Augmented renal clearance in septic patients with antibiotic blood concentration / 中国小儿急救医学

Augmented renal clearance（ARC）can be caused by the disease itself，inflammatory state，or therapeutic interventions，and is often associated with severe infections and trauma.Sepsis is one of the most important diseases with high morbidity and mortality in the world.Current studies suggest that ARC is significantly associated with inadequate antimicrobial therapy concentration in patients with sepsis，increasing the risk of clinical treatment failure.It is important to optimize the drug administration strategy for patients with ARC in sepsis，although the current clinical screening of ARC is not yet perfect.This review summarized the literature on changes in blood concentration of antibiotics and administration strategies in patients with sepsis with ARC，in order to provide appropriate medication and clinical guidance for ARC patients.

The Pharmaceutical Properties of Sulforaphane and Its Role in Tumor and Neurodegenerative Diseases / 生物化学与生物物理进展

Sulforaphane is a naturally occurring active substance derived from cruciferous vegetables with potent antioxidant and anticancer properties. Researches have shown that sulforaphane has good bioavailability and can be absorbed by the small intestine through passive transport, followed by excretion in the form of urine via the hydrophobic acid pathway. In addition, since sulforaphane is easy to be absorbed and metabolized, wrapping sulforaphane with nanomaterials can improve its bioavailability and stability, prolong its action time in human body, and better utilize its therapeutic effect. In terms of mechanism of action, sulforaphane can activate Nrf2 and HSF1 signaling pathways, induce the expression of phase II detoxification enzymes HO-1, NADPH, GST and HSP, thus regulating the concentration of oxidative stress ROS in vivo; inhibit NF-κB signaling pathway, thus suppressing the expression of inflammatory factors TNF-α, IL-1 and IL-6; regulate epigenetic modifications, thus inhibiting HDAC and DNMT, and increasing the concentration of histone H3 and H4. By regulating the expression levels of the above factors, sulforaphane can affect the occurrence and development of cancer, neurodegenerative diseases and other diseases. In recent years, several phase I/II clinical trials have shown that sulforaphane has good drug-generating properties. For example, researchers have found that patients with skin cancer have not shown any health problems and their corresponding functional problems have improved greatly after long-term use of sulforaphane. This suggests that in the future sulforaphane has a very high medicinal potential for the treatment of cancer and neurodegenerative diseases. In this paper, we review the pharmacokinetics, target of action and safety of sulforaphane and its research progress in tumor and neurodegenerative diseases to provide a reference for the future application of sulforaphane in the treatment of tumor and neurodegenerative diseases.

Effectiveness of resveratrol as a hepatoprotector in a rat model of paracetamol-induced liver injury / Eficácia do resveratrol como hepatoprotetor em modelo de rato com lesão hepática induzida por paracetamol

Objective: Evaluate the effectiveness of resveratrol as a hepatoprotector in a rat model of paracetamol-induced liver injury and its biodistribution to understand its pharmacokinetics. Methodology: As an experimental approach, animals were divided into the test group with 4 subgroups and the control group with 4 subgroups. Animals of the "treated" group were subjected to resveratrol pre-treatment for eight days, followed by intoxication with a high dose of paracetamol on the 8th day. Animals were euthanized to collect the blood and liver tissue samples 24 and 72 h after the last administration. Hepatoprotective activity was evaluated through serum levels of glycogen and hepatic enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), histological and morphometric analysis of the liver tissue. For biodistribution analysis, different organs (organs, kidneys, heart and lungs) were collected and macerated, and resveratrol was quantified using high-performance liquid chromatography. Statistical analyses of morphometry, transaminases and alkaline phosphatase measurements, and biodistribution results were performed using GraphPad Prism® 3.0. Differences between groups were compared using ANOVA, followed by the Bonferroni test. Statistical significance was set at p < 0.05. Results: Resveratrol has a hepatoprotective action against acute intoxication by paracetamol, as evidenced by the histological decrease in necrosis and inflammatory foci, preservation of glycogen and other 1,2-glycols in zone 3, and reduction of serum ALT and AST levels. An increased presence of collagen was observed in acinar zones 1 and 3 with picrosirius red staining; therefore, quantification was performed in these regions showing smaller collagen areas in the R and RP groups than in the PC and NC groups Paracetamol caused a significant reduction in the resveratrol concentration in serum and the organs studied, indicating that the antioxidant activity of resveratrol is related to its hepatoprotective action. Conclusion: Resveratrol has hepatoprotective properties and can mitigate some of the liver damage caused by high doses of paracetamol, as indicated by changes in tissue characteristics and liver enzyme levels.

Objetivo: Avaliar a eficácia do resveratrol como hepatoprotetor em modelo de rato com lesão hepática induzida por paracetamol e sua biodistribuição para compreender sua farmacocinética. Metodologia: Como abordagem experimental, os animais foram divididos em grupo teste com 4 subgrupos e grupo controle com 4 subgrupos. Os animais do grupo "tratado" foram submetidos ao pré-tratamento com resveratrol durante oito dias, seguido de intoxicação com alta dose de paracetamol no oitavo dia. Os animais foram eutanasiados para coleta de amostras de sangue e tecido hepático 24 e 72 horas após a última administração. A atividade hepatoprotetora foi avaliada através dos níveis séricos de glicogênio e de enzimas hepáticas, como aspartato aminotransferase (AST), alanina aminotransferase (ALT) e fosfatase alcalina (ALP), análise histológica e morfométrica do tecido hepático. Para análise de biodistribuição, diferentes órgãos (órgãos, rins, coração e pulmões) foram coletados e macerados, e o resveratrol foi quantificado por cromatografia líquida de alta eficiência. Análises estatísticas de morfometria, medidas de transaminases e fosfatase alcalina e resultados de biodistribuição foram realizadas utilizando GraphPad Prism® 3.0. As diferenças entre os grupos foram comparadas por meio de ANOVA, seguida do teste de Bonferroni. A significância estatística foi estabelecida em p < 0,05. Resultados: O resveratrol tem ação hepatoprotetora contra a intoxicação aguda por paracetamol, evidenciada pela diminuição histológica da necrose e dos focos inflamatórios, preservação do glicogênio e outros 1,2-glicóis na zona 3 e redução dos níveis séricos de ALT e AST. Foi observada presença aumentada de colágeno nas zonas acinares 1 e 3 com coloração picrosirius red; portanto, foi realizada quantificação nessas regiões mostrando menores áreas de colágeno nos grupos tratados com resveratrol e resveratrol associado com paracetamol do que nos grupos controles positivo e negativo. O paracetamol causou redução significativa na concentração de resveratrol no soro e nos órgãos estudados, indicando que a atividade antioxidante do resveratrol está relacionada à sua ação hepatoprotetora. Conclusão: O resveratrol possui propriedades hepatoprotetoras e pode mitigar alguns dos danos hepáticos causados por altas doses de paracetamol, conforme indicado por alterações nas características dos tecidos e nos níveis de enzimas hepáticas.

Advances in bioanalysis methods and pharmacokinetics of polymer nanopharmaceuticals / 药学学报

Polymer nanomaterials have been attracted more and more attention because of their advantages such as long circulation, reduced immunogenicity and less side effects, and have become a hot research topic in nanomaterials. However, the number of polymer nanomedicines successfully applied in clinical application is very limited, and the unsatisfactory pharmacokinetic behavior is one of the main reasons for thisresult. After polymer nanoparticles enter the body, they will release free drugs and polymer excipients. Polymer nanoparticles are the loaded drugs and free drugs are the active chemicals for efficacy, while polymer excipients may cause excipient drug interactions. Therefore, the focus of the pharmacokinetics study of polymer nanoparticles should not be only limited to the free drugs themselves, but should also focus on the loaded drugs, free drugs and polymer excipients. The dynamic changes of polymer excipients and their metabolites pose new requirements and challenges for the bioanalysis of polymer nanomedicines. The characteristics and application scope of common analytical methods for detection polymer nanomedicines including chromatographic assay will be discussed in this paper. Moreover, this review will also summarize the absorption, distribution, metabolism and excretion of polymer nanomedicines. We hope this review will provide reference for the pharmacokinetics study, safety and effectiveness evaluation of polymer nanomedicines.

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Prediction of human intestinal absorption properties based on artificial intelligence / 中国药科大学学报

@#Human intestinal absorption (HIA) is a crucial indicator for measuring the oral bioavailability of drugs.This study aims to use artificial intelligence methods to predict and evaluate the HIA of drugs in the early stages of drug discovery, thus accelerating the drug discovery process and reducing costs.This study used MOE''s 2D, 3D descriptors, and ECFP4 (extended connectivity fingerprints) to characterize the molecules and established eight models, including support vector machine (SVM), random forest (RF), and deep neural network (DNN).The results showed that the SVM model constructed using a combination of 2D, 3D descriptors and ECFP4 fingerprints was the optimal model according to comprehensive evaluation of various evaluation indicators.The area under the receiver operating characteristic curve (AUC), Matthews correlation coefficient, and Kappa coefficient of the optimal model were 0.94, 0.75, and 0.74, respectively.In conclusion, this study established a robust and generalizable machine learning model for predicting HIA properties, which can provide guidance for early molecular screening and the study of pharmacokinetic properties of drugs.

Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency / 中国药房

OBJECTIVE To establish a physiologically-based pharmacokinetic （PBPK） model of amikacin in elderly patients with renal insufficiency. METHODS PK-SIM® software was adopted for model building， optimization and simulation. The physical and chemical properties and pharmacokinetic parameters related to amikacin were collected by literature review. The PBPK model on adults was established and extrapolated to the elderly population based on the built-in human model. Data from clinical PK studies were used to optimize and validate the model. The goodness of fit， relative residual， and mean folding error （MFE） were used to evaluate the performance of forecasting. The final model was employed to simulate the exposure of amikacin in the elderly population with renal insufficiency， and the efficacy and safety of commonly used clinical dosing regimens were evaluated， and the recommended regimens were proposed. RESULTS The established PBPK model of amikacin had good prediction performance in both adult and elderly populations， with the absolute mean of relative residual value of 25%； the MFE of peak concentration （cmax） and area under the plasma concentration curve （AUC0－∞） in all simulation occasions ranged ＞0.5-＜2. The simulation results showed that， compared with healthy adults， no significant clinical difference in cmax was observed in the elderly with renal insufficiency at the same dosing regimen， but the trough concentration increased significantly due to accumulation. Prolonging the administration interval of amikacin rather than reducing the dosage was more helpful to ensure the efficacy and to reduce the occurrence of nephrotoxicity. CONCLUSIONS The PBPK model for amikacin is successfully established in the elderly patient with renal insufficiency， and shows good predictive performance.

Pharmacokinetics effect of 8 components of Baizhu Shaoyao San with processing method based on UPLC-MS/MS / 国际中医中药杂志

Objective:To explore the pharmacokinetics effect of 8 components of processed Baizhu Shaoyao San on rats.Methods:The rats were divided into processing group and unprocessing group, administered with decoction of Baizhu Shaoyao San by gavage respectively. Then, blood was collected from fundus vein at certain time to obtain the plasma. Finally, the contents of 8 components in plasma were detected and compared by UPLC-MS/MS method, and the methodology of the experiment was tested. The drug concentration in blood and the collection time of blood were analyzed by DAS software, and the time curves of different groups were obtained, the pharmacokinetic parameters were calculated.Results:The blood peak concentration, peak time, area under the drug time curve, and average residence time of 8 components in the serum of rats in the raw product group and the fried product group were different to varying degrees.Conclusion:Processed Baizhu Shaoyao San could influence the behavior of the components measured in rats, which may affect the clinical therapeutic effect of Baizhu Shaoyao San.

Application of a pharmacokinetics solving program based on Excel in pharmacokinetics teaching / 中华医学教育探索杂志

To solve the problems in the course teaching of Pharmacokinetics and change the current situation of the course, a pharmacokinetic solution program based on Excel has been developed. The program, based on Excel, is the most widely used data processing software. The data processing and drawing functions of Excel are used and encapsulated as a program by Excel-VBA. The program is specially used in pharmacokinetic teaching, which includes 25 solution templates arranged according to the 5th edition of Biopharmaceutics and Pharmacokinetics, a textbook published by the People's Medical Publishing House Co., LTD. Each solution template includes six functional areas: operation setting area, data input area, data relationship display area, return parameter output area, pharmacokinetic parameter output area and chart area. In this course, the teaching content is reorganized. Starting from a case, the concept and knowledge of pharmacokinetics are taught by explaining how to apply the program to solve case problems. After years of practice, the teaching effect has been significantly improved.

Pharmacokinetics of sugammadex in reversal of rocuronium-induced muscle relaxant residual in infants and young children undergoing daytime surgery / 中华麻醉学杂志

Objective:To investigate the pharmacokinetics of sugammadex in reversal of rocuronium-induced muscle relaxant residual in infants and young children undergoing daytime surgery.Methods:One hundred and four pediatric patients of either sex, aged 3-36 months, of American Society of Anesthesiologists Physical Status classification Ⅱ, with body mass index of 18.5-28.0 kg/m 2, diagnosed with oblique inguinal hernia and/or hydrocele, scheduled for laparoscopic high ligation of hernia sac and/or high ligation of sphingoid surgery, were included in the study. Intraoperative neuromuscle relaxation was assessed by transdermal stimulation of the ulnar nerve in the wrist using a TOF Guard monitor. Rocuronium 0.9 mg/kg, propofol 3 mg/kg, and sufentanyl 0.5 μg/kg were intravenously injected for anesthesia induction, and propofol 6-8 mg·kg -1·h -1 was intravenously infused to maintain anesthesia. The pediatric patients were divided into Ⅰgroup and Ⅱ group according to the degree of postoperative neuromuscular block. In group Ⅰ, sugammadex 2 mg/kg was intravenously injected when TOF returned to T 2 recurrence. In group Ⅱ, sugammadex 4 mg/kg was intravenously injected when the single stimulation count was 1 or 2 after tetanic stimulation. At 2 and 10 min after rocuronium administration, at the end of operation, 2 and 10 min after sugammadex administration, and when the children met the standard of leaving the resuscitation room, venous blood samples were collected for determination of plasma concentrations of rocuronium and sugammadex using ultra-high performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined using the Pheonix WinNonlin software. The onset of rocuronium and time for recovery of TOF ratio to 90% were recorded. Results:The pharmacokinetics of sugammadex was fitted to the nonlinear mixed-effect satrioventricular model.There was no significant difference in the peak concentration, area under the drug concentration-time curve, elimination half-life, apparent clearance, apparent volume of distribution, mean retention time, and time for TOF ratio returning to 90% between the two groups ( P> 0.05). Conclusions:The pharmacokinetics of sugammadex in reversal of rocuronium-induced muscle relaxant residual is fitted to a nonlinear mixed-effect satrioventricular model, and sugammadex 2 and 4 mg/kg have similar pharmacokinetics in infants and young children undergoing daytime surgery.

Methadone Reduced Nevirapine Pharmacokinetic Parameters in People Living With HIV in Malaysia

@#Introduction: The HIV epidemic in Malaysia predominantly affects males (90% of total HIV cases) mostly intravenous drugs users. Nevirapine-based of highly active antiretroviral therapy (HAART) once- or twice-daily dosage improve accessibility and effectiveness of antiretroviral treatment for HIV positive intravenous drug users (IDUs) receiving methadone maintenance treatment. Studies reported that concomitant administration of nevirapine with methadone reduced methadone plasma concentration. Since methadone and nevirapine were both known to be the substrate for cytochrome 2B6 (CYP 2B6), concomitant use of both drugs may affect nevirapine concentration too. However, methadone effect on nevirapine concentration is still unclear. This is a cross sectional study which reports how methadone co-administration affects the pharmacokinetic parameters of nevirapine in people living with HIV (PLHIV). Methods: 112 patients receiving nevirapine-based antiretroviral drugs were recruited. Seventeen were maintained with methadone without withdrawal symptoms. High-performance liquid chromatography was used to measure plasma nevirapine concentrations. Nevirapine population pharmacokinetics was modelled with a non-parametric approach using Pmetrics software. Result: According to univariate analysis, concurrent methadone administration increased the clearance of nevirapine by 25.3% (p = 0.046). Multivariate analysis showed that methadone medication was independently linked with lower nevirapine concentrations and area-under-curve (Cmin was reduced by 15.2%, p = 0.011, Cmax 19.5%; p = 0.003, AUC12 16.2%; p = 0.021 respectively). Conclusion: This study provides in-vivo evidence of methadone co-administration reducing nevirapine exposure. Since a low concentration of nevirapine will lead to treatment failure, monitoring is essential for PLHIV using both medications at the same time.

Advances in therapeutic drug monitoring of infliximab in patients with Crohn disease / 中国药房

Infliximab （IFX）， tumor necrosis factor-α inhibitor， is widely used in clinical practice for treating Crohn disease （CD）， but it is difficult to obtain the optimal therapeutic effect according to the conventional dose. It is recommended to perform therapeutic drug monitoring （TDM） for patients with poor therapeutic efficacy to guide clinical decisions. This paper reviews the pharmacokinetic characteristics of IFX， exposure-response relationship， the influencing factors of pharmacokinetic differences， and analytical methods in TDM. It is found that IFX doesn’t undergo liver or kidney metabolism， exhibits obvious exposure-response relationships in both the induction and maintenance phases of CD treatment； disease activity， albumin， antibodies to IFX （ATI） and other factors influence IFX’s exposure. It is recommended that trough concentration of IFX in the maintenance period should be kept above 3 μg/mL； the dose of IFX should be increased or medication interval should be shortened for patients with severe disease， low albumin levels and ATI formation， to promote therapeutic efficacy of IFX. It is suggested to use the same detection method for TDM of IFX in the same patient.

Research strategies and frontier technology advances in intracerebral pharmacokinetics / 中国药理学通报

The establishment of the cerebral pharmacokinetic model aims to truly reflect the disposition and course of action of drugs entering brain tissues, to ensure that brain-targeted drugs reach effective intracerebral concentrations, while preventing neurological damage from non-brain-targeted drugs, and to greatly improve effectiveness and safety. With the rapid development of research strategies and analytical techniques in the field of pharmacokinetics, intracerebral pharmacokinetic techniques have evolved from traditional brain tissue homogenization and cerebrospinal fluid extraction to in situ in vivo analysis techniques, from invasive techniques to non-invasive imaging techniques, and from the macroscopic tissue level to the microscopic cellular/subcellular level. A variety of pharmacokinetic research methods in brain are complementing each other and becoming increasingly perfect, gradually forming a comprehensive " subcellular-cellular-tissue" pharmacokinetic research system in brain, laying the foundation for elucidating the dynamic changes of drugs in brain and predicting the course of action of drugs in brain. This paper reviews the evolution and development of pharmacokinetic research strategies in brain, evaluates the advantages and limitations of various techniques and methods, and provides a reference for predicting the pharmacodynamic and toxic effects of drugs in brain tissues.

Physiological pharmacokinetic model of children and its application of modeling software / 药学学报

Developmental changes in children can affect drug disposition and clinical effects. A physiologically-based pharmacokinetic (PBPK) model is a mathematical model that can be used to predict blood drug concentrations in children and gain insight into age-dependent physiological differences in drug disposition impact. Pediatric PBPK (P-PBPK) models have attracted attention over the past decade. With the concerted efforts of academia, pharmaceutical companies, and regulatory agencies, there are more and more examples of pediatric clinical studies using PBPK models. Nevertheless, the number of P-PBPK models and their predictive performance still lag behind adult models. By referring to the literature, we study the process of children adapting to adult absorption, distribution, metabolism, and excretion (ADME) parameters and analyze the general principles of P-PBPK model establishment. In addition, we summarize the functions and application examples of commonly used P-PBPK modeling software to provide a basis for the rational application of modeling software.

Composition and morphology of Scutellariae Radix-Coptidis Rhizoma decoction co-precipitate and effect on in vivo behavior of decocting liquid / 中国中药杂志

Scutellariae Radix-Coptidis Rhizoma(SR-CR) herbal pair is commonly used in many compound prescriptions for their synergistic heat-clearing and dampness-drying properties. During the decoction process, a substantial amount of precipitate is generated. However, there have been no explicit reports on the composition, morphology, and potential effects of this precipitate on the in vivo behavior of SR-CR decoction. This study employed high-performance liquid chromatography(HPLC), high-resolution mass spectrometry, and other techniques to analyze the composition of the co-precipitate in the decoction of SR-CR. Scanning electron microscopy and mass spectrometry imaging were used to analyze its appearance and morphology. Additionally, rats were used to investigate the effects of the co-precipitate on the in vivo behavior of the main components in the SR-CR decoction. The research findings indicated that eight components, including coptisine, berberine, epiberberine, palmatine, baicalin, oroxylin A-7-O-β-D-glucuronide, wogonoside and baicalein, constituted the primary composition of the co-precipitate. Among these, baicalin and berberine hydrochloride were the most abundant, accounting for about 60% of the total weight. Moreover, the co-precipitate contained 18% tannins. Morphological analysis revealed that the particles in the SR-CR decoction precipitate were spherical microparticles with an average diameter of around 600 nm. Pharmacokinetic research demonstrated that there were significant differences in the AUC, C_(max), t_(1/2), and T_(max) of baicalin, a major component, in rats administered with lyophilized powders of the combined decoction and single decoctions of SR-CR orally, suggesting that the precipitate generated during the decoction process can affect the in vivo behavior of the main components of the SR-CR decoction. It can reduce the absorption of baicalin in the body, decrease the extent of rapid drug release, and to a certain extent, prevent adverse reactions or side effects.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes / 中南大学学报(医学版)

OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Pharmacokinetic study about compatibility of Eucommia ulmoides and Psoralea corylifolia / 中草药·英文版

OBJECTIVE@#The compatibility of Eucommia ulmoides (Eu) and Psoralea corylifolia (Pc) on the pharmacokinetic (PK) properties in the rat was explored in this study.@*METHODS@#Eu extract, Pc extract and the combined extracts (crude drug ratio was 2:1) was administered by gavage, respectively. Two PK experiments were conducted. In first one, the blood samples were collected via the occuli chorioideae vein to get the PK properties of the components. In second one, the blood samples were simultaneously collected via the internal jugular vein or portal vein at different time points and the concentrations of target ingredients were detected by LC/MS/MS to clear the location where the interaction of Eu and Pc took place in vivo.@*RESULTS@#Eight of 11 ingredients in Eu and Pc extract were determined in rat plasma. The exposure levels of geniposidic acid (GPA), aucubin (AU), geniposide (GP), pinoresinol diglucoside (PDG), psoralen glycosides (PLG) and isopsoralen glycosides (IPLG) were decreased 1/5-2/3 after administration of combined extracts. Comparing to the combined administration, the exposure of GPA and AU in plasma of single Eu administration collected via the portal vein were decreased 1/3-2/3, and the values of AUC0-24h and AUC0-∞ of GP collected from the portal vein or internal jugular vein were double increased. The other components' parameters were not significantly changed.@*CONCLUSION@#In summary, the Pc and Eu combined administration could affect the exposure of the main components of Eu extract in rats due to the changed intestinal absorption. The research on the compatibility of Pc and Eu was helpful to guide the clinical administration of Eu and Pc simultaneously.

HPLC-MS/MS method for determination of betamethasone in human plasma with application to a dichorionic twin pregnancy pharmacokinetic and placental transfers studies

Abstract Betamethasone (BET) is a synthetic glucocorticoid recommended for pregnant women at imminent risk of preterm birth before 34 weeks to reduce neonatal complications. There are different techniques to describe BET plasma quantification. However, none quantified the plasmatic concentration of BET in dichorionic (DC) twin pregnancies using LC-MS. Our objectives were to develop and validate a method for quantifying BET by LC-MS for pharmacokinetic (PK) and placental transfer studies in DC twin pregnancies. Blood samples were collected after intramuscular administration of a single BET dose containing 6 mg disodium phosphate + 6 mg acetate. BET was determined in plasma by liquid-liquid extraction. The method showed linearity in the range of 2-250 ng/mL, as well as precision and accuracy with a coefficient of variation and relative standard errors ≤ 15%. Additionally, the method presented selectivity and did not present matrix or carry-over effect. Stability tests also presented coefficient of variation and relative standard errors ≤ 15%. This is the first study which describe maternal and fetal plasma concentrations of BET in a DC twin pregnancy. The BET PK parameters were AUC0-∞, CL/F, Vd/F, Cmax, Tmax of 292.20 h*ng/mL, 39.08 L/h, 278.72 L, 25.55 ng/mL and 0.58 h, respectively. The placental transfer ratios of umbilical vein/maternal vein and intervillous space/maternal vein were 0.14 and 0.19 and 0.40 and 0.27 for both twins, respectively. However, a clinical study with more subjects is imperative to confirm this higher concentration of BET in the intervillous space

Analysis of the effect of in vitro dissolution on the pharmacokinetics of albendazole

Abstract Albendazole is an anthelmintic drug commonly used in parenchymal neurocysticercosis and cystic echinococcosis. The aim of this study was to explore whether disparities in the dissolution profiles of albendazole products lead to significant differences in pharmacokinetic parameters. Three generic products and the innovator were evaluated in vitro. Quality control tests were performed, and dissolution profiles were obtained according to the Mexican Pharmacopeia. Although all products passed the quality control tests, none of the generic products complied with the similarity factor (f 2). The product with the lowest f 2 value in respect to the reference was chosen for in vivo evaluation. The study was carried out in 12 healthy volunteers who received 400 mg of the generic or reference product according to a crossover design. No significant differences were found in Cmax and AUC for albendazole and its main metabolite, albendazole sulfoxide, between products. Two absorption peaks were observed in the pharmacokinetic profile, and a population (22%) with different absorption rates and delay time for the the second peak was found. Based on the results, due to the high variability in the absorption process the differences observed in vitro could not be observed in vivo.

A unique formulation of sodium bicarbonate buffered pantoprazole powder for oral suspension: perspectives from an active controlled cross-over bioequivalence study

Background:The aim was determining bioequivalence between pantoprazole buffered powder for oral suspension and pantoprazole enteric coated tablets under fasting conditions in healthy volunteers.Methods:In randomized cross-over study, participants were administered a single oral dose of pantoprazole powder as suspension 40 mg (sodium bicarbonate as buffer) or one enteric coated tablet of pantoprazole 40 mg, with240�ml of water as per the randomization schedule in each study period. Blood samples were collected at pre-dose and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 14, 16and 24hours post-dose. Plasmaconcentration of pantoprazole was determined with LC-MS and various pharmacokinetic parameters like Cmax, AUC0-t, AUC0-inf were compared between test and reference groups.Results:Amongst 41 subjects, Cmax(3752.4�84.6 vs. 3521.7�99.5 ng/ml)was achieved higher in less Tmaxtime (1 (0.28) vs. 2.3 (0.83) hrs)with test drug as compared to reference drug. The ratios of geometric least square mean and its 90% confidence interval on log transformed Cmax, AUC0-t and AUC0-inffor pantoprazole fall within the acceptance criteria of 80% to 125%. No adverse events were observed.Conclusions:Pantoprazole powder for oral suspension 40 mg (sodium bicarbonate as buffer) was well tolerated and bioequivalent with pantoprazole enteric coated tablets IP 40 mg in terms of rate and extent of absorption under fasting conditions. At same time, the shift in AUC to the left with reduction in Tmaxwith the new formulation is suggestive of faster rate of absorption.