ALC/ALA and Alzheimer's Patients

Acetyl-L-carnitine in Alzheimer disease: a short-term study on CSF neurotransmitters and neuropeptides

Bruno G; Scaccianoce S; Bonamini M; Patacchioli FR; Cesarino F; Grassini P; Sorrentino E; Angelucci L; Lenzi GL
Dipartimento di Scienze Neurologiche, Universita di Roma La Sapienza, Italy
Alzheimer Dis Assoc Disord (U.S.) Fall 1995, 9 (3) p128-31,

Acetyl-L-carnitine (ALCAR) is a drug currently under investigation for Alzheimer disease (AD) therapy. ALCAR seems to exert a number of central nervous system (CNS)-related effects, even though a clear pharmacological action that could explain clinical results in AD has not been identified yet. The aim of this study was to determine cerebrospinal fluid (CSF) and plasma biological correlates of ALCAR effects in AD after a short-term, high-dose, intravenous, open treatment. Results show that ALCAR CSF levels achieved under treatment were significantly higher than the ones at baseline, reflecting a good penetration through the blood-brain barrier and thus a direct CNS challenge. ALCAR treatment produced no apparent change on CSF classic neurotransmitters and their metabolite levels (homovanillic acid, 5-hydroxyindoleacetic acid, MHPG, dopamine, choline). Among CSF peptides, while corticotropin-releasing hormone and adrenocorticotropic hormone remained unchanged, beta-endorphins significantly decreased after treatment; plasma cortisol levels matched this reduction. Since both CSF beta-endorphins and plasma cortisol decreased, one possible explanation is that ALCAR reduced the AD-dependent hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity. At present, no clear explanation can be proposed for the specific mechanism of this action.

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Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease

Pettegrew J.W.; Klunk W.E.; Panchalingam K.; Kanfer J.N.; McClure R.J.
University of Pittsburgh, Western Psychiatric Institute/Clinic, A710 Crabtree Hall/GSPH, 130 DeSoto Street, Pittsburgh, PA 15261 USA
NEUROBIOL. AGING (USA), 1995, 16/1 (1-4)

In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.

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A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease

Neurology (USA), 1996, 47/3 (705-711)

A 1-year, double-blind, placebo controlled, randomized, parallel-group study compared the efficacy and safety of acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable Alzheimer's disease (AD). Subjects with mild to moderate probable AD, aged 50 or older, were treated with 3 g/day of ALCAR or placebo (1 g tid) for 12 months. Four hundred thirty-one patients entered the study, and 83% completed 1 year of treated. The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures. Overall, both ALCAR- and placebo-treated patients declined at the same rate of all primaryures during the trial. In a subanalysis by age that compared early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), we found a trend for early-onset patients on ALCAR to decline more slowly than early-onset AD patients on placebo on both primary endpoints. In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on ALCAR tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial. The study suggests that a subgroup of AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly. However, these preliminary findings are based on post hoc analyses. A prospective trial of ALCAR in younger patients is underway to test the hypothesis that young, rapidly progressing subjects will benefit from ALCAR treatment.

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Acetyl-L-carnitine and Alzheimer's disease: Pharmacological beyond the cholinergic sphere

ANN. NEW YORK ACAD. SCI. (USA), 1993, 695/- (324-326)

Since ALCAR and L-carnitine are 'shuttles' of long chain fatty acids between the cytosol and the mitochondria to undergo beta-oxidation, they play an essential role in energy production and in clearing toxic accumulations of fatty acids in the mitochondria. ALCAR has been considered of potential use in senile dementia of the Alzheimer type (SDAT) because of its ability to serve as a precursor for acetylcholine. However, pharmacological studies with ALCAR in animals have demonstrated its facility to maximize energy production and promote cellular membrane stability, particularly its ability to restore membranal changes that are age-related. Since recent investigations have implicated abnormal energy processing leading to cell death, and severity-dependent membrane disruption in the pathology of Alzheimer's disease, we speculate that the beneficial effects associated with ALCAR administration in Alzheimer patients are due not only to its cholinergic properties, but also to its ability to support physiological cellular functioning at the mitochondrial level. This hypothetical mechanism of action is discussed with respect to compelling supportive animal studies and recent observations of significant decrease of carnitine acetyltransferase (the catalyst of L-carnitine acylation to acetyl-L-carnitine) in autopsied Alzheimer brains.

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Acetyl-L-carnitine: A drug able to slow the progress of Alzheimer's disease?

ANN. NEW YORK ACAD. SCI. (USA), 1991, 640/- (228-232)

Defects in cholinergic neurotransmission do not, by themselves, constitute the sole pathophysiologic concomitants of Alzheimer's disease (AD). Recent findings point out that abnormalities in membrane phospholipid turnover and in brain energy metabolism may also characterize AD. Acetyl-L-carnitine (ALC) is an endogenous substance that, acting as an energy carrier at the mitochondrial level, controls the availability of acetyl-L-CoA. ALC has a variety of pharmacologic properties that exhibit restorative or even protective actions against aging processes and neurodegeneration. A review of a series of controlled clinical studies suggests that ALC may also slow the natural course of AD.

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Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer Type

EUR. J. CLIN. PHARMACOL. (Germany), 1992, 42/1 (89-93)

Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type. The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg.kg-1 i.v. given twice for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 2.0 g/day p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine. The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period. Following the i.v. bolum injections, the plasma concentrations showed a biphasic curve, with average t(one-half) of 0.073 h and 1.73 h, respectively. At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase. The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier. It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.

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Double-blind, placebo-controlled study of acetyl-l-carnitine in patients with Alzheimer's disease

CURR. MED. RES. OPIN. (United Kingdom), 1989, 11/10 (638-647)

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with 1 g acetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratory tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.

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Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease

Pettegrew JW; Klunk WE; Panchalingam K; Kanfer JN; McClure RJ
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, PA 15213, USA.
Neurobiol Aging (UNITED STATES) Jan-Feb 1995, 16 (1) p1-4,

In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.

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Alpha-lipoic acid as a new treatment option for Azheimer type dementia.

Arch Gerontol Geriatr 2001 Jun;32(3):275-282
Hager K, Marahrens A, Kenklies M, Riederer P, Munch G.
Department of Medical Rehabilitation and Geriatrics, Henriettenstiftung, Schwemannstrasse 19, D-30559, Hannover, Germany

Oxidative stress and energy depletion are characteristic biochemical hallmarks of Alzheimer's disease (AD), thus antioxidants with positive effects on glucose metabolism such as thioctic (alpha-lipoic) acid should exert positive effects in these patients. Therefore, 600 mg alpha-lipoic acid was given daily to nine patients with AD and related dementias (receiving a standard treatment with acetylcholinesterase inhibitors) in an open study over an observation period of, on avarage, 337+/-80 days. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (mini-mental state examination: MMSE and AD assessment scale, cognitive subscale: ADAScog). Despite the fact that this study was small and not randomized, this is the first indication that treatment with alpha-lipoic acid might be a successful 'neuroprotective' therapy option for AD and related dementias.

PMID: 11395173 [PubMed - as supplied by publisher]

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Alzheimer's Dementia/CNS Effects

Research has examined the effects of ALC in various dementias, cognitive defects and age-related disorders. These observations represent the clearest understanding and application of ALC in clinical practice. It has been established that ALC traverses the blood-brain barrier efficiently, with CSF concentrations increasing significantly via both an I.V. and oral route in patients with severe dementia.18 There are multiple mechanisms of action responsible for ALC-induced CNS changes: enhanced cholinergic neurotransmission, neuronotrophic effects (via binding of cortisol and increased nerve growth factor production in the hippocampus),muscarinic receptor changes as well as decreased free radical generation and lipofuscin deposits in animal models.18,19

Calvani, et al summarized the neuroprotective benefits of ALC in the hippocampus, prefrontal cortex, substantia nigra and muscarinic receptor portions of the brain. These included antioxidant activity, improved mitochondrial energetics, stabilization of intracellular membranes and cholinergic neurotransmission. In the 500+ patients with Alzheimer's or other age-related dementias presented in this review, it was concluded that oral ALC administration may slow the progression of degeneration. The dose of ALC varied from 1.5 grams/day to 3.0 grams/day. Patient tolerance was excellent with no clinically significant differences in side effects between the treatment and placebo groups. 20

Patients with Alzheimer's dementia showed improvement in both clinical and CNS measurements in one double-blind placebo controlled trial over a 1-year period. Although this was a small study (7 patients in the treatment group), the findings were significant in elucidating the protective/reparative effects of ALC on the neuronal membranes.21 Another study showed significant improvements in all cognitive, behavioral and emotive measurements except anxiety in a 40-day double-blind, placebo-controlled study of 40 patients with Alzheimer's. This work was particularly helpful in outlining clinical methods of patient assessment which may be applicable in the out-patient setting. 22

A study of 6 months duration on an out-patient basis showed mild improvements in tasks of attention and timing. Memory facilitation was improved only in the more impaired subset of the treatment group. This subset also showed a significant increase of ALC levels in the CSF. 23 Martignoni═s study showing increased ▀-endorphin production in response to ALC administration presents yet another potential benefit of ALC in the patient with Alzheimer's dementia because of their tendancy to have reduced ▀-endorphin levels.

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Some positive results in the above studies may be due to enhanced memory trace formation, a key issue in cognitive research. Animal models indicate that protein kinase C translocation from the cytosol (soluble form) to the neuronal membrane (particulate form) of the hippocampus and cortex may serve as a marker for memory formation. ALC is able to increase particulate protein kinase C in rat cortex at a dose (60mg/kg) that also elicits improvements in learning, providing evidence of ALC═s participation in memory formation via neuronal membrane modification. This effect was lost after long incubation times or higher concentrations of ALC, suggesting multiple control mechanisms for the protein kinase C.24

John H. Furlong N.D.

http://www.thorne.com/altmedrev/fulltext/alc1-2.html

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