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LE Magazine March 2003



Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.

The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, eight patients with Duchenne dystrophy and six patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for eight weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period.

Neurology 2000 May 9;54(9):1848-50

Creatine monohydrate increases strength in patients with neuromuscular disease.

Creatine monohydrate has been shown to increase strength in studies of young healthy subjects and in a few studies with patients. Creatine monohydrate (10 g daily for five days to 5 g daily for five days) was administered to patients with neuromuscular disease in a pilot study (Study 1; n = 81), followed by a single-blinded study (Study 2; n = 21). Body weight, handgrip, dorsiflexion, and knee extensor strength were measured before and after treatment. Creatine administration increased all measured indices in both studies. Short-term creatine monohydrate increased high-intensity strength significantly in patients with neuromuscular disease.

Neurology 1999 Mar 10;52(4):854-7

Neuroprotective effects of creatine administration against NMDA and malonate toxicity.

We examined whether creatine administration could exert neuroprotective effects against excitotoxicity mediated by N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. Oral administration of 1% creatine significantly attenuated striatal excitotoxic lesions produced by NMDA, but had no effect on lesions produced by AMPA or kainic acid. Both creatine and nicotinamide can exert significant protective effects against malonate-induced striatal lesions. We, therefore, examined whether nicotinamide could exert additive neuroprotective effects with creatine against malonate-induced lesions. Nicotinamide with creatine produced significantly better neuroprotection than creatine alone against malonate-induced lesions. Creatine can, therefore, produce significant neuroprotective effects against NMDA mediated excitotoxic lesions in vivo and the combination of nicotinamide with creatine exerts additive neuroprotective effects.

Brain Res 2000 Mar 31;860(1-2):195-8

Creatine and cyclocreatine attenuate MPTP neurotoxicity.

Systemic administration of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) produces parkinsonism in experimental animals by a mechanism involving impaired energy production. MPTP is converted by monoamine oxidase B to 1-methyl-4-phenylpyridinium (MPP+), which blocks complex I of the electron transport chain. Oral supplementation with creatine or cyclocreatine, which are substrates for creatine kinase, may increase phosphocreatine (PCr) or cyclophosphocreatine (PCCr) and buffer against ATP depletion and thereby exert neuroprotective effects. In the present study we found that oral supplementation with either creatine or cyclocreatine produced significant protection against MPTP-induced dopamine depletions in mice. Creatine protected against MPTP-induced loss of Nissl (grandular endoplasmic reticulum and ribosomes) and tyrosine hydroxylase immunostained neurons in the substantia nigra. Creatine and cyclocreatine had no effects on the conversion of MPTP to MPP+ in vivo. These results further implicate metabolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic approach, which may have applicability for Parkinson's disease.

Exp Neurol 1999 May;157(1):142-9

Role of creatine and phosphocreatine in neuronal protection from anoxic and ischemic damage.

Phosphocreatine can to some extent compensate for the lack of ATP (Adenosine Triphosphate) synthesis that is caused in the brain by deprivation of oxygen or glucose. Treatment of in vitro rat hippocampal slices with creatine increases the neuronal store of phosphocreatine. In this way it increases the resistance of the tissue to anoxic or ischemic damage. In vitro brain slices pretreatment with creatine delays anoxic depolarization (AD) and prevents the irreversible loss of evoked potentials that is caused by transient anoxia, although it seems so far not to be active against milder, not AD-mediated, damage. Although creatine crosses the blood-brain barrier poorly, its administration in vivo at high doses through the intracerebroventricular or the intraperitoneal way causes an increase of cerebral phosphocreatine that has been shown to be of therapeutic value in vitro. Accordingly, preliminary data show that creatine pretreatment decreases ischemic damage in vivo.

Amino Acids 2002;23(1-3):221-9

Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease.

The gene defect in Huntington's disease (HD) may result in an impairment of energy metabolism. Malonate and 3-nitropropionic acid (3-NP) are inhibitors of succinate dehydrogenase that produce energy depletion and lesions that closely resemble those of HD. Oral supplementation with creatine or cyclocreatine, which are substrates for the enzyme creatine kinase, may increase phosphocreatine (PCr) or phosphocyclocreatine (PCCr) levels and ATP generation and thereby may exert neuroprotective effects. We found that oral supplementation with either creatine or cyclocreatine produced significant protection against malonate lesions, and that creatine but not cyclocreatine supplementation significantly protected against 3-NP neurotoxicity. Creatine and cyclocreatine increased brain concentrations of PCr and PCCr, respectively, and creatine protected against depletions of PCr and ATP produced by 3-NP. Creatine supplementation protected against 3-NP induced increases in striatal lactate concentrations in vivo as assessed by 1H magnetic resonance spectroscopy. Creatine and cyclocreatine protected against malonate-induced increases in the conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid, biochemical markers of hydroxyl radical generation. Creatine administration protected against 3-NP-induced increases in 3-nitrotyrosine concentrations, a marker of peroxynitrite-mediated oxidative injury. Oral supplementation with creatine or cyclocreatine results in neuroprotective effects in vivo, which may represent a novel therapeutic strategy for HD and other neurodegenerative diseases.

J Neurosci 1998 Jan 1;18(1):156-63

Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative illness for which there is no effective therapy. We examined whether creatine, which may exert neuroprotective effects by increasing phosphocreatine levels or by stabilizing the mitochondrial permeability transition, has beneficial effects in a transgenic mouse model of HD (line 6/2). Dietary creatine supplementation significantly improved survival, slowed the development of brain atrophy, and delayed atrophy of striatal neurons and the formation of huntingtin-positive aggregates in R6/2 mice. Body weight and motor performance on the rotarod test were significantly improved in creatine-supplemented R6/2 mice, whereas the onset of diabetes was markedly delayed. Nuclear magnetic resonance spectroscopy showed that creatine supplementation significantly increased brain creatine concentrations and delayed decreases in N-acetylaspartate concentrations. These results support a role of metabolic dysfunction in a transgenic mouse model of HD and suggest a novel therapeutic strategy to slow the pathological process.

J Neurosci 2000 Jun 15;20(12):4389-97

Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis.

Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.

Nat Med 1999 Mar;5(3):347-50

Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance.

BACKGROUND: Cardiac creatine levels are depressed in chronic heart failure. Oral supplementation of creatine to healthy volunteers has been shown to increase physical performance. AIM: To evaluate the effects of creatine supplementation on ejection fraction, symptom-limited physical endurance and skeletal muscle strength in patients with chronic heart failure. METHODS: With a double-blind, placebo-controlled design 17 patients (age 43 to 70 years, ejection fraction < 40) were supplemented with creatine 20 g daily for 10 days. Before and on the last day of supplementation ejection fraction was determined by radionuclide angiography as was symptom-limited 1-legged knee extensor and 2-legged exercise performance on the cycle ergometer. Muscle strength as unilateral concentric knee extensor performance (peak torque, Nm at 180 degrees/s) was also evaluated. Skeletal muscle biopsies were taken for the determination of energy-rich phosphagens. RESULTS: Ejection fraction at rest and at work did not change. Performance before creatine supplementation did not differ between placebo and creatine groups. While no change was seen in the placebo group compared to baseline, creatine supplementation increased skeletal muscle total creatine and creatine phosphate by 17 +/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05), respectively. Increments were seen only in patients with < 140 mmol total creatine/kg d.w. (P < 0.05). One-legged performance (21%, P < 0.05), 2-legged performance (10%, P < 0.05), and peak torque, Nm (5%, P < 0.05) increased. Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). The increments in 1-legged, 2-legged and peak torque were significant compared to the placebo group, (P < 0.05). CONCLUSIONS: One week of creatine supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention.

Cardiovasc Res 1995 Sep;30(3):413-8

The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure.

AIMS: To assess the effects of dietary creatine supplementation on skeletal muscle metabolism and endurance in patients with chronic heart failure. METHODS: A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction was measured using handgrip dynanometry. Subjects performed handgrip exercise, 5-s contraction followed by 5-s rest for five min at 25%, 50%, and 75% of maximum voluntary contraction or until exhaustion. Blood was taken at rest and zero and two minutes after exercise for measurement of lactate and ammonia. After 30 minutes the procedure was repeated with fixed workloads of 7 kg, 14 kg and 21 kg. Patients were assigned to creatine 20 g daily or matching placebo for five days and returned after six days for repeat study. RESULTS: Contractions (median (25th, 75th interquartiles)) until exhaustion at 75% of maximum voluntary contraction increased after creatine treatment (8 (6, 14) vs 14 (8, 17), P = 0.025) with no significant placebo effect. Ammonia per contraction at 75% maximum voluntary contraction (11.6 mumol/l/contraction (8.3, 15.7) vs 8.9 mumol/l/contraction (5.9, 10.8), P = 0.037) and lactate per contraction at 75% maximum voluntary contraction (0.32 mmol/l/contraction (0.28, 0.61) vs 0.27 mmol/l/contraction (0.19, 0.49), P = 0.07) fell after creatine but not after placebo. CONCLUSIONS: Creatine supplementation in chronic heart failure augments skeletal muscle endurance and attenuates the abnormal skeletal muscle metabolic response to exercise.

Eur Heart J 1998 Apr;19(4):617-22

Nutritional assessment and muscle energy metabolism in severe chronic congestive heart failure-effects of long-term dietary supplementation.

In order to investigate nutritional status in relation to the metabolic state of skeletal muscle in patients with severe congestive heart failure, and to explore the influence of long-term dietary supplementation, 22 patients were randomized in a double-blind study to receive either a placebo (n = 13) or high caloric fluid (n = 9). Before treatment, the muscle content of adenosine triphosphate (ATP), creatine and glycogen was lower than in healthy individuals, and muscle biopsies revealed an excess of water. Two patients were found to be malnourished according to nutritional assessment criteria. Following study treatment, no significant changes occurred, either within or between the two subgroups. Thus, patients with severe congestive heart failure displayed metabolic derangement in skeletal muscle which did not seem to be explained by malnutrition.

Eur Heart J 1994 Dec;15(12):1641-50

Use of P-31 magnetic resonance spectroscopy to detect metabolic abnormalities in muscles of patients with fibromyalgia.

OBJECTIVE: To investigate the metabolic and functional status of muscles of fibromyalgia (FM) patients, using P-31 magnetic resonance spectroscopy (MRS). METHODS: Twelve patients with FM and 11 healthy subjects were studied. Clinical status was assessed by questionnaire. Biochemical status of muscle was evaluated with P-31 MRS by determining concentrations of inorganic phosphate (Pi), phosphocreatine (PCr), ATP, and phosphodiesters during rest and exercise. Functional status was evaluated from the PCr/Pi ratio, phosphorylation potential (PP), and total oxidative capacity (Vmax). RESULTS: Patients with FM reported greater difficulty in performing activities of daily living as well as increased pain, fatigue, and weakness compared with controls. MRS measurements showed that patients had significantly lower than normal PCr and ATP levels (P < 0.004) and PCr/Pi ratios (P < 0.04) in the quadriceps muscles during rest. Values for PP and Vmax also were significantly reduced during rest and exercise. CONCLUSION: P-31 MRS provides objective evidence for metabolic abnormalities consistent with weakness and fatigue in patients with FM. Noninvasive P-31 MRS may be useful in assessing clinical status and evaluating the effectiveness of treatment regimens in FM.

Arthritis Rheum 1998 Mar;41(3):406-13

High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women.

1. A randomized, double-blind, placebo-controlled trial utilizing creatine as a potential lipid-lowering agent was conducted to determine plasma lipid, lipoprotein, glucose, urea nitrogen and creatinine profiles in men and women ranging in age from 32 to 70 years. 2. Thirty-four subjects (18 men and 16 women) with total cholesterol concentrations exceeding 200 mg/dl received either a creatine supplement (5 g of creatine plus 1 g of glucose) or a glucose placebo (6 g of glucose) for 56 days. Creatine and placebo were taken orally four times a day for five days and then twice a day for 51 days. Plasma analyses were measured at baseline, four and eight weeks of treatment, and at four weeks after cessation of treatment (week 12). 3. Significant reductions in plasma total cholesterol, triacylglycerols and very-low-density lipoprotein-C occurred within the creatine monohydrate group. Minor reductions in plasma total cholesterol from baseline (233 +/- 9 mg/dl) of 6% and 5% occurred at weeks four and eight, respectively, before returning to baseline at week 12. Baseline triacylglycerols (194 +/- 21 mg/dl) and very-low-density lipoprotein-C (39 +/- 4 mg/dl) were reduced by 23% and 22% at weeks four and eight, respectively, and remained attenuated by 26% at week 12. These results remained consistent when data were separated and analysed by gender. Finally, a small, but statistically significant increase in urea nitrogen was observed in women between baseline (11.8 +/- 0.7 mg/dl) and week eight (13.8 +/- 0.7 mg/dl, P < 0.05). No significant differences were noted for low-density lipoprotein-C, high-density lipoprotein-C, total cholesterol/high-density lipoprotein ratio, glucose, creatinine, body mass, body mass index or physical activity within or between the experimental and placebo groups. However, a trend towards reduced blood glucose levels was present in males given creatine monohydrate (P = 0.051). 4. These preliminary data suggest that creatine monohydrate may modulate lipid metabolism in certain individuals. These observations may demonstrate practical efficacy to the hyperlipidemic patient as well as providing possible new mechanistic insights into the cellular regulation of blood lipid concentrations.

Clin Sci (Lond) 1996 Jul;91(1):113-8

Effect of oral creatine supplementation on muscle [PCr] and short-term maximum power output.

Our purpose was to determine the effect of creatine supplementation on power output during a 30-s maximal cycling (Wingate) test. Nine males underwent three randomly ordered tests following ingestion of a creatine supplementation (CRE), placebo (PLA), and control (CON). CRE was ingested as creatine monohydrate (CrH2O) dissolved in a flavored drink (20g.d-1 for 3 d), while PLA consisted of the drink only. Tests were performed 14 d apart on a Monarch ergometer modified for immediate resistance loading. Needle biopsies were taken from the vastus lateralis at the end of each treatment period and before the exercise test. No difference was found between conditions for peak, mean 10-s, and mean 30-s power output, percent fatigue, or post-exercise blood lactate concentration. Similarly, no difference between conditions was observed for ATP, phosphocreatine (PCr), or total creatine (TCr); however, the TCr/ATP was higher in the CRE condition (P < 0.05) than in the CON and PLA conditions. Findings suggest that 3 d of oral Cr supplementation does not increase resting muscle PCr concentration and has no effect on performance during a single short-term maximal cycling task.

Med Sci Sports Exerc 1997 Feb;29(2):216-9


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