A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene.

Lipid storage myopathy (LSM) is a heterogeneous group of lipid metabolism disorders predominantly affecting skeletal muscle by triglyceride accumulation in muscle fibers. Riboflavin therapy has been shown to ameliorate symptoms in some LSM patients who are essentially concerned with multiple acyl-CoA dehydrogenation deficiency (MADD). It is proved that riboflavin responsive LSM caused by MADD is mainly due to ETFDH gene variant (ETFDH-RRMADD). We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro, FLAD1-RRMADD). And we compared our patient together with 9 FLAD1-RRMADD cases from literature to 106 ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study on FLAD1-RRMADD and ETFDH-RRMADD were carried out. On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequent in ETFDH-RRMADD, while fibers with faint COX staining were more common in FLAD1-RRMADD. Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups. Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.

Methylcrotonyl-CoA carboxylase subunit 1 (MCCA) regulates multidrug resistance in multiple myeloma.

AIMS: This study aimed to investigate the effect and mechanism of methylcrotonyl-CoA carboxylase subunit 1 (MCCA) on multidrug resistance in multiple myeloma (MM). MATERIALS AND METHODS: The apoptosis kit and CCK-8 reagent were used to detect drug-induced cell apoptosis and viability. Immunoprecipitation, immunofluorescence staining, and protein structural simulation were used to detect the interaction between MCCA and Bad. Immunodeficient mice were injected with ARD cells and treated with bortezomib. Changes in tumor burden were recorded by bioluminescence imaging, and κ light chain content in the blood of mice was detected by enzyme-linked immunoassay. KEY FINDINGS: Patients with high MCCA expression from a primary MM dataset had superior overall survival. After treatment with different anti-MM drugs, MCCA knockdown MM (MCCA-KD) cells had higher survival rates than control knockdown (CTR-KD) cells (p < 0.05). Mechanistic studies have revealed that MCCA-KD cells had dysfunctional mitochondria with decreased Bax and Bad levels and increased Bcl-xl and Mcl-1 levels. Furthermore, that MCCA and Bad demonstrated protein-protein interactions. The half-life of Bad in MCCA-KD cells is significantly shorter than that in CTR-KD cells (7.34 vs. 2.42 h, p < 0.05). In a human MM xenograft mouse model, we confirmed that MCCA-KD tumors had a poor response to anti-MM drugs in vivo. Finally, we showed that MCCA might contribute to multidrug resistance in different human cancers, particularly in solid tumors. SIGNIFICANCE: Our findings demonstrated a novel function of MCCA in multidrug resistance. The lack of MCCA expression promoted antiapoptotic cell signaling in MM cells.

Beneficial effects of hydrogen-rich saline against spinal cord ischemia-reperfusion injury in rabbits.

Hydrogen-rich saline (HS) is reported to be a new therapeutic agent in ischemia-reperfusion (I/R)-induced organ damage. The present study was designed to investigate the beneficial effects of HS against spinal cord I/R injury and its associated mechanisms. Spinal cord ischemia was induced by infrarenal aortic occlusion for 20min in male New Zealand white rabbits. Different doses of HS were intravenously (i.v.) administered at 5min before or after the beginning of reperfusion. Moreover, the roles of mitochondrial ATP-sensitive potassium channels (mitoKATP), oxidative stress, inflammatory cytokines and apoptosis was assessed. Here, we found that I/R-challenged rabbits exhibited significant spinal cord injury characterized by the decreased numbers of normal motor neurons and hind-limb motor dysfunction, which was significantly ameliorated by 5mL/kg and 10mL/kg HS treatment before reperfusion or 10mL/kg HS treatment after reperfusion. However, the protective effects of HS treatment in spinal cord I/R injury were partially abolished by the selective mitoKATP channel blocker 5-hydroxydecanoate (5-HD). Moreover, we showed that the beneficial effects of 10mL/kg HS treatment against spinal cord I/R damage were associated with the decreased levels of oxidative products [8-iso-prostaglandin F2α (8-iso-PGF2α) and malondialdehyde (MDA)] and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1)], as well as the increased activities of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] in serum at 6h, 12h, 24h, 48h and 72h after reperfusion and in spinal cord at 72h after reperfusion. Furthermore, HS treatment (10mL/kg) reduced caspase-3 activity in the spinal cord of this model. Thus, HS may be an effective therapeutic agent for spinal cord I/R injury via activation of mitoKATP channels as well as reduction of oxidative stress, inflammatory cytokines and apoptosis.

Usefulness of rosuvastatin to prevent periprocedural myocardial injury in patients undergoing elective coronary intervention.

The aim of the present study was to investigate whether percutaneous coronary intervention-related periprocedural myocardial infarction (MI) can be suppressed more significantly with high- compared with low-dose rosuvastatin. A total of 232 patients scheduled to undergo elective percutaneous coronary intervention within 5 to 7 days were assigned to groups that would receive either 2.5 or 20 mg/day of rosuvastatin (n = 116 each). The incidence of periprocedural MI did not significantly differ between the high and low-dose groups (8.7% vs 18.7%, p = 0.052). In patients who were not taking statins at the time of enrollment, high-dose rosuvastatin significantly suppressed periprocedural MI compared with the low dose (10.5% vs 30.0%, p = 0.037). The difference was not significant in patients who were already taking statins (high vs low dose 7.6% vs 10.6%, p = 0.582). In conclusion, the incidence of percutaneous coronary intervention-related periprocedural MI was reduced more effectively by high-dose than by low-dose rosuvastatin in statin-naive patients. However, low-dose rosuvastatin is sufficient for patients who are already taking statins.

Can statin therapy reduce the risk of melanoma? A meta-analysis of randomized controlled trials.

A growing body of literature suggests that statins may have a chemopreventive potential against melanoma through pleiotropic anti-inflammatory, immunomodulatory, and antiangiogenesis mechanisms. Our aim was to examine this association through a detailed meta-analysis of randomized controlled trials (RCTs). A comprehensive search for trials published up to June 2009 was performed, reviews of each study were conducted and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the fixed- and the random-effects models. Subgroup and sensitivity analyses were also conducted. Sixteen RCTs of statins for cardiovascular outcomes, involving 62,568 individuals with a mean age of 60 years and an average follow-up of nearly 4.7 years, contributed to the analysis. We found no evidence of publication bias (P = 0.47) or heterogeneity among the studies (P = 0.25). Statin use did not significantly affect the risk of developing melanoma assuming either a fixed- (RR = 0.92, 95% CI: 0.67-1.26), or a random-effects model (RR = 0.92, 95% CI: 0.62-1.36). This neutral effect was further supported by the results of subgroup and sensitivity analyses. Our findings do not support a protective effect of statins against melanoma.

Lipid-lowering drugs in the MPTP mouse model of Parkinson's disease: fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not.

We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and attenuated the loss of tyrosine hydroxylase immunoreactivity in the striatum. The dosage of 1-methyl-4-phenyl pyridinium (MPP+) in the striatum by high-performance liquid chromatography indicated that fenofibrate did not affect MPTP metabolism. Bezafibrate had no effect and, strikingly, simvastatin and atorvastatin had a negative effect. We also demonstrated the presence of PPAR-alpha in the dopaminergic neurons of the murine substantia nigra. Our data suggest that PPAR-alpha activation by fenofibrate could have a neuroprotective effect in PD through inhibition of inflammation, oxidative stress and/or apoptosis.

Drug and medical cost effects of a drug formulary change with therapeutic interchange for statin drugs in a multistate managed Medicaid organization.

OBJECTIVE: Therapeutic interchange (TI) interventions are commonly used to manage pharmacy benefit costs. While several studies have considered the effect that TI interventions have on drug costs, most have not considered the effect they have on medical management costs. The purpose of the present study was to assess drug cost and drug therapy management costs of a TI intervention following a change in the drug formulary for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) drugs, including the conversion of atorvastatin from formulary to nonformulary status. METHODS: A retrospective, quasi-experimental within-subjects design was used in this study. Administrative claims data were obtained from a select northeastern segment of a multistate Medicaid managed care organization (MCO). To be included in the study, patients had to meet the following criteria: (1) they must have had a minimum of 3 atorvastatin prescriptions during a 6-month enrollment phase, (2) they must have been continuously enrolled throughout the 900-day study period, and (3) they must have switched from atorvastatin to another statin between April 1, 2003, and July 31, 2003. The day of the switch from atorvastatin marked for each patient the end of the 12-month pre-TI period and the beginning of the 12-month post-TI period. Two separate dependent variables were developed: (1) statin drug costs (statin cost + dispensing fee) and (2) the costs paid by the MCO for the medical management of statin therapy, including office visit costs and the medical laboratory costs of measuring lipids and creatine kinase, and of checking liver functions. To estimate expenditures over 24 months, a panel analytic technique was used that allows each patient to serve as his or her own control. Multivariate models were used to assess the effects of the TI policy while controlling for age, gender, adjunctive dyslipidemia therapy, comorbidity, presence of a prior coronary artery event, statin compliance, cardiologist management, and disease severity. RESULTS: Of the 3,636 patients who met the study inclusion criteria and were converted from atorvastatin to an alternate statin drug, 129 patients (3.5%) switched back to atorvastatin following the TI. The average statin cost per claim in the 12-month post-TI period was Dollars 70.93, 9.5% less than the average cost in the 12-month pre-TI period (Dollars 78.40). The average cost per patient per year (PPPY) for statin laboratory tests (lipid panels, creatine kinase tests, and liver function tests) increased by 31.5% to Dollars 16.15 in the post-TI period compared with Dollars 12.28 PPPY in the pre-TI period, and medical office visit costs increased by 44.9% to Dollars 20.70 PPPY in the post-TI period compared with Dollars 14.29 PPPY in the preperiod. These increased costs related to the medical management of statin therapy were overwhelmed by an 11.7% reduction in statin drug costs, from Dollars 793.69 PPPY in the pre-TI period to Dollars 701.01 PPPY in the post-TI period, resulting in a net 10.0% reduction for combined statin costs and related medical costs, from Dollars 820.27 PPPY in the pre-TI period to Dollars 737.87 in the post-TI period. After limiting the analysis to patients who did not convert from atorvastatin to pravastatin (which cost more than atorvastatin before the rebate) and controlling for the influence of potential confounders, statin expenditure decreased by 33% (P < 0.001). Multivariate models indicated no statistically significant differences in the costs related to the medical management of statin therapy after the TI compared with before the TI.

C-reactive protein, statins, and the primary prevention of atherosclerotic cardiovascular disease.

Emerging data implicate inflammation as integral to atherosclerosis and its complications. From a clinical perspective, the inflammatory biomarker C-reactive protein has demonstrated consistent predictive value in the detection of individuals at high risk for cardiovascular disease. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces C-reactive protein as well as low-density lipoprotein cholesterol, thus providing a potential additional mechanism for the reduction in cardiovascular events associated with the use of these agents. Evidence from the Air Force/Texas Coronary Atherosclerosis Prevention Study suggests that statin therapy may be effective in reducing incident coronary events among those with elevated levels of C-reactive protein but normal levels of low-density lipoprotein cholesterol. These data, along with accumulating laboratory data, support a potential anti-inflammatory benefit of statins. Large-scale, randomized trials in the primary prevention of acute coronary events among individuals without overt hyperlipidemia but with evidence of elevated C-reactive protein are now needed to directly test this hypothesis.

Likely gains in life expectancy of patients with coronary artery disease treated with HMG-CoA reductase inhibitors, as predicted by a decision analysis model.

OBJECTIVE: To estimate the likely gains in life expectancy of patients with coronary artery disease treated with HMG-CoA reductase inhibitors based on published reports and the results of the 4S and the West of Scotland Study. DESIGN: Decision analysis. MAIN OUTCOME: Four likely scenarios of the effect of treatment with HMG-CoA reductase inhibitors on the life expectancy of medically and surgically managed coronary artery disease were modelled. RESULTS: Regardless of the scenario, treatment with HMG-CoA reductase inhibitors was estimated to provide a gain in life expectancy for medically managed patients of all ages with coronary artery disease, ranging from 4.6 to 10.1 quality adjusted life years (QALYs) for a 40 year old with three vessel disease (depending on the scenario assumed), to 0.2 QALYs for a 80 year old with two vessel disease. These gains were always greater than those predicted after bypass alone. If the use of HMG-CoA reductase inhibitors produces the same reduction in cardiac mortality after bypass as it does in medically managed patients it will increase the benefits of operation except for patients with two vessel disease over 70 years of age. Conversely, if HMG-CoA reductase inhibitors do not influence the course of coronary artery disease after bypass, the benefits of operation over medical treatment with HMG-CoA reductase inhibitors are either reduced or lost completely, ranging from a loss of -5.6 QALYs for a 40 year old with two vessel disease to a gain of 1.5 QALYs for 55 to 60 year old patients with left main stem disease. CONCLUSION: Although their effect on the progression of coronary artery disease after bypass must be defined, it is probable that HMG-CoA reductase inhibitors will produce considerable gains in life expectancy for patients with coronary artery disease.

Pathophysiology and treatment of lipid perturbation after cardiac transplantation.

In this review we examine the complex interactions between lipoprotein metabolism, immunosuppressive drug therapy, and inflammation and the potential benefits of lipid-lowering drug therapy after heart transplantation. The newer formulations of cyclosporine, Neoral (Novartis Pharmaceuticals; Basle, Switzerland), and other newer agents such as tacrolimus may have advantages in regard to lipid metabolism as compared with traditional triple-drug immunosuppression. Lipoprotein levels may influence both the toxicity and efficacy of cyclosporine. Dyslipidemia may adversely influence inflammation and rejection in the allograft. Two recent clinical trials have shown that lipid-lowering therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor alone or in combination with low-density lipoprotein apheresis may confer significant benefits toward preventing transplant coronary artery disease.

Oral bile acid treatment of biliary cholesterol stones.

Cholesterol gallbladder stones can be dissolved with chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA). Response rate is 60-90%, dissolution rate 60% in stones not exceeding 1.5 cm in diameter. Mean treatment time amounts to 18 months. To improve oral litholysis: 1) UDCA was combined with the amino acid taurine, 2) CDCA and UDCA were administered in a single bedtime dose, 3) they were combined, each bile acid in half dosage, and 4) they were mixed with terpenes. Although there was some improvement with the combination therapy, final outcome is still suboptimal. Many investigations have been performed concerning gallbladder function, mucus production and nucleating factors, showing both that cholesterol supersaturation of bile is the conditio sine qua non for gallstone formation and that other factors play an additional, important role for the development of the first nidus. These factors have to be considered when therapy shall be improved. As yet oral litholysis has shown neither drug-related side effects nor lethality. It is not more expensive than surgery. Direct contact litholysis with methyl tert-butyl ether could reduce the indication for oral treatment to floating stones or patients who refuse gallbladder puncture. But although oral litholysis does not provide us with optimal results and needs further improvements, it will always keep its place in gallstone therapy.

Protective effects of propionyl-L-carnitine during ischemia and reperfusion.

When cardiac function in isolated rat hearts was impaired by subjecting them to ischemia, subsequent perfusion with propionyl-L-carnitine and related compounds increased their rate of recovery. Thus at 11 mM, both propionyl-L-carnitine and, to a lesser extent, its taurine amide, and also acetyl-L-carnitine, significantly restored cardiac function in 15 minutes after 90 minutes of either low-flow or intermittent no-flow ischemia. Carnitine itself was ineffective. Propionyl-L-carnitine also increased tissue ATP and creatine phosphate compared with controls, but did not affect the levels of long-chain acyl carnitine and coenzyme. These esters also depleted fatty acid peroxidation, as shown with malonaldehyde, and were more effective than carnitine in preventing the production of superoxide. In myocytes, propionyl-L-carnitine alone stimulated palmitate oxidation, but in rat heart homogenates, both L-carnitine and propionyl-L-carnitine did so, while acetyl-L-carnitine was actually inhibitory. Possible mechanisms for the protective action of propionyl-L-carnitine against ischemia include an increased rate of cellular transport, stimulation of fatty acid oxidation, and a reduction of free radical formation.