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Objective: To compare the pharmacokinetics and bioavailability of pirfenidone in the fasted and fed states in healthy volunteers. Methods: An open-label, randomized crossover study was conducted in 12 healthy subjects. Food effects were examined by comparing pharmacokinetic data of pirfenidone after administration of a single oral 400 mg dose under fasted or fed conditions. Plas-ma pirfenidone concentration was determined by an HPLC method and its pharmacokinetic parameters were calculated with DAS v2. 0 software. Results: Under fasted and fed conditions, the concentration-time profiles of pirfenidone were fitted a one-compartment model and the pharmacokinetic parameters were as follows: t1/2were (2. 16 ± 0. 47) and (2. 05 ± 0. 42) h;tmaxwere(0. 69 ± 0. 16)and (1. 46 ± 0. 40)h;Cmaxwere (12. 95 ± 1. 79) and (9. 16 ± 2. 87) mg·L-1;AUC0-12were (44. 97 ± 15. 06) and (36. 19 ± 14. 44) mg·h·L-1;AUC0-∞were (46. 55 ± 16. 79) and (37. 41 ± 15. 43) mg·h·L-1, respectively. When compared with that of the fasted group, tmaxwas significantly increased (P<0. 001) while Cmaxand AUC were remarkedly decreased in the fed group (P<0. 001 and P<0. 01, respectively). Conclusion: Concomitant food intake significantly influences the pharmacokinetics and bioavail-ability of pirfenidone as indicated by reducing its extent and rate of absorption, which is associated with better tolerability.
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With the deepening medical reform, people pay more attention to achieve excellent medical quality, reasonable cost and thoughtful medical service, which were the core indicators for the success of medical reform, but also were the basic requirements which medical reform should achieve.For strengthening the management of medical quality and improving medical quality, it was necessary to further develop the pharmaceutical department of medical institute and pharmaceutical care, which plays an important role in the improvement of rational use of drugs in clinical practice. With the deepening of the medical reform, graded medical system will be constantly realized and capacity of pharmaceutical care of the primary health care should be enhanced immediately.We should pay more attention to the special diseased population, which was also one of the key tasks of strengthening clinical pharmacy services.
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With the deepening medical reform, people pay more attention to achieve excellent medical quality, reasonable cost and thoughtful medical service, which were the core indicators for the success of medical reform, but also were the basic requirements which medical reform should achieve.For strengthening the management of medical quality and improving medical quality, it was necessary to further develop the pharmaceutical department of medical institute and pharmaceutical care, which plays an important role in the improvement of rational use of drugs in clinical practice. With the deepening of the medical reform, graded medical system will be constantly realized and capacity of pharmaceutical care of the primary health care should be enhanced immediately.We should pay more attention to the special diseased population, which was also one of the key tasks of strengthening clinical pharmacy services.
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Objective To retrospectively analyze adverse drug reaction ( ADR ) of Yuxingcao ( Houttuyniae Herba ) preparations, thus provide reference for post-market re-evaluation of traditional Chinese medicine injections. Methods The ADR from Chinese ADR spontaneous reporting system database from 2006 to 2008 were analyzed by descriptive statistic method. Results A total of 2 282 reports on ADR induced by Yuxingcao preparations were concluded in this study, and 98.07% ADR of the total cases ( 2 238 case ) were due to vein injection. The main ADR were anaphylactic reactions which injure multiple systems and organs.The most frequent symptoms were respiratory system damage, such as expiratory dyspnea (with the incidence rate of 27.25%).Skin and mucous membrane were the secondly susceptible (with the incidence rate of 21.35%).The ratio of serious ADR in the total case was 13.50% (308 case), rate of allergic shock was 8.37% (191 case), and 22 cases were dead. Conclusion By strengthening the ADR reporting and monitoring, the risk of traditional Chinese medicine injection could be controlled.Safety re-evaluation should be performed to overall enhance safety, effectiveness and quality control of these kinds of medicine.
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Aim To study the mechanisms of the pro-tective effect of procyanidin B2 ( PCB2 ) on the myocar-dial cell apoptosis induced by lipopolysaccharide ( LPS) . Methods Using the primary culture rat myo-cardial cells, myocardial cell injury model was induced by LPS. PCB2 low, medium and high dose groups, were cultured with 6. 25 , 12. 5 , 25. 0 μmol · L-1 PCB2 respectively in DMEM medium for 24 h continu-ously. Myocardial cell survival rate was determined by MTT colorimetric method. Cardiacmyocyte NOX activi-ty was determined by lucigen chemiluminescence meth-od . Western blot analysis was used to detect myocardi-al NADPH oxidase p47phox expression. TUNEL method was used to detect apoptosis and flow cytometry was used to determine the content of myocardial cells ROS. Results Compared with control group, the cell dam-age induced by LPS group myocardial cell survival rate significantly decreased ( P <0. 01 ) , and myocardial cell NOX activity, p47phox expression, apoptotic cell number and ROS content were significantly increased (P<0. 01). PCB2 low, medium and high dose groups cell survival rates were significantly elevated, myocar-dial cell NOX activity and p47phox expression, apoptotic cell number and the ROS content decreased significant-ly in a dose-dependent manner ( P <0. 01 ) . Conclu-sion PCB2 protects myocardial cell apoptosis induced by LPS via inhibiting the expression of NADPH oxidase activation, p47phox expression and reactive oxygen spe-cies generation.
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Aim To explore the protective effects of LPPC ( procyanidins extracted from the litchi pericarp) on cardiomyocyte apoptosis in septic rats and its mech-anisms. Methods The rats were randomly divided in-to 5 groups, and were given orally the drug for two weeks continuously. The control group ( control) and sepsis model group ( LPS ) were given distilled water once a day. LPPC low, medium and high dose groups were given LPPC 50 , 100 , 200 mg · kg-1 · d-1 re-spectively which were prepared freshly every day. After the treatment, sepsis animal models were established. Except for the control group, other groups were injec-ted LPS (lipopolysacchride, 10mg·kg-1) intraperito-neally to induce acute sepsis model. 4hrs later, rat se-rum was collected, isoenzyme ( CK-MB ) , lactate de-hydrogenase ( LDH ) and activity of aspertate amin-otransferase ( AST/GOT) were detected. Then rat car-diac tissue was obtained and cardiac tissue malondial-dehyde ( MDA ) , total antioxidant capacity ( T-AOC ) and reduced glutathione ( GSH ) content were deter-mined. TUNEL staining was performed to analyze the apoptosis of myocardial cells. Cleaved caspase-3 and TNF alpha protein expressions were analyzed by West-ern blot. Results Compared with the control group ( control) , serum of sepsis model group rats CK-MB, LDH, AST/GOT and cardiac tissue MDA content were significantly increased (P<0. 01). At the same time, the activity of cardiac tissue T-AOC and GSH de-creased obviously ( P<0. 01 ) . The apoptotic myocar-dial cells increased significantly ( P<0. 01 ) , and the expression level of cleaved caspase-3 and TNF alpha decreased obviously ( P <0. 01 ) . LPPC pretreatment significantly decreased the serum CK-MB, LDH, AST/GOT and tissue MDA content, increased tissue T AOC and GSH activity, attenuated apoptosis of rat myocardi-al cells significantly, and decreased expression level of cleaved caspase-3 and TNF alpha. Conclusion LPPC pretreatment can significantly attenuate rat myocardial cell apoptosis induced by sepsis, and the underlying mechanisms may be related to its anti-oxidative effects.
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Objective To study the effects of pirfenidone on total enzyme and isoenzyme of liver microsomal cytochrome P450 in rats. Methods The activites of liver microsomal dimethyl nitrosamine N-demethylase( NDMA )and erythromycin demethylase( ERD ) were determined. Fifty-six SD rats were randomly divided into six groups,in which they received CMC,dexamethasone 100 mg·kg-1 ,ketoconazole 40 mg·kg-1 ,pirfenidone 25,50,100 mg·kg-1 ,respectively. After administration for 6 and 12 days,livers were prepared liver microsome,the concentration of proteinum in microsome and shade selection to plasma samples were determined by spectrophotometer. Results After administration of pirfenidone for 6 days, cytochrome P450 was significantly increased in 50 and 100 mg·kg-1 pirfenidone groups,as compared with solvent control group (1%sodium carboxymethylcellulose)(P﹤0. 01). After administration of pirfenidone for 6 and 12 days,NDMA of liver microsome was not changed significantly(P﹥0. 05). ERD of liver microsome was significantly increased in 100 mg·kg-1 pirfenidone group after administration for 12 days(P﹤0. 01). Conclusion Pirfenidone can induce P450 and ERD activities in a dose-and time-dependent manner.
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Clopidogrel was believed to be superior to aspirin by the well-known CAPRIE trial. However, no other large clinical trials demonstrated the same results, but all focused on the combination use of clopidogrel with aspirin, and combination therapy in CREDO was called the "Emperor's New Clothes". However, no one overturned the results of these clinical trials by quantitatively analyzing them. We reviewed ten large-scale clinical trials about clopidogrel. On the basis of results of CAPRIE, CREDO and CHARISMA trials, we re-estimated their minimal sample sizes and their powers by three well-established statistical methodologies. From the results of CAPRIE, we inferred that the minimal sample size should be 85 086 or 84 968 but its power was only 30.70%. A huge gap existed. The same was also true of CREDO and CHARISMA trials. Moreover, in CAPRIE trial, 0 was included in the 95% confidence interval and 1 was included in the 95% confidence interval for the relative risk. There were some paradoxical data in CAPRIE trial. We are led to conclude that the results in CAPRIE, CREDO, and from the subgroup analysis in CHARISMA trials were questionable. These results failed to demonstrate that clopidogrel was superior to aspirin or that clopidogrel used in combination with aspirin was better than aspirin alone. The cost-effectiveness analyses by some previous studies were not reliable.
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<p><b>OBJECTIVE</b>To investigate the effect of dauricine on the apoptosis of neuronal cells and the expression of apoptosis-related proteins in the brain penumbra of rats induced by transient focal cerebral ischemia-reperfusion injury.</p><p><b>METHOD</b>Male SD rats were randomly divided into five groups: sham group (Sham), model group (Model), and Dauricine groups of low, middle and high doses. To make the transient focal cerebral ischemia-reperfusion injury model, the middle cerebral artery on the right side of rat was occluded by inserting a nylon suture through the internal carotid artery for 1 h, followed by reperfusion for 24 h after withdrawing the suture. Dauricine groups, different doses of Dauricine (2.5, 5, 10 mg x kg(-1) as low, middle and high dose respectively) were administered intraperitoneally at the beginning of the cerebral ischemia, and at 11 h and 23 h after reperfusion. At the same time, Sham group and Model group was administered saline as controls. Brain samples of rats were treated with paraformaldehyde perfusion fixation 24 h after blood reperfusion and then collected for making pathological sections. Apoptotic changes of neuronal cells in the brain penumbra of rat were evaluated in situ by terminal deoxyribonucleotidyl transferasemediated dUTP-digoxigenin nick end-labelling (TUNEL). Cytochrome C (Cyt-C) release and the expression of caspase -3 and caspase -9 proteins of the ischemic-reperfusion brain tissue were determined by immunohistochemistry assay.</p><p><b>RESULT</b>TUNEL-positive cells in groups of middle and high doses of dauricine (18.9 +/- 2.02 and 15.9 +/- 2.9 cells/mm2 respectively) decreased significantly compared with model group (25.5 +/- 3.3 cells/mm2, P<0.05). Cyt-C release and the expression of caspase-3 and caspase-9 proteins in groups of middle and high doses of dauricine were also inhibited compared with Model group (P<0.01).</p><p><b>CONCLUSION</b>The mechanism of the neuroprotective effect of dauricine after cerebral ischemia-reperfusion injury may parly, related with an inhibition of neuronal cells apoptosis in the penumbra.</p>
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Animals , Male , Rats , Apoptosis , Benzylisoquinolines , Pharmacology , Caspases , Metabolism , Cytochromes c , Metabolism , Dose-Response Relationship, Drug , Gene Expression Regulation , Ischemic Attack, Transient , General Surgery , Neuroprotective Agents , Pharmacology , Reperfusion Injury , Metabolism , Pathology , Tetrahydroisoquinolines , PharmacologyABSTRACT
AIM: To compare the bioavailability of the test and reference formulation of secnidazole (2 g) tablets under fasting conditions. METHODS: This bioequivalence study was carried out in 20 healthy male Chinese volunteers according to a single dose, two-sequence, crossover randomized design. Fifteen blood samples per period were collected over 96 h, and plasma secnidazole concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay and pharmacokinetic parameters were analyzed by the non-compartmental and compartmental methods. RESULTS: Plasma concentration-time profiles were adequately described by a one-compartment open model with first-order absorption. The main pharmacokinetic parameters of secnidazole test and reference tablets were as follows: tmax were (2.30±1.06) and (2.28±1.10) h, Cmax were (49.63±6.35) and (46.17±4.24) mg/L, t1/2 were (28.84±3.41) and (29.05±4.01) h, AUC0-96 were (1832.06±180.15) and (1847.14±204.14) mg·h-1·L-1, respectively. The relative bioavailability of test tablets was (99.99±11.92)%. CONCLUSION: The results indicate that the two formulations of secnidazole tablets are bioequivalent in the rate and extent of absorption.
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To determine the pharmacokinetics and bioequivalence of epinastine (EPN) hydrochloride, a promising histamine H1 receptor antagonist, in healthy Chinese volunteers under fasting conditions. METHODS: EPN hydrochloride test and reference tablets were administered as a single dose on two treatment days separated by a 1-week washout period. After dosing, serial blood samples were collected for a period of 36 h, and plasma EPN hydrochloride concentrations were determined by a validated reversed-phase HPLC method and pharmacokinetic parameters were calculated with DAS software. RESULTS: Plasma concentration-time profiles were adequately described by a two-compartment open model. The compound was rapidly absorbed and cleared slowly from plasma with a half-life of approximately 10 h. The main pharmacokinetic parameters of EPN hydrochloride test and reference tablets were as follow: tmax were (2.2±0.5) and (2.0±0.4)h, Cmax were (66±16)and (68±13)μg/L, t1/2 were(10.1±1.3) and (10.4±2.4)h, AUC0-36 were (592±88) and (601±94)μg·h·L-1, respectively. The relative bioavailability of test tablets was (99±13)%. CONCLUSION: The results indicate that the two formulations of EPN hydrochloride tablets are bioequivalent in the rate and extent of absorption.
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AIM To investigate if inhibiting neutrophil infiltration and adhesion molecules expression is a part of the mechanisms of ginsenoside Rg1 protecting from cerebral injury after cerebral ischemia-reperfusion. METHODS Rats were pretreated with ginsenoside Rg1 25, 50 and 100 mg·kg-1·d-1, ig, for 7 d, respectively, then subjected to cerebral ischemia (middle cerebral artery occlusion) for 2 h and reperfusion for 22 h. The infarct volume and the neurological deficit were determined by TTC staining and Longa's scoring, respectively. The infiltration of neutrophils was evaluated by measuring the activity of myeloperoxidase (MPO). The expressions of intercellular adhesion molecule-1 (ICAM-1) and E-selectin were analyzed by Western blot. The permeability of the blood-brain barrier was evaluated by measurement of Evans blue content in brain tissue with spectrophotometer at 4 h after reperfusion. RESULTSCompared with vehicle-treated group, ginsenoside Rg1 (50 and 100 mg·kg-1·d-1) treatment significantly reduced infarct volume and elevated permeability of blood-brain barrier, alleviated the neurological deficit, and inhibited protein expressions of ICAM-1 and E-selectin in brain tissue. CONCLUSION Ginsenoside Rg1 has protective effects on cerebral injury induced by ischemia-reperfusion through inhibiting neutrophil infiltration and expression of the adhesion molecules.
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OBJECTIVE:To provide suggestion and advice for the selection and utilization of essential drug. METHODS:WHO standards for the selection of essential drug and the formulation process of National Essential Drug?Part for Primary Medical and Health Institutions (2009 edition) were analyzed. The significance of theory and methods of pharmacoepidemiology in the selection, utilization and performance evaluation of essential drug were put forward. RESULTS & CONCLUSION:National essential drug should be selected according to evidence-based medicine and pharmacoeconomics based on pharmacoepidemiology, in order to take advantage of a drug epidemiology-based evidence-based medicine and drug selection based on economics, the study concludes. Dialectical thinking about safety and effectiveness of essential drug should be conducted.
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AIM To investigate if the beneficial effects of β-aescin on ischemia/reperfusion (I/R) induced cerebral injury are related to the inhibition of expressions of pro-inflammatory cytokines. METHODS Rats were pretreated ig with β-aescin for 7 d and then subjected to cerebral I/R injury induced by a middle cerebral artery occlusion. The infarct volume and the neurological deficit were determined by the method of TTC staining and the Longa's score. The permeability of the blood-brain barrier was evaluated by measurement of the Evans blue (EB)content in the brain with spectrophotometer. The serum contents of interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α) protein were determined by radioimmunoassay and ELISA assay. The expression of nuclear factor-κB (NF-κB) was evaluated with Western blot. RESULTS β-Aescin significantly reduced infarct volume (P<0.05 or P<0.01), ameliorated the neurological deficit and reduced the permeability of blood-brain barrier (P<0.05). Pretreated with β-aescin 30 and 60 mg·kg-1, the serum content of IL-8 and the expressions of TNF-α and NF-κB protein in brain tissue were significantly decreased (P<0.05). CONCLUSION β-Aescin has protective effects on cerebral injury through inhibiting the expression and release of the inflammatory mediators after I/R injury.
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Aim To investigate glutamate-induced [ Ca2 + ] i changes in cultured rat neonatal cortical astrocytes after hypoxia/reoxygenation, H2O2 or high concentration of L-glutamate injury. In the meantime, the effects of Gingko biloba extract (GbE) were examined. Methods [ Ca2+ ]i changes in astrocytes were monitored by laser scanning confocal microscopy with the Ca2+ sensitive fluorescent probe [ Ca2 + ] i, but decrease by ( 3.3 ± 1.6) %, (81 ± 11 ) % and ( 81 ± 7 ) %, respectively. Pretreatment with H2O2 or high concentration of L-glutamate injury were ( 135 ± 98 ) %, ( 117 ± 93 ) % and ( 89 ± 36) %,different injury. Conclusion Hypoxia/reoxygenation, H2O2 and high concentration of L-glutamate impaired astrocytes' response to exogenous L-glutamate, and then bidirectional communication between astrocytes and neurons could not take place. GbE could improve the abnormal responses and maintain the normal function of astroglical network. These effects support that GbE has potential beneficial actions against brain injury.
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AIM: To study pharmacokinetics and relative bioavailability of pantoprazole sodium enteric-coated test and reference tablets in healthy volunteers. METHODS: A single oral dose of 40 mg pantoprazole sodium enteric-coated test and reference tablets were given to 20 male healthy volunteers in a randomized two-way crossover design. Plasma concentrations of pantoprazole were determined by HPLC method. Pharmacokinetic parameters and relative bioavailability were calculated with DAS program to evaluate the bioequivalence of the two preparations. RESULTS: Plasma concentration-time profiles were adequately described by a two-compartment open model. The main pharmacokinetic parameters of pantoprazole sodium test and reference tablets were as follow: The values of Tmax were (3.18±0.54) and (3.30±0.47) h, Cmax were (2.98±0.83) and (2.91±0.87) mg·L-1, T1/2β were (1.86±0.41) and (1.72±0.48) h, AUC0-t were (9.51±3.71) and (9.77±4.55) mg·h·L-1, respectively. The relative bioavailability of test tablets was (102.3±19.6)%. CONCLUSION: The two preparations of pantoprazole sodium are bioequivalent.
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In recent years,a large number of drugs have been withdrawn from the market because of torsade de pointes(TdP) and sudden cardiac death,which pose great risks in drug application.Therefore,the different models have been developed to detect TdP liability during the early stage of drug development.In this paper,the principles and characteristics of these screening models are reviewed to give props for preclinical safety assessment.
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Aim To investigate the protective effects of breviscapine(Bre) on myocardial hypertrophy and fibrosis induced by isoproterenol (Iso) in rats and its mechanism. Methods Myocardial hypertrophy and fibrosis model of rats were induced by injection of Iso for 7 days(5 mg?kg -1?d -1,sc).From day 2～15,rats were treated with Bre 12.5 and 25 mg?kg -1?d -1 ip,the NS control and Iso model group received saline injection.On day 15,animals were killed by decapitation,monitored in terms of myocardial indexes (heart weight/boday weight, HW/BW and left ventricalar weight/body weight,LVW/BW);the contents of angio- tensin Ⅱ(AngⅡ),nitric oxide(NO) and hydroxyproline and the activity of Na+,K+-ATPase and Ca 2+-ATPase in left ventricle were assayed with radioimmunoassay and spectrophotometry,respectively. Results Compared with the NS control group, the myocardial indexes, the level of AngⅡ and hydroxyproline in left ventricle were markedly increased and NO content, activity of Na+,K+-ATPase and Ca 2+-ATPase in left ventricle were decreased in Iso model group;treatment with Bre 25 mg?kg -1?d -1 significantly reduced the myocardial index and content of AngⅡ and hydroxyproline in left ventricle,increased the NO content ,enhanced the activity of Na+,K+-ATPase and Ca 2+-ATPase.Conclusion Bre can alleviate myocardial hypertrophy and fibrosis induced by Iso in rats.
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The pharmacokinetics and relative bioavailability were studied in 18 healthy volunteers. A single oral dose of 150 mg irbesartan capsule (test) or tablet (reference) was given to each volunteer according to a randomized 2-way crossover study. The concentrations in plasma were determined by HPLC-UV method. The main parameters of irbesartan capsules were: Cmax: 1.502 +/- 0.295 micrograms/ml, tmax: 1.44 +/- 0.34 h, t 1/2: 20.21 +/- 14.71 h, AUC0-t: 11.087 +/- 3.443 micrograms/ml-1.h. The relative bioavailability of capsule to tablet was (101.4 +/- 28.9)%. The results of statistical analysis showed that two formulations were bioequivalent.
Subject(s)
Adult , Humans , Male , Angiotensin Receptor Antagonists , Biological Availability , Biphenyl Compounds , Blood , Pharmacokinetics , Capsules , Cross-Over Studies , Tablets , Tetrazoles , Blood , PharmacokineticsABSTRACT
The pharmacokinetics and relative bioavailability were studied in 18 healthy volunteers. A single oral dose of 150 mg irbesartan capsule (test) or tablet (reference) was given to each volunteer according to a randomized 2-way crossover study. The concentrations in plasma were determined by HPLC-UV method. The main parameters of irbesartan capsules were: Cmax: 1.502 +/- 0.295 micrograms/ml, tmax: 1.44 +/- 0.34 h, t 1/2: 20.21 +/- 14.71 h, AUC0-t: 11.087 +/- 3.443 micrograms/ml-1.h. The relative bioavailability of capsule to tablet was (101.4 +/- 28.9)%. The results of statistical analysis showed that two formulations were bioequivalent.