:Acetyl-L-Carnitine:

:A major cause of aging is the deterioration of the energy-producing components of the cell which results in reduced cellular metabolic activity, the accumulation of cellular debris, and eventual death of the cell. The amino acid L-carnitine helps to maintain cellular energy metabolism by assisting in the transport of fat through the cell membrane and into the mitochondria within the cell, where these fats are oxidized to produce the cellular energy ATP. This action may be synergistic with Coenzyme Q-10. ALC is also synergistic with Alpha Lipoic Acid.

Acetyl L-carnitine (ALC) is contains the amino acid L-carnitine and has similar functions, such as metabolism of food into energy. Acetyl L-carnitine (ALC) is the acetyl ester of the amino acid L-carnitine. ALC is absorbed into the bloodstream more efficiently than L-carnitine. It passes more easily through cell membranes, and is utilized more efficiently in the mitochondria of the cell. Published medical studies show ALC may provide neurological benefits, promoting a healthy nervous system and memory.

Benefits:

• ALC facilitates both the release and synthesis of Acetylcholine.
• ALC's ability to increase the synthesis of Acetylcholine occurs as a result of it donating its Acetyl group towards the production of Acetylcholine.
• ALC increases the Brain's levels of Choline Acetylase (which in turn facilities the production of Acetylcholine).
• ALC enhances the release of Dopamine from Dopaminergic Neurons and improves the binding of Dopamine to Dopamine Receptors.
• ALC improves the reaction times of persons afflicted with Cerebral Insufficiency.
• ALC (2-4 grams per day) improves walking distance without Pain in persons afflicted with Intermittent Claudication.
• ALC prevents the age-related impairment of Eyesight (by protecting the Neurons of the Optic Nerve and the Occipital Cortex of the Brain.
• ALC enhances the ability of Macrophages to function as Phagocytes.
• ALC given prior to exercise increased the maximum running speed of animals.
• ALC enhances the function of Cytochrome Oxidase (an essential enzyme of the Electron Transport System (ETS).
• ALC improves the Energy metabolism of Neurons (by enhancing the transport of Medium-Chain Saturated Fatty Acids and Short-Chain Saturated Fatty Acids across the Cell Membranes of Neurons into the Mitochondria).
• ALC inhibits the damage caused by Hypoxia.
• ALC transports Lipids into the Mitochondria of Cells.
• ALC improves Memory in persons afflicted with Age Associated Memory Impairment.
• ALC improves Mental Function where Alcohol induced cognitive Impairment exists.
• Acetyl-L-Carnitine inhibits the deterioration in Mental Function associated with Alzheimer’s Disease and slows the progression of Alzheimer’s Disease [persons afflicted with Alzheimer’s Disease exhibited significantly less deterioration in Mental Function following the administration of supplemental ALC for 12 months. This finding was verified by using nuclear magnetic resonance on the subjects].
• ALC increases Alertness in persons afflicted with Alzheimer's Disease - 2,500-3,000 mg per day for 3 months].
• ALC inhibits the toxicity of Amyloid-Beta Protein (ABP) to Neurons.
• ALC improves Attention Span in persons afflicted with Alzheimer's Disease.
• ALC improves Short Term Memory in persons afflicted with Alzheimer's Disease.
• High concentrations of ALC are naturally present in various regions of the Brain.
• ALC reverses the age-related decline that occurs in Cholinergic Receptors (i.e. the Receptors that receive Acetylcholine).
• ALC improves (eye to hand) Coordination [supplemental ALC @ 1.5 grams per day for 30 days improved eye to hand coordination in healthy, sedentary subjects by a factor of 300-400%].
• ALC improves the Interhemispheric Flow of Information across the Corpus Callosum of the Brain.
• ALC retards the decline in the number of Dopamine Receptors that occurs in tandem with the Aging Process and (more rapidly) with the onset of Parkinson's Disease.
• ALC enhances the release of Dopamine from Dopaminergic Neurons and improves the binding of Dopamine to Dopamine Receptors.
• ALC can prevent the destruction of Dopamine Receptors by MPTP (a neurotoxin capable of causing Parkinson's Disease via Dopaminergic Receptor death.
• ALC improves Attention Span and Memory in persons afflicted with Down’s Syndrome.
• ALC retards the inevitable decline in the number of Glucocorticoid Receptors that occurs in tandem with the Aging Process.
• ALC enhances the recovery of persons afflicted with Hemiplegia (Paralysis of one side of the body) and improves their Mood and Attention Span.
• ALC retards the age-related deterioration of the Hippocampus [research - rats].
• Acetyl-L-Carnitine (ALC) improves Learning ability [women aged 22 - 27 were supplemented with ALC for 30 days. Complex video game tests before and after supplementation concluded that supplemental ALC caused large increases in speed of Learning, speed of reaction and reduction in errors].
• ALC improves both Short-Term Memory and Long-Term Memory.
• ALC improves Mood [ALC improves Mood in 53% of healthy subjects].
• ALC inhibits (and possibly reverses) the degeneration of Myelin Sheaths that occurs in tandem with the progression of the Aging Process [scientific research - hyperglycemic mice treated with ALC for 16 weeks exhibited improved nerve conduction velocity and exhibited thicker Myelin Sheaths and larger myelinated Nerve Fibers].
• ALC retards the inevitable decline in the number of Nerve Growth Factor (NGF) Receptors that occurs in tandem with the Aging Process.
• ALC stimulates and maintains the growth of new Neurons within the Brain (both independently of Nerve Growth Factor (NGF) and as a result of preserving NGF) and helps to prevent the death of existing Neurons [ALC inhibits Neuron death in the Striatal Cortex, Prefrontal Cortex and the Occipital Cortex of the Brain].
• ALC inhibits the degeneration of Neurons that is implicit in Neuropathy.
• ALC rejuvenates and increases the number of N-Methyl-D-Aspartate Receptors (NMDA Receptors) in the Brain [even a single dose of ALC increases the number of functional NMDA Receptors]:
• ALC protects the NMDA Receptors in the Brain from the natural decline that occurs in tandem with the Aging Process [research - animals].
• ALC is presently being researched as a treatment for Parkinson's Disease.
• ALC inhibits the loss of Vision, degeneration of Neurons and damage to the Retina associated with Retinopathy (including Diabetic Retinopathy).
• ALC improves the quality of Sleep and reduces the quantity of Sleep required.
• ALC improves the function of (reduces the over-excitability of) Motor Nerves in persons afflicted with Spasticity.
• ALC improves Spatial Memory (an aspect of Short Term Memory that involves remembering one’s position in space).
• ALC inhibits the excessive release of Cortisol in response to Stress and inhibits the depletion of Luteinising Hormone Releasing Hormone (LHRH) and Testosterone that occurs as a result of excessive Stress.
• ALC improves Verbal Fluency.
• ALC enhances the function of Cytochrome Oxidase (also called Complex IV) - an essential enzyme of the Electron Transport System.
• ALC normalizes Beta-Endorphin levels.
• ALC reduces Stress-induced Cortisol release [research - animals].
• ALC prevents the depletion of Luteinising Hormone Releasing Hormone (LHRH) caused by exposure to excessive Stress.
• ALC retards the decline in the production of Nerve Growth Factor (NGF) that occurs in tandem with the Aging Process.
• ALC increases plasma Testosterone levels (via its influence on Acetylcholine neurotransmission in the Striatal Cortex of the Brain) and prevents the depletion of Testosterone caused by exposure to excessive Stress [research - rats].

References:

De Falco, F. A., et al. Effect of the chronic treatment with L-acetylcarnitine in Down’s syndrome. Clin Ther. 144:123-127, 1994.
Bowman, B. Acetyl-carnitine and Alzheimer’s disease. Nutr Rev. 50:142-144, 1992.
Bruno, G., et al. Acetyl-L-carnitine in Alzheimer disease: a short-term study on CSF neurotransmitters and neuropeptides. Alzheimer Dis Assoc Disord (USA). 9(3):128-131, 1995.
Calvani, M., et al. Action of acetyl L-carnitine in neurodegeneration and Alzheimer’s disease. Annals of the New York Academy of Sciences (USA). 663:483-486, 1993.
Carta, A., et al. Acetyl L-carnitine: a drug able to slow the progress of Alzheimer’s Disease? Annals of the New York Academy of Sciences (USA. 640:228-232, 1991.
Guarnaschelli, C., et al. Pathological brain ageing: evaluation of the efficacy of a pharmacological aid. Drugs under Experimental and Clinical Research. 14(11):715-718, 1988.
Passeri, M., et al. Acetyl L-carnitine in the treatment of mildly demented elderly patients. International Journal of Clinical Pharmacology Research. 10(1-2):75-79, 1990.
Pettegrew, J. W., et al. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer’s disease. Neurobiol Aging. 16:1-4, 1995.
Rai, G., et al. Double-blind, placebo controlled study of acetyl-L-carnitine in patients with Alzheimer’s dementia. Current Medical Research and Opinion. 11(10):638-647, 1989.
Sano, M., et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer’s disease. Arch Neurol. 49:1137-1141, 1992.
Sinforiani, E., et al. Neuropsychological changes in demented patients treated with acetyl-L-carnitine. International Journal of Clinical Pharmacology Research. 10(1-2):69-74, 1990.
Spagnoli, A. U., et al. Long-term acetyl-l-carnitine treatment in Alzheimer’s disease. Neurology. 41(11):1726-1732, 1991.

Caution:

Take Acetyl L-Carnitine early in the day. Some people may experience increased energy with Carnitine and especially with Acetyl L-Carnitine supplementation.

Abstracts:

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.

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.

Neuroprotective activity of acetyl-L-carnitine: studies in vitro
Forloni G; Angeretti N; Smiroldo S
Unit of Neurobiology of Alzheimer, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
J Neurosci Res (UNITED STATES) Jan 1994, 37 (1) p92-6,
The neuroprotective properties of acetyl-L-carnitine (ALCAR) were investigated in primary cell cultures from rat hippocampal formation and cerebral cortex of 17-day-old rat embryos. Chronic exposure to ALCAR (10-50 microM for 10 days) reduced the cell mortality induced by 24 hr fetal calf serum deprivation. Protection was partial when the neuronal cells, chronically treated with ALCAR (50 microM), were exposed to glutamate (0.25-1 mM) and kainic acid (250-500 microM) for were characterized with the subjects in two states of vitamin C nutriture: a depleted state, which was achieved by 4-5 wk of compliance with a vitamin C-restricted diet of less than 10 mg/d and a supplemented state, in which the subjects were given 500 mg vitamin C/d for 3 wk. Plasma and urine samples were collected for 72 h after the dose of vitamin C from depleted subjects and for 24 h from supplemented subjects and analyzed for vitamin C. Several of the pharmacokinetic indices measured were different in depleted vs supplemented subjects but none exhibited any age-related differences. This indicates that vitamin C nutriture affects vitamin C pharmacokinetics but age does not.

Clinical pharmacodynamics of acetyl-L-carnitine in patients with Parkinson's disease.
Int J Clin Pharmacol Res. 1990. 10(1-2). P 139-43
Two groups of 10 patients with Parkinson's disease received doses of either 1g acetyl-L-carnitine (ALC) per day for seven days or 2g. The effects of this drug on intermittent luminous stimulation and on nocturnal sleep patterns were studied. In both cases with either dose of ALC the effect was an improvement of the H response, sleep stages and spindling activity. However a further study of the complexity of action of acetyl-L-carnitine is necessary.

The effects of acetyl-L-carnitine and sorbinil on peripheral nerve structure, chemistry, and function in experimental diabetes
Metabolism: Clinical and Experimental (USA), 1996, 45/7 (902-907)
Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short- chain acyl-carnitine (acetyl-L-carnitine (ALC)) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 microm) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath.

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat
Metabolism: Clinical and Experimental (USA), 1996, 45/7 (865-872)
Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl- L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin- induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (Mf) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not-insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.

Primary preventive and secondary interventionary effects of acetyl-L- carnitine on diabetic neuropathy in the bio-breeding Worcester rat
Journal of Clinical Investigation (USA), 1996, 97/8 (1900-1907)
The abnormalities underlying diabetic neuropathy appear to be multiple and involve metabolic neuronal and vasomediated defects. The accumulation of long-chain fatty acids and impaired beta-oxidation due to deficiencies in carnitine and/or its esterified derivatives, such as acetyl-L-carnitine, may have deleterious effects. In the present study, we examined, in the diabetic bio-breeding Worcester rat, the short- and long-term effects of acetyl-L- carnitine administration on peripheral nerve polyols, myoinositol, Na+/K+- ATPase, vasoactive prostaglandins, nerve conduction velocity, and pathologic changes. Short-term prevention (4 mo) with acetyl-L-carnitine had no effects on nerve polyols, but corrected the Na+/K+-ATPase defect and was associated with 63% prevention of the nerve conduction defect and complete prevention of structural changes. Long-term prevention (8 mo) and intervention (from 4 to 8 mo) with acetyl-L-carnitine treatment normalized nerve PGE1 whereas 6-keto PGF(1alpha) and PGE2 were unaffected. In the prevention study, the conduction defect was 73% prevented and structural abnormalities attenuated. Intervention with acetyl-L-carnitine resulted in 76% recovery of the conduction defect and corrected neuropathologic changes characteristic of 4- mo diabetic rats. Acetyl-L-carnitine treatment promoted nerve fiber regeneration, which was increased two-fold compared to nontreated diabetic rats. These results demonstrate that acetyl-L-carnitine has a preventive effect on the acute Na+/K+-ATPase defect and a preventive and corrective effect on PGE1 in chronically diabetic nerve associated with improvements of nerve conduction velocity and pathologic changes.

Acetyl-L-carnitine corrects the altered peripheral nerve function of experimental diabetes
Metabolism: Clinical and Experimental (USA), 1995, 44/5 (677-680)
Acetyl-L-carnitine (ALC) has been shown to facilitate the repair of transacted sciatic nerves. The effect of ALC (50 mg/kg/d) on the diminished nerve conduction velocity (NCV) of rats with streptozotocin (STZ)-induced hyperglycemia of 3 weeks' duration was evaluated. The aldose reductase inhibitor, sorbinil, which is reported to normalize the impaired NCV associated with experimental diabetes, was used as a positive control. Aldose reductase inhibitors are thought to have an effect by decreasing peripheral nerve sorbitol content and increasing nerve myo-inositol. Treatment of STZ- diabetic rats with either ALC or sorbinil resulted in normal NCV. Sorbinil treatment was associated with normalized sciatic nerve sorbitol and myo- inositol; ALC treatment did not reduce the elevated sorbitol levels, but sciatic nerve myo-inositol content was no different from nondiabetic levels. Both ALC and sorbinil treatment of STZ-diabetic rats were associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic news, indicating reduced lipid peroxidation. The beneficial effects of sorbinil and ALC on the altered peripheral nerve function associated with diabetes were similar, but their effects on the polyol pathway (frequently implicated in the pathogenesis of peripheral neuropathy) were different.

Diabetic neuropathy in the rat: 1. Alcar augments the reduced levels and axoplasmic transport of substance P
RES. (USA), 1995, 40/3
This study examined the sciatic nerve axonal transport of substance P-like immunoreactivity (SPLI) and its basal content in stomach, sciatic nerve and lumbar spinal cord of 8- and 12-week alloxan-diabetic rats, respectively. One group of diabetic rats received acetyl-l-carnitine (ALCAR) throughout the experimental period. Alloxan treatment caused hyperglycemia and reduced body growth. Axonal transport of SPLI was studied by measurement of 24-hour accumulation at a ligature on the sciatic nerve. There was a marked reduction (from 50% to 100% according to the nerve segment examined) of anterograde and retrograde accumulation of SPLI in the constricted nerve of 8-week diabetic rats. In the sciatic nerve of ALCAR-treated diabetic rats, the accumulation of SPLI was comparable to control values. In the sciatic nerve, lumbar spinal cord and stomach of 12-week diabetic rats, there is a significant reduction of SPLI content. ALCAR treatment prevented SPLI loss in these tissues. Sciatic nerves showed the typical sorbitol increase and myo-inositol loss that were significantly counteracted by ALCAR. This study suggests that ALCAR treatment prevents diabetes-induced sensory neuropathy by improving altered metabolic pathways such as polyol activity and myo-inositol synthesis, and by preventing the reduction of synthesis and axonal transport of substance P.

Neural dysfunction and metabolic imbalances in diabetic rats: Prevention by acetyl-L-carnitine
DIABETES (USA), 1994, 43/12 (1469-1477)
The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction 1) in hearts from diabetic animals (in which L-carnitine levels are decreased); 2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and 3) in nondiabetic humans with ischemic heart disease. The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na+-K+-ATPase activity (decreased 50%), Mg2+- ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L- carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations 1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and 2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.

Acetyl-L-carnitine prevents substance P loss in the sciatic nerve and lumbar spinal cord of diabetic animals
INT. J. CLIN. PHARMACOL. RES. (Switzerland), 1992, 12/5-6 (243-246)
Diabetic neuropathy is a disease of peripheral nerves, characterized by axonal atrophy and degeneration that might be preceded by a marked impairment of axonal transport and by a reduced conduction velocity. Sensory nerves are particularly susceptible to diabetes. In the present report it is shown that experimental diabetes in rats causes a significant reduction of the content of the pain-related neuropeptide substance P in sciatic nerve and lumbar spinal cord. Such a loss of substance P is fully prevented by acetyl-L-camitine treatment. The neuroprotective pharmacological effect is selective and takes place without significant changes of hyperglycaemia and without modifications of the reduced rate of body growth typical of diabetic animals.

Altered neuroexcitability in experimental diabetic neuropathy: Effect of acetyl-L-carnitine
INT. J. CLIN. PHARMACOL. RES. (Switzerland), 1992, 12/5-6 (237-241)
Sciatic nerve conduction velocity (NCV) is reduced in rats made hyperglycaemic with streptozotocin (STZ). This neurophysiological dysfunction has been associated with increased nerve sorbitol and reduced nerve inositol. Treatment of STZ diabetic rats with aldose reductase inhibitors (ARls) which reduce sorbitol and increase inositol in the nerve results in normalization of NCVs. Male Wistar rats were made diabetic with 50 mg/kg of streptozotocin given intraperitoneally. Those animals with blood glucose > 300 mg/dl two weeks later were included in this study. The STZ-diabetic rats were treated with either the ARl sorbinil (40 mg/kg per day), or acetyl-L-carnitine (ALC) (300 mg/kg per day) or sterile 0.15% aqueous NaCl for 16 weeks after 4 or 8 weeks of untreated hyperglycaemia. A control group of non-diabetic rats received no treatment during the interval. Sciatic-nerve sorbitol was elevated (1.08 plus or minus 0.13 nanomol/mg wet weight vs. 0.19 plus or minus 0.03 nm/mg wet weight) and inositol was reduced (1.21 plus or minus 0.12 nm/mg ww vs. 2.02 plus or minus 0.08 nm/mg ww) in the STZ diabetic rats, which were untreated for 4 weeks. Treatment with sorbinil was associated with normalization of the tissue sorbitol (0.10 plus or minus 0.05 nm/mg ww), while ALC treatment also significantly reduced the nerve sorbitol but only to a level (0.34 plus or minus 0.08 nm/mg ww) more elevated than the normal level. The nerves of STZ animals treated with sorbinil or ALC had inositol levels no different from untreated diabetic rats. Thus, hyperglycaemic animals treated with either ALC or sorbinil had similar improvements in NCVs as the diabetic, even though the effect on nerve sorbitol was different and nerve inositol was unchanged: It appears that ALC corrects the reduced NCVs of diabetes by a method that does not alter nerve inositol levels.

Peptide alterations in automatic diabetic neuropathy prevented by acetyl-L-carnitine
CLIN. PHARMACOL. RES. (Switzerland), 1992, 12/5-6 (225-230)
Autonomic neuropathy and gastrointestinal problems are among the most common complications of diabetes. In this report it is shown that a possible correlation between the two disorders might exist, since diabetes causes a profound alteration of the peptidergic innervation of the gut. It is reported that 14 weeks after diabetes induction with alloxan the levels of substance P and methionine-enkephalin are markedly reduced throughout the intestine, while vasoactive intestinal polypeptide content is dramatically increased. Therefore the enteric innervation of diabetic animals is completely disorganized, with some systems undergoing atrophy and others undergoing hypertrophy. Treatment of diabetic animals with acetyl-L-carntinine prevents the onset of the marked peptide changes described above. The results suggest a potential for acetyl-L-carnitine in the treatment of autonomic neuropathies.

Acetyl-L-carnitine effect on nerve conduction velocity in streptozotocin-diabetic rats
ARZNEIM.-FORSCH. DRUG RES. (Germany), 1993, 43/3 (343-346)
Measurement of nerve conduction velocity (NCV) is a useful and sensitive tool for evaluating diabetes related neurological dysfunctions. The method used allows to monitor the parameter at different times in the same group of rats, so that it is possible to observe simultaneously the development of the damage in time, and to evaluate the improvement related to the treatment. The repeated oral treatment with acetyl-L-carnitine (ALC, CAS 5080-50-2) 250 mg/kg caused an improvement in NCV of the diabetic rats; the effect was higher when the treatment started early with respect to the diabetes induction. The improvement in NCV was constant in time and comparable from 2 to 6 weeks of the treatment. In conclusion, oral treatment with ALC was able to normalize the impairment of NCV in streptozotocin rats, the effect being constant in time from 2 to 6 weeks of treatment and up to 8 weeks after induction when administration started in early stage of diabetes (2-3 weeks after induction); however, at this time the NCV is already significantly decreased.

Differential effects of acetyl-L-carnitine, L-carnitine and gangliosides on nerve Na+,K+-ATPase impairment in experimental diabetes
DIABETES NUTR. METAB. CLIN. EXP. (Italy), 1992, 5/1 (31-36)
The pharmacological action of acetyl-L-carnitine and its parent compound, L-carnitine, was assessed on sciatic nerve Na+,K+-ATPase activity in streptozotocin (STZ)-diabetic rats. The two substances were injected intraperitoneally (i.p.) at the daily dose of 50 mg/kg, for 4 consecutive weeks, starting one week after induction of diabetes. A bovine brain-derived ganglioside mixture (10 mg/kg/d i.p.for 4 weeks) was used as a positive control. The data here reported show that Na+,K+-ATPase activity was reduced by 40% in diabetic nerve; such a decrease was not affected by acetyl-L-carnitine or L-carnitine treatments, but was completely counteracted by gangliosides. Furthermore, unlike gangliosides, carnitine compounds tested in in vitro models did not elicit neurite outgrowth from neuroblastoma (N2A) cells and did not potentiate the trophic effect of nerve growth factor (NGF) on dorsal root ganglion cells. Because of the potential implication of NGF deficits and loss of neuroplastic responses in diabetic neuropathy, the present results could conceivably reflect the well-known capability of gangliosides, but not of either acetyl-L-carnitine or L-carnitine, to facilitate neuronotrophic interactions and maintenance of nerve membrane functional integrity.

Acetyl-L-carnitine increases cytochrome oxidase subunit I mRNA content in hypothyroid rat liver
FEBS LETT. (Netherlands), 1990, 277/1-2 (191-193)
The effect of acetyl-L-carnitine on the quantity of the messenger RNA for the subunit I of cytochrome oxidase in the liver mitochondria of hypothyroid rat was measured by Northern blot and solution hybridization. Three hours after pre-treatment of hypothyroid rat with acetyl-L-carnitine, the level of the transcript increased strongly. This effect was also obtained when acetyl-L-carnitine was administered to T3 pre-treated hypothyroid rats. These results add further evidence to the suggestion that acetyl-L-carnitine is able to stimulate mitochondrial transcription under altered metabolic conditions.

Oxidative damage and mitochondrial decay in aging.
Proc Natl Acad Sci U S A (UNITED STATES) Nov 8 1994
We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

Effects of acetyl-L-carnitine oral administration on lymphocyte antibacterial activity and TNF-alpha levels in patients with active pulmonary tuberculosis. A randomized double blind versus placebo study.
Immunopharmacol Immunotoxicol (UNITED STATES) 1991, 13 (1-2) p135-46
Acetyl-L-carnitine (ALC), a drug for the treatment of ageing-related neuroendocrine dysfunctions, was orally administered--2 gm/day for 30 days--to 10 patients with active pulmonary tuberculosis (TBC). Lymphocyte-mediated antibacterial activity and serum levels of tumor necrosis factor (TNF)-alpha were evaluated before and after treatment, comparing the values with those of 10 TBC patients receiving placebo. Results show that by day 30, antibacterial activity remained unmodified or increased in ALC-treated subjects, while decreased in the placebo group. No influence of ALC on TNF-alpha levels was detectable. These data suggest that the host's immune responses to M. tuberculosis infection can be selectively modulated by drugs acting on the neuroendocrine axis.

Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances.
Int J Clin Pharmacol Res (SWITZERLAND) 1990, 10 (1-2) p53-7
Several immune parameters--particularly T-cell dependent immune responses--are altered in aged subjects. To test the hypothesis that they may be the consequence of more general age-related lymphocyte biochemical alterations, and particularly of the energy producing system, the effect of L-carnitine and acetyl-L-carnitine on cell proliferation was studied in peripheral blood lymphocytes from donors of different ages. The results showed that phytohaemagglutinin-induced peripheral blood lymphocyte proliferation was markedly increased in L-carnitine- or acetyl-L-carnitine-preloaded lymphocytes from young and especially from old subjects. Cells from aged subjects considerably improved their defective proliferative capability. Preliminary observations suggest that L-carnitine-preloading also protected peripheral blood lymphocytes from old donors when such cells were exposed to an oxidative stress.

Mitochondria alterations and dramatic tendency to undergo apoptosis in peripheral blood lymphocytes during acute HIV syndrome
AIDS (United Kingdom), 1997, 11/1 (19-26)
Objective: To study alterations of mitochondrial membrane potential (Deltapsi) and the propensity to undergo apoptosis in peripheral blood lymphocytes (PBL) from subjects with acute HIV syndrome; and to evaluate possible modulations of these phenomena by antioxidants that can be used in therapy, such as N-acetyl-cysteine (NAC), nicotinamide (NAM), or L-acetyl-carnitine (LAC). Methods: Mitochondrial function and the tendency of PBL to undergo spontaneous apoptosis were studied on freshly collected PBL from patients with symptomatic, acute HIV-1 primary infection, which were cultured for different durations in the presence or absence of NAC, NAM or LAC. By a cytofluorimetric method allowing analysis of Deltapsi in intact cells, we studied the function of these organelles under the different conditions. PBL apoptosis was evaluated by the classic cytofluorimetric method of propidium iodide staining, capable of revealing the typical DNA hypodiploid peak. Results: Significant Deltapsi alterations and tendency to undergo apoptosis were present in PBL from the subjects we studied. Indeed, when cultured even for a few hours in the absence of any stimulus, a consistent number of cells died. However, the presence of even different levels of NAC, NAM or LAC was able to rescue most of them from apoptosis. Both a fall in Deltapsi and apoptosis were evident in PBL collected in the earliest phases of the syndrome (before seroconversion), and changed significantly after a few days. A significant correlation was found between spontaneous apoptosis and tumour necrosis factor (TNF)-alpha or p24 plasma levels, as well as between apoptosis and the percentages of circulating CD4+ or CD8+ T cells. Conclusions: PBL from patients with acute HIV syndrome are characterized by both significant mitochondrial alterations and a dramatic tendency to undergo apoptosis. The use of NAC, NAM or LAC seems to rescue cells through a protective effect on mitochondria, a well-known target for the action of TNF-alpha and for reactive oxygen species, the production of which is strongly induced by this cytokine. Thus, our data could provide the rationale for the use of such agents in addition to antiviral drugs in primary infection.

Acetyl-L-carnitine effects on nerve conduction and glycemic regulation in experimental diabetes
Endocrine Research (USA), 1997, 23/1-2 (27-36)
Acetyl-L-Carnitine (ALC), an activator of carnitine, can accelerate nerve regeneration after experimental surgical injury in rats. In this study, we examined the ability of ALC to improve nerve conduction velocity and its effect on intravenous glucose tolerance test in streptozotocin-induced diabetic rats. Diabetic (blood glucose > 200 mg%) and normal animals were treated intraperitoneally for four weeks with ALC, 50 mg/Kg/d and 150 mg/Kg/d. Nerve conduction velocity was measured by direct exposure of sural nerve. Two-hour IVGTT was studied by measuring plasma glucose, insulin and free fatty acids after intravenous injection of glucose, 1.75 gm/Kg/body weight in animals treated either with ALC 150 mg/Kg/d or saline alone. Six weeks of STZ-induced diabetes resulted in impairment of nerve conduction velocity in animals injected with saline (16.05 plus or minus 1.09 m/s), as compared to saline-treated normals who did not receive streptozotocin (31.9 plus or minus 0.84 m/s, p<0.0005). Diabetic animals treated with ALC, 150 mg/Kg/d, preserved near normal nerve conduction (27.10plus or minus1.42 m/s), compared with the saline-treated diabetic animals (p<0.0005), but diabetic animals treated with ALC, 50 mg/Kg/d, had a non-significant increase in nerve conduction (23.68plus or minus1.6). ALC treatment had no effect on fasting or post-intravenous plasma glucose in normal or diabetic rats, although it moderately reduced baseline and 40 minute insulin levels (p<0.02) in normal rats as compared with their saline- treated counterparts. ALC treatment lowered baseline free fatty acids in normal (p<0.04) and diabetic (p<0.03) animals, and the 60 minute levels in the normal group only (p<0.003). Conclusion: ALC at a dose of 150 mg/Kg/d given for one month, produced near normalization of nerve conduction velocity in streptozotocin-induced diabetes with no adverse effects on glucose, insulin or free fatty acid levels.

Improved pallesthetic sensitivity of pudendal nerve in impotent diabetic patients treated with acetyl-L-carnitine
Acta Urologica Italica (Italy), 1996, 10/3 (185-187)
Neurogenic impotence in diabetic patients seems to be largely associated with abnormal sensory nerve conduction of pudendal nerve afferent pathways. This condition accounts for a hypoactivity in the mechanisms of erection reflex and has been described as sensory-deficit impotence. Our study investigates the pharmacological action of acetyl-L-carnitine (ALC) in the treatment of this neurological disorder. Penile biothesiometry was applied to two groups of diabetic patients, whose impotence was principally neurogenic, in order to assess their vibration perception threshold variables. The groups were treated with ALC (1,500 mg/day) and placebo, respectively. The results obtained show a significant improvement in dorsal nerve somatosensory conduction in patients treated with ALC.

Effects of acetyl- and proprionyl-L-carnitine on peripheral nerve function and vascular supply in experimental diabetes.
Metabolism (UNITED STATES) Sep 1995, 44 (9) p1209-14
L-Carnitine metabolism is abnormal in diabetes mellitus, and treatment with acetyl-L-carnitine (ALC) improves the function of cardiac muscle, retina, and peripheral nerve in experimental models. The aim was to compare the effects of ALC and proprionyl-L-carnitine (PLC) on motor and sensory nerve conduction in streptozotocin-diabetic rats and to ascertain whether their action could be mediated by a vascular mechanism. ALC and PLC treatment for 2 months after diabetes induction attenuated the development of sciatic motor nerve conduction velocity (NCV) deficits by 59.4% +/- 4.4% and 46.9% +/- 3.2%, respectively. There was a similar level of protection for sensory saphenous NCV (42.9% +/- 6.6% and 47.8% +/- 6.0%, respectively). Neither ALC nor PLC prevented the development of resistance to hypoxic conduction failure (RHCF) in sciatic nerve from diabetic rats. A 46.5% +/- 3.4% deficit in sciatic endoneurial blood flow, measured by microelectrode polarography and hydrogen clearance, in diabetic rats was partially prevented by both ALC (48.7% +/- 6.4%) and PLC (69.4% +/- 10.1%). ALC had no significant effect on blood flow in nondiabetic rats. Thus, the data show that these L-carnitine derivatives have a similar efficacy in preventing nerve dysfunction, which depends on a neurovascular action.

Serum and urine levels of levocarnitine family components in genetically diabetic rats.
Arzneimittelforschung (GERMANY) Aug 1994, 44 (8) p965-8
Serum concentration and urinary excretion of levocarnitine (L-carnitine, CAS 541-15-1) family components were evaluated in a Wistar derived strain of genetically diabetic rats BB/BB, in comparison with normal Wistar rats, and their control rats BB/WB of both sexes. BB/BB diabetic animals have lower serum concentration of total-L-carnitine (TC), L-carnitine (LC), acetyl-L-carnitine (ALC), and short chain L-carnitine esters (SCLCE) than both the strains of non-diabetic rats, as previously observed in streptozotocin diabetic rats. No or marginal variations between control and diabetic rats were detected in cumulative urinary excretion of L-carnitine family components. A strain difference was observed between Wistar and BB/WB non-diabetic rats, BB/WB showing higher serum concentration and lower cumulative urinary excretion of LC and TC than Wistar animals. Renal clearance of L-carnitine components proved to be markedly higher in BB/BB diabetic rats, as previously shown in streptozotocin rats. The reduction of serum concentration of the carnitines endogenous pool may explain this finding. The lack of an increased urinary excretion of L-carnitine components in diabetic animals despite the high increase of diuresis suggests that the saturable tubular reabsorption of L-carnitine family components also in diabetes is the primary mechanism to preserve the homeostatic equilibria of the L-carnitine family, the variation in serum concentration being attributable to the complex systemic metabolicalterations typical of diabetes. In agreement with previous investigations,male animals of all the strains showed higher serum concentration andurinary excretion of L-carnitine components as compared to females.

Acetyl-L-carnitine corrects electroretinographic deficits in experimental diabetes.
Diabetes (UNITED STATES) Aug 1993, 42 (8) p1115-8
Acetyl-L-carnitine reduces the latencies of electroretinogram oscillatory potentials in healthy humans. The effect of acetyl-L-carnitine (50mg.kg-1.day-1) on the increased electroretinogram latencies found in rats with STZ-induced hyperglycemia of 3-wk duration was evaluated. The aldosereductase inhibitor sorbinil, which has been shown to normalize abnormal electroretinogram tracings associated with STZ-induced diabetes, was used as a positive control. Aldose reductase inhibitors are thought to lower tissue sorbitol while increasing myo-inositol. The electroretinograms of the STZ-induced diabetic rats in this study were abnormal; treatment withacetyl-L-carnitine as well as sorbinil significantly improved electroretinogram b-wave amplitude and decreased the latencies of oscillatory potentials 2 and 3. Acetyl-L-carnitine treatment of STZ-induced diabetic rats did not affect hyperglycemia or erythrocyte polyol pathway activity as reflected by erythrocyte sorbitol levels. In contrast, sorbinil did reduce elevated erythrocyte sorbitol levels. This suggests that the impaired electroretinograms associated with STZ-induced diabetes may not be caused solely by increased polyol pathway activity.

Effect of acetyl-L-carnitine treatment on the levels of levocarnitine and its derivatives in streptozotocin-diabetic rats.
Arzneimittelforschung (GERMANY) Mar 1993, 43 (3) p339-42
The effect of diabetes induced by streptozotocin and that of acetyl-L-carnitine (ALC) hydrochloride (CAS 5080-50-2) treatment on the homeostasis of the levocarnitine (L-carnitine) moiety was investigated in Sprague-Dawley rats. The diabetic status was ascertained by measuring blood glucose. L-carnitine (LC), total acid soluble L-carnitine (TC) and ALC were measured in serum, tissues and urine by radioenzymatic methods. Short-chain L-carnitine esters (SCLCE) were obtained by subtracting LC from TC. Serum concentration of L-carnitine moiety was decreased in diabetic when compared to normal rats; whereas ALC oral treatment (50 and 150 mg/kg p.o. for 4 weeks) in diabetic rats increased, dose-dependently, all the components of L-carnitine moiety, SCLCE and ALC being completely restored. In the liverof diabetic rats all the analytes proved to be higher than in normal rats, mainly LC and TC. A similar trend was observed in skeletal muscle, at least with LC and TC, whereas SCLCE and ALC were not affected. The treatment with ALC increased the liver concentration of all the analytes in a dose-related way whereas in skeletal muscle only LC and TC showed an increase with the highest dose of ALC. Myocardium and kidneys showed a decrease of all the analytes in diabetes; the treatment with ALC normalized the situation in kidneys, in a dose-related way, but not in the myocardium. Urinary excretion and renal clearance of L-carnitine moiety increased in diabetes; an additional dose-related increase was observed with the ALC treatment.

[The action of carnitine-series preparations in experimental alloxan diabetes mellitus]
Eksp Klin Farmakol (RUSSIA) Jul-Aug 1992, 55 (4) p35-6
The study was undertaken to examine the effects of l-carnitine and acetyl-l-carnitine in rats and mice with experimental alloxan diabetes. The findings suggest that acetyl-l-carnitine is more effective against diabetes in increasing glucose tolerance, restoring the impaired response of glucagon to glucose, showing glycogen-sparing action than is l-carnitine.

Protective effects of propionyl-L-carnitine during ischemia and reperfusion.
Cardiovasc Drugs Ther (UNITED STATES) Feb 1991, 5 Suppl 1 p77-83
When cardiac function in isolated rat hearts was impaired by subjecting them to ischemia, subsequent perfusion with propionyl-L-carnitine and related compounds increased their rate of recovery. Thus at 11 mM, both propionyl-L-carnitine and, to a lesser extent, its taurine amide, and also acetyl-L-carnitine, significantly restored cardiac function in 15 minutes after 90 minutes of either low-flow or intermittent no-flow ischemia. Carnitine itself was ineffective. Propionyl-L-carnitine also increased tissue ATP and creatine phosphate compared with controls, but did not affect the levels of long-chain acyl carnitine and coenzyme. These esters also depleted fatty acid peroxidation, as shown with malonaldehyde, and were more effective than carnitine in preventing the production of superoxide. In myocytes, propionyl-L-carnitine alone stimulated palmitate oxidation, but in rat heart homogenates, both L-carnitine and propionyl-L-carnitine did so, while acetyl-L-carnitine was actually inhibitory. Possible mechanisms for the protective action of propionyl-L-carnitine against ischemia include an increased rate of cellular transport, stimulation of fatty acid oxidation, and a reduction of free radical formation.

Acetyl-L-Carnitine: chronic treatment improves spatial acquisition in a new environment in aged rats. J Gerontol A Biol Sci Med Sci (UNITED STATES) Jul 1995, 50 (4) pB232-36 Chronic Acetyl-L-Carnitine (ALCAR) treatment prevents some age-related memory impairment. The present experiment examined the effects of aging and ALCAR in Fischer 344 rats on retention of spatial discrimination test in a familiar environment(FE),and on the acquisition of a spatial discrimination in a novel environment (NE). Chronic ALCAR treatment enhanced spatial acquisition in the NE of rats with age-related behavioral impairments and had a slight effect on retention of the spatial discrimination in the FE. </>

[Effects of L-acetylcarnitine on mental deterioration in the aged: initial results] <> Clin Ter (ITALY) Mar 31 1990, 132 (6 Suppl) p479-510 In this paper the preliminary findings of a multicentre study on the effects of Acetyl-L-Carnitine on mildly impaired elderly are reported. Statistical analysis was carried out on 236 out of 469 subjects sampled in 42 different Italian geriatric or hospital units. Each subject was treated over 150 days, and a battery of tests (investigating cognitive functioning, emotional-affective state and relational behavior) was administered at the beginning on the treatment and the conclusion of each of its four phases. In the first and the last phases there was a 30 days placebo treatment (aimed respectively to wash-out the effects of previous drug and to assess the residual effects of the treatment), while in the second and the third ones (both 45 days long) the subjects took 1500 mg/day of Acetyl-L-carnitine. Repeated multivariate analysis of variance and of ovariance (taking as independent variables phases of treatment, age, gender, etiology and severity of mental impairment, as dependent variables the scores eithe </>

Effect of acetyl-L-carnitine on conditioned reflex learning rate and retention in laboratory animals. <> Drugs Exp Clin Res (SWITZERLAND) 1986, 12 (11) p911-6 The aim of the study was to evaluate the effects of acetyl-L-carnitine on learning and/or memory processes in laboratory animals. In the water maze test, acetyl-L-carnitine, given intraperitoneally at doses ranging from 0. 3 to 100 mg/kg, improved performances in both mice and rats. In the latter the drug also proved active when administered orally in the 3-100 mg/kg dosage range. In the pole climbing test in the rat, acetyl-L-carnitine at doses ranging from 0.03 to 10 mg/kg i.p. increased the conditioned reflex learning rate. In the passive avoidance test in the rat, significant increases in retention were observed after treatment with acetyl-L-carnitine at doses ranging from 1 to 30 mg/kg i.p. In the passive avoidance plus electroconvulsive shock test in the mouse, a-l-carnitine antagonized amnesia at doses ranging from 0.1 to 3 mg/kg i.p. </>

The effects of acetyl-l-carnitine on experimental models of learning and memory deficits in the old rat. Funct Neurol (ITALY) Oct-Dec 1989, 4 (4) p387-90 Experimental models of learning and memory deficits in aged rats can be studied by means of behavioural tests that provide an important tool for evaluating the effect of drugs on these parameters. Active and passive avoidance tests showed a clear impairment of learning and memory capacity of old rats. These tests were also used to study the behavioural effect of acetyl-l-carnitine in aged rats. The subchronic treatment with this drug was followed by a significant improvement of acquisition and retention of avoidance responses, indicating a facilitation of learning and memory capacity of aged rats. </>

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.

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.

Drug treatment of Alzheimer's disease. Effects on caregiver burden and patient quality of life.
Drugs Aging (NEW ZEALAND) Jan 1996, 8 (1) p47-55
Alzheimer's disease is a devastating illness that will become more common as the population ages. Although clinical diagnosis of the illness is not certain without histological examination of the brain, and misdiagnosis may occur, broad working criteria to help diagnose the likely presence of Alzheimer's disease are available. Thoughtful clinical evaluation improves diagnostic accuracy, and appropriately diagnosed patients are critical for involvement in research into new antidementia agents. Essential to the discovery of new drugs is careful measurement of illness response. A variety of scales--some aimed at patients, others at their caregivers, and yet others for clinicians--assess Alzheimer's disease severity, progression, symptom response, and quality of life. Of note, patient response is not the only measurement of treatment benefit today. Growing interest is also being placed on tracking the possible amelioration of caregiver 'burden'. This burden refers to the psychological, physical, and material costs of providing care for an Alzheimer's patient over long periods of time. A number of scales and questionnaires have been developed and are occasionally used. Many drugs have been tried in Alzheimer's disease, but very few have produced any benefit, and this is often modest. Ergoloid mesylates, initially thought to be effective, are now considered of little value. The cholinomimetic drugs, especially the acetylcholinesterase inhibitor tacrine, have provided a very modest benefit, slowing the progression of the illness for a number of months. No cognitive improvement has been noted with the various nootropic agents such as piracetam. Early studies with levacecarnine (acetyl-L-carnitine), a substance that facilitates the use of fatty acids, memantidine, the dimethyl derivative of amantidine, and the calcium channel blocker nimodipine, have shown some promise, but require larger, more rigorous studies. As mentioned above, documenting effects in individual patients is crucial; examining for potential benefit to caregivers is a growing part of research design. Current treatment efforts will become more sophisticated as a deeper understanding of the neurobiology of Alzheimer's disease develops. For the immediate future, the goal is not cure but slowing of the disease process. Achieving this limited goal would have a substantial impact on the financial and human costs of the illness. (58 Refs.)

Acetyl-L-carnitine restores choline acetyltransferase activity in the hippocampus of rats with partial unilateral fimbria-fornix transection.
Int J Dev Neurosci (ENGLAND) Feb 1995, 13 (1) p13-9
Transection of the fimbria-fornix bundle in adult rats results in degeneration of the septohippocampal cholinergic pathway, reminiscent of that occurring in aging as well as Alzheimer disease. We report here a study of the effect of a treatment with acetyl-L-carnitine (ALCAR) in three-month-old Fischer 344 rats bearing a partial unilateral fimbria-fornix transection. ALCAR is known to ameliorate some morphological and functional disturbances in the aged central nervous system (CNS). We used choline acetyltransferase (ChAT) and acetyl cholinesterase (AChE) as markers of central cholinergic function, and nerve growth factor (NGF) levels as indicative of the trophic regulation of the medio-septal cholinergic system. ChAT and AChE activities were significantly reduced in the hippocampus (HIPP) ipsilateral to the lesion as compared to the contralateral one, while no changes were observed in the septum (SPT), nucleus basalis magnocellularis (NBM) or frontal cortex (FCX). ALCAR treatment restored ChAT activity in the ipsilateral HIPP, while AChE levels were not different from those of untreated animals, and did not affect NGF content in either SPT or HIPP.

Acetyl-L-carnitine arginyl amide (ST857) increases calcium channel density in rat pheochromocytoma (PC12) cells.
J Neurosci Res (UNITED STATES) Feb 15 1995, 40 (3) p371-8
We used the patch clamp technique to study the effect of acetyl-L-carnitine arginyl amide (ALCAA) and of nerve growth factor (NGF) on availability of L-type Ca2+ channels in rat pheochromocytoma (PC12) cells maintained in defined medium. Channel availability was measured as number of channels in the patch x the probability of opening (n.Po). In patches from control cells, cells exposed to NGF (10 ng/ml) for six days, and cells exposed to ALCAA (1 mM) for six days, n.Po, measured during 200-240 ms pulses to -10 mV (holding potential, -60 mV), was 0.102 +/- 0.089 (5 cells), 0.173 +/- 0.083 (5 cells), and 0.443 +/- 0.261 (7 cells), respectively. The 4.3-fold increase for the ALCAA-treated cells was significantly different from control (P < 0.05), whereas that for the NGF-treated cells was not. For the same conditions, the maximum number of superimposed openings at -10 mV was 1.3 +/- 0.5 (6 cells), 1.6 +/- 0.5 (8 cells), and 3.3 +/- 1.8 (8 cells), with the value for the ALCAA-treated cells being significantly different from control (P < 0.001). Additional analysis showed that the distribution of channel open times, the time constants, and the voltage dependence of activation were not changed by prolonged exposure to ALCAA. Short-term exposure to both ALCAA as well as to the parent compound, acetyl-L-carnitine (ALCAR), did not cause an increase but rather a decrease in n.Po, and this short-term effect of both compounds was blocked by neomycin, an inhibitor of phospholipase C.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurite outgrowth in PC12 cells stimulated by acetyl-L-carnitine arginine amide.
Neurochem Res (UNITED STATES) Jan 1995, 20 (1) p1-9
Senescence of the central nervous system is characterized by a progressive loss of neurons that can result in physiological and behavioral impairments. Reduction in the levels of central neurotrophic factors or of neurotrophin receptors may be one of the causes of the onset of these degenerative events. Thus, a proper therapeutic approach would be to increase support to degenerating neurons with trophic factors or to stimulate endogenous neurotrophic activity. Here we report that acetyl-L-carnitine arginine amide (ST-857) is able to stimulate neurite outgrowth in rat pheochromocytoma PC12 cells in a manner similar to that elicited by nerve growth factor (NGF). Neurite induction by ST-857 requires de novo mRNA synthesis and is independent of the action of several common trophic factors. The integrity of the molecular structure of ST-857 is essential for its activity, as the single moieties of the molecule have no effect on PC12 cells, whether they are tested separately or together. Also, minor chemical modifications of ST-857, such as the presence of the arginine moiety at a position other than the amino one, completely abolish its neuritogenic effect. Lastly, the presence of ST-857 in the culture medium competes with the high affinity NGF binding in a dose dependent fashion. These results, although preliminary, are suggestive of a possible role for ST-857 in the development of therapeutic strategies to counteract degenerative diseases of the CNS.

Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats.
Prog Neuropsychopharmacol Biol Psychiatry (ENGLAND) Jan 1995, 19 (1) p117-33
1. There is growing evidence that the nerve growth factor protein (NGF), a neurotrophic factor for peripheral and central nervous system (CNS) neurons, may play a role in the modulation of the hypothalamo-pituitary-adrenocortical axis (HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this reduction is prevented by treatment with Acetyl-L-Carnitine (ALCAR), a chemical substance able to prevent some degenerative events associated with aging. 2. The authors studied the effect of cold stress on the low-affinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats chronically treated with ALCAR. 3. The present results show that ALCAR abolished the age-associated reduction of p75NGFR mRNA levels in the basal forebrain of old animals, but did not affect the response to stress stimuli. 4. Also, treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old animals at levels almost identical to those observed in young control animals. 5. These results suggest a neuroprotective effect for ALCAR on central cholinergic neurons exerted at the level of transcription of p75NGFR. The restoration of p75NGFR levels could increase trophic support by NGF of these CNS cholinergic neurons which are implicated in degenerative events associated with aging.

Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats.
Exp Gerontol (ENGLAND) Jan-Feb 1994, 29 (1) p55-66
The hypothesis that some neurodegenerative events associated with ageing of the central nervous system (CNS) may be due to a lack of neurotrophic support to neurons is suggestive of a possible reparative pharmacological strategy intended to enhance the activity of endogenous neurotrophic agents. Here we report that treatment with acetyl-l-carnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons. Furthermore, long-term treatment with ALCAR completely prevents the loss of choline acetyltransferase (ChAT) activity in the CNS of aged rats, suggesting that ALCAR may rescue cholinergic pathways from age-associated degeneration due to lack of retrogradely transported NGF.

Acetyl-L-carnitine affects aged brain receptorial system in rodents.
Life Sci (ENGLAND) 1994, 54 (17) p1205-14
Acetyl-L-carnitine (ALCAR), the acetyl ester of carnitine, is regarded as a compound of considerable interest because of its capacity to counteract several physiological and pathological modifications typical of brain ageing processes. In particular, it has been demonstrated that ALCAR can counteract the age-dependent reduction of several receptors in the central nervous system of rodents, such as the NMDA receptorial system, the Nerve Growth Factor (NGF) receptors, those of glucocorticoids, neurotransmitters and others, thereby enhancing the efficiency of synaptic transmission, which is considerably slowed down by ageing. The present review thus postulates the importance of ALCAR administration in preserving and/or facilitating the functionality of carnitines, the concentrations of which are diminished in the brain of old animals. (57 Refs.)

Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine.
Biochem Pharmacol (ENGLAND) Aug 4 1992, 44 (3) p577-85
Acetyl-L-carnitine (ALCAR) prevents some deficits associated with aging in the central nervous system (CNS), such as the aged-related reduction of nerve growth factor (NGF) binding. The aim of this study was to ascertain whether ALCAR could affect the expression of an NGF receptor (p75NGFR). Treatment of PC12 cells with ALCAR increased equilibrium binding of 125I-NGF. ALCAR treatment also increased the amount of immunoprecipitable p75NGFR from PC12 cells. Lastly, the level of p75NGFR messenger RNA (mRNA) in PC12 was increased following ALCAR treatment. These results are in agreement with the hypothesis that there is a direct action of ALCAR on p75NGFR expression in aged rodent CNS.

Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF.
Int J Dev Neurosci (ENGLAND) Aug 1992, 10 (4) p321-9
In vitro neuronal preparations are used to study the action mechanism of substances which are active in normal and pathological brain aging. One major concern with in vitro assays is that the use of embryonic or adult neurons may hamper an appreciation of the relevance of these substances on aged nervous tissue. In the present study for the first time cultures of aged dorsal root ganglia from 24-months-old rats were maintained in vitro up to 2 weeks. This model was used to investigate the neurotrophic/neuroprotective action of nerve growth factor and acetyl-L-carnitine. A large population of aged dorsal root ganglia neurons was responsive to nerve growth factor (100 ng/ml). Nerve growth factor induced an increase of initial rate of axonal regeneration and influenced the survival time of these neurons. Acetyl-L-carnitine (250 microM) did not affect the axonal regeneration but substantially attenuated the rate of neuronal mortality. A significant difference was evident between the acetyl-L-carnitine-treated and the untreated neurons from the first cell counting (day 3 in culture). After 2 weeks the number of aged neurons treated with acetyl-L-carnitine was almost double that of the controls. The effects of acetyl-L-carnitine on aged DRG neurons potentially explain the positive effects in clinical and in vivo experimental studies.

Acetyl-L-carnitine enhances the response of PC12 cells to nerve growth factor.
Brain Res Dev Brain Res (NETHERLANDS) Apr 24 1991, 59 (2) p221-30
We have demonstrated that treatment of rat pheochromocytoma (PC12) cells with acetyl-L-carnitine (ALCAR) stimulates the synthesis of nerve growth factor receptors (NGFR). ALCAR has also been reported to prevent some age-related impairments of the central nervous system (CNS). In particular, ALCAR reduces the loss of NGFR in the hippocampus and basal forebrain of aged rodents. On these bases, a study on the effect of NGF on the PC12 cells was carried out to ascertain whether ALCAR induction of NGFR resulted in an enhancement of NGF action. Treatment of PC12 cells for 6 days with ALCAR (10 mM) stimulated [125I]NGF PC12 cell uptake, consistent with increased NGFR levels. Also, neurite outgrowth elicited in PC12 cells by NGF (100 ng/ml) was greatly augmented by ALCAR pretreatment. When PC12 cells were treated with 10 mM ALCAR and then exposed to NGF (1 ng/ml), an NGF concentration that is insufficient to elicit neurite outgrowth under these conditions, there was an ALCAR effect on neurite outgrowth. The concentration of NGF necessary for survival of serum-deprived PC12 cells was 100-fold lower for ALCAR-treated cells as compared to controls. The minimal effective dose of ALCAR here was between 0.1 and 0.5 mM. This is similar to the reported minimal concentration of ALCAR that stimulates the synthesis of NGFR in these cells. The data here presented indicate that one mechanism by which ALCAR rescues aged neurons may be by increasing their responsiveness to neuronotrophic factors in the CNS.

Effect of acetyl-L-carnitine on forebrain cholinergic neurons of developing rats.
Int J Dev Neurosci (ENGLAND) 1991, 9 (1) p39-46
It has been shown that the endogenous compound, acetyl-L-carnitine (ALCAR), acts in the brain as a metabolic cofactor in the synthesis of acetylcholine. In these studies, ALCAR was injected into the brain of developing rats every other day for the first three weeks after birth in order to assess its effect on forebrain cholinergic neurons. The results showed that intracerebroventricular (icv) administration of ALCAR causes an increase of choline acetyltransferase (ChAT) activity and of nerve growth factor receptor expression in the striatum. Biological assays of brain tissues revealed that the level of nerve growth factor (NGF) in the hippocampus also increases. The ability of brain cholinergic tissues to respond to exogenous administration of ALCAR is discussed.

Nerve growth factor binding in aged rat central nervous system: effect of acetyl-L-carnitine.
J Neurosci Res (UNITED STATES) Aug 1988, 20 (4) p491-6
The nerve growth factor protein (NGF) has been demonstrated to affect neuronal development and maintenance of the differentiated state in certain neurons of the peripheral and central nervous system (CNS) of mammals. In the CNS, NGF has sparing effects on cholinergic neurons of the rodent basal forebrain (BF) following lesions where it selectively induces choline acetyltransferase (ChAT). NGF also induces ChAT in the areas to which BF provides afferents. In aged rats, there is a reduction in the NGF-binding capacity of sympathetic ganglia. Here, we wish to report that there is a decrease in the NGF-binding capacity of the hippocampus and basal forebrain of aged (26-month-old) rats as compared to 4-month-old controls but no change in NGF binding in cerebellum. In all instances, equilibrium binding dissociation constants did not differ significantly. Treatment of rats with acetyl-L-carnitine, reported to improve cognitive performance of aged rats, ameliorates these age-related deficits.

Carnitine and acetyl-L-carnitine content of human hippocampus and erythrocytes in Alzheimer's disease
Journal of Nutritional and Environmental Medicine (United Kingdom), 1995, 5/1 (35-39)
We have studied carnitine and acetyl-L-carnitine content of hippocampus and erythrocytes from Alzheimer's disease patients and elderly control subjects. Carnitine content was similar in erythrocytes from Alzheimer's disease patients and controls, but in contrast acetyl-L-carnitine content was significantly lower in the Alzheimer's disease patients compared with control subjects. On post-mortem samples from hippocampus, carnitine and acetyl-L-carnitine content did not differ significantly between patients when related to the protein content.

Advances in the pharmacotherapy of Alzheimer's disease
EUR. ARCH. PSYCHIATRY CLIN. NEUROSCI. (Germany), 1994, 244/5 (261-271)
The authors reviewed the literature on the agents proposed for the treatment of Alzheimer's disease (AD). Different classes of drugs have been tested for this indication including psychostimulants, anticoagulants, vasodilators, hyperbaric oxygen, hormones, nootropics, cholinomimetics, monoaminergics and neuropeptides without conclusive evidence of being beneficial for the treatment of this condition. Among the cholinomimetics recent research data seems to indicate that they might produce modest benefits in mild-to-moderate AD patients. Recently, other drugs have also been proposed including neurotrophic factors, phosphatidylserine, argistension converting enzyme (ACE) inhibitors, calcium channel blockers, acetyl-L-carnitine, xanthine derivatives, anti-inflammatory agents, aluminum chelate agents, and D-cycloserine. Of these new strategies few hold promise of more substantial benefits for AD, with the possibility of altering the course of the disease, but these drugs await confirmatory trials.

Neuroprotective activity of acetyl-L-carnitine: Studies in vitro
NEUROSCI. RES. (USA), 1994, 37/1 (92-96)
The neuroprotective properties of acetyl-L-carnitine (ALCAR) were investigated in primary cell cultures from rat hippocampal formation and cerebral cortex of 17-day-old rat embryos. Chronic exposure to ALCAR (10-50 microM for 10 days) reduced the cell mortality induced by 24 hr fetal calf serum deprivation. Protection was partial when the neuronal cells, chronically treated with ALCAR (50 microM), were exposed to glutamate (0.25-1 mM) and kainic acid (250-500 microM) for 24 hr. The neurotoxicity induced by N-methyl-D- aspartate (NMDA, 250 microM) was attenuated by the acute co-exposure with ALCAR (1 mM), the chronic treatment with ALCAR (50 microM) significantly reduced the neuronal death induced by NMDA (0.25-1 mM). Cell mortality was also investigated in ALCAR-treated hippocampal cultures chronically treated with beta-amyloid fragment 25-35. ALCAR appeared to have neuroprotective activity. This suggests an explanation of the positive results obtained with ALCAR in the treatment of Alzheimer's disease.

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.

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.

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.

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.