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Biomedical subjects

M H Brooke

Publications and source records attributed to M H Brooke.

At least 19 recordsLinked to original sources
PubMed1991

Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group.

A randomized, controlled trial of daily prednisone was conducted in 99 boys (aged 5 to 15 years) with Duchenne dystrophy to define the time course of improvement and the dose response to treatment. Prednisone at 0.3 mg/kg (n = 33), prednisone at 0.75 mg/kg (n = 34), and placebo (n = 32) were administered for 6 months. Patients were examined using manual muscle and myometry testing, timed functional testing, pulmonary function testing, and laboratory measurements at 10 days, 1 month, 2 months, 3 months, and 6 months of treatment. Boys treated with prednisone had stronger average muscle strength scores, than did boys treated with placebo as early as 10 days after starting therapy. At the 3-month visit, the boys in the group given 0.75 mg/kg of prednisone were significantly stronger than those in the group given 0.3 mg/kg of prednisone, indicating a dose response. At 6 months, significant side effects occurred in the group treated with 0.75 mg/kg of prednisone, including weight gain, cushingoid appearance, and excessive hari growth. Only weight gain was observed in the group taking prednisone at a dose of 0.3 mg/kg. Importantly, no side effects were evident at 10 days or 1 month of treatment, despite improvement in muscle strength and function. We conclude that prednisone produces a rapid increase in muscle strength in patients with Duchenne dystrophy and that this improvement is maximal at a prednisone dosage of 0.75 mg/kg or less.

Adolescent↗
PubMed1991

A comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular dystrophy.

We previously reported the results of a randomized, double-blind 6-month trial of prednisone therapy in which 102 boys aged 5 to 15 years with Duchenne muscular dystrophy received daily doses of 1.5 and 0.75 mg/kg per day and were compared with those receiving placebo. The strength and function in both prednisone-treated groups improved equally and were significantly better than in the placebo group. To compare alternate-day and daily dosing of prednisone with respect to benefits and adverse side effects, the placebo group was started on alternate-day prednisone therapy, and the treatment group regimens were changed to equivalent doses of alternate-day prednisone without breaking the double-blind nature. At the end of 6 months, the group that was changed from daily to alternate-day therapy had declined in strength back to levels observed 12 months previously, at the start of daily therapy. The group in which alternate-day therapy was started showed a significant improvement in strength at 3 months, similar in magnitude to the response of boys treated with daily therapy. However, their strength declined significantly in the subsequent 3 months compared with boys who received daily therapy. The frequency of side effects was not significantly different for alternate-day therapy compared with daily therapy. We conclude that alternate-day prednisone therapy effectively increases strength but does not sustain the improvement to the same extent as daily therapy or mitigate side effects.

Adolescent↗
PubMed1991

Glutathione depletion during experimental damage to rat skeletal muscle and its relevance to Duchenne muscular dystrophy.

1. The release of glutathione has been studied in comparison with the release of creatine kinase from isolated rat soleus muscles subjected to certain forms of experimental damage. 2. Excessive electrically stimulated contractile activity or treatment of muscles with the mitochondrial inhibitor, 2,4-dinitrophenol, induced a substantial release of both creatine kinase and glutathione and a reduction in the total glutathione content of the muscle. The time course of this release and depletion indicates that the efflux of the two molecules is not directly related and that a reduction in muscle glutathione content does not occur before cytosolic enzyme release. 3. 2,4-Dinitrophenol-stimulated release of creatine kinase was significantly reduced by the omission of external calcium from the incubation media, but glutathione release and depletion was relatively unaffected by this. Deliberate elevation of the muscle intracellular calcium content with the calcium ionophore, A23187, induced a substantial loss of creatine kinase, but had no significant effect on the release of glutathione. 4. Muscle biopsies from patients with Duchenne muscular dystrophy were found to have an elevated content of glutathione and an equivalent protein-thiol content compared with control subjects. 5. We conclude that, although release of glutathione from skeletal muscle occurs after excessive contractile activity or inhibition of mitochondrial metabolism, this is not a key step in the damaging processes leading to cytosolic enzyme release, neither is it relevant to the ongoing damage to skeletal muscle which occurs in patients with Duchenne muscular dystrophy.

2,4-Dinitrophenol↗
PubMed1991

Creatine kinase and prostaglandin E2 release from isolated Duchenne muscle.

We studied the release of creatine kinase (CK) activity and prostaglandin E2 (PGE2) from isolated strips of biceps muscle from patients with Duchenne muscular dystrophy and nondystrophic control patients. CK release was significantly higher from the dystrophic samples than controls during the initial period of incubation, but this difference reduced with time of incubation. Immediate immersal of muscle strips into calcium-free bathing medium reduced the initial difference between the efflux from dystrophic and nondystrophic samples, whereas treatment with the calcium ionophore maintained the difference between the groups throughout the period of incubation (150 minutes). These results support the hypothesis that the lack of dystrophin in Duchenne muscle leads to damage to the tissue via a failure of calcium homeostasis. PGE2 release from the muscle strips followed a similar pattern to CK activity, supporting the possibility that, at least partly, the calcium-mediated damage involves activation of phospholipid hydrolysis.

Adolescent↗
PubMed1991

Long-term benefit from prednisone therapy in Duchenne muscular dystrophy.

Two successive, 6-month, randomized, double-blind, controlled trials of prednisone showed that 0.75 mg/kg/d was the optimal dose to improve strength in boys with Duchenne muscular dystrophy (DMD). We attempted to maintain 93 boys on that dose for an additional 2 years. During the 3 years of observation, the decline in average muscle strength scores of all boys taking prednisone was 0.072 units/yr, as compared with an expected decline of 0.341 units/yr from natural history controls. The occurrence of side effects in some boys prevented maintenance of the full dose, which may have lessened the response. At the time of last visit, dosages ranged from 0.15 mg/kg to 0.75 mg/kg. In addition to maintaining their strength, several of the boys actually improved their performance in lifting kilogram weights and in some timed function tests. Treatment of DMD with prednisone significantly slows the progression of weakness and loss of function for at least 3 years.

Adolescent↗
PubMed1990

Randomized, double-blind trial of mazindol in Duchenne dystrophy.

There is evidence that growth hormone may be related to the progression of weakness in Duchenne dystrophy. We conducted a 12-month controlled trial of mazindol, a putative growth hormone secretion inhibitor, in 83 boys with Duchenne dystrophy. Muscle strength, contractures, functional ability and pulmonary function were tested at baseline, and 6 and 12 months after treatment with mazindol (3 mg/d) or placebo. The study was designed to have a power of greater than 0.90 to detect a slowing to 25% of the expected rate of progression of weakness at P less than 0.05. Mazindol did not benefit strength at any point in the study. Side effects attributable to mazindol included decreased appetite (36%), dry mouth (10%), behavioral change (22%), and gastrointestinal symptoms (18%); mazindol dosage was reduced in 43% of patients. The effect of mazindol on GH secretion was estimated indirectly by comparing the postabsorptive IGF-I levels obtained following 3, 6, 9, and 12 months in the mazindol treated to those in the placebo groups. Although mazindol-treated patients gained less weight and height than placebo-treated patients, no significant effect on IGF-I levels was observed. Mazindol doses not slow the progression of weakness in Duchenne dystrophy.

Behavior↗
PubMed1990

Fatigue testing.

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Biomechanical Phenomena↗
PubMed1979

Bicycle ergometry and gas exchange measurements in neuromuscular diseases.

Using bicycle ergometry with computerized respiratory gas exchange measurements, we compared exercise capacities in patients with various neuromuscular diseases to those in normal controls. As expected, male and female patients had significantly reduced maximum work capacities (kilopond-meters per minute per kilogram of body weight) and maximal oxygen consumptions. The oxygen cost of exercise was normal in the majority of patients, although some appeared to have abnormally high oxygen consumptions during exercise. Breathing patterns during exercise, particularly in regard to onset of hyperventilation, were similar in patients and controls.

Adolescent↗
PubMed1979

Fasting as a provocative test in neuromuscular diseases.

A 38-hr fast was used as a provocative test in patients suspected of having defects in muscle substrate utilization. In five controls and nine patients, exercise capacity and respiratory exchange ratio were determined before and at the end of the fast. Blood was collected at intervals during the fast from ten controls and nine patients for creatine kinase (CK), free fatty acids, (FFA) beta-hydroxybutyrate, acetoacetate, free and total carnitine, glucose, and alanine. Two patients with myophosphorylase deficiency had increased exercise capacity, and a marked fall in CK, and one had a lesser fall in blood glucose than normal at the end of the fast. Two patients with known lipid myopathies (carnitine deficiency and carnitine palmityl transferase deficiency) had decreased exercise capacity and apparent increased dependence on carbohydrate metabolism during the fast. Carnitine concentrations became even more abnormal in the patient with carnitine deficiency during fasting. Several patients with less well-defined defects were also significantly different from the controls in several respects, indicating that the fast might be useful for finding new defects.

Adult↗
PubMed1979

The prolonged exercise test.

The response to a standardized exercise test was investigated in 12 volunteers and 13 patients with aches, cramps, and pains. In men, creatine kinase (CK) levels peaked (up to 1600 mU per milliliter) between 10 and 20 hours after exercise. High levels of blood lactate during exercise were related to the intensity of work and to high levels of CK after exercise. The patients could be divided into several groups: (1) those with no change in blood metabolites (psychogenic); (2) those with a disproportionate rise in CK (metabolic myopathies); (3) those with a disproportionate rise of lactate (mitochondrial abnormalities); and (4) in one patient with exercise-related pains, subnormal elevation of fatty acid levels. The correlation of changes in blood lactate, CK, and fatty acids may be useful, whereas an isolated measurement, even if outside the normal range, is often meaningless.

Adult↗
PubMed1979

Increased serum creatine kinase after exercise: a sex-linked phenomenon.

The effect of 2 hours of exercise on the serum creatine kinase (CK) level was investigated in 11 men and 9 women. The mean increase of CK 24 hours after exercise was significantly greater in men. The relative lack of CK elevation in women may: (1) indicate that female muscle is less susceptible to damage by adverse factors; and (2) explain discrepancies in previous reports.

Creatine Kinase↗