Randomized, placebo‐controlled, double‐blind pilot trial of ramipril in McArdle's disease

Martinuzzi, Andrea; Liava, Alexandra; Trevisi, E.; Frare, Mara; Tonon, Caterina; Malucelli, Emil; Manners, David Neil; Kemp, Graham J.; Testa, Claudia; Barbiroli, Bruno; Lodi, Raffaele

doi:10.1002/mus.20937

Cited by 37 publications

(19 citation statements)

References 32 publications

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“…The ten patients studied include eight described in a recent randomized controlled trial of the ACE inhibitor ramipril in McArdle's disease (Martinuzzi et al 2007): each of those eight patients had three 31 P MRS studies, one pre-treatment (which is the only one used in the present, much more detailed analysis) and one at the end of each of two phases of a crossover study of ramipril vs placebo.…”

Section: Methodsmentioning

confidence: 99%

“…As described elsewhere (Martinuzzi et al 2007), subjects lay supine with a 6 cm surface coil centred on the maximum circumference of the right calf muscle. Spectra were acquired with TR = 5 s at rest (128 FIDs), during aerobic incremental plantar flexion exercise (10% lean body mass for 2 min, then increasing 5% lean body mass per minute) to the latest point which subjects reported they could tolerate without loss of force, then post-exercise recovery (64 FIDs, time resolution of 10 s, results averaged in pairs of spectra, thus halving apparent time resolution, to increase signal/noise).…”

Section: Methodsmentioning

confidence: 99%

“…efflux found in recovery from acidifying exercise, similar calculation will be possible in the recovery transition back from exercise to rest. A trial of ramipril therapy in McArdle's disease (Martinuzzi et al 2007) offered us the opportunity to test a full set of exercise and recovery data for consistency with the standard model of cellular pH buffering and to give a quantitative account of the differences from the response in normal muscle. Specifically, we aimed to test the following hypotheses: (1) that all pH and [PCr] changes in McArdle's disease are consistent with the simple model of cellular pH physiology, in which alkalinisation during exercise is due solely to PCr breakdown and the restoration of pH during recovery is due solely to the PCr resynthesis; and (2) that buffer capacity might be reduced in McArdle's disease compared to controls as an adaptation to the chronic lack of cellular acidification due to glycogenolysis.…”

Section: Introductionmentioning

confidence: 99%

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Cytosolic pH buffering during exercise and recovery in skeletal muscle of patients with McArdle’s disease

et al. 2008

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Cellular pH control is important in muscle physiology, and for interpretation of (31)P magnetic resonance spectroscopy (MRS) data. Cellular acidification in exercise results from coupled glycolytic ATP production mitigated by cytosolic buffering, 'consumption' of H(+) by phosphocreatine (PCr) breakdown, and membrane transport processes. Ex vivo methods for cytosolic buffer capacity are vulnerable to artefact, and MRS methods often require assumptions. (31)P MRS of early exercise, when pH increases unopposed by glycolysis, is conceptually simple, but limited in normal muscle by time resolution and signal-to-noise. A therapeutic trial (Martinuzzi A et al. Musc Nerve 37: 350-357, 2007) in McArdle's disease (glycogen phosphorylase deficiency), where pH does not decrease with exercise, offered the opportunity to test (31)P MRS data obtained throughout incremental plantar flexion exercise and recovery in ten McArdle's patients against the simple model of cellular pH control. Changes in pH, [Pi] and [PCr] throughout exercise and recovery were quantitatively consistent with mean +/- SEM buffer capacity of 10 +/- 1 mM/(pH unit), which was not significantly different from the control subjects under the initial-exercise conditions where the comparison could be made. The simple model of cellular acid-base balance therefore gives an adequate account of cellular pH changes during both exercise and recovery in McArdle's disease.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytosolic pH buffering during exercise and recovery in skeletal muscle of patients with McArdle’s disease

et al. 2008

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“…Recent evidence suggests that the variability in the phenotypic manifestation of McArdle disease in female patients is associated with the angiotensin-converting enzyme insertion (I)/deletion (D) halotypes. 104 Patients with the most severe phenotype (D/D genotype) have higher levels of angiotensin-converting 105 A recently conducted open-label study in 19 infants with Pompe disease showed that survival was significantly enhanced with recombinant human alglucosidase treatment (Myozyme, 20 and 40 mg/kg every 2 weeks). 106 In general, we are still lacking effective pharmacological therapy to prevent myopathy from developing and progressing.…”

Section: Treatmentmentioning

confidence: 98%

Metabolic Myopathies: Update 2009

Adel¹,

Tarnopolsky²

2009

Journal of Clinical Neuromuscular Disease

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Metabolic myopathies are inborn errors of metabolism that result in impaired energy production due to defects in glycogen, lipid, mitochondrial, and possibly adenine nucleotide metabolism. Fatty acid oxidation defects (FAOD), glycogen storage disease, and mitochondrial myopathies represent the 3 main groups of disorders, and some consider myoadenylate deaminase (AMPD1 deficiency) to be a metabolic myopathy. Clinically, a variety of neuromuscular presentations are seen at different ages of life. Newborns and infants commonly present with hypotonia and multisystem involvement (liver and brain), whereas onset later in life usually presents with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, the glycogen storage diseases result in high-intensity exercise intolerance, whereas the FAODs and the mitochondrial myopathies manifest predominately during endurance-type activity or under fasted or other metabolically stressful conditions. The clinical examination is often normal, and testing requires various combinations of exercise stress testing, serum creatine kinase activity and lactate concentration determination, urine organic acids, muscle biopsy, neuroimaging, and specific genetic testing for the diagnosis of a specific metabolic myopathy. Prenatal screening is available in many countries for several of the FAODs through liquid chromatography-tandem mass spectrometry. Early identification of these conditions with lifestyle measures, nutritional intervention, and cofactor treatment is important to prevent or delay the onset of muscle weakness and to avoid potential life-threatening complications such as rhabdomyolysis with resultant renal failure or hepatic failure. This article will review the key clinical features, diagnostic tests, and treatment recommendations for the more common metabolic myopathies, with an emphasis on mitochondrial myopathies.

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“…There is little evidence for benefit of creatine in other metabolic myopathies [46]. Angiotensin-converting enzyme (ACE) genotype is associated with disease severity in McArdle disease and, interestingly, a randomised study [47] of ramipril in eight patients showed possible benefit in those with the deletion/deletion ACE genotype. Exercise programmes of moderate intensity are beneficial in McArdle disease and mitochondrial disorders and may be helpful in other metabolic myopathies [48][49][50].…”

Section: Treatmentmentioning

confidence: 98%