Long term acetyl L carnitine treatment in Alzheimer's disease

  1. D. Ieracitano, MD

-SHOW AFFILIATIONS

  1. Mario Negri Institute for Pharmacological Research (Drs. Spagnoli, Lucca, Menasce, Bandera, Cizza, Forloni, Tettamanti, Frattura, and Tiraboschi), Milan; Department of Medical Statistics (Dr. Comelli), Istituto di Scienze Sanitarie Applicate, University of Pavia; Dipartimento di Geriatria e Gerontologia (Prof. Senin and Drs. Longo and Petrini), University of Perugia; Pio Albergo Trivulzio (Drs. Brambilla, Belloni, and Negri), Milan; Ospedale Malpighi (Prof. Cavazzuti and Drs. Salsi and Calogero), Bologna; Clinica Zucchi (Dr. Parma), Monza; Istituto Golgi (Drs. Stramba-Badiale, Vitali, and Andreoni), Abbiategrasso; Ospedale S. Orsola (Drs. Inzoli, Santus, and Caregnato), Brescia; Ospedale Giustinian (Prof. Peruzza and Drs. Favaretto and Bozeglav), Venice; Gruppo di Neuropsicologia, Clinica Neurologica I (Dr. Alberoni), University of Milan; Servizio di Psicogeriatria (Prof. De Leo and Drs. Serraiotto and Baiocchi), University of Padua; and Istituto Don Orione (Prof. Scoccia and Drs. Culotta and and Ieracitano), Milan, Italy.

ABSTRACT

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 the 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 placebo groups either in incidence or severity.


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

  • Laboratory of Neurophysics Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213 USA

Abstract

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.

Keywords

  • Magnetic resonance spectroscopy Phosphorus Phosphomonoesters Energy metabolism Phospholipid metabolism Acetyl-L-carnitine

Requests for reprints should be addressed to Jay W. Pettegrew, M.D., University of Pittsburgh, Western Psychiatric Institute and Clinic, A710 Crabtree Hall/GSPH, Room A710, 130 DeSoto St., Pittsburgh, PA 15261.

 

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

  1. R. F. Woolson, PhD

-SHOW AFFILIATIONS

  1. From the Department of Neurosciences (Drs. Thal and Tuszynski), University of California San Diego, La Jolla, and San Diego VAMC, San Diego, CA; Department of Neurological Research (Dr. Carta), Sigma Tau Pharmaceuticals, Rome, Italy; Division of Biostatistics (Drs. Clarke and Woolson), University of Iowa, Iowa City, IA; Department of Psychiatry (Dr. Ferris), New York University Medical Center, New York, NY; Alzheimer Center (Dr. Friedland), University Hospitals of Cleveland, Cleveland, OH; Mayo Clinic (Dr. Petersen), Rochester, MN; Department of Psychiatry (Dr. Pettegrew), University of Pittsburgh, Pittsburgh, PA; Suncoast Gerontology Center (Dr. Pfeiffer), University South Florida Health Sciences Center, Tampa, FL; Department of Psychiatry (Dr. Raskind), University of Washington, Seattle, WA; and Department of Neurology (Dr. Sano), Columbia University, New York, NY.
  2. Supported by Sigma Tau Pharmaceuticals, Inc.
  3. Received July 18, 1995. Accepted in final form February 28, 1996.
  4. Address correspondence and reprint requests to Dr. Leon J. Thal, Department of Neurosciences (0624), UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0624.
  1. doi: 10.1212/WNL.47.3.705Neurologyvol. 47 no. 3 705-711

ABSTRACT

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 treatment.

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 on all primary and most secondary measures 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.

NEUROLOGY 1996;47: 705-711

International Clinical Psychopharmacology:
Articles

Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease

Montgomery, Stuart A.a; Thal, L.J.b; Amrein, R.c

Abstract

The efficacy of acetyl-L-carnitine (gamma-trimethyl-β-acetylbutyrobetaine (Alcar) in mild cognitive impairment (MCI) and mild (early) Alzheimer's disease (AD) was investigated with a meta-analysis of double-blind, placebo-controlled prospective, parallel group comparison studies of at least 3 months duration. The duration of the studies was 3, 6 or 12 months and the daily dose varied between studies from 1.5–3.0 g/day. An effect size was calculated to reflect the results of the variety of measures used in the studies grouped into the categories of clinical tests and psychometric tests. The effect sizes from the categories were integrated into an overall summary effect size. The effect size for the Clinical Global Impression of Change (CGI-CH) was calculated separately. Meta-analysis showed a significant advantage for Alcar compared to placebo for the integrated summary effect [ESall scales=0.201, 95% confidence interval (CI)=0.107–0.295] and CGI-CH (ESCGI-CH=0.32, 95% CI=0.18–0.47). The beneficial effects were seen on both the clinical scales and the psychometric tests. The advantage for Alcar was seen by the time of the first assessment at 3 months and increased over time. Alcar was well tolerated in all studies.

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression.
Department of Psychiatry, School of Medicine, University of Pittsburgh, PA 15213, USA. pettegre+@pitt.edu

Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl moieties, both of which have neurobiological properties. Carnitine is important in the beta-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. Other reported neurobiological effects of ALCAR include modulation of: (1) brain energy and phospholipid metabolism; (2) cellular macromolecules, including neurotrophic factors and neurohormones; (3) synaptic morphology; and (4) synaptic transmission of multipleneurotransmitters. Potential molecular mechanisms of ALCAR activity include: (1) acetylation of -NH2and -OH functional groups in amino acids and N terminal amino acids in peptides and proteins resulting in modification of their structure, dynamics, function and turnover; and (2) acting as a molecular chaperone to larger molecules resulting in a change in the structure, molecular dynamics, and function of the larger molecule. ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population.

Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study

  • a Chemical Works of Gedeon Richter Ltd., Budapest, Hungary
  • b National Stroke Centre, Hüvösvölgyi út 116, Budapest H-1021, Hungary

Abstract

Objective: To investigate the effect of vinpocetine on cerebral blood flow (CBF) in the compromised circulation of a stroke affected hemisphere using transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) methods. Methods: 43 patients with ischemic stroke were randomized into vinpocetine (VP) and placebo group in a double blind, placebo-controlled study of the effect of a single-dose i.v. infusion of vinpocetine on cerebral blood perfusion and oxygenation. In the VP group 20 mg VP in 500 ml saline, in the placebo group 500 ml saline alone were administered. The concentrations of oxy-, reduced- and total hemoglobin were measured by NIRS frontolaterally on the side of lesion while the mean cerebral blood flow velocity (CBFV), the pulsatility index (PI) and Doppler spectral intensity (DSI) were monitored by TCD in the middle cerebral artery on the same side. Values were averaged for the first 5 min prior to the infusion and for the last 5 min of infusion and they were compared between groups. Results:The concentration of all three chromophores increased during infusion in the VP group (mean dHbT=1.03, CI95=0.84, P=0.058; mean dHbO=0.92, CI95=0.91, P=0.071; mean dHb=0.10, CI95=0.21, P=0.297). The HbT and HbO showed a substantially smaller increase in the placebo group (mean dHbT=0.31, CI95=0.74,P=0.22; mean dHbO=0.57, CI95=0.80, P=0.094) while the Hb decreased (mean dHb=−0.26, CI95=0.29,P=0.05). Comparing to the placebo group Hb increased significantly in the VP group (P=0.027) while the increase of HbO and HbT did not reach the level of significance (P=0.29 and 0.11). DSI showed a significantly larger increase in the VP than in placebo group (dDSI=25.8 CI95=8.8 [VP]; dDSI=3.3, CI95=3.7 [Placebo], P<0.005). The CBFV and PI did not differ significantly between groups. (dVm=5.0±2.98 cm/s [VP], dVm=4.1±2.57 cm/s [Placebo], P=0.28; dPI=0.08 [VP], dPI=0.09 [Placebo]; P=0.47). Conclusion: VP increases cerebral perfusion and parenchymal oxygen extraction as well. The increased perfusion was indicated by NIRS and by TCD measurement of DSI while conventional velocity and pulsatility measurements failed to detect theses effects. NIRS is a sensitive, feasible method of measuring changes in regional blood flow and tissue oxygenation in the superficial cortex.


Citation: A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction.
Balestreri, Roberto; Fontana, Luigi; Astengo, Federico
Journal of the American Geriatrics Society, Vol 35(5), May 1987, 425-430.

Abstract

  1. In a double-blind clinical trial, vinpocetine, a synthetic ethyl ester of apovincamine, was shown to effect significant improvement in 84 57–94 yr old patients with chronic cerebral dysfunction. 42 Ss received 10 mg vinpocetine 3 times a day (tid) for 30 days, then 5 mg tid for 60 days. Matching placebo tablets were given to another 42 Ss for the 90-day trial period. Ss on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment including measurements on the Clinical Global Impression Scale, the Clinical Assessment-Geriatric Scale, and the Mini-Mental Status Questionnaire. No serious side effects were noted. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Richter Gedeon Vegyészeti Gyár Rt., Farmakológiai Kutató Központ, Budapest.
Cavinton was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.
Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease.
Zhejiang Supervision and Detection Station of Drug Abuse, Zhejiang Medical University, Hangzhou, China.
AIM: To evaluate the efficacy and safety of tablet huperzine-A (Hup) in patients with Alzheimer's disease. METHODS: Using multicenter, prospective, double-blind, parallel, placebo controlled and randomized method, 50 patients were administered orally 0.2 mg (4 tablets) Hup and 53 patients were given po 4 tablets of placebo bid for 8 wk. All patients were evaluated with Wechsler memory scale, Hasegawa dementia scale, mini-mental state examination scale, activity of daily living scale, treatment emergency symptom scale, and measured with BP, HR, ECG, EEG, ALT, AKP, BUN, Cr, Hb, WBC, and urine routine.

RESULTS: About 58% (29/50) of patients treated with Hup showed improvements in their memory (P < 0.01), cognitive (P < 0.01), and behavioral (P < 0.01 functions. The efficacy of Hup was better than placebo (36%, 19/53) (P < 0.05). No severe side effect was found. CONCLUSION: Hup is a promising drug for symptomatic treatment of Alzheimer's disease.

Huperzine A, A Potential Therapeutic Agent for Treatment of Alzheimer's Disease

Abstract:

HupA is a potent, reversible and selective inhibitor of AChE with a rapid absorption and penetration into the brain in animal tests. It exhibits memory-enhancing activities in animal and clinical trials. Compared to tacrine and donepezil, HupA possesses a longer duration of action and higher therapeutic index, and the peripheral cholinergic side effects are minimal at therapeutic doses. This review article deals with a comprehensive survey of the progress in chemical and pharmacological studies of HupA including the isolation and structure elucidation, pharmacological actions, total synthesis, SAR studies and the future development of HupA.

Recently, it has been reported that HupA could reduce neuronal cell death caused by glutamate. The dual bio-activities of HupA would further enhance its value and potentiality as the therapeutic agent for Alzheimers disease


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