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Sumatriptan was introduced in 1983, as the first of the triptans, selective 5-hydroxytryptamine (5-HT1B/1D ) receptor agonists, to treat moderate to severe migraine. Migraine predominates in females. Although there have been reports of sex differences in migraine-associated features and pharmacokinetics (PKs) of some triptans, sex differences in the PKs of oral sumatriptan have never been evaluated in Korean. We conducted this study of oral sumatriptan to assess the sex differences in Korean population. Thirty-eight healthy Korean subjects who participated in two separate clinical studies receiving a single oral dose of 50 mg sumatriptan with the same protocols were included in this analysis. A total of 532 sumatriptan concentration observations were used for a population PK modeling. Validation of final population PK model of sumatriptan was performed using bootstrap and visual predictive check. The PK profile of oral sumatriptan was adequately described by a one-compartmental model with combined transit compartment model and a first-order absorption. The covariate analysis showed that the clearance of oral sumatriptan was significantly higher in males than in females (male: 444 L/h, female: 281 L/h). Our results showed that there were sex differences in the clearance of oral sumatriptan. These results encourage further studies to establish the sumatriptan pharmacokinetic-pharmacodynamic model considering sex-related PK differences, which may help to determine optimal dosing regimens for effective treatment of migraine in males and females. Clinical trial registration: CRIS Registration No. KCT0001784.
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Transtornos de Enxaqueca , Sumatriptana , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , República da Coreia , Agonistas do Receptor de Serotonina , Caracteres SexuaisRESUMO
OBJECTIVE: A consensus regarding the ideal regimen for urokinase (UK) thrombolysis subsequent to stereotactic spontaneous intracerebral hemorrhage aspiration has yet to be established. The purpose of this study is to evaluate the efficacy of UK thrombolysis relative to when the regimen is changed. METHODS: Venous blood from 30 heathy volunteers was obtained for this in-vitro study. Various concentrations of UK solution were added to microcentrifuge tubes containing the clotted blood. The efficacy of UK thrombolysis was identified by checking the weight of lysed hematoma following various time intervals with different concentrations of UK solution. Group one, the "3×4" group involved four administrations every 3 hours over 12 hours, and group two, the "6×2" group involved two administrations every 6 hours over 12 hours. RESULTS: More hematoma was lysed in the 3×4 group than the 6×2 group across all concentration levels (however, the differences were only significant between groups at the 500 and 1000 IU concentration levels, p<0.05). There were no significant differences of lysed hematoma among the various UK solution concentrations within groups. CONCLUSION: This study suggests that frequent administrations of UK thrombolysis may result in a greater degree of lysed hematoma in comparison to a higher concentration of UK.
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PURPOSE: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. METHODS: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. RESULTS: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. CONCLUSION: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.
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Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Ácido Oxônico/farmacocinética , Piridinas/farmacocinética , Neoplasias Gástricas/metabolismo , Tegafur/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Cromatografia Líquida , Estudos Cross-Over , Composição de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/sangue , Piridinas/administração & dosagem , Piridinas/sangue , República da Coreia , Neoplasias Gástricas/química , Espectrometria de Massas em Tandem , Tegafur/administração & dosagem , Tegafur/sangue , Equivalência TerapêuticaRESUMO
OBJECTIVE: While the risk of aneurysmal rebleeding induced by catheter cerebral angiography is a serious concern and can delay angiography for a few hours after a subarachnoid hemorrhage (SAH), current angiographic technology and techniques have been much improved. Therefore, this study investigated the risk of aneurysmal rebleeding when using a recent angiographic technique immediately after SAH. METHODS: Patients with acute SAH underwent immediate catheter angiography on admission. A four-vessel examination was conducted using a biplane digital subtraction angiography (DSA) system that applied a low injection rate and small volume of a diluted contrast, along with appropriate control of hypertension. Intra-angiographic aneurysmal rebleeding was diagnosed in cases of extravasation of the contrast medium during angiography or increased intracranial bleeding evident in flat-panel detector computed tomography scans. RESULTS: In-hospital recurrent hemorrhages before definitive treatment to obliterate the ruptured aneurysm occurred in 11 of 266 patients (4.1%). Following a univariate analysis, a multivariate analysis using a logistic regression analysis revealed that modified Fisher grade 4 was a statistically significant risk factor for an in-hospital recurrent hemorrhage (p =0.032). Cerebral angiography after SAH was performed on 88 patients ≤3 hours, 74 patients between 3-6 hours, and 104 patients >6 hours. None of the time intervals showed any cases of intra-angiographic rebleeding. Moreover, even though the DSA ≤3 hours group included more patients with a poor clinical grade and modified Fisher grade 4, no case of aneurysmal rebleeding occurred during erebral angiography. CONCLUSION: Despite the high risk of aneurysmal rebleeding within a few hours after SAH, emergency cerebral angiography after SAH can be acceptable without increasing the risk of intra-angiographic rebleeding when using current angiographic techniques and equipment.
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INTRODUCTION: Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. METHODS: In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. RESULTS: Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. CONCLUSION: When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. CLINICAL TRIAL REGISTRATION: https://cris.nih.go.kr CRIS KCT0001660. FUNDING: KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.
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Anlodipino , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Rosuvastatina Cálcica , Valsartana , Adulto , Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacocinética , Valsartana/administração & dosagem , Valsartana/farmacocinéticaRESUMO
To improve early renal allograft function, it is important to develop a noninvasive diagnostic method for acute T cell-mediated rejection (TCMR). This study aims to explore potential noninvasive urinary biomarkers to screen for acute TCMR in kidney transplant recipients (KTRs) using untargeted metabolomic profiling. Urinary metabolites, collected from KTRs with stable graft function (STA) or acute TCMR episodes, were analyzed using liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses were performed to discriminate differences in urinary metabolites between the two groups. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of potential urinary biomarkers. Statistical analysis revealed the differences in urinary metabolites between the two groups and indicated several statistically significant metabolic features suitable for potential biomarkers. By comparing the retention times and mass fragmentation patterns of the chemicals in metabolite databases, samples, and standards, six of these features were clearly identified. ROC curve analysis showed the best performance of the training set (area under the curve value, 0.926; sensitivity, 90.0%; specificity, 84.6%) using a panel of five potential biomarkers: guanidoacetic acid, methylimidazoleacetic acid, dopamine, 4-guanidinobutyric acid, and L-tryptophan. The diagnostic accuracy of this model was 62.5% for an independent test dataset. LC-MS-based untargeted metabolomic profiling is a promising method to discriminate between acute TCMR and STA groups. Our model, based on a panel of five potential biomarkers, needs to be further validated in larger scale studies.
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Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/urina , Transplante de Rim , Metaboloma/fisiologia , Metabolômica/métodos , Adulto , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Feminino , Rejeição de Enxerto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Linfócitos T/metabolismo , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: Although mannitol is used widely to facilitate brain retraction in cases of ruptured aneurysms, there is no consensus about the intraoperative administration of mannitol in the case of unruptured aneurysms. Accordingly, this study was conducted to identify an intraoperative mannitol administration strategy. METHODS: Mannitol was administered routinely to patients (n = 90) from January 2015 to April 2016 and not administered to patients (n = 97) from May 2016 to June 2017. The patient groups with and without mannitol administration were then compared based on the patient medical records, radiologic data, and digital recordings from an intraoperative microscope. RESULTS: The patient groups with and without mannitol administration were comparable regarding patient age, number of elderly patients, sex, and aneurysm locations. No between-group difference was identified in terms of the intradural procedural time, retraction-induced cortical injury, postoperative electrolyte imbalance, symptomatic infarction, and postoperative epidural hematomas. However, the patient group without mannitol administration showed a significantly lower incidence of chronic subdural hematomas (CSDHs) >50 mL (13.3% vs. 3.1%, P = 0.010). Moreover, a multivariate analysis revealed that an advanced age (P = 0.019), male sex (P <0.001), and mannitol administration (P = 0.040) were all statistically significant risk factors for a postoperative CSDH >50 mL following unruptured aneurysm surgery. CONCLUSIONS: Withholding the administration of mannitol during a pterional or modified procedure for unruptured aneurysms was found to reduce the postoperative occurrence of a CSDH without increasing the operative difficulties or other postoperative complications.
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Aneurisma Roto/cirurgia , Hematoma Subdural Crônico/etiologia , Aneurisma Intracraniano/complicações , Manitol/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Aneurisma Roto/tratamento farmacológico , Craniotomia/efeitos adversos , Feminino , Hematoma Subdural Crônico/cirurgia , Humanos , Incidência , Aneurisma Intracraniano/cirurgia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Fatores de Risco , Instrumentos Cirúrgicos/efeitos adversosRESUMO
Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)-induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow-derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c-Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N-(4-(diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA-mediated knockdown of ERRγ accelerated the formation of bone-resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL-stimulated phosphorylation of the nuclear factor κB (NF-κB) inhibitor IκBα and suppressed NF-κB transcriptional activity induced by RANKL or the NF-κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL-mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss.
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Macrófagos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Estrogênios/farmacologia , Regulação da Expressão Gênica , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteoporose/genética , Osteoporose/patologia , Osteoporose/prevenção & controle , Ligante RANK/farmacologia , Células RAW 264.7 , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/genética , Transdução de SinaisRESUMO
OBJECTIVE: To evaluate the combined effects of a decompressive craniectomy and prolonged selective brain hypothermia on large hemispheric infarction in a rat model. METHODS: Permanent middle cerebral artery infarction using an endovascular occlusion technique was created in rats assigned to 4 groups. Normothermia was maintained without a craniectomy in group A (n = 20) as the control, prolonged (>44 hours), selective brain hypothermic treatment was performed on group B (n = 20), a craniectomy was performed on group C (n = 18), and prolonged, selective brain hypothermic treatment using a cooling coil implanted in the craniectomy site was combined with a craniectomy for group D (n = 18). RESULTS: Group B and C exhibited a significantly reduced infarct volume when compared with the control. Furthermore, group D showed a significantly reduced infarct volume when compared with group C, plus a significantly improved neurologic score. These results for group D were associated with an increased neuronal cell count and reduced hyperactive microglia and hypertrophic astrocytes in the cortical penumbra (P < 0.01). Moreover, a greater preservation of normal-appearing axonal bundles and the blood-brain barrier was observed in the core infarct region at the caudoputamen. CONCLUSIONS: A decompressive craniectomy reduced the infarct volume and improved the neurologic outcomes in a rat model of middle cerebral artery infarction. Furthermore, when combined with prolonged selective brain hypothermia, significant additional benefits were observed for the neurologic outcomes, infarct volume, and degree of neuroinflammation.
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Craniectomia Descompressiva/métodos , Hipotermia Induzida/métodos , Infarto da Artéria Cerebral Média/terapia , Animais , Axônios/patologia , Morte Celular , Córtex Cerebral/fisiologia , Craniotomia/métodos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/patologia , Masculino , Doenças do Sistema Nervoso/fisiopatologia , Neuroglia/fisiologia , Neurônios/patologia , Neuroproteção/fisiologia , Ratos WistarRESUMO
PURPOSE: A new fixed-dose combination (FDC) formulation of 120 mg fimasartan and 20 mg rosuvastatin was developed to increase therapeutic convenience and improve treatment compliance. METHODS: A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day washout period was conducted to compare the pharmacokinetic (PK) characteristics and bioequivalence between an FDC of fimasartan/rosuvastatin and the separate co-administration of fimasartan and rosuvastatin in healthy Korean volunteers. The plasma concentrations of fimasartan and rosuvastatin were analyzed by a validated liquid chromatography-tandem mass spectrometry method, for which serial blood samples were collected for up to 48 hours post-administration of fimasartan and 72 hours post-administration of rosuvastatin, in each period. The PK parameters were calculated using a non-compartmental method. RESULTS: A total of 78 subjects completed the study. All the 90% CIs of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. The GMR and 90% CI for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the maximum plasma concentration (Cmax) for fimasartan were 0.9999 (0.9391-1.0646) and 1.0399 (0.8665-1.2479), respectively. The GMR and 90% CI for the AUC0-t and Cmax for rosuvastatin were 1.0075 (0.9468-1.0722) and 1.0856 (0.9944-1.1852), respectively. Treatment with fimasartan and rosuvastatin was generally well tolerated without serious adverse events. CONCLUSION: The new FDC formulation of 120 mg fimasartan and 20 mg rosuvastatin can be substituted for the separate co-administration of fimasartan and rosuvastatin, for the advantage of better compliance with convenient therapeutic administration.
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Compostos de Bifenilo/farmacocinética , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/sangue , República da Coreia , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/sangue , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Equivalência Terapêutica , Adulto JovemRESUMO
Purpose: Red ginseng is one of the world's most popular herbal medicines; it exhibits a wide range of pharmacologic activities and is often co-ingested with other herbal and conventional medicines. This open-label, randomized, 3-period study investigated the in vivo herb-drug interaction potential for red ginseng extract with cytochrome P-450 (CYP) enzymes and organic anion-transporting polypeptide (OATP) 1B1. METHODS: Fifteen healthy male volunteers (22-28 years; 57.1-80.8 kg) were administered a single dose of cocktail probe substrates (caffeine 100 mg, losartan 50 mg, omeprazole 20 mg, dextromethorphan 30 mg, midazolam 2 mg, and pitavastatin 2 mg) and single or multiple doses of red ginseng extract for 15 days. FINDINGS: The pharmacokinetic profiles of the probe substrates and metabolites after single- or multiple-dose administration of red ginseng extracts were comparable to the corresponding profiles of the control group. The geometric mean ratio of AUC0-t and 90% CIs for the probe substrate drugs between the control and multiple doses of red ginseng for 15 days were within 0.8 to 1.25 (CYP2C9, CYP3A4, and OATP1B1 probe substrates) or slightly higher (CYP1A2, CYP2C19, and CYP2D6 probe substrates). Additional assessments of the in vitro drug interaction potential of red ginseng extracts and the ginsenoside Rb1 on drug-metabolizing enzymes and transporters using human liver microsomes, cryopreserved human hepatocytes, and transporter-overexpressed cells were negative. IMPLICATIONS: Red ginseng poses minimal risks for clinically relevant CYP- or OATP-mediated drug interactions and is well tolerated. Clinical Research Information Service registry no.
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Sistema Enzimático do Citocromo P-450/metabolismo , Panax , Preparações de Plantas/farmacologia , Adulto , Cafeína/metabolismo , Cafeína/farmacocinética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Dextrometorfano/metabolismo , Dextrometorfano/farmacocinética , Interações Medicamentosas , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Losartan/metabolismo , Losartan/farmacocinética , Masculino , Midazolam/metabolismo , Midazolam/farmacocinética , Omeprazol/metabolismo , Omeprazol/farmacocinética , Distribuição Aleatória , Adulto JovemRESUMO
A rapid and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (P450) probe substrates and their phase I metabolites in human plasma was developed. The OATP1B1 (pitavastatin) and five P450 probe substrates, caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) and their metabolites were extracted from human plasma (50 µL) using methanol. Analytes were separated on a C18 column followed by selected reaction monitoring detection using MS/MS. All analytes were separated simultaneously within a 9 min run time. The developed method was fully validated over the expected clinical concentration range for all analytes tested. The intra- and inter-day precisions for all analytes were lower than 11.3% and 8.82%, respectively, and accuracy was 88.5â»117.3% and 96.1â»109.2%, respectively. The lower limit of quantitation was 0.05 ng/mL for dextromethorphan, dextrorphan, midazolam, and 1'-hydroxymidazolam; 0.5 ng/mL for losartan, EXP-3174, omeprazole, 5'-hydroxyomeprazole, and pitavastatin; and 5 ng/mL for caffeine and paraxanthine. The method was successfully used in a pharmacokinetic study in healthy subjects after oral doses of five P450 and OATP1B1 probes. This analytical method provides a simple, sensitive, and accurate tool for the determination of OATP1B1 and five major P450 activities in vivo drug interaction studies.
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PURPOSE: A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. METHODS: The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. RESULTS: Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan Cmax and AUC0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine Cmax and AUC0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the Cmax for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. CONCLUSION: CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.
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Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Adulto , Anlodipino/efeitos adversos , Anlodipino/sangue , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Benzoatos/efeitos adversos , Benzoatos/sangue , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Tolerância a Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Relação Estrutura-Atividade , Comprimidos , Espectrometria de Massas em Tandem , Telmisartan , Equivalência Terapêutica , Adulto JovemRESUMO
OBJECTIVE The objective of this study was to evaluate and compare the level of patient satisfaction and approach-related patient complaints between a superciliary keyhole approach and a pterional approach. METHODS Patients who underwent an ipsilateral superciliary keyhole approach and a contralateral pterional approach for bilateral intracranial aneurysms during an 11-year period were contacted and asked to complete a patient satisfaction questionnaire. The questionnaire covered 5 complaint areas related to the surgical approaches: craniotomy-related pain, sensory symptoms in the head, cosmetic complaints, palpable cranial irregularities, and limited mouth opening. The patients were asked to rate the 5 complaint areas on a scale from 0 (asymptomatic or very pleasant) to 4 (severely symptomatic or very unpleasant). Finally, the patients were asked to rate the level of overall satisfaction related to each surgical procedure on a visual analog scale (VAS) from 0 (most unsatisfactory) to 100 (most satisfactory). RESULTS A total of 21 patients completed the patient satisfaction questionnaire during a follow-up clinic visit. For the superciliary procedures, no craniotomy-related pain, palpable irregularities, or limited mouth opening was reported, and only minor sensory symptoms (numbness in the forehead) and cosmetic complaints (short linear operative scar) were reported (score = 1) by 1 (4.8%) and 3 patients (14.3%), respectively. Compared with the pterional approach, the superciliary approach showed better outcomes regarding the incidence of craniotomy-related pain, cosmetic complaints, and palpable irregularities, with a significant between-approach difference (p < 0.05). Furthermore, the VAS score for patient satisfaction was significantly higher for the superciliary approach (mean 95.2 ± 6.0 [SD], range 80-100) than for the pterional approach (mean 71.4 ± 10.6, range 50-90). Moreover, for the pterional approach, a multiple linear regression analysis indicated that the crucial factors decreasing the level of patient satisfaction were cosmetic complaints, craniotomy-related pain, and sensory symptoms, in order of importance (p < 0.05). CONCLUSIONS In successful cases in which the primary surgical goal of complete aneurysm clipping without postoperative complications is achieved, a superciliary keyhole approach provides a much higher level of patient satisfaction than a pterional approach, despite a facial wound. For a pterional approach, the patient satisfaction level is affected by the cosmetic results, craniotomy-related pain, and numbness behind the hairline, in order of importance.
Assuntos
Craniotomia/efeitos adversos , Craniotomia/métodos , Aneurisma Intracraniano/cirurgia , Satisfação do Paciente , Complicações Pós-Operatórias/epidemiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate patient attitudes toward acceptable levels of disability after decompressive surgery for malignant middle cerebral artery infarction, including impact of patient age, to improve process of surgical informed consent. METHODS: Patients who had experienced a recent minor stroke were asked to complete a questionnaire containing 2 parts: demographic information, including patient age, sex, years of education, working status, religion, and economic status, and acceptable level of disability based on modified Rankin Scale (mRS) with corresponding illustrations to explain mRS levels. RESULTS: Patient age was identified as an independent determinant of the worst acceptable mRS score with a negative correlation. For nondominant hemispheric malignant infarction, the worst acceptable mRS score was significantly lower (mean ± SD 2.0 ± 1.3) for the oldest patients (>70 years old) compared with patients <60 years old (mean ± SD 3.0 ± 0.6) and 60-70 years old (mean ± SD 3.0 ± 0.8). For dominant hemispheric malignant infarction with language impairment, all age groups showed a significantly lower value for worst acceptable mRS score (mean ± SD 1.8 ± 1.1 for patients <60 years old, 1.8 ± 1.2 for patients 60-70 years old, and 1.0 ± 1.4 for patients >70 years old). CONCLUSIONS: Patients showed different attitudes toward disability according to their age. Patients >70 years old showed the lowest worst acceptable mRS score after surgical treatment of malignant infarction. Language impairment with dominant hemispheric infarction further decreased the worst acceptable mRS score.
Assuntos
Craniectomia Descompressiva/efeitos adversos , Infarto da Artéria Cerebral Média/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Atitude , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/cirurgia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVE: The placement of a ventricular catheter for temporary cerebrospinal fluid (CSF) diversion is associated with a considerable risk of CSF infection. The authors investigated the effect of a CSF leak on CSF-related infection and the predisposing factors for a CSF leak. METHODS: Fifty-two patients who underwent external ventricular drainage (EVD) for acute hydrocephalus associated with a subarachnoid hemorrhage or intraventricular hemorrhage (IVH) were enrolled in this prospective study. A CSF leak-detection paper (small sterilized filter paper) was applied at the percutaneous catheter exit site to check for any bloody CSF leak. In addition, radiologic and clinical data were collected. RESULTS: Four of the 52 patients (7.7%) developed an EVD-related CSF infection from organisms including Staphylococcus epidermidis (n = 3) and Staphylococcus hominis (n = 1). A prolonged CSF leak >1 day was detected in 9 patients (17.3%) and revealed as a significant risk factor for CSF infection with a 44.4% positive predictive value. Moreover, an IVH >10 mL was found in 11 patients (21.2%) and revealed as a significant predisposing factor for a CSF leak at the percutaneous catheter exit. CONCLUSIONS: A prolonged CSF leak for >1 day at the percutaneous catheter exit site is a crucial risk factor for EVD-related CSF infection and an IVH >10 mL is a predisposing factor for a CSF leak.
Assuntos
Infecções Relacionadas a Cateter/epidemiologia , Vazamento de Líquido Cefalorraquidiano/epidemiologia , Drenagem , Hidrocefalia/cirurgia , Complicações Pós-Operatórias/epidemiologia , Infecções Estafilocócicas/epidemiologia , Ventriculostomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral Intraventricular/complicações , Feminino , Humanos , Hidrocefalia/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Staphylococcus epidermidis , Staphylococcus hominis , Hemorragia Subaracnóidea/complicaçõesRESUMO
OBJECTIVE: The pharmacokinetic profiles and bioequivalence of a new rosuvastatin/ezetimibe fixed-dose combination (FDC; NVP-1205) vs. rosuvastatin and ezetimibe concomitantly administered as single agents were evaluated. MATERIALS AND METHODS: In this open-label, single-dose, crossover study (NCT02029625), eligible subjects were randomly assigned in a 1 : 1 ratio to receive a single dose of rosuvastatin (10 mg) with ezetimibe (10 mg) as either a FDC or as single agents concomitantly administered under fasted conditions, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected predose and up to 96 hours postdose in each period for determination of plasma rosuvastatin and ezetimibe concentrations by liquid-chromatography tandem mass spectroscopy and calculation of pharmacokinetic parameters. RESULTS: The mean Cmax and AUC0-t values of rosuvastatin were 12.5 ng/mL and 115.6 ng×h/mL for the FDC, and 12.2 ng/mL and 115.1 ng×h/mL for the single agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of ezetimibe were 4.7 ng/mL and 67.3 ng×h/mL for the FDC, and 4.5 ng/mL and 68.2 ng×h/mL for the single agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the rosuvastatin Cmax and AUC0-t were 106.20 (96.62 - 116.74) and 102.88 (96.32 - 109.90), respectively. The GMR and 90% CI for the ezetimibe Cmax and AUC0-t were 108.96 (98.56 - 120.51) and 98.13 (92.01 - 104.66), respectively. All treatments were well tolerated during this study, with no serious adverse events reported. CONCLUSION: The rosuvastatin/ezetimibe (10/10 mg) FDC was bioequivalent to single agents concomitantly administered. A single dose of rosuvastatin/ezetimibe as the FDC or as single agents was well tolerated.â©.
Assuntos
Anticolesterolemiantes/farmacocinética , Ezetimiba/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto , Cromatografia Líquida , Estudos Cross-Over , Combinação de Medicamentos , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/efeitos adversos , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto JovemRESUMO
OBJECTIVE: This study evaluated the pharmacokinetics (PKs) and safety of a newly developed ß-lapachone (MB12066) tablet, a natural NAD(P)H:quinone oxidoreductase 1 (NQO1) substrate, in healthy male volunteers. METHODS: In a randomized, double-blind, multiple-dose, two-treatment study, 100 mg MB12066 or placebo was given twice daily for 8 days to groups of eight or three fasted healthy male subjects, respectively, followed by serial blood sampling. Plasma concentrations for ß-lapachone were determined using liquid chromatography-tandem mass spectrometry. PK parameters were obtained with non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. RESULTS: Following a single 100 mg MB12066 oral dose, maximum plasma concentration (Cmax) of ß-lapachone was 3.56±1.55 ng/mL, and the median (range) time to reach Cmax was 3 h (2-5 h). After the 8 days of 100 mg twice daily repeated dosing was completed, mean terminal half-life was determined to be 18.16±3.14 h, and the mean area under the plasma concentration vs time curve at steady state was 50.44±29.68 ng·h/mL. Accumulation index was 2.72±0.37. No serious adverse events (AEs) were reported, and all reported intensities of AEs were mild. CONCLUSION: The results demonstrated that MB12066 was safe and well tolerated in healthy volunteers and that there were no serious AEs. Accumulation in plasma with twice-daily administration was associated with a 2.72 accumulation ratio.
Assuntos
NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Cromatografia Líquida , Método Duplo-Cego , Meia-Vida , Humanos , Masculino , Naftoquinonas/efeitos adversos , Naftoquinonas/farmacocinética , Comprimidos , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
Docosahexaenoic acid (DHA), a component of omega-3 fatty acids, has been reported to protect against inflammatory bone diseases such as osteoporosis and rheumatoid arthritis. However, its exact mechanism in bone resorbing cells has not been elucidated. In this study, we investigated the effects and the molecular mechanism of DHA on the proliferation, differentiation, and survival of osteoclast lineage cells using mouse bone marrow-derived macrophages (BMMs). DHA suppressed the macrophage colony-stimulating factor (M-CSF)-induced proliferation of osteoclast precursors, BMMs, in a dose-dependent manner. The attenuated proliferation of DHA-treated BMMs was related to M-CSF inhibition that selectively decreased Akt activation and downregulated cyclin D1 and cyclin D2 expression. DHA also blocked receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation from BMMs. At the molecular level, DHA inhibited JNK, ERK, and p38 MAPKs. In addition, it inhibited NF-κB signaling cascades, as demonstrated by the suppression of RANKL-mediated IκBα phosphorylation, NF-κB subunit p65 nuclear translocation, and NF-κB transcriptional activation. Accordingly, DHA attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1). Furthermore, DHA accelerated the apoptosis of mature osteoclasts by inducing Bim expression, a critical modulator of osteoclast apoptosis. Collectively, our data demonstrate that DHA exerts an anti-osteoclastogenic effect by suppressing the proliferation and differentiation of BMMs and enhancing the apoptosis of mature osteoclasts, thereby resulting in a diminished number of bone-resorptive cells.
Assuntos
Apoptose/efeitos dos fármacos , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Osteoclastos/citologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Animais , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
Glimepiride, a third generation sulfonylurea, is an antihyperglycemic agent widely used to treat type 2 diabetes mellitus. In this study, an untargeted urinary metabolomic analysis was performed to identify endogenous metabolites affected by glimepiride administration. Urine samples of twelve healthy male volunteers were collected before and after administration of 2 mg glimepiride. These samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and then subjected to multivariate data analysis including principal component analysis and orthogonal partial least squares discriminant analysis. Through this metabolomic profiling, we identified several endogenous metabolites such as adenosine 3', 5'-cyclic monophosphate (cAMP), quercetin, tyramine, and urocanic acid, which exhibit significant metabolomic changes between pre- and posturine samples. Among these, cAMP, which is known to be related to insulin secretion, was the most significantly altered metabolite following glimepiride administration. In addition, the pathway analysis showed that purine, tyrosine, and histidine metabolism was affected by pharmacological responses to glimepiride. Together, the results suggest that the pharmacometabolomic approach, based on LC-MS/MS, is useful in understanding the alterations in biochemical pathways associated with glimepiride action.