Phosphocreatine in Cardiac Surgery Patients: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: There is experimental evidence that phosphocreatine (PCr) can decrease ischemia/reperfusion injury of the heart. The authors investigated if PCr would improve heart performance as compared with standard treatment in cardiac surgery. DESIGN: Meta-analysis of randomized controlled trials. SETTING: Hospitals. PARTICIPANTS: Adult and pediatric patients undergoing cardiac surgery. INTERVENTIONS: The ability of PCr to improve cardiac outcomes as compared with standard treatment was investigated. MEASUREMENTS AND MAIN RESULTS: PubMed/Medline, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, WANGFANG DATA, and VIP Paper Check System were searched to March 1 2017. The authors included 26 randomized controlled trials comprising 1,948 patients. Random and fixed-effects models were used to estimate odds ratio (OR) and mean difference (MD) with 95% confidence interval (CI). PCr use was associated with reduced rates of intraoperative inotropic support (27% v 44%; OR 0.47, 95% CI 0.35-0.61; p < 0.001), major arrhythmias (16% v 28%; OR 0.44, 95% CI 0.27-0.69; p < 0.001), as well as increased spontaneous recovery of the cardiac rhythm immediately after aortic declamping (50% v 34%; OR 2.45, 95% CI 1.82-3.30; p < 0.001) as compared with standard treatment. The use of PCr decreased myocardial damage and augmented left ventricular ejection fraction in the postoperative period; however, MD for these outcomes were small and do not seem to be clinically significant. CONCLUSIONS: In randomized trials, PCr administration was associated with reduced rates of intraoperative inotropic support and major arrhythmias, and increased spontaneous recovery of the cardiac rhythm after aortic declamping. Large multicenter evidence is needed to validate these findings.

Creatine Phosphate Administration in Cell Energy Impairment Conditions: A Summary of Past and Present Research.

BACKGROUND: Creatine phosphate (CrP) plays a fundamental physiological role by providing chemical energy for cell viability and activity, especially in muscle tissue. Numerous pathological conditions, caused by acute or chronic ischaemic situations, are related to its deficiency. For these reasons, it has been used as a cardioprotective agent in heart surgery and medical cardiology for many years. OBJECTIVE: This article gives a brief overview of the main characteristics of exogenous CrP. METHODS: Previous review articles on CrP were screened for relevant information and references. Results from selected studies were reviewed and classified according to the topics in this review article and provided further interesting information on the pharmacological role of this molecule. RESULTS: Besides CrP's well known cell energy and function restoring properties, new evidence is emerging regarding its antioxidant and anti-apoptotic properties. Use of CrP is well established clinically as an intraoperative and perioperative adjuvant in heart operations (valve replacement, coronary artery bypass grafting, congenital heart defect repair), and as an additional agent in medical cardiology therapy for acute myocardial infarction and acute and chronic heart failure. In particular, there are promising potential new CrP uses in neurology, such as in cerebral ischaemia and hypoxic ischaemic encephalopathy. CONCLUSIONS: This review article describes the role of CrP treatment in cardiological indications, such as cardioprotection in cardioplegia and in myocardiopathies of various etiopathogenesis, as well as in other clinical indications such as skeletal muscle rehabilitation and neurological conditions.

[Metabolic correction of structural changes in adrenal glands during experimental widespread purulent peritonitis].

Experiments on 55 male chinchilla rabbits with model widespread purulent peritonitis have been performed for determinig structural changes in adrenal glands with the aid of optical microscopy. The introduction of aerobic-anaerobic culture of E. Coli and B. Fragilis into the abdominal cavity causes expressed structural changes in parenchyma of adrenal glands within 6 hours. It is established for the first time that the administration of metabolic drugs citoflavin (containing succinic acid) and neoton (containing creatine phosphate) prevents the development of pathological structural changes in adrenal glands under conditions of experimental widespread purulent peritonitis.

[Correction of bioenergetic processes in small intestine during experimental widespread purulent peritonitis].

The functional activity of mitochondria of the muscular coat of small intestine (MCSI) has been studied in the normal state and under experimental widespread purulent peritonitis (WPP) conditions. The experiments have been carried out on a group of 55 male rabbits of chinchilla breed. It is established that, as a result of the WPP development, the functional activity of mitochondria in MCSI considerably decreases. The comparative analysis of the efficiency of metabolic drugs cytoflavin and neoton showed advantage of the citoflavin preparation, the administration of which allowed the indices of mitochondria in intact animals to be exceeded on the fifth day of postoperative period. The research results show expediency of a complex treatment of WPP using cytoflavin preparation for the normalization of biological oxidation processes and elimination of enteric insufficiency.

[Metabolic immunocorrection treatment of experimental widespread purulent peritonitis].

The effect of citoflavin and neoton preparations on the migration activity of neutrophil granulocytes under action of mitogen-induced immunocompetent blood cells, Peyer's patches, spleen and inguinal lymph was studied on a group of 55 male chinchilla rabbits with experimental model of widespread purulent peritonitis. It is established that the regulating action of immunocompetent cells on the migration of neutrophil leukocytes under the conditions of widespread purulent peritonitis is stable and widespread process, which is observed within 5 days of the postoperative period. The use of citoflavin and neoton during the postoperative period produces correction of the activity of immunocompetent cells, changing their properties in regulation of the migratory activity of neutrophil granulocytes. The effect is characteristic of both preparations and it is observed in all investigated organs, being manifested to a greater degree in immunocompetent cells of peripheral blood and Peyer's patches. Metabolic preparation citoflavin exhibits a more pronounced immunotropic action in comparison to neoton, which contains creatine phosphate.

[Structural changes in heart at experimental widespread purulent peritonitis].

Structural changes in the heart are studied at an experimental widespread purulent peritonitis. It was established that in 6 hours after initiation of peritonitis in a myocardium the severe disorders of blood circulation, interstitial edema, the phenomena of kariopyknosis, development of systemic toxic damages specifying in high speed at this disease were observed. One of the mechanism of their development is a energy deficiency. The proof of this is destructive changes of cardiomyocytes mitochondria. The comparative analysis of use of metabolic preparations "Citoflavin", containing amber acid, and "Neoton", containing phosphocreatine, for the purpose of pharmacological support of cardiac activity at an experimental widespread purulent peritonitis has revealed high efficiency of the preparation "Citoflavin". It caused more intensive decrease of inflammatory changes in a myocardium, preventing of cardiomyocytes necrobiosis, contribution to preservation of normal structure and growth of quantity of mitochondria.

[Posthypoxic myocardial ischemia in newborn: diagnosis and treatment of severe type].

Were analyzed publications devoted to the problem of diagnostics and treatment of posthypoxia myocardial ischemia. A description and estimation of the pathophysiological processes occurring in children who had perinatal hypoxia. The analysis of changes in the myocardium, and violations of intracardiac hemodynamics in newborns with posthypoxia myocardial ischemia. Describes modern methods of treatment of myocardial ischemia, including use of phosphokreatinine as a cardiotrophic therapy.

[Metabolic correction of the lipid-transport system in experimental diffuse purulent peritonitis].

The research was performed in 55 male chinchilla rabbits. For the first time the effect of metabolic preparations "citoflavin" and "neoton" of the protein-lipid spectrum of blood was studied in experimental diffuse purulent peritonitis. The development of diffuse purulent peritonitis caused negative changes in blood lipid-transport system which resulted in a decreased blood protein level and high density lipoproteins (HDL) and growth of triglycerides. In the HDL phospholipid spectrum the pathological changes are characterized by an increased lisophosphotide content and compensatory growth of the level of poliglycerophosphatides. A comparative analysis has shown that both preparations possess unidirectional action which is more pronounced in "citoflavin" than in "neoton".

[Pharmacokinetics and metabolic disposition of exogenous phosphocreatine in rats].

This article is report the study of the pharmacokinetics and metabolic disposition of exogenous phosphocreatine (PCr) in rats by means of an ion-pair HPLC-UV assay. PCr and its metabolite creatine (Cr) and related-ATP in rat plasma and red blood cell (RBC) were simultaneously determined. A blank plasma and RBC were initially run for baseline subtraction. Plasma and RBC samples were deproteinized with 6% PCA prior to HPLC. Following i.v. administration of PCr 500 mg x kg(-1) and 1 000 mg x kg(-1) the C-T curve could be described by the two-compartment model with t1/2beta 22.5-23.3 min, V(d) 0.956 4-0.978 6 L x kg(-1), CL 0.029 L. kg(-1) x min(-1). The Cr as PCr degraded product appeared as early as 2 min post i.v. dosing with t(max) 20 min, t1/2kappa (m) 40.6-42.7 min and f(m) 60%-76%. After po administration of PCr, the parent drug in plasma was undetectable, but the metabolite Cr was detected with t(max) 65-95 min, t1/2kappa (m) 56.0-57.7 min, metabolite-based bioavailability F(m) 55.02%-62.31%. PCr i.v. administration resulted in significant elevation of ATP level in RBC but not in plasma, the related-ATP in RBC was characterized by t(max) 68-83 min, t1/2kappa 49-52 min. In RBC no exogenous PCr was found but Cr was detected following i.v. administration of PCr, with the t(max) 120 min and t1/2k (m) 70 min for Cr. The above results indicate that PCr eliminates and bio-transforms in body very rapidly; K > K(m) confers ERL, instead of FRL, type upon the metabolic disposition of Cr. Following po administration of PCr, the degraded product Cr is absorbed but not the parent drug PCr. The formed Cr can be accounted for by most of i.v. and po PCr. Intravenous dosing leads apparently increased and sustained Cr and related-ATP concentration in RBC.

The myocardial protective effect of monosodium phosphate cardioplegia in cardiopulmonary bypass in infants with an atrial septal defect.

This study aimed to investigate the myocardial protective effect of liquid sodium phosphocreatine cardiac arrest in extracorporeal circulation surgery treating infants with atrial septal defects.Eighty-four infants with atrial septal defects who required extracorporeal circulation surgery treatment at our hospital from January 2016 to June 2018 were divided into an observation group and a control group through a digitally randomized method, with 42 cases in each group. The control group adopted the conventional modified St Thomas II high potassium cold liquid crystal cardiac arrest, while the observation group adopted the liquid sodium phosphocreatine cardiac arrest.The myocardial enzyme indexes of the 2 groups 3, 6, 12, and 24 hours postoperatively were higher than before establishing the cardiopulmonary bypass and the enzyme indexes of the control group at the same time were higher than that of the observation group; adenosine triphosphate, adenosine diphosphate, and other energy levels and the postoperative recovery rate energy levels of the observation group were higher than those in the control group, the difference was statistically significant (P < .05).Liquid sodium phosphocreatine cardiac arrest used in extracorporeal circulation surgery treating infants with atrial septal defects can reduce myocardial ischemia-reperfusion injury, maintain energy supply during ischemia, strengthen the St Thomas II effect, and aid postoperative cardiac function recovery of high potassium cold liquid crystal cardiac arrest used in infants with atrial septal defects and treated with extracorporeal circulation surgery.

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.

Intravenous administration of adenosine triphosphate and phosphocreatine combined with fluoxetine in major depressive disorder: protocol for a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Major depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50-75% of patients have a treatment response but require 4-6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD. METHODS: This is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items. DISCUSSION: In our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation. TRIAL REGISTRATION: NCT03138681 . Registered on 3 May 2017. First patient: 4 May 2017.

Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis.

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-ß1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.

Effect of thirty days of creatine supplementation with phosphate salts on anaerobic working capacity and body weight in men.

The purpose of this study was to determine the effect of 30 days of single-dose creatine supplementation with phosphate salts (CPS) on body weight (BW) and anaerobic working capacity (AWC) in men. Using a double-blind design, 32 men randomly received 1 serving of either CPS (5 g Cr + 4 g phosphate) (n = 17) or 20 g of dextrose as placebo (PL) (n = 15) for 30 days. AWC determined from the Critical Power Test and BW were measured at baseline, 10 days, 20 days, 30 days, and 10 days post-supplementation. Results (2 x 5 ANOVA) showed no significant differences between groups for AWC at any time point; however, BW was significantly increased at 10 days in the CPS group (1.0 kg) vs. PL (0.0 kg), and remained elevated for the duration of the study. These findings suggest that a single 5 g x d(-1) dose of CPS for 30 days increases BW but is not effective for increasing AWC in men.

Creatine phosphate administration preserves myocardial function in a model of off-pump coronary revascularization.

AIM: Off pump coronary artery bypass grafting (OPCAB) involves, and is occasionally impaired by obligatory regional myocardial ischemia, particularly with the use of proximal coronary in-flow occlusion techniques. Intracoronary shunts do not guarantee absence of distal ischemia given their small inner diameter and the presence of proximal coronary stenosis. Additional adjunctive measures to provide short-term myocardial protection may facilitate OPCAB. High-energy phosphate supplementation with creatine phosphate prior to ischemia may attenuate ischemic dysfunction. METHODS: In a rodent model of a transient coronary occlusion and myocardial ischemia, 36 animals underwent preischemic intravenous infusion of either creatine phosphate or saline, 10 minutes of proximal left anterior descending (LAD) occlusion, and 10 minutes of reperfusion. Rats underwent continuous intracavitary pressure monitoring and cellular ATP levels were quantified using a luciferin/luciferase bioluminescence assay. RESULTS: Within 2 minutes of ischemia onset, creatine phosphate animals exhibited statistically significant greater preservation of myocardial function compared to controls, an augmentation which persisted throughout the duration of ischemia and subsequent reperfusion. Furthermore, significantly greater cellular ATP levels were observed among creatine phosphate treated animals (344+/-55 nMol/g tissue, n=5) compared to control animals (160+/-9 nMol/g tissue, n=5)(p=0.014). CONCLUSIONS: A strategy of intravenous high-energy phosphate administration successfully prevented ischemic ventricular dysfunction in a rodent model of OPCAB.

The effect of exogenous creatine phosphate on myocardial injury after percutaneous coronary intervention.

OBJECTIVE: To evaluate the effect of exogenous creatine phosphate (CP) on myocardial injury after percutaneous coronary intervention (PCI). METHOD: Four hundred patients were divided to receive conventional therapy (control group) or 3-day intravenous infusion of CP after PCI (CP group). Levels of creatine kinase MB (CK-MB) and troponin I (TnI) were measured before and on postprocedural day 3. RESULTS: Postprocedural CK-MB and TnI in the CP group were significantly increased compared to the control group. In the CP group, 8.0% and 5.0% of patients had an increase in CK-MB 1 to 3 times and >3 times, respectively, which were significantly lower than that of the control group (19.0% and 9.0%, respectively); 12.0% and 10.0% of patients had an increase in TnI 1 to 3 times and >3 times, respectively, which were significantly lower than that of the control group (21.0% and 18.0%, respectively). CONCLUSION: Exogenous CP was helpful to reduce myocardial injury after PCI.

Creatine supplementation during resistance training in college football athletes.

PURPOSE: This investigation assessed the effects of a 9-wk regimen of creatine monohydrate (Cr x H2O) supplementation coupled with resistance training on body composition and neuromuscular performance in NCAA Division I football athletes. METHODS: Twenty-five subjects were randomly assigned in a double-blind, randomized placebo-controlled design, to a treatment (Cr, N = 9), placebo (P, N = 8), or control group (C, N = 8). The Cr group received 20 g.d(-1) of creatine for the first 5 d in 5-g doses, four times daily, followed by 5 g.d(-1) for the remainder of the study. Each 5-g dose was mixed with 500 mL of glucose solution (Gatorade). The P group received a placebo (sodium phosphate monohydrate; NaH2PO4 x H2O) following the exact protocol as the Cr group. The C group received no supplementation. All subjects resistance trained 4 d.wk(-1). Measurements of neuromuscular performance and body composition were made pre- and post-training after supplementation while monitoring dietary intakes. RESULTS: Repeated measures ANOVA indicated significant differences occurred between the Cr group and the other two groups (P and C) for total body weight, lean body mass, cell hydration, strength, peak torque at 300 degrees.s(-1) knee flexion, percent torque decrement, and anaerobic power and capacity. However, percent body fat, peak torque during both knee flexion and extension at 60 and 180 degrees.s(-1), peak torque at 300 degrees.s(-1) during knee extension, global muscular strength (power clean), and extracellular fluid remained statistically unchanged for all groups. CONCLUSIONS: Our findings indicate that creatine, supplemented concurrently with resistance and anaerobic training, may positively affect cell hydration status and enhance performance variables further than augmentation seen with training alone.

Creatine phosphate (Neoton) as an additive to St. Thomas' Hospital cardioplegic solution (Plegisol). Results of a clinical study.

Experimentally, creatine phosphate (CP) added to St. Thomas' Hospital cardioplegic solution (STH) improved post-ischaemic recovery of cardiac function in the rat heart. We investigated the effect of adding CP (10.0 mmol/l) to STH. Fifty open-heart surgery patients were randomized into control (STH) and treated (STH + CP) groups (25 per group). Patients underwent (a) monitoring for peri- and postoperative arrhythmias (48-h Holter monitoring). (b) quantitative birefringence assessment of intraoperative myocardial protection in left and right ventricular biopsies sampled at start of bypass (pre-isch.), end of bypass (end-isch.) and after 10 min reperfusion (post-isch.), and (c) measurement of serum creatine kinase-MB isozyme (CK-MB) values for up to 4 days postoperatively; results were assessed with respect to (d) haemodynamics and postoperative clinical outcome. Inotropic support (adrenaline) was required in three patients (12%) from each group; no patient died. All patients required defibrillation, and the number of direct current shocks required for sinus rhythm was the same in each group. The occurrence and incidence of reperfusion-induced arrhythmias were the same in both groups. Serum CK and CK-MB values were similar throughout the sampling period in both groups of patients; one patient in the control group had raised CK-MB levels postoperatively, but perioperative infarction was not indicated by the electrocardiogram.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of oral phosphocreatinine on human skeletal muscle shown by in vivo 31P-NMR.

We used the non-invasive method of in vivo phosphorus magnetic resonance spectroscopy to investigate the effect of oral administration of phosphocreatinine on muscle energy metabolism during graded work and post-exercise recovery in humans. Phosphocreatinine administration results in a smaller depletion of phosphocreatine at high work rates accompanied by a smaller cytosolic acidification during work and recovery. Our findings suggest that oral phosphocreatinine increases the readily available energy for muscle contraction by interfering directly or indirectly with the reaction equilibria involving phosphocreatine.

Antitumor activity of creatine analogs produced by alterations in pancreatic hormones and glucose metabolism.

When rats bearing the 13,762 mammary carcinoma were treated with intravenously administered creatine analogs, cyclocreatine, beta-guanidinopropionic acid or creatine phosphate on days 4 through 8 and 14 through 18 post tumor implantation, the tumor growth delay produced varied with whether the animals were drinking water or sugar water over the course of the study. The tumor growth delays increased when the animals drank sugar water from 9.3, 1.6 and 7.6 days for cyclocreatine, beta-guanidinopropionic acid and creatine phosphate, respectively, to 15.0, 6.3 and 12.6 days. Blood glucose was decreased over the course of the creatine analog treatment regimen and the skeletal muscle transport protein GLUT-4 increased 1.5 to 2-fold with the creatine analog treatments. Plasma insulin was profoundly decreased to 20-25% of normal by the creatine analog treatment while plasma glucagon levels were increased. Plasma somatostatin increased 3- to 4-fold during the administration of the creatine analogs. These results implicate alterations in pancreatic hormone balance in the antitumor activity of these creatine analogs.