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Gastric pH is an important factor that affects drug absorption, as gastric pH may lead to lower bioavailability, especially for weak-base drugs. Acid-reducing agents (ARAs) such as antacids, histamine-2 receptor antagonists, and proton pump inhibitors, are susceptible to drug-drug interactions (DDIs), potentially resulting in the loss of efficacy. Physiologically based pharmacokinetic (PBPK) modeling is an important tool for the evaluation of oral drug-drug interactions and the most commonly used models include the advanced comparative absorption and transport (ACAT) model and the advanced dissolution, absorption and metabolism (ADAM) model. These models can be used for adjustment of the dosage regimen and the screening of candidate drugs in drug development by simulating the change of gastric pH to predict the change in drug absorption. This review summarizes the theoretical basis, the most common PBPK models used to predict drug absorption, and the effects of different kinds of ARAs drugs on gastric pH. Some successful applications of PBPK modeling in predicting the effects of gastric pH on drug absorption are also presented.
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OBJECTIVE@#To explore clinical effect of cement-augmented pedicle screw combined with vertebroplasty in treating Kümmell disease with type Ⅲ.@*METHODS@#From January 2015 to December 2018, 37 patients with type Ⅲ Kümmell disease were retrospectively analyzed, including 11 males and 26 females, aged from 61 to 84 years old with an average of (68.6±4.2) years old, and the courses of disease ranged from 2 to 10 months with an average of(6.5±2.3) months. Nine patients were grade C, 20 patients were grade D and 8 patients were grade E according to Frankle grading. All patients were treated by cement-augmented pedicle screw combined with vertebroplasty. Operation time, blood loss, postoperative drainage, hospital stay and complicationswere observed after oeprtaion. Visual analogue scale(VAS), Oswestry Disability Index(ODI), height of anterior vertebral body, Cobb angle before and after operation were compared.@*RESULTS@#All patients were followed up from 12 to 60 months with an average of (22.4±10.9) months. Operation time was (240.9±77.4) min, blood loss was (315.0±149.2) ml, postoperative drainage was (220.8±72.0) ml, hospital stay was (12.6±4.7) days. One patient occurred incision redness and 1 patient occurred infection after opertaion. No loosening of bone cement occurred. Postopertaive VAS and ODI were lower than that of before opertaion(@*CONCLUSION@#Cement-augmented pedicle screw combined with vertebroplasty is a safe and effective method for the tretament of Kümmell disease with type Ⅲ.
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Aged , Female , Humans , Infant , Male , Bone Cements , Fracture Fixation, Internal , Lumbar Vertebrae/injuries , Pedicle Screws , Quality of Life , Retrospective Studies , Spinal Fractures/surgery , Thoracic Vertebrae/injuries , Treatment Outcome , VertebroplastyABSTRACT
Oral transmucosal drug delivery can be defined as the administration of drug through the oral mucosa to achieve systemic effects. It has the advantages of high bioavailability and rapid drug response. In this review, we introduce the physiology of oral mucosa, and analyze the factors affecting the pharmacokinetic properties of oral transmucosal drug delivery in detail, such as physiological barriers, different administration sites, physicochemical properties of drugs, dosage forms, and formulation strategies. In addition, we describe the methods to evaluate the pharmacokinetic properties of this delivery systems, including in vitro permeability studies, buccal absorption studies, in vivo pharmacokinetic studies and physiologically based pharmacokinetics (PBPK) modeling, which provide methods and reference for the development of oral transmucosal drug delivery systems.
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Physiologically based pharmacokinetic (PBPK) modeling is an important tool to predict pharmacokinetic or pharmacodynamic profiles in special populations, especially in children and infants where designing and conducting clinical studies is difficult. The application of PBPK modeling can effectively promote the development of pediatric drugs and their clinical use. At present, PBPK modeling of pediatric populations is mainly applied in clinical trial design, drug-drug interaction (DDI) risk assessment, and dose selection in children. This review discusses the advantages of PBPK modeling in pediatric drug research and summarizes how to extrapolate a PBPK model from adults to children. The theoretical basis for pediatric PBPK models, the modelling process and important physiological parameters during the modeling process are introduced. Some successful applications of PBPK modeling in pediatric drug research and development are also presented. This review also analyzes the current limitations and future directions of pediatric PBPK modeling.
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Objective To investigate the role of glucose-regulated protein 78 (GRP78) in sevoflurane preconditioning-induced inhibition of apoptosis in cardiomyocytes of rats.Methods The cultured cardiomyocytes of Sprague-Dawley rats were randomly divided into 5 groups (n =30 each) using a random number table:control group (group C),hypoxia-reoxgenation (H/R) group,sevoflurane preconditioning group (group S),siRNA-GRP78 group and siRNA control group.H/R was produced by 2 h exposure of cells to 95％ N2-5％ CO2 in an air-tight chamber at 37 ℃,followed by reoxygenation with 95％ O2-5％ CO2 in an air-tight chamber at 37 ℃ for 1 h.In group S,the cells were incubated with 2.5％ sevoflurane for 20 min,followed by 10-min washout before H/R.In siRNA-GRP78 group,the cells were transfected with siRNA-GRP78 100 nmol/L,and 24 h later preconditioning with sevoflurane was performed and H/R was produced.In siRNA group,cells were transfected with siRNA,and the other treatments were similar to those previously described in siRNA-GRP78 group.After treatment in each group,the expression of GRP78 in myocardial cells and cytochrome c in cytoplasm and mitochondria was detected by Western blot.Lactic dehydrogenase (LDH) and creatine kinase (CK) activities in the culture medium of each group were determined by ELISA.The apoptosis in myocardial cells was assessed by flow cytometry.Apoptotic rate was calculated.Intracellular free Ca2+ concentration ([Ca2+]i) was measured with the fluorescent probe Fura-2/ AM.The opening of mPTP was measured by fluorescence spectrophotometry.Results Compared to group C,the expression of GRP78 in myocardial cells and cytochrome c in cytoplasm was significantly up-regulated,LDH and CK activities in the culture medium,apoptotic rate and [Ca2+]i were increased,and the expression of cytochrome c in mitochondria was down-regulated in H/R group.Compared to group H/R,the expression of GRP78 in myocardial cells and cytochrome c in mitochondria was significantly up-regulated,LDH and CK activities in the culture medium,apoptotic rate,[Ca2+] i and opening of mPTP were decreased,and the expression of cytochrome c in cytoplasm was down-regulated in group S,and no significant change was found in the parameters mentioned above in siRNA group.Compared to group S,the expression of GRP78 in myocardial cells and cytochrome c in mitochondria was significantly down-regulated,LDH and CK activities in the culture medium,apoptotic rate,[Ca2+] i and opening of mPTP were increased,and the expression of cytochrome c in cytoplasm was up-regulated in group siRNA-GRP78.Conclusion GRP78 is involved in sevoflurane preconditioning-induced inhibition of apoptosis in cardiomyocytes of rats,and the mechanism is related to maintenance of intracellular Ca2+ stability and inhibition of opening of mPTP.
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This study investigated the role of glycogen synthase kinase-3β (GSK-3β) in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats. The hippocampi were dissected from aged rats which had been intraperitoneally administered lithium chloride (LiCl, 100 mg/kg) and then exposed to 1.4% isoflurane for 6 h. The expression of GSK-3β was detected by Western blotting. The mRNA and protein expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Morris water maze was employed to detect spatial memory ability of rats. The results revealed that the level of GSK-3β was upregulated after isofurane exposure. Real-time PCR analysis demonstrated that isoflurane anesthesia increased mRNA levels of TNF-α, IL-1β and IL-6, which was consistent with the ELISA results. However, these changes were reversed by prophylactic LiCl, a non-selective inhibitor of GSK-3β. Additionally, we discovered that LiCl alleviated isoflurane-induced cognitive impairment in aged rats. Furthermore, the role of GSK-3β in isoflurae-induced neuroinflammation and cognitive dysfunction was associated with acetylation of NF-κB p65 (Lys310). In conclusion, these results suggested that GSK-3β is associated with isoflurane-induced upregulation of proinflammatory cytokines and cognitive disorder in aged rats.
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Objective To study the healing response of a tissue engineered bone of bMSCs combined rFN/CDH-BCP in a rabbit model. Methods The biomimetic surface was achieved by immobilizing rFN/CDH onto biphasic calcium phosphate ceramic ( BCP) covalently. The effect of rFN/CDH-BCP on adhesion,proliferation and differentiation were evaluated comprehensively by using cell centrifugal adhesive as-say,MTT method,SEM,Alkaline phosphatase ( ALP) activity and alizarin red staining respectively. A rabbit lumbar fusion model was estab-lished by implanting bMSCs combined rFN/CDH-BCP into intertransverse process space of L4 ~L5 ,the fusion site bone formation was ob-served by imaging means,histological techniques was used to observe the new bone formation and distribution of seed cells. Results Cell centrifugal adhesive assay indicated the adherent bMSCs on rFN/CDH-BCP associated with the ligand density,the biomimetic surface posses-ses excellent biocompatibility. The ALP activity on rFN/CDH-BCP surface was the highest among all samples on the 10th day after induction (P<0. 05). On the 21st day,alizarin red staining showed that the oval-shaped and orange-red nodules,either the number or the area,distrib-uted wider on rFN/CDH-BCP surface. The results from X plain after 3 months revealed a fuzzy gap between material and bone bed,and higher cover rate of intertransverse process space with new bone deposition on rFN/CDH-BCP surface. Conclusion Histologically,rFN/CDH-BCP exhibited as interlacing bone trabecula bridging biomaterial suface and cortical bone of transverse process continously. The bone mass was much more than the ture BCP class. The comprehensive data reveals that when loaded with MSCs,rFN/CDH-BCP demonstrates superior char-acteristics of osteoconduction and osteoinduction,and substantially enhances healing capacity in vivo.
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<p><b>OBJECTIVE</b>To investigate the effects of sub-micro emulsion composition on cellular uptake and disposition of incorporated lipophilic drug.</p><p><b>METHODS</b>Sub-micro emulsions containing 10 % oil, 1.2 % lecithin and 2.25 % glycerol were prepared, and the fluorescent agent coumarin 6 was used as a model drug. The effects of oil types, co-surfactants and cationic lipid on uptake and elimination kinetics of 6-coumarin in HeLa cells were studied. The uptake mechanism of sub-micro emulsions was further investigated.</p><p><b>RESULTS</b>Oil type and Tweens had no influence on the cellular uptake. Modifications of surfactants with Span series increased the cellular influx, among which Span 20 with hydrophilic-lipophilic balance (HLB) value of 8.6 was the best enhancer. The intracellular drug level reached up to (46.09 ± 1.98)ng/μg protein which had significant difference with control group [(38.54 ± 0.34)ng/μg protein]. The positively charged emulsions significantly increased the uptake rate constant and elimination rate constant which were 4 times and 1.5 times of those in anionic groups, respectively. The uptake enhancement was also observed in cationic emulsions, cellular concentrations at plateau were (42.73 ± 0.84)ng/μg protein, which was about 3 times of that in anionic emulsions [(15.71 ± 0.74)ng/μg protein], when extracellular drug concentration kept at 100 ng/ml. Cationic emulsions delivered the payload mainly by direct drug transfer to contacted cells, while the negative ones depended on both drug passive diffusion and clathrin-mediated endocytosis of drug containing oil droplets which accounted for 20% of the intracellular drug.</p><p><b>CONCLUSION</b>Interfacial characteristic of sub-micro emulsions such as co-surfactants HLB as well as zeta potentials can influence lipophilic drug both in cellular uptake and elimination.</p>
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Humans , Anions , Cations , Coumarins , Pharmacokinetics , Emulsions , Endocytosis , HeLa Cells , Surface-Active Agents , Pharmacokinetics , Thiazoles , PharmacokineticsABSTRACT
This study investigated the role of glycogen synthase kinase-3β (GSK-3β) in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats. The hippocampi were dissected from aged rats which had been intraperitoneally administered lithium chloride (LiCl, 100 mg/kg) and then exposed to 1.4% isoflurane for 6 h. The expression of GSK-3β was detected by Western blotting. The mRNA and protein expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Morris water maze was employed to detect spatial memory ability of rats. The results revealed that the level of GSK-3β was upregulated after isofurane exposure. Real-time PCR analysis demonstrated that isoflurane anesthesia increased mRNA levels of TNF-α, IL-1β and IL-6, which was consistent with the ELISA results. However, these changes were reversed by prophylactic LiCl, a non-selective inhibitor of GSK-3β. Additionally, we discovered that LiCl alleviated isoflurane-induced cognitive impairment in aged rats. Furthermore, the role of GSK-3β in isoflurae-induced neuroinflammation and cognitive dysfunction was associated with acetylation of NF-κB p65 (Lys310). In conclusion, these results suggested that GSK-3β is associated with isoflurane-induced upregulation of proinflammatory cytokines and cognitive disorder in aged rats.
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Animals , Male , Rats , Cognition Disorders , Metabolism , Pathology , Glycogen Synthase Kinase 3 , Metabolism , Glycogen Synthase Kinase 3 beta , Inflammation , Metabolism , Pathology , Isoflurane , Neurons , Metabolism , Pathology , Rats, Sprague-DawleyABSTRACT
This article analyzes and summaries the problems and difficulties existing in the first-aid medicine's clinical teaching.Combined with his own teaching experience,the author has made some exploration on the teaching time,the way of teaching and inspection form,which has got a good teaching effect.It provids the reference and development for the clinical teaching of first-aid medicine.
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Objective To investigate the effect of ketamine on cAMP response element binding protein pbosphorylation(p-CREB)in hippocampus of neonatal rats.Methods Seventy-five 7-day old SD rats of both sexes were randomly divided into 3 groups(n=25 each):control group(group C)and 2 ketamlne groups(group K1,K2)which received 7 subcutaneous injections of ketamine 10 and 20 mg/kg respectively at 90 min intervals.The animsla were decapitated at 24 h after fwst ketamine injection.The brains were immediately removed and the hippocampi were isolated for detection of neuronal apoptosis by TUNEL.Apoptosis index wag calculated.The expression of p-CREB Wag meagured by immuno-histochemistry and the expression of BDNF mRNA and Bcl-2 mRNA was detected by RT-PCR.Cognitive function Wag agsessed using Morris water maze test at 6 weeks after first ketamine injection.Results The apoptosis index Wag significantly increased while the expression of CREB,BDNF mRNA and Bcl-2 mRNA was down-regulated in group K1 and K2 as compared with group C.The apoptosis index Wag significantly higher and the expression of p-CREB and BDNF mRNA and Bcl-2 mRNA Wag significantly lower in group K2 than in group K1.The latent period of escape was significantly longer in group K2 than in group C and K1.Conclusion Ketamine 20 mg/kg administered in neonatal rats can decrease cognitive function when they grow up by increasing neuronal apoptosis induced by down-regulatlon of the expression of p-CREB,BDNF and Bcl-2.
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Objective To study the effects of Cad-Ⅱgene on osteogenic differentiation of human mesenchymal stem cells in vitro. Methods The human marrow mesenchymal stem cells (hBMSCs) were isolated and cultured in vitro before they were divided into 2 groups. In the transfeetion group, the hBMSCs were transfeeted with Cad- Ⅱgene;in the simple osteogenic inducement group, they were cultured in the condition medium. Then the expressions of Cad- Ⅱ protein were determined and the alkaline phosphatase (ALP) activities and the expressions of ostcocalein were measured at 3, 7, 14 and 21 days for comparison between the 2 groups. Results The ALP activity and positive expression of osteoealcin were regulated significantly higher in the transfeetion group than in the simple osteogenic inducement group at different times (P <0.05). The mineralized nodes began to appear at 14 days in the 2 groups and increased with time. Conclusion Cad-Ⅱgene transfeetion can promote differentiation of hBMSCs into the osteoblasts.
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<p><b>OBJECTIVE</b>To observe the effect of compound Puerarin on collagen IV of streptozotocin-induced diabetic rats.</p><p><b>METHODS</b>Diabetic nephropathy rats were induced by intraperitoneal injection of streptozotocin (STZ). Rats were allocated randomly to control group (10), diabetes model group (10), Vitamin C group (10), Puerarin group (10), vitamin C plus Puerarin group (10). The study period lasted for 12 weeks. During and after the treatment, the general state, blood glucose levels, glycosylated hemoglobin, blood urea nitrogen, serum collagen IV, blood urea nitrogen, serum creatinine, urinary albumin excretion rate of the 24-hour, and clearance rate of creatinine collagen IV protein were determined by immunohistochemistoche analysis as well as type the gene expression of collagen IV alpha 1 mRNA were determined by in situ hybridization analysis in the kidney tissue of different groups.</p><p><b>RESULTS</b>(1) Diabetes mellitus and renal function lesion occurred in the four groups. (2) Vitamin C and Puerarin could improve the general conditions of diabetic Rats, decrease blood urea nitrogen [(8.68 +/- 0.43), (7.98 +/- 0.47) and (5.76 +/- 0.82) micromol/L, serum creatinine [(74.68 +/- 8.20), (75.52 +/- 7.98) and (58.66 +/- 6.65) mmol/L], and urinary albumin excretion rate of the 24-hour [(18.40 +/- 0.37), (17.24 +/- 0.30) and (9.97 +/- 1.27) mg/24 h x 10(-3)]; increase clearance rate of creatinine [(0.59 +/- 0.21), (0.61 +/- 0.14) and (0.69 +/- 0.32) ml/min], the expression of collage IV absorbance [(111.56 +/- 14.61), (110.78 +/- 9.69) and (95.44 +/- 9.97) ] in the diabetic Rats were significantly inhibited at the same time.</p><p><b>CONCLUSION</b>The compound Puerarin might have some functions on preventing ren by inhibiting expression of type IV collagen.</p>
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Animals , Male , Rats , Collagen Type IV , Diabetes Mellitus, Experimental , Drug Therapy , Metabolism , Diabetic Nephropathies , Drug Therapy , Metabolism , Isoflavones , Pharmacology , Therapeutic Uses , Phytotherapy , Rats, Sprague-DawleyABSTRACT
[Objective]To study the expression of Cad-Ⅱ gene in bone marrow mesenchymal stem cells(MSCs) transfected with Cad-ⅡcDNA after autografted into the bone defects. [Method]The experimental model of ilium segment defect was established in 20 Japanese white rabbits.The rabbit MSCs were isolated,cultured and expanded in vitro,and then the MSCs,transfected with Cad-Ⅱ and compounded with collagen sponge were autografted into the ilium segment defect.At 4 weeks of operation,the MSCs/ collagen sponge were excised,and the expression of Cad-Ⅱ was evaluated with RT-PCR and immunohistochemical methods.[Result]All of the bone defects treated with implants exhibited new bone formation at 4 weeks postoperatively.In the transfection group,Cad-Ⅱ gene mRNA expression was higher than that in the control group(P
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30 ml) undergoing minimally invasive evacuation of intracranial hematoma from January 1999 to October 2002 in our department were analyzed retrospectively. The changes of IL 1, IL 6, and IL 8 in hematoma fluid were observed continuously. The content of IL 1 was determined by radioimmunassay and IL 6, IL 8 by ELISA methed. Results IL 1, IL 6, and IL 8 were observed at 6 12 h after hypertensive cerebral hemorrhage, and showed different changes in acute stage. Conclusion Inflammatory cytokines are involved in the pathological process of cerebral hemorrhage.
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Objective To investigate the protective effect of endotoxin pretreatment on hippocampal neurons in rat forebrain following ischemia reperfusion and its possible mechanism. Methods Rat forebrain ischemia reperfusion model was used. The effects of endotoxin pretreatment on the changes of superoxide dismutase (SOD), glutathione peroxidase (GSH PX) and malondialdehyde (MDA) activities and the neuron count in CA1 region were observed. Results Pretreament with endotoxin before cerebral ischemia enhanced the activities of SOD and GSH PX but decreased MDA level and the number of ischemic neurons in CA1 region. Conclusion Endotoxin pretreatment can protect the neurons in rat forebrain against ischemia reperfusion injury. The mechanism may be associated with the enhancement of endogenous antioxidant activity in central nervous system.
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Objective To determine the effects and significance of endotoxin preconditioning on iNOS activity,nNOS activity in rat cerebral cortex,hippocampus and cerebella region after global brain ischemia/reperfusion.Methods Global ischemia for 20 min was made by four-vessel occlusion model(4-vo) in 60 Wistar rats,among which 30 were injected of 20 ?g/kg MPL through caudal vein 24 h before model establishment.Another 8 rats undergoing sham operation served as controls.The dynamic change of iNOS activity,nNOS activity and neuron density of the cerebral cortex,hippocampus and cerebella region were observed at 1,4,8 h after reperfusion. Results The activity of iNOS and nNOS decreased significantly after endotoxin preconditioning in the regions mentioned above,as compared with that of rats only undergoing the ischemia/reperfusion.The neuron number in rat hippocampus decreased after ischemia/reperfusion,but no significant difference was found between control and endotoxin preconditioning groups.Conclusion The activity of iNOS and nNOS changed significantly after global brain ischemia/reperfusion.That endotoxin preconditioning decreased iNOS and nNOS activities may be the protective mechanism.
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Objective To determine the protective effects of endotoxin preconditioning on the brain ischemic injury and explore its protective mechanism. Methods Global ischemia for 20 min by four-vessel occlusion model was used in 140 Wistar rats, in which 70 rats were pretreated with MPL at dose of 20 ?g/kg 24 h before global ischemia. Another 10 Wistar rats served as normal controls. Ischemic neurons and neuron density of the hippocampal CA1 region, MPO activity, TNF-? activity, IL-1? activity were assayed at 4, 12, 24, 48, 72, 120, 168 h after reperfusion. Results Pretreatment with endotoxin produced significant reductions in ischemic neuron number, MPO activity, TNF-? activity and IL-1? activity. Conclusion Endotoxin preconditioning protects brain from subsequent ischemic injury, in which the suppression of cellular inflammation may be the protective mechanism.
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Objective To observe the relationship between the changes of plasma D dimer in pathogenic course and prognosis in patients with acute cerebral infarction(ACI). Methods Changes in plasma D dimer levels of 93 patients with ACI and 20 cases healthy persons were detected dynamically by Latex semi quantitative method. The relation between D dimer levels and focus size, severity of infarction and prognosis were analyzed. Results There was significant difference( P
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Objective To explore the possibility of piezoelectric microarray immunosensor for the detection of Agkistrodon acutus venom. Methods Microarray immunosensor with quartz crystal of 10 MHz AT-cut and 2?5 gold-coated electrodes was prepared. The thiol-treated venom antibody was immobilized by a self assembling device for the detection of the standard fluid for different concentrations of the venom. Results Experimental results showed that the optimal concentration of the antibody was 3.0 g/ml with the response time of 40 minutes. The piezoelectric immunosensor could well respond to homologous venoms. Within the range of 0.1~4.0 g/ml, the frequency shifts were linearly dependent on the venom concentration. Conclusion Piezoelectric microarray immunosensor for the detection of Agkistrodon acutus venom is of high specificity of response, high sensitivity, and simple operation without marking. The technique of piezoelectric microarray immunosensor is possible to test snakebite quickly, quantitatively, and instrumentally.