Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia

BACKGROUND: According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin. With the immediate-release (IR) formulation of fluvastatin, the maximal dose of 80 mg is recommended to be administered in divided doses (40 mg BID). An extended-release (ER) formulation of fluvastatin at a higher dose (fluvastatin ER 80 mg) was designed to provide greater LDL-C lowering with QD dosing. Use of this formulation should bring more patients into compliance with target LDL-C levels. OBJECTIVE: This analysis compared the efficacy and tolerability of fluvastatin ER 80 mg QD and fluvastatin IR 40 mg QD in lowering total cholesterol, LDL-C, triglyceride, and apolipoprotein (apo) B levels and raising high-density lipoprotein cholesterol (HDL-C) and apo A-I levels in patients with hypercholesterolemia over a 12-week treatment period. METHODS: This was a prospective, multicenter, double-blind, double-dummy, randomized, parallel-group, active-controlled study Patients with primary hypercholesterolemia who qualified for lipid-lowering drug therapy based on NCEP ATP II guidelines were randomized to fluvastatin ER 80 mg QD or fluvastatin IR 40 mg QD, and treated for 12 weeks. RESULTS: A total of 173 patients were randomized to treatment: 86 to the fluvastatin ER 80-mg group and 87 to the fluvastatin IR 40-mg group. Compared with fluvastatin IR 40 mg, fluvastatin ER 80 mg produced greater mean reductions in LDL-C (32% vs 22%, respectively; P < 0.001). For each of the 3 coronary heart disease (CHD) risk groups (defined by the NCEP), as well as for the total population studied, more patients from the fluvastatin ER 80-mg group than the IR 40 group achieved NCEP ATP II target LDL-C levels (79% vs 47%, respectively [P = NS], for patients with < 2 risk factors; 58% vs 15%, respectively [P < 0.001], for patients with > or = 2 risk factors; and 40% vs 14%, respectively [P = 0.012], for patients with CHD). The 80-mg ER dose of fluvastatin provided 9.1% greater LDL-C lowering than the 40-mg IR dose. The incidence of elevations in transaminase levels was low and similar for both doses, with 1 patient in each of the treatment groups being discontinued due to repeated elevation of transaminases > 3 x the upper limit of normal (ULN). Clinically relevant elevations in creatine kinase (ie, > or = 10x ULN) were not observed with either dose. Nine patients (5 in the fluvastatin ER group and 4 in the fluvastatin IR group) discontinued because of adverse events. CONCLUSIONS: Treatment with fluvastatin ER 80 mg resulted in greater reductions in LDL-C, total cholesterol, and apo B levels compared with fluvastatin IR 40 mg, with clinically equivalent reduction in triglyceride levels and elevation of HDL-C levels. Furthermore, there were few tolerability concerns of clinical relevance with either formulation and no clinically meaningful difference in the tolerability parameters between the 2 formulations. For patients with higher baseline LDL-C levels, and for patients who require greater LDL-C lowering, it may be appropriate to initiate therapy with fluvastatin ER 80 mg. Use of the higher starting dose likely would bring a greater proportion of high-risk patients into compliance with NCEP ATP II target LDL-C levels and would provide LDL-C lowering that is in the same range that has been proved in clinical trials to be associated with reductions in CHD event rates.     

SMA valiant trial: A prospective,double‐blind,placebo‐controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy

Introduction: An open‐label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12‐month, double‐blind, cross‐over study of VPA in ambulatory SMA adults. Methods: There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6‐month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. Results: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. Conclusions: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults. Muscle Nerve 49 : 187–192, 2014     

The Role of MeCP2 in Brain Development and Neurodevelopmental Disorders

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Rett syndrome, the primary disorder caused by mutations in the X-linked MECP2 gene, is characterized by a period of cognitive decline and development of hand stereotypies and seizures following an apparently normal early infancy. In addition, MECP2 mutations and duplications are observed in a spectrum of neurodevelopmental disorders, including severe neonatal encephalopathy, X-linked mental retardation, and autism, implicating MeCP2 as an essential regulator of postnatal brain development. In this review, we compare the mutation types and inheritance patterns of the human disorders associated with MECP2. In addition, we summarize the current understanding of MeCP2 as a central epigenetic regulator of activity-dependent synaptic maturation. As MeCP2 occupies a central role in the pathogenesis of multiple neurodevelopmental disorders, continued investigation into MeCP2 function and regulatory pathways may show promise for developing broad-spectrum therapies.     

Disease-related conditions in relatives of patients with hemochromatosis

BACKGROUND: Hemochromatosis occurs in approximately 5 white people per 1000 and is usually due to homozygosity for mutations in the HLA-linked HFE gene. Although screening has been proposed, the proportion of homozygotes with conditions related to hemochromatosis is uncertain. METHODS: We studied the prevalence of disease-related conditions among relatives of probands with hemochromatosis. We identified probands who presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. We identified homozygous relatives, mainly siblings, on the basis of HLA identity with the proband and by HFE genotyping. Disease-related conditions were cirrhosis, hepatic fibrosis, elevated amino-transferase values, and hemochromatotic arthropathy. RESULTS: We identified 214 homozygous relatives of 291 homozygous probands. Of the 113 men in this group (mean age, 41 years), 96 (85 percent) had iron overload, and 43 (38 percent) had at least one disease-related condition. Of the 52 men over 40 years of age, 27 (52 percent) had at least one disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68 percent) had iron overload, and 10 (10 percent) had at least one disease-related condition. Of the 43 women over 50 years of age, 7 (16 percent) had at least one disease-related condition. If the proband had a disease-related condition, relatives who were men were more likely to have morbidity than if the proband had no disease-related condition. CONCLUSIONS: A substantial number of homozygous relatives of patients with hemochromatosis--more commonly men than women--have conditions related to hemochromatosis that have yet to be detected clinically.     

RAB22 and RAB163/mouse BRCA2: Proteins that specifically interact with the RAD51 protein

The human RAD51 protein is a homologue of the bacteria RecA and yeast RAD51 proteins that are involved in homologous recombination and DNA repair. RAD51 interacts with proteins involved in recombination and also with tumor suppressor proteins p53 and breast cancer susceptibility gene 1 (BRCA1). We have used the yeast two-hybrid system to clone murine cDNA sequences that encode two RAD51-associated molecules, RAB22 and RAB163. RAB163 encodes the C-terminal portion of mouse BRCA2, the homologue of the second breast cancer susceptibility gene protein in humans, demonstrating an in vitro association between RAD51 and BRCA2. RAB22 is a novel gene product that also interacts with RAD51 in vitro. To detect RAD51 interactions in vivo, we developed a transient nuclear focus assay that was used to demonstrate a complete colocalization of RAB22 with RAD51 in large nuclear foci.     

Assessment of pruritus characteristics and impact on burn survivors

The goal of this cross-sectional study was to characterize and describe persistent postburn pruritus. Cause and treatment of postburn itch is elusive. It has been suggested that burn survivors with persistent pruritus should be divided into acute itch (≤6 months postinjury) and chronic itch (>6 months postinjury) because the cause of itch may be different. Cross-sectional data of itch characteristics reported here are from the baseline data of a prospective, randomized, double-blind, controlled pilot study of 23 subjects with frequent and bothersome postburn pruritus. Subjects self-completed validated scales for variables of itch sensation, affect of itch, and severity. Variables of quality of life, frequency, pain and itch intensity, skin condition, scar, and medication were also recorded. Itch frequency revealed that 87% of subjects experienced itching daily, 96% experienced three or more episodes a day, and 52% had episode durations lasting 5 to 30 minutes per incidence. Itch was reported as unbearable by 94% of subjects with chronic itch and by 86% of subjects with acute itch, whereas bothersome was 88 and 100%, respectively. Itch sensation dimension of stinging was 74% in both acute and chronic itch subjects. Crawling and burning sensations were often severe. Potential itch triggers and relief activities were identified. Differences in sensory and affective itch components were detected between acute and chronic itch subjects. Combinations of itch mechanisms probably contribute to the development of and changes in pruritus. Characterizing the sensation and affective itch dimensions in conjunction with inflammation, burn injury, recovery, scar maturation, medication, and psychological status should better elucidate postburn itch.     

Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11‐q13 duplication autism spectrum disorder

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) that bioaccumulate in lipid‐rich tissues are of concern as developmental neurotoxicants. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental factors implicated in autism‐spectrum disorders. The relationship between POP levels and DNA methylation patterns in individuals with and without neurodevelopmental disorders has not been previously investigated. In this study, a total of 107 human frozen postmortem brain samples were analyzed for eight PCBs and seven PBDEs by GC‐micro electron capture detector and GC/MS using negative chemical ionization. Human brain samples were grouped as neurotypical controls (n = 43), neurodevelopmental disorders with known genetic basis (n = 32, including Down, Rett, Prader‐Willi, Angelman, and 15q11‐q13 duplication syndromes), and autism of unknown etiology (n = 32). Unexpectedly, PCB 95 was significantly higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls. Interestingly, samples with detectable PCB 95 levels were almost exclusively those with maternal 15q11‐q13 duplication (Dup15q) or deletion in Prader‐Willi syndrome. When sorted by birth year, Dup15q samples represented five out of six of genetic neurodevelopmental samples born after the 1976 PCB ban exhibiting detectable PCB 95 levels. Dup15q was the strongest predictor of PCB 95 exposure over age, gender, or year of birth. Dup15q brain showed lower levels of repetitive DNA methylation measured by LINE‐1 pyrosequencing, but methylation levels were confounded by year of birth. These results demonstrate a novel paradigm by which specific POPs may predispose to genetic copy number variation of 15q11‐q13. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.