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Cerebrospinal fluid surrounds and supports the central nervous system, including the ventricles and subarachnoid spaces. Cerebrospinal fluid should be an important source of biomarkers for central nervous system diseases because it is in direct contact with the central nervous system. Many studies are reported on cerebrospinal fluid proteomics, highlighting many recent progresses. Here, we review recent advances in proteomics technology and clinical application of cerebrospinal fluid.

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Pharmacokinetics plays a key role in rational use of medicines.Many factors can affect the drug's pharmacokinetics.Previous studies mainly focused on the impact of hypoxia on hepatic drug metabolizing enzyme,but uncommon on drug transporters.Actually,drug transporter is a key factor for activation of the drugs transport across the cell membrane into the inside of cells,such as multidrug resistance protein (MDR),breast cancer resistance protein (BCRP),multidrug resistance associated protein (MRP),organic cation transporter (OCT),organic anion-transporting polypeptide (OATP),organic anion transporter (OAT),qligopeptide transporter (PEPT),etc.They are widely present in the small intestine villus epithelial cells,renal tubular epithelial cells,hepatocytes and biliary epithelial cells.They play a very important role in drug absorption,distribution,metabolism and excretion.The changes in drug transporters under hypoxia in intestinal could affect the bioavailability of drugs;the changes in drug transporters in organs could affect drug's distribution,subsequent drug's indications and adverse reactions;the changes in drug transporters in liver and kidney could affect the metabolism and excretion rate of drugs,thereby the drug's residence time and half-life.

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Objective To investigate the effects on myocardial mitochondria-related indexes in rats after rapid elevation to 3 400 m altitude and myocardial protection effects with metoprolol.Methods Male Wistar rats were randomly divided into three groups with 12 rats in each group as follows,group A(normal group,55 m above sea level),group B(hypoxia group, 3 400 m above sea level),group C(metoprolol group,3 400 m above sea level).Heart rate and blood pressure were measured during the rapid transfer from the plain(Shanghai 55 m)to plateau of 3 400 m.Then,the rats were anesthetized with chloral hydrate.The blood was collected from the abdominal aorta and blood gas indexes were measured.The heart tissue was homog-enized.The oxidativee stress related parameters,such as superoxide dismutase(SOD),malondialdehyde(MDA)and nitric ox-ide(NO)were assayed.The mitochondrial function related parameters,such as complexes-Ⅰ,Ⅱ,Ⅲ,Ⅳ,succinate dehydro-genase(SDH),malate dehydrogenase(MDH)and adenosine triphosphate(ATP)were measured.Results After the rats were exposed to high altitude,the blood oxygen tension and oxygen saturation in the metoprolol group were increased in com-parison with the hypoxia group.Compared with the normal group,the content of MDA in the hypoxia group was increased sig-nificantly,while the content of SOD and NO were decreased significantly(P<0.01),the mitochondrial complex Ⅰ,Ⅱ,Ⅲand Ⅳ were also decreased 44.49%,32.38%,34.43% and 20.16%.Compared with hypoxia group,the MDA was decreased by 13.72%,while SOD and NO were increased by 25.73% and 168.55%,the activity of mitochondrial complexes were also increased by 44.92%,33.73%,37.11% and 10.09% for metoprolol group.The respiratory chain SDH and MDH in hypoxic group were decreased by 29.51% and 42.79% and the activity of Na+-K+-ATPase,Ca2+-Mg2+-ATPase and T-ATPase were decreased by 20.24%,27.56% and 33.32% in comparison with the normal group.After intervention with metoprolol,SDH and MDH were increased by 47.36% and 88.57% separately,the activities of Na+-K+-ATPase,Ca2+-Mg2+-ATPase and T-ATPase were also increased by 31.92%,26.95%,44.93% in comparison with hypoxia group.Those results indicated that metoprolol can increase ATPase activity.Conclusion Under the condition of acute hypoxia at 3 400 m above sea level,myocar-dial injury is related to the changes of oxidative stress and mitochondrial-related enzyme activity.Metoprolol helps to normalize the related indicators and provides the protection for myocardial injury caused by hypoxia.

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Objective To investigate the anti-hypoxia effects of octacosane and the petroleum ether extract from Saus-surea Involucrate(PESI)on the water,sugar,lipid and protein metabolism of mice at simulated high altitude.Methods The healthy adult male BALB/C mice were randomly divided into normal control group,hypoxic model group,acetazolamide group, the petroleum ether of Saussurea involucrata group and octacosane group.Drugs were administered i.v 20 mins before the mice were exposed to a simulated high altitude of 6 000 m for 8 hours in an animal decompression chamber.The mice were sacrificed at the end of 8 hours.Organ water content,organ indexes and metabolism indicators of sugar,protein and lipid were deter-mined.Results The edema of heart,brain and lung was reduced notably(P<0.05,P<0.01)in the mice received PESI at 200 mg/kg and octacosane at 100 mg/kg.In the treated groups,the increase of blood sugar,muscle glycogen,TG(triglycer-ide),TC(total cholesterol)were all significantly inhibited,the decrease of liver glycogen,the protein content of heart and brain was also remarkably blocked(P<0.05,P<0.01).Conclusion PESI and octacosane effectively regulate the metabolism of hypoxic mice and reserve the body′s energy for survival by lowering the basic metabolism.

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Objective To study pharmacodynamics of the effective anti-hypoxia components in the petroleum ether ex-tract of Saussurea Involucrate(PESI)and octacosane.Methods PESI and octacosane were first evaluated by normobaric hy-poxia model,acute decompression model and followed by chemical induced hypoxic models with potassium cyanide,sodium ni-trite and isoprenaline hydrochloride poisoning.Results PESI and octacosane can effectively prolong the survival time of hypo-baric hypoxic mice(P<0.01)and reduce the mortality of acute hypobaric hypoxia mice(P<0.01)in a dose-dependent man-ner.Anti-hypoxic potency of PESI and octacosane obtained by chemical induced hypoxic model indicated that they significantly increase survival time(P<0.05)of hypoxia mice than acetazolamide.Conclusion PESI and octacosane have good anti-hypoxia activity.

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Objective To investigate the effect of hypoxia with cold on the heart and brain damage in rats by simulating 6 000 m high altitude at different exposure time,established a rat model of acute mountain sickness for the related mechanism studies.Methods 32 healthy male Wistar rats were randomly divided into normal control group,hypoxia with cold 1 d,3 d and 5 d group,8 rats in each group.The normal control group was kept in the plain environment(1 500 m)without any treat-ment.The other three groups were placed in large hypobaric hypoxia chamber to simulate 6 000 m altitude with different ex-posed times.HE staining was used to observe the pathological changes of heart and brain tissue.The changes of biochemical indexes were measured to evaluate the damage of heart and brain tissue at different hypoxia times.Results HE staining showed that hypoxia with cold induced rat heart and brain damage with different degrees.The myocardial tissue damage was in-creased with exposure time.The most serious brain damage happened in day 3.Compared with the normal control group,the content of MDA and LD in the myocardial tissue of hypoxia rats were significantly increased(P<0.05 or P<0.01)with pro-longed time,while the contents of GSH,T-SOD and the activity of Na+K+-ATPase were reduced(P<0.05 or P<0.01). The content of MDA in brain tissue was significantly increased at day 1 and day 3(P<0.05 or P<0.01).LD content was sig-nificantly increased(P<0.05)with time.The content of GSH,the activity of T-SOD and Na+K+-ATPase were significantly reduced in day 3(P<0.05).Conclusion Simulating an altitude of 6 000 m caused obvious damage on the heart and brain tis-sues of rats.The degree of damage was related to the exposure time to hypoxia with cold.The decrease of body′s antioxidant capacity,the increase of free radicals and energy metabolism disorders are important factors leading to heart and brain injury.

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Objective To investigate anti-hypoxia activity and protective effects of Lishukang capsule on rat brain tissue at simulated high altitude hypoxia.Methods The anti-hypoxic activity of Lishukang capsule was evaluated with normobaric hypoxia test and acute hypobaric hypoxia test in mice.In addition,rats were exposed to large hypobaric hypoxia chamber stim-ulating 8 000 m altitude.The pathological changes of rat brain tissue before and after hypoxia were observed.The oxidative stress indicators and metabolism parameters in brain were measured.Results The low,medium and high Lishukang doses can effectively prolong the survival time of mice(P<0.01)in the dose dependent manner.The medium and high Lishukang doses were significantly better than those of Rhodiola rosea capsules(P<0.05 or P<0.01).The low,medium,high Lishukang dose groups reduced the mortality of acute hypobaric hypoxia mice(P<0.01)with dose dependent effects.The mice mortality in medium and high dose groups was lower than that of Rhodiola rosea group(P< 0.01).Compared with normal control group,the hypoxic model rats exhibited pathological injury in the brain tissue after exposure to hypobaric hypoxia stimulating 8 000 m altitude.The contents of MDA,H2O2,NO,LD and LDH activity increased significantly(P<0.05 or P<0.01), while the activities of SOD,CAT,GPX were significantly decreased(P<0.05 or P<0.01).After pretreatment with Lishu-kang capsule,the pathological damage of rat brain tissue was alleviated and the content of MDA,NO in the brain tissue was re-duced(P<0.05 or P<0.01).The levels of H2O2,LD content and LDH activity in medium and high dose groups were signifi-cantly decreased(P<0.05 or P<0.01).The activities of SOD,CAT and GPX in high dose group were significantly increased(P<0.05).Conclusion Lishukang capsule has good anti-hypoxia activity.It provides protective effect for the injuries induced by hypobaric hypoxia in rats.The mechanism may related to the improvement of antioxidant capability,reduction of free radical damage and amelioration of energy metabolism.

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Acute mountain sickness (AMS ) is a self-limiting medical condition characterized by headache ,nausea ,fa-tigue ,dizziness ,and insomnia .AMS usually occurs after rapid ascent to high altitudes in non-altitude acclimatized individuals . Extensive studies have been done on AMS ,but knowledge on the mechanism ,prevention and treatment are still limited .It will help the prevention and treatment of AMS with deep understanding of its risk factors and mechanisms .In this article ,we sys-tematically reviewed the diagnosis ,risk factors ,developing mechanisms ,preventions and treatments of AMS .

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OBJECTIVE:To investigate the effects of different operation methods on the residual amount of docetaxel. METH-ODS:60 Docetaxel injections were selected and divided into two groups,i.e. standard operation method was adopted in group A (30 injections),and clinical common operation method was used in group B(30 injections). Docetaxel injections were placed for 5,10 or 15 minutes respectively,and drained. Residual liquid was collected to calculate residual amount. The difference of residual amount,due to preparation method and standing time,were compared between two groups. RESULTS:After placing for 5,10 or 15 min,the volume and amount of residual liquid in group B were significantly higher than in group A(P<0.05). In same group, the volume and amount of residual liquid after placing for 10 and 15 min were all lower than that after placing for 5 min(P<0.05 or P<0.01);the volume and amount of residual liquid after placing for 15 min were lower than that after placing for 10 min(P<0.05). CONCLUSIONS:The standard operation of pharmacy dispensing staff is very important to reduce the residual amount of docetaxel,and guarantee safe,effective and sufficient medication. It is suggested that clinical staff should abide by standard opera-tion method.

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Objective To explore the improving effect of L-leucine on memory impairment in plateau and the mecha-nism. Methods After successfully trained in the 8-arm radial maze,50 male Kunming mice were selected and randomly divid-ed into normoxic control group (NC group),model group,and L-leucine (low,medium and high dose) groups.Animals in L-leu-cine groups were intragastrically given 0.473 g?kg-1 ,0.945 g?kg-1 and 1.89 g?kg-1 L-leucine for 7 days and those in NC and model control groups were administered the same volume of purified water for the same period of time.At the 4th day of the treat-ment,the mice in the model control group and L-leucine groups were placed in a large low-pressure and low-oxygen chamber to simulate low-pressure hypoxic environment of the plateau (7 500 m,3 d).The 8-arm radial maze was used to measure the spatial learning and memory ability of mice and dry-wet method to measure the water content of brain tissue.HE staining was employed to observe the cell morphological changes in CA1 region of the hippocampus.The expression levels of mTOR,P70S6K and 4E-BP1 mRNA in the hippocampus were detected by SYBR Green real-time PCR. Results The reference memory error ( RME) ,total error ( TE) ,testing time ( TT) ,and water content of brain tissue were significantly increased,the neuron injury was exacerbated in CA1 region of the hippocampus,and the expression levels of mTOR and P70S6K mRNA were markedly decreased in model control group when compared with those in NC group (P<0.05 or P<0.01).These indexes,however,were significantly improved in L-leu-cine groups,especially in high-dose group. Conclusion L-leucine can improve memory impairment in plateau,and the mecha-nism may involve the activation of mTOR and its downstream substrates (4E-BP1 and P70S6K).

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OBJECTIVE:To establish a method for the content determination of peoniflorin in Danggui shaoyao powder,and provide a reference for controlling the quality of the preparation. METHODS:HPLC was performed on the column of Symmetry C18 with mobile phase of acetonitrile-water(containing 0.1% phosphoric acid)(14∶86,V/V)at a flow rate of 1.0 ml/min,detection wavelength was 230 nm,column temperature was 20℃,and injection volume was 20μl. RESULTS:The linear range of peoniflo-rin was 10-80 μg/ml(r=0.999 3);RSDs of precision,stability and reproducibility tests were lower than 2%;recovery was 98.3%-104.9%(RSD=2.0%,n=9). CONCLUSIONS:The method is simple,accurate and specific,and can be used for the con-tent determination of peoniflorin in Danggui shaoyao powder.

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OBJECTIVE:To establish a method for the content determination of icariin in Kangguzhi zengsheng tablet,and pro-vide a basis for improving the quality standard. METHODS:HPLC was performed on the column of Hypersil ODS2 C18 with mo-bile phase of acetonitrile- water(27∶73,V/V)at a flow rate of 1.0 ml/min,detection wavelength was 270 nm,column temperature was 25℃,and injection volume was 10μl. RESULTS:The linear range of icariin was 3-60μg/ml(r=0.999 9);limit of quantita-tion was 11.2 μg/ml,limit of detection 4.3 μg/ml;RSDs of precision,stability and reproducibility tests were lower than 2.0%;re-covery was 99.00%-100.67%(RSD=0.63%,n=6). CONCLUSIONS:The method is simple,accurate and reproducible,and can be used for the content determination of icariin in Kangguzhi zengsheng tablet.

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A series of pathological, physiological, and biochemical changes, even anatomical histological changes happen while humans arrive at the high plateau region from plain area. There is a certain relationship between the body's compensatory or decompensated adjustments to the environment and the changes of absorption, distribution, metabolism, and excretion of drugs. The objective of the study is to observe the effects of acute exposure to high altitude at 4,010 m on pharmacokinetics of propranolol in rats, and to provide basis and new ideas to adjust drug dosage and administration, so as to promote rational drug use in high altitude. 28 healthy male wistar rats were randomly divided into four groups, group A and B which were in plain area; group C and D which were acutely exposed to high altitude by aviation; group A and C were used for pharmacokinetics determination of propranolol, while group B and D had no drug administration for physiological and pathological changes research at high altitude. The pharmacokinetics of propranolol significantly changed; area under curve, C max (the peak concentration), mean residence time, and t 1/2 (the biological half-life) increased significantly by 481.72, 398.94, 44.87, and 58.77 %, respectively; clearance and V (apparent volume of distribution) decreased by 81.50 and 70.56 %, respectively, after acute exposure to high altitude at 4,010 m; Analytic results show that pH, buffer base, base excess, ctCO2 (content of total carbon dioxide), sO2 (oxygen saturation of arterial blood), pO2 (oxygen tension of arterial blood), and cNa(+) severely decreased by 2.43, 630.00, 311.00, 11.48, 91.38, 76.22, and 2.82 %, respectively, while pCO2 (carbon dioxide tension of arterial blood) and cCl(-) significantly increased by 47.40 and 6.76 %. Lactate dehydrogenase and total protein significantly decreased by 58.44 and 26.82 %, while total bilirubin and alkaline phosphatase severely increased by 338 and 24.94 % after acute exposure to high altitude at 4,010 m. Pathological research shows that alveolar wall is hyperemic, edematous, and incrassate; alveolus epithelium becomes hyperplastic while neutrophilic granulocytes infiltrate; brain neurons are edematous and perivascular space occurred; neurons of seahorse are metamorphic and karyopyknotic; mesangial cells are hyperplastic in kidney glomerulus tissue. We should reduce the dosage or extend the dosing interval in high altitude to maintain the drug concentration in therapeutic window since velocity of metabolism and excretion are reduced.

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Mitochondria are the main places of cellular respiration as well as the citric acid cycle and oxidative phospho‐rylation .It plays an important role in controlling the life and death of cells .Mitochondrial dysfunction leads to a series of human diseases such as ischemia‐reperfusion injury ,sepsis and diabetes .Mitochondrial become an attractive target for drug transporters strategy and therapeutic targets for neurodegeneration .Although the molecular mechanisms responsible for mitochondria media‐ted disease processes are not fully elucidated yet ,the oxidative stress appears to be critical .Accordingly ,strategies are being de‐veloped for the targeted delivery of antioxidants to mitochondria .The prospect of development of mitochondrial targeted drugs with anti‐oxidative stress protection is tempting .Mitochondrial targeting antioxidants were the antioxidant drugs which took mi‐tochondria as the target site .In this review ,weintroduced the conception and classification of mitochondrial targeted antioxidants and the research progress of disease treatment by mitochondrial targeted antioxidants .

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OBJECTIVE@#To observe the effect of aminophylline on physiological and pathological changes in acute exposure to high altitude in rats.@*METHODS@#A total of 21 male Wistar rats were randomly divided into a plain group (altitude 55 m), a high altitude hypoxia group (altitude 4 300 m), and a high altitude hypoxia plus aminophylline group. After 5 days, blood from orbital venous was collected for analyzing biochemical parameters. Blood from abdominal aorta was collected for analyzing the parameters of blood gas. The tissues of brain, lung, and kidney were dissected for pathological observation.@*RESULTS@#Compared with the plain group, the parameters of LDH, ALP, Urea and cCl? in the hypoxia group or the aminophylline treatment group were significantly increased (P<0.01), while the parameters of ALB, Cr, SatO₂, Hb, Hct, PaCO₂, PaO₂2, BB and BE were significantly reduced (P<0.01). Compared with the hypoxia group, the parameters of Cr, pH, Hct, cNa⁺, cCl⁻ in the aminophylline treatment group were significantly increased (P<0.01), while AST, ALT, ALB, PaCO₂ and cK⁺ were significantly decreased (P<0.01 or P<0.05). Pathological results showed the brain, lung and liver tissues were obviously damaged in the hypoxia group compared with that in the plain group. These damages were significantly attenuated by aminophylline.@*CONCLUSION@#Aminophylline can improve blood gas and biochemical parameters in acute exposure to high altitude in rats. It can protect rat brain, lung and liver from the damage caused by acute high altitude, which may be related its effects on relaxation of bronchial smooth muscle and inhibition of inflammation.

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<p><b>OBJECTIVE</b>To investigate the influence of a sudden increase of altitudes (within 2500 m) in winter on cardiomyocyte functions in rats.</p><p><b>METHODS</b>Thirty male Wistar rats were randomly divided into groups A (55 m), B (1520 m), and C (2260 m) and subjected to simulated conditions at the indicated altitudes in winter for 3 days. Blood gas analysis, venous blood biochemistry, and measurements of SOD activity and myocardial concentrations of MDA and NO were performed. Histopathological changes in the left ventricle were observed with HE staining and electron microscopy.</p><p><b>RESULTS</b>Blood pH and PCO2 did not differ significantly between the 3 groups, but PO2 and BE in groups B and C decreased significantly compared with those in group A (P<0.01). Compared with group A, the rats in group C showed obviously increased myocardial enzymes, MYB, Tn-I, and MDA contents (P<0.01) with significantly decreased SOD activity (P<0.05); both groups B and C showed significantly decreased NO content in the myocardium (P<0.01). Histopathologically, the myocardial fiber in group C showed irregular alignment, disruption, and mitochondrial expansion.</p><p><b>CONCLUSION</b>A sudden increase of altitude to 2260 m in winter can potentially cause hypoxic cardiomyocyte damage as a result of oxidative and environmental stresses.</p>

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To summarize the advances in mechanisms of damage and treatments of cerebral ischemia and reperfusion and fore -casts future research directions .The existing achievements in literatures were summarized .Cerebral ischemia and reperfusion damage were related to inflammatory response , intracellular calcium overload , free radicals injury , release of excitatory amino acids and other factors.The treatments included reducing ischemia time , blocking glutamate receptors , free radical scavenging , inhibition of apoptosis , reducing inflammation , and promoting neuronal growth , etc.Multi-target treatment would be future directions in treatment of cerebral ischemia.

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<p><b>OBJECTIVE</b>To investigate the changes in hepatic functions and activities of CYP1A2 and CYP3A4 in rats after acute exposure to high altitude.</p><p><b>METHODS</b>Twelve healthy male Wistar rats were randomly divided into control group and exposure group for acute exposure to normal and high altitude (4010 m) environment. Blood samples were collected from the vena orbitalis posterior for detection of the hepatic function. Hepatic pathologies of the rats were examined microscopically with HE staining. Liver microsomes were extracted by differential centrifugation to assess the activities of CYP1A2 and 3A4 using P450-GloTM kit.</p><p><b>RESULTS</b>In rats with acute exposure to high altitude, AST, ALT, and ALP all increased significantly by 48.50%, 47.90%, and 103.02%, respectively, and TP decreased significantly by 17.80% as compared with those in rats maintained in normal altitude environment (P<0.05). Pathological examination of the liver revealed edema of the central vein of the liver and hepatocyte karyopyknosis in rats after acute exposure to high altitude, which also resulted in significantly lowered activities of CYP1A2 and 3A4 in the liver (by 96.56% and 43.53%, respectively).</p><p><b>CONCLUSION</b>Acute exposure to high altitude can cause obvious liver injuries and lowered activities of CYP1A2 and 3A4 in rats to severely affect drug metabolism in the liver and result in increased concentration, prolonged half-life and reduced clearance of drugs.</p>

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<p><b>OBJECTIVE</b>To study the pharmacokinetics of propranolol and metoprolol in rats after acute exposure to high altitude.</p><p><b>METHODS</b>Wistar rats were randomly assigned into 4 groups for treatment with intragastric administration of propranolol or metoprolol after acute exposure to high altitude (4010 m) or normal altitude (50 m). Venous blood samples were collected from the rats at different time points after drug administration to determine the drug concentrations in the plasma and plasma ultrafiltrate using liquid chromatography-mass spectrometry (LC-MS/MS).</p><p><b>RESULTS</b>The protein binding rate of propranolol was significantly increased but that of metoprolol remained unchanged after acute exposure to high altitude. Compared with the rats exposed to normal altitude, the rats with acute exposure to high altitude showed significant alterations in the pharmacokinetic parameters of the drugs, shown by increased Cmax and AUC, prolonged t1/2 and MRT, and lowered Clz/F of propranolol, and by increased Tmax and prolonged t1/2 and MRT of metoprolol without obvious changes of the parameters of the compartmental model.</p><p><b>CONCLUSION</b>Significant changes in the pharmacokinetics of propranolol and metoprolol occur in rats after acute exposure to high altitude possibly in relation to, apart from the changes in plasma protein binding ratio and blood gas, alterations in metabolic enzyme activities, increased blood viscosity, and species and general conditions of the animals.</p>

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Objective:To establish an HPLC method for the content determination of salvianolic acid B in Ansheng Yizhi cap-sules. Methods:A Hypersil ODS2 C18 column(150 mm × 4. 6 mm,5 μm) was used and methanol-water-formic acid (40∶60∶1) was used as the mobile phase. The detection wavelength was at 286 nm. The flow rate was 1. 0 ml·min-1 and the sample size was 10 μl. Results:The calibration curve of salvianolic acid B was linear within the range 7. 75-77. 51 μg·ml-1(r=0. 999 6). The average re-covery was 98. 17%(RSD=1. 79%, n=6). Conclusion:The method is simple, accurate and repeatable, which can be used in the quality control of Ansheng Yizhi capsules.