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Schedule of administration of adriamycin and candesartan. ip, intraperitoneally; po, per os; qd, everyday.
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Introduction
It has been reported that the chemotherapeutic agent, adriamycin, not only has an effect on the myocardium but also on the arteries. The aim of this study is to elucidate effects of adriamycin and an angiotensin receptor blocker, candesartan, on collagen and elastin of the aorta in rats.
Methods
Twenty four male 8-week-old Wistar-Kyot...
Contexts in source publication
Context 1
... study protocol was approved by the institutional re- view board for Animal Research of Yeouido St. Mary's Hospital (no: YEOUIDO-2012-13-01). Twenty four male 8-week-old Wistar-Kyoto rats were used. The rats were kept in cages under conditions of a room temperature of 20°C, a relative humidity of 60%, and a day/night cycle of 12 h. The rats had free access to food and water in cages. The rats were divided into four groups: control (C), adriamycin-treated (AD), candesartan-treated (CA), adriamycin-and candesartan-treated (AD + CA). The rats were weighed at the beginning of the experiment. In the AD and AD + CA groups, 2.5 mg/kg of adria- mycin (Ildong Pharmaceuticals Co., Anseong, Korea) was injected intraperitoneally six times for 6 weeks ( Figure 1) [7]. In the C and CA groups, normal saline of the same volume was injected by using the same method at the same time as the AD and AD + CA groups. In the CA and AD + CA groups, 10 mg/kg/day of candesartan (AstraZeneca, Zoetermeer, The Netherlands) was admi- nistered orally with a sonde (Figure 1). In the C and AD groups, normal saline of the same volume was admi- nistrated orally by using the same method at the same time as the CA and AD + CA groups. After 6 weeks, the rats were weighed and placed under anesthesia by zoletil (Virbac, Carros, France), the sternum was incised longi- tudinally, and the heart and the aorta were exposed. The rats were euthanized by injection of potassium chloride into both ventricles. After cardiac arrest, the aorta was extracted from the proximal ascending aorta to bifur- cation of both iliac ...
Context 2
... study protocol was approved by the institutional re- view board for Animal Research of Yeouido St. Mary's Hospital (no: YEOUIDO-2012-13-01). Twenty four male 8-week-old Wistar-Kyoto rats were used. The rats were kept in cages under conditions of a room temperature of 20°C, a relative humidity of 60%, and a day/night cycle of 12 h. The rats had free access to food and water in cages. The rats were divided into four groups: control (C), adriamycin-treated (AD), candesartan-treated (CA), adriamycin-and candesartan-treated (AD + CA). The rats were weighed at the beginning of the experiment. In the AD and AD + CA groups, 2.5 mg/kg of adria- mycin (Ildong Pharmaceuticals Co., Anseong, Korea) was injected intraperitoneally six times for 6 weeks ( Figure 1) [7]. In the C and CA groups, normal saline of the same volume was injected by using the same method at the same time as the AD and AD + CA groups. In the CA and AD + CA groups, 10 mg/kg/day of candesartan (AstraZeneca, Zoetermeer, The Netherlands) was admi- nistered orally with a sonde (Figure 1). In the C and AD groups, normal saline of the same volume was admi- nistrated orally by using the same method at the same time as the CA and AD + CA groups. After 6 weeks, the rats were weighed and placed under anesthesia by zoletil (Virbac, Carros, France), the sternum was incised longi- tudinally, and the heart and the aorta were exposed. The rats were euthanized by injection of potassium chloride into both ventricles. After cardiac arrest, the aorta was extracted from the proximal ascending aorta to bifur- cation of both iliac ...
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Citations
... These effects on the vasculature by cardiotoxic AC can be explained by the putative endothelial toxicity of AC through oxidative stress and direct DNA-damage acting on vascular endothelial cells, leading to apoptosis and endothelial dysfunction (36). It has also been reported that AC leads to decreased elastin and increased collagen content, suggesting a possible structural derangement caused by AC (37). Like AC, radiotherapy induces oxidative stress (38) leading to inflammation and fibrosis that acts locally in the irradiated area (39). ...
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Results: Fifty-three CCS (20–30 years, 35 men) and 53 sex-matched controls were studied. The CCS cohort was divided by the median dose of anthracyclines into a low anthracycline dose (LAD) group (50–197 mg/m ² , n = 26) and a high anthracycline dose (HAD) group (200–486 mg/m ² , n = 27). Carotid distensibility index (DI) and endothelial function determined by PAT-RHI were both lower in the CCS groups compared with controls ( p < 0.05 and p = 0.02). There was no difference in carotid intima media thickness. Atherogenic apolipoprotein-B (Apo-B) and the ratio between Apo-B and Apoliprotein-A1 (Apo-A1) were higher in the HAD group compared with controls ( p < 0.01). Apo-B/Apo-A1-ratio was over reference limit in 29.6% of the HAD group, in 15.4% of LAD group, and in 7.5% of controls ( p = 0.03). Measured lipid markers (low density lipoprotein and total cholesterol and triglycerides) were higher in both CCS groups compared with controls ( p < 0.05). Systolic and diastolic function were measurably decreased in the HAD group, as evidenced by lower EF ( p < 0.001) and lower é-wave ( p < 0.005) compared with controls. CCA DI correlated with Apo-B/Apo-A1-ratio and Apo-A1. Follow-up time after treatment correlated with decreased left ventricular ejection fraction ( p = 0.001).
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... In an animal study, chronic administration of doxorubicin resulted in cardiotoxicity and was associated with a 2-fold increase in plasma renin activity, the enzyme responsible for initiating the renin-angiotensin system. 28,29 Evidence suggests that gender differences exist in terms of renin-angiotensin-aldosterone system function. Miller et al. showed that women achieved considerably lower angiotensin II sensitivity than men at lower dosages, suggesting that women may require lower dosages of ARB than men. ...
Background
There is no proven primary preventive strategy for doxorubicin‐induced subclinical cardiotoxicity (DISC), especially among patients without a cardiovascular (CV) risk. We investigated the primary preventive effect on DISC of the concomitant use of angiotensin receptor blockers (ARBs) or beta‐blockers (BBs), especially among breast cancer patients without a CV risk.
Methods
A total of 385 patients who were scheduled for doxorubicin chemotherapy were screened. Among them, 195 patients of the study populations were included and were randomly divided into two groups [candesartan 4 mg q.d. vs. carvedilol 3.125 mg q.d.] and patients who were unwilling to take one of the medications were evaluated as controls. The primary outcomes were the incidence of early DISC (DISC developing within 6 months after chemotherapy), and late DISC (DISC developing only at least 12 months after chemotherapy).
Result
Compared with the control group (8 out of 43 patients (18.6%)), only the candesartan group (4 out of 82 patients (4.9%)) showed a significantly lower incidence of early DISC (p = 0.022). Compared with the control group, the candesartan group demonstrated a significantly reduced decrease in left ventricular ejection fraction (LVEF) throughout the study period [−1.0% vs. −3.00 (p < 0.001) at the first follow‐up, −1.10% vs. −3.40(p = 0.009) at the second follow‐up].
Conclusions
Among breast cancer patients without a CV risk treated with doxorubicin‐containing chemotherapy, subclinical cardiotoxicity is prevalent and concomitant administration of low‐dose candesartan might be effective to prevent an early decrease in LVEF. Further large‐scale, randomized controlled trials will be needed to confirm our findings.
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Cardiotoxicity is a well-known complication following treatment with anthracyclines. However, they are still widely used in chemotherapy for breast cancer, lymphoma, leukemia, and sarcoma, among others. Patient clinical characteristics, such as age, sex, comorbidities, anthracycline dose and infusion schedule, and the combined anti-cancer agents used, are diverse among cancer types. It is difficult to recommend guidelines for the prevention or management of anthracycline-induced cardiotoxicity applicable to all cancer types. Therefore, anthracycline-induced cardiotoxicity remains a major limitation in the proper management of cancer patients treated with an anthracycline-combined regimen. Efforts have been extensive to determine the mechanism and treatment of anthracycline-induced cardiotoxicity. Because cardiotoxicity causes irreversible damage to the myocardium, prevention is a more effective approach than treatment of cardiotoxicity after symptomatic or asymptomatic cardiac dysfunction develops. This article will review the pathophysiological mechanisms of anthracycline-induced cardiotoxicity and strategies for protecting the myocardium from anthracycline.
Doxorubicin (Dox), an effective chemotherapeutic, can cause cumulative dose-dependent cardiovascular toxicity, which may manifest as vascular dysfunction leading to long-term end-organ damage. Currently, there are no effective treatments to mitigate Dox-induced vascular damage in cancer patients, particularly pediatric patients. We showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone, mitigated cardiac damage in Dox-treated juvenile rats. In this study assessing aortic stiffness, juvenile male and female rats were administered a clinically equivalent dose of Dox (21-24 mg/kg) over 6 weeks, in the presence and absence of Ang-(1-7) [24 µg/kg/h]. Aortic function was measured using echocardiography. Ang-(1-7) reduced the Dox-mediated increase in pulse wave velocity, a measure of arterial stiffness (males: p<0.05; females: p<0.001) as compared in control animals. Dox decreased aortic lumen diameter (p<0.0001) and increased wall thickness (p<0.01) in males, which was attenuated by Ang-(1-7). In male but not female aortic arches, Dox increased media hypertrophy (p<0.05) and reduced elastin content (p<0.001), which were prevented by Ang-(1-7). Conversely, Dox increased fibrosis (p<0.0001) in juvenile female rats, which was reduced by Ang-(1-7). Adjunct Ang-(1-7) prevented the Dox-induced increase in total cell and nuclear pERK1/2 in the aortic intima and media of male rats and nuclear pSMAD2 in the intimal and medial regions of the aortic arches of both sexes. These results demonstrate that Ang-(1-7) attenuated Dox-induced aortic dysfunction in both sexes of juvenile rats, albeit through different mechanisms, suggesting that Ang-(1-7) may serve as an effective adjuvant to ameliorate cardiovascular and long-term end-organ damage in pediatric patients produced by anthracyclines.
Introduction
Doxorubicin (DOX) is a chemotherapeutic agent used in cancer treatment. Its use is limited by later toxicity to the cardiovascular system (CVS). Cellular senescence has been proposed as one mechanism of DOX toxicity. It has also been suggested that senescence reduction can improve the condition in many pathologies. We hypothesised that vildagliptin treatment can reduce senescence and thus improve the relaxation of vascular smooth muscle (VSM) in the aorta of a rat DOX model.
Methods
The rats received DOX and were treated with vildagliptin for 6 weeks. Thereafter, the rats were sacrificed, and the aorta prepared for measurements of VSM relaxation and RNA isolation to detect the level of senescence markers. To further prove the antisenescence effect of the main vildagliptin effector glucagon-like peptide 1(GLP-1), VSM cells (VSMCs) were incubated with DOX and treated with GLP-1. Subsequently, senescence was detected by senescence-associated beta-galactosidase (SA-β-gal) and by the presence of senescence markers.
Results
DOX in rats caused diminished relaxation of VSM to sodium nitrate and caused an increase in the senescence mRNA markers p16Ink4a and p27Kip1 and the senescence-associated secretory phenotype (SASP) IL-6 and IL-8. Vildagliptin treatment led to improved relaxation and a reduction in senescence and SASP markers. Furthermore, in VSMCs DOX increased SA-β-gal activity, p16Ink4a, p27Kip1, IL-6 and IL-8, and GLP1 treatment led to a decrease of both senescence and SASP markers.
Conclusion
In summary we conclude that vildagliptin can reduce senescence and improve relaxation of vascular smooth muscle in the aorta of DOX-treated rats, and GLP-1 can reduce senescence of DOX-treated VSMCs. These data suggest that incretin-based drugs are promising candidates for patients suffering from late doxorubicin cardiovascular toxicity.
It has been reported that the chemotherapeutic agent, adriamycin, not only has an effect on the myocardium but also on the arteries. The aim of this study is to elucidate effects of adriamycin and an angiotensin receptor blocker, candesartan, on collagen and elastin of the aorta in rats.
Twenty four male 8-week-old Wistar-Kyoto rats were divided into four groups: control (C) group, adriamycin-treated (AD) group, candesartan-treated (CA) group, and adriamycin- and candesartan-treated (AD + CA) group. Adriamycin of 2.5 mg/kg/wk was administered intraperitoneally one time per week for 6 weeks, and candesartan of 10 mg/kg/day was administered orally everyday for 6 weeks. After 6 weeks, the rats were sacrificed and the aortas were harvested. Hematoxylin-eosin staining, Verhoff’s elastic, and Goldner’s trichrome staining were performed for histopathologic analyses. Tunica media thickness, collagen, and elastic area fractions were measured quantitatively with a computerized digital image analyzer.
Tunica media thickness in the CA and AD + CA groups was significantly lesser than that in the C and AD groups, respectively. The AD and AD + CA groups had a tendency of lower elastin area fraction than the C and CA groups, respectively. Collagen area fraction in the AD + CA group was significantly lower than that in the AD group. There were no significant differences of collagen/elastin ratio between groups.
These findings suggest that adriamycin has a tendency of decreasing the quantity of elastin fibers and candesartan cannot mitigate the effects of adriamycin on elastin fibers.
