Adult ; Antihypertensive Agents ; administration & dosage ; therapeutic use ; Cardiomyopathy, Dilated ; diagnosis ; drug therapy ; Echocardiography ; Humans ; Male ; Valsartan ; administration & dosage ; therapeutic use

European Medicines Agency withdrew valsartan from European market in July 2018 because it was contaminated with carcinogen, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). Medicines and Healthcare Products Regulatory Agency also found the same contamination and withdrew it from England market. US Food and Drug Administration followed the action after confirming its contamination. Ministry of Food and Drug Safety (MFDS) conducted testing all the valsartans at Korean market and withdrew some of them from market after confirming the contamination with NDMA. MFDS provided the pharmaceutical companies and laboratory institutions with the manual for testing both NDMA and NDEA and educated relevant personnels. MFDS also evaluated the health impact of the contaminated valsartan on the hypertensive patients who took the valsartan, which was shown to be very low risk of additional cancer incidence. MFDS pronounced strengthening of the safety management for the raw materials of the medicines. For guaranteeing the safety of medicines, more comprehensive drug safety management system from developing new drugs to consuming the medicines should be established. For achieving such a goal, active participation of all the stakeholders of the medicines including governmental agencies including MFDS and Ministry of Health and Welfare, the National Assembly, healthcare professionals, pharmaceutical companies, mass media, and general population including patients should be needed.
Antihypertensive Agents ; Delivery of Health Care ; Diethylnitrosamine ; Dimethylnitrosamine ; England ; Humans ; Incidence ; Mass Media ; Safety Management ; United States Food and Drug Administration ; Valsartan

OBJECTIVETo investigate the impact of antihypertensive medication timing on degree and stability of blood pressure (BP) lowering in patients with moderate and severe essential hypertension.

METHODSNinety patients were randomly assigned to take Valsartan and Felodiping together in the morning (group A), Valsartan in the morning and Felodiping in the evening (group B) or Felodiping in the morning and Valsartan in the evening (group C, n = 30 each). The morning dosage was titrated if the goal blood pressure was not achieved. Ambulatory blood pressure monitoring (ABPM) was performed on the first and 14(th) day of medication.

RESULTSThe BP reductions during nighttime and twenty-four in group B and C hours were similar (P > 0.05) but were significant more than those in group A (P < 0.05). The smoothness indexes of mean systolic, mean arterial blood pressure during nighttime and twenty-four in group B and C were similar but significantly higher than that in group A (P < 0.05). The smoothness index of diastolic pressure at nighttime in group B and C was similar but significantly higher than that in group A (P < 0.05).

CONCLUSIONMore significant and stable antihypertensive effects could be achieved by taking the two antihypertensive medications separately in the morning and at evening compared that taken the two drugs together in the morning.

Antihypertensive Agents ; administration & dosage ; Blood Pressure ; drug effects ; Drug Administration Schedule ; Drug Therapy, Combination ; Felodipine ; administration & dosage ; Humans ; Hypertension ; drug therapy ; Tetrazoles ; administration & dosage ; Valine ; administration & dosage ; analogs & derivatives ; Valsartan

OBJECTIVETo evaluate the efficacy and safety of a once daily valsartan/amlodipine 80/5 mg combination tablet in Chinese mild to moderate hypertensive patients without adequate blood pressure control by monotherapy.

METHODSTwo multicenter, randomized, double-blind, double dummy, active-controlled, parallel group trials were conducted. After a washout period (no medication) of 1-4 weeks, patients with Mean Sitting Diastolic Blood Pressure (MSDBP) > or = 95 mm Hg (1 mm Hg = 0.133 kPa) and < 110 mm Hg received a monotherapy of either Amlodipine 5 mg (in study 1) or valsartan 80 mg (in study 2) for 4 weeks. Patients with MSDBP > or = 90 mm Hg and < 110 mm Hg at the end of the monotherapy period were randomized to receive valsartan/amlodipine 80/5 mg treatment, or continue with the monotherapy.

RESULTSIn study 1, compared with amlodipine 5 mg, valsartan/amlodipine 80/5 mg once daily further reduced mean sitting systolic blood pressure (MSSBP)/MSDBP 4.4/3 mm Hg (P < 0.0001). In study 2, compared with valsartan 80 mg, valsartan/amlodipine 80/5 mg once daily further reduced MSSBP/MSDBP 6.4/4.2 mm Hg (P < 0.0001). The blood pressure (BP) control rates (BP < 140/90 mm Hg) of combination treatment group were 71.0% and 71.2% respectively, and significantly higher than the monotherapy groups in both trials. Incidence of adverse events was comparable in monotherapy and combination therapy groups.

CONCLUSIONOur results showed that valsartan/amlodipine 80/5 mg was superior to amlodipine 5 mg or valsartan 80 mg alone in lowering blood pressure and BP control in patients with mild to moderate hypertension not adequately controlled with amlodipine 5 mg or valsartan 80 mg monotherapy. No new or unexpected safety issues were identified with valsartan/amlodipine combination therapy compared with monotherapy.

Adult ; Amlodipine ; administration & dosage ; Antihypertensive Agents ; administration & dosage ; Blood Pressure ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Hypertension ; drug therapy ; Male ; Middle Aged ; Tetrazoles ; administration & dosage ; Valine ; administration & dosage ; analogs & derivatives ; Valsartan

To increase the dissolution rate and extent of valsartan, valsartan nanosuspensions have been prepared. Controlled precipitation assisted with sonication is utilized to prepare valsartan nanosuspensions, the concentration of the drug, stabilizer and costablizer had a great effect on the stability of the preparation according to the pre-experiment. So the method of central composite design-response surface is used to optimize the prescription based on the above three factors and the particle size as the response value. The software Origin 8.0 is used to draw the view of the three-dimensional effects and 2D contour map, to get the optimal prescription area. Valsartan nanosuspensions were prepared. The mean diameter and zeta potential are about 216.6 nm and -57.7 mV, respectively. Compared with the microsuspensions and commercial preparation, the dissolution of valsartan nanosuspensions was faster and the bioavailability can be enhanced to some extent.
Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; chemistry ; Biological Availability ; Chemical Precipitation ; Drug Stability ; Nanoparticles ; administration & dosage ; chemistry ; ultrastructure ; Particle Size ; Research Design ; Solubility ; Suspensions ; Ultrasonics ; methods ; Valsartan ; administration & dosage ; chemistry

Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).
Administration, Intravenous ; Administration, Oral ; Animals ; Antihypertensive Agents ; administration & dosage ; blood ; pharmacokinetics ; Apigenin ; administration & dosage ; blood ; isolation & purification ; pharmacokinetics ; Bile ; metabolism ; Chromatography, High Pressure Liquid ; Drug Interactions ; Erigeron ; chemistry ; Glucuronates ; administration & dosage ; blood ; isolation & purification ; pharmacokinetics ; Male ; Metabolic Clearance Rate ; Multidrug Resistance-Associated Proteins ; metabolism ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Valsartan ; administration & dosage ; blood ; pharmacokinetics

The study aims to evaluate the bioequivalence of valsartan hydrochlorothiazide tablets, and to investigate the potential cause of bioinequivalence. This was a single-center study with an open, randomized double-way crossover design. Test and reference preparations containing 160 mg of valsartan and 25 mg of hydrochlorothiazide were given to 36 healthy male volunteers. Plasma concentrations of valsartan and hydrochlorothiazide were determined simultaneously by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated, while the bioequivalence between test and reference preparations were evaluated. The dissolution profiles of test and reference preparations in four different mediums were determined via dissolution test and HPLC. The similarity was investigated according to the similarity factors (f2). The F(o-t) and F(0-infinity) were (139.4 +/- 65.2)% and (137.5 +/- 61.2)% for valsartan of test preparations. It led to get the conclusion that test and reference preparations were not bioequivalent for valsartan. A significant difference was observed between test and reference tablets in the valsartan dissolution test of pH 1.2 hydrochloric acid solution. The key factor of the bioinequivalence might be that dissolution of valsartan in acid medium has marked difference between two preparations.
Administration, Oral ; Adolescent ; Adult ; Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Antihypertensive Agents ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Area Under Curve ; Chromatography, Liquid ; Cross-Over Studies ; Drug Liberation ; Humans ; Hydrochlorothiazide ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Male ; Tablets ; Tandem Mass Spectrometry ; Therapeutic Equivalency ; Valsartan ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Young Adult

Animals ; Chemokine CCL2 ; analysis ; genetics ; Diabetes Mellitus, Experimental ; drug therapy ; physiopathology ; Drug Therapy, Combination ; Fatty Acids, Monounsaturated ; administration & dosage ; Indoles ; administration & dosage ; Kidney ; drug effects ; physiopathology ; Male ; NF-kappa B ; analysis ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Tetrazoles ; administration & dosage ; Transcription Factor RelA ; Valine ; administration & dosage ; analogs & derivatives ; Valsartan

BACKGROUNDPodocyte has inflammatory role in the development of diabetic nephropathy (DN). Mycophenolate mofetil (MMF), an anti-inflammatory agent, can suppress macrophage infiltration and reduce renal injury in streptozotocin-induced diabetic rats. Angiotensin II receptor blocker (ARB), another renal protecting agent, can decrease podocyte loss in DN. In this study, we detected the expression levels of monocyte chemoattractant protein-1 (MCP-1) and nephrin to evaluate podocyte's role in inflammatory reaction in DN, observe and compare the effect of MMF alone and in combination with valsartan, on preventing podocyte loss in streptozotocin (STZ) induced diabetic rats.

METHODSDiabetic model was constructed in uninephrectomized male Wistar rats by single peritoneal injection of STZ (65 mg/kg). The successfully induced diabetic rats were randomly divided into four groups: diabetes without treatment group (DM), valsartan treated group (DMV), MMF treated group (DMM), and combined therapy group (DMVM). Normal rats of the same sibling were chosen as control (NC). At the end of the 8th week, serum biochemistry, 24-hour urinary protein (UP) and the ratio of kidney weight/body weight (RWK/B) were measured. The rats were sacrificed for the observation of renal histomorphology through light and electron microscope. Nephrin, desmin and MCP-1 levels were detected by semi-quantitative immunohistochemical assays. Real-time quantitative PCR was used to detect the mRNA levels of nephrin and MCP-1.

RESULTSCompared with group NC, serum glucose level, 24-hour UP and RWK/B in group DM were significantly higher (P < 0.01), and the nephrin mRNA level in DM group was significantly lower (P < 0.05). The nephrin mRNA expression levels in group DMV, DMM and DMVM were all higher than that of DM group (P < 0.05) and no significant differences were found among the three treatment groups (P > 0.05). Treatment with MMF, valsartan or their combination could significantly decrease the 24-hour UP and RWK/B, and suppress glomerulosclerosis and interstitial fibrotic lesions in diabetic rats. In diabetic rats, the high expressions of desmin and MCP-1 in kidney were suppressed by valsartan, MMF or their combination.

CONCLUSIONSPodocytes are involved in the inflammatory reaction of diabetic rats. MMF could suppress MCP-1 and desmin expression, enhance nephrin expression, and attenuate proteinuria in diabetic rats. The combined therapy of valsartan and MMF did not show any superiority over monotherapies on renal protection. MMF may have renoprotective effect in early stages of diabetic nephropathy through preventing podocytes loss and anti-inflammatory activity.

Animals ; Chemokine CCL2 ; analysis ; Desmin ; analysis ; Diabetic Nephropathies ; drug therapy ; pathology ; Drug Therapy, Combination ; Immunohistochemistry ; Male ; Membrane Proteins ; analysis ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; therapeutic use ; Podocytes ; drug effects ; pathology ; Rats ; Rats, Wistar ; Tetrazoles ; administration & dosage ; therapeutic use ; Valine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Valsartan

Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; Animals ; Coronary Angiography ; Coronary Restenosis ; prevention & control ; Coronary Vessels ; pathology ; Drug Delivery Systems ; Immunohistochemistry ; Rabbits ; Receptor, Angiotensin, Type 1 ; analysis ; Receptor, Angiotensin, Type 2 ; analysis ; genetics ; physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Stents ; Tetrazoles ; administration & dosage ; Valine ; administration & dosage ; analogs & derivatives ; Valsartan