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Aims: Angiotensin receptor blockers have been shown to reduce heart failure hospitalization and cardiovascular mortality in men and women with heart failure with reduced ejection fraction (HFrEF). It is unknown whether there are differences between men and women in achieved dose and treatment discontinuation due to adverse events of candesartan., Methods and Results: We conducted a post hoc analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. A total of 3172 men and 1106 women with HFrEF [left ventricular ejection fraction (LVEF) ≤ 40%] in New York Heart Association class II-IV were randomized to candesartan or placebo. Every 2 weeks, patients were up-titrated from 4 or 8, to16, to 32 mg once daily, unless a higher dose was contraindicated or not tolerated. Women were older (66 vs. 64 years), had a higher LVEF (29.9% vs. 28.6%), and had more hypertension (54% vs. 47%) than men. The mean achieved dose of candesartan was 21.5 ± 12.6 mg in men and 20.7 ± 12.9 mg in women (P = 0.19). In both the candesartan and placebo groups, cardiovascular death and heart failure hospitalizations were higher in men and women who achieved lower dose levels. Event rates for achieved dose levels of 0, 4 or 8, 16, and 32 mg candesartan were 20.8, 17.2, 14.0, and 10.1 per 100 person-years in men, respectively, and 23.6, 13.7, 14.0, and 9.1 per 100 person-years in women, respectively. In each of the achieved dose levels, there was no sex difference in the proportion of patients with an event, neither in the candesartan group nor in the placebo group (P-value for all > 0.05). There was no significant interaction between sex and treatment-related discontinuation for hypotension (P = 0.520), an increase in creatinine (P = 0.102), and hyperkalaemia (P = 0.905)., Conclusions: In a randomized clinical trial in patients with HFrEF, men and women achieved similar doses of candesartan. Primary event rates and treatment-related discontinuation due to adverse events were also similar between men and women., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Obesity is a key risk factor for many diseases, as cardiovascular disorders, diabetes, infertility, osteoarthritis, sleep apnea, non-alcoholic fatty liver disease (NAFLD) as well as increased risk for many cancers. Telmisartan and Candesartan cilexetil are angiotensin II receptor blockers which had proven to involve in pathogenesis of obesity and NAFLD., Aims: This work is designed to explore the possible mitigated effects of Telmisartan and Candesartan cilexetil on weight gain and fatty liver in high fat diet (HFD) fed rats., Main Methods: The HFD rat model was achieved with induction of NAFLD. For Seven weeks either telmisartan or candesartan were orally administered at doses of 5 and 10 mg/kg respectively once daily. The effects of both drugs were evaluated by measurements of rat's body weight, food intakes, length, body mass index (BMI), liver weight, inguinal and interscapular fat weights. In addition, we assayed lipid profile, liver functions tests, serum inflammatory cytokines, adipokine and leptin. Lastly, liver and adipose tissue histopathological structures were evaluated., Key Findings: at end of experiment, telmisartan and candesartan were highly effective in decreasing rat's body weight from (213.1±2.68 to 191.2±2.54 and 203.5±5.89 gm , respectively), BMI, liver weight, fat weights in addition reduced serum levels of lipid and liver enzymes. Also, inflammatory cytokines were reduced with repaired histopathological insults in liver by significantly damped NAFLD score from (6.5 ±0.17 to 1±0 and 4 ±0, respectively) and decreased areas of adipocytes from (21239.12 to 5355.7 and 11607.1 um 2 , respectively)., Significance: Telmisartan and candesartan have therapeutic potential against obesity and NAFLD induced by HFD in rats. All the previous indices showed more improvement in telmisartan than candesartan group., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2-mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium-hydrogen-exchanger-3 positive proximal-convoluted-tubules; ACE2-ubiquitination was decreased by candesartan, accompanied with increased ubiquitin-specific-protease-48 (USP48). In candesartan-treated mouse renal proximal-convoluted-tubule cells, ACE2 abundances and activities were increased while ACE2-ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex-differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2-ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan-like-drug choice in men and women prone to coronavirus infections., (© 2024 Federation of American Societies for Experimental Biology.)

Background: The standard treatment for Kawasaki disease is immunoglobulin therapy, but the high frequency of coronary sequelae in immunoglobulin-refractory cases indicates a need for further improvement in treatment., Methods: Kawasaki disease-like vasculitis was induced in 5-week-old DBA/2 mice by intraperitoneal administration of 0.5 mg Candida albicans water-soluble fraction (CAWS) daily for 5 days followed by daily administration of candesartan, an angiotensin receptor blocker. The vasculitis suppression effect was confirmed histologically and serologically in mice sacrificed at 28 days after the start of candesartan., Results: The area of inflammatory cell infiltration at the aortic root was 2.4±1.4% in the Control group, 18.1±1.9% in the CAWS group, and 7.1±2.3%, 5.8±1.4%, 7.6±2.4%, and 7.9±5.0% in the CAWS+candesartan 0.125-mg/kg, 0.25-mg/kg, 0.5-mg/kg, and 1.0-mg/kg groups, respectively (p=0.0200, p=0.0122, p=0.0122, and p=0.0200 vs. CAWS, respectively). The low-dose candesartan group also showed significantly reduced inflammatory cell infiltration. A similar trend was confirmed by immunostaining of macrophages and TGFβ receptors. Measurement of the inflammatory cytokines IL-1β, IL-6, and TNF-α confirmed the anti-vasculitis effect of candesartan., Conclusions: Candesartan inhibited vasculitis even at clinical doses used in children, making it a strong future candidate as an additional treatment for immunoglobulin-refractory Kawasaki disease.

Purpose: d-galactose induces neuroinflammation and memory deficit via oxidative stress. Candesartan is an angiotensin II-receptor blocker and has proved neuroprotective properties. This study aimed to investigate the neuroprotective effect of candesartan against d-galactose induced neuroinflammation and memory deficit via autophagy., Methods: Twenty-eight male Wistar rats aged 3 months were divided into four equal groups: control (vehicle), d-gal (100 mg/kg d-galactose), cand (1 mg/kg candesartan), and cand+d-gal (100 mg/kg d-galactose & 1 mg/kg candesartan). All treatments were given orally and daily for 4 weeks. Assessment of memory was done using Morris water maze (MWM) test. Brain tissue was assessed for malondialdehyde (MDA), total thiol, catalase activity, glial fibrillary acidic protein (GFAP) and gene expression of TNF-α, GDNF-1 as well as autophagy genes (Beclin 1 and ATG 5)., Results: Prophylactic treatment of candesartan in d-galactose-treated rats significantly (p < 0.001) reduced oxidative stress via reduction of MDA as well as elevation of catalase activity and total thiol levels. Additionally, candesartan prophylactic treatment significantly increased gene expression of GDNF-1 and decreased gene expression of TNF-α. Furthermore, candesartan significantly increased the expression of autophagy related gene (Beclin 1 and ATG 5) in cand+d-gal treated rats. These results were supported by the histopathological findings which showed that candesartan prevented the neuronal injury in the cerebral cortex and hippocampus and decreased GFAP positive cells of the d-galactose-treated rats. Moreover, MWM test showed that candesartan significantly improved memory deficit in cand+d-gal treated rats., Conclusion: Candesartan prevents d-galactose-induced neurotoxicity and memory deficit via activating autophagy and decreasing oxidative stress. Therefore, candesartan was a good candidate for age-related neurodegenerative disorders and memory deficit., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6-8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.

Schizophrenia is a severe mental disorder with complex etiopathogenesis. Based on its neurodevelopmental features, an animal model induced by "two-hit" based on perinatal immune activation followed by peripubertal unpredictable stress was proposed. Sex influences the immune response, and concerning schizophrenia, it impacts the age of onset and symptoms severity. The neurobiological mechanisms underlying the influence of sex in schizophrenia is poorly understood. Our study aimed to evaluate sex influence on proinflammatory and oxidant alterations in male and female mice exposed to the two-hit model of schizophrenia, and its prevention by candesartan, an angiotensin II type 1 receptor (AT1R) blocker with neuroprotective properties. The two-hit model induced schizophrenia-like behavioral changes in animals of both sexes. Hippocampal microglial activation alongside the increased expression of NF-κB, and proinflammatory cytokines, namely interleukin (IL)-1β and TNF-α, were observed in male animals. Conversely, females presented increased hippocampal and plasma levels of nitrite and plasma lipid peroxidation. Peripubertal administration of low-dose candesartan (0.3 mg/kg PO) prevented behavioral, hippocampal, and systemic changes in male and female mice. While these results indicate the influence of sex on inflammatory and oxidative changes induced by the two-hit model, candesartan was effective in both males and females. The present study advances the neurobiological mechanisms underlying sex influence in schizophrenia and opens new avenues to prevent this devasting mental disorder., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan., (© 2021. The Pharmaceutical Society of Korea.)

Background : Genetic variants of coding genes related to blood pressure regulation participate in the pathogenesis of hypertension and determines the response to specific antihypertensive drugs. G protein-coupled receptor kinase 4 (GRK4) and its variants are of great importance in pathogenesis of hypertension. However, little is known about role of GRK4 variants in determine circadian rhythm of blood pressure and response to candesartan in hypertension. The aim of this study was to analyze the correlation of GRK4 variants and circadian rhythm of blood pressure, and to explore their effect on antihypertensive efficiency of candestartan. Methods: In this study, a total of 1239 cases were eligible, completed ambulatory blood pressure monitoring (ABPm) observation and exon sequencing of G protein-coupled receptor kinase 4 (GRK4). ABPm was obtained before and after 4-week treatment of candesartan. Diurnal variation of systolic blood pressure and antihypertensive effect of candesartan were then assessed. Results: Compared to GRK4 wild type (GRK4-WT), patients with GRK4 variants were more likely to be non-dippers ( odds ratio (OR) 6.672, 95% confidence interval (CI) 5.124-8.688, P < .001 ), with GRK4 A142V (OR 5.888, 95% CI 4.332-8.003, P < .001), A486V (OR 7.102, 95% CI 5.334-9.455, P < .001) and GRK4 R65L (OR 3.273, 95% CI 2.271-4.718, P < .001), respectively. Correlation analysis revealed that non-dippers rhythm of blood pressure were associated with GRK4 variants (r = .420, P < .001), with GRK4 A142V (r = .416, P < .001), A486V (r = .465, P < .001) and GRK4 R65L (r = .266, P < .001), respectively. When given 4-week candesartan, patients with GRK4 variants showed better antihypertensive effect as to drop in blood pressure (24 h mSBP, 21.21 ± 4.99 vs 12.34 ± 4.78 mmHg, P < .001 ) and morning peak (MP-SBP, 16.54 ± 4.37 vs 11.52 ± 4.14 mmHg, P < .001 ), as well as greater increase in trough to peak ratio (SBP-T/P, . 71 ± .07 vs .58 ± .07, P < .001 ) and smoothness index (SBP-SI, 1.44 ± .16 vs 1.17 ± .11, P < .001 ) than those with GRK4 WT. Conclusion: This study indicates that hypertensive patients with GRK4 variants are more likely to be non-dippers. What's more, patients with GRK4 variants possess a significantly better antihypertensive response to candesartan than those with GRK4 WT.

In recent years, many studies have reported the frequent detection of antihypertensive agents such as sartans (olmesartan, valsartan, irbesartan and candesartan) in the influents and effluents of wastewater treatment plants (WWTPs) and in the superficial waters of rivers and lakes in both Europe and North America. In this paper, the degradation pathway for candesartan (CAN) was investigated by simulating the chlorination process that is normally used to reduce microbial contamination in a WWTP. Twelve isolated degradation byproducts (DPs), four of which were isolated for the first time, were separated on a C-18 column by employing a gradient HPLC method, and their structures were identified by combining nuclear magnetic resonance and mass spectrometry and comparing the results with commercial standards. On the basis of these results, a mechanism of formation starting from the parent drug is proposed. The ecotoxicity of CAN and its DPs was studied by conducting a battery of ecotoxicity tests; bioassays were performed using Aliivibrio fischeri (bacterium), Daphnia magna (planktonic crustacean) and Raphidocelis subcapitata (alga). The ecotoxicity results shed new light on the increased toxicity of DPs compared with the parent compound.

Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus . Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits ( p < 0.001) than the treatment with Eucalyptus or Candesartan alone ( p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.

Cyclodextrins (CDs) are widely used in the pharmaceutical industry as transporters of lipophilic drugs due to their amphiphilic nature. The detailed study of the molecular interactions of drug complexes with CDs is very important in designing the best formulation for the transportation of lipophilic drugs. The drug: CD binding should be strong enough so that the complex is stable in the aquatic environment of the extracellular fluids, but also not very strong in order for the drug to be capable for being released in the proximity of the target receptor. In a recent study, we investigated the ΔG of binding between the commercially available, nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-B-CD) and the antihypertensive drug candesartan cilexetil (CC), with the use of steered (or biased) molecular dynamics (sMD) and umbrella sampling method. This chapter describes comprehensively how to perform sMD and umbrella sampling in order to calculate the ΔG binding of CC to the 2-HP-B-CD.

Introduction: Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial., Methods: A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR)., Results: Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups., Conclusion: A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

During the last decades, much attention has been focused on SNEDDS approach to resolve concerns of BCS II class drugs with accentuation on upgrading the solubility and bioavailability. The present hypothesis confirms the theory that SNEDDS can reduce the impact of food on Candesartan solubilization, thereby offering the potential for improved oral delivery without co-administration with meals. The present studies describe quality-by-design-based development and characterization of Candesartan loaded SNEDDS for improving its pharmacodynamic potential. D-optimal mixture design was used for systematic optimization of SNEDDS, which showed globule size of 13.91 nm, more rapid drug release rate of >90% in 30 min and 16 s for self-emulsification. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated up to 1.99- and 1.10-fold enhancement in dissolution rate from SNEDDS over pure drug and marketed tablet. In vivo pharmacodynamic investigation also showed superior antihypertensive potential of SNEDDS in normalizing serum lipid levels as compared to pure drug and marketed tablet that was executed on male Wistar rats. Overall, this paper reports successful systematic development of candesartan-loaded SNEDDS with distinctly improved biopharmaceutical performance. This research work interpreted a major role of SNEDDS for enhancing the rate of dissolution and bioavailability of poorly water soluble drugs.

Excessive vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling and stroke during hypertension. Blockade of Angiotensin (AngII) type 1 receptor (AT 1 R) is shown to effectively attenuate VSMC proliferation and vascular remodeling, while the mechanisms underlying these protective effects are unclear. Here, we investigated whether the amelioration of VSMC proliferation mediated by candesartan, an AT 1 R blocker, could be associated with miRNA regulation. Based on the published data in rat aortic smooth muscle cells (RASMCs), we discovered that candesartan specifically reversed the AngII-induced decrease of miR-301b level in RASMCs and human aortic smooth muscle cells (HASMCs). Knockdown of miR-301b abolished candesartan-mediated inhibition of HASMC proliferation via promoting cell cycle transition. Computational analysis showed that miR-301b targets at 3'UTR of STAT3. MiR-301b upregulation inhibited the luciferase activity and protein expression of STAT3, whereas miR-301b knockdown increased STAT3 luciferase activity and expression. Furthermore, downregulation of STAT3 markedly abrogated the effects of miR-301b inhibition on candesartan-mediated HASMC proliferation, invasion, and migration. Collectively, this study suggests that miR-301b may be a novel molecular target of candesartan and provides a new understanding for the mechanisms underlying the cardiovascular effects of candesartan.

Diabetic retinopathy is a major cause of vision loss in adults. Novel eye-drop formulations of candesartan and irbesartan are being developed for its cure or treatment. To support a preclinical trial in rabbits, it was critical to develop and validate a new LC-MS/MS method for simultaneous quantification of candesartan and irbesartan in rabbit eye tissues (cornea, aqueous humor, vitreous body and retina/choroid). Eye tissue samples were first homogenized in H 2 O-diluted rabbit plasma. The candesartan and irbesartan in the supernatants together with their respective internal standards (candesartan-d 4 and irbesartan-d 4 ) were extracted by solid-phase extraction. The extracted samples were injected onto a C 18 column for gradient separation. The MS detection was in the positive electrospray ionization mode using the multiple reaction monitoring transitions of m/z 441 → 263, 445 → 267, 429 → 207, and 433 → 211 for candesartan, candesartan-d 4 , irbesartan and irbesartan-d 4 , respectively. For the validated concentration ranges (2-2000 and 5-5000 ng/g for candesartan and irbesartan, respectively), the within-run and between-run accuracies (% bias) were within the range of -8.0-10.0. The percentage CV ranged from 0.6 to 7.3. There was no significant matrix interference nor matrix effect from different eye tissues and different rabbits. The validated method was successfully used in the Good Laboratory Practice (GLP) study of rabbits., (© 2020 John Wiley & Sons, Ltd.)

Cardiovascular diseases and hypertension in particular are major health risks worldwide and the improvement on their treatment will be beneficial for the human health. AT1R antagonists belong to the sartans family that targets the renin-angiotensin aldosterone system (RAAS) through blocking the hormone angiotensin II to exert its detrimental effects in pathological states. As a consequence, they are beneficial to treat hypertension, diabetes related kidney failure and hyperaemic episodes. Long unbiased Molecular Dynamics (MD) simulations are performed in order to explore candesartan's possible 2D and 3D diffusion mechanisms towards AT1R receptor. 3D diffusion mechanism is referred to the direct binding of the AT1 antagonist candesartan to the AT1R 3D structure (PDB ID: 4YAY). 2D diffusion mechanism involves first, the incorporation of candesartan in the bilayer core and then its localization on the AT1R binding cavity, through a diffusion mechanism. The obtained results indicate that membranes interact significantly with the neutral form of candesartan, which is indeed approaching the receptors' active site through diffusion via the lipids. On the other hand, the deprotonated form of the drug is interacting with AT1R's extracellular loop and fails to enter the membrane, pointing out the importance of the pH microenvironment around the receptor. To validate the calculated diffusion coefficients of the drug in the lipid bilayers 2D DOSY NMR experiments were recorded and they were in good agreement. Information on the impact that has the interaction of candesartan with the membrane is very important for the rationally design and development of potent ARBs. Thus, its conformational features as well as its localization in the membrane core have to be thoroughly explored., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A novel, precise, accurate and rapid HPLC-UV method was developed, optimised and fully validated for simultaneous estimation of pitavastatin (PIT) and candesartan (CAN) in rat plasma using telmisartan as an internal standard. Following liquid-liquid extraction of the analytes from plasma, chromatographic separation was accomplished on a Waters Reliant C18 column (4.6 × 250 mm, 5 µm) using ACN-5 mM Sodium acetate buffer (80:20, v/v; pH adjusted to 3.5 with acetic acid) as mobile phase at a flow rate of 0.8 mL/min and wavelength of 234 nm. The calibration curves were linear over the concentration ranges of 2-400 ng/mL and 3-400 ng/mL for pitavastatin and candesartan respectively. The method when validated as per US-FDA guidelines was found to be precise as well as accurate. Extraction recovery observed for both analytes was above 90% as well as reproducible and consistent. Stability studies showed the samples to be stable over a long period covering from sample collection to final analysis. The method was successfully applied to investigate pharmacokinetic interaction between PIT and CAN in wistar rats. The mean plasma concentration-time curves of PIT and CAN showed that single PIT as well as CAN show similar pharmacokinetic properties to those obtained when co-administrated with each other (P value >0.05). Hence, there is no evidence for a potential drug-drug interaction between PIT and CAN. This information provides evidence for clinical rational use of CAN and PIT in cardiovascular patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Microglia are diverse cells that acquire different functional phenotypes in response to microenvironment in which they reside. Several transcriptional regulators have been identified that regulate different microglia phenotypes. They are mainly stimulated into two opposing phenotypes, classically (M1) and alternatively (M2) phenotype. Regulating microglia polarization from M1 to M2 state has been suggested as a potential therapeutic approach in treatment of CNS disorders. Candesartan, an angiotensin II type I receptors antagonist, exerts beneficial effects for antioxidant, anti-inflammation, neurotrophic, and anti-apoptotic function. However, the effect of candesartan on microglia polarization and underlying mechanisms remain unknown. In this study, the resting microglia were stimulated to M1 microglia with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), and then treated with vehicle or candesartan for 24 h. RT-PCR was utilized to detect the mRNA expression of microglia phenotype markers and inflammatory cytokines. Microglia phenotype markers and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway were determined by western blot. A neuron-microglia co-culture system was used to determine whether candesartan could ameliorate the neurotoxic effect of M1 microglia to oxygen-glucose deprivation (OGD) neuron. Candesartan treatment reduced the expression of M1 markers, and increased M2 markers. Meanwhile, candesartan reduced fluorescence intensity and protein level of M1 marker and enhanced M2 marker. Candesartan also regulated the neuroinflammatory response via reducing the release of pro-inflammatory cytokines and increasing anti-inflammatory cytokines in LPS + IFN-γ stimulated BV2 cells. Candesartan markedly inhibited the protein level of TLR4, the phosphorylation of IKBα and p65, and suppressed nuclear translocation of NF-κB p65. BAY 11-7085, a NF-κB inhibitor, remarkably enlarged the inhibitory effect of candesartan on NF-κB pathway. In addition, M1 phenotype microglia exacerbated post-OGD N2a cells death and LDH release, whereas candesartan reversed such neurotoxic effect. Candesartan treatment may ameliorate stroke-induced neuronal damage through shifting microglia to M2 phenotype in a TLR4/NF-κB-dependent manner.

A simple, precise and accurate HPLC method was developed, optimized and validated for simultaneous determination of rosuvastatin and candesartan in rat plasma using atorvastatin as an internal standard. Solid-phase extraction was used for sample cleanup and its subsequent optimization was carried out to achieve higher extraction efficiency and to eliminate matrix effect. A quality by design approach was used, wherein three-level factorial design was applied for optimization of mobile phase composition and for assessing the effect of pH of the mobile phase using Design Expert Software. Adequate separation for both analytes was achieved with a Waters C 18 column (250 × 4.6 mm, 5 μm) using acetonitrile-5 mm sodium acetate buffer (70:30, v/v; pH adjusted to 3.5 with acetic acid) as a mobile phase at a flow rate of 1.0 mL/min and wavelength of 254 nm. The calibration curves were linear over the concentration ranges 5-150 and 10-300 ng/mL for rosuvastatin (ROS) and candesartan (CAN), respectively. The validated method was successfully applied to a pharmacokinetic study in Wistar rats and the data did not reveal any evidence for a potential drug-drug interaction between ROS and CAN. This information provides evidence for clinical rational use of ROS and CAN., (© 2019 John Wiley & Sons, Ltd.)

Intestinal pathophysiological alterations have recently been revealed to be implicated in the pathogenesis of hypertension, necessitating further investigations to better understand the intestinal effects of anti-hypertensive drugs. The current study thus investigated the pharmacological implications of a commonly used first-line angiotensin II type 1 receptor blocker, candesartan cilexetil, on the intestinal barrier impairment and gut dysbiosis in spontaneously hypertensive rats (SHRs). The results revealed that candesartan treatment protected against ileal and colonic pathologies and increased the intestinal expression of genes encoding tight junction proteins such as cingulin, occludin and tight junction protein 1 in SHRs. Serum level of lipopolysaccharides-binding protein was increased in candesartan-treated SHRs, supporting the notion that candesartan treatment provided protection against hypertension-associated impairment of intestinal barrier. Candesartan treatment also increased the amount of fecal short-chain fatty acids (SCFAs) including acetic acid, propionic acid, and butyric acid in SHRs. Fecal 16S rDNA sequencing further revealed that candesartan treatment normalized hypertension-altered ratio of Firmicutes to Bacteroidetes in SHRs. Most notably, candesartan treatment counteracted hypertension-associated diminishment of lactic acid-producing genus Lactobacillus. Taken together, the current study demonstrates for the first time that candesartan treatment alleviates hypertension-associated pathophysiological alterations in the gut, increases microbial production of SCFAs and preserves gut Lactobacillus under hypertensive conditions, which sheds novel light on the pharmacological implications of candesartan in the treatment of hypertension., (Copyright © 2019. Published by Elsevier Masson SAS.)

Purpose: The aim of this study was to evaluate the blood pressure-lowering and cholesterol-lowering effects of a fixed-dose combination therapy using candesartan (CND)/rosuvastatin (RSV) compared with CND or RSV monotherapy in patients with hypertension and hypercholesterolemia., Methods: This study was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 394 patients were screened. After a 4-week run-in period, 219 of these patients with hypertension and primary hypercholesterolemia were randomized. Patients received 1 of 3 regimens for 8 weeks: (1) CND 32 mg/RSV 20 mg, (2) RSV 20 mg, or (3) CND 32 mg. The primary outcome variables were changes in the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the percentage changes in LDL-C from baseline to the drug treatment at 8 weeks. The secondary outcome variables were percentage changes of total cholesterol, triglycerides, HDL-C, non-HDL-C, apolipoprotein B, apolipoprotein A-I, high-sensitivity C-reactive protein, and glucose metabolic indices, including percentage changes of the homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and hemoglobin A 1c . Tolerability of combination therapy was compared with other monotherapy groups., Findings: The percentage changes of LDL-C were -48.6% (from 157.2 to 80.1 mg/dL) in the RSV group and -49.8% (from 160.2 to 78.9 mg/dL) in the CND/RSV group from baseline to the end of 8 weeks of treatment. Mean SBP and DBP were significantly decreased in the CND/RSV and CND groups after 8 weeks (P < 0.001 for all); however, no significant differences were found between the 2 groups. Total cholesterol levels, triglycerides, non-HDL-C, and apolipoprotein B were significantly reduced in the CND/RSV and RSV groups, with no significant differences between the groups compared with the CND group (P < 0.001 for all). The percentage changes of HOMA-IR, adiponectin, and hemoglobin A 1c had no significant differences between the combination groups and monotherapy groups. However, in a 2-sample t test, HOMA-IR was significantly decreased in the CND/RSV group compared with the RSV group in nondiabetic patients (mean [SD] percentage change of HOMA-IR, -8.7% [37.6%] vs 17.1% [53.1%]; P = 0.048). There were no significant differences in metabolic indices between the diabetic groups. Adverse events in the CND/RSV group were similar to those in the monotherapy group., Implications: Once-daily fixed-dose combination therapy with CND/RSV is an effective, tolerable, convenient treatment option for patients with essential hypertension and hypercholesteremia. ClinicalTrials.gov identifier: NCT02770261., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: Uncertainty persists over the effects of blood pressure-lowering treatment in acute intracerebral hemorrhage (ICH). We assessed the effects of treatment with candesartan in acute ICH and according to different types of hematoma., Methods: Post-hoc analysis of the Scandinavian Candesartan Acute Stroke Trial, a randomized- and placebo-controlled, double-masked trial of candesartan in patients with any stroke within the acute phase (<30 hours) and high systolic blood pressure (≥140 mm Hg). We collected baseline computed tomography scans of participants with ICH, and characterized hematoma volume (planimetric approach), location (deep versus lobar or infratentorial), hemisphere side, and presence of intraventricular hemorrhage. The trial's 2 coprimary effect variables were the composite endpoint of vascular death, stroke or myocardial infarction, and functional outcome at 6 months according to the modified Rankin scale. We used Cox, ordinal, and binary logistic regression for analysis and adjusted for key, predefined prognostic variables., Results: Of 274 participants with ICH, computed tomography scans were available in 205 patients (74.8%). There were no significant differences between the candesartan and placebo groups with respect to hematoma volume (median 15.6 mL versus 13.5 mL, P = .96), deep location (77% versus 72%, P = .64), right hemisphere (49% versus 51%, P = .46), and presence of intraventricular hemorrhage (18% versus 11%, P = .22). Candesartan was associated with a significant increase in poor functional outcome in patients with deep hematoma (adjusted common odds ratio 2.27, 95% confidence interval 1.23-4.18, P = .009, P for interaction .015), but there was no differential effect on functional outcome or vascular events in any of the other imaging subgroups., Conclusions: Candesartan was not associated with any beneficial effect when initiated in the acute phase of ICH, a possible adverse effect on functional outcome in patients with deep hematomas cannot be ruled out by this study alone., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The objective of this study was to improve candesartan cilexetil (CC) efficacy by formulating nanocrystals via solid dispersion (SD) technique using tromethamine (Tris). SD was prepared by solvent evaporation at different drug carrier ratios, evaluated for particle size, vitro dissolution studies, TEM, FTIR, and X-ray powder diffraction. Ex vivo , in vivo pharmacokinetic parameters were conducted on selected formulae compared to drug suspension and marketed product. Size analysis demonstrated formation of particles in the nanorange lower than 300 nm. A burst drug release followed by an improved dissolution was observed indicating instant formation of nanocrystals along with amorphization as confirmed by X-ray diffraction. FTIR studies suggested the absence of chemical interaction between Tris and CC. TEM revealed formation of irregular oval nanoparticles. SD-1:5 has higher apparent permeability coefficient compared to CC suspension. Furthermore, the pharmacokinetic results proved the ability of the formed nanoparticles to enhance the efficacy of CC compared to drug suspension and marketed product. In conclusion, using of Tris as alkaline esterase activator carrier could be a promising tool to bypass the controversial effect of esterase enzymes that may be a source for inter-individual variations affecting ester prodrug candidates' efficacy.

The effects of candesartan and irbesartan, antagonists of the type I angiotensin II receptor, were investigated on allergic asthma. The antigen-induced degranulation was measured by evaluating β-hexosaminidase activity in vitro. Additionally, a murine ovalbumin-induced allergic asthma model was used to test the in vivo efficacy. It was observed that while candesartan inhibited the antigen-induced degranulation in rat RBL-2H3 mast cells, irbesartan did not. Administration of candesartan and irbesartan decreased the number of immune cells in the bronchoalveolar lavage fluid and reduced the expression of Th2 (IL-4, IL-5, and IL-13) and Th1 cytokines (IL-2 and IFN-γ) in the lung tissues of mice with ovalbumin-induced allergic asthma. Histological studies revealed that both antagonists reduced inflammation and mucin production in the lungs. Therefore, these findings provide evidence that candesartan and irbesartan could have potential applications as anti-allergic agents., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Impact Statement: Cisplatin is a commonly used drug in the treatment of solid tumors and its application is associated with testicular toxicity. The effect of candesartan in cisplatin-induced testicular toxicity and its fundamental mechanism of action were investigated. Candesartan had certainly repaired the testicular injury and ameliorated both biochemical and histopathological changes. Candesartan mitigated the gonadotoxicity induced by cisplatin via antioxidative, anti-inflammatory, and antiapoptotic actions.

Background and Objectives: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria., Design, Setting, Participants, & Measurements: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing., Results: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo ( P <0.001 each) as well as for candesartan cilexetil 8 mg versus placebo ( P <0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated., Conclusions: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria., (Copyright © 2019 by the American Society of Nephrology.)

Renin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-β-cyclodextrin (2-HP-β-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state 13 C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The 13 C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-β-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-β-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.

This study pointed to estimate the possible protective impacts of candesartan and/or epigallocatechin-3-gallate (EGCG) against gentamicin-induced nephrotoxicity. The current work revealed that gentamicin significantly elevated relative kidney weight and the serum level of creatinine and urea. Also, renal level of malondialdehyde was significantly increased with a concurrent decrease in renal glutathione-S-transferase and superoxide dismutase activities. Moreover, renal levels of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (p38-MAPK) were increased together with the elevation of tumor necrosis factor-alpha and interleukin-1 beta levels after gentamicin treatment. In addition, caspase-3 expression was elevated, and histological examination revealed extreme alterations enlightening inflammation, degeneration, and necrosis. Pretreatments with candesartan and/or EGCG attenuated gentamicin-induced nephrotoxicity. Importantly, the altered expression of p38-MAPK and NF-κB may play a significant role in the protective mechanisms exerted by candesartan and EGCG. Coadministration of candesartan and EGCG exhibited more profound response compared with the monotherapy., (© 2018 Wiley Periodicals, Inc.)

Objective: The comparison of antihypertensive effects between telmisartan and candesartan in patients with essential hypertension has been investigated in several small studies. The results were not consistent. We performed this meta-analysis determining the antihypertensive effect of telmisartan versus candesartan in these patients., Methods: We searched Pubmed, Web of Science, and Cochrane Central for all published studies comparing the antihypertensive effects between telmisartan and candesartan in patients with essential hypertension., Results: The antihypertensive effects were assessed in 302 patients included in 4 trials with a mean follow-up of 10 ± 4 weeks. There were no significant differences between telmisartan and candesartan in reduction of systolic blood pressure (SBP) and diastolic BP (DBP) in patients with essential hypertension (weighted mean differences (WMD) for SBP 1.98 mm Hg (95% confidence interval (CI), -0.53, 4.49), p > 0.05; WMD for DBP 0.26 mm Hg (95% CI, -1.65, 2.16), p > 0.05), respectively. In a sub-analysis including 2 randomized studies, there was not a significant difference for the reduction of SBP (WMD 0.90 (95% CI, -2.88, 4.68) mm Hg, p > 0.05) or DBP (WMD -0.80 (95% CI, -3.40, 1.81) mm Hg, p > 0.05) treated with telmisartan or candesartan., Conclusions: This meta-analysis provides the evidence that the antihypertensive effects of telmisartan and candesartan are similar on SBP and DBP reduction in patients with essential hypertension, suggesting that strict designed randomized controlled trial would be helpful to compare antihypertensive effects of angiotensin II receptor blockers (ARBs) and improve the choice of ARBs in antihypertensive therapy.

Background: The present study reports the formation of a cocrystal of candesartan with the coformer methyl paraben, its characterization and determination of its bioavailability. Candesartan is a poorly water-soluble drug having an anti-hypertensive activity. The recent patents on the cocrystals of the drugs Progesterone (US9982007B2), Epalrestat (EP2326632B1), Gefitinib (WO2015170345A1), and Valsartan (CN102702118B) for enhancement of solubility, helped in selection of the drug for this work., Methods: Candesartan cocrystal was prepared by solution crystallization method. The formation of a new crystalline phase was characterized by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) and Powder X-ray Diffraction (PXRD) studies. Saturation solubility studies were carried out in ethanol: water (50:50 % v/v) mixture. The dissolution studies were conducted in 900 ml of phosphate buffer at pH 7.4(I.P.) with 0.7% w/w of Tween 20 at 50 rpm, maintained at a temperature of 37±0.5°C in a USP type II dissolution apparatus. The pharmacokinetic behavior of candesartan and its cocrystal was thereof investigated in male Wistar rats., Results: There was 6.94 fold enhancement in the solubility of candesartan after its cocrystallization. The dissolution profile of the cocrystal exhibited significant improvement in solubility at 60 and 120 minutes and it remained stable in ethanol: water (50:50%v/v) mixture for 48 h as confirmed by PXRD studies. The AUC0-24of the cocrystal was found to be increased by 2.9 fold in terms of bioavailability as compared to the pure drug., Conclusion: The prepared cocrystal was found to be relatively more soluble than the pure drug and also showed an enhanced oral bioavailability as compared to the pure drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

BACKGROUND : We hypothesized that the 5-oxo-1,2,4-oxadiazole moiety of azilsartan (AZL), which represents a small difference in the molecular structures of AZL and candesartan (CAN) [angiotensin II type 1 receptor (AT 1 R) blockers], may be responsible for the molecular effects of AZL. METHODS : We examined the binding affinities of AZL and CAN to AT 1 R, along with their ability to block receptor activity. A competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) assay were performed using wild-type (WT) and mutants AT 1 R-transfected cells. RESULTS : The binding affinities of CAN and AZL were reduced by > 5-fold for Y35F, W84F, R167K, K199Q and I288A compared with WT. In addition, AZL showed a > 5-fold reduction in its binding affinity to V108A. CAN and AZL exhibited > 20-fold and > 100-fold reductions in binding affinity to R167K, respectively. The loss of binding affinity of AZL to R167K was greater than that of CAN. CAN-7H exhibited a > 10-fold reduction in binding affinity to R167K compared with CAN. On the other hand, the binding affinity of AZL-7H to R167K was comparable to that of AZL. While 10 -6 M CAN and CAN-7H partly blocked Ang II-induced IP production in R167K, 10 -6 M AZL and AZL-7H did not. In addition, 10 -6 M CAN, but not 10 -6 M AZL, partly blocked Ang II-induced ERK activation in R167K. CONCLUSIONS : The interaction between 5-oxo-1,2,4-oxadiazole in AZL and Arg 167 in the AT1R appears to be more important than the interaction between the tetrazole ring in CAN and Arg 167 .

Introduction: Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress., Aims: To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity., Methods: A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy., Results: During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period., Conclusion: The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

The angiotensin receptor blocker losartan mitigated cerebrovascular and cognitive deficits in mouse models of Alzheimer disease, in line with some clinical evidence of reduced onset and progression to Alzheimer disease. We investigated whether these benefits apply to another angiotensin receptor blocker, namely candesartan. Adult transgenic mice overexpressing a mutated form of the human APP (amyloid precursor protein) and wild-type controls were treated with vehicle or candesartan (cohort 1: 2 months, 1 mg/kg per day, osmotic subcutaneous minipumps; cohort 2: 5 months, 10 mg/kg per day in drinking water). Candesartan largely restored endothelial and smooth muscle function and reduced neuroinflammation in both cohorts, without improving sensory evoked cerebral blood flow responses. Candesartan exerted restorative effects on the reduced number of Ki67-immunopositive proliferating cells in the granule cell layer of the hippocampus but not on that of DCX (doublecortin)-positive immature granule cells, despite normalizing the length of their dendritic projections in the molecular layer. Amyloid plaque load and impaired cognitive function were unaltered by candesartan, and blood pressure was decreased in treated APP and wild-type mice. Overall, findings show that candesartan shared several advantages reported previously for losartan, but it exhibited limited cognitive benefits and stronger blood pressure lowering effects. The choice of angiotensin receptor blocker may thus be critical for therapeutic efficacy in patients with vascular diseases at high risk of developing Alzheimer disease.

Purpose: To evaluate the pharmacokinetics and pharmacodynamics of candesartan and amlodipine in the absence and presence of each other in healthy subjects., Methods: This study consisted of two parts: part 1, the effect of amlodipine on candesartan; part 2, the effect of candesartan on amlodipine. Each part was designed as a randomized, open-label, two-sequence, two-period, two-intervention crossover study with 20 subjects and performed separately in different populations. Pharmacokinetic assessments were performed over 48 hours for candesartan in part 1 and 72 hours for amlodipine in part 2 after drug administration on Day 10. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events., Results: For both candesartan and amlodipine, the 90% confidence intervals for the geometric mean ratios of area under the concentration-time curve from time zero to the time of dosing interval of 24 hours and maximum concentration after drug administration fell within the bioequivalence acceptance criteria. Although this study was conducted in normotensive subjects, blood pressure lowering effects were observed in all intervention groups and co-administration of candesartan and amlodipine reduced blood pressure more than amlodipine alone, but similar to candesartan alone. No serious adverse event was reported throughout the study, and all treatment emergent adverse events were mild to moderate in severity and were recovered without sequelae., Conclusion: Co-administration of candesartan and amlodipine did not change the systemic exposure of each drug alone in healthy subjects. The administration of candesartan 32 mg alone, amlodipine 10 mg alone, and co-administration of candesartan and amlodipine were well tolerated during the study., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In this study, the in vitro and in vivo interchangeability between generic candesartan 16 mg and the branded formulation was assessed. The in vitro release of these products was conducted in 3 pH media (1.2, 5.0, and 6.8), and similarity factors (f 2 ) were calculated. This bioequivalence study was a randomized, 2-period crossover study that included 42 healthy adult male subjects under fasting conditions with a 9-day washout. The pharmacokinetic (PK) parameters AUC 0-last , AUC 0-∞ , and C max , t max , and the elimination half-life time were assessed based on the plasma concentrations of candesartan, using a newly developed and validated liquid chromatography-tandem mass spectrometry bioanalytical method with acceptable degrees of linearity, sensitivity, precision, and accuracy. The geometric mean (ng·h/mL) of the AUC 0-∞ for the test and brand was 1595.49 and 1620.54, respectively, and the C max (ng/mL) was 160.91 and 160.88, respectively. The 90%CIs of geometric mean ratios (test-to-reference ratios) were 98.26%, 98.45%, and 99.86% for AUC 0-last , AUC 0-∞ , and C max respectively. These PK parameters lie within the US Food and Drug Administration- and European Medicines Agency-specified bioequivalence limit (80%-125%). Both products were well tolerated by all the subjects. The tested drug product was bioequivalent to the reference drug and had the same safety profile., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Aims: We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40-49%]., Methods and Results: In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow-up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient-years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient-years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient-years in HFmrEF (HR 0.76, 95% CI 0.61-0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient-years in HFpEF (HR 0.95, 95% CI 0.79-1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58-0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33-0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59-1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%., Conclusion: Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Angiotensin II type 1 receptor blockers (ARBs) are widely used as antihypertensive drugs. Candesartan is an ARB that has also been known for its anticancer effects but the exact molecular mechanism is remaining elusive. In this research, we showed for the first time that candesartan treatment significantly sensitized human lung adenocarcinoma cells to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by targeting TRAIL-DR5. TRAIL selectively kills cancer cells by binding to death receptors on the cell membrane, beyond the levels causing minimal toxicity in normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients are resistant to TRAIL treatment in clinical trials due to inactivation of the death receptors during cytoprotective autophagy. The molecular mechanisms underlying candesartan-induced TRAIL-mediated apoptosis involved the downstream of AMPK phosphorylation resulting inhibition of autophagy flux, recruitment of death receptor 5 (DR5) and activation of apoptotic caspase cascade. Candesartan treatment also inhibits the expression of anti-apoptotic protein c-FLIP. Furthermore, blocking DR5 signaling using DR5 siRNA negatively regulated the apoptotic pathway and also induced autophagy flux, demonstrating the cytoprotective role of autophagy responsible for treatment resistance. This suggests that candesartan can be used to sensitize tumors to TRAIL treatment and may represent a useful strategy for human adenocarcinoma patients to overcome TRAIL resistance. Candesartan in combination with TRAIL also could be a novel therapeutic treatment for patients presenting both conditions of hypertension and lung cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study was designed to investigate the possible synergism of amlodipine and candesartan on the reduction of blood pressure (BP) in hypertensive rats. The end organ protection was also observed. In acute experiment, spontaneously hypertensive rats (SHRs) were treated with intragastric administration of amlodipine (0.5, 1, 2, 3 mg/kg), candesartan (1, 2, 3, 4, 6, 8 mg/kg), and 14 different combinations to find the possible ratio of synergistic interaction. In two kidneys, one clip (2K1C) rats, the effects of amlodipine (1 mg/kg), canderastan (2 mg/kg) and their combination on BP reduction were also observed. In chronic study, SHRs were treated with amlodipine (1 mg/kg), candesartan (2 mg/kg), and their combination for 5 months. Organ damage evaluation was performed after BP recording. The probability sum test (q test) was used to evaluate the synergistic action. There is a synergistic interaction between amlodipine and candesartan on BP reduction. The optimal dose ratio is 1:2. The synergistic effect was also confirmed by 2K1C hypertensive rats. In chronic study, this combination (1:2) possessed an obvious synergism on the reduction of BP and BP variability (BPV) and protection on end organs. Multiple regression analysis showed that heart and aortic hypertrophy indexes and glomerular damage parameters were positively related to BP and BPV. In conclusion, combination of amlodipine and candesartan exhibited a potent antihypertensive effect and possessed an obvious synergism on BP reduction and organ protection in hypertension. The optimal proportion was 1:2. BP and BPV reduction may both importantly contribute to end organ protection., (© 2017 John Wiley & Sons Australia, Ltd.)

Aims: Alzheimer's disease (AD) pathology is associated with brain inflammation involving microglia and astrocytes. The renin-angiotensin system contributes to brain inflammation associated with AD pathology. This study aimed to investigate the role of candesartan, an angiotensin II type 1 receptor blocker, in modulation of glial functions associated with AD., Methods: Focusing on the role of candesartan in glial inflammation, we evaluated inflammatory mediators' levels, secreted by lipopolysaccharide-induced microglia following candesartan treatment. Also, short-term intranasal candesartan effects on amyloid burden and microglial activation were investigated in 5 familial AD mice., Results: Candesartan showed anti-inflammatory effects and shifted microglial activation toward a more neuroprotective phenotype. Candesartan decreased the lipopolysaccharide-induced nitric oxide synthase and cyclooxygenase-2 expression levels, which was accompanied by an induction of arginase-1 expression levels and enhanced Aβ 1-42 uptake by microglia. Moreover, intranasally administered candesartan to AD mice model significantly reduced the amyloid burden and microglia activation in the hippocampus., Conclusions: These results thus shed light on the neuroprotective role of candesartan in the early stage of AD, which might relate to modulation of microglial activation states., (© 2018 John Wiley & Sons Ltd.)

Background: Candesartan is one of the standard antihypertensive drug belonging to AT1R angiotensin receptor blockers (ARBs) group. Beneficial effects of this drug in the treatment of hypertension are well recognized. In this study we tested a hypothesis that candesartan could alleviate age-related memory decline., Methods: Aged and young rats have been treated with candesartan (0.1mg kg -1 ) for 21days and then underwent a battery of behavioral tests: for assessment of long-term memory (Passive avoidance test - PA), recognition memory (Object recognition test - OR), locomotor functions (Open field - OF) and anxiety behavior (Elevated plus maze - EPM)., Results: Aged rats (2-years-old) displayed clear declining tendency in the retrieval of passive avoidance behavior showing thus increased forgetting. Prolonged administration of candesartan significantly (p<0.01) reversed this phenomenon causing recall measured as the avoidance latency, and surprisingly also showed the tendency to recall deterioration observed in the young rats. More optimistic results were achieved in the OR, where candesartan significantly improved recognition memory (p<0.001) of aged rats who performed even better than the young ones (p<0.05)., Conclusions: It appears that candesartan potently abolishes some kinds of aging-induced memory impairments and cognitive declines in aged rats, but in some circumstances it may even could increase the damage of memory. It seems that the use of sartans in the treatment of hypertension for patients with associated cognitive impairment, or for people in risk groups for such disorders can be an interesting alternative., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

The aim of the present work is to answer the question is it possible to replace the ester prodrug candesartan cilexetil (CC) by its active metabolite candesartan (C) to bypass the in vivo variable effect of esterase enzymes. A comparative physicochemical evaluation was conducted through solubility, dissolution, and stability studies; additionally, ex vivo permeation and in vivo studies were assessed. C demonstrated higher solubility over CC at alkaline pH. Moreover, dissolution testing using the pharmacopeial method showed better release profile of C even in the absence of surfactant in the testing medium. Both drugs demonstrated a slight degradation in acidic pH after short-term stability. Instead, shifting to alkaline pH of 6.5 and 7.4 showed superiority of C solution stability compared to CC solution. The ex vivo permeation results demonstrated that the parent compound C has a significant (P < 0.05) enhanced permeation compared to its prodrug from CC, that agreed with in vivo results in which C suspension reached significantly (P < 0.05) higher C max of 1.39 ± 0.59 μg/mL at T max of 0.66 ± 0.11 h, while CC suspension reached C max of 0.47 ± 0.22 μg/mL at T max of 2.00 ± 0.27 h, a lag period of 40 min is needed prior to detection of any absorbed CC in plasma. Those findings are not in agreement with the previously reported rationale on the prodrug formation owing to the poor permeability of the parent compound, suggesting the possibility of marketing the parent drug candesartan for clinical use similarly to azilsartan and its prodrug.

Background and Aim: Increasing evidence confirms that potassium channels are essential for lymphocyte activation, suggesting an involvement in the development of hypertension. Moreover, chronic inflammation is regarded as a direct or indirect manifestation of hypertension, highlighting the theoretical mechanisms. In this study, we investigated changes in KCa3.1 potassium channel expression in the blood of hypertensive and healthy Kazakh people in north-west China., Methods: Flow cytometry technology was used for T-lymphocyte subtype analysis. Changes in the messenger RNA and protein expression of the KCa3.1 potassium channel in CD4 + T lymphocytes were detected using real-time quantitative polymerase chain reaction and western blots, using CD4 + T-cell samples from hypertensive Kazakh patients divided into candesartan and TRAM-34 treatment groups, and healthy case controls. Peripheral blood CD4 + T lymphocytes were activated and proliferated in vitro and then incubated for 0, 24, and 48 h under various treatment conditions. Changes in CD4 + T-lymphocytic proliferation were determined using Cell Counting Kit-8 and electron microscope photography., Results: Expression of KCa3.1 was significantly higher in the hypertensive patients than in the controls (p < 0.05). Compared with the healthy group, Kazakh hypertensive patients had a reduced proportion of CD4 + T lymphocytes (p < 0.05).Candesartan and TRAM-34 intervention for 24 h and 48 h inhibited the expression of Kv1.3 and KCa3.1 at mRNA and protein level (p < 0.05)., Conclusions: Increase in functional KCa3.1 channels expressed in CD4 + T lymphocytes of Kazakh patients with hypertension was blocked by candesartan, providing theoretical support for hypertension treatment at the cellular ion channel level. Candesartan may potentially regulate hypertensive inflammatory responses by inhibiting T-lymphocytic proliferation and KCa3.1 potassium channel expression in CD4 + T lymphocytes.

Arterial hypertension is a highly manageable disorder due to a variety of drugs available for its treatment. Since the late 1990s, angiotensin II receptor blockers have been widely prescribed, achieving appropriate control in patients' blood pressure. Few cases of serious adverse effects have been reported to date. Here, we present a case of acute hepatocellular injury secondary to candesartan administration. Further studies should be performed in patients who present with this adverse effect, in order to prevent more serious outcomes., (© 2017 The British Pharmacological Society.)

Two bioavailability/bioequivalence studies were carried out to evaluate the pharmacokinetics of candesartan cilexetil 16-mg tablet formulations. A pilot study was used to optimize the formulation and manufacturing process prior to conducting the definitive study. The pilot study was a single-dose, randomized, 2-period crossover, and the definitive study was a single-dose, randomized, 3-period, 6-sequence crossover study in healthy adults. In the pilot study the test formulation was 24% and 18% greater for C max and AUC, respectively, compared with the innovator product. Following optimization two 16-mg candesartan cilexetil tablet formulations were taken forward into the second bioavailability study.  Eighteen healthy fasted adult subjects were dosed with either the test formulations or the innovator. The pharmacokinetic parameters C max , AUC 0-t , and AUC 0-∞ of candesartan were investigated together with safety and tolerability. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for candesartan, C max , AUC 0-t , and AUC 0-∞ were within the boundary of 0.8-1.25 for one of the test formulations (formulation 2). For test formulation 3 the 90%CI of GMR for C max was above (133%) the upper limit of 125% for bioequivalence. Test formulation 2 was found to be bioequivalent and met internationally acceptable regulatory requirements., (© 2016, The American College of Clinical Pharmacology.)

A novel, precise, sensitive and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of a novel drug combination, candesartan (CAN) and chlorthalidone (CHL), in human plasma. Chromatographic separation was achieved on Waters Acquity UPLC BEH C 18 (50 × 2.1 mm, 1.7 μm). Mobile phase consisting of 1 mm ammonium acetate in water-acetonitrile (20:80 v/v) was used. The total chromatographic runtime was 1.9 min with retention times for CAN and CHL at 0.7 and 1.1 min respectively. Ionization and detection of analytes and internal standards was performed on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and negative ionization mode. Quantitation was done to monitor protonated precursor → product ion transition of m/z 439.2 → 309.0 for CAN, 337.0 → 189.8 for CHL and 443.2 → 312.1 for candesartan D4 and 341.0 → 189.8 for chlorthalidone D4. The method was validated over a wide dynamic concentration range of 2.0-540.0 ng/mL for candesartan and 1.0-180.0 ng/mL for chlorthalidone. The validated method was successfully applied for the assay of CAN and CHL in healthy volunteers., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: In the last decades, the studies performed on the field of endothelial dysfunction confirmed the fact that the starting point of this pathology is the inflammation. Several inflammatory biomarkers had been discovered and studied, ones showing systemic inflammation, and others being more specific biomarkers and showing the local inflammation. Pentraxin-3 (PTX3) is a new inflammatory biomarker, from the same family as high-selectivity C-reactive protein (hs-CRP), but it is a more specific biomarker, due to its local production: the endothelial cells and not the liver like in the case of hs-CRP., Aims: Several antihypertensive classes of drugs seem to have a positive impact on reducing the local endothelial inflammation, beyond their effect of lowering the blood pressure, so this study aims to analyze the effect of candesartan on the two inflammatory biomarkers: PTX3 and CRP, compared with other antihypertensive drugs, in hypertensive patients with endothelial dysfunction., Methods: A total of 365 patients were included in the study: 127 hypertensive patients were under treatment with candesartan, 134 patients were under treatment with other hypotensive medication (beta blockers, calcium channel blockers, and diuretics), both groups with controlled values of blood pressure, and 104 were normotensive persons. Classical methods of assessing the endothelial function were correlated with these biochemical markers., Results: The patients treated with candesartan had a significant lower value of PTX3 and hs-CRP, compared with those under treatment with other antihypertensive medication as follows: PTX3: 0.61 ± 0.49 vs 0.95 ± 1.04 ng/ml, P = 0.006 and hs-CRP: 0.19 ± 0.20 vs 0.20 ± 0.22 mg/dl, P = 0.54., Conclusions: Candesartan decreases PTX3 and hs-CRP plasma levels more powerful than other classes of antihypertensive drugs (beta blockers, calcium channel blockers, and diuretics), so we may assume that candesartan has a more potent action in reversing endothelial dysfunction and that it offers a higher vascular protection than other classes of antihypertensive drugs. We are suggesting that this new biochemical marker, PTX3, might be better and more specific marker for endothelial dysfunction, than hs-CRP.

Purpose: Intensive blood pressure (BP) lowering is important for the treatment of hypertension; however, it has been a challenge to achieve target BP in many patients. The purpose of this study was to explore the optimal dosage of a fixed-dose combination of candesartan cilexetil (CAN) and amlodipine besylate (AML), by examining the tolerability and efficacy of CAN/AML combination therapy compared with those of monotherapy with either drug in patients with essential hypertension., Methods: This Phase II multicenter, randomized, double-blind clinical trial enrolled patients aged 19 years or older with essential hypertension, defined as a mean sitting diastolic BP (msDBP) between 95 and 115 mm Hg, and a mean sitting systolic BP (msSBP) of <200 mm Hg after a 2-week placebo run-in period. A total of 635 patients were screened, of whom 439 were randomized to receive treatment; 425 patients were included in the full analysis set (combination therapy, 212; monotherapy, 213). Participants were randomly assigned to receive 1 of 8 treatments: CAN (8 or 16 mg), AML (5 or 10 mg), CAN/AML (8 mg/5 mg, 8 mg/10 mg, 16 mg/5 mg, or 16 mg/10 mg), once daily for 8 weeks., Findings: After 8 weeks of treatment, changes in msDBP were significantly greater in the groups receiving CAN/AML combination therapies compared with monotherapies at matched doses, with the exception of CAN 8 mg/AML 10 mg versus AML 10 mg. The response to treatment and the achievement of target BP (both msSBP and msDBP) at week 8 were significantly greater overall in the groups that received combination therapy versus monotherapy. All medications were relatively well tolerated in each group., Implications: Eight-week administration of CAN/AML (8 mg/5 mg, 16 mg/5 mg, and 16 mg/10 mg) resulted in a significantly greater BP reduction than that with CAN or AML monotherapy, and was determined to be well tolerated. ClinicalTrials.gov identifier: NCT02944734., (Copyright © 2017. Published by Elsevier Inc.)

Arsenic exposure can cause several cardiovascular diseases, including hypertension, atherosclerosis and microvascular disease. Earlier, we reported that arsenic-mediated enhancement of angiotensin II (AngII) signaling can impair vascular physiology. Here, we investigated whether the AT 1 receptor (AT 1 R) blocker candesartan can ameliorate the arsenic-induced hypertensive vascular remodeling in rats and whether the amelioration could relate to attenuation in vascular AngII and TGF-β signaling. Rats were exposed to sodium arsenite (50ppm) through drinking water for 90 consecutive days. Candesartan (1mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. Non-invasive blood pressure was recorded weekly in conscious rats, while AngII-induced change in mean arterial pressure in anaesthetized rats was measured by invasive method on the 91st day. On this day, blood was collected from other animals for measuring AngII level. Western blot of AT 1 , AT 2 and TβRII receptors; ELISA of PTK, RasGAP, ERK-1/2, TGF-β and CTGF; immunohistochemistry of phosphorylated Smad3, Smad4 and collagen III, hydroxyproline/total collagen estimation, collagen deposition by Masson's trichrome staining and histomorphometry were carried out in thoracic aorta. Arsenic increased non-invasive systolic, diastolic and mean arterial pressure. Further, AngII caused concentration-dependent incremental change in mean arterial pressure in the arsenic-exposed rats. Arsenic upregulated AT 1 and TβRII receptor proteins; elevated the levels of PTK, ERK-1/2, TGF-β and CTGF, decreased RasGAP level and augmented the immunoreactivities of Smad3, Smad4 and collagen III. Arsenic also increased hydroxyproline/total collagen level, proliferation of collagen fibres and thickness of aortic wall and collagenous adventitia. Candesartan normalized blood pressure, regularized receptor expressions, MAP kinase and TGF-β signaling, restored collagen deposition and regressed aortic thickness. Our results demonstrate that candesartan can ameliorate the arsenic-mediated systemic hypertension and vascular remodeling in rats by regularizing the signaling pathways of AngII and TGF-β., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin-angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate-high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate-high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes., (© 2016 The Author(s).)