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Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine.

ABSTRACT: Intracellular calcium [Ca²⁺]_i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca²⁺]_i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25?mg/kg/day), DFP (75?mg/kg/day), DFX (20?mg/kg/day), NAC (100?mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca²⁺ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca²⁺]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca²⁺]i homeostasis, only DFP?+?NAC restored cardiac [Ca²⁺]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP?+?NAC was more effective than any monotherapy in restoring cardiac [Ca²⁺]_i homeostasis, leading to restored myocardial contractility in iron-overloaded rats.

SUBMITTER: Wongjaikam S

PROVIDER: S-EPMC5347387 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine.

Wongjaikam Suwakon S Kumfu Sirinart S Khamseekaew Juthamas J Chattipakorn Siriporn C SC Chattipakorn Nipon N

Scientific reports 20170313

Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed w ...[more]

PMID: 28287621

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Project description:BackgroundPatients with ?-thalassaemia major experience chronic iron overload due to regular blood transfusions. Chronic iron overload can be treated using iron-chelating therapies such as desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) monotherapy, or DFO-DFP combination therapy.ObjectivesThis study evaluated the relative cost effectiveness of these regimens over a 5-year timeframe from a UK National Health Service (NHS) perspective, including personal and social services.MethodsA Markov model was constructed to evaluate the cost effectiveness of the treatment regimens over 5 years. Based on published randomized controlled trial evidence, it was assumed that all four treatment regimens had a comparable effect on serum ferritin concentration (SFC) and liver iron concentration (LIC), and that DFP was more effective for reducing cardiac morbidity and mortality. Published utility scores for route of administration were used, with subcutaneously administered DFO assumed to incur a greater quality of life (QoL) burden than the oral chelators DFP and DFX. Healthcare resource use, drug costs (2010/2011 costs), and utilities associated with adverse events were also considered, with the effect of varying all parameters assessed in sensitivity analysis. Incremental costs and quality-adjusted life-years (QALYs) were calculated for each treatment, with cost effectiveness expressed as incremental cost per QALY. Assumptions that DFP conferred no cardiac morbidity, mortality, or morbidity and mortality benefit were also explored in scenario analysis.ResultsDFP was the dominant strategy in all scenarios modelled, providing greater QALY gains at a lower cost. Sensitivity analysis showed that DFP dominated all other treatments unless the QoL burden associated with the route of administration was greater for DFP than for DFO, which is unlikely to be the case. DFP had >99 % likelihood of being cost effective against all comparators at a willingness-to-pay threshold of £20,000 per QALY.ConclusionsIn this analysis, DFP appeared to be the most cost-effective treatment available for managing chronic iron overload in ?-thalassaemia patients. Use of DFP in these patients could therefore result in substantial cost savings.

Dataset Information

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine.

Publications

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine.

Similar Datasets

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