Disease relevance of valsartan

• Treatment with valsartan also resulted in significant improvements in NYHA class, ejection fraction, signs and symptoms of heart failure, and quality of life as compared with placebo (P<0.01) [1].
• CONCLUSIONS: Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension [2].
• Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001) [3].
• METHODS: Patients with MI in the Valsartan in Acute Myocardial Infarction (VALIANT) registry were divided into those with (n = 1423) and without (n = 3968) heart failure (HF), and the use of either echocardiography or cardiac catheterization for LV assessment in each group was compared along with associated baseline characteristics [4].
• This was associated with tubular and glomerular hypertrophy and AGE accumulation, which could be antagonized by valsartan [5].

Psychiatry related information on valsartan

• Erectile dysfunction was a complaint of 15 patients with carvedilol (13.5%), one patient with valsartan (0.9%), and one patient in the placebo group [6].
• METHODS: Male Otsuka Long Evans Tokushima Fatty rats, 8-week-old, were divided into four groups as follows: valsartan (V) group (10 mg/kg, n = 12), telmisartan (T) group (5 mg/kg, n = 12), amlodipine (A) group (2 mg/kg, n = 12), and control (C) group (n = 12) [7].
• RESULTS: Compared with routine therapy group, patients treated with valsartan had decreased secretion of IL-1beta in PBMCs after stimulated by lipopolysaccharide (2857+/-643 vs. 2146+/-508 pg/ml, P<0.05) [8].

High impact information on valsartan

• In vitro treatment of younger WKY rat and SHR coronary arteries with the nonpeptide angiotensin II (AT1) receptor antagonist valsartan 10(-5) mol/L (n = 3 for each) fully suppressed contractions to angiotensin II 10(-7) mol/L [9].
• High glucose-induced JAK2 activation was blunted by both ACE inhibition (100 nmol/l ramipril) and AT1 antagonism (1 mumol/l valsartan), thus revealing that the effects are mediated by autocrine Ang II production [10].
• Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts [3].
• NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment [3].
• In the first study arm, Sprague-Dawley rats received a continuous infusion of AGE-modified rat serum albumin (RSA) or unmodified RSA for 4 wk with or without the angiotensin receptor type 1 antagonist valsartan [5].

Chemical compound and disease context of valsartan

• Eighteen patients with a proteinuria >1 g/24 h after 6 mo of treatment with ramipril at 5 mg/d were assigned to receive in random order ramipril at 10 mg/d, valsartan at 160 mg/d, or combined ramipril at 5 mg/d and valsartan at 80 mg/d in addition to their antihypertensive treatment [11].
• CONCLUSIONS: The data show that valsartan is at least as effective as amlodipine in the treatment of mild to moderate hypertension [12].
• Ang II infusion was associated with hypertension, which was prevented by valsartan, but not PD123319 [13].
• In 4-week-old dTGR, long-term treatment with ACE inhibition (cilazapril), AT1 receptor blockade (valsartan), and human renin inhibition (RO 65-7219) (each drug 10 mg/kg by gavage once a day for 3 weeks) completely prevented the development of albuminuria [14].
• Valsartan/Hydrochlorothiazide: a review of its use in the management of hypertension [15].

Biological context of valsartan

• Valsartan inhibited the upregulation of NHE-1 mRNA and protein but had no effect on NBC-1 mRNA expression and translation [16].
• Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure: Valsartan heart failure trial (Val-HeFT) echocardiographic data [17].
• Consistent with the data on clinical events, patients randomized to valsartan showed improvements in physiologic variables, such as ejection fraction, left ventricular internal diameter in diastole, and plasma neurohormone levels [18].
• CONCLUSION: These data are consistent with the pharmacokinetics of valsartan in that biliary excretion is the main route of elimination [19].
• L-NAME 3.7 nmol x kg(-1) x min(-1) improved PBF autoregulation by lowering PBF to the range of 100 to 140 mm Hg of perfusion pressure, and this effect was attenuated or abolished by valsartan in innervated and denervated kidneys, respectively [20].

Anatomical context of valsartan

• Treatment with valsartan or combination therapy normalized the total and type I collagen (p < 0.001) as well as TGF-beta 1 mRNA level (p < 0.01) in the septum and was associated with the suppression of macrophages and myofibroblasts in the infarct zone (p < 0.01) [21].
• Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action [22].
• RESULTS: Valsartan abolished angiotensin II-induced vasoconstriction and, more importantly, also ET-1-induced vasoconstriction in the skin microcirculation (ET-1 placebo versus valsartan, - 33 +/- 10 PU versus +33 +/- 21 PU for CC [P = .02] and -71 +/- 25 PU versus +108 +/- 21 PU for CT/TT [P < .001]) [23].
• The mRNA and protein levels of GLUT4 in the soleus muscle were increased after repeated intravenous administration of valsartan in STZ-diabetic rats for 3 days [24].
• Incubation of myocytes (6-9 h) with the angiotensin II (ATII) receptor blockers saralasin or valsartan (1 microM) significantly augmented these currents [25].

Associations of valsartan with other chemical compounds

• In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level [26].
• Rats were treated with placebo, the angiotensin-converting enzyme inhibitor ramipril (1 mg/kg/day), the AT1 receptor antagonist valsartan (10 mg/kg/day) or the AT2 receptor antagonist PD 123319 (30 mg/kg/day) [16].
• METHODS: Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study [27].
• With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan [27].
• We used a laser Doppler imager to evaluate skin perfusion changes after injection of ET-1, angiotensin II, and norepinephrine (10(-18), 10(-16), and 10(-14) mol) after oral intake of the angiotensin II receptor antagonist valsartan (80 mg) or placebo [23].

Gene context of valsartan

• In wild-type fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase (TIMP)-1, and these increases were inhibited by valsartan, an AT1 receptor blocker, but augmented by PD123319, an AT2 receptor antagonist [28].
• Based on our estimation, the relative contribution of OATP1B1 to the uptake of valsartan in human hepatocytes depends on the batch, ranging from 20 to 70% [29].
• Among the recombinant CYP enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5 and 4A11), CYP2C9 notably catalysed 4-hydroxylation of valsartan [30].
• Serum TNF-alpha (9.1 +/- 8.6 pg/mL to 6.1 +/- 1.0 pg/mL, P = 0.006) and IL-6 (9.3 +/- 1.7 pg/mL to 8.9 +/- 1.4 pg/mL, P = 0.005) were significantly reduced after treatment with valsartan [31].
• Moreover, Ang II stimulated tyrosine phosphorylation of EGF receptor and p85alpha subunit of PI 3-K accompanied by an increase in their association, which was inhibited by valsartan, and enhanced by PD123319 [32].

Analytical, diagnostic and therapeutic context of valsartan

• However, valsartan had no effect on increased filtration fraction associated with an AGE-RSA infusion [5].
• Exposure to valsartan in patients with mild (n = 6) or moderate (n = 6) impaired liver function (Child's-Pugh classification) and matching (sex, age, and weight) healthy volunteers (n = 12) was studied after oral administration of a single dose of 160 mg valsartan [19].
• Clinical trials have demonstrated that the combination of valsartan 80 or 160mg with hydrochlorothiazide 12.5 or 25mg is significantly more effective than either drug alone [33].
• Conversely, a single, exploratory randomised trial demonstrated that the selective AT1R antagonist valsartan significantly reduced stent restenosis after PCI [34].
• RESULTS: A single intravenous injection of valsartan decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats [24].

References