.In vitro studies revealed that UDP-glucuronosyltransferase produced two metabolites: A204-4455, formed via mirogabalin acylglucuronide, and a ring-opened form of mirogabalin N-glucuronide.Mirogabalin was absorbed almost completely, and was eliminated via urine. A part of the orally administered dose of mirogabalin was metabolized through glucuronidation at the amine and carboxylic acid moiety, which represents the primary metabolic pathway.
Assuntos
Compostos Bicíclicos com Pontes , Administração Oral , Fezes , Voluntários Saudáveis , Humanos , Ligantes , MasculinoRESUMO
AIM: We aimed to perform a systematic review and meta-analysis to examine the efficacy and safety of mirogabalin in patients with diabetic peripheral neuropathic pain (DPNP). METHODS: We searched four databases from inception to 1st July 2020. We included all randomised controlled trials (RCTs) which assessed the effectiveness and safety of mirogabalin in patients with DPNP. We evaluated the quality of the included RCTs using the Cochrane risk of bias assessment tool. We pooled dichotomous outcomes as risk ratios and continuous outcomes as mean differences with 95% confidence intervals, both under the random- or fixed-effects model. RESULTS: Three RCTs matched our inclusion criteria with a total of 1732 patients with DPNP: 1057, 534 and 141 patients received mirogabalin, placebo and pregabalin, respectively. The quality of included RCTs was marked as moderate-to-high. Mirogabalin treatment was significantly associated with a significant reduction in the average daily pain score (ADPS) compared with placebo over 7 weeks. Compared with pregabalin, mirogabalin was significantly associated with more decrease in ADPS only after 3, 4 and 5 weeks. The proportion of patients with ≥30% and ≥50% reduction in the ADPS was significantly higher in the mirogabalin vs placebo and pregabalin groups. Compared with placebo, mirogabalin was significantly associated with more adverse events of dizziness, increased weight, peripheral oedema and somnolence. The safety profile was comparable between mirogabalin and pregabalin. CONCLUSIONS: Our systematic review and meta-analysis revealed that in patients with DPNP, mirogabalin treatment was superior to placebo and pregabalin in decreasing the ADPS over time. Besides, mirogabalin was largely safe and associated with some adverse events that could be managed conservatively.
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Diabetes Mellitus , Neuralgia , Analgésicos/uso terapêutico , Compostos Bicíclicos com Pontes , Humanos , Neuralgia/tratamento farmacológico , Pregabalina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoAssuntos
Perna (Membro) , Dedos do Pé , Humanos , Diagnóstico Diferencial , Dor/diagnóstico , Feminino , Síndrome , Idoso , Transtornos Somatoformes/diagnóstico , MasculinoRESUMO
OBJECTIVE: To evaluate the effects of mirogabalin on patient-reported pain and sleep interference in diabetic peripheral neuropathic pain (DPNP). SUBJECTS: Adults (≥18 years) with type 1 or 2 diabetes, glycosylated hemoglobin of 10% or less at screening, and DPNP for six months or more were eligible for participation. METHODS: Subjects (N = 452) were randomly assigned (2:1:1:1:1:1:1) to receive placebo, dose-ranging mirogabalin (5, 10, 15, 20, 30 mg/day), or pregabalin (300 mg/day) for five weeks. Secondary efficacy end points studied here included patient global impression of change (PGIC), modified brief pain inventory (BPI), and average daily sleep interference score (ADSIS). Correlation plots were generated to examine the relationship between ADSIS and average daily pain score (ADPS). RESULTS: At week 5, significant reductions in ADSIS were observed in the mirogabalin 15, 20, and 30 mg/day groups, compared with placebo (P < 0.05). Baseline ADSIS and ADPS were strongly correlated (R2 = 0.4407), as were mean changes from baseline in ADSIS and ADPS at week 5 (R2 = 0.6694). The mirogabalin 30 mg/day group showed significant improvement compared with placebo in four of six BPI subscales at end point; the mirogabalin 15 mg/day group showed significant improvement in three of six BPI subscales (P < 0.05). At end of treatment, the percentage of subject with PGIC status of "much improved or better" was greater in all mirogabalin dose groups than in the placebo group (P < 0.05). A low incidence of treatment-related adverse events was reported for mirogabalin. CONCLUSIONS: Results support the effectiveness of mirogabalin in improving patient-reported pain and sleep interference in DPNP.
Assuntos
Compostos Bicíclicos com Pontes/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuralgia/tratamento farmacológico , Medição da Dor , Sono/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pregabalina/uso terapêutico , Resultado do Tratamento , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
INTRODUCTION: There is no approved effective drug for diabetic peripheral neuropathic pain (DPNP) in China. Gabapentinoids including mirogabalin have shown promise, although data in Chinese patients are scarce. METHODS: This phase 3, multicenter, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of mirogabalin for treating DPNP in China. Mirogabalin was administered at 5 mg twice daily for the first week and uptitrated to 15 mg twice daily for a total duration of 14 weeks. The primary efficacy endpoint was the change from baseline in weekly average daily pain score (ADPS) at week 14; secondary endpoints included the ADPS responder rate, Short-Form McGill Pain Questionnaire visual analogue scale score, patient global impression of change (PGIC), average daily sleep interference score (ADSIS), EuroQol 5-dimensions 5-levels (EQ-5D-5L), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Of 393 patients (mirogabalin, n = 196; placebo n = 197), the mean age was 58.2 years (mirogabalin, 58.7 years; placebo, 57.7 years) and 54.2% were male (mirogabalin, 56.1%; placebo, 52.3%). Mirogabalin elicited a greater change from baseline in the weekly ADPS vs. placebo at week 14: least-squares mean difference (95% confidence interval) vs. placebo - 0.39 (- 0.74, - 0.04), p = 0.0301. PGIC, ADSIS, and EQ-5D-5L data reflected significantly better improvements for patients receiving mirogabalin vs. placebo. The incidence of TEAEs was 75.0% and 75.1% in the mirogabalin and placebo groups, respectively. Most TEAEs were mild or moderate, and the incidence of TEAEs leading to treatment discontinuation was 2.6% in the mirogabalin group and 1.5% in the placebo group. CONCLUSIONS: Although the effect size of mirogabalin was reduced due to the placebo effect, mirogabalin is a safe and effective treatment option for Chinese patients with DPNP. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04094662.
RESUMO
BACKGROUND/AIM: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN. RESULTS: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects. CONCLUSION: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.
Assuntos
Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Taxoides , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Pessoa de Meia-Idade , Taxoides/efeitos adversos , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Idoso , Adulto , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Compostos Bicíclicos com Pontes/uso terapêutico , Compostos Bicíclicos com Pontes/efeitos adversos , Compostos Bicíclicos com Pontes/administração & dosagem , Estadiamento de Neoplasias , Assistência Perioperatória/métodos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Hidrocarbonetos Aromáticos com PontesRESUMO
Chronic penile pain (CPP) is a debilitating condition characterized by persistent penile pain, often accompanied by lower urinary tract symptoms and sexual dysfunction, severely impacting quality of life. Treatment options are limited. We report a case of a 38-year-old man with severe CPP effectively treated with mirogabalin. Initially diagnosed with balanitis, his symptoms evolved to include severe penile pain and mental instability, and he was unresponsive to standard treatments. After multiple failed therapies, mirogabalin was introduced, resulting in significant pain reduction and improved mental health within days. This case highlights mirogabalin's potential efficacy in treating CPP with neuropathic characteristics, suggesting it as a viable treatment option for similar cases. Further studies are warranted to explore its broader applicability.
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NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.
Assuntos
Gabapentina , Humanos , Gabapentina/farmacologia , Animais , Ligação Proteica , Subunidades Proteicas/metabolismo , Subunidades Proteicas/química , Células HEK293 , Ácido gama-Aminobutírico/metabolismo , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Canais de Cálcio Tipo N/metabolismo , Canais de Cálcio Tipo N/genética , Pregabalina/farmacologia , Canais de Cálcio/metabolismo , Compostos Bicíclicos com PontesRESUMO
Introduction: Atopic dermatitis (AD) is one of the most prevalent intractable chronic itch diseases worldwide. In recent years, new molecular-targeted drugs have emerged, but side effects and economic challenges remain. Therefore, since it is important for AD patients to have a wider range of treatment options, it is important to explore new therapeutic agents. Gabapentinoids, gabapentin and pregabalin, have been shown to be effective for the clinical treatment of several chronic itch. Recently, mirogabalin (MGB) was developed as a novel gabapentinoid. MGB is a drug for neuropathic pain and has a margin of safety between its side effects and the analgesic effect for animal experiments. Herein, we showed that MGB exhibited an antipruritic effect in a mouse model of AD using NC/Nga mice. Methods and results: The oral administration of MGB (10 mg/kg) inhibited spontaneous scratching behavior in AD mice and its effect was dose dependently. Then, when MGB (10 mg/kg) was orally administrated to healthy mice, it did not affect motor function, including locomotor activity, wheel activity, and coordinated movement. Moreover, gabapentin (100 mg/kg) and pregabalin (30 mg/kg), inhibited spontaneous scratching behavior in AD mice and decreased motor function in healthy mice. Furthermore, intracisternal injection of MGB (10 µg/site) significantly suppressed spontaneous scratching behavior in AD mice. Discussion: In summary, our results suggest that MGB exerts an antipruritic effect via the spinal dorsal horn using NC/Nga mice. We hope that MGB is a candidate for a novel therapeutic agent for AD with relatively few side effects.