CoQ10 Levels Research Articles

Investigation of ischemia modified albumin and coenzyme Q10 levels in obese children with metabolic syndrome

Abstract Introduction The aim of this study was to analyze serum ischemia modified albumin (IMA) and plasma CoQ10 levels and to evaluate their correlation with insulin resistance (homeostatic model assessment, HOMA) and lipid profile in obese children with and without metabolic syndrome (MS). Methods Thirty-one obese with MS, 30 obese without MS and 34 healthy children aged 6–18 years were included in the study. Serum IMA was measured by colorimetric method, plasma CoQ10 levels were measured by HPLC. Serum glucose, total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol and insulin were analyzed. Results IMA levels were found to be significantly higher (p<0.001) while the CoQ10 levels were significantly lower (p<0.001) in obese children with and without MS compared to controls. IMA and CoQ10 significantly correlated with each other and metabolic parameters. Furthermore, IMA and CoQ10 levels did not significantly differ between obese children with and without MS, while glucose, insulin levels and HOMA were significantly higher (p<0.001) in obese children with MS than obese without MS and controls. Conclusions Based on the high levels of IMA, low CoQ10 and association with HOMA and lipid profile; we suggest that obese children may have oxidative damage, lipid peroxidation and cardiometabolic risk.

Coenzyme Q10 and Utility in Heart Failure: Just Another Supplement?

Heart failure affects 5.1 million people in the USA annually. It accounts for a frequent cause of hospitalizations and disability. Patients with congestive heart failure have lower plasma levels of CoQ10, which is an independent predictor of mortality in this patient population. It has been hypothesized that a deficiency of CoQ10 can play a role in the development and worsening of heart failure, and that oral supplementation can possibly improve symptoms and survival in these patients. Based on previous small studies and meta-analyses, the use of CoQ10 in heart failure suggested an improvement ejection fraction, stroke volume, cardiac output, and cardiac index with CoQ10 supplementation, however most of these small studies appeared to be underpowered to result in any significant data. The results of the recent Q-SYMBIO trial demonstrated an improvement in heart failure symptoms with a significant reduction in major adverse cardiovascular events and mortality.

The effect of coenzyme Q10 on venous ischemia reperfusion injury

BackgroundCoenzyme Q10 (CoQ10) is a lipid-soluble benzoquinone with antioxidant features that make it important in the treatment of ischemia reperfusion injury. In this study, we aimed to investigate the beneficial effect of CoQ10 in the treatment of venous ischemia/reperfusion injury. MethodsEighteen Sprague–Dawley male rats were randomly divided into two equal groups: the control group and an experimental group (n = 9 rats). The experimental group received CoQ10 orally, and the control group received a control diet for 8 wk. An inferior epigastric island flap was raised, and the inferior epigastric vein was clamped for 9 h; the flap was then reperfused. All rats were sacrificed on postoperative day 5. The flap survival rate and levels of CoQ10, malondialdehyde, glutathione, and superoxide dismutase were assessed, and flap tissues were examined under a light microscope (×200 magnification) after being stained with Hematoxylin & Eosin. ResultsThe flap survival rate and levels of CoQ10, glutathione, and superoxide dismutase were significantly higher, but level of malondialdehyde was lower in the experimental group. The mean flap survival rates and plasma levels of CoQ10 were 51% ± 24% and 251 ± 11 ng/mL in the control group, whereas they were 88% ± 7% and 692.8 ± 79.7 ng/mL in the experimental group with statistically significant differences (P < 0.001). Polymorphonuclear leukocyte infiltration was higher, and surface epithelial integrity was more impaired in the control group. ConclusionsWe concluded that CoQ10 supplementation has a beneficial effect on venous ischemia and/or reperfusion injury and improves flap survival rate.

Disruption of the human COQ5-containing protein complex is associated with diminished coenzyme Q10 levels under two different conditions of mitochondrial energy deficiency

BackgroundThe Coq protein complex assembled from several Coq proteins is critical for coenzyme Q6 (CoQ6) biosynthesis in yeast. Secondary CoQ10 deficiency is associated with mitochondrial DNA (mtDNA) mutations in patients. We previously demonstrated that carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) suppressed CoQ10 levels and COQ5 protein maturation in human 143B cells. MethodsThis study explored the putative COQ protein complex in human cells through two-dimensional blue native-polyacrylamide gel electrophoresis and Western blotting to investigate its status in 143B cells after FCCP treatment and in cybrids harboring the mtDNA mutation that caused myoclonic epilepsy with ragged-red fibers (MERRF) syndrome. Ubiquinol-10 and ubiquinone-10 levels were detected by high-performance liquid chromatography. Mitochondrial energy status, mRNA levels of various PDSS and COQ genes, and protein levels of COQ5 and COQ9 in cybrids were examined. ResultsA high-molecular-weight protein complex containing COQ5, but not COQ9, in the mitochondria was identified and its level was suppressed by FCCP and in cybrids with MERRF mutation. That was associated with decreased mitochondrial membrane potential and mitochondrial ATP production. Total CoQ10 levels were decreased under both conditions, but the ubiquinol-10:ubiquinone-10 ratio was increased in mutant cybrids. The expression of COQ5 was increased but COQ5 protein maturation was suppressed in the mutant cybrids. ConclusionsA novel COQ5-containing protein complex was discovered in human cells. Its destabilization was associated with reduced CoQ10 levels and mitochondrial energy deficiency in human cells treated with FCCP or exhibiting MERRF mutation. General significanceThe findings elucidate a possible mechanism for mitochondrial dysfunction-induced CoQ10 deficiency in human cells.

Omega-3 LCPUFA supplement: a nutritional strategy to prevent maternal and neonatal oxidative stress.

There is controversy about fish-oil supplementation and oxidative damage. This ambiguity should be explored to elucidate its role as modulator of oxidative stress, especially during gestation and postnatal life. This is the objective of this study. One hundred ten pregnant women were divided in two groups: control group CT (400 mL/day of the control dairy drink); supplemented group FO (400 mL/day of the fish oil-enriched dairy drink (±400-mg EPA-DHA/day)). Different biomarkers of oxidative damage were determined in the mother's at enrolment, at delivery and at 2.5 and 4 months postpartum and newborns at delivery and at 2.5 months postpartum. Omega-3 LC-PUFA supplementation during pregnancy and lactation decreased plasma hydroperoxides especially in newborn at delivery (P = 0.001) and 2.5 months (P = 0.006), increased superoxide dismutase (SOD) and catalase (CAT) in mothers at delivery (P = 0.024 (SOD)) and after 2.5 months (P = 0.040 (CAT)) and in newborns at 2.5 months (P = 0.035 (SOD); P = 0.021 (CAT)). Also, supplementation increased α-tocoferol in mothers at 2.5 months (P = 0.030) and in umbilical cord artery (P = 0.039). Higher levels of CoQ10 were found in mothers at delivery (P = 0.039) as well as in umbilical cord vein (P = 0.024) and artery (P = 0.036). Our supplementation prevents the oxidative stress in the mother and neonate during the first months of postnatal life, being a potential preventive nutritional strategy to prevent functional alterations associated with oxidative stress that have an important repercussion for the neonate development in the early postnatal life.

Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes.

BackgroundCoenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease.ResultsTo determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease.ConclusionsOur study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BackgroundCoenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress.MethodsWe performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships.ResultsFifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study.ConclusionsCoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis.Trial RegistrationThis clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009.

Characterization of Proteins Associated with the Coenzyme Q Biosynthetic Complex and Analyses of Phosphorylated Coq Proteins in Yeast Mitochondria

Coenzyme Q (also termed ubiquinone or CoQ) is an electron carrier in the mitochondrial respiratory chain that functions as an essential component in energy metabolism and serves as a vital lipid soluble antioxidant. Patients with CoQ defects suffer from various health disorders, such as kidney disease, neurodegenerative diseases, ataxia, and cardiovascular complications. Additionally, aging has also been linked to decreased CoQ levels. Saccharomyces cerevisiae serves as an excellent model for studies on CoQ biosynthesis and function because it is both a simple model and is highly conserved with respect to human CoQ biosynthesis. In yeast, several of the eleven proteins (Coq1p‐Coq9p, Yah1p, and Arh1p) necessary for the biosynthesis of CoQ6 have been shown to be associated in a high molecular mass complex that localizes in the inner mitochondrial membrane, and has been termed the 'CoQ‐synthome'. Here we identify other potential protein partners that co‐purify with several of the Coq polypeptides and appear to be required for efficient Q biosynthesis. We use co‐immunoprecipitation techniques, Western blotting, blue native PAGE, lipid analysis, yeast cell growth assays, phosphorylation enrichment, and liquid chromatography‐tandem mass spectrometry to identify novel associated proteins and phosphorylation modifications sites of the Coq polypeptides. Elucidating their biosynthetic role in regulatory processes, such as phosphorylation, will aid our understanding and treatment of multiple diseases caused by CoQ‐deficiencies and will provide novel insight regarding longevity and issues related to aging in humans.

The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene.

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype–phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9Q95X and Coq9R239X), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9Q95X mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9R239X mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype–phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

Hplc estimation of coenzyme Q(10) redox status in plasma after intravenous coenzyme Q(10) administration

The pharmacokinetics of the total pool of coenzyme Q(10) (Co(10)), its oxidized (ubiquinone) and reduced (ubiquinol, CoQ(10)H₂) forms have been investigated in rats plasma during 48 h after a single intravenous injection of a solution of solubilized CoQ(10) (10 mg/kg) to rats. Plasma levels of CoQ(10) were determined by HPLC with spectrophotometric and coulometric detection. In plasma samples taken during the first minutes after the CoQ(10) intravenous injection, the total pool of coenzyme Q(10) and proportion of CoQ(10)H₂ remained unchanged during two weeks of storage at -20°C. The kinetic curve of the total pool of coenzyme Q(10) corresponds to a one-part model (R² = 0.9932), while the corresponding curve of its oxidized form fits to the two-part model. During the first minutes after the injection a significant portion of plasma ubiquinone undergoes reduction, and after 7 h the concentration of ubiquinol predominates. The decrease in the total plasma coenzyme Q(10) content was accompanied by the gradual increase in plasma ubiquinol, which represented about 90% of total plasma CoQ(10) by the end of the first day. The results of this study demonstrate the ability of the organism to transform high concentrations of the oxidized form of CoQ(10) into the effective antioxidant (reduced) form and justify prospects of the development of parenteral dosage forms of CoQ(10) for the use in the treatment of acute pathological conditions.

MYOPATHY AS A SIDE EFFECT OF STATIN THERAPY: MECHANISMS OF DEVELOPMENT AND PROSPECTS FOR TREATMENT

Statins are lipid-lowering drugs with proven efficacy that reduce cardiovascular risk and are well tolerated by most patients. Myopathy as a side effect of statin therapy is one of the most common reasons for their withdrawal. Its severity can range from asymptomatic increase of serum CPK to life-threatening rhabdomyolysis. Therefore it is necessary to remember about the possibility of its occurrence. The exact molecular mechanisms of muscle damage by statins are still unknown. Various hypotheses are suggested in this respect: fatty acid oxidation disorders, mitochondrial dysfunction, increased protein degradation in myocytes due to changes in atrogin-1 and ubiquitin activity, activation of autoimmune processes, intracellular depletion of essential metabolites, destabilization of cell membranes, impaired expression of genes involved in apoptosis and protein degradation. The theory that the reduction of intramuscular CoQ10 level is the cause of myopathy prevails. Additional intake of CoQ10 seems promising, but is not evidence-based.

Amniotic coenzyme Q10: is it related to pregnancy outcomes?

Coenzyme Q10 (CoQ10 or ubiquinone) is an essential component of the mitochondrial electron transport chain and is also present in various cellular membranes and in plasma lipoproteins. Diabetes, cardiovascular, neurodegenerative, and preeclampsia diseases are all associated with an alteration of CoQ10 level or its redox status. During pregnancy, we note that the plasma content of CoQ10 is significantly higher than amniotic. In the fetal growth restriction group, amniotic total CoQ10 levels were significantly higher versus healthy, while the amniotic oxygen radical absorbing capacity level was significantly lower. A significant negative correlation was observed between amniotic total CoQ10 and birthweight. Our observation leads to the hypothesis that the amniotic midtrimester CoQ10 content may be a marker of subsequent obstetric complications.

Epicardial fat tissue thickness is correlated with diminished levels of co-enzyme Q10, a major antioxidant molecule among hemodialysis patients

ObjectivesAccelerated atherosclerosis is the major cause of mortality in patients on chronic maintenance hemodialysis (HD). Epicardial fat tissue (EFT) is a new risk factor in cardiovascular disease (CVD). The aim of this study was to evaluate the relation between plasma coenzyme Q10 levels (Co-Q10) which is a potent physiologic antioxidant and EFT thickness in HD patients. Design and methodsSeventy one chronic HD patients and 65 age and sex matched healthy individuals were included in the study. Plasma Co-Q10 levels were performed by high-performance liquid chromatography (HPLC) measurements. EFT was measured by transthoracic echocardiograpy (TTE) performed with a VIVID 7 instrument. ResultsPlasma Co-Q10 levels (1.36±0.43 vs 2.53±0.55, p<0.001) were significantly lower in HD patients compared to controls. EFT was significantly increased in HD patients compared to healthy controls (6.53±1.01 vs. 5.79±1.06mm respectively, p<0.001). Correlation analysis showed that plasma Co-Q10 levels were inversely correlated with EFT (r=−0.263, p<0.05). Multiple linear regression analysis was used to define independent determinants of EFT in HD patients. According to linear regression analysis, age, BMI, total cholesterol and Co-Q10 levels were found to be independent predictors of EFT (adjusted r2=0.38, p<0.001). ConclusionThis study demonstrated that EFT thickness was significantly higher among HD patients compared to healthy controls. In addition; this study was the first to demonstrate an inverse correlation between EFT thickness and Co-Q10 levels in this patient population.

Effects of various squalene epoxides on coenzyme Q and cholesterol synthesis

2,3-Oxidosqualene is an intermediate in cholesterol biosynthesis and 2,3:22,23-dioxidosqualene act as the substrate for an alternative pathway that produces 24(S),25-epoxycholesterol which effects cholesterol homeostasis. In light of our previous findings concerning the biological effects of certain epoxidated all-trans-polyisoprenes, the effects of squalene carrying epoxy moieties on the second and third isoprene residues were investigated here. In cultures of HepG2 cells both monoepoxides of squalene and one of their hydrolytic products inhibited cholesterol synthesis and stimulated the synthesis of coenzyme Q (CoQ). Upon prolonged treatment the cholesterol content of these cells and its labeling with [3H]mevalonate were reduced, while the amount and labeling of CoQ increased. Injection of the squalene monoepoxides into mice once daily for 6days elevated the level of CoQ in their blood, but did not change the cholesterol level. The same effects were observed upon treatment of apoE-deficient mice and diabetic GK-rats. This treatment increased the hepatic level of CoQ10 in mice, but the amount of CoQ9, which is the major form, was unaffected. The presence of the active compounds in the blood was supported by the finding that cholesterol synthesis in the white blood cells was inhibited. Since the ratio of CoQ9/CoQ10 varies depending on the experimental conditions, the cells were titrated with substrate and inhibitors, leading to the conclusion that the intracellular isopentenyl-PP pool is a regulator of this ratio. Our present findings indicate that oxidosqualenes may be useful for stimulating both the synthesis and level of CoQ both in vitro and in vivo.

A comparative study into alterations of coenzyme Q redox status in ageing pigs, mice, and worms

Coenzyme Q derivatives (CoQ) are lipid soluble antioxidants that are synthesized endogenously in almost all species and function as an obligatory cofactor of the respiratory chain. There is evidence that CoQ status is altered by age in several species. Here we determined level and redox-state of CoQ in different age groups of pigs, mice and Caenorhabditis elegans. Since these species are very different with respect to lifespan, reproduction and physiology, our approach could provide some general tendencies of CoQ status in ageing organisms. We found that CoQ level decreases with age in pigs and mice, whereas CoQ content increases in older worms. As observed in all three species, ubiquinone, the oxidized form of CoQ, increases with age. Additionally, we were able to show that supplementation of ubiquinol-10, the reduced form of human CoQ10 , slightly increases lifespan of post-reproductive worms. In conclusion, the percentage of the oxidized form of CoQ increases with age indicating higher oxidative stress or rather a decreased anti-oxidative capacity of aged animals.

Serum Coenzyme Q10 Levels and Oxidative Status in Patients with Fibromyalgia Syndrome

Objectives: The aim of this study was to determine the relationship between serum coenzyme Q10 [CoQ10] levels and symptoms of fatigue associated with fibromyalgia syndrome [FMS].Methods: Patients diagnosed with primary FMS and domographically matching healthy normal controls [HNCs] were sought to participate in the study. The total antioxidant status, total oxidative status, and CoQ10 levels were measured in blood samples from the patients and the controls.Results: A total of 40 patients with FMS and 30 HNCs were recruited. There were no statistically significant differences between the two groups in regard to C-reactive protein, mean erythrocyte sedimentation rate, mean age, and mean body mass index [p > 0.05]. The mean time from symptom onset to diagnosis for the FMS patients was 2.88 years, and the average number of tender points was 14. The serum CoQ10 levels were significantly lower in the FMS patients compared with the HNC group [p = 0.000]. The serum total oxidative status and oxidative stress index levels were higher, and the serum total antioxidant status levels were lower in the FMS patients compared with those of the HNC group [p < 0.05]. The visual analog scale [VAS] pain scores and the VAS fatigue scores were significantly higher in the FMS group than in the HNC group [p = 0.000]. The serum CoQ10 levels were negatively correlated with the mean Modified Fatigue Impact Scale scores [p = 0.02, r = 0.30], VAS pain scores [p = 0.00, r = 0.38], and VAS fatigue scores [p = 0.03, r = 0.28].Conclusions: The CoQ10 deficiency may contribute to the etiopathogenesis of FMS fatigue.

Cardioprotection with Intravenous Injection of Coenzyme Q10 is limited by Time of Administration after Onset of Myocardial Infarction in Rats

Objective: Coenzyme Q 10 (CoQ 10 ) levels are decreased in patients with cardiovascular diseases. The bioavailability of orally ingested CoQ 10 is limited to 2–3%, and long-term administration is required to increase the level of CoQ10 in myocardium for cardioprotection. Intravenous (IV) administration of solubilized CoQ10 immediately after coronary occlusion has been shown to increase myocardial levels rapidly and to protect against cardiac ischemia. The aim of this study was to determine the length of time following onset of myocardial infarction (MI) for which a single IV administration of CoQ 10 was cardioprotective. Methods: A single IV injection of solubilized CoQ10 (30 mg/kg, 1 ml/kg) or saline (1 ml/kg) was administered at either minute 60 or minute 180 after the onset of MI induced by coronary artery ligation in rats. Results: Twenty-one days after injection, CoQ 10 levels were still high in both the 60 and 180 minute groups. Rats treated with CoQ10 60 min after ligation had a significantly larger mass of viable left ventricle (LV) myocardium, limited LV dilatation, and improved cardiac contractile and relaxation capacity compared with controls. CoQ10 levels were significantly correlated with LV end-systolic volume (r=-0.65), end-diastolic volume (r=-0.56), ejection fraction (r-=0.67), and LV relaxation (r=-0.64) (p<0.001). IV administration of CoQ 10 180 min after occlusion prevented signs of right ventricle hypertrophy but did not limit LV damage. Conclusion: A single IV injection of solubilized CoQ 10 (30 mg/kg) at minute 60 effectively limited LV damage and deterioration of function after coronary ligation in rats; however, the same protective effects were not seen with CoQ 10 injection administered at minute 180.

Parenteral CoQ10 Formulation (BPM31510) Significantly Improves Survival In Animal Model Of Leukemia Including The Resolution Of Paraplegia Due To Brain Metastasis

Abstract Leukemia cells exhibit alterations in intermediary metabolism similar to other cancers, wherein ATP sourcing is shunted from mitochondrial oxphos towards glycolytic preponderance (Warburg Effect) to meet oncogenic proliferative demands. A consequence of this metabolic switch is the simultaneous short-circuit of the programmed death pathways, leading to a immortalization program in cancer cells including leukemia. Delivery of high levels of CoQ10 in a lipid nanodispersion mixture (BPM31510) has been demonstrated to preferentially shift metabolic networks from glycolysis towards mitochondrial-centric oxphos and recapitulation of apoptotic pathways in various cancers in vitro and in vivo models. Given the centrality of the Bcl-2 involvement in the etiology of leukemia, this study focused on investigation of the effectiveness of BPM31510 in animal models of erythroid and myeloid leukemia. Human acute erythro-leukemia (K562) and acute myeloid leukemia (KG1) models were developed in immune-compromised mice. The mice (total n=120 for each model respectively) were randomized into four (n=30/group) treatment groups: Untreated (control); BPM31510 (75 mg/kg, once/day); chemotherapy (Adriamycin [5mg/kg; once/wk]+AraC [25mg/kg; 5 days] and BPM31510+chemotherapy. All dosing were intravenous and followed a protocol of 3wk treatment followed by 1wk rest. In both leukemia models, combination of BPM31510 with chemotherapy was associated with significant increase in survival compared to other groups. BPM31510 alone improved survival compared to chemotherapy in myeloid leukemia, not in erythroleukemia model. In a separate study, a rat (Fisher 344) chloroleukemia (MIA C51) model of CNS leukemia was developed that demonstrated paraplegia and urinary retention as a result of brain metastasis. Administration of BPM31510 (50 mg/kg/day, IP) was associated with complete resolution of limb paralysis demonstrating the ability of BPM31510 in penetrating into the CNS. Moreover, BPM31510 (50 mg/kg/day, IP) administration was associated with significant increase in survival in animals with metastasis to the lungs and liver. The data provides encouraging evidence of the potential translational use of CoQ10 containing BPM31510 in the treatment of leukemia. A Phase 1 study in relapse acute leukemia is to be started shortly. Disclosures: Narain: Berg: Employment. Akmaev:Berg: Employment. Benaim:Berg: Employment. Sarangarajan:Berg: Employment. Jimenez:Berg: Membership on an entity’s Board of Directors or advisory committees.

Effect of cooking and in vitro digestion on the stability of co-enzyme Q10 in processed meat products

The use of CoQ10 fortification in the production of a functional food has been demonstrated in the past but primarily for dairy products. This study aimed to determine the bio-accessibility of CoQ10 in processed meat products, beef patties and pork breakfast sausages, fortified with CoQ10. Both the patties and sausages were fortified with a micellarized form of CoQ10 to enhance solubility to a concentration of 1mg/g of sample (NovaSolQ®). An assay was developed combining in vitro digestion and HPLC analysis to quantify the CoQ10 present in fortified products (100mg/g). The cooking retention level of CoQ10 in the products was found to be 74±1.42% for patties and 79.69±0.75% for sausages. The digestibility for both products ranged between 93% and 95%, sausages did have a higher digestibility level than patties but this was not found to be significant (P<0.01).

P.17.10 New ETFDH mutations in a group of Italian patients with Riboflavin-Responsive Multiple Acyl-CoA Dehydrogenase Deficiency (RR-MADD)

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a rare autosomal recessive disorder of the electron transfer flavoproteins. Three clinical forms have been described: two with neonatal onset (I and II), and a late-onset form (type III). Type III patients manifest with proximal myopathy, sometimes with hepatomegaly and encephalopathy. Mutations in ETFDH has been often associated with a Riboflavin response in those patients. We report, herein, clinical, biochemical and molecular genetic features in five Italian RR-MADD patients. Clinically, all patients variably presented with acute recurrent episodes of myalgias, exercise intolerance, rhabdomyolysis and proximal muscle weakness. Serum CK was elevated (from 1000 to 8000 UI/L) as well as lactacidemia. Medium- and long-chain acyl carnitines were increased in all subjects. Muscle biopsy showed a vacuolar myopathy with lipid storage. Total and free muscle carnitines were reduced whereas muscle CoQ10 levels were normal. Oral Riboflavin treatment (400 mg/die) resulted in a dramatic improvement of clinical conditions of all patients. Mutational analysis of ETFDH identified seven novel mutations: 5 missense mutations, a 2-base-pair deletion in the coding region and one splice-site mutation. Our data confirm that blood acylcarnitine profile are sensitive and predictive markers for MADD diagnosis whereas muscle CoQ10 levels may be normal. We identified seven novel ETFDH mutations, all located in conserved domains. These new changes were distinct from the others described in previous reported cases but, also our group of patients, dramatically responded to Riboflavin administration.