Antitumor Effects of Laminaria Extract Fucoxanthin on Lung Cancer.

Lung cancer is the leading cause of cancer mortality worldwide and non-small-cell lung cancer (NSCLC) is the most common type. Marine plants provide rich resources for anticancer drug discovery. Fucoxanthin (FX), a Laminaria japonica extract, has attracted great research interest for its antitumor activities. Accumulating evidence suggests anti-proliferative effects of FX on many cancer cell lines including NSCLCs, but the detailed mechanisms remain unclear. In the present investigation, we confirmed molecular mechanisms and in vivo anti-lung cancer effect of FX at the first time. Flow cytometry, real-time PCR, western blotting and immunohistochemistry revealed that FX arrested cell cycle and induced apoptosis by modulating expression of p53, p21, Fas, PUMA, Bcl-2 and caspase-3/8. These results show that FX is a potent marine drug for human non-small-cell lung cancer treatment.

Oestrogen upregulates L-type Ca²âº channels via oestrogen-receptor- by a regional genomic mechanism in female rabbit hearts.

In type-2 long QT (LQT2), adult women and adolescent boys have a higher risk of lethal arrhythmias, called Torsades de pointes (TdP), compared to the opposite sex. In rabbit hearts, similar sex- and age-dependent TdP risks were attributed to higher expression levels of L-type Ca(2+) channels and Na(+)-Ca(2+) exchanger, at the base of the female epicardium. Here, the effects of oestrogen and progesterone are investigated to elucidate the mechanisms whereby I(Ca,L) density is upregulated in adult female rabbit hearts. I(Ca,L) density was measured by the whole-cell patch-clamp technique on days 0-3 in cardiomyocytes isolated from the base and apex of adult female epicardium. Peak I(Ca,L) was 28% higher at the base than apex (P < 0.01) and decreased gradually (days 0-3), becoming similar to apex myocytes, which had stable currents for 3 days. Incubation with oestrogen (E2, 0.1-1.0 nm) increased I(Ca,L) (∼2-fold) in female base but not endo-, apex or male myocytes. Progesterone (0.1-10 µm) had no effect at base myocytes. An agonist of the α- (PPT, 5 nm) but not the ß- (DPN, 5 nm) subtype oestrogen receptor (ERα/ERß) upregulated I(Ca,L) like E2. Western blots detected similar levels of ERα and ERß in male and female hearts at the base and apex. E2 increased Cav1.2α (immunocytochemistry) and mRNA (RT-PCR) levels but did not change I(Ca,L) kinetics. I(Ca,L) upregulation by E2 was suppressed by the ER antagonist ICI 182,780 (10 µm) or by inhibition of transcription (actinomycin D, 4 µm) or protein biosynthesis (cycloheximide, 70 µm). Therefore, E2 upregulates I(Ca,L) by a regional genomic mechanism involving ERα which is a known determinant of sex differences in TdP risk in LQT2.

Effect of daurisoline on HERG channel electrophysiological function and protein expression.

Daurisoline (1) is a bis-benzylisoquinoline alkaloid isolated from the rhizomes of Menispermum dauricum. The antiarrhythmic effect of 1 has been demonstrated in different experimental animals. In previous studies, daurisoline (1) prolonged action potential duration (APD) in a normal use-dependent manner. However, the electrophysiological mechanisms for 1-induced prolongation of APD have not been documented. In the present study, the direct effect of 1 was investigated on the hERG current and the expression of mRNA and protein in human embryonic kidney 293 (HEK293) cells stably expressing the hERG channel. It was shown that 1 inhibits hERG current in a concentration- and voltage-dependent manner. In the presence of 10 µM 1, steady-state inactivation of V(1/2) was shifted negatively by 15.9 mV, and 1 accelerated the onset of inactivation. Blockade of hERG channels was dependent on channel opening. The expression and function of hERG were unchanged by 1 at 1 and 10 µM, while hERG expression and the hERG current were decreased significantly by 1 at 30 µM. These results indicate that 1, at concentrations below 30 µM, exerts a blocking effect on hERG, but does not affect the expression and function of the hERG channel. This may explain the relatively lower risk of long QT syndrome after long-term usage.

Nano titanium dioxide induces the generation of ROS and potential damage in HaCaT cells under UVA irradiation.

Nano titanium dioxide (nano-TiO2) is frequently used in cosmetics, especially in sunscreen. Nano-TiO2 has been reported to be an efficient photocatalyst, which is able to produce reactive oxygen species (ROS) under UVA irradiation. However, the effects and mechanisms of skin toxicity caused by nano-TiO2 remain unclear. In this study, we explored the cytotoxicity and oxidative stress induced by nano-TiO2 under UVA irradiation with different crystal forms (anatase, rutile and anatase/rutile) and sizes (4 nm, 10 nm, 21 nm, 25 nm, 60 nm) in human keratinocyte HaCaT cells. Intracellular distribution of nano-TiO2, cell viability, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), super oxide dismutase (SOD) activity and Malondialdehyde (MDA) content were measured. The results showed that nano-TiO2 (10-200 microg/ml) significantly reduced cell viability in a dose-dependent manner in HaCaT cells. The cell viability was 76.9%, 60.2%, and 44.1% following nano-TiO2 (4 nm), nano-TiO2 (10 nm) and P25 treatment at the concentration of 200 microg/ml, respectively (P < 0.01). Nano-TiO2 induced ROS resulted in oxidative stress in these cells by reducing SOD and increasing MDA levels. The MMP of the cells was decreased significantly (P < 0.01) while the apoptosis rate was increased. Anatase and amorphous forms of nano-TiO2 showed higher cytotoxicity than the rutile form. The results indicated that nano-TiO2 could induce the generation of ROS and damage HaCaT cells under UVA irradiation.

Revaluation of clopidogrel: let the data speak for themselves.

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.

Inhibitory effects of dauricine on early afterdepolarizations and L-type calcium current.

We have previously reported that dauricine exerted antiarrhythmic effects on various experimental arrhythmias. To further clarify its mechanism, the effects of dauricine on action potential duration (APD), early afterdepolarizations (EADs), triangulation, which is defined as the repolarization time from APD at 30% level (APD30) to APD at 90% level (APD90), and L-type calcium current (I(Ca-L)) were studied using standard microelectrode techniques on rabbit papillary muscles and whole-cell patch clamp techniques on single myocytes isolated from rabbits by enzymatic digestion, respectively. Cardiac hypertrophy was induced by coarctating the abdominal aorta of rabbits. The results showed that in papillary muscles of hypertrophied rabbits, 1 micromol/L dofetilide, a selective IKr blocker, prolonged APD50 and APD90 and induced EADs (4/6, p < 0.01) with hypokalemia ([K+]o = 2.7 mmol/L). Dauricine inhibited EADs (p < 0.01) and shortened the prolonged APD (p < 0.01). In single myocytes, dauricine also inhibited EADs induced by dofetilide, hypokalemia, and hypomagnesaemia. Dauricine decreased the triangulation and reduced the peak amplitude of I(Ca-L) at all potentials tested. Dauricine shifted the steady-state activation curves to the right and steady-state inactivation curves to the left and prolonged the tau value of the recovery curve. These results suggest that dauricine inhibits EADs and this effect may be associated with its blockade of I(Ca-L).

[Effect of dauricine on apoptosis and expression of apoptogenic protein after transient focal cerebral ischemia-reperfusion injury in rats].

OBJECTIVE: 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. METHOD: 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. RESULT: 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). CONCLUSION: 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.

Development and validation of an LC-MS method with electrospray ionization for quantitation of digoxin in human plasma and urine: application to a pharmacokinetic study.

A highly sensitive and specific LC-MS method was developed and validated for the quantification of digoxin in human plasma and urine using d5-dihydrodigoxin as internal standard (IS). The assay procedure involved extraction of digoxin and IS from human plasma with chloroform-isopropanol (95:5, v/v). Chromatogrphic separation was achieved on a Spherisorb ODS2 column using a gradient mobile phase with 5 mmol/L ammonium acetate in water with 1% acetic acid and acetonitrile. The mass spectrometer was operated in the selected ion monitoring mode using the respective [M+K](+) ions, m/z 819.4 for digoxin and m/z 826.4 for IS. The method was proved to be accurate and precise at linearity range of 0.12-19.60 ng/mL in plasma with a correlation coefficient (r(2)) of >or=0.9968 and 1.2-196.0 ng/mL in urine. The limit of quantification achieved with this method was 0.12 ng/mL in plasma and 1.2 ng/mL in urine. The intra- and inter-assay precision and accuracy values were found to be within the assay variability limits as per the FDA guidelines. The developed assay method was successfully applied to a pharmacokinetic study in human volunteers following intravenous administration of digoxin.

Single- and multiple-dose pharmacokinetics of pirfenidone, an antifibrotic agent, in healthy Chinese volunteers.

A randomized, dose-escalating study evaluated the pharmacokinetics of single and multiple oral doses of pirfenidone, a promising antifibrotic agent, in 48 healthy Chinese volunteers. The effects of sex and food on the pharmacokinetics of pirfenidone were also evaluated. Pharmacokinetics was determined from serial blood samples obtained up to 12 hours after administration of single 200-, 400-, or 600-mg doses of pirfenidone and after multiple doses of 400 mg administrated 3 times daily (tid). Plasma levels of pirfenidone and areas under the curve were found to be proportional to dose. Pirfenidone was rapidly absorbed (t(max) = 0.33-1 hours) and cleared (t((1/2)) = 2-2.5 hours). Pharmacokinetic parameters after multiple doses were similar to those after single doses. Food had a significant effect (P < .01) on the extent of absorption (AUC(0-infinity) = 37.4 +/- 15.4 mg x h/L [fed] vs 46.6 +/- 16.8 mg x h/L [fasted]), rate of absorption was considerably (P < .001) prolonged (t(max) = 1.5 +/- 0.4 hours [fed] vs 0.7 +/- 0.2 hours [fasted]), and peak concentrations were significantly (P < .001) decreased (C(max) = 9.2 +/- 2.9 mg/L [fed] vs 13.0 +/- 1.8 mg/L [fasted]). No significant sex differences were noted for pharmacokinetic variables. Pirfenidone was well tolerated. These results support a tid regimen of pirfenidone for the management of idiopathic pulmonary fibrosis. Concomitant intake of food will reduce the rate and extent (about 20%) of absorption, which is associated with better tolerability of pirfenidone.

[Pharmacokinetics and distribution of 5-Fu magnetic albumin deuto-microsphere in normal and tumor-bearing mice].

To observe the pharmacokinetic and tissue-distribution characters of 5-flourouracil magnetic albumin deuto-microsphere (5-Fu-MAD) in normal and tumor-bearing mice, HPLC method for the determination of 5-Fu in plasma and tissues was established and applied to determine 5-Fu in mouse plasma and tissue samples. A Flame atomic absorption spectrometer was used to detect the iron concentration in mouse tissue. Plasma concentration-time curves of free 5-Fu, 5-Fu-MAD and 5-Fu-MAD plus the magnetic frame (MF) conformed to two compartment model of first order absorption and they had C(max) of 34.9, 7.95 and 5.97 mg x L(-1); T1/2 (Ke) of 22.26, 76.0 and 124.6 min, V(d) of 3.28, 30.7 and 66.1 L x kg; AUC(0-t), of 233.9, 78.3 and 50.2 mg x min x L(-1); AUC(0-infinity) of 237.2, 89.3 and 68.1 mg x min x L(-1), respectively. The distribution of 5-Fu and iron was the highest in the plenty blood perfusion organs like the liver, tumor, spleen and lung, while lower in the kidney and heart and lowest in brain and muscle. The tissue distribution of muscle and tumor increased significantly when a magnetic frame was inserted there. The pharmacokinetics and tissue distribution of 5-Fu-MAD exhibited sustained-release and target characteristics.

Tolerability and Pharmacokinetics of Hydronidone, an Antifibrotic Agent for Hepatic Fibrosis, after Single and Multiple Doses in Healthy Subjects: an Open-Label, Randomized, Dose-Escalating, First-in-Human Study.

BACKGROUND AND OBJECTIVES: Hydronidone is a novel pyridine derivative with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics of hydronidone in healthy subjects. Effects of sex and food on hydronidone pharmacokinetics were also evaluated. METHODS: A randomized, dose-escalating, first-in-human study was conducted in 88 subjects. Five cohorts of 34 subjects received a single dose of hydronidone capsules at 15-120 mg, and two cohorts of 12 subjects received 90 and 120 mg of hydronidone thrice daily for 7 days, and six subjects received 60 mg of hydronidone thrice daily for 28 days to assess the safety and tolerability. In 36 subjects, hydronidone pharmacokinetics were investigated following oral administration of single (30, 60, and 120 mg) and multiple (60 mg, thrice daily) doses of hydronidone. RESULTS: Plasma concentrations of hydronidone and area under the concentration-time curve were found to be proportional to dose. Hydronidone was rapidly absorbed [median time to maximum plasma concentration (t max) = 0.33-0.63 h] and cleared [terminal elimination half-life (t 1/2) = 1.72-3.10 h]. Pharmacokinetic parameters after multiple doses were similar to those after single dose. Food had a significant affect (P < 0.01) on the extent and rate of absorption. No significant sex differences were noted for pharmacokinetic variables. CONCLUSION: Hydronidone was well tolerated and rapidly absorbed, and concomitant intake of food reduced rate and extent (about 20 %) of absorption in healthy volunteers. There was no accumulation following multiple doses of hydronidone. These results support a 60 mg thrice-daily regimen for management of hepatic fibrosis and further development of hydronidone (registered at ClinicalTrials.gov as ChiCTR-ONC-12002899).

Effects of Gingko biloba extract on gap junction changes induced by reperfusion/reoxygenation after ischemia/hypoxia in rat brain.

Gap junction communication between astrocytes plays an important role in the brain. The purpose of this study was to investigate the effects of Gingko biloba extract (GBE) on the changes of connexin 43 (Cx43) mRNA and protein expression levels of rat cortex and hippocampus induced by ischemia-reperfusion and astrocyte gap junction intercellular communication (GJIC) induced by hypoxia-reoxygenation. After 2 hours of middle cerebral artery occlusion (MCAO) followed by 24 hours of reperfusion, there was obvious neurological deficit in rats. Cx43 mRNA and protein expression levels of rat cortex and hippocampus in the ischemia hemisphere were decreased significantly. When GBE at doses of 50 and 100 mg/kg body weight was administrated by p.o. daily for 7 days, the neurological deficit was improved, and lower Cx43 mRNA and protein expression levels induced by ischemia-reperfusion were recovered to normal. The i.p. injection of nimodipine (0.7 mg/kg weight body) also showed improvement on neurological deficit and Cx43 expression levels. Astrocyte GJIC was measured by the fluorescence recovery after photobleaching (FRAP). Hypoxia-reoxygenation induced a significant decrease in GJIC. Pretreatment with GBE (100 mg/l) and nimodipine (1.6 mg/l) significantly prevented the hypoxia-reoxygenation inhibition of GJIC. These results suggest that GBE could exert its neuroprotective effects by improvement of Cx43 expression and GJIC induced by hypoxia/ischemia-reoxygenation/ reperfusion injury.

Effects of gingko biloba extract on glutamate-induced [Ca2+]i changes in cultured cortical astrocytes after hypoxia/reoxygenation, H2O2 or L-glutamate injury.

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 fluo-3. RESULTS: After astrocytes were impaired by hypoxia/reoxygenation, H2O2 (50 micromol x L(-1)) or L-glutamate (0.25 mmol x L(-)), the exogenous glutamate (27 micromol x L(-1)) could not induce increase of [Ca2+]i, but decrease by (3.3 +/- 1.6)%, (81 +/- 11)% and (81 +/- 7)%, respectively. Pretreatment with GbE (10 mg x L(-1)) could not improve injured astrocytic glutamate response. But after pretreatment with GbE (100 mg x L(-1)), glutamate-induced [Ca2+]i elevation of astrocytes after hypoxia/reoxygenation, H2O2 or high concentration of L-glutamate injury were (135 +/- 98)%, (117 +/- 93)% and (89 +/- 36)%, respectively. Nimodipine (1.6 mg x L(-1)) could also reverse the abnormal response of astrocytes after 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.

[Effect of sinomenine on adjuvant arthritis and its mechanisms].

OBJECTIVE: To discuss the anti-inflammatory mechanism of sinomenine on inflammatory media in joint of adjuvant arthritis rats. METHOD: Rats were randomly divided into the normal group and the model group, the prednisone group, the small, medium, large of sinomenine group (30, 60, 120 mg x kg(-1)). Except for the rats in the normal group, animals were modeled to adjuvant arthritiswith freund's complete adjuvant. The arthritis index (AI) and the swelling degree of paws were recorded, and the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were determined. RESULT: Compared with the normal group, the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were increased significantly in the model group (P < 0.05). Compared with the model group, it was shown to exert a dramatic inhibitory effect on secondary reaction of freund's adjuvant arthritis of rats, and the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were significantly decreased in the sinomenine group (P < 0.05). CONCLUSION: Sinomenine has a remarkable treatment effect on RA. It is via NO to inhibit the activity of cytokines and decrease the level of inflammation mediators, which may be one of its curing RA mechanism.

[Effects of ginkgolides on gene expression of hepatic cytochrome P-450 in rats].

OBJECTIVE: To observe the effects of ginkgolides on gene expression of hepatic cytochrome P-450 in rats. METHOD: Sprague-Dawley rats were administered ginkgolides (100 mg x kg(-1) body weight) through oral gavage once daily for four consecutive days. The level of gene expression in liver tissues was analyzed by competitive reverse transcription-polymerase chain reaction (competitive RT-PCR). RESULT: A single and prospective band of CYP1A1, CYP1A2, CYP2B1/B2, CYP2C11, CYP2E1, CYP4A1 and cyclophilin was observed after polymerase chain reaction (PCR) when the reactive system of reverse transcription (RT) had no target RNA, which confirmed the competitor had a specific capacity to bind to the CYP or cyclophilin primer. CYP1A1 mRNA was not dectectable in the livers of untreated control rats and ginkgolides-treated rats. The levels of CYP2C11 and CYP2E1 were not changed by ginkgolides treatment. In contrast, the levels of gene expression for CYP1A2 and CYP2B1/B2 were decreased, however, the levels of gene expression for CYP3A1 and CYP4A1 in ginkgolides group were distinctly increased compared with the control. CONCLUSION: A specific effect of ginkgolides on cytochrome P-450 gene expression was observed in this investigation. Ginkgolides had various effects on different cytochrome P-450 isoforms.

Awareness and attitudes of healthcare professionals in Wuhan, China to the reporting of adverse drug reactions.

BACKGROUND: A voluntary procedure for reporting adverse drug reactions (ADRs) was formally put in place in 1989. However, only a small proportion of ADR reports are actually forwarded to the national monitoring center. To identify the reasons for underreporting, the authors investigated the awareness and attitudes of healthcare professionals (doctors, nurses, and administrators) toward the ADR system in China. In addition, the authors sought to formulate approaches to improve the current ADR reporting system. METHODS: Structured interviews were carried out in 16 hospitals selected from 27 municipal hospitals in Wuhan, Hubei Province, China. A questionnaire survey of a stratified random sample of approximately 15% of healthcare professionals in each selected hospital was conducted during February to March 2003. RESULTS: The response rate of this survey was 85%. One thousand six hundred and fifty-three questionnaires were used in the final analysis. Only 2.7% of the healthcare professionals had a correct understanding to the definition of ADR. Eighty-nine point two percent of the healthcare professionals had encountered ADRs. Ninety-four percent of them were aware of the need to report these to the ADR monitoring center. However, only 28.5% of doctors, 22.8% of nurses, and 29.7% of administrators actually submitted a report. For the most part, they reported ADRs to the hospital pharmacy (66.0%), to other departments in the hospital (72.5%), and to the pharmaceutical industry (23.0%), rather than to the national monitoring center (2.9%) or regional monitoring center (9.5%). Severe or rare ADRs and ADRs to new products were generally perceived to be significant enough to report. Sixty-two point one percent of the healthcare professionals had encountered ADRs, yet not reported them to anybody. The major reasons for not reporting included no knowledge of the reporting procedure (71.4%), unavailability of the reporting center mailing address (67.9%), unavailability of the ADR report form (60.4%), lack of knowledge of the existence of a national ADR reporting system (52.2%), and belief that the ADR in question was already well known (44.1%). CONCLUSIONS: Healthcare professionals in Wuhan, China have little basic knowledge of ADR and of the voluntary reporting system. The main reasons for underreporting were lack of basic knowledge about ADRs and the voluntary reporting procedure. Education and training of healthcare professionals is needed to improve the current ADR reporting system.

Study on the pharmacokinetics and relative bioavailability of irbesartan capsules in healthy volunteers.

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.

Protective effects of sodium beta-aescin on ischemia-reperfusion injury in rat brain.

AIM: To investigate the protective effects of sodium beta-aescin on cerebral ischemia-reperfusion injury in rats. METHODS: Rats were pretreated with sodium beta-aesein for 7 d and then subjected to cerebral ischemia-reperfusion injury induced by a middle cerebral artery occlusion (MCAO). The neurological outcome was evaluated by the Longa's method; The infarct volume was assessed by hemmatoxylin-Eosin staining and the cerebral water content was measured by dry weight method. The activities of SOD, GSH-Px, CAT, Na+ -K+ -ATPase and the MDA content were measured in the cortex and hippocampus of ischemic and non-ischemic hemisphere. RESULTS: Sodium beta-aescin significantly reduced the volume of cerebral infarct and water content, and ameliorated the neurological deficit (P < 0.05). In vehicle-treated rats, the activities of SOD, GSH-Px and Na+ -K+ -ATPase in the cortex and hippocampus of ischemic hemisphere were all decreased (P < 0.01) , while the CAT activity was slightly elevated and the MDA of content was significantly increased (P < 0.01) compared with the sham-operated group. After treated with sodium beta-aescin, the effects on recovery of SOD, GSH-Px, Na+ -K+ -ATPase activities were observed (P < 0.05), and the MDA content was reduced (P < 0.05). CONCLUSION: These results showed that pretreatment with sodium beta-aescin can attenuate brain injury and its antioxidant activity on rats which encountered cerebral ischemia-reperfusion.

[Protective effect of procyanidins from the seedpod of the lotus on myocardial ischemia and reperfusion injury in rat].

AIM: To study the protective effect of procyanidins from the seedpod of the lotus (LSPC) on myocardial ischemia and reperfusion in rats. METHODS: Myocardial injury model was made by ligating the coronary artery for 30 min followed by reperfusion for 45 min in anesthetized rat and 30 min of ischemia followed by 30 min of reperfusion in the isolated rat heart. All animals were given the medicine or normal saline before the experiment. ET, Ang I, Ang II in the serum, the MDA content, SOD activity, NO level, the recovery rate of coronary flow (CF) and heart rate (HR) after reperfusion and CK, XO from the myocardial cells were observed. RESULTS: LSPC was shown to inhibit the release of ET, Ang II (P < 0.05) , and the increase of MDA content (P < 0.05). It was also found to increase the SOD activity (P < 0.05) and NO level (P < 0.01). LSPC was found to increase the recovery rate of the coronary flow (CF) and heart rate (HR) after reperfusion (P < 0.05 or P < 0.01), decrease the release of CK from the myocardial cells (P < 0.01), depress the XO activity of myocardial tissue (P < 0.05), as well as improve the myocyte ultrastructural pathological injury. CONCLUSION: The anti-ischemia effect of LSPC was related to the mechanism of scavenging the oxygen free radicals directly, cutting off the source of free radicals, reducing tissue peroxidation, stabilizing the cells membrane, depressing the production of EDCF and increasing the NO level as well.

Study on pharmacokinetics of scutellarin in rabbits.

AIM: To establish a solid phase extraction-high performance liquid chromatographic (SPE-HPLC) method for determining plasma scutellarin concentration, and study its pharmacokinetics after i.v. breviscapine in rabbits. METHODS: Methanol-water-phosphoric acid (50:50:0.5) mixture was used as mobile phase, Nucleosil C18 column (250 mm x 4.6 mm ID) was selected. The wavelength of UV detection was 335 nm. Fifteen rabbits, randomized into 3 groups, were given breviscapine i.v. at the dose of 10, 20 and 40 mg.kg-1. Scutellarin in plasma was determined by SPE-HPLC method. RESULTS: Linearity was obtained over the range of 0.02-10.0 mg.L-1 of scutellarin. The method recovery was 96.15%-99.31%; the within-day and between-day RSDs were all below 10%. After i.v. 10, 20 and 40 mg.kg-1 of breviscapine to rabbits, the concentration-time curve of scutellarin fitted to a three compartment model. The main pharmacokinetic parameters showed no significant difference between low and medium doses, but the difference was significant between high dose and other doses. CONCLUSION: This assay method was accurate, sensitive, simple and suitable for the measurement of plasma scutellarin concentration. The pharmacokinetic characteristics were found to fit a three-compartment model following i.v. injection of breviscapine to rabbits. The changes of drug concentration in vivo exhibited linear kinetics ove the dosage range of 10-20 mg.kg-1, but when the dosage was 40 mg.kg-1, the linear kinetic properties disappeared.