Re: Re: Roy Walford, CR and ALS

[Guest guest]

At 01:38 PM 11/24/2006, citpeks wrote:

>The article below is from 2003, but it has an interesting

>implication

>about dietary choices and CR.

>Researchers Combine a Common Dietary Supplement with an Antibiotic

>to

>Treat Lou Gehrig's Disease

>

><http://www.ninds.nih.gov/news_and_events/news_articles/news_article_als_combin\

ation_treatment.htm>http://www.ninds.nih.gov/news_and_events/news_articles/news_\

article_als_combination_treatment.htm

The study cited was done in a mouse model of ALS, not in human

patients. Since then two clinical trials of creatine have been done

in humans with ALS without much evidence of benefit.

Fadden

References:

Neurology. 2004 Nov 9;63(9):1656-61.

A clinical trial of creatine in ALS.

Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M,

Urbinelli

L, Qureshi M, Zhang H, Pestronk A, Caress J, Donofrio P, Sorenson E,

Bradley W,

Lomen-Hoerth C, Pioro E, Rezania K, Ross M, Pascuzzi R,

Heiman- T,

Tandan R, Mitsumoto H, Rothstein J, -Palmer T, Mac D,

Burke D; NEALS

Consortium.

Department of Neurology, SUNY Upstate Medical University, 750 East

Street,

Syracuse, NY 13104, USA. shefnerj@...

BACKGROUND: Mitochondrial dysfunction occurs early in the course of

ALS, and the

mitochondria may be an important site for therapeutic intervention.

Creatine

stabilizes the mitochondrial transition pore, and is important in

mitochondrial

ATP production. In a transgenic mouse model of ALS, administration of

creatine

prolongs survival and preserves motor function and motor neurons.

METHODS: The

authors conducted a randomized double-blind, placebo controlled trial

on 104

patients with ALS from 14 sites to evaluate the efficacy of creatine

supplementation in ALS. The primary outcome measure was maximum

voluntary

isometric contraction of eight upper extremity muscles, with

secondary outcomes

including grip strength, ALS Functional Rating Scale-Revised, and

motor unit

number estimates. Patients were treated for 6 months, and evaluated

monthly.

RESULTS: Creatine was tolerated well, but no benefit of creatine

could be

demonstrated in any outcome measure. CI analysis showed that the

study, although

powered to detect a 50% or greater change in rate of decline of

muscle strength,

actually made an effect size of greater than 23% unlikely. It was

also

demonstrated that motor unit number estimation was performed with

acceptable

reproducibility and tolerability, and may be a useful outcome measure

in future

clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g

per day in

ALS must be small. Other agents should be considered in future

studies of

therapeutic agents to address mitochondrial dysfunction in ALS. In

addition,

motor unit number estimation may be a useful outcome measure for

future clinical

trials in ALS.

Ann Neurol. 2003 Apr;53(4):437-45.

A randomized sequential trial of creatine in amyotrophic lateral

sclerosis.

Groeneveld GJ, Veldink JH, van der Tweel I, Kalmijn S, Beijer C, de

Visser M,

Wokke JH, Franssen H, van den Berg LH.

Department of Neurology, University Medical Center Utrecht, The

Netherlands.

Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure.

In a

transgenic mouse model of ALS, creatine monohydrate showed a

promising increase

in survival. We performed a double-blind, placebo-controlled,

sequential

clinical trial to assess the effect of creatine monohydrate on

survival and

disease progression in patients with ALS. Between June 2000 and

December 2001,

175 patients with probable, probable-laboratory supported, or

definite ALS were

randomly assigned to receive either creatine monohydrate or placebo

10 gm daily.

A sequential trial design was used with death, persistent assisted

ventilation,

or tracheostomy as primary end points. Secondary outcome measurements

were rate

of decline of isometric arm muscle strength, forced vital capacity,

functional

status, and quality of life. The trial was stopped when the null

hypothesis of

indifference was accepted. Creatine did not affect survival

(cumulative survival

probability of 0.70 in the creatine group vs 0.68 in the placebo

group at 12

months, and 0.52 in the creatine group vs 0.47 in the placebo group

at 16

months), or the rate of decline of functional measurements. Creatine

intake did

not cause important adverse reactions. This placebo-controlled trial

did not

find evidence of a beneficial effect of creatine monohydrate on

survival or

disease progression in patients with ALS.

CNS Drugs. 2004;18(14):967-80.

The role of creatine in the management of amyotrophic lateral

sclerosis and

other neurodegenerative disorders.

Ellis AC, Rosenfeld J.

Carolinas Neuromuscular/ALS Center, Charlotte, North Carolina 28203,

USA.

amy.ellis@...

Creatine is consumed in the diet and endogenously synthesised in the

body. Over

the past decade, the ergogenic benefits of synthetic creatine

monohydrate have

made it a popular dietary supplement, particularly among athletes.

The anabolic

properties of creatine also offer hope for the treatment of diseases

characterised by weakness and muscle atrophy. Moreover, because of

its cellular

mechanisms of action, creatine offers potential benefits for diseases

involving

mitochondrial dysfunction. Recent data also support the hypothesis

that creatine

may have a neuroprotective effect. Amyotrophic lateral sclerosis

(ALS) is

characterised by progressive degeneration of motor neurons, resulting

in

weakening and atrophy of skeletal muscles. In patients with this

condition,

creatine offers potential benefits in terms of facilitating residual

muscle

contractility as well as improving neuronal function. It may also

help stabilise

mitochondrial dysfunction, which plays a key role in the pathogenesis

of ALS.

Indeed, the likely multifactorial aetiology of ALS means the combined

pharmacodynamic properties of creatine offer promise for the

treatment of this

condition. Evidence from available animal models of ALS supports the

utility of

treatment with creatine in this setting. Limited data available in

other

neuromuscular and neurodegenerative diseases further support the

potential

benefit of creatine monohydrate in ALS. However, few randomised,

controlled

trials have been conducted. To date, two clinical trials of creatine

monohydrate

in ALS have been completed without demonstration of significant

improvements in

overall survival or a composite measure of muscle strength. These

trials have

also posed unanswered questions about the optimal dosage of creatine

and its

beneficial effects on muscle fatigue, a measure distinct from muscle

strength. A

large, multicentre, clinical trial is currently underway to further

investigate

the efficacy of creatine monohydrate in ALS and address these

unresolved issues.

Evidence to date shows that creatine supplementation has a good

safety profile

and is well tolerated by ALS patients. The purpose of this article is

to provide

a short, balanced review of the literature concerning creatine

monohydrate in

the treatment of ALS and related neurodegenerative diseases. The

pharmacokinetics and rationale for the use of creatine are described

along with

available evidence from animal models and clinical trials for ALS and

related

neurodegenerative or neuromuscular diseases.

Brain Res. 2005 Oct 5;1058(1-2):183-8. Epub 2005 Sep 6.

Neurochemical correlates of differential neuroprotection by long-term

dietary

creatine supplementation.

Pena-Altamira E, Crochemore C, Virgili M, Contestabile A.

Department of Biology, University of Bologna, Via Selmi 3, 40126

Bologna, Italy.

Dietary supplementation with creatine has proven to be beneficial in

models of

acute and chronic neurodegeneration. We report here data on the

neurochemical

correlates of differential protection of long-term creatine

supplementation in

two models of excitotoxicity in rats, as well as in the mouse model

for ALS

(G93A mice). In rats, the fall in cholinergic and GABAergic markers

due to the

excitotoxic death of intrinsic neurons caused by intrastriatal

infusion of the

neurotoxin, ibotenic acid, was significantly prevented by long-term

dietary

supplementation with creatine. On the contrary, creatine was unable

to recover a

cholinergic marker in the cortex of rats subjected to the excitotoxic

death of

the cholinergic basal forebrain neurons. In G93A mice, long-term

creatine

supplementation marginally but significantly increased mean lifespan,

as

previously observed by others, and reverted the cholinergic deficit

present in

some forebrain areas at an intermediate stage of the disease. In both

rats and

mice, creatine supplementation increased the activity of the

GABAergic enzyme,

glutamate decarboxylase, in the striatum but not in other brain

regions. The

present data point at alterations of neurochemical parameters marking

specific

neuronal populations, as a useful way to evaluate neuroprotective

effects of

long-term creatine supplementation in animal models of

neurodegeneration.