An Insight Into Intestinal Microbiota of Spontaneously Hypertensive Rats After Valsartan Administration
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It has been proven a close relationship between intestinal microbiota and hypertension. Valsartan is a widely used ARB antihypertensive drug; so far, the effect of valsartan on intestinal microbiota remains largely unexplored. Herein, we evaluated the composition, structure and metabolites of intestinal microbiota of spontaneously hypertensive rats (SHRs) after valsartan administration. In the present study, valsartan administration decreased intestinal microbiota diversity, altered gut microbiota composition, leading to 192 unique OTUs deficiency ( vs WKY rats) and 10 unique OTUs deficiency ( vs SHRs) and did not prove impaired intestinal mucosal barriers. Valsartan decreased the production of isobutyric acid and isovaleric acid in SCFAs. Our findings revealed valsartan administration induced far-reaching and robust changes to the intestinal microbiota of SHRs and provided a better understanding of the relationship between efficacy of valsartan and gastrointestinal tract reaction.Objective To study the intervention effect of valsartan on expression of connexin 43 (Cx43) protein in angiotensinⅡ(AngⅡ)-stimulated cardiomyocytes.Methods Cultured rat cardiomyocytes were randomly divided into control group,1.0 X 10~(-6) mol/L AngⅡgroup,and 1.0×10~(-6) mol/L valsartan group which was further divided into 1.0×10~(-6) mol/L valsartan group (group A),l.0×~(-6) mol/L valsartan group(group BO,and 1.0×10~(-7)mol/L valsartan group (group C).Intervention effect of valsartan on Cx43 protein expression in cardiomyocytes after 24 h exposure to AngⅡwas detected by flow cytometry and immunofluorescence,respectively.Results The expression level of Cx43 protein in cardiomyocytes was significantly higher in AngⅡgroup than in control group and valsartan group.Conclusion AngⅡup-regulates and valsartan down-regulates the expression of Cx43 protein in a dose-dependent manner through the typeⅠAngⅡreceptor signal pathway.Up-regulated expression of Cx43 protein may be related with hypertrophy of cardiomyocytes.
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i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremophor EL. Oral administration may be attractive because it may circumvent the use of Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs, has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug efflux pump, which is abundantly present in the gastrointestinal tract. Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its major metabolites were determined during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tolerated and did not induce gastrointestinal toxicity or myelosuppression. Cremophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.
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The study was to investigate the pharmacokinetic behaviors of cyclosporin A in mice by transdermal delivery of flexible liposomes and oral administration of the marketed preparation. Time courses of drug concentration in blood, kidney and skin were determined after application of flexible liposomes onto the mice skin non-occlusively. Pharmacokinetic behaviors were compared with those in oral administration of Sandimmun Neoral ○R . The relative bioavailability of transdermal delivery versus oral administration was (82.51±5.45)%. The ratio of AUC in kidney was (150.6±15.62)%. Flexible liposomes deposited much more drug in skin than Sandimmun Neoral ○R did. Results showed that flexible liposomes can transport cyclosporin A through mouse skin efficiently and drug tended to be accumulated in tissues rich of fat, like kidney and skin.
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Pharmacodynamics
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Valsartan is a potent, orally active non-peptide tetrazole derivative and selectively inhibits angiotensin II receptor type 1 which causes reduction in blood pressure and is used in treatment of hypertension. The risk of heart disease mortality decreased significantly as flavonoid intake increased. Interestingly, the flavonoid-containing foodscontain a high amount of Quercetin. The objective of this study was to evaluate the influence of quercetin on the pharmacokinetics of valsartan. In vivo studies were performed on rats. Rats were treated with quercetin (10 mg/kg) and valsartan (10 mg/kg), blood samples were collected at 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 h. Plasma concentration of valsartan was estimated by Reverse Phase (RP-HPLC). Quercetin significantly increases the plasma concentration of valsartan and peak concentration (70.45 µg/mL) was achieved at 3.5 h. In vitro studies were performed on rat intestinal everted sacs. The transport of valsartan from serosal side to mucosal side decreased from 53.12 ± 1.27 to 40.15 ± 0.45 µg/mL in the presence of quercetin and from 53.12 ± 1.27 to 28.68 ± 0.31 µg/mL in the presence of verapamil (standard P-glycoprotein (P-gp) inhibitor) at 120 min. Verapamil is a potent P-gp and CYP3A4 inhibitor. Quercetin is a P-gp inhibitor and may be an inhibitor of CYP3A4. The simultaneous administration of quercetin significantly increases the intestinal absorption and decreases the efflux of valsartan. The observed effect may be beneficial to develop oral valsartan dosage forms using safe P-gp inhibitor (quercetin) to improve its oral bioavailability.
Telmisartan
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[Objective]Observed SMI valsartan combined with Western medicine treatment of chronic congestive heart failure treatment.[Method]Using randomized controlled method,180 cases of hospitalized patients were randomly divided into three groups,the control group,60 cases of conventional treatment.Valsartan Valsartan group of 60 patients 80mg/times,1 times/day,orally,conventional treatment with the control group.Valsartan group,60 cases SMI 25mL +5% glucose injection 100mL infusion,1/d;valsartan,conventional treatment with valsartan group and control group.30d is a course of continuous treatment.Observation of clinical symptoms,cardiac function(stroke volume-SV,cardiac output-CO,ejection fraction-EF),adverse reactions.Continuous treatment of a course of treatment,to determine efficacy.[Results]Clinical valsartan combination group than the control group(P 0.05,P 0.01),the combination group than valsartan group(P 0.05);cardiac function improved in each group(P 0.05,P 0.01),valsartan group and combination group than the control group(P 0.05,P 0.01),the combination group than valsartan group(P 0.05);cardiac function in each group were improved(P 0.05,P 0.01),valsartan group and combination group than the control group(P 0.05,P 0.01),the combination group than valsartan group(P 0.05).[Conclusion]SMI valsartan combined with Western medicine treatment of chronic heart failure,can improve heart function,enhance the effect.
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