Effect of Fufang Danshen Pill on Bone Marrow Stem Mobilization when Myocardial Scathe

Objective：To investigate the effect of Fufang Danshen pill on bone marrow stem mobilization during myocardial scathe. Methods：Rat models with expansionary myocardial disease were established by Pituitrin and Furazolidone. Experimental rats were divided into the contrast group, the myocardial scathe group （MS group）, the myocardial scathe and Fufang Dansben pill group （ MS ＋ FD group） and the myocardial scathe and fluvastatin group （ MS ＋ FT group）. The ratio of CD34^＋ cells was examined at the 1^st, 3^nl and 6^th weekend. Index of heart structure and function including LVESD, LVEDD. LYEF, LVEDP and dp/dtmax were evaluated at the 6^th weekend. The HW/BW index was calculated. Results：In the MS group, the index of HW/BW, LVESD, LVEDD and LVEDP were obviously increased （P 〈 0.01 ） and index of dp/ dtmax and LVEF were obviously decreased （P 〈 0.05 ）. The ratio of CD34^＋ cells was significantly improved at the 1^at weekend and then reduced slowly with no difference from that of the contrast group at the 6th weekend. Compared the MS ＋ FD group and the MS ＋ FT group with the MS group, the index of HW/BW, LYESD, LYEDD and LYEDP of were signifi cantly decreased （ P 〈 0.05 ） and index of dp/dtmax and LVEF were increased （P 〈 0.01 ）. The ratio of CD34^＋ cells was significantly higher at the 1^st, 3^nl and 6^th weekend, but had no statistic meaning at 3^nl and 6^th weekend （P 〉 0.05 ）. Conclusion：Pituitrin and Furazolidone can be used to establish rat models with expansionary myocardial disease. There has bone marrow stem mobilization during the early period of myocardial scathe. Fufang Danshen pill has effect on improving bone marrow stem mobilization, lightening the expansionary degree of heart and protecting the heart function. The effect of Fufang Danshen pill is as same as that of fluvastatin.

Inhibitory effect of fluvastatin on ileal ulcer formation in rats induced by nonsteroidal antiinflammatory drug

AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs)cause gastrointestinal damage as one of their side effects in humans and experimental animals. Lipid peroxidation plays an important role in NSAID-induced ulceration. The aim of this study was to investigate the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors on the ulceration in small intestines of rats.METHODS: The effects of three HMG-CoA reductase inhibitors, fluvastatin, pravastatin and atorvastatin on ileal ulcer formation in 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT)-treated rats were examined. Antioxidative activity of the inhibitors was measured by a redox-linked colorimetric method.RESULTS: Fluvastatin, which was reported to have antioxidative activity, repressed the ileal ulcer formation in rats treated with BFMeT an NSAIDs. However, the other HMG-CoA reductase inhibitors (pravastatin and atorvastatin)did not repress the ileal ulcer formation. Among these HMG-CoA reductase inhibitors, fluvastatin showed a significantly stronger reducing power than the others(pravastatin, atorvastatin).CONCLUSION: Fluvastatin having the antioxidaitive activity suppresses ulcer formation in rats induced by NSAIDs.

The influence of genetic polymorphisms in drug metabolism enzymes and transporters on the pharmacokinetics of different fluvastatin formulations

The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed.The administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 d.Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d.The lower exposure following ER was observed.For ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated doses.In vitro study demonstrated that when the concentration of fluvastatin was low(<1μmol/l),the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1521TT(K m=0.18μmol/l)was faster than that with SLCO1B1521CC(K m=0.49μmol/l),On the other hand,when concentration reached to higher level(>1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the same.It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations.We recommend that formulation should be incorporated into future pharmacogenomics studies.

Expression of Serum and Glucocorticoid-inducible Kinase1 in Diabetic Rats and Its Modulation by Fluvastatin

The expression of serum and glucocorticoid-induced protein kinase in the renal cortex of diabetic rats was examined, and the function of signal transduction mediated by SGK1 in diabetic nephropathy and its modulation by fluvastatin were also investigated. 24 male Wistar rats were randomly divided into normal control group （n = 8）, diabetic nephropathy group （n = 8） and fluvastatin-treated diabetic nephropathy group （15 mg/kg/d, n=8）. The metabolic parameters were measured at the 8th week. The expression of transforming growth factor β1 （TGF-β1） and fibronectin （FN） was immunohistochemically examined. The expression of SGK1 was detected by RT-PCR and Western blot, and CTGF mRNA was assessed by RT-PCR. As compared to DN, blood glucose, 24-h urinary protein, Cer and kidney weight index were all decreased and the weight was increased obviously in group F. At the same time, mesangial cells and extracellular matrix proliferation were relieved significantly. The levels of cortex SGK1 mRNA and protein were up-regulated, and both TGF-β1 and FN were down-regulated by fluvastatin. The mRNA of SGK1 was positively correlated with the CTGF, TGF-β1 and FN. SGK1 expression is markedly up-regulated in the renal cortex of DN group and plays an important role in the development and progress of diabetic nephropathy by means of signal transduction. Fluvastatin suppressed the increased SGKlmRNA expression in renal cortex and postponed the development of diabetic nephropathy.

Simultaneous Release of a Hydroxy-Methylglutaryl Coenzyme A Reductase Inhibitor and a Glycoprotein IIb/IIIa Antagonist from a Thermoresponsive NiPAAm/NtBAAm Copolymer System

While deployment of intracoronary stents has been shown to reduce restenosis, stenting can also damage the endothelial monolayer lining the vessel wall, leading to possible in-stent thrombosis. Local drug delivery from stent surfaces represents a means of delivering therapeutic doses of drug directly to the target site. The aim of this study was to elute fluvastatin, which can inhibit vascular smooth muscle cell proliferation, and xemilofiban, which prevents platelet adhesion and aggregation, together in bioactive concentrations from the same copolymer system. Combined elution from thermoresponsive N-isopropylacrylamide (NiPAAm)/N-tert-butylacrylamide (NtBAAm)-derived copolymer systems was achieved using microgels (NiPAAm/NtBAAm 65/35 wt/wt) randomly dispersed in 85/15 matrices. Fluvastatin elution from 5 mm films over a 14-day period showed initial burst release, which leveled off. Of the total incorporated (8.33 ± 0.21 nmol, n=4), 68.5 % was eluted during this period. Xemilofiban release was measured in terms of its ability to inhibit platelet adhesion, using a microfluidic system. To investigate the influence of location and hydrophobicity on elution of bioactivity, three separate systems were employed. While elution of anti-adhesive activity from the system containing xemilofiban-loaded matrices was more dramatic in the short term, a more sustained level of inhibition was achieved when xemilofiban had been incorporated into microgels. All samples investigated for anti-adhesive activity also decreased human coronary artery smooth muscle cell proliferation. Therefore xemilofiban has potential as an agent for preventing in-stent thrombosis. Our study has demonstrated the feasibility of using this novel matrix/microgel system to regulate simultaneous release of both agents in bioactive concentrations.

Optimized combinations of statins and azoles against Acanthamoeba trophozoites and cysts in vitro

Objective: To evaluate the combination of several statins(atorvastatin, fluvastatin and simvastatin) and azoles(voriconazole, posaconazole and itraconazole) against Acanthamoeba spp. Methods: The efficiency of the different drug combinations against the trophozoite stage of different Acanthamoeba strains were evaluated by Alamar Blue assay. Effect on the cyst stage was observed by inverted microscope. Cytotoxicity of combinations of azoles and statins was evaluated by measuring the release of lactate dehydrogenase from a murine macrophage cell line. Results: Combinations of any of the tested statins and voriconazole or posaconazole were more efficient in inhibiting Acanthamoeba compared to statins or azoles individually. The drug combinations at the combined inhibitory concentrations 50% showed lower toxicity compared to that of the compounds alone.Conclusions: The combinations of statins together with voriconazole and posaconazole are more efficient than these drugs alone, and these combinations have lower cytotoxicity in mammalian cell lines.

Silencing of Bcl-2 gene expression by siRNA transfection in- hibits the protective effect of fluvastatin against cell apoptosis in human aortic endothelial cells

Objective To study the protective effect of fluvastatin,one of the HMG-CoA reductase inhibitors (statins),against oxygen radical-induced oxidative damages in human aortic endothelial cell,and the role of Bcl-2 in this protection.Methods Human aortic endothelial cells with or without Bcl-2 siRNA transfection were subjected to 1-100 nM of fluvastatin and 100 la hydrogen peroxide for 24 hours.Bcl-2 mRNA and protein expression were measured by Taqman quantitative PCR and Western blotting.Cell apoptosis was measured by normal and fluorescent microscopy and Cell Death Detection ELISA.Results In the Bcl-2-expressed cells,fluvastatin significantly reversed hydrogen peroxide-induced microscopic apoptosis and apoptotic DNA fragmentation,which were accompanied by a markedly upregulation of Bcl-2 expression by fluvastatin.However,the endothelial protection by fluvastatin was completely lost in Bcl-2 siRNA transfected cells.Conclusion Fluvastatin protects human endothelial cells against oxygen radical-induced cell apoptosis in vitro,and this protection seemed to be mediated in a Bcl-2 dependent pathway.(J Geriatr Cardil 12008;5:33-38)

Synthesis, Characterization, Crystal Studies of (E)-3-(3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl) Acrylaldehyde

We have synthesized and developed single crystals of the title compound (E)-3-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) acrylaldehyde, which is a key intermediate of anti-cholesterol fluvastatin drug. It crystallized under orthorhombic system with a space group Pna21. The dihedral angle between the indole mean plane and 4-F-phenyl ring was observed to be 111.5 (3)° in the title molecule. Further, strong hydrogen bonds were not found in the crystal structure.

Effect of fluvastatin combined with β-receptor-blockers on cardiac function and peripheral blood NF-κB and sST2 in patients with coronary heart disease complicated with heart failure

Objective: To investigate the effects of fluvastatin combined with β-receptor-blockers on cardiac function and peripheral blood NF-κB and sST2 in patients with coronary heart disease (CHD) complicated with heart failure. Methods: A total of 90 CHD patients complicated with heart failure from September 2016 to September 2017 were selected and randomly divided into the control group and the observation group, with 45 cases in each group. The control group was treated with arotinolol and the observation group was treated with arotinolol combined with fluvastatin. The clinical efficacy of the two groups after treatment was compared. The cardiac function index, blood lipid index, inflammatory factor and serum NF-κB and sST2 levels were detected and compared between the two groups. Results: The effective rate of the observation group was significantly higher than that of the control group (P<0.05). After treatment, the cardiac function indexes of the two groups were significantly improved (P<0.05). The LVEF and LVFS of the observation group were significantly higher than those of the control group, and LVEDD and LVESD of the observation group were significantly lower those of the control group (P<0.05). The serum lipid index and inflammatory factors of the two groups were significantly decreased after treatment. The hs-CRP, TNF-α, TC and LDL-C of the observation group were significantly lower than those of the control group after treatment (P<0.05). After treatment, the serum NF-κB and sST2 were significantly decreased in both groups, and the serum NF-κB and sST2 in the observation group were significantly lower than those in the control group. There was no significant difference in the incidence of adverse reactions between the two groups (P<0.05). Conclusions: Fluvastatin combined with β-receptor-blockers can reduce the level of blood lipid and inflammatory factors more effectively and improve the clinical efficacy of the CHD patients complicated with heart failure. It can effectively reduce serum NF-κB and sST2 more effectively and improve prognosis.

Efficient photocatalytic degradation of statin via optimization on ZnIn_(2)S_(4)/Bi_(2)WO_(6) Z-scheme heterostructure

Statins are widely used in the treatment of hyperlipidemia disease,which are refractory in the municipal sewage treatment plant.The photocatalytic degradation of statins by the Z-scheme heterostructured photocatalyst is confirmed,but the degradation mechanism of statins needs to be further revealed.In this study,the effects of photocatalyst dosage,solution pH and humic acid(HA)on the photocatalysis of fluvastatin by ZnIn_(2)S_(4)/Bi_(2)WO_(6) Z-scheme heterostructured photocatalyst(ZIS/BWO photocatalyst)were investigated and the degradation mechanism was proposed.Results showed that adsorption of fluvastatin was improved with the increase of photocatalyst dosage,but photoinduced desorption and light scattering resulted in the decrease of the removal of fluvastatin with high dosage.0.2 g/L of the ZIS/BWO photocatalyst was optimal dosage.65.21%of fluvastatin was removed at pH=9,because high concentration of OH^(-)was conducive to produce·OH.The change of pH,competition of photons and active sites,and trapping of reactive oxygen species(ROS)by carboxyl group of HA combined to inhibit the photocatalysis of fluvastatin in the presence of HA.The C–C,C=C and C–N bonds of fluvastatin were attacked by a variety of ROS to generate degradable intermediates that were easily mineralized to H_(2)O and CO_(2).

Effects of Fluvastatin on Characteristics of Stellate Ganglion Neurons in a Rabbit Model of Myocardial Ischemia

Background：Stellate ganglion （SG） plays an important role in cardiovascular diseases.The electrical activity of SG neurons is involved in the regulation of the autonomic nervous system.The aim of this research was to evaluate the effects offluvastatin on the electrophysiological characteristics of SG neurons in a rabbit model of myocardial ischemia （MI）.Methods：The MI model was induced by abdominal subcutaneous injections of isoproterenol in rabbits.Using whole-cell patch clamp technique,we studied the characteristic changes of ion channels and action potentials （APs） in isolated SG neurons in control group （n =20）,MI group （n =20） and fluvastatin pretreated group （fluvastatin group,n =20）,respectively.The protein expression of sodium channel in SG was determined by immunohistochemical analysis.Results：MI and the intervention of fluvastatin did not have significantly influence on the characteristics of delayed rectifier potassium channel currents.The maximal peak current density of sodium channel currents in SG neurons along with the characteristics of activation curves,inactivation curves,and recovery curves after inactivation were changed in the MI group.The peak current densities of control group,MI group,and fluvastatin group （n =10 in each group） were-71.77 ± 23.22 pA/pF,-126.75 ± 18.90 pA/pF,and-86.42 ± 28.30 pA/pF,respectively （F=4.862,P =0.008）.Fluvastatin can decrease the current amplitude which has been increased by MI.Moreover,fluvastatin induced the inactivation curves and post-inactive recovery curves moving to the position of the control group.But the expression of sodium channel-associated protein （Nav 1.7） had no significantly statistical difference among the three groups.The percentages of Nav 1.7 protein in control group,MI group,and fluvastatin group （n =5 in each group） were 21.49 ± 7.33%,28.53 ± 8.26%,and 21.64 ± 2.78%,respectively （F =1.495,P =0.275）.Moreover,MI reduced the electrical activity of AP and increased amplitude of AP,fluvastatin pretreatment could recover amplitude and electrical activity of AP.The probability of neurons induced continuous APs were 44.44%,14.29%,and 28.57% in control group,MI group,and fluvastatin group,respectively.Conclusions：Fluvastatin pretreatment can recover electrophysiology characteristics of ion channel and AP in SG neurons in a rabbit model of MI.It could be considered as potential method for treating coronary heart diseases.

A near-infrared fluorescent probe for monitoring fluvastatin-stimulated endogenous H_2S production

Most reported fluorescent probes have limitations in practical applications in living systems due to the strong autofluorescence background,construction of probes with near-infrared（NIR） fluorescence emission is an accessible approach for addressing this challenge.We here designed a NIR fluorescent probe for monitoring the endogenous production of H2S in living cells.The designed probe showed significant NIR fluorescence turn-on response to H2S with high selectivity,enabling the sensitive detection H2S.Importantly,the probe could be applied in monitoring the endogenous production of H2S in raw 264.7 macrophages.This study showed that fluvastatin can promote the activity of cystathionineγ-lyase（CSE） for generation H2S.

Fluvastatin protects against puromycin aminonucleoside-induced podocyte injury by inhibiting TRPC6

In the present study,we aimed to investigate the effect of puromycin aminonucleoside(PAN)on the expression and distribution of transient receptor potential canonical 6(TRPC6)of murine podocytes and further study the protective mechanism of fluvastatin on podocyte injury by TRPC6 in vitro.Podocytes were treated by PAN at different doses and at different time points.The expressions of TRPC6 at mRNA and protein levels were assessed.An immunofluorescent assay was used to observe the distribution of TRPC6.Cultured podocytes were then divided into four groups.The expressions of TRPC6 at mRNA and protein levels were measured.The intracellular calcium concentration of podocytes was measured with a laser-scanning confocal microscope.The paracellular permeability to BSA was evaluated using Millicell-PCF Inserts.The expressions of TRPC6 at mRNA and protein levels were increased in a dose and time-dependent manner after exposure to PAN.Immunofluorescence showed that the expression intensity of TRPC6 was significantly increased,and the distribution of TRPC6 was changed after PAN was applied to podocytes.With fluvastatin intervention,PAN-induced up-regulation of TRPC6 was significantly reversed.The ratio of the peak value of intracellular calcium to the basic calcium value in the PAN group was significantly higher after TRPC6 was activated by OAG,while it is obviously reversed under the action of fluvastatin.The podocyte permeability was significantly increased after 48 h of PAN treatment,while the above situation was effectively improved after fluvastatin intervention.The changes of distribution and expression of TRPC6 were related to podocyte injury induced by PAN.Fluvastatin could exert its protective effects on podocytes by down-regulating TRPC6.

Fluvastatin and the Breast Cancer Risk:A Meta-analysis of Observational Studies

Multiple studies have investigated the associations between fluvatatin and the risk of breast cancer(BC),but their results were conflicting.A meta-analysis of observational studies published regarding this subject was conducted in the present study.It aims to estimate the associations between fluvastatin use and the risk of BC.Pubmed and chinese national knowledge infrastructure(CNKI) database was searched up to January,2015 to identify eligible observational studies,and the Newcastle-Ottawa Scale(NOS) was used to assess quality of the studies.Pooled relative risk(RR) estimates and 95% confidence intervals(CIs) were calculated(fixed effect model:Mantel-Haenszel).Heterogeneities were evaluated before the calculation.A sensitivity analysis was also conducted.In total,four studies contributed to the analysis.Overall,fluvastatin use negatively correlated with BC risk(RR = 0.74,95 % CI = 0.58,0.95).In conclusion,fluvastatin use may reduce the risk of BC,but more research is needed to confirm this finding.