|
Recent research has clarified many of the clinical applications
of L-Carnitine and its related compounds, leading into new areas of potential
use. Promising therapeutic applications of an ester form of carnitine,
acetyl-L-Carnitine (ALC) are derived from observations that this compound
readily crosses the blood- brain barrier and improves neuronal energetics and
repair mechanisms while modifying acetylcholine production in the CNS. Studies
show that HIV infection and CFIDS, AlzheimerÍs dementia and depression of the
elderly, and diabetic neuropathies may respond positively to ALC administration.
Effects of ALC on ethyl alcohol (ETOH) metabolism have been observed and hold
significant potential in preventing sequelae of habitual ETOH abuse. (Alt Med
Rev 1996;1(2):85-93)
L-Carnitine is synthesized in mammalian liver, kidney and brain tissue with
lysine, methionine and vitamin C among the required substrates and co-factors.
The main body stores are in skeletal and cardiac muscle. Acetyl-L-Carnitine is
one of the esters of carnitine and is found along with free plasma carnitine and
other acyl esters of varying chain length.1 The formation of ALC originates with cytoplasmic thiokinase (See Figure
1) which forms acylcoenzyme A from free-fatty acids, ATP and Coenzyme A
(CoA). This substance is combined with carnitine to form acylcarnitine via
carnitine palmitoyltransferase I. Entry into the mitochondrial matrix occurs
through an exchange system of acylcarnitine/carnitine via
carnitine-acylcarnitine translocase. For each acylcarnitine molecule traversing
the inner mitochondrial membrane, a molecule of carnitine is shuttled out. On
the inner mitochondrial membrane, carnitine palmitoyltransferase II converts
acylcarnitine to carnitine, liberating acylCoA. Finally, the production of ALC
and CoA from carnitine and acetylCoA (obtained via ß oxidation of acyl CoA)
occurs via carnitine acetyltransferase present in the mitochondrial matrix.2
Carnitine and its esters prevent toxic accumulations of fatty acids and acyl
CoA (in the cytoplasm and mitochondria, respectively) while providing acetyl CoA
for energy generation in the mitochondria. ALCÍs enzymatic formation in the
mitochondrial matrix is reversible, providing free Coenzyme A and acetyl CoA
which can readily be exchanged across membranes, thus providing metabolic energy
to intracellular organelles.3 Carnitine acetyltransferase is a reversible enzyme
system which appears to be linked with choline acetyltransferase (ChAT), thereby
supplying intracellular acetylcholine while the opposite reaction liberates
acetylCoA. This mechanism can explain the improved cholinergic neurotransmission and
enhanced intracellular energetics observed in ALC research.4, 5 Studies in
humans and guinea pigs have shown that supplemental choline is able to decrease
the urinary excretion of carnitine while resulting in increased muscle carnitine
stores, giving further evidence of this enzymatic linkage.6 HIV infection presents numerous problems related to the carnitines. Human and
animal studies show an increased urinary excretion of carnitine when
pivampicillin is administered. Animal studies indicate that pivampicillin
interferes with myocardial carnitine metabolism subsequent to pivalocarnitine
formation in the heart, leading to increased excretion. AZT can result in muscle
carnitine depletion, contributing to the lipid accumulation and mitochondrial
dysfunction characteristic of this myopathy. Malabsorption may decrease
carnitine availability at the cellular level, while HIV-related renal
dysfunction may increase excretion of the compound. Thus it is postulated that a
subgroup of HIV-infected individuals are burdened with secondary carnitine
deficiencies.7-9 ALC and L-CarnitineÍs effect on leukocyte proliferation and production of
tumor necrosis factor-a (TNF-a) provide new potential applications of the
compounds in HIV-infected individuals. Both mitogenic and antigenic
proliferation of lymphocytes have been increased with LC and ALC in vitro.7 Peripheral blood monocytes in AIDS patients are low in intracellular
carnitine. Serum levels may be high, low or normal and is therefore unreliable
as an indicator of carnitine metabolism.10,11 Peripheral blood monocytes from
HIV-infected individuals were cultured with the mitogen PHA and ALC for 48
hours. PHA-induced proliferation was significantly improved and a dimunition of
TNF-a released by the cultured monocytes was also observed to be significant. As
TNF-a has a key role in HIV-mediated apoptotic cell destruction, decreased
levels of this cytokine may have protective effects on CD4+ cell populations.12
In a brief clinical trial with AIDS patients, L-Carnitine was administered (6
g/day for 14 days) and lymphocyte proliferation improved in response to mitogen
stimulation. Importantly, the increased monocyte production did not lead to
increased HIV proliferation. TNF-a levels were decreased and ß-2 microglobulin,
an indicator of HIV progression to AIDS was also diminished.13,14 Thus, LC and
ALC represent novel approaches in complementary treatment of HIV infections and
may correct secondary carnitine deficiencies found in these patients. Another potential application of ALC involving immunomodulation is in the
management of Chronic Fatigue Syndrome (CFS). Low serum levels of ALC have been
observed in many CFS patients. The clinical presentation of marked fatigue
correlates with periods of low serum ALC while periods of recovery are
characterized by higher levels of ALC. 15 Further implications for ALC treatment
of CFS patients are findings that plasma levels of ß-endorphin and cortisol are
raised in humans given an I.V. bolus of ALC.16 As abnormal cortisol levels have
been observed in some patients with CFS, and the myalgic symptoms in this
condition are well known, ALC administration might be particularly helpful in
normalizing HPA perturbations via feedback mechanisms and decreasing myalgic
pain via peripheral neuron response to ß-endorphin.17 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 AlzheimerÍs 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 AlzheimerÍs 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 AlzheimerÍs. 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 MartignoniÍs study showing
increased ß-endorphin production in response to ALC administration presents yet
another potential benefit of ALC in the patient with AlzheimerÍs dementia
because of their tendancy to have reduced ß-endorphin levels. 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 ALCÍs 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 The effects of ALC on cortisol levels have been varied. In one 40-day study
of depressed elderly adults, significant normalization of elevated cortisol
levels and improved scores on mood assessments resulted from ALC administration
(0.5g/qid p.o.). In 43% of the patients, the treatment was so successful that
they were determined to be in clinical remission.25 This supports an earlier
study of 24 depressed adults treated over a 2-month period where the depressive
symptoms improved to a high degree of significance, especially in the group with
the most severe clinical presentation.26 However, in the study by Martignoni,
with non-depressed healthy male volunteers, the intravenous administration of
ALC raised cortisol levels along with ß-endorphin. It appears that ALC may have
an amphoteric effect on cortisol levels, raising or lowering levels according to
HPA feedback mechanisms. Peripheral neuropathy associated with diabetes mellitus (DM) is extremely
common, approaching over 28% of some populations.27 Various mechanisms of
neuronal damage have been postulated, including polyol pathway generation of
sorbitol and free radical damage. Reduced nerve conduction velocities occur in
DM and have led to experimental models assessing this function in rats. Animals
given ALC after experimental diabetes induction have improved nerve conduction
velocities.28,29 Correction of abnormal enteric peptides associated with
autonomic neuropathies was also observed in animal models. 30 Human studies also show beneficial effects of ALC in neuropathies.
Intramuscular administration of the compound given to 63 patients with painful
neuropathy for 15 days showed significant improvement in motility and subjective
measures.31 A small double-blind study in humans again using the I.M. route of
administration, showed highly significant improvement in painful neuropathies.
Again the anti-oxidant function of ALC was believed to be a likely mechanism of
action.32 The changes which occur in CNS tissue of aged laboratory animals as well as
tissue samples from humans have both structural and metabolic components. One of
these changes is the reduced surface contact area found in dendritic networks.
The capacity for recovery and expansion of the dendritic network does, however,
remain present in older individuals.33 ALC was administered orally to rats over
a 6-22 month period after which brain synaptic tissue was evaluated for size and
number of junctions. The expected decline in synaptic contact area was partially
reversed in the treatment groups.34 Human studies confirm the impact ALC can have on neurological function.
Bonavita observed significant improvements in aged subjects participating in a
40-day, double-blind trial with oral ALC, 3 g/day. The first changes tended to
relate to spatial recognition, judgment and depression; second-phase changes
centered on short and long-term memory, self-care, and sociability. Intravenous
administration of ALC elicited increased visual evoked potential amplitude among
both healthy volunteers and patients with various dementias. The changes
persisted over a 50-90 minute period, showing the rapid clearing of the
substance by renal tubular mechanisms. 35 Repair of tissue atrophy after neuronal damage is a function of the length of
denervation time and rate of regeneration of neuronal tissue. In a comparison
study of the nerve-regeneration effects of L-Carnitine and ALC, there were
significant improvements in the ALC group of animals compared to the L-Carnitine
group. This was postulated to be related to ALCÍs unique ability to supply
acetyl groups for mitochondrial energy production.36 Clinical applications of the neuro-regenerative effects of ALC were
investigated in an experimental model of post-ischemic cerebral injury. In a
simulation of the cerebral ischemia present after cardiac arrest, ALC was
administered intravenously to canines. Their recovery was assessed via
neurologic deficit scores and neurochemical markers. The ALC group fared
significantly better than controls in post-ischemic recovery parameters. 37 Acetyl-L-Carnitine is a substance which retains the well-known effects of
L-Carnitine on muscle tissue; i.e., long-chain fatty acid transport for ATP
production within the mitochondria. ALCÍs further impact on both skeletal muscle
and the myocardium include antioxidant effects leading to less lipid
peroxidation, thus protecting exercising muscle tissue from free-radical
damage.38 Additionally, it may improve cardiolipin levels in the aged heart, a
substance which maintains crucial membrane factors in cardiac mitochondria and
thus ensures efficient phosphate transport for energy. In a rat mitochondrial
model, it was shown that ALC administered to aged animals returned cardiolipin
levels to that of young ones. 39 Cerebral and peripheral circulation are apparently affected differently by
administration of ALC. Ten patients with recent cerebral vascular accidents were
given ALC intravenously which resulted in acute enhancement of cerebral blood
flow to areas of ischemia via sensitive SPEC tomography assessments.40 In
evaluation of patients with peripheral arterial occlusive disease, two studies
show that the effect of carnitine esters on improved walking distance was due to
metabolic vs. hemodynamic changes and that L-Propionylcarnitine was clearly
superior to L-Carnitine in this effect. These studies demonstrate the ability of
carnitine esters to positively influence tissue energetics which may prove
beneficial in a chronic administration model.41,42 A number of interesting reports on the relationship between hepatic
detoxification of ethanol and carnitines have been produced. It is observed that
pretreatment of both rats and chickens with carnitines resulted in a prolonged
half-life of ethanol in the blood.43,44 Additionally, a protective effect on
prenatal ethanol damage to thalamic and cortical regions in rats was observed
with administration of ALC.47 Two studies by Cha and Sachan with isolated rat
hepatocytes harvested after pretreatment with ALC elucidate the mechanism of
these interesting effects. An inhibition of alcohol dehydrogenase was present
and significantly increased when the nicotinamide adenine dinucleotide:ALC ratio
was low. It was also shown that L-Carnitine itself was much less effective at
producing this inhibition.47,48 As a final addition to these findings of great
therapeutic interest, oral administration of ALC was shown to improve the
cognitive impairments of 55 chronic alcoholics.48 We may infer from this work that patients with high ethanol intake may have
prolonged ethanol half-life if they are concurrently taking ALC supplementation.
This effect may be due in part to low niacin levels and could be modified by
niacin administration. ALCÍs cerebro-thalamic protection observed in rat pups
exposed to ethanol prenatally and the apparent hepato-protective effects
observed in models of chronic alcohol use provide exciting possibilities for
preventing the intergenerational sequelae of high ethanol intake. In 130 patients studied by Spagnoli, et al over a one-year duration, the
administration of oral ALC (2 grams/day) slowed the progression of AlzheimerÍs
disease. Patients in the treatment group experienced significant positive
effects, ascertained by neuropsychological tests, in a variety of areas. At the
3-month mark, agitation was experienced by 11% of patients taking ALC and 6% of
patients taking placebo, a difference which was not statistically significant.
The incidence of agitation in both groups decreased to 7% by the 6-month
follow-up.49 Adverse reactions occurred in a small study of 36 patients with
AlzheimerÍs dementia. Eight of the 11 withdrawals from the active group reported
nausea/vomiting or agitation/aggression within the first 14 days of the trial.
No laboratory abnormalities were noted in the study. It was suggested that
administration of the ALC follow a meal to minimize symptoms.50 In addition to the minor adverse reactions to ALC from the above human
trials, a cautionary note may be extrapolated from rat studies whereby an
intracerebral injection of ALC induced epileptic phenomena.51 Another researcher
found however, no changes in cell excitability and no epileptic discharges in
ALC- treated rats exposed to high-frequency stimulation.19 From the clinical and
experimental research, it seems prudent to: As ALC is easily transported across the blood-brain barrier, multiple
benefits in CNS function have been observed in human studies. Models of aging,
stroke, AlzheimerÍs dementia, diabetic neuropathy and neuropeptide release have
been positively influenced by ALC administration. Acetyl-L-Carnitine is able to
exert profound effects on some depressed patients with high cortisol levels and
participates in immunomodulatory mechanisms which hold promise in the treatment
of HIV infection. ALC modifies ethanol metabolism in animal models;
paradoxically increasing the half-life of ethanol while decreasing hepatic
damage. Because of ALCÍs excellent tolerability, with infrequent and often temporary
side effects, it has great potential of being a safe and efficacious therapeutic
compound. Oral doses from 1.5 grams to 3.0 grams per day are typically in the
therapeutic range for most conditions, the I.M. route was used for treatment of
neuropathy. Although many of ALCÍs effects overlap those of L-Carnitine, the
vast experience with the simpler compound in ischemic heart disease should not
be abandoned. For conditions regarding CNS and neuronal damage, the L-Acetyl
form of carnitine is clearly superior. With additional research and clinical
trials, future applications of ALC hold exciting promise in the practice of
complementary medicine. 1. Goa KL, Brogden A. L-Carnitine, a preliminary review of its
pharmacokinetics, and its therapeutic use in ischaemic cardiac disease and
primary and secondary carnitine deficiencies in relationship to its role in
fatty acid metabolism. Drugs 1987;34:1-24. 2. HarperÍs Review of Biochemistry, 23rd Ed. R.K. Murray,D.K. Granner, P.A.
Mayes and V.W. Rodwell; Eds. Appleton-Lange Medical Publications pp 220-223.
3. Calvani M, Carta A. Clues to the mechanism of action of acetyl-L-carnitine
in the central nervous system. Dementia 1991;2:1-6. 4. White HL, Scates PW. Acetyl l-carnitine as a precursor of acetylcholine.
Neurochem Res 1990;15:597-601. 5. Piovesan P, Quatrini G, Pacifici L, et al. Acetyl-l- carnitine restores
choline acetyltransferase activity in the hippocampus of rats with partial
unilateral fimbria-fornix transection. Int J Devl Neuroscience 1995;13:13-19.
6. Daily JW, Sachan DS. Choline supplementation alters carnitine homeostasis
in humans and guinea pigs. J Nutr 1995;125:1938-1944. 7. Famularo G, Tzantzoglou S, Santini G, et al. L-carnitine - a partner
between immune response and lipid metabolism. Mediators Inflamm 1993;2: s29-s32.
8. Diep QN, Brors O, Bohmer T. Formation of pivaloylcarnitine in isolated rat
heart cells. Biochem Biophys Acta 1995;1259:161-165. 9. Mintz M. Carnitine in human immunodeficiency virus type I infection /
acquired immune deficiency syndrome. J Child Neurol 1995;10:s40-s44. 10. DeSimone C, Tzantzglou S, Jirillo E, et al. L-carnitine deficiency in
AIDS patients. AIDS 1992;6:203-205. 11. DeSimone C, Famularo G, Tzantzoglou S, et al. Carnitine depletion in
peripheral blood mononuclear cells from patients with AIDS: effect of oral
L-carnitine. AIDS 1994; 8:655-660. 12. Famularo G, DeSimone C. Apoptosis, anti-apoptotic compounds and TNF-a
release. Immunol Today 1994;5:495-496. 13. Famularo G, DeSimone C. A new era for carnitine? Imunol Today 1995;
16:211-213. 14. DeSimone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine
improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol
Immunotoxicol 1993;15:1-12. 15. Kuratsune H, Yamaguti K, Takahashi M, et al. Acylcarnitine deficiency in
chronic fatigue syndrome. Clin Infect Dis 1994:18; s62-s67. 16. Martignoni E, Facchinetti F, Sances G, et al. Acetyl-L-carnitine acutely
administered raises ß-endorphin and cortisol plasma levels in humans. Clin
Neuropharmacol 1988;11:472-477. 17. Blalock JE. The syntax of immune-neuroendocrine communication. Immunol
Today 1994;15:504-511. 18. Parnetti L, Gaiti A, Mecocci P, et al. 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 1992;42:89-93. 19. Davis S, Markowska AL, Wenk GL, et al. Acetyl-L-carnitine: behavioral,
electrophysiological, and neurochemical effects. Neurobiol Aging
1993;14:107-115. 20. Calvani M, Carta A, Caruso G, et al. Action of acetyl-l-carnitine in
neurodegeneration and AlzheimerÍs disease. Ann NY Acad Sci 1992;663:483-486.
21. Pettigrew JW, Klunk WE, et al. Clinical and neurochemical effects of
acetyl-l-carnitine in AlzheimerÍs disease. Neurobiol of Aging: 1995;16:1-4. 22. Bonavita E. Study of the efficacy and tolerability of L-acetylcarnitine
therapy in the senile brain. Int J Clin Pharmacol Ther Tox 1986;24:511-516. 23. Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study
of acetyl levocarnitine in patients with alzheimerÍs disease. Arch Neurol 1992;
49:1137-1141. 24. Pascale A, Milano S, Corsico N, et al. Protein kinase C activation and
anti-amnesic effect of acetyl-L-carnitine:in vitro and in vivo studies. Eur J
Pharmacol 1994;265:1-7. 25. Gecele M, Francesetti G, Meluzzi A. Acetyl-Lcarnitine in aged subjects
with major depression: clinical efficacy and effects on the circadian rhythm of
cortisol. Dementia 1991;2:333-337. 26. Tempesta E, Casella L, Pirrongelli C, et al. L-acetylcarnitine in
depressed elderly subjects. A cross-over study vs. Placebo. Drugs Exp Clin Res
1987; 13:417-423. 27. Young MJ, Boulton AJM, Macleod AF, et al. A multicentre study of the
prevalence of diabetic peripheral neuropathy in the United Kingdom hospital
clinic population. Diabetalogica 1993;36:150-154. 28. Lowitt S, Malone JI, Salem AF, et al. Acetyl-L-carnitine corrects the
altered peripheral nerve function of experimental diabetes. Metabolism 1995;
44:677-680. 29. Merry AC, Kamijo M, Lattimer S, et al. Long-term prevention and
intervention effects of acetyl-L-carnitine on diabetic neuropathy in BB/W-rats.
Diabetes 1994;43:108A. 30. Gorio A, DiGiulo AM, Tenconi B, et al. Peptide alterations in autonomic
diabetic neuropathy prevented by acetylcarnitine. Int J Clin Pharm Res
1992;12:225-230. 31. Onofrj M, Fulgente T, Melchionda D, et al. L-acetylcarnitine as a new
therapeutic approach for peripheral neuropathies with pain. Int J Clin Pharm Res
1995;15:9-15. 32. Quatraro A, Roca P, Donzella C, et al. Acetyl-l-carnitine for symptomatic
diabetic neuropathy. Diabetalogica 1995;38:123. 33. Bertoni-Freddari C, Fattoretti P, Casoli T, et al. Morphological adaptive
response of the synaptic junctional zones in the human dentate gyrus during
aging and alzheimerÍs disease. Brain Res 1990;517:69-75. 34. Bertoni-Freddari C, Fattoretti, P, Casoli T, et al. Dynamic morphology of
the synaptic junctional areas during aging: the effect of chronic
acetyl-L-carnitine administration. Brain Res 1994;656:359-366. 35. Gambi D, Onofrj M, Calvani M, et al. Neurophysiological studies of
L-acetylcarnitine administration in man. Drugs Exp Clin Res 1989;15:435-446.
36. Fernandez E, Pallini R, Gangitano C, et al. Effects of L-carnitine,
L-acetylcarnitine and gangliosides on the regeneration of the transected sciatic
nerve in rats. Neurological Res 1989;11:57-62. 37. Rosenthal RE, Williams R, Yolanda BA, et al. Prevention of postischemic
canine neurological injury through potentiation of brain energy metabolism by
acetyl-L-carnitine. Stroke 1992;23:1312-1318. 38. DiGiacomo C, Latteri F, Fichera C, et al. Effect of acetyl-L-carnitine on
lipid peroxidation and xanthine oxidase activity in rat skeletal muscle.
Neurochem Res 1993;18:1157-1162. 39. Paradies G, Ruggiero FM, Gadaleta MN, et al. The effect of aging and
acetyl-L-carnitine on the activity of the phosphate carrier and on the
phospholipid compostion in rat heart mitochondria. Biochem BiophysiActa
1992;1103:324-326. 40. Postiglione A, Soricelli A, Cicerano U, et al. Effect of acute
administration of lac on cerebral blood flow in patients with chronic cerebral
infarct. Pharmacol Res 1991;23:241-246. 41. Sabba C, Berardi E, Antonica G, et al. Comparison between the effect of
l-propionylcarnitine, l-carnitine and nitroglycerine in chronic peripheral
arterial disease: a haemodynamic double blind echo-doppler study. Eur Heart J
1994;15:1348-1352. 42. Brevetti G, Perna S, Sabba C, et al. Superiority of L-propionylcarnitine
vs. L-carnitine in improving walking capacity in patients with peripheral
vascular disease: an acute, intravenous, double-blind, cross-over study. Eur
Heart J 1992; 13: 251-255 43. Smith MO, Cha YS, Sachan DS. Carnitine prolongs the half-life of ethanol
in broilers. Comp Biochem Physiol Physiol 1994;109:177-180. 44. Sachan DS, Berger R. Attenuation of ethanol metabolism by supplementary
carnitine in rats. Alcohol 1987;4:31-35. 45. Santarelli M, Granato A, Sbriccoli A, et al. Alterations of the
thalamo-cortical system in rats prenatally exposed to ethanol are prevented by
concurrent administration of acetyl-L-carnitine. Brain Res 1995;698:241-247.
46. Cha YS, Sachan DS. Acetylcarnitine-mediated inhibition of ethanol
oxidation in hepatocytes. Alcohol 1995;12:289-294. 47. Sachan DS, Cha YS. Acetylcarnitine inhibits alcohol dehydrogenase.
Biochem Biophys Res Comm 1994;203:1496-1501. 48. Tempesta E, Troncon R, Janiri L, et al. Role of acetyl-L-carn itine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin
Pharm Res 1990 X(1-2):101-107. 49. Spagnoli A, Lucca U, Menasce G, et al.
Long-term acetyl-L-carnitine treatment in AlzheimerÍs disease. Neurology
1991;41:1726-1732. 50. Rai G, Wright G, Scott L, et al. Double-blind, placebo controlled study
of acetyl-L-carnitine in patients with AlzheimerÍs dementia. Curr Med Res Opin
1990;11:638-647. 51. Fariello RG, Zeeman E, Golden GT, et al. Transient seizure activity
induced by acetylcarnitine. Neuropharmacol 1984;23:585-587. |