Price range: 1-2 containers: $19.95 each.   3-5: $18.95.   6+: $17.95

The ingredients in Brain Boosters work by promoting the health of mitochondria (the energy-producing elements of cells), by supplying antioxidants to fight harmful free radicals, and by improving the circulation of blood to the brain. 

In addition, a growing body of research in the neurosciences is establishing connections between these nutrients and possible treatments for Alzheimer’s disease, diabetes, dementia, and general mental deterioration.

 

(Click for listing of ingredients.)


THE EIGHT BRAIN BOOSTERS:

GINKGO BILOBA EXTRACT
Ginkgo extracts are among the most widely studied and prescribed treatments in Europe to alleviate the symptoms of age-related cognitive decline. Studies have demonstrated the ability of this herb to improve circulation in the brain and to increase mental alertness and concentration. Ginkgo has been shown to improve short-term memory, alertness, reaction time, and mental abilities. The study, which was published in the Journal of the American Medical Association and approved by Harvard Medical School and the New York Institute for Medical Research, provides tremendous evidence for the value of Ginkgo Biloba Extract. Current Ginkgo Biloba research shows promising benefits in the treatment of Alzheimer s disease. (MORE INFO.)

ACETYL-L- Carnitine (ALCAR)
ALCAR has been shown to protect brain cells against age-related degeneration and to improve mood, memory, and cognition.  It helps in the conversion of choline to acetylcholine, a key neurotransmitter in the body. ALCAR also increases the release of sufficient levels of acetylcholine necessary for transmission of messages in the brain from one nerve cell to another.  ALCAR reduces the risk of Alzheimer's disease and may slow its progression with those affected by this debilitating disease. It's also being used to treat Parkinson's disease quite successfully. A summary of research surrounding these developments can be found below.
(MORE INFO.)

ST. JOHN 'S WORT EXTRACT
This herb is considered an effective treatment by many for depression and anxiety, and its use as such dates back hundreds of years. St. John’s Wort supports emotional balance and mental well-being. It provides support for the healthy function of the nervous system. It is one of the most studied herbal treatments available on the market today. The studies indicate that St. John’s Wort is effective in supporting a positive mental outlook and mood. (MORE INFO.)

L-GLUTAMINE
Thought to increase concentration, this amino acid is known to play an important role in helping to combat stress, elevate energy levels in the brain, and increase mental alertness. Glutamine users often report more energy, less fatigue, and a better mood. L-glutamine's major function is that it serves as "fuel" for the brain. It is the only compound besides glucose (blood sugar) which can be used by the brain for energy. It has also been shown to improve the IQ's of mentally deficient children.  As an amino acid, L-Glutamine is important to the immune system, and has also been investigated for its role in wound healing. (MORE INFO.)

DMAE (dimethylarsinoyl ethanol)
Formerly sold as a prescription medication, DMAE is available today as a dietary supplement. Like ALCAR, DMAE is thought to have a direct effect on the production of the neurotransmitter acetylcholine. Most people notice being more alert and focused within a couple of hours after taking DMAE, with the effects lasting most of the day. DMAE is recommended to be taken in the early part of the day. It is especially effective when combined with the mind boosting effect of Acetyl-L-Carnitine. (MORE INFO.)

BACOPIN
Bacopin helps improve memory by facilitating the repair of damaged synapses, the protein network in the brain where signals are transmitted from one neuron to another. Bacosides are naturally occurring chemical compounds found in Bacopin which help to fortify kinase, the protein in the body responsible for replacing worn-out neurons with new ones.  Bacopin assists the body in keeping healthy neurons. Each capsule contains 50 mg Extract, standardized for 20% (20mg) bacosides A and B, the active constituents of Bacopa Monnieri that have been shown in scientific studies to nutritionally support healthy memory and concentration. (MORE INFO.)

VINPOCETIN
Vinpocetin was introduced into clinical practice in Europe more than two decades ago for its role in cerebrovascular disorders and related symptoms. It is effective at helping the brain use oxygen and energy more efficiently.  Vinpocetin helps increase levels of glucose consumption by the brain for increased energy to brain cells, easier circulation through brain capillaries, and improved cerebral blood flow. In a double blind clinical trial patients on Vinpocetin scored consistently better in all cognitive evaluations. No side effects were reported.(MORE INFO.)


 
PHOSPHATIDYLSERINE COMPLEX

Phosphatidylserine is a natural nutrient found as part of the cell membrane of cells. Phosphatidylserine is most notably found in the cell membrane of neurons, comprising about 7 to 10 percent of its lipid content and has been shown to dampen the ACTH and cortisol response to physical stress.
(Pub-Med, National Institutes of Health)
(MORE INFO)

 

 

 

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Journal Citations, articles, scientific studies:

GINKGO BILOBA


GINKGO BILOBA EXTRACT

By  James Balch, M.D.

Promoting Blood Flow
Ginkgo biloba acts on the blood vessels to improve blood flow, which means the body can proceed with its natural way of fighting free radicals and healing itself of any damage. At the same time, the herb acts as an antioxidant to neutralize free radicals, preventing them from damaging the body any further.

Ginkgo biloba may also help with other ailments. By improving circulation, the herb can ease dizziness, migraine headaches and a perpetual ringing in the ears that doctors call tinnitus. Some people who take ginkgo biloba also experience an improvement in their breathing, which reduces the hardening of the arteries that arteriosclerosis causes. On top of that, gingko is widely used to improve concentration and memory.

A Long History
Ginkgo biloba is one of the oldest herbal remedies known, dating back at least five thousand years. Traditionally, people have made tea out of the leaves of the ginkgo tree. Unfortunately, the leaves stink. You can avoid the smell and get the same benefits from standard extracts that are available as supplements in health food stores and natural food grocers. A typical dosage is 80 to 150 milligrams per day.

Copyright � 1999 WebMD, Inc. All rights reserved.

Does Ginkgo Biloba Reverse Aging?

By  Deborah Messecar, Ph.D., R.N.

I read in an article that ginkgo biloba reverses aging. Is this true?
Ginkgo biloba is an herb that has received acclaim as a memory enhancer and anti-aging product. It's now among the ten most popular dietary supplements sold in the United States.
Although it has long been used in traditional Chinese medicine for lung disorders, ginkgo extract has more recently been used in Europe and North America against the symptoms of aging. It is believed to stimulate circulation and oxygen flow to the brain, which can improve problem-solving and enhance memory.

Effects of ginkgo
May increase blood flow in cerebrovascular disease May improve poor circulation in the limbs Improves memory and alertness Improves communication, orientation and mobility Improves symptoms of vertigo and tinnitus

In a group of older people with mobility problems, ginkgo improved pain-free walking distance by as much as 30 percent. Long-term ginkgo use appears to reduce cardiovascular risks. It has also been shown to improve the cognitive function of Alzheimer's Disease patients.
Differences in the production, labeling and marketing of this extract make it essential that consumers scrutinize the products they buy in order to maximize positive benefits while minimizing risks.

Before purchasing a product, you should inspect the label. Manufacturers are now required to label their products with nutritional labeling that lists ingredients in descending order. Look for information on the label that indicates that a standardized extract of 24 percent ginkgo flavonglycosides and 6 percent terpenes has been used to prepare the product. The flavonoids are antioxidants. Both flavonoids and terpenes are believed to help protect brain function. Because herbal medicines are made from crude extracts of plants, look to see if there is any indication that the manufacturing process has removed any pesticides that may have been used in the plant cultivation.

In addition, the product should have an expiration date. Don't expect to feel it right away. It may be several weeks before any effect will be noticeable. Many people also believe that it's a good idea to give the body a rest periodically by taking some time off from using the extract, for example, by taking one month off after six months of use.

It is also important to be aware that herbal medicines can have drug interactions with other herbal preparations you may be taking, or with other over the counter or prescription medicines. For this reason, you should consult with your physician or pharmacist before taking any herbal preparation. For example, ginkgo diminishes the blood's ability to clot. It should definitely not be taken with anticoagulants such as coumadin or aspirin. With very large doses, side effects of ginkgo can include diarrhea, nausea, vomiting, irritability and restlessness.
The American Botanical Council has recently published the Complete German Commission E Monographs, which describe the potential therapeutic applications of a variety of herbal medicines

Copyright � 1999 WebMD, Inc. All rights reserved.

How Does Ginkgo Biloba Work?
Ginkgo biloba extract (GBE) increases blood flow to the brain by inhibiting blood platelet aggregation and by regulating blood vessel elasticity; it has been shown to improve blood flow through both major blood vessels and capillaries. Ginkgo is also a powerful antioxidant. Ginkgo biloba extract has two major groups of components, ginkgo flavonglycosides and terpene lactones. Its efficacy depends on their proper balance and a standardized extraction method has been developed to ensure that balance. Basically, these two constituents or groups of constituents are responsible for ginkgo biloba's two main properties: the ability to inhibit blood platelet aggregation (which allows for greater flow of blood to the brain and extremities) and its strong antioxidant properties (which exert a protective influence over the brain and CNS).

Ginkgo Biloba's Use in Alzheimer's Disease
GBE is beneficial in the early treatment of Alzheimer's disease. It has been proven effective in stopping the advancement of Alzheimer's disease, in improving the mental function of elderly people having suffered several "mini-strokes", and if the patient's dementia is caused by lack of blood flow to the brain, it can reverse the problem.

Possible Ginkgo Biloba Side Effects
Side effects are rare with use of the standardized extract. Mild gastrointestinal upset occurs in less than 1 percent of patients in clinical studies. Some patients with poor blood flow to the brain (i.e., cerebrovascular insufficiency) may experience a mild, transient headache for the first one or two days of use. There are no known interactions with commonly prescribed drugs. The current German Commission E monograph lists no contraindications to the use of ginkgo during pregnancy or lactation.1

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SUMMARY OF RESEARCH ON
ACETYL-L-CARNITINE (ALCAR)

Acetyl-L-carnitine in Alzheimer disease: a short-term study on CSF neurotransmitters and neuropeptides
Bruno G; Scaccianoce S; Bonamini M; Patacchioli FR; Cesarino F; Grassini P; Sorrentino E; Angelucci L; Lenzi GL
Dipartimento di Scienze Neurologiche, Universita di Roma La Sapienza, Italy
Alzheimer Dis Assoc Disord (U.S.) Fall 1995, 9 (3) p128-31.


Acetyl-L-carnitine (ALCAR) is a drug currently under investigation for Alzheimer disease (AD) therapy. ALCAR seems to exert a number of central nervous system (CNS)-related effects, even though a clear pharmacological action that could explain clinical results in AD has not been identified yet. The aim of this study was to determine cerebrospinal fluid (CSF) and plasma biological correlates of ALCAR effects in AD after a short-term, high-dose, intravenous, open treatment. Results show that ALCAR CSF levels achieved under treatment were significantly higher than the ones at baseline, reflecting a good penetration through the blood-brain barrier and thus a direct CNS challenge. ALCAR treatment produced no apparent change on CSF classic neurotransmitters and their metabolite levels (homovanillic acid, 5-hydroxyindoleacetic acid, MHPG, dopamine, choline). Among CSF peptides, while corticotropin-releasing hormone and adrenocorticotropic hormone remained unchanged, beta-endorphins significantly decreased after treatment; plasma cortisol levels matched this reduction. Since both CSF beta-endorphins and plasma cortisol decreased, one possible explanation is that ALCAR reduced the AD-dependent hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity. At present, no clear explanation can be proposed for the specific mechanism of this action.

Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease
Pettegrew JW; Klunk WE; Panchalingam K; Kanfer JN; McClure RJ
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, PA 15213, USA.
Neurobiol Aging (UNITED STATES) Jan-Feb 1995, 16 (1) p1-4,
In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.

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

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

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


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


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

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


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

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

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

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

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

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

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

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

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


Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease
Pettegrew J.W.; Klunk W.E.; Panchalingam K.; Kanfer J.N.; McClure R.J.
University of Pittsburgh, Western Psychiatric Institute/Clinic, A710 Crabtree Hall/GSPH, 130 DeSoto Street, Pittsburgh, PA 15261 USA
NEUROBIOL. AGING (USA), 1995, 16/1 (1-4)
In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.

A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease
Neurology (USA), 1996, 47/3 (705-711)
A 1-year, double-blind, placebo controlled, randomized, parallel-group study compared the efficacy and safety of acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable Alzheimer's disease (AD). Subjects with mild to moderate probable AD, aged 50 or older, were treated with 3 g/day of ALCAR or placebo (1 g tid) for 12 months. Four hundred thirty-one patients entered the study, and 83% completed 1 year of treated. The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures. Overall, both ALCAR- and placebo-treated patients declined at the same rate of all primaryures during the trial. In a subanalysis by age that compared early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), we found a trend for early-onset patients on ALCAR to decline more slowly than early-onset AD patients on placebo on both primary endpoints. In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on ALCAR tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial. The study suggests that a subgroup of AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly. However, these preliminary findings are based on post hoc analyses. A prospective trial of ALCAR in younger patients is underway to test the hypothesis that young, rapidly progressing subjects will benefit from ALCAR treatment.

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

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

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

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

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

Acetyl-L-carnitine: A drug able to slow the progress of Alzheimer's disease?
ANN. NEW YORK ACAD. SCI. (USA), 1991, 640/- (228-232)
Defects in cholinergic neurotransmission do not, by themselves, constitute the sole pathophysiologic concomitants of Alzheimer's disease (AD). Recent findings point out that abnormalities in membrane phospholipid turnover and in brain energy metabolism may also characterize AD. Acetyl-L-carnitine (ALC) is an endogenous substance that, acting as an energy carrier at the mitochondrial level, controls the availability of acetyl-L-CoA. ALC has a variety of pharmacologic properties that exhibit restorative or even protective actions against aging processes and neurodegeneration. A review of a series of controlled clinical studies suggests that ALC may also slow the natural course of AD.

Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer Type
EUR. J. CLIN. PHARMACOL. (Germany), 1992, 42/1 (89-93)
Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type. The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg.kg-1 i.v. given twice for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 2.0 g/day p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine. The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period. Following the i.v. bolum injections, the plasma concentrations showed a biphasic curve, with average t(one-half) of 0.073 h and 1.73 h, respectively. At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase. The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier. It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.

Double-blind, placebo-controlled study of acetyl-l-carnitine in patients with Alzheimer's disease
CURR. MED. RES. OPIN. (United Kingdom), 1989, 11/10 (638-647)
A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with 1 g acetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratory tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.

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ST. JOHN’S WORT EXTRACT

St. John's Wort Helps Beat the Blues, Study Says

By Dan Ferber WebMD Medical News

Dec. 9, 1999 (Urbana, Ill.) -- Extracts of the herb St. John's wort can safely help mildly depressed people beat the blues, according to research to be published in the Dec. 11 issue of the British Medical Journal. But while the herb extract was more effective than placebo, it fared no better than imipramine, a tricyclic antidepressant used widely in Europe that is available only by prescription.

Depression affects nearly one in ten Americans each year, costing the nation up to $44 billion in treatment costs and lost productivity. The American Psychiatric Association estimates that depressed individuals have a greater than 80% chance of being successfully treated.

But some people don't seek medical help because of the stigma involved, and seek to self-medicate with St. John's wort and other remedies. In addition, extracts of the herb are widely prescribed in Europe, and in Germany they are prescribed more than any other antidepressant. But clinical trials that have purported to demonstrate the effectiveness of St. John's wort remain disputed because some researchers say they were not properly designed.

To settle the question, Karl-O Hiller of the Steiner Arznelmeitel in Berlin and his colleagues compared the effects of St. John's wort extracts, imipramine, and a placebo on 263 moderately depressed people.

The patients took three capsules a day of the herb extract, the prescription drug, or a sugar pill, and all pills were adjusted to look and taste the same. After eight weeks, the doctors judged the extent of the patient's depression using a questionnaire called the Hamilton depression rating scale that measures depressive symptoms.

St. John's wort extract eased depressive symptoms significantly more than placebo pills and to about the same extent as imipramine, the authors write. And both the herbal remedy and the drug improved the patients' scores on a questionnaire that gauged quality of life. According to the researchers, St. John's wort extract "may thus be considered as an alternative first choice treatment in most cases of mild to moderate depression without psychotic symptoms."

Other experts called the study encouraging, but in some ways inconclusive. "What's important is the fact that St. John's wort is better than placebo after eight weeks, and that certainly is encouraging for concluding that St. John's wort extract is effective in [treating] depression, at least for the short term," says Benedetto Vitiello, MD, of the National Institute for Mental Health, who is coordinating a study comparing St. John's wort with the antidepressant Zoloft (sertraline hydrochloride)
.
Vitiello also notes that the St. John's wort used in the study may not even be available in the U.S. In Germany, St. John's wort extracts and other herbal remedies are carefully regulated by government agencies. But no such controls exist in the U.S. because of a 1994 law that forbade the FDA regulating so-called natural products like St. John's wort.

"It's like tea or coffee -- there is a different concentration of ingredients," Vitiello says. "That is the major risk for the consumer -- they don't know what they're buying."

� 1999 WebMD Inc. All rights reserved.

 

 

New York Times….September 10, 1997
Personal Health: An Herb for Depression

By Jane E. Brody

The highly popular drug Prozac and its synthetic rivals may soon be in for competition in this country from a natural herb for the treatment of mild to moderately severe depression.

The herb, St. John's wort, is already by far the favored therapy for depression in Germany, where it has been used therapeutically for centuries. In 1994, about 66 million daily doses of St. John's wort were prescribed by German doctors, who turn to other drugs only when the herbal remedy fails to work.

Most of the research on the herb, which is also used to treat other common physical and emotional disorders, has been conducted in Germany. Researchers there report that it is decidedly better than placebos in medical trials and at least as good as some prescription antidepressants for treating the milder forms of depression. It is also much cheaper and appears to cause far fewer side effects than commonly prescribed antidepressants, making it a potentially preferable alternative to drugs like Prozac. While Prozac costs, on average, $80 a month, a regimen of St. John's wort costs about $10 a month. And unlike Prozac, which causes distressing side effects in about one-quarter of patients, the herb has been shown in studies to cause side effects in fewer than 10 percent of patients, and, in most cases, those side effects are reported to be mild.

But before you dump your Prozac, Paxil, Zoloft or other prescribed antidepressant in favor of this increasingly popular herb, a more discriminating look at the evidence -- pro and con -- for the safety and effectiveness of St. John's wort is in order.

The Herb and Its Effects

St. John's wort ("wort" is Old English for plant) is a weed, Hypericum perforatum, that grows prolifically on disturbed ground like roadsides. It was named for St. John the Baptist, whose birthday is celebrated on June 24, when the plant usually puts forth its yellow blooms. Like other plants, it contains many different chemicals, which alone or in combination may account for its reputed therapeutic effects. Scientists do not yet know which substances in St. John's wort are responsible for its apparent antidepressant activity or how they may act. Neither is it known why St. John's wort has been reported to have antiviral activity (researchers are currently investigating it as an adjunct to other AIDS drugs that suppress H.I.V. production), as well as the ability to relieve menstrual discomfort and winter blues and to bolster immunity.

What they do know is that there is more to St. John's wort than hearsay and health-food-store claims. A review of 23 well-designed clinical trials published last summer in The British Medical Journal concluded, based on 15 placebo-controlled trials, that extracts of St. John's wort "are more effective than placebo for the treatment of mild to moderately severe depressive disorders."

The review also found evidence from eight other studies that St. John's wort may work as well as some other drugs in countering mild depression, but the research team, from Munich, Germany, and San Antonio, called for more exacting studies comparing the herb with standard antidepressants like Prozac.

The researchers noted that the studies of St. John's wort involved relatively small numbers of patients and that the diagnosis of depression varied from study to study and did not always adhere to the stringent criteria used in the United States. Furthermore, the preparation (liquid extracts or capsules or tablets made from ground-up plants) differed from study to study, as did the medication's potency and dosages, and none of the trials lasted longer than eight weeks. So while few short-term side effects were reported, the possible long-term hazards of St. John's wort remain unknown. Although no adverse effects have been detected in long-term users in Germany, only a long-term controlled clinical study can give the herb a clean bill of health.

There is no requirement that such studies be done before the herb is sold in this country. Since it is sold as a dietary supplement, the Food and Drug Administration does not approve or disapprove it, and no documentation is required of its safety or usefulness, the kind of information required for prescription antidepressants. Because it is classified as a dietary supplement, its label may not claim that it has a specific effect in alleviating depression.

There are side effects that have been associated with St. John's wort, including mild gastrointestinal discomfort (usually relieved by taking the medication with meals and a large glass of liquid), fatigue, dry mouth, dizziness, skin rashes and itching. Such side effects were reported by 2.4 percent of patients in one large study. At high doses, it may also increase sensitivity to sunlight, an effect that so far has been found only in cattle that graze heavily on it.

On the other hand, the prescription antidepressants commonly cause distressing side effects like sexual dysfunction, diarrhea, difficulty with concentration, a decrease in reaction time, drowsiness and bad reactions to alcohol.

Use With Caution

St. John's wort is not for everyone, and no one who is depressed should start taking it without first consulting a mental health practitioner who is expert in diagnosing and treating depression. That is especially important for people who are severely depressed or suicidal, because St. John's wort may not be potent enough to counter severe depression. Also, even mild depression may require more than medication. Some form of psychotherapy is often needed to prevent relapses.

If you are now on a prescription antidepressant, do not add St. John's wort to the regimen or abandon the prescribed drug in its favor. When combined with other serotonin-enhancing drugs, like Prozac, St. John's wort may result in a serotonin overload, causing sweating, agitation, confusion and tremor. See your doctor before making any changes.

St. John's wort should not be used by pregnant or nursing women or young children because of the lack of safety information.

Keep in mind that the F.D.A. does not approve the preparations of St. John's wort on the shelves of health-food stores and pharmacies and that no agency checks these preparations for contents or potency. You are at the mercy of the manufacturer; the bottle may or may not contain what the label says.

You should also keep in mind that, like prescription antidepressants, St. John's wort does not work right away. It takes about four weeks to have a significant antidepressant effect, though you are likely to notice some improvement within two weeks. Since long-term safety studies are lacking, Dr. Zuess does not recommend the use of St. John's wort for more than a year.


Research findings

Research findings before these recent warnings medical, confidence in St John's wort - known in Latin as Hypericum perforatum - relied heavily on a paper published in the British Medical Journal in August 1996. This research, which took a randomised overview of clinical trials carried out on St John's wort, showed that it was more effective as an antidepressant than placebo. It also appeared to be as good as prescribed antidepressants and to have fewer side effects, but these last two findings were not conclusive.

It is interesting to note that the researchers, all German scientists, observed that when they began their work in 1994, they could not find a single trial on St John's wort in the English language. Herbal remedies are extensively used in Germany and St John's wort is available on prescription there. In 1994, 66 million prescriptions for the remedy were issued without any reported cases of ill effects.

A more recent trial involving 263 people, also carried out in Germany and published in the British Medical Journal in December 1999, showed that St John's wort was better than placebo (dummy pills) and as good as the commonly prescribed antidepressant imipramine. The herbal remedy had fewer side effects and the researchers concluded it showed promise for the long-term treatment of moderate depression.

It is also widely used by Americans who want to treat their own depression, but Dr P. Murali Doraiswamy, a psychiatrist at Duke University, North Carolina, spoke of his reservations at a recent conference, claiming that some of the studies were too small to be reliable and that long-term data was lacking. He also pointed out that the herb had not been compared with the most effective prescription drugs like Prozac and Zoloft.

Scientific reviewers called St John's wort promising but unproven, Dr Doraiswamy said, adding that many of his own patients had tried it, but often irregularly and at incorrect doses. Because depression is a serious illness and a major cause of suicide, he said the trend to self-medicate was worrying. Several studies of St John's wort are now in progress in the United States. In the meantime, Dr Doraiswamy said, the jury is still out.

A herbalist's view

Keith Robertson, a qualified herbalist who practises in Glasgow and is Director of Education at the Scottish School of Herbal Medicine, told NetDoctor: 'St John's wort is a gentle herb which I have been prescribing for about 10 years for mild depression. I have not had any problems with it and it seems to work very well.

'It is always better to see herbalists because they usually prescribe four or more remedies at a time. When you buy the tablets over the counter you don't get the whole plant, which can have up to a thousand ingredients. It is the synergy of the different constituents that makes the remedy. I advise patients to have it as a tea or in a tincture - a solution of alcohol. If they cannot consult a herbalist, it is possible to buy the tea or tincture from a herbal shop or by mail order or the Internet.

'Over-the-counter tablets of St John's wort are made up of a standardised extract of hypericin, the active ingredient, without the other substances in the herb. I am concerned that people are taking St John's wort in this way.

'After a few weeks, I usually change the remedy for something else. People shouldn't necessarily take St John's wort in any form all the time. My advice is to give it up when you feel better to see if the depression returns. Unlike prescription antidepressants, herbal medicines work really fast. Keep it for when you need it.

'I am quite convinced that hypericum is safe and that it works to relieve depression if taken at the recommended doses. As with all medication, it shouldn't be mixed with other drugs without consulting a doctor.'

Care is advised

Professor Alasdair Breckenridge, chairman of the Committee on Safety of Medicines, said doctors should in future ask patients if they are using herbal remedies before prescribing for them. Warnings to appear on the bottles alongside the pretty pictures of the flowering herbs are being prepared urgently.

Meanwhile, is St John's wort a way forward for the mildly depressed? Probably, but proceed with caution. As Michael McIntyre, chairman of the European Herbal Practitioners Association, summed it up: 'Herbal medicines are potentially very effective and therefore should be prescribed and taken with care. Just because something is natural does not mean it is safe.'

RETURN TO INGREDIENTS LIST



L-GLUTAMINE

L-glutamine is a protein amino acid found in proteins of all life forms. It is classified as a semi-essential or conditionally essential amino acid. This means that under normal circumstances the body can synthesize sufficient L-glutamine to meet physiological demands. However, there are conditions where the body cannot do so. Recently, L-glutamine has come to be regarded as one of the most important of the amino acids when the body is subjected to such metabolic stress situations as trauma (including surgical trauma), cancer, sepsis and burns. Under such conditions, L-glutamine becomes an essential amino acid, and it is therefore very important to ensure adequate intakes of the amino acid in order to meet the increased physiological demands created by these situations.

L-glutamine is the most abundant amino acid in the body, and plasma glutamine levels are the highest of any amino acid. L-glutamine is predominantly synthesized and stored in skeletal muscle. The amino acid L-glutamate is metabolized to L-glutamine in a reaction catalyzed by the enzyme glutamine synthase, a reaction which, in addition to L-glutamate, requires ammonia, ATP and magnesium.

L-glutamine is a very versatile amino acid and participates in many reactions in the body. It is important in the regulation of acid-base balance. L-glutamine allows the kidneys to excrete an acid load, protecting the body against acidosis. This is accomplished by the production of ammonia, which binds hydrogen ions, to produce ammonium cations that are excreted in the urine along with chloride anions. Bicarbonate ions are simultaneously released into the bloodstream. L-glutamine helps protect the body against ammonia toxicity by transporting ammonia, in the form of L-glutamine's amide group, from peripheral tissues to visceral organs, where it can be excreted as ammonium by the kidneys or converted to urea by the liver.

The amide group can also participate in other metabolic activities, as can the amino group of L-glutamine. L-glutamine serves as the most important nitrogen shuttle, supplying nitrogen for metabolic purposes (from glutamine-producing tissues, such as skeletal muscle) to glutamine-consuming tissues.

L-glutamine participates in the formation of purine and pyrimidine nucleotides, amino sugars (such as glucosamine), L-glutamate and other amino acids, nicotinamide adenine dinucleotide and glutathione. It also participates in protein synthesis, energy production and, if necessary, the production of D-glucose and glycogen. Importantly, L-glutamine can serve as the primary respiratory substrate for the production of energy in enterocytes and lymphocytes. L-glutamine is considered an immunonutrient, and supplemental L-glutamine is used in medical foods for such stress situations as trauma, cancer, infections and burns.

The typical dietary intake of L-glutamine is 5 to 10 grams daily. Most dietary L-glutamine comes from animal and plant proteins. Small amounts of free L-glutamine are found in vegetable juices and fermented foods, such as miso and yogurt. L-glutamine is the amide of L-glutamic acid. Its molecular formula is C5H10N2O3, and its molecular weight is 146.15 daltons.

L-glutamine is also known as 2-aminoglutaramic acid, levoglutamide, (S)-2, 5-diamino-5-oxopentaenoic acid and glutamic acid 5-amide. Its one-letter abbreviation is Q, and it is also abbreviated as Gln. The terms L-glutamine and glutamine are used interchangeably. D-glutamine, the stereoisomer of L-glutamine, does not have, as far as is known, biological activity. L-glutamine is not very soluble in water, and aqueous solutions are unstable at temperatures of 22 to 24 degrees Celsius. For these reasons, the more soluble and more stable glutamine dipeptides are used as delivery forms of L-glutamine in total parenteral nutrition (TPN) solutions. See Glutamine Peptides.

HOW L-GLUTAMINE SUPPLEMENTS WORK:

Supplemental L-glutamine may have immunomodulatory, anticatabolic/anabolic and gastrointestinal mucosal-protective actions. It may also have antioxidant activity.

Supplemental L-glutamine's possible immunomodulatory role may be accounted for in a number of ways. L-glutamine appears to play a major role in protecting the integrity of the gastrointestinal tract and, in particular, the large intestine. During catabolic states, the integrity of the intestinal mucosa may be compromised with consequent increased intestinal permeability and translocation of Gram-negative bacteria from the large intestine into the body.

The demand for L-glutamine by the intestine, as well as by cells such as lymphocytes, appears to be much greater than that supplied by skeletal muscle, the major storage tissue for L-glutamine. L-glutamine is the preferred respiratory fuel for enterocytes, colonocytes and lymphocytes. Therefore, supplying supplemental L-glutamine under these conditions may do a number of things. For one, it may reverse the catabolic state by sparing skeletal muscle L-glutamine. It also may inhibit translocation of Gram-negative bacteria from the large intestine. L-glutamine helps maintain secretory IgA, which functions primarily by preventing the attachment of bacteria to mucosal cells.

L-glutamine appears to be required to support the proliferation of mitogen-stimulated lymphocytes, as well as the production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). It is also required for the maintenance of lymphokine-activated killer cells (LAK). L-glutamine can enhance phagocytosis by neutrophils and monocytes. It can lead to an increased synthesis of glutathione in the intestine, which may also play a role in maintaining the integrity of the intestinal mucosa by ameliorating oxidative stress.

The exact mechanism of the possible immunomodulatory action of supplemental L-glutamine, however, remains unclear. It is conceivable that the major effect of L-glutamine occurs at the level of the intestine. Perhaps enteral L-glutamine acts directly on intestine-associated lymphoid tissue and stimulates overall immune function by that mechanism, without passing beyond the splanchnic bed.

The anticatabolic/anabolic activity of supplemental L-glutamine can be explained by its effect in sparing skeletal muscle L-glutamine stores.

Following ingestion, L-glutamine is absorbed from the lumen of the small intestine into the enterocytes. Absorption is efficient and occurs by an active transport mechanism. Some metabolism of the amino acid takes place in the enterocytes. L-glutamine that is not metabolized in the enterocytes enters the portal circulation from whence it is transported to the liver, where again some portion of the amino acid is metabolized. L-glutamine not metabolized in the liver enters the systemic circulation, where it is distributed to the various tissues of the body. L-glutamine participates in various metabolic activities, including the formation of L-glutamate catalyzed by the enzyme glutaminase. It also participates in the synthesis of proteins, glutathione, pyrimidine and purine nucleotides and amino sugars. The transport of L-glutamine into cells is via an active process. L-glutamine is eliminated by glomerular filtration and is almost completely reabsorbed by the renal tables.

STUDIES SUPPORTING THE USE OF L-GLUTAMINE:

Amino acid mixture improves training efficiency in athletes.
Author:                       Ohtani,-M; Sugita,-M; Maruyama,-K
Citation:         J-Nutr. 2006 Feb; 136(2): 538S-543S
Abstract:        This review discusses some of the beneficial effects of a dietary amino acid supplement on muscle function, fatigue, and recovery in exercising athletes. The supplement, a mixture of amino acids that included the branched-chain amino acids, arginine and glutamine, was studied chronically at several daily dose levels for extended periods of time (10, 30, and 90 d). Outcome variables included physical measures of muscle strength, fatigue and damage, and blood indices of muscle damage and oxygen-carrying capacity. One beneficial effect of the amino acid supplement was a quicker recovery from the muscle fatigue that followed eccentric exercise training. A dose-response study of the amino acid mixture at 2.2, 4.4, and 6.6 g/d for 1 mo showed that at the highest dose, indices of blood oxygen-carrying capacity were increased and those of muscle damage were decreased at the end of the trial. When the amino acid mixture was given for 90 d to elite rugby players during training at a dose of 7.2 g/d, a blood-component analysis indicated improvements in the oxygen-carrying capacity of the blood. Together, the studies suggest that the amino acid supplement contributed to an improvement in training efficiency through positive effects on muscle integrity and hematopoiesis.

Effect of glutamine supplementation on diarrhea, interleukin-8 and secretory immunoglobulin A in children with acute diarrhea.
Author:                       Yalcin,-S-S; Yurdakok,-K; Tezcan,-I; Oner,-L
Citation:         J-Pediatr-Gastroenterol-Nutr. 2004 May; 38(5): 494-501
Abstract:        OBJECTIVE: Glutamine is an important fuel for rapidly dividing cells such as enterocytes and lymphocytes. Exogenous glutamine supplementation in catabolic states preserves intestinal mucosal structure and function, decreases bacterial translocation, and supports normal immunologic responses. This study was planned to assess the effect of glutamine supplementation on duration and severity of diarrhea and to assess its immunomodulatory effect by measuring serum interleukin-8 (IL-8) and salivary immunoglobulin A (sIgA) in children with acute diarrhea. METHODS: In this placebo-controlled, double-blind and randomized trial, 6- to 24-month-old otherwise healthy children admitted to the Diarrheal Diseases Training and Treatment Center with acute diarrhea received either 0.3 g/kg/day of glutamine (n = 63) or placebo (n = 65) for 7 days. Serum IL-8 and sIgA levels were determined on admission and 7 days later. All cases were followed until the diarrheal episode ended. Anthropometric measurements and history of subsequ ent infectious diseases were monitored monthly for 3 months after treatment. RESULTS: Mean duration of diarrhea in the glutamine treated group was significantly shorter than that of the placebo group (3.40 +/- 1.96 days, 4.57 +/- 2.48 days, respectively; P = 0.004). No differences in serum IL-8 and sIgA were found between groups on admission or 1 week later. During 3 month follow-up, mean weight gain and incidence of infectious diseases were similar in both groups. CONCLUSION: Duration of diarrhea was shorter in children supplemented with glutamine. The beneficial impact of glutamine supplementation seems to be through effects on gastrointestinal mucosa rather than the host immune response.

Nutritional supplement use among college athletes and their sources of information.
Author:                       Froiland,-K; Koszewski,-W; Hingst,-J; Kopecky,-L
Citation:         Int-J-Sport-Nutr-Exerc-Metab. 2004 Feb; 14(1): 104-20
Abstract:        A survey was conducted to examine the source of information and usage of nutritional supplements in 115 male and 88 female varsity athletes at a Division I university. The survey asked each athlete to define supplement, and report supplement use and type, source of information, and reasons for use. Supplement use frequencies were determined, and comparisons were made between gender and sport. Eighty-nine percent of the subjects had or were currently using nutritional supplements. Many athletes did not consider sports drinks and calorie replacement products as supplements. Females were more likely to take calcium and multivitamins, and males had significant intake for ginseng, amino acids, glutamine, hydroxy-methyl-buterate (HMB), weight gainers, whey protein, and Juven. The most frequently used supplements overall were energy drinks (73%), calorie replacement products of all types (61.4%), multivitamin (47.3%), creatine (37.2%), and vitamin C (32.4%). There was also significant supplement use noted per sport. Females were more likely to obtain information from family members regarding supplementation, and males from a store nutritionist, fellow athletes, friends, or a coach. Female athletes were more likely to take supplements for their health or because of an inadequate diet, while men reported taking supplements to improve speed and agility, strength and power, or for weight/muscle gain.

Glutamine: recent developments in research on the clinical significance of glutamine.
Author:                       Melis,-G-C; ter-Wengel,-N; Boelens,-P-G; van-Leeuwen,-P-A
Citation:         Curr-Opin-Clin-Nutr-Metab-Care. 2004 Jan; 7(1): 59-70
Abstract:        PURPOSE OF REVIEW: The aim of this review is to describe the clinical relevance of supplementation of glutamine from the recent literature. First, new basic research is examined and subsequently recent clinical trials and a metaanalysis are illustrated. RECENT FINDINGS: Glutamine has a major impact on the functionality of the immune system. It has recently been established that glutamine not only has a protective effect on cells of the immune system, but also on other cells of the body, for instance cardiomyocytes. Evidence is accumulating for an effect of glutamine via glutathione, heat shock proteins as well as taurine. Another area of interest is the way glutamine enhances gut barrier function. More and more research is concentrating on the positive effect of glutamine on the gut-associated lymphoid tissue. SUMMARY: Based on a recent meta-analysis and up-to-date clinical trials, we may conclude that glutamine has a beneficial effect on infectious complications and reduces hospital stay. In critically ill patients glutamine supplementation may reduce morbidity and mortality. The greatest effect was observed in patients receiving high dose parenteral glutamine. A recent study with high dose enteral glutamine demonstrated a reduced mortality in the glutamine supplemented group. In the future more trials with larger numbers of participants are needed, especially with high do se enteral glutamine in the perioperatively and the intensive care unit setting.

Glutamine deprivation facilitates tumour necrosis factor induced bacterial translocation in Caco-2 cells by depletion of enterocyte fuel substrate.
Author:                       Clark, E C : Patel, S D : Chadwick, P R : Warhurst, G : Curry, A : Carlson, G L Citation:         Gut. 2003 Feb; 52(2): 224-30
Abstract:        BACKGROUND AND AIMS: Factors that induce luminal bacteria to cross the intestinal epithelium following injury remain poorly defined. The aim of this study was to investigate the interaction between glutamine metabolism, energy supply, and inflammatory mediators in determining the translocation of non-pathogenic bacteria across cultured enterocytes. METHODS: The effect of tumour necrosis factor alpha (TNF-alpha) on translocation of Escherichia coli C25 across Caco-2 epithelial monolayers was studied in the presence of products and inhibitors of glutamine metabolism. Simultaneous measurements of transepithelial electrical resistance (TEER) and flux of lucifer yellow were used to assess effects on the paracellular pathway. Lactate dehydrogenase release was used to monitor enterocyte integrity. Imaging of monolayers in these experimental conditions was undertaken with transmission electron microscopy. RESULTS: Exposure to basolateral TNF-alpha (20 ng/ml) for six hours induced translocation of E coli across Caco-2 but only if accompanied by simultaneous glutamine depletion (pless than 0.01). Translocation was inhibited by addition of glutamine for two hours (pless than 0.01) but not by an isonitrogenous mixture of non-glutamine containing amino acids. Inhibition of glutamine conversion to alpha-ketoglutarate, but not blockade of glutathione or polyamine synthesis, also induced translocation in the presence of TNF-alpha. Manipulations that induced bacterial translocation were associated with a marked reduction in enterocyte ATP levels. No effect of these treatments on paracellular permeability or lactate dehydrogenase release was observed. Conditions in which translocation occurred were associated with the presence of bacteria within enterocyte vacuoles but not the paracellular space. CONCLUSIONS: In inflammatory conditions, the availability of glutamine as an enterocyte fuel substrate is essential for the preservation of a functional barrier to microorganisms. In conditions of acute glutamine depletion, cytokine mediated bacterial translocation appears to be primarily a transcellular process.

Prevention of chemotherapy and radiation toxicity with glutamine.
Author:                       Savarese,-D-M; Savy,-G; Vahdat,-L; Wischmeyer,-P-E; Corey,-B
Citation:         Cancer-Treat-Rev. 2003 Dec; 29(6): 501-13
Abstract:        GOALS OF THE WORK: Malignancy produces a state of physiologic stress that is characterized by a relative deficiency of glutamine, a condition that is further exacerbated by the effects of cancer treatment. Glutamine deficiency may impact on normal tissue tolerance to antitumor treatment, and may lead to dose reductions and compromised treatment outcome. Providing supplemental glutamine during cancer treatment has the potential to abrogate treatment-related toxicity. We reviewed the available data on the use of glutamine to decrease the incidence and severity of adverse effects due to chemotherapy and/or radiation in cancer patients. METHODS: We performed a search of the MEDLINE database during the time period 1980-2003, and reviewed the English language literature of both human and animal studies pertaining to the use of glutamine in subjects with cancer. We also manually searched the bibliographies of published articles for relevant references. MAIN RESULTS: The available evidence suggests that glutamine sup plementation may decrease the incidence and/or severity of chemotherapy-associated mucositis, irinotecan-associated diarrhea, paclitaxel-induced neuropathy, hepatic veno-occlusive disease in the setting of high dose chemotherapy and stem cell transplantation, and the cardiotoxicity that accompanies anthracycline use. Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury. CONCLUSIONS: The role of glutamine in the prevention of chemotherapy and radiation-induced toxicity is evolving. Glutamine supplementation is inexpensive and it may reduce the incidence of gastrointestinal, neurologic, and possibly cardiac complications of cancer therapy. Further studies, particularly placebo-controlled phase III trials, are needed to define its role in chemotherapy-induced toxicity.

Glutamine supplementation in vitro and in vivo, in exercise and in immunodepression.
Author:                       Castell,-L
Citation:         Sports-Med. 2003; 33(5): 323-45
Abstract:        In situations of stress, such as clinical trauma, starvation or prolonged, strenuous exercise, the concentration of glutamine in the blood is decreased, often substantially. In endurance athletes this decrease occurs concomitantly with relatively transient immunodepression. Glutamine is used as a fuel by some cells of the immune system. Provision of glutamine or a glutamine precursor, such as branched chain amino acids, has been seen to have a beneficial effect on gut function, on morbidity and mortality, and on some aspects of immune cell function in clinical studies. It has also been seen to decrease the self-reported incidence of illness in endurance athletes. So far, there is no firm evidence as to precisely which aspect of the immune system is affected by glutamine feeding during the transient immunodepression that occurs after prolonged, strenuous exercise. However, there is increasing evidence that neutrophils may be implicated. Other aspects of glutamine and glutamine supplementation are also addressed.

Nutritional support for wound healing.
Author:                       MacKay,-D; Miller,-A-L
Citation:         Altern-Med-Rev. 2003 Nov; 8(4): 359-77
Abstract:        Healing of wounds, whether from accidental injury or surgical intervention, involves the activity of an intricate network of blood cells, tissue types, cytokines, and growth factors. This results in increased cellular activity, which causes an intensified metabolic demand for nutrients. Nutritional deficiencies can impede wound healing, and several nutritional factors required for wound repair may improve healing time and wound outcome. Vitamin A is required for epithelial and bone formation, cellular differentiation, and immune function. Vitamin C is necessary for collagen formation, proper immune function, and as a tissue antioxidant. Vitamin E is the major lipid-soluble antioxidant in the skin; however, the effect of vitamin E on surgical wounds is inconclusive. Bromelain reduces edema, bruising, pain, and healing time following trauma and surgical procedures. Glucosamine appears to be the rate-limiting substrate for hyaluronic acid production in the wound. Adequate dietary protein is absolutely essential for proper wound healing, and tissue levels of the amino acids arginine and glutamine may influence wound repair and immune function. The botanical medicines Centella asiatica and Aloe vera have been used for decades, both topically and internally, to enhance wound repair, and scientific studies are now beginning to validate efficacy and explore mechanisms of action for these botanicals. To promote wound healing in the shortest time possible, with minimal pain, discomfort, and scarring to the patient, it is important to explore nutritional and botanical influences on wound outcome.

Effects of an oral mixture containing glycine, glutamine and niacin on memory, GH and IGF-I secretion in middle-aged and elderly subjects.
Author:                       Arwert,-L-I; Deijen,-J-B; Drent,-M-L
Citation:         Nutr-Neurosci. 2003 Oct; 6(5): 269-75
Abstract:        Aging is associated with declining activity of the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis and with a decrease in cognitive function. The stimulatory effect of an orally administered nutritional supplement, mainly containing glycine, glutamine and niacin on the GH-IGF-I axis and on mood and cognition was investigated. Forty-two healthy subjects (14 men and 28 women, age