Uncovering the Therapeutic Potential of Phosphocreatine in Diabetic Retinopathy: Mitigating Mitochondrial Dysfunction and Apoptosis via JAK2/STAT3 Signaling Pathway.

Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.

Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial.

AIMS: Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. METHODS AND RESULTS: The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2 ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. CONCLUSIONS: Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

Protective effects of phosphocreatine on human vascular endothelial cells against hydrogen peroxide-induced apoptosis and in the hyperlipidemic rat model.

Phosphocreatine (PCr) has been shown to have a cardio-protective effect during cardiopulmonary resuscitation (CPR). However, little is known about its impact on atherosclerosis. In this study, we first evaluated the pharmacological effects of PCr on antioxidative defenses and mitochondrial protection against hydrogen peroxide (H2O2) induced human umbilical vascular endothelial cells (HUVECs) damage. Then we investigated the hypolipidemic and antioxidative effects of PCr on hyperlipidemic rat model. Via in vitro studies, H2O2 significantly reduced cell viability and increased apoptosis rate of HUVECs, while pretreatment with PCr abolished its apoptotic effect. PCr could reduce the generation of ROS induced by H2O2. Moreover, PCr could increase the activity of SOD and the content of NO, as well as decrease the activity of LDH and the content of MDA. PCr could also antagonize H2O2-induced up-regulation of Bax, cleaved-caspase3, cleaved-caspase9, and H2O2-induced down-regulation of Bcl-2 and p-Akt/Akt ratio. In addition, PCr reduced U937 cells' adhesion to H2O2-stimulated HUVECs. Via in vivo study, PCr could decrease MDA, TC, TG and LDL-C levels in hyperlipidemic rats. Finally, different-concentration PCr could increase the leaching of TC, HDL, and TG from fresh human atherosclerotic plaques. In conclusion, PCr could suppress H2O2-induced apoptosis in HUVECs and reduce hyperlipidemia through inhibiting ROS generation and modulating dysfunctional mitochondrial system, which might be an effective new therapeutic strategy to further prevent atherosclerosis.

[The possibilities of improving the treatment of chronic heart failure according to the results of a multicenter observational study BYHEART].

AIM: To study the efficacy and safety of exogenous phosphocreatine (EF) in patients with chronic heart failure (CHF). MATERIALS AND METHODS: The all-Russian prospective observational study BYHEART included 842 patients who were treated with EF. Before and after the course of EF therapy, the following studies were conducted: a questionnaire on the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and a clinical condition assessment scale (SHOCK), transthoracic echocardiography with an assessment of the left ventricular ejection fraction, a 6-minute walk test, determination of the level of pro-natriuretic N-terminal peptide (NT-proBNP), glomerular filtration rate. All patients before the course of EF received long-term optimal drug therapy of CHF. RESULTS: Statistical analysis was carried out in the general group of patients (n=842), as well as in groups of patients A (n=418, the course of treatment of EF is less than 20 g /course) and group B (n=424, the course of treatment of EF is greater than or equal to 20 g/course). The results obtained demonstrate a positive effect of the use of the course of therapy of EF in patients with CHF on the quality of life (QOL), reverse left ventricular remodeling, functional class of CHF, as well as the concentration of NT-pro-BNP, especially in the group of patients who received more than 20 grams of the medication. CONCLUSION: The use of EF is a promising pharmacological method of treatment in addition to optimal drug therapy in patients with CHF.

Clinical Efficacy of Creatine Phosphate Sodium and/or Vitamin C in the Treatment of Children with Viral Myocarditis: A Meta-Analysis.

Background: This study performed a meta-analysis to explore the clinical efficacy of creatine phosphate sodium (CPS) and/or vitamin C for viral myocarditis (VMC) in children, to provide guidance for its clinical treatment. Methods: A literature search was performed on PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang databases to obtain published clinical randomized controlled trials (RCTs) on CPS and/or vitamin C for VMC in children, with a time span from 2013 to 2022. Relevant data was extracted and meta-analysis was performed using the statistical software Stata 16.0. Results: A total of 723 studies were retrieved and 19 studies were finally included for meta-analysis, with a total of 1,957 patients. The meta-analysis results showed that the observation group (conventional treatment + CPS and/or vitamin C) was superior to the control group (conventional treatment alone) in treatment effective rate (OR = 3.60, 95% CI (2.55, 5.07), and P < 0.001). Additionally, the observation group had lower levels of cardiac troponin-I (SMD = - 2.63, 95% CI (- 3.51, - 1.76), and P < 0.001), creatine kinase isoenzyme (SMD = -2.78, 95% CI (- 3.53, - 2.03), and P < 0.001), lactate dehydrogenase (SMD = -1.95, 95% CI (- 2.49, - 1.42), and P < 0.001), aspartate aminotransferase (SMD = -0.87, 95% CI (- 1.84, 0.09), and P = 0.076), tumor necrosis factor-α (SMD = -3.90, 95% CI (- 4.47, - 3.06), and P < 0.001), and higher superoxide dismutase levels (SMD = 2.48, 95% CI (1.64, 3.33), and P < 0.001). Except aspartate aminotransferase, there were significant differences between the two groups in the other parameters. Conclusion: CPS and/or vitamin C treatment could greatly improve the treatment, protect myocardial function, and relieve inflammatory response in children with VMC.

Creatine phosphate administration in cardiac ischemia-reperfusion injury in rats: focus on differences between preconditioning, perconditioning, and postconditioning protocols.

The aim of this study was to examine and compare the influence of preconditioning, perconditioning, and postconditioning with creatine phosphate (PCr) on functional recovery and production of prooxidants in isolated rat hearts subjected to ex vivo ischemic-reperfusion (I-R) injury on a Langendorff apparatus. Wistar albino rats (male, n = 40) were divided into four groups: control and groups in which PCr (0.5 mmol/L, 5 min) was perfused before (Pre group), after (Post group), or during (Per group) ex vivo induced ischemia. PCr application was associated with the great benefits of preserving cardiac contractility (in Pre group 100.96% for +(dP/dt max) and 97.61% for -(dP/dt max), in Per group 96.72% for +(dP/dt max) and 95.60% for -(dP/dt max), and in Post group 143.84% for +(dP/dt max) and 104.36% for -(dP/dt max) in relation to the stabilization). In addition, PCr application prevented the increase in prooxidative markers during I-R injury in all therapeutic modalities. The most intensive benefits in the current investigation were observed when PCr was applied during the period of ischemia because the lowest fluctuations in the parameters of cardiac function and oxidative stress were observed. Overall, the results of this study highlight PCr-induced cardioprotection with promising prospects for future clinical use.

Melatonin pretreatment modulates anti-inflammatory, antioxidant, YKL-40, and matrix metalloproteinases in endotoxemic rat lung tissue.

We aimed to investigate the effects of melatonin administered before and during endotoxemia on the lung tissue of rats, cytokine, YKL-40, matrix metalloproteinase (MMP) and inhibitor levels, oxidative stress parameters, and energy balance. Sepsis was induced with lipopolysaccharide (LPS), the cell wall molecule of gram negative bacteria. Rats were divided into four groups, Control, LPS (Escherichia coli O127:B8, 20 mg/kg), melatonin (10 mg/kg), and melatonin+LPS (M+LPS). After injections, lung tissues samples were taken for experimental analyses. YKL-40, thiobarbituric acid reactive substances (TBARS), glutathione reductase (GR), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) enzymes levels were measured, high-energy components were analyzed; tumor necrosis factor-alpha (TNF-α), MMP-2, YKL-40, MMP-9, myeloperoxidase (MPO), tissue inhibitors of matrix metalloproteinase (TIMP)-1, and interleukin (IL)-10 immunoreactivities were investigated. In LPS group, YKL-40, creatine phosphate (both, p < 0.05), SOD, GR, adenosine mono-phophate (AMP), adenosine tri-phosphate (ATP) (for all, p < 0.01) were significantly decreased, while TBARS and adenosine di-phosphate (ADP) levels were increased (p < 0.01, p < 0.05; respectively) compared to other groups. MMP-2 and -9, TIMP-1, TNF-α, IL-10, and MPO immunoreactivity were investigated in LPS group. On the contrary, in M+LPS group, MMP-9, TIMP-1 immunoreactivities were not found and IL-10 and MMP-2 immunoreactivities were found with little involvement. In M+LPS group, YKL-40, GR, AMP, ATP, creatine phosphate (for all, p < 0.05), and SOD (p < 0.01) levels were significantly increased and TBARS levels were decreased (p < 0.05). In our study, we suggest that melatonin exerts a protective and curative effect by reducing the matrix metalloproteinase levels responsible for tissue damage balance, stimulating the release of antioxidant enzymes, regulating cytokines and energy balance during endotoxemia.

Protection of Exogenous Phosphocreatine for Myocardium in Percutaneous Coronary Intervention Related to Inflammation.

OBJECTIVES: Although injury of myocardium after percutaneous coronary intervention (PCI) has been reported, the mechanism and effect of exogenous phosphocreatine (PCr) supplementation on the injury are yet to be elucidated. Biomarkers, such as interleukin-6 (IL-6) and variations in white blood cells for inflammation, and serum cardiac troponin I (cTnI) for myocardial injury are examined. METHODS: A total of 105 patients undergoing PCI were included and randomly divided into two groups: control (treated with routine hydration therapy) and PCr (treated with additional intravenous infusion of exogenous PCr). The serum levels of biomarkers were detected at administration and 4, 12, 24, and 48 h after PCI, with natural logarithmic (loge) transformation of data when modeling assumptions were not fulfilled. RESULTS: The level of loge-transformed IL-6 increased in both groups, especially at 12 and 24 h after the operation, and that of PCr group was less than the control group at 48 h. The content of loge-transformed cTnI was significantly increased in both groups, while that of the PCr group was markedly lower than the control group at all time points after PCI. Moreover, the ratio of neutrophils was elevated at all time points after PCI, while that of the PCr group was lower at 48 h, and the variations in the ratio of lymphocytes showed opposite results. CONCLUSIONS: Exogenous phosphocreatine reduces stent implantation, triggers inflammation manifested as decreased serum levels of IL-6 and the aggregation of neutrophils, and protects the myocardium of the patients undergoing PCI. These findings provided the potential mechanism and treatment for myocardial injury associated with PCI.

Effect of norepinephrine combined with sodium phosphocreatine on cardiac function and prognosis of patients with septic shock.

Septic shock (SS) leads to a high mortality rate for sepsis patients. Norepinephrine (NE) is a preferred vasoactive agent in SS treatment. This study aimed to assess the effects of NE at different administration time and NE combined with SP treatment on the cardiac function and prognosis of SS.SS patients received NE treatment at different administration time and NE combined with SP treatment were enrolled in this study. The serum levels of cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), ejection fraction (EF), and pressure-adjusted heart rate (PAR) value were analyzed to evaluate cardiac function. The 28-day survival information was collected and assessed using the Kaplan-Meier method and log-rank test.The cardiac function of SS patients was improved significantly by NE treatment, especially in the patients received NE at 2 h after fluid infusion, which evidenced by the increased BNP and cTnI levels and EF% and the decreased RAP. In the NE-2 h group, SS patients had a better 28-day survival rate compared with those patients in NE-1 h and -3 h groups. Furthermore, the significantly improved cardiac function and survival outcomes were found in patients received NE combined SP treatment.Taken together, this study results show that NE administration at 2 h after fluid infusion may be the optimal time point for the treatment of SS and NE combined with SP treatment can improve early cardiac dysfunction and 28-day survival outcomes in patients with SS.

Protection of diabetes-induced kidney injury by phosphocreatine via the regulation of ERK/Nrf2/HO-1 signaling pathway.

Diabetic nephropathy is the most common long-term complication of diabetes mellitus. The Methylglyoxal (MGO) production is mainly by metabolic pathways, such as lipolysis and glycolysis, its increases in the DM enhances oxidative stress and plays a crucial role in the diabetic nephrotic pathogenesis. Phosphocreatine (PCr) can improve lipopolysaccharide, ox-LDL-induced atherosclerosis, and alleviate vascular endothelial cell injury in diabetes. The aim of our present study is to examine the potential role of phosphocreatine (PCr) as a molecule protects against diabetes-induced Kidney Injury in-vitro and in-vivo through ERK/Nrf2/HO-1 signaling pathway. NRK-52E cells treatment with PCr obviously suppressed MGO-induced change of viability, apoptosis, coupled with decreased Bax/Bcl-2ratio, casapse-9 and caspase-3expressions. We determined the generation of reactive oxygen species (ROS) using membrane permeable fluorescent probe DCFH-DA as well as intracellular calcium by flow cytometry. ERK, Nrf2 and HO-1 expressions were determined by Western blot. PCr pretreatment significantly returned the oxidative stress enzymes to normal condition in-vitro and in-vivo. PCr pretreatment significantly reduced apoptosis, calcium and ROS production, induced by MGO, in NRK-52E cells. Moreover, pretreatment with PCr significantly inhibited cleaved caspase-3, cleaved caspase-9 and p-ERK expressions, while increased Nrf-2 and HO-1 expressions. Furthermore, PCr pretreatment significantly decreased p-ERK expression of MGO-induced injury in NRK-52E cells transfected with p-ERK cDNA. In conclusion, the renal protective effect of PCr in-vitro and in-vivo depends on suppressing apoptosis and ROS generation through ERK mediated Nrf-2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the diabetic nephropathy treatment.

The efficacy observation of ulinastatin combined with creatine phosphate sodium in pediatric viral myocarditis.

OBJECTIVE: This study aimed to compare the efficacy and safety of ulinastatin combined with creatine phosphate sodium and ribavirin combined with creatine phosphate sodium in the treatment of pediatric viral myocarditis. PATIENTS AND METHODS: 155 children with viral myocarditis in the Xuzhou Children's Hospital, were retrospectively analyzed. 80 of them received ulinastatin combined with creatine phosphate sodium, and were regarded as observation group; other 75 patients received ribavirin combined with creatine phosphate sodium and were regarded as the control group. The therapeutic efficacy of the two groups was observed, the improved condition of myocardial enzyme indicator and myocardial troponin I (cTn I) in the two groups were compared before and after the treatment. RESULTS: The total effective rates of the patients in the observation group and the control group were 93.75% and 76.00%, respectively. The clinical efficacy of the observation group was better than that of the control group (p<0.05). The electrocardiogram improvement condition of the observation group was better than that of the control group (p<0.05); after the treatment, the expression levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), Creatine Kinase (CK-MB), and cTn I in the observation group were (313.37±9.42) U/L, (29.38±4.97) U/L, (23.67±2.89) U/L, (0.12±0.02) µg/L, respectively. The expression levels of LDH, AST, CK-MB, and cTn I in the control group were (322.43±12.32) U/L, (33.43±5.14) U/L, (26.22±3.37) U/L, (0.24±0.04) µg/L. The levels of myocardial enzyme and cTn I in the observation group and the control group after the treatment were lower than that before the treatment (p<0.05), while the level of myocardial enzyme and cTn I in the observation group after the treatment was significantly lower than that in the control group (p<0.05). CONCLUSIONS: The results indicated that, compared with ribavirin combined with creatine phosphate sodium, ulinastatin combined with creatine phosphate sodium had better clinical efficacy in the treatment of pediatric viral myocarditis. It could significantly improve the level of myocardial enzyme indicator and cTn I, and had certain clinical and promotional values and application values.

Potential possibility of phosphocreatine usage in internal medicine.

Adenosintriphosphate is basic unit of cellular energetics, although during situations of high energy demand, cell had developed metabolic inert molecules - phosphagens - including phosphocreatine. Nowadays there are not so many recent publications describing positive effect of phosphocreatine supplementation., its potential benefit in supplementation is mainly in cardiology - acute myocardial infarction, acute or chronic heart failure. Another field of medicine with potential use of phosphocreatine is nephrology - in dialysis patients, or in psotemnopausal women in prevention of osteoporosis. In following article, we present review of studies describing positive effect of using phosphocreatine in specific group of patients in internal medicine. Key words: ATP - ischemia - phosphagens - phosphocreatine.

Effect of creatine phosphate sodium on bispectral index and recovery quality during the general anaesthesia emergence period in elderly patients: A randomized, double-blind, placebo-controlled trial.

Objective To evaluate the effect of creatine phosphate sodium on bispectral index (BIS) and recovery quality during the general anaesthesia emergence period in elderly patients. Methods This randomized, double-blind, placebo-controlled study enrolled patients undergoing transabdominal cholecystectomy under general anaesthesia. Patients were randomly assigned to receive either creatine phosphate sodium (1.0 g/100 ml 0.9% saline; group P) or 100 ml 0.9% saline (group C) over 30 minutes during surgical incision. The BIS values were recorded at anaesthesia induction (T0), skin incision (T1), cutting the gallbladder (T2), suturing the peritoneum (T3), skin closure (T4), sputum suction (T5), extubation (T6) and 1 min (T7), 5 min (T8), 10 min (T9), and 15 min (T10) after extubation. The anaesthesia duration, operation time, waking time, extubation time, consciousness recovery time, time in the postanaesthesia care unit (PACU), and the Steward recovery scores at T7, T8, T9 and T10 were recorded. Results A total of 120 elderly patients were randomized equally to the two groups. Compared with group C, the BIS values were significantly higher in group P at T5, T6, T7 and T8; and the Steward recovery scores at T7 and T8 were significantly higher in group P. The waking time, extubation time, consciousness recovery time and time in the PACU were significantly shorter in group P compared with group C. Conclusion Creatine phosphate sodium administered during transabdominal cholecystectomy can improve BIS values and recovery following general anaesthesia in elderly patients.

Role of Exogenous Phosphocreatine in Chemotherapy-induced Cardiomyopathy.

The 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen is widely used in the management of breast cancer. The common cardiotoxic effects of doxorubicin include congestive heart failure and left ventricular dysfunction, and those of cyclophosphamide include pericarditis, myocarditis, and congestive heart failure. It has been postulated that cardiotoxicity of 5-fluorouracil presents as coronary artery diseases (eg, angina). Cardiomyopathy is a common outcome following treatment with the FAC regimen. We report on a 52-year-old woman with cardiomyopathy following chemotherapy and radiation therapy. The patient did not respond well to b-blockers and angiotensin-converting enzyme inhibitors. After the addition of exogenous phosphocreatine, the patient's cardiac condition improved significantly.

[RESULTS OF TREATMENT IN PATIENTS, SUFFERING STENOSIS OF CAROTID ARTERIES IN COMBINATION WITH DISEASES OF OTHER SYSTEMS].

Results of treatment in 2010 - 2015 yrs of 187 patients, suffering haemodynamically significant stenosis of carotid arteries, on background of upcoming surgical treatment of the lower extremities tissues chronic ischemia, an ischemic heart disease or diseases of digestive system, were analyzed. In generalized atherosclerosis and an acute disorder of the brain blood circulation in anamnesis it is necessary to conduct the carotid arteries affection screening. In haemodynamically significant stenosis of carotid arteries in patients, suffering an ischemic heart disease and the digestive system diseases, as a first stage a carotid endarterectomy was performed for reduction of the occurrence risk for ischemic insult after operation performed for the main disease.

[PROPHYLAXIS OF COGNITIVE DEFICIENCY WHILE PERFORMING ЕNDARTERECTOMY IN PATIENTS, SUFFERING STENOTIC AFFECTIONS OF CAROTID ARTERIES: THE ROLE OF MULTIDISCIPLINARY APPROACH].

Efficacy of the cognitive deficiency prophylaxis was studied in patients, suffering stenotic affection of carotid arteries. Application of intraoperative neuroprotection, using neoton, have permitted to reduce the reperfusion syndrome signs rate from 35.6 to 3.4%, аnd the cognitive deficiency level as well, causing the general occurrence risk of intraoperative or early morbidity lowering. It is expedient to apply the multidisciplinary approach for guaranteeing of adequate quality of clinical monitoring for cognitive functions.

Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.

BACKGROUND: Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review. OBJECTIVES: To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups. AUTHORS' CONCLUSIONS: Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Cardiac protection with phosphocreatine: a meta-analysis.

Phosphocreatine (PCr) plays an important role in the energy metabolism of the heart and a decrease in its intracellular concentration results in alteration of myocardium energetics and work. We conducted a meta-analysis of all randomized and matched trials that compared PCr with placebo or standard treatment in patients with coronary artery disease or chronic heart failure or in those undergoing cardiac surgery. We systematically searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials and Google Scholar up to 1 November 2015, for pertinent trials. The primary outcome was all-cause mortality. Secondary outcomes included inotrope use, ejection fraction (EF), peak creatinine kinase-myocardial band (CK-MB) release and the incidence of major arrhythmias, as well as spontaneous recovery of the heart performance in the subgroup of patients undergoing cardiac surgery with cardiopulmonary bypass. We pooled odds ratio (OR) and mean difference (MD) using fixed- and random effects models. We identified 41 controlled trials, of them 32 were randomized. Patients receiving PCr had lower all-cause mortality when compared with the control group [61/1731 (3.5%) vs 177/1667 (10.6%); OR: 0.71, 95% CI: 0.51-0.99; P = 0.04; I(2) = 0%; with 3400 patients and 22 trials included]. Phosphocreatine administration was associated with higher LVEF (MD: 3.82, 95% CI: 1.18-6.46; P = 0.005; I(2) = 98%), lower peak CK-MB release (MD: -6.08, 95% CI: -8.01, -4.15; P < 0.001; I(2) = 97%), lower rate of major arrhythmias (OR: 0.42; 95% CI: 0.27-0.66; P < 0.001; I(2) = 0%), lower incidence of inotropic support (OR: 0.39, 95% CI: 0.25-0.61; P < 0.001; I(2) = 56%) and a higher level of spontaneous recovery of the heart performance after cardiopulmonary bypass (OR: 3.49, 95% CI: 2.28-5.35; P < 0.001; I(2) = 49%) when compared with the control group. In a mixed population of patients with coronary artery disease, chronic heart failure or in those undergoing cardiac surgery, PCr may reduce all-cause short-term mortality. In addition, PCr administration was associated with improved cardiac outcomes. Owing to the pharmacological plausibility of this effect and to the concordance of the beneficial effects of PCr on several secondary but important outcomes and survival, there is urgent need for a large multicentre randomized trial to confirm these findings.

Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease.

Creatine is of paramount importance for maintaining and managing cellular ATP stores in both physiological and pathological states. Besides these "ergogenic" actions, it has a number of additional "pleiotropic" effects, e.g., antioxidant activity, neurotransmitter-like behavior, prevention of opening of mitochondrial permeability pore and others. Creatine supplementation has been proposed for a number of conditions, including neurodegenerative diseases. However, it is likely that creatine's largest therapeutic potential is in those diseases caused by energy shortage or by increased energy demand; for example, ischemic stroke and other cerebrovascular diseases. Surprisingly, despite a large preclinical body of evidence, little or no clinical research has been carried out in these fields. However, recent work showed that high-dose creatine supplementation causes an 8-9 % increase in cerebral creatine content, and that this is capable of improving, in humans, neuropsychological performances that are hampered by hypoxia. In addition, animal work suggests that creatine supplementation may be protective in stroke by increasing not only the neuronal but also the endothelial creatine content. Creatine should be administered before brain ischemia occurs, and thus should be given for prevention purposes to patients at high risk of stroke. In myocardial ischemia, phosphocreatine has been used clinically with positive results, e.g., showing prevention of arrhythmia and improvement in cardiac parameters. Nevertheless, large clinical trials are needed to confirm these results in the context of modern reperfusion interventions. So far, the most compelling evidence for creatine and/or phosphocreatine use in cardiology is as an addition to cardioplegic solutions, where positive effects have been repeatedly reported.

Phosphocreatine protects against LPS-induced human umbilical vein endothelial cell apoptosis by regulating mitochondrial oxidative phosphorylation.

Phosphocreatine (PCr) is an exogenous energy substance, which provides phosphate groups for adenosine triphosphate (ATP) cycle and promotes energy metabolism in cells. However, it is still unclear whether PCr has influenced on mitochondrial energy metabolism as well as oxidative phosphorylation (OXPHO) in previous studies. Therefore, the aim of the present study was to investigate the regulation of PCr on lipopolsaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs) and mitochondrial OXPHO pathway. PCr protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c (Cyt C), Ca(2+), reactive oxygen species and subsequent activation of caspases, and increasing Bcl2 expression, while suppressing Bax expression. More importantly, PCr significantly improved mitochondrial swelling and membrane potential, enhanced the activities of ATP synthase and mitochondrial creatine kinase (CKmt) in creatine shuttle, influenced on respiratory chain enzymes, respiratory control ratio, phosphorus/oxygen ratio and ATP production of OXPHO. Above PCr-mediated mitochondrial events were effectively more favorable to reduced form of flavin adenine dinucleotide (FADH2) pathway than reduced form of nicotinamide-adenine dinucleotid pathway in the mitochondrial respiratory chain. Our results revealed that PCr protects against LPS-induced HUVECs apoptosis, which probably related to stabilization of intracellular energy metabolism, especially for FADH2 pathway in mitochondrial respiratory chain, ATP synthase and CKmt. Our findings suggest that PCr may play a certain role in the treatment of atherosclerosis via protecting endothelial cell function.