Pantethine: A review of its biochemistry and therapeutic applications Pantethine is the stable disulfate form of pantetheine, the metabolic substrate which constitutes the active part of Coenzyme-A (CoA) molecules and acyl carrier proteins. Because pantethine is located nearer to Coenzyme-A than is pantothenic acid in the biosynthetic pathway of Coenzyme-A, it has been suggested it will have clinical benefits in conditions where pantothenic acid is not effective, and clinical trials with pantethine appear to prove this argument. Oral administration of pantethine has consistently shown an ability to favorably impact a variety of lipid risk factors in persons with hypercholesterolemia, arteriosclerosis, and diabetes. Pantethine administration positively affects parameters associated with platelet lipid composition and cell membrane fluidity. (Alt. Med. Rev. 1997;2(5):365-377) Pantethine, which is known to be converted

to Coenzyme-A, has been reported to have antiarrhythmic action on experimental cardiac arrhythmias Using standard microelectrode techniques, the electrophysiological effects of pantethine under hypoxic (95% N2 + 5% CO2) perfusion were studied. Hypoxia decreased resting membrane potential, action potential amplitude and maximum velocity of phase 0 and shortened action potential duration and effective refractory period. Application of pantethine 5 X 10(-3) Gm/ml under hypoxic perfusion prolonged action potential duration and effective refractory period significantly. Prolongation of action potential duration by pantethine might be caused by an increase in intracellular ATP. The findings in this study could be an explanation of the possible antiarrhythmic effects of pantethine. Hayashi H, Kobayashi A, Terada H, Nagao B, Nishiyama T, Kamikawa T, Yamazaki N. Effects of pantethine on action potential of canine papillary muscle during hypoxic perfusion. In: Jpn Heart J (1985 Mar) 26(2):289-96. Preclinical and Clinical Studies with Cysteamine and Pantethine 1. Cysteamine is formed by degradation of Coenzyme-A (CoA) and causes somatostatin (SS), prolactin and noradrenaline depletion in the brain and peripheral tissues. 2. Cysteamine influences several behavioral processes, like active and passive avoidance behavior, open-field activity, kindled seizures, pain perception and SS-induced barrel rotation. 3. Cysteamine has several established (cystinosis, radioprotection, acetaminophen poisoning) and theoretical (HuntingtonÕs disease, prolactin-secreting adenomas) indications in clinical practice. 4. Pantethine is a naturally occurring compound which is metabolized to cysteamine. 5. Pantethine depletes SS, prolactin and noradrenaline with lower efficacy compared to that of cysteamine. 6. Pantethine is well tolerated by patients and has been suggested to treatment of atherosclerosis. The other possible clinical indications (alcoholism, ParkinsonÕs disease, instead of cysteamine) are discussed. Vecsei L, Widerlov E. Preclinical and clinical studies with cysteamine and pantethine related to the central nervous system. Prog Neuropsychopharmacol Biol Psychiatry 1990;14:835-862. Controlled evaluation of Pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia Pantethine (P), the stable disulphate form of pantetheine, major component and precursor of Coenzyme-A, was evaluated within a double-blind protocol (8 weeks for P or for a corresponding placebo) in 29 patients, 11 with type IIB hyperlipoproteinemia, 15 with type IV, and 3 with an isolated reduction of high density lipoprotein cholesterol (HDL-C) levels. In type IIB patients, P (300 mg t.i.d.) determined a highly significant lowering of plasma total and low density lipoprotein (LDL) associated cholesterol (-13.5% for both parameters). In the same patients, HDL-C levels increased about 10% at the end of treatment. Switching from P to placebo was associated with a rapid return to the baseline cholesterolemia. Both in type IIB and type IV patients, plasma triglyceride levels were reduced around 30%, when P was given as the first treatment; when it was preceded by placebo, reductions were less striking (respectively, -17.8% for type IIB and -13.0% for type IV, at the end of P treatment). HDL-C levels were not increased by P, either in type IV, and in the patients with low HDL cholesterolemia. In type IV, LDL cholesterol levels showed a variable response to P: they tended to increase when below 132 mg/dl, prior to treatment, and to be reduced when above this level. This study provides evidence for a significant hypocholesterolemic effect of P, a natural compound free of overt side effects. It also indicates that P may raise HDL-C levels in type IIB patients, while moderately reducing triglyceridemia. Gaddi A, Descovich GC, Noseda G,et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis 1984;50:73-83. Hyperlipidemia, diabetes and atherosclerosis: efficacy of treatment with Pantethine The hypolipidemizing effects of pantethine were investigated by the authors in 37 hypercholesterolemic and/or hypertriglyceridemic patients. Of these, 21 were also diabetic, in a satisfying glucidic compensation, in order to verify the action of this drug also in this metabolic condition. The study was carried out for three months and during this period the patients were given pantethine at the dose of 600 mg/day orally. At the 30th, the 60th, the 90th day of treatment the following parameters were controlled: cholesterolemia, HDL cholesterol, apolipoproteins A and B, triglyceridemia, systolic and diastolic arterial pressure, uricemia, body weight. Thirty days after suspending the treatment, the parameters were controlled again to detect a possible rebound effect. The results were analyzed on the whole case-record, subdividing the patients in dislipidemic and diabetic-dislipidemic, and on the basis of the FredricksonÕs classification. Pantethine induced in all groups a quick and progressive decrease of cholesterolemia, triglyceridemia, LDL cholesterol and Apolipoproteins B with increased HDL cholesterol and Apolipoproteins A. After suspending the treatment, there is a clear inversion of the state of these parameters. The authors conclude that the present work shows that pantethine, a natural and atoxic substance, an important component of Coenzyme-A, is efficacious in determining a clear tendency towards normalization of the lipidic values. Arsenio L, Caronna S, Lateana Met al. Hyperlipidemia, diabetes and atherosclerosis: efficacy of treatment with pantethine. Acta Biomed Ateneo Parmense 1984;55:25-42. Comparison of the efficacy of Pantethine, acipimox, and bezafibrate on plasma lipids and index of cardiovascular risk in diabetics with dyslipidemia Atherosclerotic manifestations are more common and precocious in diabetics than in the general population. Due to the increased cardiovascular risk, a primary or secondary (to diabetes mellitus) lipoprotein disorder in diabetics has to be carefully considered. 27 diabetics (15 NIDDM and 12 IDDM) with dyslipidemia (14 type IV, 8 type IIa and 5 type IIb) were divided in 3 groups and treated with 3 different hypolipemic drugs (Group A: pantethine 600 mg/day; Group B: acipimox 500 mg/day; Group C: bezafibrate 600 mg/day) to test their efficacy and acceptancy. Body weight, Hb A1-c, serum lipoproteins have been measured before and during the 6 months treatment. A significant variation of lipidemic pattern was observed in Group C: a decrease of cholesterol (-20%), triglycerides (-40%), LDL (-24.4%) and apo B (-26.8%) with an increase of HDL (+23.6%). Pantethine and acipimox were more effective on triglycerides (-37.7% and -23.3% respectively). Cardiovascular risk (CT tot/CT HDL) was significantly reduced with acipimox and normalized with bezafibrate. Tonutti L, Taboga C, Noacco C. Comparison of the efficacy of pantethine, acipimox, and bezafibrate on plasma lipids and index of cardiovascular risk in diabetics with dyslipidemia. Minerva Med 1991;82:657-663. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance Hyperlipemia is a very frequent complication of the diabetic patient on dialysis. There is difficulty of treatment with the diet, because the dietary restriction already imposed on these patients and the secondary effects and toxicity of the available drugs in uremics aggravate the problem. We have treated 22 diabetic patients on dialysis (8 on hemodialysis and 14 on continuous ambulatory peritoneal dialysis) suffering from hyperlipemia with pantethine, a physiological substance and coenzyme A precursor in the Krebs cycle. With the administration of an oral dose of 900 mg/day we obtained a reduction of total cholesterol (275 +/- 72 vs. 231 +/- 54 mg/dl; p less than 0.001), very-low-density lipoprotein (VLDL)-cholesterol (66 +/- 36 vs. 46 +/- 18 mg/dl; p less than 0.01) and triglycerides (332 +/- 182 vs. 227 +/- 90 mg/dl; p less than 0.01) at 2 months. High-density lipoprotein (HDL)-cholesterol did not change, but the total cholesterol/HDL-cholesterol ratio decreased significantly (p less than 0.05). Total cholesterol, VLDL and triglycerides showed a progressive and significant reduction at 4 and 6 months. No changes were observed in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, uric acid, blood glucose and glycosylated hemoglobin. Gastric discomfort in 2 patients and pruritus in another one were the secondary effects related. Pantethine was shown to be a very effective hypolipemic agent in diabetic patients on dialysis with a great tolerance. Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol 1991;11:32-36. Lipoprotein changes induced by Pantethine in hyperlipoproteinemic patients: adults and children Following a brief outline of current knowledge concerning atherosclerosis and its treatment, the authors describe the results obtained by treating with pantethine (900-1200 mg daily for 3 to 6 months) a series of 7 children and 65 adults suffering from hypercholesterolemia alone or associated with hypertriglyceridemia (types IIa and IIb of FredricksonÕs classification). Pantethine treatment produced significant reduction of the better known risk factors (total cholesterol, LDL-cholesterol, triglycerides, and apo-B) and a significant increase of HDL-cholesterol (signally HDL2) and apolipoprotein A-I. The authors conclude with a discussion of these results and of the possible role of pantethine in the treatment of hyperlipoproteinemia, in view of its perfect tolerability and demonstrated therapeutic effectiveness. Bertolini S, Donati C, Elicio N, et al. Lipoprotein changes induced by pantethine in hyperlipoproteinemic patients: adults and children. Int J Clin Pharmacol Ther Toxicol 1986;24:630-637. Evaluation of the cholesterol-lowering effectiveness of Pantethine in women in perimenopausal age Cardiovascular diseases are the main cause of death also in women. Their incidence, rapidly growing in the perimenopausal period, is related to serum levels of total cholesterol and its LDL fraction. It was also shown that the peroxidation of LDL is an additional factor in the genesis of atherosclerotic vascular disease. As long-term treatments with synthetic lipid-lowering drugs may cause undesirable side effects, while pantethine is known to be well tolerated, we treated 24 hypercholesterolemic women (total serum cholesterol greater than or equal to 240 mg/dl), in perimenopausal age (range: 45-55 years, mean +/- SD = 51.6 +/- 2.4) with 900 mg/day of pantethine. This is a precursor of coenzyme A, with an antiperoxidation effect in vivo, and our aim was to confirm its lipid lowering activity in this particular type of patients. After 16 weeks of treatment, significant reductions of total cholesterol, LDL-cholesterol and LDL-C/HDL-C ratio could be observed. No remarkable changes of the main laboratory parameters (fasting blood sugar, B.U.N., creatinine, uric acid) were seen. Efficacy percentages of the treatment were about 80%. None of the patients complained of adverse reactions due to the treatment with pantethine. In conclusion, we suggest that pantethine should be considered in the long-term treatment of lipid derangements occurring in the perimenopausal age. Binaghi P, Cellina G, Lo Cicero G, et al. Evaluation of the cholesterol-lowering effectiveness of pantethine in women in perimenopausal age. Minerva Med 1990;81:475-479. Pantethine, diabetes mellitus and atherosclerosis. Clinical study of 1045 patients After a review of the clinical studies on the treatment of diabetic patients with pantethine, the authors discuss the results obtained in a postmarketing surveillance (PMS) study on 1045 hyperlipidemic patients receiving pantethine (900 mg/day on average). Of these patients, 57 were insulin-dependent (Type I) and 241 were non insulin-dependent (Type II) diabetics. Beyond the epidemiological considerations made possible by a PMS study, the authors show that pantethine brought about a statistically significant and comparable improvement of lipid metabolism in the three groups of patients, with very good tolerability. Pantethine should therefore be considered for the treatment of lipid abnormalities also in patients at risk such as those with diabetes mellitus. Donati C, Bertieri RS, Barbi G. Pantethine, diabetes mellitus and atherosclerosis. Clinical study of 1045 patients. Clin Ter 1989;128:411-422. Lowering effect of Pantethine on plasma beta-thromboglobulin and lipids in diabetes mellitus Pantethine in a dosage of 600 mg for the first 3 months, and in a dosage of 1200 mg for the second 6 months was given to 16 diabetics in whom plasma beta-thromboglobulin was raised (greater than 50 ng/ml). Plasma beta-TG levels decreased significantly with pantethine treatment for 9 months. Plasma triglyceride, total cholesterol, apo E and apo CII levels decreased significantly after 9 months. Plasma LDL-C and atherogenic index (LDL-C/HDL-C ratio or apo B/apo AI ratio) tended to decrease with treatment. It is concluded that administration of pantethine may be beneficial in the prevention of diabetic angiopathy because of its lowering effect on plasma beta-TG, lipids and apolipoproteins. Eto M, Watanabe K, Chonan N, Ishii K. Lowering effect of pantethine on plasma beta-thromboglobulin and lipids in diabetes mellitus. Artery 1987;15:1-12. Therapeutic efficacy of Pantothenic Acid preparations in ischemic heart disease patients The therapeutic effectiveness of the pantothenic acid drugs: calcium pantothenate and pantethine, was studied in 182 patients with coronary heart disease and stable angina of effort. It is shown that both the drugs produce favourable effects on certain parameters of hemodynamics, on the metabolism of lipids, riboflavin and ascorbic acid. It is recommended that the administration of calcium pantothenate in a dose of 300 mg/day, during 3 weeks, be included into the combined treatment of coronary patients with no manifest disorders of lipid metabolism. Patients with manifest hyperlipidemia should be administered pantethine in a dose of 500 mg/day. Borets VM, Lis MA, Pyrochkin VM, et al. Therapeutic efficacy of pantothenic acid preparations in ischemic heart disease patients. Vopr Pitan 1987 Mar-Apr;(2):15-17. Effect of oral treatment with Pantethine on platelet and plasma phospholipids in IIa hyperlipoproteinemia In a single-blind, crossover, completely randomized study, the effects of oral treatment with pantethine or placebo on fatty acid composition of plasma and platelet phospholipids were investigated in 10 IIa hyperlipoproteinemic patients. A significant decrease of total cholesterol and total phospholipids was observed both in plasma and in platelets after a twenty-eight-day treatment. In plasma, pantethine induced a decrease of the ratio sphingomyelin/phosphatidylcholine. Moreover, a relative increase of n3-polyunsaturated fatty acids both in plasma and in platelet phospholipids and a decrease of arachidonic acid in plasma phospholipids were observed. These results indicate that pantethine can affect plasma and platelet lipid composition with possibly favorable influences on the determinants of cell membrane fluidity. Prisco D, Rogasi PG, Matucci M, et al. Effect of oral treatment with pantethine on platelet and plasma phospholipids in IIa hyperlipoproteinemia. Angiology 1987;38:241-247. Effectiveness of long-term treatment with Pantethine in patients with dyslipidemia A one-year clinical trial with pantethine was conducted in 24 patients with established dyslipidemia of FredricksonÕs types II A, II B, and IV, alone or associated with diabetes mellitus. The treatment was well tolerated by all patients with no subjective complaints or detectable side effects. Blood lipid assays repeated after 1, 3, 6, 9, and 12 months of treatment revealed consistent and statistically significant reductions of all atherogenic lipid fractions (total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B) with parallel increases of high-density lipoprotein cholesterol and apolipoprotein A. The results were equally good in patients with uncomplicated dyslipidemia and in those with associated diabetes mellitus. The authors conclude that pantethine (a drug entity related to the natural compound, pantetheine) represents a valid therapeutic support for patients with dyslipidemia not amenable to satisfactory correction of blood lipids by diet alone. Arsenio L, Bodria P, Magnati G, et al. Effectiveness of long-term treatment with pantethine in patients with dyslipidemia. Clin Ther 1986;8:537-545. Pantethine improves the lipid abnormalities of chronic hemodialysis patients: results of a multicenter clinical trial In the course of a post-marketing surveillance program on the effectiveness and tolerability of pantethine in the treatment of hyperlipidemia, the effects of the drug were explored in 31 patients with dyslipidemia undergoing chronic hemodialysis. The mean duration of treatment was 9 months (min. 7 months, max. 24 months), with oral doses of 600 to 1200 mg of pantethine daily (mean daily dosage 970 mg). Improvement was noted in terms of total blood cholesterol in the 7 patients with basal hypercholesterolemia (p less than 0.01) and highly significant reduction of serum triglycerides. No variations of HDL-cholesterol or total Apo-A were detected. None of the patients experienced any adverse effects from the treatment. In the light of extensive experience with the drug, plus the results of this study, the authors conclude by stressing the importance of an effective and readily tolerated product, such as pantethine, for the treatment of dyslipidemia in patients on chronic hemodialysis. Donati C, Barbi G, Cairo G, et al. Pantethine improves the lipid abnormalities of chronic hemodialysis patients: results of a multicenter clinical trial. Clin Nephrol 1986;25:70-74. Changes in fatty acid composition of the single platelet phospholipids induced by Pantethine treatment In a single-blind cross-over study the effect of oral treatment with pantethine on plasma and platelet lipid composition was evaluated in 20 patients with dyslipidaemia (7 IIa, 7 IIb and 6 Iv type). In plasma significant decreases of total cholesterol and triglycerides with increase of high density lipoprotein-cholesterol were observed. In platelets pantethine treatment significantly reduced phospholipid and cholesterol content. In addition gas-chromatographic analysis showed a reduction of saturated and monounsaturated and a relative increase of polyunsaturated fatty acid content of platelet phospholipids. A selective relative increase was observed of some n-3 polyunsaturated fatty acids like eicosapentaenoic and docosahexaenoic acid whereas arachidonic acid decreased. The present study indicates a favourable influence of pantethine not only on plasma but also on platelet lipids which could be of value in delaying the development of atherosclerosis in dyslipidaemic patients. Gensini GF, Prisco D, Rogasi PG, et al. Changes in fatty acid composition of the single platelet phospholipids induced by pantethine treatment. Int J Clin Pharmacol Res 1985;5:309-318. Acetyl-L-Carnitine Clinical Studies and Research Acetyl-L-Carnitine in aged subjects with major depression: Clinical efficacy and effects on the circadian rhythm of cortisol The relationship between depression and alterations in circadian rhythms has received much attention in recent times. In particular abnormalities in cortisol rhythm can be viewed as an endocrine correlate of depression. Circadian rhythms are normalized under recovery. The objective was to make an evaluation of clinical and biological effectiveness of acetyl-L-carnitine (ALC). ALC has been investigated for treatment in cognitive effects of elderly people. The efficacy of ALC in treating major depression has been reported in more recent ALC studies. In this double-blind study the antidepressant activity of ALC versus placebo was evaluated. We have selected 28 aged depressed subjects, meeting DSM III R criteria for Major Depression. Cortisol mean levels, cortisol rhythms and depressive symptoms have been evaluated in patients before and after ALC or placebo treatment. The results of the trial showed significantly higher clinical and biological efficacy for ALC as compared to placebo. Gecele M, Francesetti G, Meluzzi A Acetyl-L-Carnitine in aged subjects with major depression: clinical efficacy and effects on the circadian rhythm of cortisol. Dementia 2:333-337; 1991. Acetyl-L-Carnitine in depressed elderly subjects. A cross-over study vs placebo An open, cross-over study was performed on a population of 24 geriatric patients hospitalized because of depressive syndrome. They were subdivided, according to Hamilton's Scale as modified for the aged, into low-and high-score subgroups. The study period covered 2 months. Half the patients received acetylcarnitine for 1 month and placebo thereafter (Group A); the other half received placebo and acetylcarnitine thereafter (Group B). Statistical evaluation was twofold: parametrical analysis of variance was carried out on 4 subgroups (A1, A2, B1, and B2) and analysis of the score percentage modifications before and after treatment was performed on Groups A and B. The experimental results showed that acety-L-carnitine treatment was highly effective and statistically significant in subgroups A1/B1, A2/B2, A1, B1, and B2. In particular, it should be noted that depressive tendencies were significantly modified in most groups, whereas general somatic symptoms as well as anxiety, asthenia and sleep disturbances proved to be little affected. Clinical evaluation, carried out by calculation of modifications in pre-and post-treatment score percentages, provided clear evidence that acetylcarnitine was particularly effective in patients showing more serious clinical symptoms. The drug caused no side-effects at the doses and regimens used. Tempesta, E. et al. L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo. Drugs Exp Clin Res 13:417-423; 1987. Effects of Acetyl-L-Carnitine on mental deterioration in the aged: initial results 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 phase 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 covariance (taking as independent variables phases of treatment, age, gender, etiology and severity of mental impairment, as dependent variables the scores either of each test administered or of groups of items and as covariants the level of depression and the sensitivity to placebo effect) showed that drug treatment significantly increased the effectiveness of performance on all the measures of cognitive functioning and of emotional-affective state and on some scores of the relational behavior. Age resulted significantly influential on cognitive functioning and relational behavior, but not on emotional-effective state. Severity of mental impairment significantly influenced also several measures of cognitive functioning and relational behavior, while less consistent results were shown for gender and etiology of mental impairment. The placebo effect, although significant for some cognitive processes, was lower than that of treatment. There findings suggest that Acetyl-L-Carnitine treatment is effective against the outcomes of mental impairment in the cognitive (in particular, for memory functioning and constructional thinking) and emotional-affective domains, while its effects on relational behavior are less consistent, probably because they are partly biased in the subjective evaluation of caregivers and relatives by factors such as age and levels of mental impairment and depression. Cipolli C; Chiari G. Effects of L-acetylcarnitine on mental deterioration in the aged: initial results. Clin Ter 132:479-510; 1990. Effect of Acetyl-L-Carnitine on geriatric patients suffering from dysthymic disorders Sixty senile subjects (60-80 years old) with dysthymic disturbances as defined by DSM III (Cat. 390.40) were randomized into two homogeneous groups, one of which was given acetyl-L-carnitine (3 g/day per os) while the other received a placebo. After a washout phase of one week, each patient was evaluated by scoring on the Hamilton Rating Scale for Depression and the Beck Depression Inventory, as well as the Sandoz Clinical Assessment-Geriatric. These tests were administered at the beginning of the trial, prior to drug administration, and repeated during the treatment phase after 30 and 60 days. The results showed that treatment with acetyl-L-carnitine induced a significant reduction, as compared to the placebo (p less than 0.002), in the severity of depressive symptoms and also a significant improvement (p less than 0.0027) in the items measuring the quality of life. Bella R; Biondi R; Raffaele R; Pennisi G. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res 10:355-360; 1990. Neuropsychological changes in demented patients treated with Acetyl-L-Carnitine This study was carried out on 24 patients suffering from mild to moderate dementia. The diagnosis of dementia was made according to DSM III criteria. Patients with cerebrovascular pathologies were excluded by using Hachinski Ischaemic Score less than or equal to 4 and computerized tomography parameters. Patients with depression (Hamilton Rating Scale for Depression greater that or equal to 18) were excluded. All the patients, after a wash-out period of two weeks were treated on a simple blind method with acetyl-l-carnitine (No. = 12 patients) and Piracetam (12 patients) by intravenous route (two weeks) followed by an oral one for a further 10 weeks. A battery of clinical neuropsychological tests was applied to evaluate the cognitive, attentive and behavioural aspects. The results, analysed by non-parametric variance analysis (Friedman Test) show a statistically significant improvement of the behaviour profile, of attention and of psychomotricity in the patients treated with acetyl-l-carnitine. No significant improvement was found in the Piracetam group. Sinforiani E, et al. Neuropsychological changes in demented patients treated with acetyl-l-carnitine. Int J Clin Pharmacol Res 10:69-74; 1990. Double-blind, placebo-controlled study of Acetyl-L-Carnitine in patients with Alzheimer's dementia 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. Rai G, et al. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia. Curr Med Res Opin 11:638-647; 1990. Long-term Acetyl-L-Carnitine treatment in Alzheimer's disease In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and the placebo groups either in incidence or severity. Spagnoli A, et al. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology 41:1726-1732; 1991. Action of Acetyl-L-Carnitine in neurodegeneration and Alzheimer's disease Acetyl-L-carnitine (ALC) is formed by acetylation of carnitine through the carnitine acetyltransferase activity. ALC can be freely exchanged across membranes and can provide acetyl groups from which to regenerate acetyl-CoA. ALC was first considered a cholinergic agent because of its structural similarity to acetylcholine. Experimental studies demonstrated that ALC promotes acetylcholine synthesis and release and induces ChAT and muscarine receptor agonist activity. Moreover, ALC is also able to reverse hippocampal and prefrontal neuronal loss and lipofuscin accumulation in aged animals, even improving learning and memory performances in the same animals. On the other hand, ALC defends aged cells against lipid peroxidation, increasing the amount of antioxidizing agents as reduced glutathione and ubiquinol. Furthermore, in aged mitochondria, ALC also sustains the activity of complex I and complex IV of the electron transport chain, favors the coupling of oxidative phosphorylation, reverses impairment of DNA/RNA transcriptase, and restores the age-induced impaired turnover of mitochondrial inner membrane proteins. Therefore, according to this evidence, ALC must be considered a neuroprotective agent, especially in dementia, because of the following properties: (a) antioxidizing action; (b) mitochondrial energy supply; (c) membrane stability function; and (d) cholinergic transmission enhancement. Calvani M, et al. Action of acetyl-L-carnitine in neurodegeneration and Alzheimer's disease. Ann NY Acad Sci 663:483-486; 1992. Acetyl-L-Carnitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere 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's 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 in 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 acetylation to acetyl-L-carnitine) in autopsied Alzheimer brains. Carta A, et al. Acetyl-L-carnitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere. Ann NY Acad Sci 695:324-326; 1993.