RESUMO
BACKGROUND: Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells. METHODS: Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves. RESULTS: Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 µg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice. CONCLUSION: These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.
Assuntos
Adenocarcinoma/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Compostos Organoplatínicos/toxicidade , Peptídeos/farmacologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Peçonhas/farmacologia , Adenocarcinoma/patologia , Animais , Antineoplásicos/toxicidade , Neoplasias do Colo/patologia , Exenatida , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuritos/efeitos dos fármacos , Oxaliplatina , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/citologia , Nervo Isquiático/efeitos dos fármacosRESUMO
Oxaliplatin causes severe peripheral neuropathy. In this study, we examined hypomyelination in the peripheral nerve in oxaliplatin-induced neuropathy rat model. Gene expression of neuregulin 1 (NRG1), a myelination regulatory factor, is reduced in the dorsal root ganglion (DRG) in DNA microarray analysis. Oxaliplatin increased the g-ratio and reduced levels of myelin protein zero in sciatic nerve, suggesting the hypomyelination. Moreover, oxaliplatin reduced NRG1 mRNA levels in the DRG and decreased levels of cleaved NRG1 type III protein in the sciatic nerve. Our results indicate that oxaliplatin induces hypomyelination and reduced NRG1 expression.
Assuntos
Antineoplásicos/farmacologia , Neuregulina-1/metabolismo , Compostos Organoplatínicos/farmacologia , Polirradiculoneuropatia , Nervo Isquiático/metabolismo , Animais , Axônios/patologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Neuregulina-1/genética , Análise de Sequência com Séries de Oligonucleotídeos , Oxaliplatina , Polirradiculoneuropatia/induzido quimicamente , Polirradiculoneuropatia/metabolismo , Polirradiculoneuropatia/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Fatores de TempoRESUMO
AIMS: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic peripheral neuropathies. We previously reported that repeated administration of neurotropin prevents oxaliplatin-induced mechanical allodynia by inhibiting axonal degeneration in rats. In the present study, we investigated the analgesic effect of a single administration of neurotropin on oxaliplatin-induced neuropathy in rats. MAIN METHODS: Oxaliplatin (4mg/kg) was administered intraperitoneally twice a week for 4weeks. Cold hyperalgesia was assessed using the acetone test and mechanical allodynia was evaluated using the von Frey test. KEY FINDINGS: Repeated injection of oxaliplatin induced cold hyperalgesia on day 5 and mechanical allodynia on day 28. A single administration of neurotropin transiently relieved both pain behaviors. The analgesic effect of neurotropin was inhibited by pretreatment with 5-HT1A, 5-HT2, 5-HT3, and α2 receptor antagonists and by monoamine depletion. Moreover, the analgesic effect of neurotropin was abolished by intrathecal injection of pertussis toxin, a Gi protein inhibitor. SIGNIFICANCE: These results suggest that neurotropin is effective in relieving oxaliplatin-induced neuropathy, and that Gi protein-coupled receptors in the monoaminergic descending pain inhibitory system may be involved in the analgesic effect of neurotropin. Neurotropin may have clinical potential for the treatment of oxaliplatin-induced neuropathies.
Assuntos
Analgésicos/farmacologia , Neuralgia/induzido quimicamente , Compostos Organoplatínicos , Polissacarídeos/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Analgésicos/uso terapêutico , Animais , Masculino , Neuralgia/tratamento farmacológico , Oxaliplatina , Polissacarídeos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Medula Espinal/metabolismoAssuntos
Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Náusea/induzido quimicamente , Náusea/prevenção & controle , Paclitaxel/efeitos adversos , Substância P/fisiologia , Vômito/induzido quimicamente , Vômito/prevenção & controle , Animais , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Substância P/metabolismoAssuntos
Antineoplásicos/efeitos adversos , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Ácidos Borônicos/efeitos adversos , Bortezomib , Temperatura Baixa/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Hiperalgesia/induzido quimicamente , Oxaliplatina , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Pirazinas/efeitos adversos , Transtornos de Sensação/induzido quimicamente , Transtornos de Sensação/prevenção & controle , Vincristina/efeitos adversos , Vitamina B 12/administração & dosagem , Vitamina B 12/análogos & derivadosAssuntos
Acetilcisteína/administração & dosagem , Antineoplásicos/efeitos adversos , Glutationa/administração & dosagem , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/prevenção & controle , Vimblastina/análogos & derivados , Antineoplásicos/administração & dosagem , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , VinorelbinaRESUMO
STUDY OBJECTIVE: To evaluate the efficacy and safety of aprepitant added to standard antiemetic regimens used in high-dose chemotherapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT). DESIGN: Retrospective medical record review. SETTING: Hematology ward of a university hospital in Japan. PATIENTS: Of 88 patients treated with high-dose chemotherapy followed by allo-HSCT, 46 received aprepitant and granisetron as antiemetic therapy (between April 1, 2010, and December 31, 2011), and 42 received granisetron alone (between April 1, 2008, and March 31, 2010). INTERVENTIONS: Patients in both groups received 3 mg of granisetron intravenously 30 minutes before the administration of anticancer drugs. In the aprepitant group, 125 mg of aprepitant was administered orally 60-90 minutes before the administration of the first moderately to highly emetogenic anticancer drug. On the following days, 80 mg of aprepitant was administered orally every morning. The mean administration duration of aprepitant was 3.3 days (range 3-6 days). MEASUREMENTS AND MAIN RESULTS: The primary objective was to evaluate the percentage of patients who achieved complete response (CR; no vomiting and none to mild nausea). The CR rate in the aprepitant group was significantly higher than that in the control group (48% vs 24%, p=0.02). Multivariate analysis showed that nonprophylactic use of aprepitant was associated with failure to achieve CR (odds ratio [OR] 2.92; 95% confidence interval [CI] 1.13-7.99, p=0.03). The frequency of abdominal pain was lower in the aprepitant group (9% vs 25%, p=0.03). Rates of other frequently observed adverse drug events were similar between groups. There was no significant difference in neutrophil engraftment (median 18 vs 17 days), platelet engraftment (median 32 vs 32 days), the incidence of acute graft-versus-host-disease (63% vs 55%, p=0.52), viral infection (74% vs 67%, p=0.49), or 1-year overall survival (63% vs 62%, p=0.90) between the two groups. CONCLUSIONS: The addition of aprepitant to granisetron increases the antiemetic effect without influencing transplantation-related toxicities in allo-HSCT.
Assuntos
Antieméticos/efeitos adversos , Antieméticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Morfolinas/efeitos adversos , Morfolinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Aprepitanto , Quimioterapia Combinada , Feminino , Granisetron/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Náusea/prevenção & controle , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/prevenção & controleRESUMO
For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT3 antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 min before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60-90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1-2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT.
Assuntos
Antieméticos/administração & dosagem , Granisetron/administração & dosagem , Morfolinas/administração & dosagem , Náusea/prevenção & controle , Antagonistas dos Receptores de Neurocinina-1/administração & dosagem , Vômito/prevenção & controle , Adulto , Idoso , Antieméticos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aprepitanto , Povo Asiático , Feminino , Granisetron/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Antagonistas dos Receptores de Neurocinina-1/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Intravenous injection of bendamustine often causes venous irritation and also deteriorates the patient's quality of life. Thus, we evaluated the risk factors associated with venous irritation induced by bendamustine in patients with follicular lymphoma or mantle cell lymphoma. We also evaluated the effectiveness of intervention of changing the preparation procedure for bendamustine. All data were retrospectively collected from the electronic medical record system. In the initial analysis of the total 43 courses of bendamustine therapy, most patients (88%) were administered bendamustine with 250 mL of diluent according to the bendamustine package insert in Japan. The median concentration of bendamustine solution (0.56 mg/mL vs. 0.24 mg/mL) and the incidences of venous irritation (66% vs. 0%, p=0.01) were significantly different between the patients receiving bendamustine at 250 mL and 500 mL of diluent. Based on this result, we proposed changing the final volume of bendamustine dissolution from 250 to 500 mL, which is recommended in other countries. After this intervention, the incidence of venous irritation was significantly reduced from 58 to 20% (p=0.02). The incidence of venous irritation increased in a concentration-dependent manner (≤0.40 mg/mL: 6%; 0.41-0.60 mg/mL: 62%, p<0.001; >0.60 mg/mL: 75%, p<0.001). We conclude that a high concentration bendamustine solution is a risk factor for venous irritation and that 500 mL of diluent is ideal. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be 0.40 mg/mL or less.
Assuntos
Antineoplásicos/administração & dosagem , Irritantes/administração & dosagem , Compostos de Mostarda Nitrogenada/administração & dosagem , Dor/prevenção & controle , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Cloridrato de Bendamustina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/induzido quimicamente , Rituximab , VeiasRESUMO
PURPOSE: Antiemetic effectiveness and safety of aprepitant in patients with hematologic malignancy receiving multiday chemotherapy were evaluated. METHODS: All data were retrospectively collected from the Kyushu University Hospital's electronic medical record system. Patients age 20 years or older with hematologic malignancies who received multiday chemotherapy were included in the study. All patients received 3 mg of granisetron i.v. 30 minutes before chemotherapy administration. Patients in the aprepitant group received 125 mg of aprepitant orally 60-90 minutes before administration of the first moderately to highly emetogenic chemotherapy (day 1). On day 2 or thereafter, an 80-mg oral dose of aprepitant was administered in the morning for up to five days. The primary endpoint was the percentage of patients who achieved complete response (CR). RESULTS: A total of 42 patients were treated with aprepitant and granisetron as antiemetic prophylaxis between April and December 2010 (aprepitant group), and 40 patients were treated with only granisetron between March 1, 2009, and March 31, 2010, before the introduction of aprepitant. The percentage of patients who achieved CR in the aprepitant group was significantly higher than that in the control group (p = 0.01). Factors that were significantly associated with non-CR included the prophylactic use of aprepitant and chemotherapies containing ≥4 g/m(2)/day of cytarabine. The rates of adverse drug events (ADEs) did not significantly differ between groups. CONCLUSION: The addition of aprepitant to granisetron increased the antiemetic effect without influencing ADEs in patients treated with moderately to highly emetogenic multiday chemotherapy for hematologic malignancies.
Assuntos
Antieméticos/uso terapêutico , Morfolinas/uso terapêutico , Náusea/prevenção & controle , Vômito/prevenção & controle , Administração Oral , Adulto , Idoso , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aprepitanto , Quimioterapia Combinada , Feminino , Granisetron/administração & dosagem , Granisetron/efeitos adversos , Granisetron/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Náusea/induzido quimicamente , Estudos Retrospectivos , Resultado do Tratamento , Vômito/induzido quimicamente , Adulto JovemRESUMO
Oxaliplatin-based chemotherapy has been widely used for colorectal cancer. However, it causes severe acute and chronic peripheral neuropathies. Recently, we reported that calcium channel blockers prevent the oxaliplatin-induced cold hyperalgesia in rats. The purpose of this study was to determine whether the treatment with calcium channel blockers prevents the peripheral neuropathy during oxaliplatin therapy. The electronic medical charts for patients who received modified FOLFOX6 regimen from January 2008 to December 2010 were evaluated. Of the 200 patients who received modified FOLFOX6 therapy, 84 patients were excluded due to the exclusion criteria. Calcium channel blockers had been taken by 26 of 69 male patients, but only three of 47 female patients. Therefore, in the present analysis, the male data of the groups with and without calcium channel blockers (n=26 and 43, respectively) were compared. The cumulative incidence curve of acute neuropathy was significantly lower in the group with calcium channel blockers (P=0.0438, log-rank test), whereas there was no difference between these groups in the cumulative incidence curve of chronic neuropathy (P=0.4919, log-rank test). The present study indicated that calcium channel blockers inhibit the development of acute peripheral neuropathy in patients receiving modified FOLFOX6 therapy.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Incidência , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos RetrospectivosRESUMO
RATIONALE: Obsessive-compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD. OBJECTIVES: In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior. METHODS: The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated. RESULTS: Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble-burying behavior in ddY mice. The selective GABA(A) receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA(B) receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA(A) receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg). CONCLUSIONS: These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA(A) receptor-dependent mechanism.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Ácido gama-Aminobutírico/metabolismo , Animais , Antipsicóticos/administração & dosagem , Baclofeno/administração & dosagem , Baclofeno/farmacologia , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Carbamazepina/administração & dosagem , Carbamazepina/farmacologia , Relação Dose-Resposta a Droga , Lamotrigina , Carbonato de Lítio/administração & dosagem , Carbonato de Lítio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Muscimol/administração & dosagem , Muscimol/farmacologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Receptores de GABA-A/efeitos dos fármacos , Triazinas/administração & dosagem , Triazinas/farmacologia , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologiaRESUMO
The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15-30 µg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400 mg twice on Day 1, followed by 400 mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72 h after the initial loading dose (C(min)(72 h)) and at steady state (C(ss)(min)). The percentage of observed C(min)(72 h) in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C(min)(72 h) was <10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C(min)(72 h) and C(ss)(min) of 15 µg/mL and 20-25 µg/mL, respectively. The percentage of C(min)(72 h) and C(ss)(min) in the range 15-30 µg/mL was 43-65% and 61-82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15-30 µg/mL.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Peso Corporal , Rim/fisiologia , Teicoplanina/administração & dosagem , Teicoplanina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos EstatísticosRESUMO
Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Amitriptyline has widely been used in patients with painful neuropathy. In this study, we investigated the effect of amitriptyline on the oxaliplatin-induced neuropathy in rats. Repeated administration of amitriptyline (5 and 10 mg/kg, p.o., once a day) reduced the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia and reversed the oxaliplatin-induced increase in the expression of NR2B protein and mRNA in rat spinal cord. These results suggest that amitriptyline is useful for the treatment of oxaliplatin-induced neuropathy clinically.
Assuntos
Amitriptilina/administração & dosagem , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Compostos Organoplatínicos/toxicidade , Animais , Relação Dose-Resposta a Droga , Masculino , Compostos Organoplatínicos/antagonistas & inibidores , Oxaliplatina , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca(2+)/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca(2+) influx, in the oxaliplatin-induced mechanical allodynia in rats. RESULTS: An increase of CaMKII phosphorylation was found in the spinal cord (L(4-6)) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats. CONCLUSIONS: These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/enzimologia , Compostos Organoplatínicos/efeitos adversos , Animais , Antipsicóticos/uso terapêutico , Benzilaminas/uso terapêutico , Hiperalgesia/induzido quimicamente , Masculino , Oxaliplatina , Fenóis/uso terapêutico , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sulfonamidas/uso terapêutico , Trifluoperazina/uso terapêuticoRESUMO
In the present study, we examined the effect of N-acetyl-L-cysteine (NAC), a glutamate-modulating agent, on marble-burying behavior in mice. Fluvoxamine (30 mg/kg, p.o.) and mirtazapine (3 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. Similarity, NAC (150 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. On the other hand, the antioxidant α-tocopherol (10, 30, and 100 mg/kg, p.o.) had no effect on the marble-burying behavior. These results suggest that the glutamatergic system is involved in the marble-burying behavior, and NAC may be useful for treatment of OCD.
Assuntos
Acetilcisteína/farmacologia , Antipsicóticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Animais , Fluvoxamina/farmacologia , Masculino , Mianserina/análogos & derivados , Mianserina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Mirtazapina , alfa-Tocoferol/farmacologiaRESUMO
We examined the role of 5-hydroxytryptamine(2C) (5-HT(2C)) receptors in marble-burying behavior in mice. When administered alone, the selective 5-HT(2C) agonist WAY161503 (3 mg/kg) inhibited marble-burying behavior. Moreover, the selective 5-HT(2C) antagonist SB242084 (3 mg/kg) reversed the inhibition of marble-burying behavior by 2,5-dimethoxy-4-iodoamphetamine (DOI) (1 mg/kg) or WAY161503 (3 mg/kg). Similarly, SB242084 (1 mg/kg) reversed the inhibition of marble-burying behavior by fluvoxamine (30 mg/kg) or paroxetine (3 mg/kg). These results suggest that 5-HT(2C) receptors play a role in marble-burying behavior in mice.
Assuntos
Comportamento Animal/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Aminopiridinas/farmacologia , Anfetaminas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Paroxetina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologiaRESUMO
Vancomycin chloride (VCM), a glycopeptide antibiotic, is widely used for the therapy of infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is a major adverse effect in VCM therapy. In this study, we investigated the cellular mechanisms underlying VCM-induced renal tubular cell injury in cultured LLC-PK1 cells. VCM induced a concentration- and time-dependent cell injury in LLC-PK1 cells. VCM caused increases in the numbers of annexin V-positive/PI-negative cells and TUNEL-positive cells, indicating the involvement of apoptotic cell death in VCM-induced renal cell injury. The VCM-induced apoptosis was accompanied by the activation of caspase-9 and caspase-3/7 and reversed by inhibitors of these caspases. Moreover, VCM caused an increase in intracellular reactive oxygen species production and mitochondrial membrane depolarization, which were reversed by vitamin E. In addition, mitochondrial complex I activity was inhibited by VCM as well as by the complex I inhibitor rotenone, and rotenone mimicked the VCM-induced LLC-PK1 cell injury. These findings suggest that VCM causes apoptotic cell death in LLC-PK1 cells by enhancing mitochondrial superoxide production leading to mitochondrial membrane depolarization followed by the caspase activities. Moreover, mitochondrial complex I may play an important role in superoxide production and renal tubular cell apoptosis induced by VCM.
Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Mitocôndrias/metabolismo , Superóxidos/metabolismo , Vancomicina/farmacologia , Animais , Caspases/metabolismo , Citocromos c/metabolismo , Citometria de Fluxo , Marcação In Situ das Extremidades Cortadas , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Células LLC-PK1 , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/enzimologia , Superóxido Dismutase/metabolismo , SuínosRESUMO
Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 µM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and L-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.