BACKGROUNDAngiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

METHODSTwo-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA).

RESULTSPAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).

CONCLUSIONSAT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Aged ; Aged, 80 and over ; Angiotensin Receptor Antagonists ; therapeutic use ; Blood Platelets ; drug effects ; Blotting, Western ; Cell Line ; Cyclooxygenase 2 ; blood ; Female ; Humans ; Hypertension ; drug therapy ; Male ; Platelet Aggregation ; drug effects ; Real-Time Polymerase Chain Reaction ; Tetrazoles ; therapeutic use ; Thrombosis ; blood ; drug therapy ; Thromboxane B2 ; blood ; Valine ; analogs & derivatives ; therapeutic use ; Valsartan

OBJECTIVETo observe the effect of Tripterygium glycosides (TG) on the expression of hypoxia-inducible factor-1α and endothelin-1 in the kidney of diabetic rats and explore the possible mechanism underlying the protective effect of TG against diabetic nephropathy.

METHODSSixty 8-week-old male SD rats were randomly divided into normal control group (n=10) and streptozotocin-induced diabetes mellitus (DM) model group (n=50). The diabetic model rats were then randomly divided into DM group, low-dose (8 mg/kg) and high-dose (16 mg/kg) TG treatment groups, and Irbesartan (50 mg/kg) treatment group. After 8 weeks, the levels of blood glucose (BG), 24-h urine protein (24 h Upro), serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. The pathological changes in the renal tissues were examined by optical microscopy, and the mean glomerular area (MGA) and mean glomerular volume (MGV) were measured with pathological image analysis. Immunohistochemical and Western blotting were used to detect the expression of HIF-1α and ET-1 protein in the renal tissue, and their mRNA expressions were detected using real-time fluorescence quantitative PCR.

RESULTSHIF-1α and ET-1 expression increased in the kidney of diabetic rats. Compared with the diabetic model rats, the rats receiving TG and Irbesartan treatment showed decreased levels of Scr, BUN, 24h Upro, MGA and MGV, improved renal histopathology, and reduced expression of HIF-1α and ET-1 mRNA and protein in the renal tissue. These changes were more obvious in high-dose TG treatment group. Correlation analysis showed that the expression of HIF-1α was positively correlated with that of ET-1, and they were both positively correlated with kidney weight index (KW/BW), 24 h Upro, MGA, and MGV.

CONCLUSIONHIF-1α and ET-1 are overexpressed in the kidney of diabetic rats. TG can improve kidney damage in diabetic rats and delay the development of diabetic nephropathy by inhibiting the HIF-1α and ET-1 expression.

Animals ; Biphenyl Compounds ; pharmacology ; Blood Glucose ; Blood Urea Nitrogen ; Creatinine ; blood ; Diabetes Mellitus, Experimental ; metabolism ; Endothelin-1 ; metabolism ; Glycosides ; pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Kidney ; drug effects ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Tetrazoles ; pharmacology ; Tripterygium ; chemistry

BACKGROUND/AIMS: Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial. METHODS: Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders. RESULTS: The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12-27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P=0.674]. The response rate (55.6% vs. 61.5%, P=0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups. CONCLUSIONS: The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended.
Adolescent ; Adult ; Aged ; Antihypertensive Agents/*therapeutic use ; Benzimidazoles/*therapeutic use ; Blood Pressure ; Drug Therapy, Combination ; Female ; Humans ; Hypertension, Portal/complications/*drug therapy ; Liver Cirrhosis/complications/diagnosis ; Male ; Middle Aged ; Propranolol/*therapeutic use ; Prospective Studies ; Tetrazoles/*therapeutic use ; Treatment Outcome ; Young Adult

OBJECTIVETo observe the efficacy and safety of Qizhi Jiangtang Capsule (QJC) in treating stage 3b diabetic kidney disease (DKD) patients with macroalbuminuria.

METHODSPatients who conformed to the diagnostic criteria of stage 3b DKD were randomly assigned to two groups according to random digital table, the experiment group and the control group, 84 in each group. All patients received a two-week elution period, and then were treated with basic Western therapy. Patients in the experiment group took QJC, 5 pills per time, 3 times a day, while those in the control group took Valsartan Capsule 160 mg each time, once daily. The observation period of follow-ups was limited within 6 months, and the time points were set as the baseline, 1st month, 3rd month, and 6th month. Systolic blood pressure (SBP), diastolic blood pressure (DBS), 24 h urine protein quantitative (24 h UPQ), plasma albumin (ALB), and serum creatinine (SCr) were detected and recorded, and estimated glomerular filtration rate (eGFR) was calculated. The occurrence of hypoglycemic reaction, coagulation disorder, gastrointestinal tract reaction, allergy, hyperkalemia, doubling of creatinine, and overall adverse events were observed and recorded at same time.

RESULTSFinally 81 patients in the experiment group and 80 patients in the control group were effectively included. Compared with the baseline level, SBP and DBS obviously decreased in the control group at month 1 of treatment (P < 0.05), and more significantly decreased at month 6 of treatment (P < 0.01). SBP at month 1, 3, and 6 of follow-ups; DBS at month 6 of follow-ups was lower in the control group than in the experiment group (P < 0.05). At month 1, 3, and 6 of follow-ups, 24 h UPQ of the experiment group was significantly lower than the baseline level (P < 0.01). It was also significantly lower than the level of the control group at the same time point (P < 0.05). There was no significant difference in 24 h UPQ at month 1, 3, and 6 of follow-ups between the control group and the baseline level (P > 0.05). ALB of the experiment group showed an increasing trend. It was significantly higher than the baseline level at month 6 (P < 0.05), which was also higher than that of the control group at same period (P < 0.05). There was no significant difference in the ALB level in the control group (P > 0.05). SCr of two groups showed an increasing trend. SCr of the experiment group was significantly higher at month 1, 3, and 6 follow-ups than the baseline level (P < 0.05). But the increment of SCr was higher in the control group than in the experimental group, and obviously higher than the baseline levels (P < 0.05). eGFR of both groups showed a decreasing trend. The decrement was higher in the control group than in the experimental group (P < 0.05). The proportion of progression of renal functions at month 1, 3, and 6 of follow-ups in the experimental group was 0.0% (0 case), 9.55% (8 cases), and 21.4% (18 cases), while they were 8.3% (7 cases), 21.4% (18 cases), and 40.5% (34 cases) in the control group. There was no statistical difference in the proportion of progression of renal functions between the two groups at month 3 and 6 of follow-ups (P < 0.05). There was no statistical difference in the incidence of adverse reactions between two groups (P > 0.05).

CONCLUSIONQJC could effectively reduce urinary protein of patients with stage 3b DKD, and delay the progression of renal functions.

Adult ; Albumins ; analysis ; Albuminuria ; drug therapy ; Blood Pressure ; drug effects ; Creatinine ; blood ; Diabetic Nephropathies ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Glomerular Filtration Rate ; Humans ; Male ; Middle Aged ; Tetrazoles ; therapeutic use ; Treatment Outcome ; Valine ; analogs & derivatives ; therapeutic use ; Valsartan

PURPOSE: Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown. MATERIALS AND METHODS: We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35). RESULTS: Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0+/-10.2% versus 11.8+/-9.7%, p=0.61, and 286.3+/-54.7 versus 295.7+/-53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5+/-17.9% versus 28.3+/-16.6%, p=0.02, and 207.3+/-68.2 versus 241.3+/-76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7+/-8.7% to 15.8+/-18.4%, p=0.08, and from -18.6+/-58.0 to -61.9+/-84.3, p=0.08). CONCLUSION: Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.
Adult ; Aged ; Blood Platelets/drug effects ; Cross-Over Studies ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/*administration & dosage ; Prospective Studies ; Receptors, Purinergic P2Y12/metabolism ; Tetrazoles/*administration & dosage ; Thrombosis/drug therapy ; Ticlopidine/administration & dosage/*analogs & derivatives ; Time Factors ; Treatment Outcome

KR-31543, (2S, 3R, 4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethyoxymethyl-3-hydroxy-2-methyl-2H-1-benz opyran is a new neuroprotective agent for ischemia-reperfusion damage. It has also been reported that KR-31543 has protective effects on lipid peroxidation and H2O2-induced reactive oxygen species production. In this study, we investigated the anti-inflammatory and anti-atherogenic properties of KR-31543. We observed that KR-31543 treatment reduced the production of MCP-1, IL-8, and VCAM-1 in HUVECs, and of MCP-1 and IL-6 in THP-1 human monocytes. We also examined the effect of KR-31543 on monocytes migration in vitro. KR-31543 treatment effectively reduced the migration of THP-1 human monocytes to the HUVEC monolayer in a dose-dependent manner. We next examined the effects of this compound on atherogenesis in LDL receptor deficient (Ldlr-/-) mice. After 10 weeks of western diet, the formation of atherosclerotic lesion in aorta was reduced in the KR-31543-treated group compared to the control group. The accumulation of macrophages in lesion was also reduced in KR-31543 treated group. However, the plasma levels of total cholesterol, HDL, LDL, and triglyceride were not affected by KR-31543 treatment. Taken together, these results show that KR-31543 has anti-inflammatory properties on human monocytes and endothelial cells, and inhibits fatty streak lesion formation in mouse model of atherosclerosis, suggesting the potential of KR-31543 for the treatment for atherosclerosis.
Animals ; Aorta/pathology ; Atherosclerosis/blood/*drug therapy/pathology ; Benzopyrans/*pharmacology/therapeutic use ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Diet ; Disease Models, Animal ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Inflammation Mediators/*metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Macrophages/metabolism ; Mice ; Mice, Transgenic ; Monocytes/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Receptors, CCR2/metabolism ; Receptors, LDL/genetics ; Tetrazoles/*pharmacology/therapeutic use ; Transendothelial and Transepithelial Migration/drug effects ; Triglycerides/blood ; Vascular Cell Adhesion Molecule-1/metabolism

BACKGROUND AND OBJECTIVES: The aim of this study was to confirm the predictive cut-off values for P2Y12 reaction units (PRU) and aspirin reaction units (ARU) and to evaluate the clinical impact of VerifyNow(R) assays. SUBJECTS AND METHODS: From November 2007 to October 2009, 186 eligible patients were prospectively recruited. Post-treatment platelet reactivity was measured by VerifyNow(R) assays within 12 to 24 hours after intervention, followed by standard dual maintenance dose therapy for 1 year. All patients had scheduled clinical follow-ups at 1, 3, 6, and 12 months. RESULTS: The rate of low responders to clopidogrel, aspirin, and both drugs were 41.4%, 10.2%, and 3.8%, respectively. The predictive factors for low responsiveness to clopidogrel (PRU > or =240) were female sex, age, and non-use of cilostazol medication in our univariate analysis and age > or =65 years and non-use cilostazol in the multivariate analysis. The predictors of low responsiveness to aspirin (ARU > or =550) were male sex and age in both univariate and multivariate analyses. There was no significant difference in the clinical event rate with a cut-off value of PRU > or =240 or ARU > or =550 for 30 days and 1-year (p>0.05). CONCLUSION: Hyporesponsiveness to antiplatelet agents (namely aspirin and clopidogrel) was identified in about half of the patients. The cut-off point of PRU > or =240 or ARU > or =550 did not confer predictive value for 30-day or 1-year clinical event rates in patients who had undergone coronary intervention with drug-eluting stents.
Aspirin ; Blood Platelets ; Coronary Artery Disease ; Drug-Eluting Stents ; Female ; Follow-Up Studies ; Humans ; Male ; Multivariate Analysis ; Platelet Aggregation Inhibitors ; Platelet Function Tests ; Prospective Studies ; Stents ; Tetrazoles ; Ticlopidine

OBJECTIVETo investigate the effects and safety of Western medicine combined with Chinese medicine (CM) based on syndrome differentiation in the treatment of elderly polarized hypertension (PHPT), or isolated systolic hypertension with low diastolic blood pressure (DBP).

METHODSA total of 125 elderly patients with PHPT were randomly assigned to two groups: 59 in the control group treated by Western medicine and 66 in the intervention group treated by Western medicine combined with CM treatment. Based on syndrome differentiation, the patients in the intervention group were further divided into subgroups of yang-qi deficiency and yin-qi deficiency. All subjects were treated with Western medicine of Amlodipine Besylate Tablets and Irbesartan Tablets (or Irbesartan and Hydrochlorothiazide Tablets), to decrease their systolic blood pressure (SBP) slowly to 125-135 mm Hg in 2-6 weeks. In the intervention group, Shiyiwei Shenqi Capsule was given additionally to the subgroup of yang-qi deficiency at the dosage of 3-5 capsules, thrice a day, while Dengzhan Shengmai Capsule was given additionally to the subgroup of yin-qi deficiency at the dosage of 2 capsules, 2-3 times per day. For all subjects, SBP, pulse pressure (PP), and DBP were measured before treatment and at the terminal of a 6-week treatment. For subjects in the intervention group, left ventricular ejection fraction (LVEF) was also recorded.

RESULTSAfter a 6-week treatment, the SBP in the two groups and the PP in the intervention group decreased significantly compared to those before treatment (P<0.05), while the PP in the control group showed no significant difference between prior and post-treatment (P>0.05). After treatment, the DBP in the control group decreased (P>0.05), while the DBP and LVEF in the intervention group showed an increase tendency although it had no statistical significance (P>0.05). When subjects in the intervention group were classified further by the course of disease, the DBP and LVEF of subjects whose course of disease were less than 2 years, increased significantly after treatment (P<0.05).

CONCLUSIONWestern medicine combined with CM treatment based on syndrome differentiation was safer and more effective than Western medicine alone in the treatment of elderly PHPT, because it not only reduced SBP but also improved DBP, which might lower the incidence of the cardiovascular and cerebrovascular events.

Aged ; Amlodipine ; adverse effects ; pharmacology ; therapeutic use ; Antihypertensive Agents ; adverse effects ; pharmacology ; therapeutic use ; Biphenyl Compounds ; adverse effects ; pharmacology ; therapeutic use ; Blood Pressure ; drug effects ; Diastole ; drug effects ; Drugs, Chinese Herbal ; adverse effects ; pharmacology ; therapeutic use ; Female ; Humans ; Hypertension ; drug therapy ; physiopathology ; Male ; Stroke Volume ; drug effects ; Syndrome ; Tetrazoles ; adverse effects ; pharmacology ; therapeutic use

No abstract available.
Benzimidazoles ; Blood Pressure ; Stroke ; Tetrazoles

BACKGROUND: Valsartan is an angiotensin II receptor blocker and is used for patient with hypertension. Although response to valsartan varies each individual, there is no study about factors affecting the variability of valsartan response. METHODS: To investigate the effects of valsartan on the baseline characteristics of blood pressure, single group, open label, pre- and post-comparison clinical study was conducted. Total 21 male Korean volunteers were enrolled. Each subject was administered no drugs in first period and valsartan 80 mg (Diovan HCT) in second period. For pharmacodynamic analysis, 24 hours blood pressure changes were monitored by ambulatory blood pressure monitoring. Twenty-four hour blood pressure changes were matched to valsartan concentration and analyzed by correlation analysis. Changes in blood pressure pattern were also analyzed. Subjects were divided into responder, non-responder, and reverse responder according to pre- and post- 24 hours blood monitoring results. For determination of pharmacokinetic parameters, plasma concentration of valsartan was measured by a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters including area under the plasma concentration versus time curve from 0 hour to the last measurable concentration (AUCt), area under the plasma concentration versus time curve extrapolated to infinity, maximum plasma concentration (Cmax), and time required to reach maximum plasma concentration (Tmax) were calculated by noncompartmental models in the BA-CALC 2008 program ver. 1.0.0. RESULTS: There were no significant associations between blood pressure changes and pharmacokinetic parameters of valsartan. Blood pressure pattern change analysis showed significant results. For AUCt, total amount of absorbed valsartan was 25,808 +/- 6,863.0 ng.hr/mL, 20,683 +/- 8,782.7 ng.hr/mL, and 12,502 +/- 5,566.6 ng.hr/mL in responder, non-responder, and reverse responder, respectively (p = 0.041). In C max, maximum concentration of valsartan was 4,314 +/- 1,522.6 ng/mL, 2,588 +/- 1,273.9 ng/mL, and 2,056 +/- 1,075.5 ng/mL, respectively. CONCLUSIONS: These results showed that response to valsartan was not associated with blood concentration in healthy volunteers and changes in blood pressure patterns to valsartan might be associated with the amount of drugs which are absorbed to subjects.
Blood Pressure ; Blood Pressure Monitoring, Ambulatory ; Humans ; Hypertension ; Male ; Mass Spectrometry ; Plasma ; Receptors, Angiotensin ; Tetrazoles ; Valine ; Valsartan