Effect of Intravenous Administration of Liposomal Prostaglandin E1 on Microcirculation in Patients with ST Elevation Myocardial Infarction Undergoing Primary Percutaneous Intervention

Background：Several studies have demonstrated that primary percutaneous coronary intervention （PCI） can result in reperfusion injury.This study aims to investigate the effectiveness of liposomal prostaglandin E l （Lipo-PGE1,Alprostadil,Beijing Tide Pharmaceutical Co.,Ltd.） for enhancing microcirculation in reperfusion injury.In addition,this study determined the optimal administration method for acute ST elevation myocardial infarction （STEMI） patients undergoing primary PCI.Methods：Totally,68 patients with STEMI were randomly assigned to two groups：intravenous administration ofLipo-PGE 1 （Group A）,and no Lipo-PGE1 administration （Group B）.The corrected thrombolysis in myocardial infarction （TIMI） frame count （cTFC） and myocardial blush grade （MBG） were calculated.Patients were followed up for 6 months.Major adverse cardiac events （MACE） were also measured.Results：There was no significant difference in the baseline characteristics between the two groups.The cTFC parameter in Group A was significantly lower than Group B （18.06 ± 2.06 vs.25.31 ± 2.59,P ＜ 0.01）.The ratio of final MBG grade-3 was significantly higher （P ＜ 0.05） in Group A （87.9％） relative to Group B （65.7％）.There was no significant difference between the two groups in final TIMI-3 flow and no-reflow.Patients were followed up for 6 months,and the occurrence of MACE in Group A was significantly lower than that in Group B （6.1％ vs.25.9％ respectively,P ＜ 0.05）.Conclusions：Myocardial microcirculation of reperfusion injury in patients with STEMI,after primary PCI,can be improved by administering Lipo-PGE1.

Comparison of the Concentrations of Lidocaine in Different Body Fluids/Tissues after Subarachnoid Space and Intravenous Administration of a Lethal Dose of Lidocaine

The objective of the study was to compare the concentration of lidocaine in different body fluids/tissues after subarachnoid space and intravenous administrations of a lethal dose of lidocaine.Totally 18 dogs were used in the experiment.Six dogs were given subarachnoid anesthesia,another were given an intravenous injection of a dose of 75 mg/kg weight of lidocaine hydrochloride in 5 min and the last 6 dogs were used as the blank control dogs and given a subarachnoid space injection or a femoral artery injection of the same volume of sodium chloride.As soon as its vital signs disappeared,each dog was dissected and the specimen,such as brain,cerebrospinal fluid(CSF)in lateral ventricle,CSF in subarachnoid space,spinal cord(cervical spinal cord,thoracic spinal cord,lumbar spinal cord,and waist spinal cord),heart,lung,liver,spleen,kidney,bile,urine,heart blood,peripheral blood,muscle in injection location,and muscle in no injection location,were collected for analysis of lidocaine immediately.Analysis was performed with gas chromatography‑mass spectrometry(GC‑MS).From the maximum to the minimum,the order of lidocaine concentration detected in the subarachnoid space‑administered dogs was as follows:CSF in subarachnoid space,waist spinal cord,thoracic spinal cord,CSF in lateral ventricle,lumbar spinal cord,cervical spinal cord,lung,kidney,muscle in injection location,heart,brain,spleen,heart blood,liver,peripheral blood,bile,muscle in no injection location,and urine.The order of lidocaine concentration detected in the intravenously administered dogs was as followed:Kidney,heart,lung,spleen,brain,liver,peripheral blood,bile,heart blood,cervical spinal cord,thoracic spinal cord,muscle in injection location,lumbar spinal cord,muscle in no injection location,CSF in subarachnoid space,urine,and CSF in lateral ventricle.The maximum concentration of lidocaine was detected in the subarachnoid space CSF of subarachnoid space‑administered dead dogs,while in intravenously injected dead dogs,the maximum concentration of lidocaine was detected in the kidney.Our study provides some useful data for the forensic identification of epidural anesthesia accidents to decide the way the lidocaine enters the body.

Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury

To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 106 rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells.

Inhalation treatment of lung cancer: the influence of composition, size and shape of nanocarriers on their lung accumulation and retention

Objective： Various nanoparticles have been designed and tested in order to select optimal carriers for the inhalation delivery ofanticancer drugs to the lungs. Methods： q-he following nanocarriers were studied： micelles, liposomes, mesoporous silica nanoparticles （MSNs）, poly propyleneimine （PPI） dendrimer-siRNA complexes nanoparticles, quantum dots （QDs）, and poly （ethylene glycol） polymers. All particles were characterized using the following methods： dynamic light scattering, zeta potential, atomic force microscopy, in vitro cyto- and genotoxicity. In vivo organ distribution of all nanopartides, retention in the lungs, and anticancer effects of liposomes loaded with doxorubicin were examined in nude mice after the pulmonary or intravenous delivery. Results： Significant differences in lung uptake were found after the inhalation delivery of lipid-based and non-lipid-based nanoparticles. The accumulation ofliposomes and miceUes in lungs remained relatively high even 24 h after inhalation when compared with MSNs, Q Ds, and PPI dendrimers. There were notable differences between nanoparticle accumulation in the lungs and other organs 1 and 3 h after inhalation or intravenous administrations, but 24 h after intravenous injection all nanoparticles were mainly accumulated in the liver, kidneys, and spleen. Inhalation delivery of doxorubicin by liposomes significantly enhanced its anticancer effect and prevented severe adverse side effects of the treatment in mice bearing the orthotopic model of lung cancer. Conclusion： The results of the study demonstrate that lipid-based nanocarriers had considerably higher accumulation and longer retention time in the lungs when compared with non-lipid-based carriers after the inhalation delivery. These particles are most suitable for effective inhalation treatment of lung cancer.

Intranasal insulin neuroprotection in ischemic stroke

Acute ischemic stroke（AIS）is a leading cause of death and long-term disability in the USA and worldwide.Significant advances in the last two decades have resulted in the introduction of intravenous tissue plasminogen activator and more recently catheter based endovascular interventions in selected patients（Berkhemer et al.,2015;Goyal et al.,2015）.

A Novel Thermosensitive In-situ Gel of Gabexate Mesilate for Treatment of Traumatic Pancreatitis:An Experimental Study

Gabexate mesilate（GM） is a trypsin inhibitor,and mainly used for treatment of various acute pancreatitis,including traumatic pancreatitis（TP）,edematous pancreatitis,and acute necrotizing pancreatitis. However,due to the characteristics of pharmacokinetics,the clinical application of GM still needs frequently intravenous administration to keep the blood drug concentration,which is difficult to manage. Specially,when the blood supply of pancreas is directly damaged,intravenous administration is difficult to exert the optimum therapy effect. To address it,a novel thermosensitive in-situ gel of gabexate mesilate（GMTI） was developed,and the optimum formulation of GMTI containing 20.6%（w/w） P-407 and 5.79%（w/w） P188 with different concentrations of GM was used as a gelling solvent. The effective drug concentration on trypsin inhibition was examined after treatment with different concentrations of GMTI in vitro,and GM served as a positive control. The security of GMTI was evaluated by hematoxylin-eosin（HE） staining,and its curative effect on grade Ⅱ pancreas injury was also evaluated by testing amylase（AMS）,C-reactive protein（CRP） and trypsinogen activation peptide（TAP）,and pathological analysis of the pancreas. The trypsin activity was slightly inhibited at 1.0 and 5.0 mg/m L in GM group and GMTI group,respectively（P〈0.05 vs. P-407）,and completely inhibited at 10.0 and 20.0 mg/m L（P〈0.01 vs. P-407）. After local injection of 10 mg/m L GMTI to rat leg muscular tissue,muscle fiber texture was normal,and there were no obvious red blood cells and infiltration of inflammatory cells. Furthermore,the expression of AMS,CRP and TAP was significantly increased in TP group as compared with control group（P〈0.01）,and significantly decreased in GM group as compared with TP group（P〈0.01）,and also slightly inhibited after 1.0 and 5.0 mg/m L GMTI treatment as compared with TP group（P〈0.05）,and significantly inhibited after 10.0 and 20.0 mg/m L GMTI treatment as compared with TP group（P〈0.01）. HE staining results demonstrated that pancreas cells were uniformly distributed in control group,and they were loosely arranged,partially dissolved,with deeply stained nuclei in TP group. Expectedly,after gradient GMTI treatment,pancreas cells were gradually restored to tight distribution,with slightly stained nuclei. This preliminary study indicated that GMTI could effectively inhibit pancreatic enzymes,and alleviate the severity of trauma-induced pancreatitis,and had a potential drug developing and clinic application value.

Comparative pharmacokinetic studies of borneol in mouse plasma and brain by different administrations

Borneol,a monoterpenoid alcohol,is used widely,particularly in combined formulas for preventing and curing cardiovascular and cerebrovascular diseases in traditional Chinese medicine.In order to understand the blood and brain pharmacokinetics after intravenous,intranasal,or oral administration and to investigate the superiority and feasibility of intranasal administration,a simple gas chromatographic (GC) method with flame ionization detection (FID) was developed for the quantification of borneol.Blood samples and brain were collected from mice at 1,3,5,10,20,30,60,90,and 120 min after intravenous,intranasal,or oral administration of borneol at a dosage of 30.0 mg/kg.Sample preparations were carried out by liquid-liquid extraction with an internal standard solution of octadecane.The pharmacokinetic parameters were calculated by the software of Kinetica.The calibration curves were linear in the range of 0.11-84.24 μg/ml and 0.16-63.18 μg/g for borneol in plasma and brain,respectively.The methodological and extraction recoveries were both in the range of 85%-115%.The intra-day and inter-day variabilities for plasma and brain samples were ≤5.00% relative standard deviation (RSD).The absolute bioavailabilities F of intranasal and oral administrations were 90.68% and 42.99%.The relative brain targeted coefficients Re of intranasal and oral administrations were 68.37% and 38.40%.The GC-FID method developed could be applied to determination and pharmacokinetic study.The borneol from injection was distributed and metabolized fast without absorption process.The borneol from oral administration was distributed more slowly and had the lowest absolute bioavailability.Nasal administration of borneol was quickly absorbed into the blood and brain,was easy to use and had a greater safety than infection,which makes it worthy of further development as an administration route for encephalopathy treatment.

Enhancing effect of natural borneol on the absorption of geniposide in rat via intranasal administration

Both geniposide （Ge） and natural borneol （NB） are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. The concentrations of Ge in plasma were determined by reversed-phase high-performance liquid chromatography （HPLC） after intranasal administration of Ge （4 mg/kg） alone and combined with different doses （0.08, 0.8, and 8 mg/kg） of NB. The intravenous administration was given as a reference （4 mg/kg of Ge and 8 mg/kg of NB）. Compared with the intravenous administration, the absolute bioavailability of Ge was 76.14% through intranasal administration combined with NB. Compared with the intranasal administration of Ge alone, Ge could be absorbed rapidly in the nasal cavity combined with NB; the peak time of Ge in the plasma became shorter （3-5 min vs. 40 min）; the peak concentration became higher （1.32-4.25 IJg/ml vs. 0.67 ug/ml）; and, the relative bioavailability of Ge combined with NB was 90.3%-237.8%. The enhancing effect was attenuated as the dose of NB decreased. The results indicated that NB can accelerate the absorption of Ge dose-dependently in the nasal cavity.

Quercetin-3-O-β-D-glucopyranosyl-(4→1)-α-L-rhamnoside metabolites in the rat using UPLC-Q-TOF/MS

Ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF/MS) and the MetabolynxTM software, combined with mass defect filtering, were applied to identity the metabolites of quercetin-3-O-β-D-glucopyranosyl-(4→1)-α-L-rhamnoside(QGR) in rats after intravenous administration. MSE was used for simultaneous acquisition of precursor ion information and fragment ion data at high and low collision energy in one analytical run, which facilitated the rapid structural characterization of eight metabolites in rat plasma, urine and bile. The results indicated that methylation and glucuronidation were the major metabolic pathways of QGR in vivo. The present study provided important information about the metabolism of QGR which will be useful for fully understanding the mechanism of action of this compound. Furthermore, this work demonstrated the potential of the UPLC-Q-TOF/MS approach using Metabolynx for rapid and automated research of the metabolites of natural products.