piperidines and Muscular-Dystrophies

Topics: Alzheimer Disease; Animals; Asthma; Dermatitis, Atopic; Drug Design; Enzyme Inhibitors; Humans; Intramolecular Oxidoreductases; Leukodystrophy, Globoid Cell; Lipocalins; Muscular Dystrophies; Niacinamide; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyrimidines; Rhinitis, Allergic, Perennial; Spinal Cord Injuries; Thiazoles

Muscular dystrophies (MDs) include different inherited diseases that all result in progressive muscle degeneration, impaired locomotion and often premature death. The major focus of MD research has been on alleviating the primary genetic deficit - using gene therapy and myoblast-transfer approaches to promote expression of the deficient or mutated genes in the muscle fibers. Although promising, these approaches have not yet entered into clinical practice and unfortunately for MD patients, there is currently no cure. Thus, the development of complementary and supportive therapies that slow disease progression and improve patients' quality of life is critically important. The main features of MDs are sarcolemmal instability and increased myofiber vulnerability to mechanical stress, resulting in myofiber degeneration. Fibrosis, with progressive replacement of muscle tissue, is a prominent feature in some MDs, preventing complete regeneration and hampering muscle functions. TGFβ is the leading candidate for activating fibroblasts and eliciting overproduction of extracellular matrix (ECM) proteins. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of TGFβ signaling, inhibits the activation of fibroblasts and their ability to synthesize ECM, regardless of their origin or location. In animal models of MDs with prominent muscle fibrosis, halofuginone treatment has resulted in both prevention of collagen production in young animals and resolution of established fibrosis in older ones: the reduction in muscle collagen content was associated with improved muscle histopathology and major improvements in muscle function. Recently, these halofuginone-dependent improvements were also observed in MD with minor fibrosis involvement, probably due to a direct effect of halofuginone on muscle cells, resulting in myotube fusion that is dependent on Akt and MAPK pathway activation. In summary, halofuginone improves muscle histopathology and muscle functions in various MDs, via inhibition of muscle fibrosis on the one hand, and increased myotube fusion on the other.

Topics: Animals; Collagen; Fibrosis; Gene Expression Profiling; Humans; Mice; Mice, Inbred mdx; Models, Biological; Muscle, Skeletal; Muscular Dystrophies; Muscular Dystrophy, Animal; Phosphorylation; Piperidines; Quinazolinones; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Topics: Amyloid beta-Peptides; Animals; Crystallography, X-Ray; Drug Design; Humans; Hypersensitivity; Inflammation; Intramolecular Oxidoreductases; Lipocalins; Molecular Chaperones; Muscular Dystrophies; Pain; Piperidines; Prostaglandin D2; Protein Conformation; Sleep

Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials.

Topics: Adult; Animals; Child; Child, Preschool; Collagen Type I; Cytoskeletal Proteins; Diaphragm; Homozygote; Humans; Immunohistochemistry; Membrane Proteins; Mice, Inbred C57BL; Mice, Inbred mdx; Microfilament Proteins; Muscle, Skeletal; Muscular Dystrophies; Myofibroblasts; Phosphorylation; Piperidines; Quinazolinones

Ullrich congential muscular dystrophy (UCMD) is a severe form of congenital muscular dystrophy manifesting axial muscle contractures and distal joint hyperlaxity. Severe hypotonia and associated respiratory failure may occur early in the disease process. Given the various associated orthopedic conditions, anesthetic management may be required during surgical interventions to correct skeletal deformities or these patients may present with surgical conditions unrelated to their primary illness. We present a 4-year-old with UCMD who required operative intervention for a ruptured appendix. Anesthetic care implications included the need for a rapid airway control to limit the risks of aspiration due to the intra-abdominal process, choice of neuromuscular blocking agent for rapid sequence intubation, associated airway issues related to micrognathia and limited mouth opening, and the potential for involvement of the cardiovascular and respiratory systems. The perioperative management of patients with UCMD is discussed including the use of propofol and remifentanil for rapid sequence intubation to avoid the need for neuromuscular blocking agents.

Topics: Anesthetics, Intravenous; Appendectomy; Appendicitis; Child, Preschool; Female; Humans; Muscular Dystrophies; Perioperative Care; Piperidines; Propofol; Remifentanil; Rupture, Spontaneous

Smooth muscle involvement is relatively common in myotonic muscular dystrophy (MMD). The effects of cisapride on gallbladder motor function in myotonic patients have been investigated in 10 alithiasic patients and in 10 healthy volunteers. Gallbladder volumes were measured by ultrasonography in fasting state and 15, 30, 45 and 60 min after milk intake. The patients were treated with cisapride for two months, after which they underwent a second ultrasonographic examination. Gallbladder emptying was slower and less effective in dystrophic patients than in healthy volunteers. Cisapride was found to improve gallbladder kinetics (efficacy of contraction and rate of emptying) in patients affected with myotonic muscular dystrophy.

Topics: Adult; Cisapride; Female; Gallbladder; Humans; Kinetics; Liver Function Tests; Male; Muscular Dystrophies; Piperidines; Serotonin Antagonists; Ultrasonography