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1.
Artigo em Inglês | MEDLINE | ID: mdl-39039947

RESUMO

Sufentanil is frequently used as an anesthetic agent in cardiac surgery owing to its cardiovascular safety and favorable pharmacokinetics. However, the pharmacokinetics profiles of sufentanil in patients undergoing cardiopulmonary bypass (CPB) surgery remain less understood, which is crucial for achieving the desired level of anesthesia and mitigating surgical complications. Therefore, this study aimed to develop a population pharmacokinetic model of sufentanil in patients undergoing CPB surgery and elucidate the clinical factors affecting its pharmacokinetic profile. Adult patients who underwent cardiac surgery with CPB and were administered sufentanil for anesthesia were enrolled. Arterial blood samples were collected to quantify plasma concentrations of sufentanil and clinical laboratory parameters, including inflammatory cytokines. A population pharmacokinetic model was established using nonlinear mixed-effects modeling. Simulations were performed using the pharmacokinetic parameters of the final model. Overall, 20 patients were included in the final analysis. Sufentanil pharmacokinetics were modeled using a two-compartment model, accounting for CPB effects. Sufentanil clearance increased 2.80-fold during CPB and warming phases, while the central compartment volume increased 2.74-fold during CPB. CPB was a significant covariate affecting drug clearance and distribution volume. No other significant covariates were identified despite increased levels of the inflammatory cytokines, including IL-6, IL-8, and TNF-α during CPB. The simulation indicated a 30 µg loading dose and 40 µg/h maintenance infusion for target-controlled infusion. Additionally, a bolus dose of 60 µg was added at CPB initiation to adjust for exposure changes during this phase. Considering the target sufentanil concentrations, a uniform dosing regimen was acceptable for effective analgesia.

2.
Sci Rep ; 14(1): 6515, 2024 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499634

RESUMO

Human pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal tumor of the exocrine pancreas. Cannabinoids extracted from the hemp plant Cannabis sativa have been suggested as a potential therapeutic agent in several human tumors. However, the anti-tumor effect of cannabinoids on human PDAC is not entirely clarified. In this study, the anti-proliferative and apoptotic effect of cannabinoid solution (THC:CBD at 1:6) at a dose of 1, 5, and 10 mg/kg body weight compared to the negative control (sesame oil) and positive control (5-fluorouracil) was investigated in human PDAC xenograft nude mice model. The findings showed that cannabinoids significantly decreased the mitotic cells and mitotic/apoptotic ratio, meanwhile dramatically increased the apoptotic cells. Parallelly, cannabinoids significantly downregulated Ki-67 and PCNA expression levels. Interestingly, cannabinoids upregulated BAX, BAX/BCL-2 ratio, and Caspase-3, meanwhile, downregulated BCL-2 expression level and could not change Caspase-8 expression level. These findings suggest that cannabinoid solution (THC:CBD at 1:6) could inhibit proliferation and induce apoptosis in human PDAC xenograft models. Cannabinoids, including THC:CBD, should be further studied for use as the potent PDCA therapeutic agent in humans.


Assuntos
Canabinoides , Cannabis , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Humanos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Camundongos Nus , Xenoenxertos , Proteína X Associada a bcl-2 , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2
3.
Front Vet Sci ; 9: 867575, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937289

RESUMO

Background: Pancreatic cancer is considered a rare type of cancer, but the mortality rate is high. Cannabinoids extracted from the cannabis plant have been interested as an alternative treatment in cancer patients. Only a few studies are available on the antitumor effects of cannabinoids in pancreatic cancer. Therefore, this study aims to evaluate the antitumor effects of cannabinoids in pancreatic cancer xenografted mouse model. Materials and Methods: Twenty-five nude mice were subcutaneously transplanted with a human pancreatic ductal adenocarcinoma cell line (Capan-2). All mice were randomly assigned into 5 groups including negative control (gavage with sesame oil), positive control (5 mg/kg 5-fluorouracil intraperitoneal administration), and cannabinoids groups that daily received THC:CBD, 1:6 at 1, 5, or 10 mg/kg body weight for 30 days, respectively. Xenograft tumors and internal organs were collected for histopathological examination and immunohistochemistry. Results: The average tumor volume was increased in all groups with no significant difference. The average apoptotic cells and caspase-3 positive cells were significantly increased in cannabinoid groups compared with the negative control group. The expression score of proliferating cell nuclear antigen in positive control and cannabinoids groups was decreased compared with the negative control group. Conclusions: Cannabinoids have an antitumor effect on the Capan-2-derived xenograft mouse model though induce apoptosis and inhibit proliferation of tumor cells in a dose-dependent manner.

4.
J Pharm Sci ; 110(8): 3061-3068, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33819461

RESUMO

R7072 is a fully human monoclonal antibody (mAb) exerting anti-tumor activity via blockade of insulin like growth factor 1 receptor. The tumoral interstitial concentrations are anticipated to be better surrogates of active site concentrations than commonly used serum concentrations for pharmacokinetic-pharmacodynamic correlation of anti-tumor mAbs. Previously, a large-pore microdialysis technique for measuring tissue interstitial concentrations of R7072 in non-tumor bearing mice was established. In the current studies, the serum pharmacokinetics of R7072 were assessed and tissue interstitial concentrations were measured by large-pore microdialysis following intravenous and intraperitoneal administration of R7072 in tumor bearing mice. R7072 exhibited nonlinear pharmacokinetics in the studied dose range. Tumor and subcutaneous interstitial concentration data suggested some delay in tissue distribution after dosing. A dose-dependent increase in the ratio of tumor interstitial to serum concentration was observed indicating target-mediated drug disposition in tumor tissue. However, subcutaneous interstitial to serum concentration ratios were similar across the doses as observed previously in non-tumor bearing mice. A two-compartment population pharmacokinetic model with subcutaneous and tumor as open-loop compartments comprising of parallel linear and non-linear elimination from serum, linear disposition from subcutaneous interstitium and non-linear disposition from tumor interstitium was developed to simultaneously describe the pharmacokinetic data from all matrices.


Assuntos
Antineoplásicos Imunológicos , Neoplasias , Animais , Anticorpos Monoclonais/metabolismo , Camundongos , Microdiálise , Neoplasias/tratamento farmacológico , Distribuição Tecidual
5.
J Pharm Sci ; 105(11): 3233-3242, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27671236

RESUMO

Microdialysis is a validated and well-established technique for recovering and measurement of exogenous as well as endogenous small molecules in the interstitial spaces of various tissues. Microdialysis of large molecular weight compounds has become possible due to the availability of large molecular weight cutoff membranes and is being explored extensively. There are increasing reports of successful recovery of large molecules such as proteins, cytokines, and neuropeptides using microdialysis. This is not only useful for studying protein expression but also for clinical evaluation of disease biomarkers in different tissues. Large pore microdialysis along with open flow microperfusion offers great promise in determining interstitial tissue concentrations of therapeutic proteins including monoclonal antibodies and helps in understanding their pharmacokinetic-pharmacodynamic relationship.


Assuntos
Citocinas/metabolismo , Substâncias Macromoleculares/metabolismo , Microdiálise/métodos , Tecido Adiposo/metabolismo , Animais , Encéfalo/metabolismo , Citocinas/análise , Derme/metabolismo , Humanos , Substâncias Macromoleculares/análise , Peso Molecular , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo
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