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1.
Life Sci ; 265: 118755, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33189826

RESUMO

AIMS: The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties. MAIN METHODS: Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 × 106), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively. KEY FINDINGS: OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1ß and TNF-α spinal levels did not differ between mice with or without sensory neuropathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-ß, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment. SIGNIFICANCE: MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.


Assuntos
Transplante de Células-Tronco Mesenquimais , Oxaliplatina/toxicidade , Oxirredução , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Células Receptoras Sensoriais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Interleucina-1beta/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Oxirredução/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/terapia , Reação em Cadeia da Polimerase em Tempo Real , Teste de Desempenho do Rota-Rod , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Medicine (Baltimore) ; 99(50): e23564, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327312

RESUMO

BACKGROUND: Peripheral neurotoxicity (PN) is a frequent side effect of oxaliplatin treatment, and also is its dose-limiting toxicity. Studies have confirmed that ω-3 polyunsaturated fatty acids (ω-3 PUFAs) had a neuroprotective effect. However, the efficacy of ω-3 PUFAs on the prevention of oxaliplatin-related neurotoxicity remains unclear. We assessed the effect of ω-3 PUFAs on the neurotoxicity in colon cancer patients treated by oxaliplatin combined with capecitabine. METHODS: In a randomized, double-blind, placebo-controlled study, 179 patients with colon cancer receiving oxaliplatin combined with capecitabine were recruited, and randomly assigned to take ω-3 PUFAs, 640 mg t.i.d during chemotherapy and 1 month after the end of the treatment or placebo. All patients were treated with chemotherapy for 6 treatment cycles. The incidence and severity of PN were evaluated, and the nerve conduction was measured before the onset of chemotherapy and 1 month after treatment. In addition, the quality of life was also accessed using Chinese version of European organization for research and treatment of cancer quality of life questionnaire. RESULTS: The incidence of PN in the ω-3 PUFAs group and placebo group was 52.22% and 69.66%, respectively (P = .017). In addition, there was a significant difference in the severity of PN between the 2 groups (P = .017). In terms of motor and sensory nerve conduction, the sensory action potentials amplitude of sural nerve in the ω-3 PUFAs group and placebo group after chemotherapy treatment were (15.01 ±â€Š3.14) and (13.00 ±â€Š3.63) µ V respectively, suggesting there was a significant difference in the 2 groups (P = .000). In addition, the mean score of the global health-status/quality of life was obviously higher in the ω-3 PUFAs group than that in the placebo group. CONCLUSION: ω-3 PUFAs seem to reduce the incidence and severity of oxaliplatin-related neurotoxicity, and improve the quality of patients' life, indicating it is expected to be a potential drug for the treatment of oxaliplatin-related neurotoxicity.


Assuntos
Capecitabina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Oxaliplatina/toxicidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Capecitabina/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/etiologia , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Qualidade de Vida , Inquéritos e Questionários
3.
Cancer Treat Rev ; 91: 102112, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33091698

RESUMO

BACKGROUND: Oxaliplatin represents a main component of cytotoxic treatment regimens in colorectal cancer (CRC). Given its efficacy, oxaliplatin is frequently re-administered in the context of the continuum of care in metastatic CRC (mCRC). However, efficacy and tolerability of this therapeutic strategy has not been comprehensively assessed. METHODS: We performed a systematic review of the literature on September 19th 2020, according to PRISMA criteria 2009. The research was performed on PubMed, ASCO Meeting Library, ESMO library and ClinicalTrials.gov for citations or ongoing trials. RESULTS: 64 records were retrieved and 13 included in the systematic review: 8 full-text articles, 4 abstracts and 1 ongoing clinical trial. According to readministration timing, studies were classified as rechallenge/reintroduction (n = 8) or stop & go/intermittent therapeutic strategies (n = 4). The studies presented wide heterogeneity in terms of efficacy (Response Rate 6-31%; Disease Control Rate 39-79%; median Progression-Free Survival 3.1-7 months). Those patients who received retreatment after prior adjuvant oxaliplatin or exploiting a stop-&-go strategy appeared to achieve better outcomes. However, no formal comparisons on treatment outcomes were feasible. The most frequent grade 3 or higher adverse events were hematologic toxicities (5-27%), peripheral neuropathy (5-14%) and hypersensitivity reactions (5-20%). CONCLUSIONS: Retreatment with oxaliplatin for mCRC is practiced based on scarce and heterogeneous data indicating efficacy and manageable toxicity. The best strategy to exploit this approach remains to be defined, and the most promising research avenue to improve therapeutic index of oxaliplatin is represented by selection of responder patients whose tumors harbor molecular defects in the DNA damage repair pathway.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/secundário , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Retratamento , Resultado do Tratamento
4.
PLoS One ; 15(10): e0239758, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33057367

RESUMO

OBJECTIVE: People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today. DESIGN: This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART. METHODS: Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders. RESULTS: Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen. CONCLUSIONS: Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.


Assuntos
Antirretrovirais/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Variação Genética/genética , Proteína da Hemocromatose/genética , Ferro/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Adulto , Antirretrovirais/uso terapêutico , Feminino , Ferritinas/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Hemocromatose/genética , Heterozigoto , Humanos , Masculino , Neuralgia/induzido quimicamente , Neuralgia/genética , Receptores da Transferrina/genética
5.
J Pharmacol Exp Ther ; 375(3): 430-438, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33008871

RESUMO

Paclitaxel-associated peripheral neuropathy (PN), a major dose-limiting toxicity, significantly impacts patients' quality of life/treatment outcome. Evaluation of risk factors often ignores time of PN onset, precluding the impact of time-dependent factors, e.g., drug exposure, needed to comprehensively characterize PN. We employed parametric time-to-event (TTE) analysis to describe the time course of risk of first occurrence of clinically relevant PN grades ≥2 (PN2+, n = 105, common terminology criteria v4.0) and associated patient/treatment characteristics, leveraging data from 365 patients (1454 cycles) receiving paclitaxel every 3 weeks (plus carboplatin AUC = 6 or cisplatin 80 mg/m2) for ≤6 cycles. Paclitaxel was intravenously administered (3 hours) as standard 200-mg/m2 doses (n = 182) or as pharmacokinetic-guided dosing (n = 183). A cycle-varying hazard TTE model linking surge in hazard of PN2+ to paclitaxel administration [PN2+ proportions (i.e., cases per 1000 patients), 1st day, cycle 1: 4.87 of 1000; cycle 6: 7.36 of 1000] and linear decline across cycle (last day, cycle 1: 1.64 of 1000; cycle 6: 2.48 of 1000) adequately characterized the time-varying hazard of PN2+. From joint covariate evaluation, PN2+ proportions (1st day, cycle 1) increased by 1.00 per 1000 with 5-µmol·h/l higher paclitaxel exposure per cycle (AUC between the start and end of a cycle, most relevant covariate), 0.429 per 1000 with 5-year higher age, 1.31 per 1000 (smokers vs. nonsmokers), and decreased by 0.670 per 1000 (females vs. males). Compared to 200 mg/m2 dosing every 3 weeks, model-predicted cumulative risk of PN2+ was significantly higher (42%) with 80 mg/m2 weekly dosing but reduced by 11% with 175 mg/m2 dosing every 3 weeks. The established TTE modeling framework enables quantification and comparison of patient's cumulative risks of PN2+ for different clinically relevant paclitaxel dosing schedules, sparing patients PN2+ to improve paclitaxel therapy. SIGNIFICANCE STATEMENT: Characterization of risk factors of paclitaxel-associated peripheral neuropathy (PN) typically involves time-independent comparison of PN odds in patient subpopulations, concealing the impact of time-dependent factors, e.g., changing paclitaxel exposure, required to comprehensively characterize PN. We developed a parametric time-to-event model describing the time course in risk of clinically relevant paclitaxel-associated PN, identifying the highest risk in older male smokers with higher paclitaxel area under the plasma concentration-time curve between the start and end of a cycle. The developed framework enabled quantification of patient's risk of PN for clinically relevant paclitaxel dosing schedules, facilitating future dosing decisions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Análise de Variância , Humanos , Modelos Estatísticos , Paclitaxel/uso terapêutico , Qualidade de Vida , Risco , Fatores de Tempo
6.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5061-5064, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019124

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of neurotoxic chemotherapeutic agents. Recent studies have suggested clinical utility of limb hypothermia in reducing CIPN. However, conventional cooling methods such as ice packs are unable to provide thermoregulated cooling and cause frostbites. Cooling modalities offering thermoregulation have been developed for sports injury and orthopaedic indications, but not explored for preventing CIPN. This study aims to determine the safety, tolerability and optimal parameters of three cooling modalities for delivery of limb hypothermia in healthy subjects, prior to testing in cancer patients for prevention of CIPN. Healthy subjects underwent limb hypothermia by either: continuous-flow cooling, cryocompression or frozen gloves. Skin temperatures and tolerance scores were monitored. Overall, 58 subjects underwent limb hypothermia. No adverse events were observed barring transient erythema. Both continuous-flow cooling and cryocompression are feasible, safe and tolerable methods for delivery of limb hypothermia. Cryocompression achieved lower skin temperatures than continuous-flow cooling with similar safety profiles. Frozen gloves were minimally tolerated. Cryocompression may provide greater efficacy in preventing CIPN, with clinical trials currently underway.


Assuntos
Antineoplásicos , Hipotermia Induzida , Hipotermia , Doenças do Sistema Nervoso Periférico , Antineoplásicos/efeitos adversos , Extremidades , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente
8.
Int J Clin Oncol ; 25(12): 2035-2043, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32926227

RESUMO

BACKGROUND: For unresectable or recurrent advanced gastric adenocarcinoma (AGC), tri-weekly administration of nanoparticle albumin-bound paclitaxel (nab-PTX) at 260 mg/m2 achieved a response rate of 27.8% in a phase II trial in Japan. However, frequent neutropenia and peripheral neuropathy limit its use in clinical settings. We, thus, conducted a single-arm phase II trial to investigate the efficacy and safety of a reduced dose (220 mg/m2) of tri-weekly nab-PTX. METHODS: Eligible patients included those with AGC and ECOG performance status of 0-2 who had received one or more prior chemotherapy containing fluoropyrimidine regimens. A reduced dose of nab-PTX (220 mg/m2) was administered tri-weekly. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity (RDI) and proportion of patients receiving subsequent chemotherapy. RESULTS: Among 33 patients enrolled, 32 were treated with protocol therapy. RR was 3.1% [95% confidence interval (CI), 0-16.2%], which did not reach the protocol-specified threshold (p = 0.966). DCR was 37.5% (95% CI, 21.1-56.3%). Median OS and PFS were 6.3 (95% CI, 4.4-14.2) and 2.2 (95% CI, 1.8-3.1) months, respectively. RDI was 97.8%. Twenty (62.5%) patients received subsequent chemotherapy. Toxicity was relatively mild with the most common grade ≥ 3 adverse events being neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). CONCLUSION: Tri-weekly nab-PTX with a reduced dose (220 mg/m2) is not recommended for AGC in a second-line or later setting, despite demonstrating less toxicity than at 260 mg/m2. Clinical trial registration The OGSG1302 trial was registered with UMIN-CTR as UMIN000000714.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Albuminas/uso terapêutico , Anorexia/induzido quimicamente , Anorexia/epidemiologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Paclitaxel/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do Tratamento
9.
Klin Padiatr ; 232(6): 331-333, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32877958

RESUMO

Vincristine is at the core of many treatment protocols for childhood malignancies. The major dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN) which may cause morbidity and disrupt curative treatment. Several studies have tried to identify pharmacogenetic biomarkers for susceptibility to vincristine-induced toxicity (Egbelakin A et al., Pediatr Blood Cancer 2011; 56: 361-367. Aplenc R et al., Br J Haematol 2003; 122: 240-244. Diouf B et al., JAMA 2015; 313: 815-823. Zgheib NK et al., Pharmacogenet Genomics, 2018; 28: 189-195. Gutierrez-Camino A et al., Pharmacogenet Genomics 2016; 26: 100-102. Wright GE et al., Clin Pharmacol Ther 2019; 105: 402-410. Kayilioglu H et al., J Pediatr Hematol Oncol 2017; 39(6): 458-462). A major limitation of these studies is that VIPN is difficult to measure objectively using only clinical examination and clinical scales. This is especially true for children, who are often unable to report or grade symptoms such as paresthesia, numbness, and pain. Furthermore, some studies are questioning the validity of currently available neuropathy grading scales (Postma TJ et al., Ann Oncol 1998; 9: 739-744). Our group recently showed that electrophysiological studies can be used with great accuracy for early detection of VIPN (Kavcic M et al., J Pediatr Hematol Oncol 2017; 39: 266-271). In the previous study, we found that VIPN presents with primary axonal involvement and is more pronounced on motor neurons (Kavcic M et al., J Pediatr Hematol Oncol 2017; 39: 266-271).


Assuntos
Proteínas Associadas aos Microtúbulos/genética , Condução Nervosa , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Vincristina/efeitos adversos , Criança , Genótipo , Humanos , Dor , Vincristina/uso terapêutico
10.
PLoS One ; 15(9): e0239126, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941465

RESUMO

Paclitaxel is a representative anticancer drug that induces chemotherapy-induced peripheral neuropathy (CIPN), a common side effect that limits many anticancer chemotherapies. Although PINK1, a key mediator of mitochondrial quality control, has been shown to protect neuronal cells from various toxic treatments, the role of PINK1 in CIPN has not been investigated. Here, we examined the effect of PINK1 expression on CIPN using a recently established paclitaxel-induced peripheral neuropathy model in Drosophila larvae. We found that the class IV dendritic arborization (C4da) sensory neuron-specific expression of PINK1 significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype. In contrast, knockdown of PINK1 resulted in an increase in thermal hypersensitivity, suggesting a critical role for PINK1 in sensory neuron-mediated thermal nociceptive sensitivity. Interestingly, analysis of the C4da neuron morphology suggests that PINK1 expression alleviates paclitaxel-induced thermal hypersensitivity by means other than preventing alterations in sensory dendrites in C4da neurons. We found that paclitaxel induces mitochondrial dysfunction in C4da neurons and that PINK1 expression suppressed the paclitaxel-induced increase in mitophagy in C4da neurons. These results suggest that PINK1 mitigates paclitaxel-induced sensory dendrite alterations and restores mitochondrial homeostasis in C4da neurons and that improvement in mitochondrial quality control could be a promising strategy for the treatment of CIPN.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Proteínas de Drosophila/genética , Hiperalgesia/induzido quimicamente , Hiperestesia/induzido quimicamente , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Proteínas Serina-Treonina Quinases/genética , Animais , Modelos Animais de Doenças , Drosophila , Expressão Gênica , Técnicas de Silenciamento de Genes , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Hiperestesia/genética , Hiperestesia/fisiopatologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia
11.
Am J Clin Oncol ; 43(9): 654-659, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889836

RESUMO

OBJECTIVE: By using the Korean Pancreatic Cancer (K-PaC) registry, we compared the clinical outcomes of FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GNP) in patients with metastatic pancreatic cancer (MPC). METHODS: We constructed a web-based database of 3748 anonymized patients diagnosed with pancreatic ductal adenocarcinoma. MPC patients who received first-line FFX or GNP were enrolled. Overall survival (OS), progression-free survival, grade III to IV toxicity, and cross-over treatment were analyzed. RESULTS: A total of 413 patients (232 vs. 181, FFX vs. GNP; all data are presented in this sequence) were eligible. Median age was 63 years (60 vs. 69 y) with 43% (39% vs. 47%) comprising female individuals. The major metastatic sites were the liver (64%), peritoneum (25%), and distant lymph nodes (18%). The median OS was 11.5 versus 12.7 months (hazard ratio [HR]=0.87, 95% confidence interval [CI]: 0.68-1.12, P=0.286), and median progression-free survival was 7.5 versus 8.1 months (HR=0.92, 95% CI: 0.70-1.20, P=0.517), respectively. The frequency of grade III to IV febrile neutropenia was higher in the FFX group (18% vs. 11%, P=0.040), and that of peripheral neuropathy was higher in the GNP group (8% vs. 14%, P=0.046). The chance to receive second-line chemotherapy was higher in the GNP group (45% vs. 56%, P=0.036). In the cross-over treatment, the median OS of the FFX-GNP group (n=43) and the GNP-FFX group (n=47) was 16.8 versus 17.7 months (HR=0.79, 95% CI: 0.44-1.41, P=0.425). CONCLUSIONS: FFX and GNP showed similar efficacy and comparable toxicity in MPC patients. Although the GNP group had a higher chance to receive second-line chemotherapy, they did not have improved overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Peritoneais/secundário , Idoso , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Ductal Pancreático/secundário , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Neutropenia Febril/induzido quimicamente , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Intervalo Livre de Progressão , Sistema de Registros , República da Coreia , Taxa de Sobrevida , Resultado do Tratamento
12.
Asia Pac J Clin Oncol ; 16(5): e257-e262, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32893979

RESUMO

INTRODUCTION: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse events that can limit a patient's quality of life during/after chemotherapy. However, no appropriate methods have been established yet for monitoring the risk of progression of OIPN. METHODS: A simple assessment tool using gem clips, the CLIP test, was established and its performance in predicting the risk of progression to ≥grade 2 peripheral sensory neuropathy (CTCAE ver. 4.0) was investigated in patients receiving chemotherapy with oxaliplatin. RESULTS: Among 101 patients included in this study, 71 patients developed CTCAE ≥grade 1 peripheral neuropathy (grade 1, n = 67; grade 2, n = 4) at a median of 63 (range, 14-259) days after the start of treatment. Of the 67 patients with grade 1 peripheral neuropathy, 17 showed progression to ≥grade 2 neuropathy after a median interval of 84 (range, 21-246) days. Of these patients, 27 showed a positive result of the CLIP test at a median of 91 (range, 14-224) days, excluding one patient who already showed a positive result of the test at the baseline. Therefore, the risk ratio for the development of CTCAE ≥grade 2 peripheral neuropathy was 8.3 in the patients who showed a positive result on the CLIP test. Multivariate analysis confirmed that a positive results on the CLIP test was significantly correlated with the risk of future development of CTCAE ≥grade 2 peripheral neuropathy (odds ratio, 9.37; P = 0.002). CONCLUSION: A positive result on the CLIP test predict is predictive of the risk of progression of OIPN during chemotherapy with oxaliplatin.


Assuntos
Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Qualidade de Vida/psicologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/farmacologia , Estudos Prospectivos
13.
Braz J Med Biol Res ; 53(11): e10263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32965323

RESUMO

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.


Assuntos
Doenças do Sistema Nervoso Periférico , Amifostina/uso terapêutico , Animais , Antineoplásicos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle
14.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892275

RESUMO

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Indução de Remissão , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
15.
Int J Clin Oncol ; 25(12): 2066-2074, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32761281

RESUMO

BACKGROUND: Colorectal carcinoma (CRC) is widely treated by chemotherapy based on an intensely neurotoxic drug: oxaliplatin (OXL). We objective to evaluate prospectively the orofacial neurotoxicity during FLOX (fluorouracil + leucovorin + OXL) chemotherapy. METHODS: So, 46 patients with CRC were prospectively evaluated during FLOX chemotherapy by 3 cycles (C) of 6 weeks (W) each. We weekly applied the orofacial section of the Acute and Chronic Neuropathy Questionnaire of Common Toxicity Criteria for Adverse Events of the National Cancer Institute of the United States of America (Oxaliplatin-specific neurotoxicity scale). Patients were asked the following concerning the severity (scores 0-5) of orofacial symptoms: jaw pain, eyelids drooping, throat discomfort, ear pain, tingling in mouth, difficulty with speech, burning or discomfort of the eyes, loss of any vision, feeling shock/pain down back and problems breathing. We summed the scores (0-50) and evaluated the clinicopathological data. Friedman/Dunn, Chi square and multinomial regression logistic tests were used (SPSS 20.0, p < 0.05). RESULTS: There was a significant increase in sum of orofacial neurotoxicity from baseline to C1.W3, C2.W1 and C3.W5 (p < 0.001) due increase in scores of jaw pain (p < 0.001), eyelids drooping (p = 0.034), throat discomfort (p < 0.001), ear pain (p = 0.034), tingling in mouth (p = 0.015), burning/discomfort of your eyes (p < 0.001), loss of any vision (p < 0.001), feeling shock/pain down back (p < 0.001), problems with breathing (p = 0.045), but not difficulty with speech (p = 0.087). Women (p = 0.021) and young patients (p = 0.027) had significant higher prevalence of orofacial neurotoxicity. CONCLUSIONS: FLOX-related orofacial neurotoxicity begins acutely and remains long term with increased incidence in women and younger patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Face , Feminino , Fluoruracila/administração & dosagem , Humanos , Incidência , Leucovorina/administração & dosagem , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Boca/efeitos dos fármacos , Síndromes Neurotóxicas/epidemiologia , Oxaliplatina/administração & dosagem , Doenças do Sistema Nervoso Periférico/epidemiologia , Estudos Prospectivos
16.
Brain ; 143(8): 2421-2436, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830219

RESUMO

Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na+ current in medium but not small neurons. The increase in TTX-S Na+ current density is likely mediated by Nav1.6, because in the absence of Nav1.6 channels, vincristine failed to alter TTX-S Na+ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Células Receptoras Sensoriais/metabolismo , Vincristina/toxicidade , Animais , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos
17.
Sci Rep ; 10(1): 14154, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843690

RESUMO

The cool sensor transient receptor potential melastatin channel 8 (TRPM8) is highly expressed in trigeminal and dorsal root ganglia, playing a key role in cold hypersensitivity associated to different peripheral neuropathies. Moreover, these channels are aberrantly expressed in different cancers, and seem to participate in tumor progression, survival and invasion. Accordingly, the search for potent and selective TRPM8 modulators attracted great interest in recent years. We describe new heterocyclic TRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates afforded highly substituted ß-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the configuration. These derivatives behave as TRPM8 antagonists in the Ca2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure ß-lactams 24a and 29a (IC50, 1.4 and 0.8 µM). Two putative binding sites by the pore zone, different from those found for typical agonists and antagonists, were identified by in silico studies for both ß-lactams and KPs. ß-Lactams 24a and 29a display antitumor activity in different human tumor cell lines (micromolar potencies, A549, HT29, PSN1), but correlation with TRPM8 expression could not be established. Additionally, compound 24a significantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy.


Assuntos
Analgésicos/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Piperazinas/uso terapêutico , Canais de Cátion TRPM/antagonistas & inibidores , beta-Lactamas/uso terapêutico , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Temperatura Baixa/efeitos adversos , Simulação por Computador , Citofotometria , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxaliplatina/toxicidade , Técnicas de Patch-Clamp , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Piperazinas/síntese química , Piperazinas/farmacologia , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/farmacologia
18.
Sci Rep ; 10(1): 14170, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843706

RESUMO

Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological 'senolytic' agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN.


Assuntos
Compostos de Anilina/farmacologia , Senescência Celular/efeitos dos fármacos , Cisplatino/toxicidade , Neurônios/patologia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Sulfonamidas/farmacologia , Animais , Biomarcadores , Células Cultivadas , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Genes Transgênicos Suicidas , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Cultura Primária de Células
19.
Oral Dis ; 26 Suppl 1: 149-152, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862548

RESUMO

OBJECTIVES: Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects 40% of HIV-infected individuals treated with antiretroviral therapy (ART). The most salient symptom of the neuropathy is pain, which frequently is moderate-to-severe intensity, associated with reduced activities and physical function, sleep disruption, increased severity of depression, and anxiety. Yet, evidence for managing painful HIV-SN is poor. The purpose of this study was to verify by scientific evidence the neuropathy complication in HIV/AIDS patients to develop effective pain management strategies. METHODS: Design: Systematic review. DATA SOURCES: PubMed (MEDLINE), Cochrane, www.controlled-trials.com. SELECTION CRITERIA: the filter "English" was used, timeframed searched was 2009-2019, randomized controlled trials (RCT). Keywords were verified in MeSH "Peripheral Nervous System Disease" and "Antiretroviral Agents" or "Antiretroviral therapy." REVIEW METHOD: the PRISMA flowchart was used. RESULT: A systematic search following PRISMA guidelines was carried out, and 12 specific articles/studies on the subject were selected. The results revealed that HIV therapy, aging, body mass index, height, and systemic conditions influence neuropathy conditions in HIV/AIDS patients. The multistudies focused on pain management approaches such as administration of pain medication, drug combination to prevent side effects, or ART with minimal side effects. CONCLUSION: Sensory neuropathy is a frequent complication of HIV infection and ART. An understanding of the mechanism and pathophysiology of neuropathy in HIV is urgently required to develop alternative treatment modalities and to evaluate preventive strategies.


Assuntos
Síndrome de Imunodeficiência Adquirida , Antirretrovirais , Infecções por HIV , Doenças do Sistema Nervoso Periférico , Antirretrovirais/efeitos adversos , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
PLoS One ; 15(8): e0236264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750060

RESUMO

BACKGROUND: Extensively drug-resistant tuberculosis (XDR TB) is a very serious form of tuberculosis that is burdened with a heavy mortality toll, especially before the advent of new TB drugs. The Democratic Republic of the Congo (DRC) is among the countries most affected by this new epidemic. METHODS: A retrospective analysis was performed of the records of all patients with pre- and extensively drug-resistant tuberculosis hospitalized from January 1, 2015 to December 31, 2017 and monitored for at least 6 months to one year after the end of their treatment in Kinshasa; an individualized therapeutic regimen with bedaquiline for 20 months was built for each patient. The adverse effects were systematically monitored. RESULTS: Of the 40 laboratory-confirmed patients, 32 (80%) patients started treatment, including 29 preXRB and 3 XDR TB patients. In the eligible group, 3 patients (9.4%) had HIV-TB coinfections. The therapeutic success rate was 53.2%, and the mortality rate was 46.8% (15/32); there were no relapses, failures or losses to follow-up. All coinfected HIV-TB patients died during treatment. The cumulative patient survival rate was 62.5% at 3 months, 53.1% at 6 months and 53.1% at 20 months. The most common adverse events were vomiting, Skin rash, anemia and peripheral neuropathy. CONCLUSION: The new anti-tuberculosis drugs are a real hope for the management of Drug Resistant tuberculosis patient and other new therapeutic combinations may improve favorable outcomes.


Assuntos
Antituberculosos/administração & dosagem , Diarilquinolinas/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adolescente , Adulto , Idoso , Anemia/induzido quimicamente , Anemia/epidemiologia , Antituberculosos/efeitos adversos , Efeitos Psicossociais da Doença , República Democrática do Congo/epidemiologia , Diarilquinolinas/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Exantema/induzido quimicamente , Exantema/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/epidemiologia , Adulto Jovem
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