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1.
Glia ; 67(8): 1434-1448, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31179602

RESUMO

Microglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time-lapse two-photon imaging and whole-cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid-induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony-stimulating factor 1 receptor (CSF-1R) pathway. Pharmacological inhibition of CSF-1R reduced seizure-induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF-1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.


Assuntos
Proliferação de Células , Gliose/fisiopatologia , Microglia/fisiologia , Monócitos/fisiologia , Estado Epiléptico/fisiopatologia , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Morte Celular , Modelos Animais de Doenças , Gliose/etiologia , Hipocampo/fisiopatologia , Ácido Caínico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Neurônios/fisiologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Estado Epiléptico/complicações , Técnicas de Cultura de Tecidos
2.
Support Care Cancer ; 25(11): 3407-3416, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28551844

RESUMO

PURPOSE: Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Given that extensive animal data suggest that minocycline may prevent chemotherapy-induced neurotoxicity, the purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and the P-APS. METHODS: Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks and were randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a matching placebo. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy to measure P-APS and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment, to measure CIPN. RESULTS: Forty-seven patients were randomized. There were no remarkable differences noted between the minocycline and placebo groups for the overall sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components, which evaluate tingling, numbness and shooting/burning pain in hands and feet. However, patients taking minocycline had a significant reduction in the daily average pain score attributed to P-APS (p = 0.02). Not only were no increased toxicities reported with minocycline, but there was a significant reduction in fatigue (p = 0.02). CONCLUSIONS: Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted.


Assuntos
Antibacterianos/uso terapêutico , Minociclina/uso terapêutico , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Antibacterianos/farmacologia , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Minociclina/farmacologia , Projetos Piloto
3.
Support Care Cancer ; 24(12): 5059-5068, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27534963

RESUMO

PURPOSE: Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. METHODS: Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. RESULTS: Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. CONCLUSIONS: Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Paclitaxel/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/tratamento farmacológico
4.
Neurobiol Dis ; 41(3): 661-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21145397

RESUMO

Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral neuropathy in 30% of patients. Peripheral neuropathy is the dose limiting side effect, which has no preventative therapy. We have previously shown that cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria. We now demonstrate that cisplatin also directly binds to mitochondrial DNA (mtDNA) with the same binding affinity as nDNA. Cisplatin binds 1 platinum molecule per 2166 mtDNA base pairs and 1 platinum molecule per 3800 nDNA base pairs. Furthermore, cisplatin treatment inhibits mtDNA replication as detected by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and inhibits transcription of mitochondrial genes. The relative reduction in mtDNA transcription is directly related to the distance the gene is located from the transcription initiation point, which implies that randomly formed platinum adducts block transcription. Cisplatin treated DRG neurons exhibit mitochondrial vacuolization and degradation in vitro and in vivo. Taken together, this data suggests that direct mtDNA damage may provide a novel, distinct mechanism for cisplatin-induced neurotoxicity separate from the established nDNA damage pathway.


Assuntos
Cisplatino/metabolismo , Cisplatino/toxicidade , Dano ao DNA/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Gânglios Espinais/patologia , Neurônios/patologia , Animais , Células Cultivadas , Dano ao DNA/fisiologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley
5.
Mol Pain ; 6: 15, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20205720

RESUMO

BACKGROUND: Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. RESULTS: In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR), we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG) neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG) were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. CONCLUSION: These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.


Assuntos
Cisplatino/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Antineoplásicos/toxicidade , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/fisiopatologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Doenças do Sistema Nervoso Periférico/fisiopatologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Canal de Cátion TRPA1 , Canais de Cátion TRPM/efeitos dos fármacos , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/genética , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Canais de Potencial de Receptor Transitório/metabolismo
6.
Mol Pain ; 5: 9, 2009 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-19245717

RESUMO

BACKGROUND: Cisplatin has been in use for 40 years for treatment of germ line and other forms of cancer. Oxaliplatin is approved for treatment of metastatic colorectal cancer. Thirty to forty percent of cancer patients receiving these agents develop pain and sensory loss. Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients. RESULTS: We have established mouse models of cisplatin and oxaliplatin-induced neuropathy using doses similar to those used in patients. Adult male C57BL6J mice were treated with daily intraperitoneal injection for 5 days, followed by 5 days of rest, for two cycles. Total cumulative doses of 23 mg/kg cisplatin and 30 mg/kg oxaliplatin were used. Behavioral evaluations included cold plate, von Frey, radiant heat, tail immersion, grip strength and exploratory behavior at baseline and at weekly intervals for 8 weeks. Following two treatment cycles, mice in the cisplatin and oxaliplatin treatment groups demonstrated significant mechanical allodynia compared to control mice. In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws. CONCLUSION: We have therefore established a model of platinum drug-induced painful peripheral neuropathy that reflects the differences in early thermal pain responses that are observed in patients treated with either cisplatin or oxaliplatin. This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies.


Assuntos
Cisplatino/efeitos adversos , Temperatura Alta/efeitos adversos , Hiperalgesia/etiologia , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxaliplatina
7.
J Orthop Res ; 36(5): 1487-1497, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29068480

RESUMO

Phlpp protein phosphatases are abnormally abundant within human osteoarthritic articular chondrocytes and may contribute to the development of osteoarthritis. Mice lacking Phlpp1 were previously shown to be resistant to post-traumatic osteoarthritis. Here a small molecule with therapeutic properties that inhibits Phlpp1 and Phlpp2 was tested for its ability to slow post-traumatic OA in mice and to stimulate anabolic pathways in human articular cartilage from OA joints. PTOA was induced in male C57Bl/6 mice by surgically destabilizing the meniscus. Seven weeks after surgery, mice received a single intra-articular injection of the Phlpp inhibitor NSC117079 or saline. Mechanical allodynia was measured with von Frey assays, mobility was tracked in an open field system, and cartilage damage was assessed histologically. A single intra-articular injection of the Phlpp inhibitor NSC117079 attenuated mechanical allodynia and slowed articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor 7 weeks after injury maintained normal activity levels, while those in the control group traveled shorter distances and were less active 3 months after the joint injury. NSC117079 also increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2, and PKC) in human articular chondrocytes. Our results indicate that Phlpp inhibitor NSC117079 is a novel osteoarthritis disease modifying drug candidate that may have palliative affects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1487-1497, 2018.


Assuntos
Antraquinonas/farmacologia , Cartilagem Articular/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Sulfonamidas/farmacologia , Idoso , Idoso de 80 Anos ou mais , Animais , Antraquinonas/administração & dosagem , Cartilagem Articular/metabolismo , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Injeções Intra-Articulares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiologia , Osteoartrite/metabolismo , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/fisiologia , Sulfonamidas/administração & dosagem , Microtomografia por Raio-X
8.
Neurotoxicology ; 27(6): 992-1002, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16797073

RESUMO

Cisplatin has been in use for 40 years, primarily for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Neurotoxicity occurs in up to 30% of patients and is dose-limiting for both drugs. The neuropathy is characterized by selective sensory loss in the extremities. Cisplatin treatment is associated with high levels of Pt-DNA binding and apoptosis of dorsal root ganglion (DRG) neurons. In this study, we directly compared the effects of oxaliplatin on DRG in vitro. Compared with cisplatin, oxaliplatin formed fewer Pt-DNA adducts following 6, 12, 24, and 48h (0.007ng Pt/mug DNA, 0.012ng/microg, 0.011ng/microg, 0.011ng/microg versus 0.014ng/microg, 0.022ng/microg, 0.041ng/microg, 0.030ng/microg), respectively. These findings closely correlated with data on cell survival where equimolar concentrations of oxaliplatin induced less cell death than cisplatin. Oxaliplatin-induced DRG death was associated with the morphological characteristics of apoptosis defined by 4'-6-diamidino-2-phenylindole and annexin/propidium iodide staining. Death was completely inhibited by the caspase inhibitor z-VAD-fmk. Our results demonstrate that both compounds cause apoptosis of DRG neurons but compared to cisplatin, oxaliplatin forms fewer Pt-DNA adducts and is less neurotoxic to DRG neurons in vitro.


Assuntos
Gânglios Espinais/citologia , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Platina/farmacocinética , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Anexinas/metabolismo , Contagem de Células/métodos , Células Cultivadas , Cisplatino/toxicidade , DNA/metabolismo , Adutos de DNA/efeitos dos fármacos , Adutos de DNA/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Embrião de Mamíferos , Feminino , Neuritos/efeitos dos fármacos , Neurônios/citologia , Fármacos Neuroprotetores/farmacologia , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Gravidez , Ratos , Ratos Sprague-Dawley
9.
J Clin Oncol ; 33(30): 3416-22, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26282635

RESUMO

PURPOSE: Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. METHODS: Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. RESULTS: Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). CONCLUSION: Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Doença Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Cálcio/uso terapêutico , Doença Crônica , Neoplasias do Colo/tratamento farmacológico , Método Duplo-Cego , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Compostos de Magnésio/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Doenças do Sistema Nervoso Periférico/prevenção & controle
10.
Pain ; 111(1-2): 13-21, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15327804

RESUMO

To compare the efficacy and adverse effects of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with naproxen, a non-steroidal anti-inflammatory drug, and placebo in the treatment of painful temporomandibular joints (TMJs). In this randomized, double-blind, placebo-controlled trial, 68 subjects with painful TMJs secondary to disc-displacement with reduction, received celecoxib 100 mg twice a day; naproxen, 500 mg twice a day; or placebo for 6 weeks. Subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analogue scale, maximal comfortable mandibular opening, and quality of life (SF-36), at baseline (1 week after discontinuing previous analgesic therapy) and again after 6 weeks of drug treatment. Naproxen significantly reduced the symptoms of painful temporomandibular joint disc-displacement (TMJ DD) with reduction as determined by most efficacy measures. Significant improvement in pain intensity occurred within 3 weeks of treatment, and was sustained throughout the 6-week study. Clinically significant improvement in mandibular range of motion was observed for naproxen compared to celecoxib and placebo. Celecoxib showed slightly better pain reduction than placebo, but was not significantly effective for temporomandibular disorder pain. Celecoxib and naproxen were well tolerated, with similar number of reported adverse effects. Dual COX-1 and COX-2 inhibition with naproxen was demonstrated to be effective for the treatment of painful TMJs, as seen by significant improvement in clinical signs and symptoms of TMJ DD with reduction compared to celecoxib and placebo. Inhibition of both COX isozymes is needed to achieve effective analgesia for this type of musculoskeletal pain.


Assuntos
Inibidores de Ciclo-Oxigenase/administração & dosagem , Dor Facial/tratamento farmacológico , Naproxeno/administração & dosagem , Sulfonamidas/administração & dosagem , Transtornos da Articulação Temporomandibular/complicações , Adulto , Celecoxib , Doença Crônica , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/efeitos adversos , Dor Facial/etiologia , Feminino , Humanos , Isoenzimas/antagonistas & inibidores , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Naproxeno/efeitos adversos , Placebos , Prostaglandina-Endoperóxido Sintases , Pirazóis , Qualidade de Vida , Amplitude de Movimento Articular , Sulfonamidas/efeitos adversos , Resultado do Tratamento
11.
J Clin Invest ; 124(1): 72-4, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24355918

RESUMO

Oxaliplatin, a commonly used chemotherapeutic agent, is associated with both acute and chronic neurotoxicity. Chronic sensory neuropathy can be dose limiting and may have detrimental effects on patients' quality of life. Preclinical studies provide an understanding of the pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) and may be important for developing effective preventative interventions. In this issue of the JCI, Coriat and colleagues used an animal model and a human pilot trial to evaluate the use of mangafodipir to reduce CIPN. Although many pilot clinical studies have reported promising data, larger clinical trials have repeatedly been unable to confirm these preliminary results. Thus, no agents are currently clinically recommended for the prevention of CIPN.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/administração & dosagem , Ácido Edético/análogos & derivados , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Fosfato de Piridoxal/análogos & derivados , Animais , Ácido Edético/administração & dosagem , Feminino , Humanos , Masculino , Oxaliplatina , Fosfato de Piridoxal/administração & dosagem
12.
PLoS One ; 8(1): e54161, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23326593

RESUMO

BACKGROUND: Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice. RESULTS: An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment. CONCLUSION: Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.


Assuntos
Hiperalgesia/induzido quimicamente , Neuralgia/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Poli(ADP-Ribose) Polimerases , Animais , Antineoplásicos/toxicidade , Benzimidazóis/administração & dosagem , Benzimidazóis/síntese química , Cisplatino/toxicidade , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/metabolismo
13.
J Oral Maxillofac Surg ; 60(12): 1389-99, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12464999

RESUMO

PURPOSE: An undetermined number of patients with temporomandibular joint (TMJ) symptoms have been treated with intra-articular disc implants composed of Teflon ethylene/propylene or Teflon polytetrafluoroethylene and aluminum oxide (Proplast-Teflon; Vitek, Houston, TX). These implants have shown the potential to fragment in situ resulting in nonbiodegradable particles that stimulate a giant cell reaction and lead to degeneration of local structures, pain, and limitation of mandibular opening. We examined the possible relationship between TMJ implants and persistent pain, responses to sensory stimuli, quality of life, and systemic immune dysfunction. PATIENTS AND METHODS: This case series (32 patients) were referred from university-based orofacial pain centers and private practices from across the United States. Laboratory and clinical assessments evaluated orofacial pain symptoms, neurologic function, clinical signs and symptoms of rheumatologic disease, physical function, systemic measures of immune function, and behavioral measures. RESULTS: We found that TMJ implant patients appeared to have altered sensitivity to sensory stimuli, a higher number of tender points with a diagnosis of fibromyalgia, increased self-report of chemical sensitivity, higher psychologic distress and significantly lower functional ability. Systemic illness or autoimmune disease was not evident in this series of TMJ implant patients. CONCLUSIONS: Significant problems were noted on clinical assessment of TMJ implant patients. This is a US government work. There are no restrictions on its use.


Assuntos
Artroplastia de Substituição/efeitos adversos , Dor Facial/etiologia , Prótese Articular/efeitos adversos , Qualidade de Vida , Transtornos da Articulação Temporomandibular/cirurgia , Articulação Temporomandibular/cirurgia , Adulto , Análise de Variância , Artroplastia de Substituição/psicologia , Doenças Autoimunes/etiologia , Exposição Ambiental , Feminino , Fibromialgia/etiologia , Humanos , Imunofenotipagem , Prótese Articular/psicologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Politetrafluoretileno/efeitos adversos , Proplast/efeitos adversos , Amplitude de Movimento Articular , Estatísticas não Paramétricas , Articulação Temporomandibular/imunologia , Articulação Temporomandibular/fisiologia , Transtornos da Articulação Temporomandibular/psicologia
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