RESUMO
Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Arctium , Carcinoma Adenoescamoso/sangue , Carcinoma Ductal Pancreático/sangue , Medicamentos de Ervas Chinesas/uso terapêutico , Furanos/uso terapêutico , Ácido Láctico/sangue , Lignanas/uso terapêutico , Neoplasias Pancreáticas/sangue , Extratos Vegetais/uso terapêutico , Antineoplásicos Fitogênicos/farmacocinética , Arctium/química , Área Sob a Curva , Biomarcadores/sangue , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/farmacocinética , Furanos/farmacocinética , Gluconeogênese/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Lignanas/farmacocinética , Fígado/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , GencitabinaRESUMO
PURPOSE: To investigate the ocular effect of intravenous administration of a phosphodiesterase type 3 inhibitor (NSP-805) and to compare the effect of NSP-805 with that of a calcium antagonist (nicardipine hydrochloride) on chorio-retinal blood flow in anesthetized albino rabbits. METHODS: Twenty-four female albino rabbits (weighting 2.0-4.0 kg) were anesthetized with intravenous injection. NSP-805(40 micrograms/kg and 100 micrograms/kg) and nicardipine of 40 micrograms/kg were intravenously administrated to the anesthetized rabbits. Intravenously administration of 20% dimethyl sulfoxide (DMSO) was used as a vehicle. Chorio-retinal blood flow was measured with a laser Doppler flowmeter at baseline and every 20 minutes after intravenous administration for 120 minutes. Heart rates and systemic blood pressure were monitored. Baseline measurements were compared with every 10 minutes after intravenous administration. Differences between the drug groups and vehicle group were analyzed. RESULTS: After administration of a low dose of NSP--805 (40 micrograms/kg) and nicardipine (40 micrograms/kg), the chorio-retinal blood flow was significantly increased (p < 0.05). A high dose NSP-805(100 micrograms/kg) reduced systemic blood pressure significantly, but the increase of chorio-retinal blood flow was less than that at the low dose of NSP-805(40 micrograms/kg) and nicardipine (40 micrograms/kg). Chorio-retinal blood flow in the NSP 805(40 micrograms/kg) and nicardipine (40 micrograms/kg) groups was significantly increased over that in the control group (20% DMSO) (p < 0.05). CONCLUSION: The results suggest that the NSP-805 has the potential of increasing chorio-retinal blood flow in rabbit eyes.