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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. [ABSTRACT FROM AUTHOR]

Background: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. Methods: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. Results: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. Conclusion: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC. [ABSTRACT FROM AUTHOR]

Candesartan is an antihypertensive agent that acts on an angiotensin II receptor. Candesartan cilexetil is a prodrug that is converted into the active form of candesartan during intestinal absorption. This study aimed to assess the pharmacokinetics and bioequivalence of a reference and a test formulation of candesartan cilexetil tablets in healthy Chinese volunteers. A randomized, open-label, single-dose, crossover study was conducted with two treatment periods. Forty-eight healthy Chinese volunteers participated under fasted conditions. Qualified subjects were randomly divided into two groups (1:1 ratio) to receive either the test or reference formulation first. A washout period of 14 days separated the administration of the two formulations. Blood samples were collected at specific time points and analyzed for candesartan concentration using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). The maximum concentration (Cmax), the AUC from time zero to the last measured time point (AUC0-t) and the AUC from time zero to infinity (AUC0-∞) fell within the bioequivalence range of 80% to 125%. These results suggest that the test and reference formulations of candesartan cilexetil tablets are bioequivalent, meaning they have similar rates and extents of absorption in healthy Chinese volunteers. No serious adverse events or side effects were reported throughout the study. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of prior chronic treatment with angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin-receptor blockers (ARBs), both as a group and by active ingredient, on severity (risk of hospitalization and mortality), progression of and susceptibility to COVID-19. Methods: We conducted a multiple population-based case–control study in Galicia (north-west Spain). The study data were sourced from medical, administrative and clinical databases. We assessed: (1) risk of hospitalization, by selecting all patients hospitalized due to COVID-19 with PCR + as cases, and a random sample of subjects without a PCR + as controls; (2) COVID-19 mortality risk; (3) risk of disease progression; and (4) susceptibility to SARS-CoV-2, considering all patients with PCR + as cases, and the same subjects used in the previous model as controls. Adjusted odds ratios (aORs) were calculated. Results: ACEIs and ARBs were shown to decrease the risk of hospitalization (aOR = 0.78 [95%CI 0.69–0.89] and aOR = 0.80 [95%CI 0.72–0.90] respectively), risk of mortality (aOR = 0.71 [95%CI 0.52–0.98] and aOR = 0.69 [95%CI 0.52–0.91] respectively), and susceptibility to the virus (aOR = 0.88 [95%CI 0.82–0.94] and aOR = 0.92 [95%CI 0.86–0.97] respectively). By active ingredient: use of enalapril was associated with a significantly lower risk of hospitalization (aOR = 0.72 [95%CI 0.61–0.85]), mortality (aOR = 0.59 [95%CI 0.38–0.92]) and susceptibility to COVID-19 (aOR = 0.86 [95%CI 0.79–0.94]); and use of candesartan was associated with a decreased risk of hospitalization (aOR = 0.76 [95%CI 0.60–0.95]), mortality (aOR = 0.36 [95%CI 0.17–0.75]) and disease progression (aOR = 0.73 [95%CI 0.56–0.95]). Conclusion: This large-scale real-world data study suggest that enalapril and candesartan are associated with a considerable reduction in risk of severe COVID19 outcomes. [ABSTRACT FROM AUTHOR]

Abstract 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.

Background: Hypertension is a prevalent health condition with severe implications for cardiovascular health. Combination therapy involving Candesartan and Nifedipine has emerged as a promising approach for managing hypertension due to the synergistic effects of these medications. Methods: This study aimed to develop a Design of Experiment (DoE) based Green High-Performance Liquid Chromatography (HPLC) method for the simultaneous estimation of Candesartan and Nifedipine in a combined dosage form. Reversed-phase HPLC was utilized with UV-Vis spectrophotometry for detection. DoE principles were applied to optimize chromatographic conditions, including pH, ethanol percentage in the mobile phase, and flow rate. Results: Optimal chromatographic separation was achieved using a composite mobile phase comprising ethanol and potassium dihydrogen phosphate buffer (45:55, v/v) at pH 3.7, with a flow rate of 1 mL/min. Statistical analysis confirmed the significance of these parameters in achieving efficient separation. The developed method exhibited high precision, accuracy, and reliability across various validation parameters, including specificity, linearity, repeatability, and robustness. Conclusion: The proposed DoE-based Green HPLC method offers a sustainable and efficient approach for the simultaneous estimation of Candesartan and Nifedipine in hypertension management. By integrating green chemistry principles with systematic method development, this method provides a reliable analytical tool for routine quality control purposes in pharmaceutical formulations containing these medications. [ABSTRACT FROM AUTHOR]

Background: As the survival of patients with malignant neoplasms is improving, the urgent need for cardioprotective agents to counteract toxic effects of chemotherapy is growing.Objective: To compare the cardioprotective efficacy of sacubitril/valsartan and candesartan in women with chronic heart failure and baseline reduced left ventricular ejection fraction (LVEF) during a 5-year prospective follow-up after chemotherapy for breast cancer.Materials and methods: In this randomized study, 127 women with chronic heart failure and reduced LVEF after radical surgical treatment of breast cancer received potentially cardiotoxic adjuvant polychemotherapy (fluorouracil+ doxorubicin + cyclophosphamide). In addition, the patients received sacubitril/valsartan at a dose of up to 97/103 mg twice daily (n = 63) or candesartan at a dose of up to 32 mg once daily (n = 65), and this treatment was monitored for 5 years.Results: The combination of sacubitril/valsartan was significantly superior to candesartan in improving left ventricular function and reducing the burden of ventricular arrhythmias and the risk of cardiovascular death (P = .039) at the long-term follow-up. Sacubitril/valsartan group and candesartan group did not differ in terms of mortality due to breast cancer progression or recurrence (P = .628).Conclusions: Sacubitril/valsartan can be considered an effective and safe option for protecting the cardiovascular system during potentially cardiotoxic polychemotherapy for breast cancer in patients with chronic heart failure and baseline reduced LVEF.

Objective: In this retrospective cross‐sectional real‐world evidence study from the Danish Headache Center (DHC), a national tertiary headache center in Denmark, we sought to identify potential pharmacological agents for the treatment of new daily persistent headache (NDPH). Background: NDPH is an enigmatic headache disorder with abrupt onset and chronic duration for which evidence‐based treatments are lacking. NDPH is a diagnosis of exclusion, for which secondary headaches must be ruled out and the etiology remains idiopathic. The sparse investigations of this disorder have not yielded a pathophysiological basis and no effective treatment for NDPH has been found. Methods: All patients with an NDPH diagnosis at the DHC were enrolled (n = 64). First, we reviewed the records of all patients with an NDPH diagnosis to evaluate whether they fulfilled the diagnostic criteria. Next, we extracted all the trialled acute and prophylactic pharmacological interventions for the included patients. Then, pharmacological interventions that had been tried in ≥ 20 patients were analyzed post hoc with efficacy as the outcome, which was stratified in five effect categories ("no effect," "partial effect," "full effect," "partial effect and cessation due to adverse events," and "full effect and cessation due to adverse events"). Descriptive statistical analysis was performed, and the results were schematically presented (see Table 2). Results: Fifty‐one patients out of 64 were found to fulfill NDPH criteria and were included in the study. The drugs tried by ≥ 20 patients were amitriptyline (n = 34), candesartan (n = 27), and mirtazapine (n = 20). No patients experienced a complete effect with these drugs while 9% (3/34), 26% (7/27), and 15% (3/20) experienced a partial effect with no adverse events that led to treatment discontinuation, respectively. The remaining patients experienced either no effect or a partial effect with adverse events leading to treatment discontinuation. Conclusion: In this study we add real‐world evidence to suggest that prophylactic drugs conventionally used for treating chronic migraine and chronic tension‐type headache have limited utility for treating NDPH; however, a partial response in 26% of patients using candesartan and 15% of patients using mirtazapine warrants further investigation in randomized double‐blinded placebo‐controlled trials. Plain Language Summary: New daily persistent headache (NDPH) is a chronic headache for which the cause remains unknown and with no established evidence‐based treatments. In our retrospective study from the Danish Headache Center, we explored potential medication solutions for NDPH in 51 patients. Candesartan and mirtazapine showed some benefit for patients with NDPH in 26% and 15% of our patients, respectively, highlighting a need for further investigations into the potential benefits of these drugs. [ABSTRACT FROM AUTHOR]

• Hippocampal microglial AT1R may contribute to cognitive impairment caused by CCH. • Microglial AT1R cKO can reduce microglial inflammatory responses and activation. • Candesartan may be a feasible drug for ameliorating cognitive impairments. • Ctss, Fcer1g, Tyrobp play an essential role in cognitive impairment caused by CCH. Chronic cerebral hypoperfusion (CCH) can cause vascular cognitive impairment and dementia. AT1R, angiotensin II type I receptor, plays a vital role in central nervous system pathologies, but its concrete function in vascular dementia is still unclear. Herein, we investigated the effects of AT1R during CCH by conditional knockout of the microglial AT1R and candesartan treatment. Using the bilateral carotid artery stenosis (BCAS) model, we found that the AT1R is crucial in exacerbating CCH-induced cognitive impairment via regulating microglial activation. The levels of AT1R were increased in the hippocampus and the hippocampal microglia after CCH induction. Microglial AT1R conditional knockout ameliorated cognitive impairment by reducing inflammatory responses and microglial activation, and so did candesartan treatment. However, we observed restoration of cerebral blood flow (CBF) but no significant neuronal loss in the hippocampus at 28 days after BCAS. Finally, we screened three hub genes (Ctss, Fcer1g, Tyrobp) associated with CCH. Our findings indicated that microglial expression of AT1R is critical for regulating neuroinflammation in CCH, and AT1R antagonism may be a feasible and promising method for ameliorating CCH-caused cognitive impairment. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is an associated condition that occurs together and increases the risk of heart disease and diabetes. These conditions include high blood pressure, high blood sugar, and high body mass index (BMI) in terms of cholesterol and triglyceride levels. Most of the elderly population may administer three drugs to control the above conditions. Therefore, this study aims to develop an analytical assay for the precise analysis of three components and to formulate a Self-Nanoemulsifying Drug-Delivery System (SNEDDS) loaded with three drugs: Rosuvastatin Calcium (RC; antilipidemic), Glibenclamide (GB; antidiabetic), and Candesartan Cilexetil (CC; antihypertensive). A design of the experiment was developed at a level of 32, and the influence of column temperature and flow rate was studied in terms of retention time, peak area, peak asymmetry, and resolution. The assay was subjected to several studies to ensure its validation. Under the optimized conditions—column temperature at 50 °C and flow rate at 0.25 mL/min—the three drugs, RC, GB, and CC, are separated. Their retention times are 0.840, 1.800, and 5.803 min, respectively. The assay was valid in terms of linearity, accuracy, and precision. Moreover, the developed assay shows a good tolerance against any change in the condition. The assay was tested also to separate the drugs in a pharmaceutical formulation as SNEDDs. The assay successfully separates the drug with a good resolution. [ABSTRACT FROM AUTHOR]

Introduction: Effectiveness of candesartan in migraine prevention is supported by two randomized controlled trials. We aimed to assess the effectiveness, tolerability, and response predictors of candesartan in the preventive treatment of migraine. Methods: Observational, multicenter, prospective cohort study. The 50%, 75% and 30% responder rates, between weeks 8–12 and 20–24, were compared with the baseline. Treatment emergent adverse effects were systematically evaluated. Response predictors were estimated by multivariate regression models. Results: Eighty-six patients were included, 79.1% females, aged 39.5 (inter-quartile range [IQR] 26.3–50.3), with chronic migraine (43.0%), medication overuse headache (55.8%) and a median of two (inter-quartile range: 0.75–3) prior preventive treatments. At baseline patients had 14 (10–24) headache and 8 (5–11) migraine days per month. The 30%, 50% and 75% responder rates were 40%, 34.9% and 15.1% between weeks 8–12, and 48.8%, 36%, and 18.6% between weeks 20–24. Adverse effects were reported by 30 (34.9%) and 13 (15.1%) patients between weeks 0–12 and 12–24, leading to discontinuation in 15 (17.4%) patients. Chronic migraine, depression, headache days per month, medication overuse headache, and daily headache at baseline predicted the response between weeks 20–24. Conclusion: Candesartan effectiveness and tolerability in migraine prevention was in line with the clinical trials' efficacy. Trial registration: The study protocol is registered in ClinicalTrials.gov (NCT04138316). [ABSTRACT FROM AUTHOR]

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 um2 , 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: An oxidative stress and angiotensin II (Ang II) contribute significantly in the pathogenesis of diabetic nephropathy (DN). Therefore, interventions targeting these factors are anticipated to significantly contribute to inhibiting the progression of diabetic kidney disease. Objectives: The aim of this study was to assess the impact of a combination of rosmarinic acid (RA) and angiotensin receptor blockers (ARBs) in preventing mesangial expansion and reducing glomerular volume in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: We observed experimental animals, 16 adults male Wistar rats, which were randomly grouped into 4 groups (n=4 per group): negative and positive control groups and diabetic rats treated with RA 75 mg/kg and candesartan 1 mg/kg (treatment group 1) and RA therapy 75 mg/kg and losartan 2.5 mg/kg (treatment group 2). Following 8 weeks of therapy, the renal histology was assessed to evaluate mesangial expansion and glomerular volume. Results: In comparison to the positive control, treatment group 1 demonstrated a significant inhibition of mesangial expansion (MD: -19.92; 95% CI: -21.97, -17.87; P < 0.001) and decreased glomerular volume (MD: 2669.06; 95% CI: 2066.31, 3271.80; P < 0.001). Similarly, treatment group 2 significantly inhibited mesangial expansion (MD: -19.21; 95% CI: -21.26, -17.16; P < 0.001) and decreased glomerular volume (MD: 2488.04; 95% CI: 1885.29, 3090.78; P < 0.001) compared to the positive control. While treatment group 1 exhibited better effects than treatment group 2, although the difference was not statistically significant. Conclusion: In STZ-induced diabetic rats, combination therapy of RA with candesartan or losartan can inhibit mesangial expansion and decrease glomerular volume. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficacy of a combination therapy involving calcium dobesilate and candesartan in the treatment of proliferative diabetic retinopathy and its impact on the transforming growth factor b1 (TGF-b1), vascular endothelial growth factor (VEGF) and interleukin-19 (IL-19) levels in the vitreous humor. Methods: Between January 2020 and May 2023, 112 patients with proliferative diabetic retinopathy from Handan City Eye Hospital, China were enrolled in this study. They were divided into two groups: study group (n = 56) - orally administered 500 mg of calcium dobesilate combined with 50 mg of candesartan daily - and control group (n = 56), received calcium dobesilate only. Patients began treatment with calcium dobesilate and candesartan as soon as diabetic retinopathy was diagnosed. Treatment efficacy, changes in hemorrhage area, macular thickness and best-corrected visual acuity were assessed before and after treatment (for a duration of 60 days). Results: Study group had significantly higher (p < 0.05) treatment efficacy compared to control group, achieving a total effective rate of 92.86 %. It also exhibited reduced hemorrhage area and macular thickness, which were significantly lower (p < 0.05) than those in control group. Best-corrected visual acuity was significantly higher in the study group (p < 0.05) followed by improved peak systolic velocity and end-diastolic velocity after treatment (p < 0.05). Additionally, TGF-b1, VEGF and IL-19 levels in the vitreous humor were significantly lower in study group compared to control group (p < 0.05). Conclusion: The combination of calcium dobesilate and candesartan demonstrates significant therapeutic efficacy in treating proliferative diabetic retinopathy while reducing the TGF-b1, VEGF and IL-19 levels in the vitreous humor. Large-scale studies are needed to validate these findings and delve into treatment mechanisms and long-term effects. [ABSTRACT FROM AUTHOR]

The study was performed with a dual approach to develop and validate analytical method for poorly water soluble candesartan cilexetil by enhancing its solubility employing cosolvency technique. In order to enhance drug's solubility based on its solubility characteristics, phosphate buffer (pH 6.8):ethanol (95 % v/v) mixture at 90:10 proportion was used along with Tween 80 (1 % v/v). Solubility of candesartan cilexetil in phosphate buffer (pH 6.8) enhanced due to the addition of cosolvent ethanol and Tween 80. Developed method obeyed Beer-Lambert's law in the concentration range between 3-21 µg/ml. The regression coefficient at the wavelength 232 nm was 0.999. The analysis of tablets by the proposed method indicated a good correlation between estimated and labelled claims. Recovery studies showed that any small difference in drug concentration could be accurately determined. Low values of limit of detection and limit of quantitation indicated that the proposed method is sensitive, economic, accurate, precise, and robust for routine analysis of candesartan cilexetil in bulk and dosage forms. [ABSTRACT FROM AUTHOR]

No communicable diseases are a growing concern in the field of cardiovascular disease, where the use of amlodipine and candesartan, two antihypertensive drugs, has gained significant attention as a commonly used treatment strategy. Bromothymol blue and bromocresol green were used as reagents in UV spectrophotometry to test amlodipine and candesartan. The results obtained were in the dual-ion method, assuming a linear range between 5 and 55 μg mL−1 at pH = 11.5. The optimal dye volume is 0.7 mL. The temperature at which maximum absorption occurred was recorded at 25 °C, with corresponding recovery percentages of 98.2312 % and 102.2449 %. The range of relative standard deviation values is 0.02154–0.096745. The cloud results have a linear range extending from 1 to 55μg mL−1. Thus, at pH = 11, the most appropriate dye volume is 1 mL. The observed recovery rates for this procedure are 98.1045 % and 100.5664 %, respectively. The relative standard deviation (RSD%) results range from 0.013205 % to 0.02427 %. The above spectral estimates were performed with a high level of accuracy, uniformity, and responsiveness. The methods described in this study have been applied in specific contexts.

Diabetes mellitus is a metabolic disease that raises the odds of developing stroke. Candesartan has been used to prevent stroke due to its inhibitory effects on blood pressure, angiogenesis, oxidative damage, and apoptosis. However, oral candesartan has very limited bioavailability and efficacy due to its weak solubility and slow release. The study aimed to develop a nasal formulation of candesartan-loaded liposomes containing ethanol and propylene glycol (CLEP) to improve candesartan's delivery, release, permeation, and efficacy as a potential diabetes-associated stroke treatment. Using design expert software, different CLEP formulations were prepared and evaluated in vitro to identify the optimum formulation, which.The selected optimum formulation composed of 3.3% phospholipid, 10% ethanol, and 15% propylene glycol significantly increased the release and permeation of candesartan relative to free candesartan by a factor of 1.52 and 1.47, respectively. The optimum formulation significantly reduced the infarction after stroke in rats; decreased flexion, spontaneous motor activity, and time spent in the target quadrant by 70%, 64.71%, and 92.31%, respectively, and enhanced grip strength by a ratio of 2.3. Therefore, nasal administration of the CLEP formulation could be a potential diabetes-associated stroke treatment.

OBJECTIVE: The aim of this study was to explore the protective effect of candesartan against cisplatin-induced kidney damage, with a specific focus on the growth differentiation factor 15 (GDF-15) pathway. MATERIALS AND METHODS: 24 adult female Wistar rats, with a weight range of 200-210 grams, were enrolled in the study. Eight rats were included as a normal control group and did not receive any medication. 16 rats were administered cisplatin at a dosage of 2.5 mg/kg/day twice a week for 4 weeks (total dose 20 mg/kg). Then, they were randomly divided into two groups and treated with 1 ml/kg/day tap water or 8 mg/kg/day candesartan via oral gavage daily for 4 weeks. At the end of the treatment period, animals were sacrificed, and their kidneys were assessed histologically. In addition, plasma malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), creatinine, and GDF-15 levels were assessed. RESULTS: Treatment with candesartan resulted in a significant rise in serum GDF-15 levels and a significant reduction in levels of serum MDA, TNF-α, IL-6, and creatinine compared to the cisplatin and saline group. Candesartan treatment effectively protected the kidney injury, and histopathological examinations of the kidneys confirmed these results. CONCLUSIONS: This study demonstrates that candesartan alleviates cisplatin-induced renal toxicity by further increasing GDF-15, downregulating inflammatory markers, and reducing oxidative stress. [ABSTRACT FROM AUTHOR]

Atherosclerosis is an inflammatory disease characterized by the accumulation of arterial plaque. Diabetes mellitus stands out as a major risk factor for atherosclerosis. Candesartan is a potent angiotensin II receptor antagonist that enhances arterial blood flow and reduces insulin resistance. However, oral candesartan has limited activity because of its low bioavailability, water solubility, hepatic first-pass degradation, and efficacy. The current study aims to develop nasal candesartan-loaded invasome (CLI) drops to improve candesartan's permeation, release, and bioavailability as a potential treatment for diabetes-associated atherosclerosis. Design expert software was used to prepare various CLI formulations to determine the impact of the concentrations of ethanol, cineole, and phospholipid. The desirability index was used to estimate the optimized formulation composition to maximize entrapment efficiency and minimize vesicle size. The optimized formulation had a 1% ethanol concentration, a 1.5% cineole concentration, and a 2.32% phospholipid concentration. The selected optimized formulation was then tested in a rat model of diabetes and atherosclerosis to evaluate its activity. The results showed that nasal CLI drops significantly raised serum HDL levels by a ratio of 1.42 and lowered serum glucose, cholesterol, triglycerides, LDL, and VLDL levels by 69.70%, 72.22%, 36.52%, 58.0%, and 65.31%, respectively, compared with diabetic atherosclerotic rats, throwing an insight on the potential for promising anti-diabetic and anti-atherosclerotic activities. Additionally, atherosclerotic lesions were improved in rats treated with CLI, as shown in histopathology. In conclusion, the results of this investigation showed that treatment with nasal CSN-loaded invasome formulation drops prevented the initiation and progression of diabetes-associated atherosclerosis. [ABSTRACT FROM AUTHOR]

Background and purpose: The production of metallo‐β‐lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost‐effective approach to fight infections caused by carbapenem resistant pathogens. Experimental approach: The nitrocefin hydrolysis assay was employed to screen potential New Delhi metallo‐lactamase‐1 (NDM‐1) inhibitors from a commercially available U.S. Food and Drug Administration (FDA) approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP‐MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time‐dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy. Key results: Twelve FDA‐approved compounds were initially screened to inhibit the ability of NDM‐1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid were demonstrated to inhibit all tested metallo‐β‐lactamases and showed an in vitro synergistic bactericidal effect with meropenem against metallo‐β‐lactamases‐producing bacteria. Dexrazoxane, embelin and candesartan cilexetil are metal ion chelating agents, while the inhibition of NDM‐1 by nordihydroguaiaretic acid involves its direct binding to the active region of NDM‐1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models. Conclusions and implications: Our observations indicated that dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid are promising carbapenem adjuvants against metallo‐β‐lactamases‐positive carbapenem resistant bacterial pathogens. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to develop a rapidly dissolving tablet containing an antihypertensive drug, candesartan cilexetil (CAND). The research work focused on improving solubility and in vitro dissolution of drugs using spherical agglomeration technique. Spherical agglomerates of CAND were developed using PVPK-30 as polymer and dichloromethane as bridging liquid. A spherical agglomerate of CAND was used to formulate fast dissolving tablet (FDT) with different superdisintegrants like Crospovidone and Cross carmellose sodium. The prepared powder blend was evaluated for different pre-compression parameters like solubility, compressibility index, Hausner's ratio and flow property and post-compression parameters including in vitro dissolution study. The solubility of prepared agglomerates was found to be 0.15 to 0.91 mg mL-1, and it was higher than the pure drug (0.00071 mg mL-1). In vitro drug release study of optimized batch of FDT has shown 95.47 % of drug release. From the results, it was revealed that the prepared FDT using the agglomeration technique might be used to enhance the solubility and bioavailability of CAND to augment acute and chronic hypertension therapy. [ABSTRACT FROM AUTHOR]

The following research aimed to enhance solubility by loading candesartan cilexetil into nanosuspension. Candesartan cilexetil-loaded nanosuspension was prepared with the aid of Design-Expert® software. A technique of solvent evaporation was employed to produce nanosuspensions from hydroxyl propyl methyl cellulose (HPMC E5), polyvinyl pyrrolidone (PVP K-30), and poloxamer (PXM 188). The optimised nanosuspensions' particle size and polydispersity index (PDI) were 64.65 nm and 0.059, respectively. The entrapment efficacy (EE %) and drug loading (DL %) were 86.75 and 10.17%, respectively. The atomic force microscopy (AFM) revealed spherical and smooth nanoparticles. The Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) revealed pure, crystalline and conjugated drugs inside the nanosuspension. The release study confirmed 90% release within 10 min. No significant changes in particle sizes over three months were found, indicating stable nanoparticles. Saturated solubility of the candesartan cilexetil powder and loaded nanosuspension was 63.3 ± 6 and 344.7 ± 16 µg.ml-1, respectively, revealing more than five times increase in solubility. Candesartan cilexetil-loaded nanosuspensions were successfully prepared using different combinations of PVP K-30, HPMC E-5 and PXM 188 in various concentrations. Solubility was enhanced by loading the payload into nanosuspensions [ABSTRACT FROM AUTHOR]

Candesartan cilexetil (CAN) is administered for treating hypertension and heart failure. CAN suffers poor oral bioavailability, owing to limited aqueous solubility, and first-pass metabolism. Solusomes (novel Soluplus® enriched nano-vesicular carriers) combine the merits of Soluplus®, and the traditional liposomes. They were explored to increase CAN solubility, allow a high drug release rate, and improve the oral drug bioavailability. Solusomes were developed via thin film hydration technique utilizing lipid (phosphatidylcholine; PC) and polymeric solubilizer (Soluplus®; Solu). S6 system comprising PC (0.1% w/v), CAN and Soluplus® (at 1:5 ratio; w/w), following a 5 min sonication period, was the optimum one with respect to drug entrapment efficiency (83.5 ± 2.6%), drug loading (11.9 ± 0.3%), particle size and shape (377.2 ± 12.1 nm, spherical), zeta-potential (−19.6 ± 2.1 mV), saturated drug solubility (32.09 ± 0.71 µg/mL), drug released % after 1 h (68 ± 0.9%), and stability. Significantly higher Cmax (969.12 ± 46.3 ng/mL), shorter median Tmax (1h), and improved relative bioavailability (≈ 6.8 folds) in rabbits could evidence the potential of S6 system in enhancing oral CAN bioavailability. S6 solusomes act as dual platform to improve the oral drug bioavailability and maintain effective drug concentration for a prolonged period. [ABSTRACT FROM AUTHOR]

This study aimed to develop a mixed polymeric micelle formulation incorporating candesartan cilexetil (CAND) drug to enhance its oral bioavailability for the better treatment of hypertension. A Box–Behnken design was utilized to optimize the CAND-incorporated mixed polymeric micelles formulation (CAND-PFLC) consisting of Pluronics (P123 and F68) and lecithin (LC). The optimized CAND-PFLC micelles formulation was characterized for size, shape, zeta potential, polydispersity index (PDI), and entrapment efficiency (%EE). An in vitro release study, ex vivo permeability investigation, and an in vivo pharmacokinetic analysis were carried out to evaluate the performance of the formulation. The optimized CAND-PFLC micelles formulation demonstrated a spherical shape, a particle size of 44 ± 2.03 nm, a zeta potential of −7.07 ± 1.39 mV, a PDI of 0.326 ± 0.06, and an entrapment efficiency of 87 ± 3.12%. The formulation exhibited excellent compatibility, better stability, and a noncrystalline nature. An in vitro release study revealed a faster drug release of 7.98% at gastric pH in 2 hrs and 94.45% at intestinal pH within 24 hrs. The ex vivo investigation demonstrated a significantly enhanced permeability of CAND, with 94.86% in the micelle formulation compared to 9.03% of the pure drug. In vivo pharmacokinetic analysis showed a 4.11-fold increase in oral bioavailability of CAND compared to the marketed formulation. The CAND-PFLC mixed micelle formulation demonstrated improved performance compared to pure CAND, indicating its potential as a promising oral drug delivery system for the effective treatment of hypertension. [ABSTRACT FROM AUTHOR]

Abstract Background Today, heart failure is one of the leading causes of death and disability in most developed and developing countries. By 2030, more than 23.3 million people are projected to die of cardiovascular diseases each year, and the prevalence of heart failure is expected to increase by 25%. One of the preventive interventions is pharmacological interventions which can be used to reduce the complications of cardiovascular diseases such as heart failure. One of the most important pharmacological interventions in patients with heart failure is the use of antihypertensive drugs such as candesartan, enalapril, and valsartan. This study aimed to compare the cost-utility of candesartan, enalapril, and valsartan in patients with heart failure using the Markov model in Iran in 2020. Methods In the present study, a four-state Markov model was designed to compare the cost-utility of candesartan, enalapril, and valsartan for a hypothetical cohort of 10,000 heart failure patients older than 24 years. The payers’ perspective was used to calculate the costs. The Markov states included outpatients with heart failure, patients with heart failure admitted to general hospital wards, patients with heart failure admitted to the intensive care units (ICUs), and death. The effectiveness measure in this study was the quality-adjusted life years (QALYs). The one-way and probabilistic sensitivity analyses were used to determine the robustness of the results. The TreeAge Pro 2011 software was used for data analysis. Results The results showed that the average expected costs and QALYs were 119645.45 USD and 16.15 for valsartan, 113,019.68 USD and 15.16 for enalapril, and 113,093.37 USD and 15.06 for candesartan, respectively. Candesartan was recognized as the dominated option. Because the calculated incremental cost-effectiveness ratio (ICER) value (6,692.69 USD) was less than the threshold value (7,256 USD), valsartan was cost-effective compared to enalapril. The results of the cost-effectiveness acceptability curve showed that at the threshold of 7,256 USD, valsartan had a 60% chance of being cost-effective compared to enalapril. The results of one-way and probabilistic sensitivity analyses confirmed the robustness of the results. Moreover, the results showed that ICU (1,112 USD) had the highest cost among cost items. Conclusion According to the results, it is recommended that health policymakers consider the use of valsartan by cardiologists when designing clinical guidelines for the treatment of patients with heart failure.

Background: We report a case of a patient with HER2-positive gastric cancer with marked tongue swelling during the second cycle of S-1, oxaliplatin, and trastuzumab. Case presentation: The patient was a 74-year-old male, who was taking an angiotensin II receptor blocker (ARB) for pre-existing hypertension, with no history of allergies, diagnosed with HER2-positive gastric cancer, treated with tegafur, gimeracil, and oteracil potassium (S-1) and oxaliplatin for the first cycle, and trastuzumab was added from the second cycle. Three weeks after initiation, during an outpatient visit, grade 2 oral mucositis and significant enlargement of the patient's tongue were observed. Due to the risk of airway obstruction, the patient was referred to an otolaryngologist. After examination, hereditary angioedema was ruled out, and treatment was discontinued in view of ARB-induced angioedema. However, the tongue swelling did not improve markedly. Considering disease progression due to the discontinuation of chemotherapy, it was decided to change S-1 to capecitabine and continue treatment, and chemotherapy was resumed. Conclusions: Angioedema has been reported to be hereditary and drug-related, and angiotensin-converting enzyme (ACE) inhibitors and ARBs have also been reported to lead to drug-related adverse events. Since the patient had oral mucositis at the time of onset and was taking an ARB, it is thought that oxaliplatin and S-1(SOX), and trastuzumab during ARB therapy induced oral mucositis, leading to the development of angioedema. [ABSTRACT FROM AUTHOR]

This study aimed to determine the role of oxidative stress produced by the renin–angiotensin system (RAS) in cataract formation in streptozotocin-induced diabetic rats (STZ) using angiotensin II receptor blockers (ARBs). Rats were treated with streptozotocin and orally administered candesartan (2.5 mg/kg/day) or a normal diet for 10 weeks until sacrifice. Cataract progression was assessed through a slit-lamp examination. Animals were euthanized at 18 weeks, and the degree of cataract progression was evaluated. Oxidative stress was also assessed. In STZ-treated rats, lens opacity occurred at 12 weeks. Cataract progression was inhibited in the ARB-treated group compared with the placebo group (p < 0.05). STZ-treated rats exhibited upregulated angiotensin-converting enzyme (ACE) gene expression than control rats. Oxidative stress-related factors were upregulated in the placebo-treated group but suppressed in the ARB-treated group. A correlation coefficient test revealed a positive correlation between ACE gene expression and oxidative stress-related factors and a negative correlation between ACE and superoxide dismutase. Immunostaining revealed oxidative stress-related factors and advanced glycation end products in the lens cortex of the placebo-treated group. The mechanism of diabetic cataracts may be related to RAS, and the increase in focal ACE and angiotensin II in the lens promotes oxidative stress-related factor production. [ABSTRACT FROM AUTHOR]

Introduction: SLNs have a surfactant-stabilized solid lipid core. They circumvent liquid lipid constraints and increase drug stability. Lipids promote oral medication absorption through the lymphatic pathway and replace hepatic first-pass metabolism. Using a 2-factor, 3-level, 3² full factorial design, the researchers optimized percentage Encapsulation Efficiency (%EE), drug content, and particle size to enhance the candesartan cilexetil-loaded SLN formulation. Materials and Methods: The BCS class II low soluble Candesartan was used to formed as SLN and optimized utilizing independent variables Imwitor 900K and tween 60 concentrations and dependent factors %EE, drug content, and particle size. FTIR showed no drug-excipient interaction. Along with in vitro drug release. Results: The optimized 13 formulations had %EE from 78.47 to 94.61, drug concentration from 57 to 107%, and particle size from 357 to 705 nm. SEM showed that certain particles were coagulated and near-spherical, supporting particle size and dispersion. C-SLN-7 released 60.39% and C-SLN-12 46.4% during 24 hr in vitro. BCS class II low soluble CC's calibration curve was a straight line with an R² value of 0.9978, indicating the drug's standard curve. The improved SLN formulation may improve oral bioavailability of poorly soluble medicines. Conclusion: The enhanced SLN formulation of candesartan cilexetil increased encapsulation efficiency, drug content, particle size, and in vitro drug release. Changes in lymphatic absorption may improve oral absorption of highly lipophilic medicines. The work sheds light on SLNs' lipophilic drug delivery potential. [ABSTRACT FROM AUTHOR]

The present study hypothesized that chronic administration of candesartan will not only improve the sensitivity of alpha-adrenergic receptors to adrenergic agonists but also modulate the expression of angiotensin receptors (AT1a) and sodium chloride cotransporter (NCC) mRNAs. Animals were divided into four groups WKY control; WKY received candesartan (WKY-CST, 10 mg/kg), SHR control, and SHR received candesartan (SHR-CST). Plasma, urine samples, and mean arterial pressure (MAP) were taken on days 0, 21, and 28. Acute studies determined the renal vasoconstrictor actions of Ang II, noradrenaline (NA), phenylephrine (PE), and methoxamine (ME). The overall mean drops in renal cortical blood perfusion (RCBP) to NA, PE, ME, and Ang II were significantly increased in WKY-CST and SHR-CST when compared to the respective control. Expression of AT1a mRNA in the kidney of WKY-CST and SHR-CST were increased 11 folds and 8 folds respectively when compared to internal control (ß-actin). Expression of NCC MRNA in the kidney of WKY-CST and SHR-CST were 10 folds and 6 folds respectively when compared to internal control. Candesartan restores the functional responsiveness of alpha-adrenergic receptors in normal and spontaneously hypertensive rats by alleviating mean arterial pressure, enhancing renal cortical blood perfusion, and increasing the functional capabilities of the kidney by modulating renal tubular and glomerular functions. Secondly, chronic administrations of candesartan in SHR regulated the expression of AT1a mRNA and NCC mRNA in SHR rat kidneys when compared to SHR control rats. [ABSTRACT FROM AUTHOR]

Background: Today, heart failure is one of the leading causes of death and disability in most developed and developing countries. By 2030, more than 23.3 million people are projected to die of cardiovascular diseases each year, and the prevalence of heart failure is expected to increase by 25%. One of the preventive interventions is pharmacological interventions which can be used to reduce the complications of cardiovascular diseases such as heart failure. One of the most important pharmacological interventions in patients with heart failure is the use of antihypertensive drugs such as candesartan, enalapril, and valsartan. This study aimed to compare the cost-utility of candesartan, enalapril, and valsartan in patients with heart failure using the Markov model in Iran in 2020. Methods: In the present study, a four-state Markov model was designed to compare the cost-utility of candesartan, enalapril, and valsartan for a hypothetical cohort of 10,000 heart failure patients older than 24 years. The payers' perspective was used to calculate the costs. The Markov states included outpatients with heart failure, patients with heart failure admitted to general hospital wards, patients with heart failure admitted to the intensive care units (ICUs), and death. The effectiveness measure in this study was the quality-adjusted life years (QALYs). The one-way and probabilistic sensitivity analyses were used to determine the robustness of the results. The TreeAge Pro 2011 software was used for data analysis. Results: The results showed that the average expected costs and QALYs were 119645.45 USD and 16.15 for valsartan, 113,019.68 USD and 15.16 for enalapril, and 113,093.37 USD and 15.06 for candesartan, respectively. Candesartan was recognized as the dominated option. Because the calculated incremental cost-effectiveness ratio (ICER) value (6,692.69 USD) was less than the threshold value (7,256 USD), valsartan was cost-effective compared to enalapril. The results of the cost-effectiveness acceptability curve showed that at the threshold of 7,256 USD, valsartan had a 60% chance of being cost-effective compared to enalapril. The results of one-way and probabilistic sensitivity analyses confirmed the robustness of the results. Moreover, the results showed that ICU (1,112 USD) had the highest cost among cost items. Conclusion: According to the results, it is recommended that health policymakers consider the use of valsartan by cardiologists when designing clinical guidelines for the treatment of patients with heart failure. [ABSTRACT FROM AUTHOR]