Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

Effect of epicatechin consumption on the inflammatory pathway and mitochondria morphology in PBMC from a R350P desminopathy patient: A case report.

Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and strength. In desminopathy, inflammation affects muscle homeostasis and repair, and contributes to progressive muscle deterioration. Mitochondria morphology was also suggested to affect desminopathy progression. Epicatechin (Epi)-a natural compound found in cacao-has been proposed to regulate inflammatory signaling and mitochondria morphology in human and animal models. Hence, we hypothesize chronic Epi consumption to improve inflammatory pathway and mitochondria morphology in the peripheral blood mononuclear cells (PBMCs) of a desminopathy R350P patient. We found that 12 weeks of Epi consumption partially restored TRL4 signaling, indicative of inflammatory signaling and mitochondria morphology in the desminopathy patient. Moreover, Epi consumption improved blood health parameters, including reduced HOMA-IR and IL-6 levels in the desminopathy patient. This indicates that Epi consumption could be a useful tool to slow disease progression in desminopathy patients.

Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular. Guía para padres y cuidadores / Clinical practice guide for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy. Guide for parents and caregivers

La Guía desarrollará recomendaciones para la atención integral de pacientes con sospecha o diagnóstico de distrofia muscular de Duchenne, Becker, miotónica, facioescapulohumeral y de cinturas. No están incluidos los pacientes con distrofias musculares congénitas (enfermedad de Ullrich, síndrome de espina rígida, enfermedad multinúcleo, distrofia muscular congénita por déficit de Merosina), ni con la distrofia muscular Emery Dreifuss.

Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular. Guía para los profesionales de la salud / Clinical practice guide for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy. Guide for health professionals

La Guía desarrollará recomendaciones para la atención integral de pacientes con sospecha o diagnóstico de distrofia muscular de Duchenne, Becker, miotónica, facioescapulohumeral y de cinturas. No están incluidos los pacientes con distrofias musculares congénitas (enfermedad de Ullrich, síndrome de espina rígida, enfermedad multinúcleo, distrofia muscular congénita por déficit de Merosina), ni con la distrofia muscular Emery Dreifuss.

Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular. Guía completa / Clinical practice guide for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy. Complete guide

La Guía desarrollará recomendaciones para la atención integral de pacientes con sospecha o diagnóstico de distrofia muscular de Duchenne, Becker, miotónica, facioescapulohumeral y de cinturas. No están incluidos los pacientes con distrofias musculares congénitas (enfermedad de Ullrich, síndrome de espina rígida, enfermedad multinúcleo, distrofia muscular congénita por déficit de Merosina), ni con la distrofia muscular Emery Dreifuss.

Ascorbic acid protects the diaphragm muscle against myonecrosis in mdx mice.

OBJECTIVE: Oxidative stress contributes to myonecrosis in the dystrophin-deficient fibers of mdx mice and in Duchenne's muscular dystrophy. We examined the effects of ascorbic acid (AA), an antioxidant and free radical scavenger, on the dystrophic diaphragm muscle. METHODS: Mdx mice (14 d old) received AA for 14 d. Control mdx mice received saline. The muscle damage was visualized by the penetration of Evans blue dye into myofibers and the extent of inflammation was assessed by histologic analysis. Creatine kinase levels were measured for the biochemical evaluation of muscle fiber degeneration. The levels of tumor necrosis factor-α (a proinflammatory cytokine) and 4-hydroxynonenal (a marker of lipid peroxidation) were analyzed by immunoblotting. RESULTS: Ascorbic acid decreased creatine kinase levels, myonecrosis, inflammation, and the levels of tumor necrosis factor-α and 4-hydroxynonenal. CONCLUSION: The present results suggest that AA plays a protective role in dystrophic muscle degeneration, possibly by decreasing reactive oxygen species, and support further investigations of AA as a potential therapy for dystrophinopathies.

Distrofia muscular de Duchenne: efecto de la administración de vitamina E sobre la luminiscencia urinaria / Effects of vitamin E supplementation on urinary luminescence in patients with Duchenne muscular dystrophy

Background: Urinary luminescence is increased in patients with Duchenne muscular dystrophy, probably due to the higher oxidative stress present in this disease. Aim: To assess the effects of vitamin E supplementation on urinary luminescence in children with Duchenne muscular dystrophy. Patients and methods: Eighteen children with muscular dystrophy aged 12.2 years old and nine control children aged 10 years old, received 400 IU/day of vitamin E during one month. Prior to supplementation and twice a week thereafter, spot urine samples were obtained to measure urinary luminescence in a scintillation counter. Results: There was a wide variability in urinary luminescence within and between children. Mean values decreased after vitamin E supplementation in six of nine controls and in 12 of 18 children with muscular dystrophy. Conclusions: Vitamin E supplementation significantly decreases urinary luminescence in healthy children and in patients with Duchenne muscular dystrophy. Therefore, it could be useful or the treatment of this disease

[Duchenne muscular dystrophy. Effects of vitamin E administration on urinary luminescence]. / Distrofia muscular de Duchenne. Efecto de la administración de vitamina E sobre la luminiscencia urinaria.

BACKGROUND: Urinary luminescence is increased in patients with Duchenne muscular dystrophy, probably due to the higher oxidative stress present in this disease. AIM: To assess the effects of vitamin E supplementation on urinary luminescence in children with Duchenne muscular dystrophy. PATIENTS AND METHODS: Eighteen children with muscular dystrophy aged 12.2 years old and nine control children aged 10 years old, received 400 IU/day of vitamin E during one month. Prior to supplementation and twice a week thereafter, spot urine samples were obtained to measure urinary luminescence in a scintillation counter. RESULTS: There was a wide variability in urinary luminescence within and between children. Mean values decreased after vitamin E supplementation in six of nine controls and in 12 of 18 children with muscular dystrophy. CONCLUSIONS: Vitamin E supplementation significantly decreases urinary luminescence in healthy children and in patients with Duchenne muscular dystrophy. Therefore, it could be useful for the treatment of this disease.

Perspectivas em doenças neuromusculares: 1. Distrofia muscular de Duchenne / Perspective in neuromuscular diseases: 1. Duchenne muscular dystrophy

Nos últimos anos, as pesquisas em doenças neuromusculares tiveram um avanço, muito grande, graças à genética, imunologia e comprovaçåo de diversas hipóteses do passado. Fica muito difícil falar sobre todos os avanços dos últimos anos e cobrir todos os pontos, numa área que se encontra em plena evoluçåo, em uma única conferência. Portanto, decidi abordar alguns aspectos que acho importante e que teråo repercussöes no futuro

Steroids in Duchenne muscular dystrophy--deflazacort trial.

We conducted a double blind controlled trial in 28 Duchenne muscular dystrophy (DMD) patients with Deflazacort (DF), an oxazoline derivative of prednisolone which reduces its side-effects. Myometric muscle strength measurements, Scott Score and timed tests showed statistically significant improvement for the treated group (P less than 0.05). Side-effects after 9 months of treatment included mild cushingoid appearance in four patients (28%) and moderate in only one (7%), increased appetite in seven (50%), increased body hair in four (28%), irritability and hyperactivity in three (21%). Increased body weight was not prominent and was controlled with dietary measures. No patient had to be withdrawn from medication. More research and long-term follow-up are needed in order to establish the mechanism of improvement and the consequences of long-term steroid administration in DMD. In this regard DF appears as an alternative to prednisone preserving its benefits but with fewer side-effects.

Effect of chronic administration of verapamil in Duchenne muscular dystrophy.

1. In DMD patients the effect of chronic treatment with verapamil was investigated in the p-nitrophenylphosphatase from erythrocytes, the CK and LDH in serum and the functional activity of the muscle. 2. A different behaviour in the p-nitrophenylphosphatase from untreated compared to treated DMD patients and controls is supported by the following findings: (a) values of "n" altered in F- inhibition of the enzyme with Hill coefficients -1.43, -2.18 and -2.19; (b) Arrhenius plots between 16 and 40 degrees C with inflection points for the enzyme from treated DMD patients and controls and not from untreated DMD patients. 3. Although CK and LDH in serum and the muscular evaluation showed no statistical difference between both groups, evidence is presented that in treated DMD patients the interaction membrane-enzyme is different from untreated DMD patients.

Nocturnal rhythm of growth hormone in Duchenne patients: effect of different doses of mazindol and/or cyproheptadine.

Human growth hormone (hGH) inhibition may be beneficial for Duchenne muscular dystrophy (DMD) patients and slow the rate of progression of the disease. The purpose of the present investigation was 1) to assess, before any therapeutic trial, the natural growth hormone (GH) rhythm during physiological sleep in DMD patients and in normal control boys of comparable age; 2) to evaluate the effect of different doses of two potential GH inhibitors on nocturnal GH secretion in DMD patients receiving mazindol (1-4 mg), cyproheptadine (4-8 mg), or both drugs. The results from the present investigation showed 1) wide variability in nocturnal GH secretion before medication; 2) no correlation between nocturnal GH concentration and height, age, bone age, L-dopa provocative test, or Tanner staging; and 3) no consistent effect on GH release after mazindol, cyproheptadine therapy, or combined therapy.

Effect of mazindol on growth hormone levels in patients with Duchenne muscular dystrophy.

Human growth hormone (HGH) inhibition may be beneficial in Duchenne muscular dystrophy (DMD) and slow down the rate of progression of the disease. The purposes of the present investigation were: 1) to assess, through pharmacological stimuli (L-dopa test), the HGH response in untreated DMD patients, and 2) to evaluate the inhibitory effect of mazindol on HGH levels as a potential treatment for DMD. In 55 DMD patients, HGH levels were measured through the L-dopa test, and 40 received mazindol. After 1 year, there was wide variability in the individual response to mazindol. An apparent diminution in the mean HGH level was observed in the whole group of patients; this was statistically significant after 3 and 6 months but not after 9 and 12 months of treatment. The results suggest that this drug is not effective for arresting growth or inhibiting HGH secretion for a prolonged period of time.

Evolución clínica de la enfermedad de Sudeck tratada con Calcitonina Sintética de Salmón / Clinical of Sudeck's disease treated with salmon synthetic calcitonin

En un estudio doble ciego comparativo con un grupo placebo y a corto plazo, se incluyeron 16 pacientes con diagnóstico clínico y radiológico de enfermedad de Sudeck. A 8 pacientes se les administró Calctonina Sintética de Salmon a dosis de 100 UL al día por vía IM durante 15 días mientras a los 8 pacientes restantes se les administró una ampolleta de placebo al día de aspecto idéntico al principio activo por la misma vía y durante el mismo periodo de tiempo. Se estudió la evolución de los síntomas del padecimeinto tales como dolor, edema local, aumento de la temperatura e hiperemia en ambos grupos al inicio y a los 5, 10 y 15 días de tratamiento. Se observó una mejoría en 6 de los 8 pacientes del grupo calcitonina (75%), siendo dicha mejoría significativa comparándola con la obtenida en el grupo placebo, en el que únicamente un paciente (12.5%) respondió favorablemente. Respecto a la tolerancia, esta fue buena para el medicamento ya que sólo un paciente (12.5%) presentó efectoss secundarios que obligaron la suspensión del tratamiento. Se concluyó que la calcitonia sintética de salmón es una excelente alternativa para el tratamiento de la enfermedad de Sudeck