Scientific Monograph

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CONTENTS

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1. Introduction
Neurodegenerative diseases are major contributors to disability and disease, with Alzheimer's and Parkinson's diseases the most prevalent. Neurodegenerative diseases result from deterioration of neurons, which over time will lead to neurodegeneration and disabilities resulting from this. Alzheimer's disease is the most common neurodegenerative disease and Parkinsons disease is the second most common neurodegenerative disease. Initial treatment is dependent on diagnosis of underlying disorder. At present, there are few therapies for the wide range of neurodegenerative diseases. Scientists have discovered several different forms of carnitine that, in addition to bolstering energy production, produce health benefits that include protecting against neurodegenerative diseases, alleviating depression, stimulating nerve growth, and improving heart function. Alzheimer's disease is the most common neurodegenerative disease and Parkinsons disease is the second most common neurodegenerative disease. Levacecarnine is the most widely studied carnitine supplement. It readily crosses the blood-brain barrier and thus confers powerful protective effects on nerve tissue and the central nervous systemenhancing mood, restoring energy, and alleviating nerve pain. This monograph will examine the role of levacecarnine in addressing the neurogenerative diseases, alongwith other clinically proven benefits of this dietary supplement.

2. Neurodegenerative diseases
2.1. Diabetic peripheral neuropathic pain (DPNP) A common neurological disorder in India
Peripheral neuropathies constitute an important group of disorders in neurological practice. Peripheral neuropathy is a disorder that involves segmental demyelination and axonal degeneration of the peripheral nerves. The most common diseases to compromise the vasa nervosum (the blood vessels that supply peripheral nerves) and cause infarction of nerve fascicles are diabetes mellitus and periarteritis nodosa. Peripheral neuropathy has a prevalence of 12-50% in patients with diabetes mellitus. The progression of diabetic neuropathy is a function of the duration of disease and the level of hyperglycaemia. It has been estimated that up to 50% of patients with diabetes mellitus will develop neuropathy. In India it is estimated that presently 19.4 million individuals are affected by diabetes, which is likely to go up to 57.2 million by the year 2025. It has been estimated that up to 50% of patients with diabetes mellitus will develop neuropathy.

% of patients with evidence of neuropathy

30% 25% 20% 15% 10% 5% 0% 19.1%

Fig. 2: Percentage of diabetic patients with neuropathy

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In India it is estimated that presently 19.4 million individuals are affected by diabetes, which is likely to go up to 57.2 million by the year 2025. In a study of neuropathy among South Indian type 2 diabetic patients attending a diabetes centre, it was found that 19.1% of the patients had evidence of neuropathy. The prevalence of neuropathy increased with increase in age (p < 0.001) and duration of diabetes (p < 0.001).

number of new cases of dementia in the Asia-Pacific region is projected to increase from 4.3 million new cases per year in 2005 to 19.7 million new cases by 2050. The dementia epidemic is a certainty because the numbers of people with dementia increase with an ageing population. And those aged over 60 in the Asia Pacific will increase from under 10% today to 25% of the total population by 2050 and those over 80 years from 1% to 5% of the population.

2.2. Dementia in the Asia Pacific region: the Epidemic is here (A 2006 report)
About 1% of people aged 65 to 69 years in the world have dementia, and this proportion increases with age to approximately 60% for people older than 95 years. The clinical features of dementia include an acquired global impairment of intellect, memory and changes in personality. Number of new dementia cases in the Asia-Pacific region is projected to increase from 4.3 million new cases per year in 2005 to 19.7 million new cases by the year 2050. As per this report by the Asia Pacific member organisations of Alzheimers Disease International, the
70 60 50

Prevalence & Incidence of dementia in India

18000 16000 14000
000 People

12000 10000 4974.6 1714.4

2005
Incidence

8000 3248.5 6000 4000 2000 0

2005
Prevalence

1026.8

2005

Fig. : Prevalence and Incidence of dementia in India.

As per Asia-Pacific Consensus Statement On Dementia, the number of people with dementia in the Asia-Pacific region will more than double, by the year 2025. This increase will be much more rapid than that occurring in the West.

millions

40 30 20 10 0 2006 2010 2015 2020 2025 2030 2035 2040 2045 2050

2.3. Alzheimers disease The most common form of dementia in the world
Alzheimers disease is mainly a neurological disorder where a person slowly and progressively starts losing

China

India

Other

Fig. Total Prevalence: China, India and Other regional, 2005-50

5541.8

16290

his memory due to gradual loss of brain cells. It is the most common form of dementia (loss of intellectual ability) and is the fourth leading cause of deaths in adults.
6% 8%

2.4. Stroke Enormous socioeconomic burden to India

A stroke occurs when a blood vessel that supplies the brain with oxygen and nutrients either bursts or becomes clogged by a clot or some other particle. Nerve cells in the affected area begin to die within minutes. This same process occurs in a heart attack, which is why strokes are now being referred to as "brain attacks. Age-related brain injuries, including stroke, are a major cause of physical and mental disabilities. Stroke increases risk for dementia and Alzheimer's disease.
1.0 0.9

12%
Alzheimers Brain Injury

56% 14%

Multi Infarct Dementia Multiple Causes Parkinsons Diseases

4%

Other Causes

Fig. Causes of dementia

History of Stroke No History of Stroke

Alzheimer's disease has emerged as the most common type of dementia in the elderly. Age is the most important risk factor for Alzheimer's disease. The number of people with the disease doubles every 5 years beyond age 65. In 2006, the worldwide prevalence of Alzheimers disease was 26.6 million. By 2050, 1 in 85 persons worldwide will have Alzheimers disease. The biggest increase in Alzheimers disease would occur in Asia. The number of cases will rise from 12.65 million in 2006 to 62.85 million in 2050 in Asia. If interventions could delay both disease onset and progression of Alzheimers disease by a modest 1 year, there would be nearly 9.2 million fewer cases of the disease in 2050.

0.8 0.7 Cumulative Risk 0.6 0.5 0.4 0.3 0.2 0.1 0.0 65 70 75 Age, y 80 85 90

Fig. Cumulative risk of Alzheimer disease by age. Individuals with stroke (n=188) showed increased frequency of Alzheimer disease at eachage vs. those individuals without a history of stroke (n=1578).

A study investigated the association between a clinical history of stroke and subsequent risk of Alzheimers disease in a 1766 elderly recipients without dementia. The annual incidence for Alzheimers disease was 5.2% among individuals with stroke vs. 4% for those without stroke. Hazards ratio for Alzheimers disease among those with a history of stroke was 1.6 (95% confidence interval, 1.0-2.4) vs. those without stroke. Thus stroke is associated with Alzheimers disease among elderly individuals. The observed association

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between stroke and AD might relate to an underlying systemic vascular disease process, or alternatively, to the additive effects of stroke and AD pathologic features, leading to an earlier age at onset of disease. Another study examined the association between stroke and changes in cognitive function over time in 1271 elderly persons without dementia or cognitive decline. Stroke was associated with a more rapid decline in memory performance. The association between stroke and decline in memory performance was strongest for men. Men were especially vulnerable to these effects. Stroke continues to be a common cause of death and disability in India.

The cardinal clinical manifestations include bradykinesia, rest tremor, rigidity, and postural instability. The symptoms appear first around the age of 60, though in 15% of the cases, they occur before the age of 50. It is estimated that one in every 100 persons over the age of 60 is affected by Parkinson's disease.

The mortality and morbidity resulting from cerebro and cardio vascular diseases are a major and increasing public health problem in India. Stroke continues to be a common cause of death and disability in India. The prevalence of stroke in India was estimated as 203 per 100,000 population above 20 years, amounting to a total of about 1 million cases. Thus India will face an enormous socio-economic burden to meet the costs of stroke.

Fig. Man with Parkinsons Disease

In India, Anglo-Indians are found to be less prone to the disease. While 19.5% of Indians at large have Parkinson's disease, only 4% of Anglo-Indians are affected. In India, drug-induced Parkinsonism is common.

2.5. Parkinsons disease the alarming statistics

Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's nd motor skills and speech. Parkinsons disease is the 2 most common neurodegenerative disease, affecting approximately 1% of the population older than age 65 years.

2.6. Depression Common prevalence in India

Clinical depression (also called major-depressive disorder or unipolar depression) is a common psychiatric disorder, characterized by a persistent lowering of mood, loss of interest in usual activities and diminished ability to experience pleasure. Depression

should be treated, because it causes patients excess disability and suffering and is associated with distress among caregivers. Depression is a common cause of disability in the elderly. Among its consequences are reduced life satisfaction and quality, social deprivation, loneliness, increased use of health and home care services, cognitive decline, impairments in activities of daily living, suicide, and increased nonsuicide mortality.

3. Levacecarnine
Levacecarnine is a food for special dietary uses which can help improve memory, depression and boost mental abilities. Let us now review the properties and benefits of this molecule.

3.1. L-carnitine & its function

L-Carnitine has been described as a conditionally essential nutrient for humans. Carnitine (and its racemic form L-carnitine) is an endogenous substance, which participates in the synthesis of natural chemical products of the cell by facilitating transacetylation. Carnitine is present in cells and tissues as free carnitine and as acyl-derivatives, of which levacecarnine is one. About 98% of body L-carnitine is present in skeletal and cardiac muscle.
CH3 H3C + N CH3
L-Carnitine

In India, prevalence rates for all mental disorders was observed to be 65.4 per 1000 population. In India, prevalence rates for all mental disorders was observed to be 65.4 per 1000 population. Prevalence rates for affective disorders (depression) was 31.2 per 1000 population respectively. The urban morbidity rate for all mental disorders was 2 per 1000 higher than the rural rate.

O H2 C CH OH H2 C C O

2.7. Mild cognitive impairment Common prevalence in India

Mild cognitive impairment (MCI) is a recently described syndrome that is currently thought of as a transition phase between healthy cognitive ageing and dementia. Mayo Clinic researchers have found that mild cognitive impairment, a disorder considered a strong early predictor of Alzheimer's disease, is prevalent among the elderly and increases with age and fewer years of education. The increase of mild cognitive impairment with age parallels the risk elevation with age seen in previous studies of Alzheimer's disease. This means that 12-20% of the entire population of those over age 70 may have either mild cognitive impairment or dementia.

Fig. : Structure of L-Carnitine

Mitochondria

Fatty acid NAD+ & FAD NADH & FADH 2 Acetyl CoA Electron transport chain Proton gradient ATP production

Citric acod cycle

NAD & FAD NADH & FADH 2

Fig. : Fatty acid oxidation inside the mitochondria

Scientific Monograph

Functions of L-carnitine
Carnitine functions as a shuttle between the cytoplasm and mitochondria for long chain fatty acids. Carnitine facilitates the transport of long-chain fatty acids into the mitochondria to get oxidized and produce fuel and the removal of excess short chain and medium chain fatty acids that accumulate during normal and abnormal metabolism. Tissue levels of carnitine in animals, including humans, decrease with age, thus reducing the integrity of the mitochondrial membrane.

agonist of mitochondrial function, a neuronal growth factor and with an antioxidant effect on CNS neurons. Levacecarnine is described as a drug agonist of mitochondrial function, a neuronal growth factor and with an antioxidant effect on CNS neurons.

3.3. Levacecarnine Reverses mitochondrial decay with age

Mitochondria are the cellular organelles that provide ATP for metabolism and help to maintain calcium homeostasis within the cell. Damage that compromises these key functions may adversely affect survival of the organism. Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. The decay of mitochondria with age impairs cellular metabolism and leads to cellular decline. Mitochondrial membrane potential, respiratory control ratios and cellular oxygen consumption decline with age, and oxidant production increases.

3.2. Levacecarnine - Introduction

Levacecarnine (acetyl-L-carnitine) is formed in the mitochondria by carnitine acetyltransferase, which combines L-carnitine with an acetyl group from CoA. Levacecarnine is then transported across the inner mitochondrial membrane by carnitine acetyltranslocase, where it diffuses out of the mitochondria into the cytoplasm and serves as a source of acetyl groups for cytosolic proteins. The acetyl group also provides for the generation of acetylcholine.
CH3 H3C + N CH3 H2 C CH O C
Acetyl-L-Carnitine

O H2 C C O

CH3
Fig. : Mitochondria

Fig. : Structure of Levacecarnine (levacecarnine)

Levacecarnine is a mitochondrial metabolite that facilitates the movement of fatty acids into the mitochondria for energy and is also used to generate acetyl coenzyme A. Levacecarnine is described as a

Pathogenesis of mitochondrial decay

w Oxidative damage: Enhanced mitochondrial

susceptibility to oxidative damage is suggested by the decline with age in cellular antioxidant levels,

coupled with increased oxidant production and increased lipid unsaturation in the inner mitochondrial membrane. The resultant oxidative damage to mitochondria may compromise their ability to meet the steady energy demands of the brain. w electron transport chain: Mutations in Altered genes that encode mitochondrial proteins could compromise mitochondria by altering components of the electron transport chain, resulting in inefficient electron transport and increased superoxide production. w Damaged structure: Mitochondrial DNA, proteins, and lipids are oxidatively damaged and metabolically interconnected, and their decay could cause the age-associated decline in mitochondrial function. Elevated levels of oxidized proteins would decrease efficiency of electron transport and would further increase oxidant production. w Damaged cardiolipin & change in membrane potential: Cardiolipin, an important phospholipid in the mitochondrial membrane, serves as a cofactor for a number of critical mitochondrial transport proteins and declines significantly with age. The significant loss of cardiolipin in aging may be in part because of greater oxidative damage and/or reduced biosynthesis. Its loss with age could severely compromise the ability of mitochondria to generate ATP in quantities sufficient to meet cellular energy demands. Loss of cardiolipin, coupled with oxidation of key proteins, may directly impact the ability of mitochondria to maintain their membrane potential. Levacecarnine protects neuronal cells from neurotoxin- and oxidant-induced toxicity and oxidative damage.

Benefits with levacecarnine in reversing mitochondrial decay

Some of the mitochondrial decay can be reversed in aged animals by feeding them levacecarnine. In feeding studies in old rats, levacecarnine improves the age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age-associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltrasferase. It protects neuronal cells from neurotoxin- and oxidantinduced toxicity and oxidative damage.

30
Cardiolipin (g per 106 Cells)

25 20 15 10 5 0
Young Old Old+ALCAR

Fig. : Cardiolipin levels extracted from hepatocytes from old and young rats ALCAR supplementation restores this level to that of young rats. ALCAR = levacecarnine

Cardiolipin was extracted from hepatocytes of rats and the levels were assessed by HPLC. Results show that mitochondria in cells from old rats have significantly lower cardiolipin when compared with cells isolated from young rats. Levacecarnine supplementation restores this level to that of young rats. Levacecarnine can not only improve fatty acid transport into mitochondria, but also has a remarkable ability to maintain the structure and function of the mitochondrial inner membrane. Levacecarnine

Scientific Monograph

supplementation significantly reverses the ageassociated decline of mitochondrial membrane potential.

reductase, which converts glucose to sorbitol and then to fructose (polyol pathway), appears to play a dominant role.
w Myoinositol depletion: Inositols are involved in

3.4. Levacecarnine Protecting against painful diabetic neuropathy

3.4.1. Pathogenesis of diabetic neuropathy
The most common form of peripheral neuropathy is diabetic distal symmetric sensorimotor polyneuropathy (DPN), whose clinical signs and symptoms are a progressive development of asthenia, paraesthesia, tactile and vibratory hypoaesthesia, hypo- or areflexia, and, in advanced stages, ulcers and deformation of the lower extremities, ultimately even leading to amputation. DPN is the most common late complication of diabetes and is commonly associated with neuropathic pain.

neural transmission. Myoinositol levels in nerves of diabetic humans were shown to be reduced. Thus motor nerve conduction velocity (MNCV) was slowed in diabetic humans. Hyperglycemia probably inhibits both inositol transport into cells and renal tubular reabsorption of inositol.
w Decreased Na /K -ATPase and PKC activity: In
+ +

the peripheral nerve, increased shunting of excessive glucose through the polyol pathway is associated with decreased protein kinase C (PKC) + and Na+/K -ATPase activities. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis and excessive apoptosis. Imbalances in PKC may result in decreased synthesis of NO via impaired NOsynthase activity resulting in vasoconstriction. Na+,K(+)-ATPase is an ubiquitous membrane enzyme that allows the extrusion of three sodium ions from the cell and two potassium ions from the extracellular fluid. Because this ubiquitous enzyme maintains the membrane electrical potential and allows repolarization, disturbances in its activity can alter the process of nerve conduction velocity (NCV).
w Vascular dysfunction: Vascular dysfunction is

Fig. : Diabetic Neuropathy

Pathogenesis of diabetic neuropathy is multifactorial; some causative factors are as follows: w Increase in aldose reductase activity: An abnormally increased activity of the enzyme aldose

important in the pathogenesis of peripheral complications of diabetes.

w Microvascular abnormalities: Microvascular

abnormalities lead to reduced blood flow and neural

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hypoxia, altered fatty acid metabolism, oxidative stress and impaired production of growth factors by neurons and Schwann cells.
w Reduced availability of acetyl groups: The

reduced availability of acetyl groups that are necessary for the synthesis of phospholipid structures may have a primary role in the pathogenesis of DPN
w Deficiency of levacecarnine: A deficiency of

levacecarnine has been shown to cause damage to the myelin sheath. Indeed, the role of levacecarnine in the regenerative process of the nerve has been demonstrated in several preclinical studies. Studies have investigated whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic neuropathy. It was found that in rats with streptozotocin-induced diabetes of 4-6 weeks duration, urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%).

in diabetic patients with complications was almost 25% lower than in diabetic patients with no complications. Serum-free L-carnitine in retinopathy, hyperlipidemia and neuropathy case subgroups were 39.03+/-9.89, 39.63+/-8.99 and 40.44+/-12.50 micromol/l, respectively (P>0.05). Thus the mean serum-free Lcarnitine concentration in the case group was significantly lower than its mean concentration level in the control group, 39.63+/-8.99 vs. 53.42+/-0.93 micromol/l, respectively (P<0.001). On the basis of the study results, carnitine supplementation in diabetic patients, especially in patients with diabetes complications, might be useful. Preliminary studies of levacecarnine in patients with peripheral neuropathies have shown promising results. Levacecarnine has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies. Levacecarnine in type 1 DPN targets a multitude of underlying mechanisms and is therefore more likely to be effective on a broader spectrum of the underlying pathogenesis of DPN.
60
Serum-free L-carnitine levels (mmol/l)

P>0.05
39.03 39.63 40.44

53.42

A deficiency of levacecarnine has been shown to cause damage to the myelin sheath. When corrected, the early functional deficits in DPN are usually normalized. If not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function.

50 40 30 20 10 0
Retinopathy Hyperlipidemia Neuropathy Control

Fig. : Serum-free L-carnitine (micromole/L) deficiency seen in Retinopathy, Hyperlipidemia and Neuropathy subgroups in diabetics.

3.4.2. Benefits of levacecarnine in DPN

In type II diabetic women with and without complications, the mean serum-free L-carnitine levels

Administration of exogenous levacecarnine offers the following benefits in diabetic neuropathy: w Recovery of nerve conduction velocity (NCV) & stimulation of nerve growth factor (NGF):

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Abnormalities of nerve conduction parameters are considered a sensitive and reliable measure for the diagnosis of diabetic neuropathy and are strongly correlated with clinical endpoints. NCV is an expression of the speed of neural propagation in the largest myelinated nerve fibres and is, therefore, greatly affected by myelin integrity, whereas the response amplitude is influenced by the density of large myelinated axons and their synchronous activation. Increased availability of acetyl groups by levacecarnine enhances neural metabolism in vitro through stimulation of NGFs. Increased availability of acetyl groups by levacecarnine enhances neural metabolism in vitro through stimulation of nerve growth factors. In clinical studies, levacecarnine treatment significantly improved electrophysiological parameters, which are among the most accurate and reliable markers of disease progression in diabetic patients with peripheral neuropathies. In clinical studies, levacecarnine treatment resulted in a significant improvement of motor nerve conduction

velocity (MNCV) and of sensory nerve conduction velocity (SNCV) in patients with both mono- and polyneuropathies. A study found that low levels of NGF, diabetic neuropathy and impaired NCV are inter-related, suggesting that levacecarnine may be able to correct electrophysiological deficits by modulating NGF activity. w Decreased neuropathic pain: The beneficial effects of levacecarnine were observed on a clinical endpoint such as pain. After 12 months of treatment, mean VAS scores for pain were significantly reduced from baseline by 39% in levacecarninetreated patients (p < 0.0 vs. baseline) vs. 8% in placebo recipients. w Proposed mechanism of pain relief by levacecarnine: Activation of receptor - mGlu2* induces reduction in pain (antinociception) in several pain models in rodents. Levacecarnine up-

600
mGlu2 mRNA expression (% change)

500
p<0.05 p<0.01 240 1 days

50

400 300 200 100 0

VAS scale of pain in (mm)

40

30

p<0.05

20

10

p<0.01

100 0
Baseline
LAC

30 6 Months
Placebo

12 Months

60 120 minutes

Time after LAC treatment (250M every 12hr)

Fig. : Change from baseline in pain intensity on the VAS after 6 and 12 months of treatment with levacecarnine (LAC) [n = 95] vs. placebo (n = 104).

Fig. : Time course analysis of mGlu2 and mGlu3 mRNA expression after LAC treatment. LAC=levacecarnine.

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regulates the expression of mGlu2 in the dorsal root ganglia and in the dorsal horn of the spinal cord.
* The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor which are active through an indirect metabotropic process. mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter.

w Increased synthesis of acetyl choline: It has been shown that the endogenous compound, acetyl-Lcarnitine acts in the brain as a metabolic cofactor in the synthesis of acetylcholine. w Increased nerve growth factor: In an animal study, levacecarnine was assessed for its effect on forebrain cholinergic neurons in the brain of developing rats. The results showed that levacecarnine increased nerve growth factor receptor expression in the striatum. The level of NGF in the hippocampus also increases. w Increased neuronal maturation and survival: Levacecarnine increased maturation of cultured cerebellar granule cells neurons. Levacecarnine treatment also increased neuronal survival. we a s e d n e r v e f i b r e r e g e n e r a t i o n : Incr Levacecarnine can accelerate nerve regeneration after experimental surgical injury in rats. Clinical trials utilizing levacecarnine have shown beneficial effects on nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Clinical trials utilizing levacecarnine have shown beneficial effects on nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. w Prevention of substance P loss: 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 levacecarnine treatment. It is reported that 14 weeks after inducing diabetes induction with alloxan, the levels of substance P are markedly reduced throughout the intestine. Treatment of diabetic animals with levacecarnine prevents the onset of the marked peptide changes. w Correction of levels of Na + /K -ATPase, myoinositol and vascular dysfunction: In preclinical studies, substitution with levacecarnine + corrects perturbations of neural Na+/K -ATPase, myoinositol, nitric oxide (NO), prostaglandins, and lipid peroxidation, all of which play important early pathogenetic roles in DPN. Levacecarnine supplementation has an early beneficial effect on Na1/K1-ATPase activity, suggesting that depletion + + of acetyl-L-carnitine effects Na /K -ATPase activity in peripheral nerve fiber via metabolic pathways alternate to the polyol pathway.
200
161.8
+

Na /K - ATPase activity in Sciatic Nerves (mmol ADP/mg wet wt per h)

128.6

160 120

143.7

159.3

105.2

80 40 0
4 Months
Non-treated control Non-treated Diabetics

8 Months
Control on ALC Diabetics on ALC

ALC=levacecarnine in animal model

Fig. : Effect of 4 and 8 months levacecarnine treatments on Sciatic Nerve Glucose, Sorbitol, Fructose and Myoinositol Levels, and Na+/K+-ATPase Activity in Sciatic Nerves.

85.3

89.9

97

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w Correction of levels of PKC: Levacecarnine treatment of acutely diabetic streptozotosin rats prevents transient nerve myoinositol depletion, probably by correcting PKC-regulated Na+ + dependent myoinositol transport and Na /K ATPase activity. w Enhanced antioxidant activity: Levacecarnine reduces oxidative stress. Levacecarnine was associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic nerve, indicating reduced lipid peroxidation. weased production of membrane Incr phospholipids. w Changes in microvascular protein permeability. w Improvement in vibration perception: The improvement in vibration perception by levacecarnine is suggestive of repair of large myelinated fibers. The improvement in vibration perception by levacecarnine is suggestive of repair of large myelinated fibers.

function in patients with diabetes mellitus. Therefore, levacecarnine deserves consideration as a potential treatment capable of delaying or halting the neurodegenerative processes that underlie diabetic neuropathy. Owing to the good safety profile of levacecarnine, early initiation of levacecarnine therapy would be justified in DPN, with potentially greater benefits.

3.5. Slowing dementia & Alzheimers disease with levacecarnine

You have to begin to lose your memory, if only in bits and pieces, to realize that memory is what makes our lives...Our memory is our coherence, our reason, our feeling

3.5.1. Pathophysiology of dementia and Alzheimers disease

The clinical features of dementia include an acquired global impairment of intellect, memory and changes in personality. The memory impairment is suspected of being linked to the loss of cholinergic neurons. Studies

w Favorable safety profile: Levacecarnine treatment was well tolerated and did not induce significant changes in vital signs or haematology/biochemistry parameters, thus indicating a lack of specific organ damage even after prolonged use. In all studies (including this one), the tolerability of levacecarnine was good during both intramuscular and oral treatment phases, with a low incidence of mild adverse events, mostly gastrointestinal. Long-term treatment with levacecarnine may prevent the progressive loss of cardiac sympathetic nervous

Fig. : Alzheimers disease

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have demonstrated both loss of cholinergic neurons and lower levels of the synthetic enzyme choline acetyl transferase in the brains of people affected by dementia. Another clear finding is of widespread cell death and synaptic membrane damage, which may be mediated by abnormal energy processing and the production of free radicals. Alzheimers disease (AD) is a neurodegenerative disorder characterized pathologically by senile plaques, neurofibrillary tangles and synapse loss. The major constituent of senile plaques is amyloid-beta peptide (A 142), a hallmark of AD.

shown to decrease mitochondrial function assessed by MTT reduction by 50% vs. untreated control.
w Apoptotic neuronal cell death: Several studies

suggest that A 142 -induced oxidative stress leads to apoptotic neuronal cell death that can be inhibited by antioxidants.
w Decreased levels of GSH: Abeen shown to 142 has

deplete glutathione (GSH) levels. Additionally, GSH levels decrease with age, leaving neurons vulnerable to oxidative damage initiated by A 142. Consequently, A lead to depletion of GSH 142 may as an available antioxidant in neurons.
w Induces loss of neuronal network and neuronal

Central role of A pathogenesis 142 in the of AD:

w Oxidative stress: The brain has a high oxygen

4-Hydroxy-2-nonenal (HNE) is a highly reactive product of lipid peroxidation of unsaturated lipids. In mediator of oxidative stress and neurotoxicity. A 142 Alzheimers disease, HNE-induced oxidative toxicity is involved in free-radical formation that induces is a well-described model of oxidative stress-induced damage to neurons in vitro. neurodegeneration. GSH plays a key role in antioxidant defense, and HNE exposure causes an initial depletion of GSH that leads to gradual toxic accumulation of A oxidative stress leads to apoptotic neuronal 142-induced reactive oxygen species. Decreased cell survival of cell death that can be inhibited by antioxidants. neurons treated with HNE correlated with increased protein oxidation (protein carbonyl, 3-nitrotyrosine) w Protein oxidation and lipid peroxidation: A and lipid peroxidation (HNE) accumulation. 142 has been shown to induce protein oxidation and lipid peroxidation in vitro and in vivo. Markers of 3.5.2. Levacecarnine - Pathway of oxidative stress include 3-nitrotyrosine (3-NT) in benefits in dementia & Alzheimers AD.

consumption rate, abundant lipid content, and relatively low availability of antioxidant enzymes compared with other tissues, which makes this organ particularly susceptible to oxidative stress. A 142 is a

apoptosis: Neurons that were exposed to A 142 for 24 hr showed loss of neuronal network, membrane blebbing, and cell shrinkage, processes that are normally associated with apoptotic cell death.

disease

w Inhibits A 142-mediated dysfunction: A 142 was

Levacecarnine is described as having several

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Scientific Monograph

properties beneficial in dementia. A presynaptic mechanism is proposed for the effect of levacecarnine on cholinergic neurotransmission. That is, levacecarnine induces an increase in acetylcholine release, as measured by microdialysis in the caudateputamen and hippocampus. Levacecarnine may promote membrane stabilization, via its ability to increase adenosine levels. The hydrophobic acetyl moiety of levacecarnine improves the ability of this drug to cross the blood-brain barrier and to be taken up by neuronal tissue. With levacecarnine, there was a maximal significant decrease in protein oxidation and lipid peroxidation.

formed by the reaction of reactive nitrogen species (RNS) with proteins and is reported to be elevated in AD brain. On treatment with levacecarnine, there was a maximal significant decrease in protein oxidation (P < 0.05) and lipid peroxidation (P < 0.01). 2. Inhibits A mitochondrial 1 4 2 -mediated dysfunction: Pretreatment of neurons with 100 lM levacecarnine (2 hr prior) followed by A 142 showed significant (P < 0.01) dose-dependent protection of mitochondrial function vs. that induced by A 142 alone. 3. Protection of mitochondria from oxidative damage: Mitochondria are particularly vulnerable to oxidative damage, and mitochondrial dysfunction has been observed in AD brain. Levacecarnine promoted neuronal survival and mitochondrial activity in a concentrationdependent manner. Pretreatment of neurons with 100 lM levacecarnine protected these cells against A 142-mediated loss of mitochondrial function, protein oxidation, loss of neuronal network and apoptotic cells. 4. Protects against A 142-induced loss of neuronal network and neuronal apoptosis: Neurons pretreated with levacecarnine 2 hr prior to addition of A 142, showed intact networks and cell bodies similar to those of control (untreated) neurons. Thus pretreatment of neurons with levacecarnine followed by addition of A 142 resulted in a significant reduction in apoptotic cells similar to the reductions in control cells (P < 0.01). 5. Protects against HNE-induced cytotoxicity: Pretreatment of primary cortical neuronal cultures

160 140 120

% Control
** * *

*P < 0.01, **P <0.05 vs. control.

** * * *

100 80 60 40 20 0
ol nt r Co ) 0 0 0 50 75 10 42 10 20 10 R R R R (1R R CA CA CA CA CA CA AB AL AL AL AL AL AL

(Conc. in micromolar)

Fig. : Protective effect of ALCAR (levacecarnine) against Ab142-induced oxidative stress, in terms of decreased protein oxidation (protein carbonyls).

As per animal & human studies, levacecarnine has the following neurobiological effects beneficial in dementia and Alzheimers disease: 1. Inhibits A 142-induced protein oxidation and lipid peroxidation: Protein carbonyls are elevated in vulnerable regions of AD brain and in brain treated in vivo with A 142. A significant increase in protein carbonyls (P < 0.05) or 3-NT (P < 0.01) levels, respectively, was induced in neurons following 24 hr of treatment with A is 142. 3-NT

16

with levacecarnine and alpha-lipoic acid significantly attenuated HNE-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Levacecarnine prolonged survival of cultured brain cells after exposure to neurotoxic stimuli.

of age-associated cognitive dysfunction, including tests of the Morris water maze for spatial memory, active avoidance learning, discrimination learning, radial maze, and long-term memory performance in the split-stem T-maze. These tests show that levacecarnine improves the age-associated decline of learning and memory in old animals. 9. Reversal of mitochondrial decay: Oxidative mitochondrial decay contributes to aging and cognitive decline, some of which can be reversed with levacecarnine. Levacecarnine has been shown to reverse age-related deficits in mitochondrial function. 10. Delay in cognitive decline: Levacecarnine improved brain measures of membrane phospholipid and high-energy phosphate metabolism, which corresponded with a delay in subjects cognitive decline. 11. Prevents or slows age-related memory impairment: Memory loss is accompanied but not necessarily caused by accumulation of oxidative damage to lipids, proteins, and nucleic acids, and by mitochondrial decay, all of which can disrupt neuronal function. Levacecarnine supplementation prevents or slows age-related memory impairment by means of increased neurotransmitter production and maintains synaptic contacts and levels of certain hormonal receptors. Feeding levacecarnine and alpha lipoic acid to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function. 12. Essential safety: Levacecarnine has been found to be safe in dementia patients with few reported adverse effects.

6. Better energy metabolism: Levacecarnine normalized alterations in cerebral membrane and energy metabolism during recovery from ischaemia. Levacecarnine substantially improves neurological outcome in cerebral ischemia and reperfusion. 7. Better brain resistance to neurotoxic stimuli: Levacecarnine prolonged survival of cultured brain cells after exposure to neurotoxic stimuli. 8. Better cognitive functioning: Levacecarnine improved cognitive functioning. One of the mechanisms for improvement of cognition is that levacecarnine helps the brain maintain a constant supply of energy by boosting the levels of phospholipid precursors for membrane synthesis. In animals, the effect most studied is improvement
200 180 160 140
% Control ** * ** * * * * *P < 0.01, **P <0.05 vs. control.

120 100 80 60 40 20 0
ol ntr Co AB

) 0 0 0 75 50 10 42 10 20 10 R R R (1R R R CA CA CA CA CA CA AL AL AL AL AL AL

(Conc. in micromolar)

Fig. : Protective effect of ALCAR (levacecarnine) against Ab142-induced oxidative stress, in terms of decreased protein oxidation (3-nitrotyrosine).

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Scientific Monograph

13. Treats depression & fatigue symptoms: Levacecarnine has been used to treat older patients with depression and fatigue symptoms. 14. Upregulation of the antioxidant GSH: Levacecarnine has been shown to facilitate transport of the compound across the bloodbrain barrier and elevates the nigral levels of GSH. Levacecarnine treatment followed by addition of A total GSH levels significantly (P < 142 raised 0.01) to 80% of control.

3.6. Levacecarnine Benefits in stroke

3.6.1. Pathophysiology of stroke
After myocardial infarction, even if an individual survives initial resuscitative efforts, ischemic damage to the brain occurring during cardiac arrest and reperfusion often results in neurological morbidity or mortality. During periods of normal cerebral perfusion, viability of neuronal tissue is maintained through oxidative metabolism of glucose, with resultant ATP production.

16 14

GSH (micromolar)

12 10 8 6 4 2 0
ol ntr Co R CA AL 10 R CA AL 50 R CA AL 75 R CA AL 10 0 R CA AL 0 20

Fig. : Increase in GSH levels with ALCAR (levacecarnine) in a dose dependent manner

The significant effect on early AD and mild impairment and the less significant effect on Alzheimers disease (AD) patients may suggest that levacecarnine is more effective in preventing and slowing the progression of AD than in treating severe AD. The significant effect on early Alzheimers disease (AD) and mild impairment and the less significant effect on AD patients may suggest that levacecarnine is more effective in preventing and slowing the progression of AD than in treating severe AD.

Fig. : Stroke

The anoxia that accompanies complete cerebral ischemia results in complete cessation of aerobic metabolism, followed by rapid depletion of glucose as a result of anaerobic glycolysis. Inhibition of energy metabolism leads to an effectively complete elimination of ATP within the first several minutes of ischemia, resulting in a loss of neuronal ionic homeostasis with resultant cellular efflux of potassium and influx of sodium and calcium. For brain tissue to recover from this ischemic insult, mitochondria must be rapidly reenergized during reperfusion so that ATP can once again be produced and ionic homeostasis

18

restored. Restoration of normal energy metabolism may, however, be initially retarded due to the mitochondrial injury that occurs during even brief periods of ischemia. Levacecarnine has been shown to regenerate nerves; provide protection against glutamate and ammonia-induced toxicity to the brain; and to reverse the effects of heart aging in animals. Neuronal oxidative metabolism may be suppressed long after initiation of reperfusion. This leads to a secondary, late failure of brain energy metabolism with increased levels of brain lactate and significantly lowered levels of brain ATP seen at 4 hours. Thus to maintain neuronal viability after resuscitation from cardiac arrest, rapid and prolonged cellular reenergization must be promoted to counteract the degradative processes begun during ischemia. Further, glutamate mediated intracellular calcium accumulation and free radical generation are thought to be major mechanisms that contribute to cell death in hypoxic-ischemic brain injury.

Benefits of levacecarnine in stroke patients are as follows: w Reduction of neurologic damage post-ischemia: Levacecarnine attenuates neurologic damage after brain ischemia and reperfusion in canines. A study of an animal model showed that a significant degree of the postischemic neurologic injury was reversible through the use of levacecarnine. Levacecarnine can increase the metabolic rate of mitochondria, thus improving mitochondrial oxygen utilization in these systems, making this a potentially useful drug to counteract some of the effects of ischemic injury to the brain.
w Neuroprotective: Levacecarnine exerts a

significant neuroprotective effect when administered immediately after reperfusion from transient global cerebral ischemia. In an animal study, postischemic treatment with levacecarnine improved early clinical recovery and prevented significant weight loss in a rat model of focal cerebral ischemia.
Experimental group Control 10-Minute arrest 2-Hour ROSC 2-Hour ROSC+ALCAR 24-Hour ROSC 24-Hour ROSC+ALCAR Lactate n 8 11 5 6 4 5
(mmol g-1 wet wt)

Pyruvate
(mmol g-1 wet wt)

Lactate/ Pyruvate
(mmol g-1 wet wt)

3.6.2. Levacecarnine shows multiple benefits in stroke patients

Levacecarnine has been shown to regenerate nerves; provide protection against glutamate and ammoniainduced toxicity to the brain; and to reverse the effects of heart aging in animals. Levacecarnine administered to stroke patients brought improvements in memory, cognition, and task performance. The hydrophobic acetyl moiety of levacecarnine improves the ability of this drug to cross the blood-brain barrier and to be taken up by neuronal tissue.

1.90.2 12.50.5* 4.30.2* 2.00.4 4.52.1 2.50.9

1267 527* 16041 19724 9623 18421

16.32.2 29144* 34.36.9 9.51.1 49.822 12.53.0

Values are mean SEM. n, Number of dogs; ROSC, restoration of spontaneous circulation; ALCAR, acetyl-L-carnitine. * p<0.01 compared with control group. p<0.01 compared with 2-hour ROSC group. p<0.05 compared with control group. p<0.05 compared with 24-hour ROSC group.
Table 2: Frontal Cortex Lactate and Pyruvate Levels After Cardiac Arrest in Dogs

w Improves mitochondrial oxygen utilization:

Levacecarnine can increase the metabolic rate of

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Scientific Monograph

mitochondria, thus improving mitochondrial oxygen utilization in these systems, making this a potentially useful drug to counteract some of the effects of ischemic injury to the brain.
w Reduces potentiator of ischemic injury:

Carnitine can stimulate aerobic pyruvate metabolism, thereby inhibiting flux of pyruvate to lactic acid, a known potentiator of ischemic injury. In an animal study, tissue lactate levels and lactate/pyruvate ratios remained elevated after 2 hours of reperfusion in dogs not treated with levacecarnine.
w Reduction of oxidative stress markers: The

and KA-induced neurotoxicity, decreased glutamate-induced neuronal cell death from 36.142.95% to 17.592.25%; (P<0.001) and KAinduced neuronal cell death from 21.40.41 to 13.41.38%; (P<0.001). Protective effect of lcarnitine may result from its antioxidant activity because free radical generation is a common result in either glutamate- or kainic acid (KA)-induced neurotoxicity.
w Inhibits excitotoxicity: The presence of acetyl-l-

antioxidant mechanism of levacecarnine is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid.
w Protects from glutamate and KA-induced

carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders.
w Inhibition of mitochondrial permeability

transition

neurotoxicity: L-carnitine protects against glutamate- and KA-induced neurotoxicity. 10- 4 M Lcarnitine, the most effective dose in both glutamate-

3.7. Levacecarnine Benefits in Parkinsons disease

3.7.1. Pathogenesis of Parkinsons disease

50%

40%
% neuronal cell death

36.14%

30%
21.40%

20%

17.59% 13.40%

10%

The cardinal clinical manifestations of Parkinsons disease include bradykinesia, rest tremor, rigidity, and postural instability. The cause of the illness is a selective degeneration of dopaminergic neurons in the substantia nigra compacta. Mitochondrial defects are implicated in the pathogenesis of Parkinsons disease (PD). Investigation of mitochondrial dysfunction in PD gained momentum with the finding that a synthetic

0%
Glutamate-induced
Without treatment

KA-induced
After treatment with L-carnitine

Fig. : 10-4 M L-carnitine decreased glutamate-induced neuronal cell death (P<0.001) and KA-induced neuronal cell death (P<0.001).

20

opiate contaminant, MPTP (N-methyl-4-phenyl1,2,3,6-tetrahydropyridine), induces acute, permanent parkinsonism via its active metabolite, MPP+ (1methyl-4-phenyl-2,3,-dihydropyridinium), a mitochondrial complex I inhibitor. MPP+ is preferentially taken up by dopamine neurons and selectively inhibits complex I of the electron transport chain.

3.7.2. Consequences of Complex I inhibition in Parkinsons disease

In mitochondria, electron transport chain (ETC) produces ATP. Complex I (NADH dehydrogenase) is the first of four multisubunit protein complexes in the mitochondrial electron transport chain responsible for converting energy from cellular metabolism into the proton gradient used by complex V to generate ATP. Complex I is the largest of the ETC macrocomplexes in the mitochondria. Complex I inhibition has several potentially damaging consequences, including: w Damage to neurons: Complex I inhibition can damage human dopaminergic neurons, as demonstrated by acute MPTP toxicity.
w Oxidative stress: Increased formation of reactive

N CH3

MPTP
N+ CH3

MPP+
Fig. : Structure of MPTP and MPP+

In idiopathic Parkinsons disease, there is a 30-40% decrease in complex I activity in the substantia nigra, as well as reduced staining for complex I subunits. Reduced complex I activity in Parkinsons disease platelets has been reported in several studies. Cybrids made from individuals with Parkinsons disease show selective reductions in complex I activity, as well as increased free radical production, and an increased susceptibility to the MPTP metabolite MPP+. Mitochondrial defects are implicated in the pathogenesis of Parkinsons disease.

oxygen species (ROS) creates oxidative damage within the cell. Electron transport chain dysfunction could lead to loss of the proton gradient, impaired ATP production and a bioenergetic defect. Increased oxidative damage to lipids, DNA and proteins has been observed in PD substantia nigra pars compacta (SNpc), along with decreased levels of reduced glutathione.
w Further damage of complex I : Internal ROS

production can lead to oxidative damage and more impairment of the catalytic core of complex I.
w Decreased ATP production

Thus PD is a brainwide mitochondrial disease in which complex I dysfunction is likely to play a significant pathogenic role.

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Scientific Monograph

3.7.3. Some other factors implicated in pathogenesis of PD

Rotenone: Rotenone, a highly lipophilic organic pesticide, readily crosses the blood-brain barrier and cell membranes without specific, active transport. Rotenone is known to be a high-affinityspecific inhibitor of complex I of the electron transport chain. An inhibitor of complex I of the electron transport chain, which acts uniformly throughout the brain, produces a selective degeneration of nigrostriatal neurons. Further, rotenone induces apoptosis via enhancing the amount of mitochondrial reactive oxygen species production.
100 90

In Parkinsons disease, agents that may improve mitochondrial function or exert antioxidative effects could be neuroprotective. Cardiolipin: In Parkinsons disease, mice lacking the presynaptic protein a-synuclein exhibited a 22% reduction in CL mass in the brain and reduction in CL content of polyunsaturated fatty acids. There was a 23% reduction in phosphatidylglycerol (PG), a CL precursor, suggesting that the CL biosynthesis pathway may be selectively impaired. These alterations were associated with a 15% reduction in linked complex I/III activity of the electron transport chain - a critical factor in the development of Parkinsons disease. Creatine/phosphocreatine system: The creatine/phosphocreatine system functions as a spatial energy buffer between the cytosol and mitochondria. The potential of creatine to be protective can be illustrated in numerous models of neurodegeneration.

Relative ATP Level (% of control)

80 70 60 50 40 30 20 10 0 0 200 400 600 800 1000

3.7.4. Benefits of levacecarnine in Parkinsons disease

Rotenone (nM)

Fig. : Inhibitory effects of rotenone on cellular ATP levels. ATP values are expressed as percent of control.

3-nitroproprionic acid: 3-nitropropionic acid (3-NP) is an irreversible inhibitor of complex II. 3-NPA inhibits irreversibly succinate dehydrogenase, localized in the mitochondrial inner membrane, and complexes II and III of the respiratory chain and the tricarboxylic acid cycle. These effects decrease ATP levels, leading to changes in the neuronal membrane potential. Histological and neurochemical analyses have demonstrated that systemic administration of 3NPA to mature rats induces striatal damage.

If mitochondrial defects and oxidative damage play a role in the pathogenesis of PD, then one would suspect that agents that may improve mitochondrial function or exert antioxidative effects could be neuroprotective. The hydrophobic acetyl moiety of levacecarnine improves the ability of this drug to cross the bloodbrain barrier and to be taken up by neuronal tissue. Levacecarnine demonstrates the following benefits in PD: w Action on 3-NP, MPTP and rotenone: Carnitine and levacecarnine attenuate neuronal damage produced by 3-nitroproprionic acid, rotenone and MPTP in vitro. Levacecarnine improves nerve regeneration in rats. Levacecarnine accelerated the

22

maturation of cerebellar neurons in vitro, activated nerve growth factor receptors, and prevented the loss of substance P in the peripheral nerves in diabetic animals.
w Strengthens mitochondrial structure and

w Anti-apoptotic action: Levacecarnine seems to

possess antiapoptotic properties. Levacecarnine administration to HIV-1-infected subjects decreased the levels of apoptotic CD4 T-cells.

activity with increased cardiolipin and creatine/phosphocreatine levels: Carnitine delays mitochondrial depolarization in response to a variety of stressors including oxidative damage. Levacecarnine increases cellular respiration, mitochondrial membrane potential and cardiolipin levels in hepatocytes of 24-month-old rats. After ischemia reperfusion in rats, levacecarnine resulted i n a m o r e r a p i d r e c o v e r y o f AT P, creatine/phosphocreatine and lactate levels. Dietary administration of levacecarnine and/or R-alphalipoic acid improved age-related mitochondrial structural decay in hippocampal neurons in old rats.
w Anti-oxidant action: Levacecarnine elevates

3.8. Levacecarnine Benefits in averting and managing depression

Aging and disease often bring on their own unique forms of depression. Scientists now understand the particular chemistry of these types of depression, and are finding that levacecarnine actually improves the brains structure and function, which can help alleviate certain forms of depression. A study showed that supplementing cancer patients with carnitine for just one week resulted in marked improvements in depression score, sleep disruption and fatigue scores. In a clinical trial, scientists examined two elderly depressed men and found large amounts of high-energy fat metabolites - phosphomonesters [PME(s - tau(c))]in their brains, indicating poor energy utilization by the brains own tissues. This failure of the brain to function optimally resulted in a chemically induced depression. When the men supplemented with levacecarnine, the levels of these molecules fell and they experienced significant improvements in their depression rating scale. levacecarnine treatment also resulted in increasing levels of the prefrontal phosphocreatine (PCr), which correlated with the depression scale. Thus in the prefrontal region, the mildly depressed subjects compared with controls had elevated PME(s - tau(c)) levels which normalized after 12 weeks of levacecarnine and increased PCr levels after levacecarnine treatment. Depression often occurs in those suffering from

levels of glutathione (GSH) in the brains of mice. Several factors explain why glutathione is so beneficial in Parkinsons disease. Glutathione's powerful antioxidant activity protects the brain from free radical damage. Glutathione has been shown to be very effective in protecting the nerves in the substantia nigra from being destroyed by oxidative stress. Glutathione increases the sensitivity of the brain to dopamine. Glutathione treatments considerably improve some of the symptoms of Parkinson's disease including difficulties with rigidity, walking, movement, coordination and speech. A marked reduction of tremor has been observed as well as a decrease in depression.

Levacecarnine elevates levels of glutathione (GSH) in the brains of mice.

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Scientific Monograph

illnesses such as cancer, diabetes, and heart disease. A study showed that supplementing cancer patients with carnitine for just one week resulted in marked improvements in depression score, sleep disruption, and fatigue scores. In such patients, nutritional factors are among the postulated causes of fatigue, a highly prevalent symptom in the cancer population, with serious impact on patients' quality of life. Deficiency of the micronutrient carnitine may play a role by reducing energy production through fatty acid oxidation. Such quality-of-life improvements are critical and can make the difference between improvement and decline. Recently, doctors tested acetyl-L-carnitine against the mood-stabilizing drug amisulpride. They found that acetyl-L-carnitine was just as effective as amisulpride in treating depression, without any of the drugs side effects.

gastrointestinal tract and the liver. Although base of free L-carnitine is highly water soluble, the absolute bioavailability is relatively low, being in the range between 15 and 20%. In aging or in conditions of disease, levacecarnine is better absorbed and more efficiently crosses the blood-brain barrier as compared to L-carnitine. Levacecarnine is more widely used than L-carnitine in animal research and clinical trials to gain metabolic benefits to the brain, heart, and other organs.
Relative bioavailability of Levacecarnine vs. base of free L-carnitine 61 14 66 20

Free carnitine Total carnitine

Table 2: Relative bioavailability of Levacecarnine vs. base of free L-carnitine based on the areas under the curve values (AUCs) for plasma free and total carnitine at the time interval between 0 and 32 hours.

3.9. Levacecarnine Protects memory in mild cognitive impairment

An analysis of 21 clinical trials of acetyl-L-carnitine in the treatment of mild cognitive impairment and mild Alzheimers disease in rats showed that it has demonstrated significant efficacy versus placebo. Clinical studies in humans demonstrating positive effects of Acetyl-L-carnitine may slow or reverse mild cognitive impairment and the progression of dementia in Alzheimer's diseas

The hydrophobic acetyl moiety of levacecarnine improves the ability of this drug to cross the bloodbrain barrier and to be taken up by neuronal tissue.

3.11. Levacecarnine Proven longterm safety

In a meta-analysis of 16 human clinical trials in patients with dementia, levacecarnine appeared to have no common or serious adverse effects in most studies. In studies where levacecarnine was given to Alzheimers disease patients at doses of 1.5-3.0 g/day for two to six months, no serious side effects were observed. In aging or in conditions of disease, levacecarnine is better absorbed and more efficiently crosses the blood-brain barrier as compared to L-carnitine. Levacecarnine treatment was well tolerated and did not induce significant changes in vital signs or haematology/biochemistry parameters, thus indicating

3.10. Levacecarnine Better absorption vs. L-carnitine

Levacecarnine is a small molecule and can only be absorbed through an active transport mechanism. The acetyl group is easily removed both in the

24

a lack of specific organ damage even after prolonged use.

numbers and regenerating nerve fiber clusters.

Change in sural nerve morphometry 500 mg levacecarnine 144.1 28.9 -14 197 -3.3 8.0 Placebo 132.6 37.8 -98 352 -27.9 9.1

4. Levacecarnine Clinical trials

4.1. Levacecarnine in diabetic neuropathy
Study objective: Two multicenter, double-blind, placebo-controlled, randomized, 52-week clinical trials evaluated two doses of levacecarnine in patients with diabetic neuropathy. The design of the two studies was identical, administering levacecarnine at two doses (500 or 1,000 mg) given three times a day (t.i.d.) for 1 year. Patietns, duration and treatment: Levacecarnine at 2 doses (500 or 1,000 mg) was given 3 times a day for 1 year. Intention-to-treat patients amounted to 1,257 or 93% of enrolled patients. Efficacy end points: Efficacy end points were sural nerve morphometry, nerve conduction velocities, vibration perception thresholds, clinical symptom scores, and a visual analogue scale for most bothersome symptom, most notably pain. Results: w ro v e d s u r a l n e r v e m o r p h o m e t r y : Imp Morphometric evaluations of sural nerve biopsies revealed a significant increase in the score for all biopsy parameters in the 500-mg levacecarnine arm (P=0.027), with a significant increase in fiber numbers (P=0.049) and a significant increase in regenerating clusters (P=0.033). The significant value of the OBrien rank score was mainly due to the increase in fiber numbers. Data showed significant improvements in sural nerve fiber

OBrien rank score for all biopsy parameters Fiber numbers Regenerating clusters

Table 2: Changes in sural nerve morphometry with 500mg levacecarnine vs. placebo

w Improvement of vibration perception threshold:

In one patient cohort, the scores for all vibratory parameters revealed significant improvements in patients treated with 1,000 mg levacecarnine t.i.d. vs. placebo (P = 0.007). Vibration perception improved significantly in the fingers in both the 500and 1,000-mg levacecarnine t.i.d. groups (P = 0.040 and P = 0.010) and in the toes in the 1,000-mg t.i.d. group (P = 0.047). In another patient cohort, patients treated with 1,000 mg levacecarnine t.i.d. showed significant (P=0.041) improvement in vibration perception in the fingers only.
1000 mg levacecarnine Scores for all vibratory parameters
Table :

Placebo 1,452 571

1,300 571

w Significant improvement in pain: Pain as the most

bothersome symptom showed significant improvement in one study and in the combined cohort taking 1,000 mg levacecarnine. The pooled cohorts treated with 1,000 mg levacecarnine t.i.d. showed significant improvements at both 26 (P=0.031) and 52 (P=0.025) weeks. In one patient cohort, patients treated with 1,000 mg levacecarnine t.i.d. showed significant improvements at both 26 and 52 weeks (P = 0.021 and P = 0.024, respectively), whereas in the other patient cohort, no improvements were demonstrated at either time

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Scientific Monograph

CBF (ml/min x 100g)

point. Thus 1,000 mg levacecarnine t.i.d. for 52 weeks showed beneficial effects on pain in 27% of neuropathic diabetic patients who reported pain as the most bothersome symptom at baseline. In both the cohorts, patients who showed the greatest benefit in pain reduction with 1,000 mg levacecarnine t.i.d. after 52 weeks of treatment were those with type 2 diabetes (P=0.055 and P = 0.11, respectively), adequate drug compliance (P = 0.01 and 0.37, respectively), and HbA1c >8.5% (P = 0.009 and P=0.017, respectively). In the pooled studies, the responsiveness of pain to levacecarnine treatment was inversely related to duration of diabetes. patients with pain as the most bothersome symptom showed improvements in the score for all clinical symptom scores (P = 0.03), postural dizziness (P = 0.03), and paresthesia (P = 0.09).
1.0
Effect Size (%)

Baseline

Post-treatment

48
46

46

44
43 43 42

42

40
Placebo ALC

Fig. : Significant improvement in cerebral blood flow with levacecarnine vs. placebo.

0.8 0.6 0.4 0.2 0

0-5 yrs of DM (N=42) 5-10 yrs of DM (N=66) 10-15 yrs of DM (N=129)

Conclusions: Neuropathic pain can result from overstimulation of nociceptive fibers due to nerve fiber damage. There exists a correlation between active nerve fiber degeneration and dysesthetic pain. The study demonstrates that levacecarnine treatment presumably inhibited active fiber degeneration, as suggested by the morphometric data, thereby minimizing dysesthetic pain. Thus levacecarnine treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy. Levacecarnine treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy.

Fig. : Effect size of levacecarnine treatment on pain as a function of diabetes (DM) duration. The data represent the pooled cohort.

w tolerated: In the total population, pain, Well

paresthesia, and hyperesthesia were reported by significantly fewer patients taking 1,000 mg levacecarnine compared with placebo (P = 0.026, P = 0.023, and P = 0.025, respectively). The incidence of other adverse events did not differ between placebo and patients on an active drug.

4.1. Levacecarnine in diabetic neuropathy

Study design and objective: A multicentre (n = 20), randomized, double-blind, placebo-controlled, parallel-group study was performed to investigate the efficacy and tolerability of levacecarnine vs. placebo in

26

improving altered electrophysiological parameters (NCV and amplitude) and pain in patients with diabetic neuropathy. Patients, treatment and duration: 333 patients meeting clinical and/or neurophysiological criteria for diabetic neuropathy (distal symmetric polyneuropathy or multineuropathy) were enrolled. Patients were randomized to treatment with levacecarnine or placebo. Levacecarnine (or placebo) was started intramuscularly at a dosage of 1000 mg/day for 10 days and continued orally at a dosage of 2000 mg/day for the remainder of the study (355 days). Patients treated with levacecarnine showed a statistically significant improvement in mean nerve conduction velocity and amplitude vs. placebo. Main outcome parameters: The main efficacy parameter was the effect of treatment on 6- and 12month changes from baseline in nerve conduction
Acetyl-L-carnitine Parameter Nerve conduction velocity (m/sec) SN ulnar SN sural SN median MN ulnar MN peroneal MN median Amplitude SN ulnar (V) SN sural (V) SN median (V) MN ulnar (mV) MN peroneal (mV) MN median (mV) 89 48 17 80 19 12 5.03.2 5.43.7 14.16.2 7.23.5 5.82.2 3.81.1 0.60.7 +0.91.0a +1.01.8b +0.81.6a +1.12.5 +0.81.6 89 51 17 93 82 17 42.55.1 33.56.7 45.95.5 46.04.8 37.54.2 48.24.9 +1.52.7a +3.96.2 +1.92.6 +2.02.3
a

velocity (NCV) and amplitude in the sensory (ulnar, sural and median) and motor (median, ulnar and peroneal) nerves. The effect of treatment on pain was also evaluated by means of a visual analogue scale (VAS). Results: w ro v e m e n t i n e l e c t ro p h y s i o l o g i c a l Imp parameters: Among the 294 patients with impaired electrophysiological parameters at baseline, those treated with levacecarnine showed a statistically significant improvement in mean NCV and amplitude vs. placebo (p < 0.01). The greatest changes in NCV (at 12 months) were observed in the sensory sural nerve (+5.7 m/sec in the levacecarnine group vs. +1.0 m/sec in the placebo group), sensory ulnar nerve (+2.9 vs. +0.1 m/sec, respectively) and motor peroneal nerve (+2.7 vs. 0.2 m/sec), whereas the greatest changes in amplitude were recorded in the motor peroneal nerve (+2.2 vs. +0.1mV).

Placebo change at month 12 +2.93.2

a a

no.

baseline

change at month 6

no.

baseline

change at month 6 +02.3 +0.52.7 +0.32.7 +0.72.9 +0.22.2 -0.61.4 -0.30.7 -0.10.5 -0.82.3 00.9 +0.32.2 -0.10.3

change at month 12 +0.12.0 +1.02.8 +0.21.6 +0.23.0 -0.22.2 -0.91.5 -0.20.8 00.8 -0.41.7 +0.11.4 +0.12.0 -0.10.3

74 44 18 82 70 15 74 42 18 68 13 11

44.05.1 35.23.1 43.38.2 45.94.1 38.23.6 48.04.7 6.74.5 5.62.7 16.15.8 7.64.6 5.72.6 4.21.2

+5.76.8

+1.42.1
a a

+1.72.4b +2.33.0 +2.72.1

a a

+1.33.8

+1.63.7a 1.00.9 +1.51.4a +2.31.9a +1.41.8a +2.21.9a +0.81.3

b

a - p<0.01 vs placebo; b - p<0.05 vs placebo; MN = motor nerve, SN = sensory nerve Table 2: Electrophysiological data (nerve conduction velocity and amplitude) by treatment group for randomized subjects with evaluable baseline measurements. Values are means standard deviation

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Scientific Monograph

w Reduction of pain: After 12 months of treatment,

mean VAS scores for pain were significantly reduced from baseline by 39% in levacecarninetreated patients (p < 0.0 vs. baseline) compared with 8% in placebo recipients. At both endpoints (6 and 12 months), the reduction of VAS scores seen in levacecarnine-treated patients was significantly greater than the small decrease observed in placebo recipients (p < 0.05 at month 6 and p < 0.01 at month 12)
LAC Placebo

showed a moderate to marked improvement from baseline, whereas 32.7 vs. 68.7% showed a slight or no change.
w safety: Levacecarnine was well tolerated over Good

the study period. Conclusions: levacecarnine is effective and well tolerated in improving neurophysiological parameters and in reducing pain over a 1-year period. levacecarnine is a promising treatment option in patients with diabetic neuropathy. LAC is effective and well tolerated in improving neurophysiological parameters and in reducing pain over a 1year period. LAC is a promising treatment option in patients with diabetic neuropathy.

50
VAS scale of pain (mm)

*p < 0.05, **p < 0.01

40 * 30 ** 20 10 0
Baseline 6 months 12 months

Fig. : Change from baseline in pain intensity on the VAS after 6 and 12 months of treatment with levacecarnine (LAC) [n = 95] vs. placebo (n = 104).

4.3. Meta-analysis of Levacecarnine benefits in 16 trials in dementia

Study design and objective: Meta-analysis of sixteen double-blind randomized controlled trials to establish whether levacecarnine is clinically effective in the treatment of people with dementia. Patients, duration and treatment: Individuals with a clinical diagnosis of any type of dementia and of any severity were included in the review. The included trials are of widely different durations (12 to 52 weeks).They were treated with levacecarnine at any dose or placebo.

w Clinical improvement: According to the

investigators overall clinical evaluation, after 12 months of treatment, 67.3% of levacecarninetreated vs. 23.1% of placebo-treated patients

% patients showing moderate to marked improvement from baseline

100% 80% 60% 40% 23.1% 20% 0%

LAC Placebo

67.3%

Fig. : % patients showing moderate to marked improvement from baseline with levacecarnine or placebo

Scales used for assessing outcomes: Outcomes were simplified into main areas: cognition, severity of dementia, functional ability and clinician impression. All trials assessed the cognitive effects of

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levacecarnine; in addition most considered severity of dementia, functional ability and clinical global impression. Some of the scales tested: w Cognitive scales used included MMSE (MiniMental State Examination). w of individual cognitive skills included digit Tests span, verbal fluency and Reys test. Global impression was assessed using the Clinical Global Impression (CGI) scale. w Severity of dementia was measured with tests including Blessed Dementia Rating Scale (BDS). Results: w Improvement in cognitive measures: Nine trials reported an improvement in the treatment group in terms of cognitive measures Nine trials reported an improvement in the treatment group in terms of cognitive measures with levacecarnine.
w Improvement in cognitive scales: Two trials

2.5
Odds ratio in favour of ALC in terms of CGI-I

2.33 1.9

2.0 1.5 1.0 0.5 0

12 weeks

24 weeks

Fig. : Odds ratio in favor of levacecarnine in terms of CGI-I

w Positive changes in BDS: Assessments of severity

using the BDS reported treatment effect in favor of levacecarnine in 3 trials. w tolerated: Levacecarnine appeared to have no Well common or serious adverse effects in most studies.

4.4. Levacecarnine in patients with Alzheimer disease

Study objective and design: A 1-year, double-blind, placebo-controlled, randomized, parallel-group study compared the efficacy and safety of levacecarnine with placebo in patients with probable Alzheimer's disease (AD). A subanalysis was later done as per age that compared early-onset patients (aged </=65 years at study entry) with late-onset patients (>66 at study entry). Patients and treatment: Subjects with mild to moderate probable AD (aged >/=50) were treated with 3 g/day of levacecarnine or placebo (1 g tid) for 12 months. 431 patients entered the study. 83% completed 1 year of treatment. Outcome: The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures.

reported improvements in the MMSE. In the metaanalysis of cognitive scales, there was a statistically significant treatment effect on MMSE at 24 weeks (WMD 0.69, 95% CI 0.09 to 1.29, P = 0.02). w Improvement in cognitive skills: Three trials found improvements in subscales testing cognitive skills including verbal fluency, Reys test and digit span. w Positive changes in global impression: When considering CGI, six studies found differences in one or more subgroups, when comparing levacecarnine vs. placebo. When considering clinical global impression (CGI-I), there were statistically significant treatment effects in favour of levacecarnine at 12 and 24 weeks, (Odds ratio (OR) 1.90, 95% Confidence Interval (CI) 1.31 to 2.76) and (OR 2.33, 95% CI 1.31 to 4.14) but not at 52 weeks (OR 0.91, 95% CI 0.58 to 1.43).

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% response rate

Results: w levacecarnine and placebo-treated patients Both declined at the same rate on all primary secondary measures during the trial. w In the subanalysis, early-onset patients on levacecarnine declined more slowly than earlyonset AD patients on placebo on both primary endpoints. w In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on levacecarnine tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial. Early-onset patients on levacecarnine declined more slowly than early-onset AD patients on placebo on both primary endpoints. Conclusions: A subgroup of AD patients aged 65 or younger may benefit from treatment with levacecarnine whereas older individuals might do more poorly.

cognitive functions, functional status and behavioural symptoms. Results: Increased response rate: The response rate, which was 38% after AChE-I treatment, increased to 50% after the addition of levacecarnine, indicating that the combination of these two drugs may be a useful therapeutic option in AD patients.
50% 38%

50% 40% 30% 20% 10% 0%

AChE-I treatment

AChE-I + levacecarnine

Fig. : response rate with AChE-I treatment alone and after addition of levacecarnine

4.5. Levacecarnine in Alzheimer's disease patients unresponsive to acetylcholinesterase inhibitors

Study design and objective: An open study was done to evaluate the effect of levacecarnine in association with donepezil or rivastigmine in mild AD patients unresponsive to acetylcholinesterase inhibitors (AChE-I). Patients and evaluation: 23 patients with mild AD who had not responded to treatment with AChE-I were treated with levacecarnine (2 g/day orally for 3 months). Clinical effects were evaluated by assessing

Compared to AD patients on placebo, levacecarnine - treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores.

4.6. Levacecarnine in Alzheimers disease

Study objective: A double-blind, placebo study assessed the benefits of levacecarnine in probable Alzheimer's disease patients vs. placebo. Patients and duration: Levacecarnine 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

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probable AD patients and 21 age-matched healthy controls over the course of 1 year. Results: w Lesser deterioration of mental status and test score: Compared to AD patients on placebo, levacecarnine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. w Normalization of phosphomonoester levels: Decrease in phosphomonoester levels was normalized in the levacecarnine-treated but not in the placebo-treated patients. w Normalization of high-energy phosphate levels: Similar normalization of high-energy phosphate levels was observed in the levacecarnine-treated but not in the placebo-treated patients. Conclusion: This is the first direct in vivo demonstration of a beneficial effect of levacecarnine on both clinical and CNS neurochemical parameters in AD.

Results: Improvement in cerebral blood flow: No changes were observed after placebo injection (43 +/- 12 ml/min x 100 g versus 43 +/- 10 ml/min x 100 g). CBF increased (from 42 +/- 9 ml/min x 100 g to 46 +/- 9, P<0.05) in both ipsilateral and contralateral hemisphere, the ischaemic area, but not in the stroke corresponding zone. Conclusion: Levacecarnine at the i.v. dosage of 1.5 g acutely enhanced CBF in patients with chronic cerebral infarct.

4.8. L-carnitine for treatment of depression & fatigue in cancer patients with carnitine deficiency
Study objective: An open-label, dose-finding study determined the safety and maximally tolerated dose (MTD) of 1 week of L-carnitine supplementation in cancer patients with fatigue and carnitine deficiency. Patients and treatment: 15 cancer patients with carnitine deficiency participated in the trial. They were administered L-carnitine supplementation for one week. Outcome measures: Outcome measures were fatigue (BFI score), depression (CES-D), sleep disruption (ESS), and performance status (Karnofsky). Results: w Increased carnitine levels: Preliminary data analysis of 13 patients showed that total carnitine increased from 30.0 +/- 6.9 to 41.0 +/- 12.1 (mean +/- SD) after 1 week of supplementation (P = 0.01), and free carnitine increased from 24.3 +/- 6.1 to 33.8 +/- 9.8 (P = 0.004).

4.7. Levacecarnine in chronic cerebral infarct

Study objective: The effect of levacecarnine on cerebral blood flow (CBF) was evaluated in patients with chronic cerebrovascular disease, who suffered an ischaemic stroke at least 6 months before the study. Patients and treatment: The study was done on 20 patients with chronic cerebrovascular disease, who suffered an ischaemic stroke at least 6 months before the study. A single high dose (1.5 g) of levacecarnine was intravenously administered to 10 patients, while sodium acetate (as placebo) was injected to 10 other subjects. Cerebral blood flow (ml/min x 100 g) was evaluated before and 45 min after the injection.

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w Improvement in fatigue score: Median (min, max)

w T0 (placebo treatment for 30 days) Phase w T1 and T2 (levacecarnine 1500 mg/day for Phases

BFI score at baseline was 73 (46, 82) versus 50 (3, 82) after 1-week supplementation (P = 0.009). w Improvement in depression score: CES-D score at baseline was 29 (16, 42) and 22 (8, 32) after 1 week (P = 0.028). w Improvement in sleep disruption: ESS at baseline was 46.5 (0, 69) and 30.4 (0, 72) after 1 week (P = 0.015). Karnofsky score did not change significantly (P = 0.38).

90 days)
w T3 (further 30 days of placebo treatment). Phase

Drug efficacy was evaluated according to changes occurring from the beginning to the end of the tests which evaluate either whole and specific cognitive performances, or emotional-affective and relational behaviour. Results: w Improvement in mental state: The cognitive sphere evaluated by MMSE showed a significant increase in the total score at the end of levacecarnine treatment (p < 0.0001). The Randt Memory Test also revealed that levacecarnine treatment improved the items tested: the total score and the memory index increased significantly and the favourable effect persisted after levacecarnine was discontinued. w Improvement in depression: The emotionalaffective area showed a significant improvement in the total score of the GDS after levacecarnine therapy. The positive results were confirmed by the Hamilton Rating Scale (p < 0.0001). w Improvement in stress: The behavioural-relational aspects evaluated by the Family Stress Scale showed a significant decrease in the total score after treatment (p < 0.0004). The same trend was observed in the scores for instability and negative feeling. w Safety: No significant adverse drug reaction occurred during the trial.

100 80 60 40 29 22 20 0
BFI score
Baseline

73

Score

50

46.5 30.4

CES-D

ESS

After 1 week ALC treatment

Fig. : Changes in BFI, CES-D and ESS scores at baseline and after one week of levacecarnine treatment

4.9. Levacecarnine in case of mental decline in the elderly

Study objective: A single-blind, multicentre trial evaluated the favorable effects of levacecarnine in mild mental impairment in the elderly Patients: 481 subjects were enrolled in 44 geriatric and neurologic units following a strict selection criteria: age, Mini Mental State Examination (MMSE) Global Deterioration Scale and Geriatric Depression Scale (GDS). After the initial screening and enrollment, the trial was run for 150 days in four phases:

There is significant improvement of several performances during and after LAC treatment in mild mental impairment in the elderly.

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Conclusion: There is significant improvement of several performances during and after levacecarnine treatment in mild mental impairment in the elderly. Other reports indicate that this drug may be effective in the treatment of dementia.

5. Levacecarnine Consumer information

Brand name- ELKAR Composition- Each ELKAR TABLET contains 500 mg of levacecarnine hydrochloride. Serving recommendation and direction for use- One ELKAR 500 mg tablet to be taken by mouth twice or thrice daily with or with out meals. ContraindicationsELKAR TABLETS contain lactose. It is contraindicated in patients suffering from intolerance to sugar (lactose & galactose etc.). ELKAR TABLETS are not recommended for pregnant & breast feeding women, children and for person having high blood pressure, kidney and liver problems. ELKAR tablet is a food for special dietary uses which can help improve memory, depression and boost mental abilities. It can be safely consumed by diabetics.

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6. Conclusion
prevalence rates for all mental disorders In India, was observed to be 65.4 per 1000 population. facilitates the transport of long-chain Carnitine fatty acids into the mitochondria to get oxidized and produce fuel and the removal of excess short chain and medium chain fatty acids that accumulate during normal and abnormal metabolism. Tissue levels of carnitine in animals, including humans, decrease with age, thus reducing the integrity of the mitochondrial membrane. Levacecarnine is L-acetyl carnitine. This hydrophobic acetyl moiety improves the ability of carnitine to cross the blood-brain barrier and to be taken up by neuronal tissue. Levacecarnine has several properties beneficial in Parkinsons disease, dementia, Alzheimers disease, diabetic neuropathy, stroke and depression Levacecarnine can not only improve fatty acid transport into mitochondria, but also has a remarkable ability to maintain the structure and function of the mitochondrial inner membrane. Levacecarnine significantly reverses the ageassociated decline of mitochondrial membrane potential and mitochondrial decay Levacecarnine elevates levels of the powerful antioxidant - glutathione in brain. Levacecarnine improved cognitive functioning and prevents/slows age-related memory impairment A deficiency of levacecarnine has been shown to cause damage to the myelin sheath. II diabetic women with and without In type complications, the mean serum-free L-carnitine levels in diabetic patients with complications was

almost 25% lower than in diabetic patients with no complications. studies, levacecarnine treatment resulted In clinical in a significant improvement of motor nerve conduction velocity (MNCV) and of sensory nerve conduction velocity (SNCV) in patients with both mono- and diabetic polyneuropathies. trials utilizing levacecarnine have shown Clinical beneficial effects on nerve fibre regeneration, despite relatively late initiation in the natural history of diabetic polyneuropathy. Levacecarnine administered to stroke patients brought improvements in memory, cognition, and task performance. Levacecarnine exerts a significant neuroprotective effect when administered immediately after transient global cerebral ischemia. Levacecarnine treatment in depression resulted in increasing levels of the prefrontal phosphocreatine (PCr), which correlated with the depression scale. Levacecarnine is as effective as amisulpride in treating depression, without any of the drugs side effects. Levacecarnine has been found to be well-tolerated. Therefore, levacecarnine deserves consideration as a potential treatment capable of improving Parkinsons disease, Alzheimers disease, dementia, diabetic neuropathy, stroke and depression.

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17. www.dancewithshadows.com/business/pharma/ alzheimer-rise-asia.asp. 18. Alzheimer A. Arch Neurol. 1967;21:109-110. 19. www.ninds.nih.gov/disorders/alzheimersdisease /alzheimersdisease.htm 20. Brookmeyer et al. Alzheimer's & Dementia: The Journal of the Alzheimer's Association July 2007; Vol. 3 (Issue 3):186-191. 21. www.johnshopkinshealthalerts.com/alerts/ hypertension_stroke/JohnsHopkinsHealthAlerts HypertensionStroke_916-1.html 22. Petcu EB, Sfredel V, Platt D, Herndon JG, Kessler C, Popa-Wagner A. Gerontology. 2007 Dec 21 [Epub ahead of print]. 23. Lawrence S. Honig, et al. Arch Neurol. 2003;60:1707-17. 24. Christiane Reitz et al. Arch Neurol. 2006;63:571576. 25. www.hindu.com/2006/12/19/stories/20061219 04320500.htm 26. Tapas Kumar BANERJEE et al. Neurology Asia 2006; 11 : 1 4. 27. Gupta R, Joshi P, Mohan V, Reddy KS, Yusuf S. Heart. 2008 Jan;94(1):16-26. 28. Praful M Dalal. International Journal of Stroke 2006; 1 (3), 164166. 29. http://en.wikipedia.org/wiki/Parkinson's_disease. 30. Frontline Volume 19 - Issue 09, Apr. 27 - May 12, 2002. 31. http://en.wikipedia.org/wiki/Clinical_depression. 32. Brian Draper et al. Psychiatr Serv 50:1151-1153, September 1999. 33. Palsson S et al. Int Clin Psychopharmacol. 1997;12(suppl 2):S3-S13.

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