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[LifeMirage]

Idebenone: The Ultimate Anti-Aging Drug
By James South MA

Idebenone (IDB) is a synthetic analog (variant) of one of life's most essential biochemicals, coenzyme Q10 (CoQ10). CoQ10 is an important antioxidant component of the lipid (fatty) membranes that surround all cells, as well as the lipid membranes surrounding the various organelles ("little organs"), such as mitochondria & microsomes, inside cells.

CoQ10 is also an important member of the "Electron Transport Chain" (ETC) within mitochondria, which are the "power plants" of the cell. Most of the oxygen we breathe is used inside the ETC to produce much of the ATP bioenergy that powers virtually every activity of our cells and bodies. Without CoQ10, or a good substitute, human life quickly ends, and IDB is a "better CoQ10" that has been extensively researched the past 15 years.

CoQ10's pro-oxidant action
When blood flow is seriously reduced to any part of the body, as in a heart attack, stroke, trauma, shock, or chronic poor blood circulation- cellular/ mitochondrial oxygen (O2) levels quickly drop in the affected region. Yet because O2 is 7-8 times more soluble in the lipid zones of cell membrane, compared to the watery compartments of the cell, there is still sufficient O2 remaining in the membranes of cells and organelles, as well as in the ETC, to auto-oxidize CoQ10. As the CoQ10 auto-oxidizes, free radicals are rapidly formed in massive numbers. These free radicals quickly damage cell/ organelle structure and function, as well as rapidly halt ATP energy generation by the ETC. Brain and spinal cord cells are especially prone to such damage, & may be irreparably damaged or even destroyed within minutes.

Why Idebenone is superior to CoQ10
Enter IDB to the rescue! Studies have shown that under the same cellular low oxygen conditions that cause CoQ10 to act as a pro-oxidant producer of damaging free radicals, IDB prevents the free radical damage and maintains relatively normal cell ATP levels. In short, while IDB can effectively substitute for CoQ10's positive & life essential functions, it doesn't have CoQ10's free radical producing and energy crashing "dark side" which occurs under hypoxic (low O2) conditions.
IDB's potential benefits fall into 5 categories: Antiaging, Energy enhancement, Cognition enhancement, Organ protector & Protector against excitatory amino acid neurotoxicity.

Idebenone - The anti-aging benefits
The mitochondrial power plants produce over 90% of all cellular ATP bioenergy. They are also generally the richest sites in CoQ10 (or IDB). Mitochondrial DNA (mtDNA) allows mitochondria to reproduce them-selves.

While the DNA in a cell nucleus comes from both our parents, mtDNA comes exclusively from our mother's mtDNA. There are typically two or three copies of mtDNA in each mitochondrion, with average 1000 mitochondria per cell. Because mtDNA exists in the "heart of the fiery furnace" where electron "sparks" are constantly leaking as ATP is produced in the ETC, mtDNA is far more prone to free radical electron damage than is the DNA in our cell nuclei that contains the "blueprint" for our entire organism.

At the same time, the repair capacity of mtDNA is much less than that of our cell nucleus DNA. As a consequence, over the course of a lifetime our mtDNA becomes ever more damaged, and the mitochondria produced there from become ever more ineffective at energy generation. Studies comparing heart tissue from young people with that from elderly people have shown almost no significant mitochondrial dysfunction in young hearts, with significant, often severe mitochondrial dysfunction in elderly hearts.

The cells that are most susceptible to mitochondrial energy depletion with advancing age are the brain, skeletal muscle and heart muscle cells. IDB thus offers a prime anti-aging effect here in several ways. Unlike CoQ10, even under the low O2 conditions that may occur periodically over a lifetime, IDB will serve as a powerful mitochondrial free radical quencher, lessening the ever-increasing mtDNA damage that occurs with age.

IDB will work even better than CoQ10 within the ETC to keep energy production high, even under hypoxic conditions. This is especially critical to brain and heart cells that may be rapidly damaged during low ATP production episodes that occur due to poor tissue oxygenation.

Idebenone - Energy enhancement
Iron is a "dual edged sword." It is absolutely essential for life; it plays a central role in ATP generation in the ETC. Yet iron can also be a powerful initiator of free radical production and cell structural damage, especially under low O2 conditions.
This occurs, for example, during stroke, and during the gradual onset of Parkinson's disease. Studies have shown that IDB can tightly couple oxidation to energy production. This prevents iron ions from wastefully and toxically, diverting O2 to producing free radicals inside the mitochondria, instead of energy.
Studies have shown that IDB can almost completely eliminate this, diverting 10% of cellular O2 away from toxic iron induced free radical generation, to beneficial ATP energy production under hypoxic conditions. Mild cellular hypoxia can occur even from intense exercise, or even from mild exercise done by out of shape "couch potatoes."

Idebenone - Cognition enhancement
A variety of studies using brain cells, (animal and humans) have shown IDB's ability to enhance brain structure and function. Human and animal studies have demonstrated that IDB can enhance serotonin production, even under far less than optimal conditions, as e.g. with a very low tryptophan diet, or in patients with cerebrovascular dementia.

IDB has enhanced cholinergic nerve function and consequent learning ability even under hypoxic conditions, or when an anti-cholinergic drug (Scopolamine) was administered. IDB has increased cellular catecholamine (dopamine, adrenalin and noradrenanlin) production by enhancing cellular uptake of the precursor amino-acid tyrosine. IDB enhances long-term potentiation in hippocampal nerve cells, a key part of memory formation and consolidation. IDB has restored glucose (brain fuel) utilization and ATP production in ischemic (poor blood flow) rat-brain.

IDB has been shown to enhance general cerebral metabolism, lessen the damage from strokes, and has been used to treat Alzheimer's and other dementias. And like Piracetam, IDB has been shown to promote information transfer across the corpus callosum, the membrane separating the right and left-brain hemispheres. This is turn may promote the union/ integration of the logical (yang) & intuitive (yin) halves of the brain/mind.

Idebenone - Organ protector
As our organs age or are damaged, we age and are damaged. Over a lifetime, blood flow to our organs diminishes due to arteriosclerosis and less efficient heart pumping. This reduces O2 dependent energy production needed for repair, reproduction and normal function of the organ cells. Free radical damage accumulates over time, leaving ever more dead, dying or dysfunctional cells within organs.

At some point a critical threshold is reached when too many cells within an organ are dysfunctional, and they can no longer sustain the organ's life and function. Then the organ- heart, brain, liver etc. fails. IDB protects organs in many ways; it cushions them against hypoxic (low O2) and/ or ischemic (poor blood flow) damage. IDB enhances both normal and hypoxic ATP energy generation. Each cell in our organs must produce the energy it needs for life and health; cells cannot "borrow" energy from each other.

Idebenone - The free radical quencher
IDB is a powerful antioxidant, more so than CoQ10, and in some studies is 30-100 times more effective, than Vitamin E or Vinpocetine as a free radical quencher within the brain cells. IDB lessens the free radical induced mtDNA damage that accumulates acceleratingly over a lifetime, slowing organ damage and aging.

Glutamic acid and aspartic acid are the two chief EAA (excitatory amino acid) neurotransmitters in the human brain. Without them we would be "mental vegetables." Yet under certain conditions, e.g. stroke or traumatic brain injury- excessive amounts of EAA's accumulate in the fluid surrounding brain cells, causing damage and even death to nerve and glial cells through free radical mechanisms.
EAA toxicity is at least partly responsible for the neurotoxicity of the recreational drug "Ecstasy or MDMA." Studies over the past 30 years have also shown that excessive dietary intake of EAA's may also damage brain structure/ function, especially in children or EAA sensitive adults. The 2 main dietary sources of EAA's are the flavor enhancer MSG (monosodium glutamate) and the artificial sweetener aspartame (Nutrasweet®). Also many processed foods contain "hydrolized vegetable protein, yeast extract, soy protein isolate" and similar ingredients that are mostly EAA's.

In studies with various types of nerve cell, as well as oligodendroglial cells (which make up the protective myelin sheaths surrounding many nerves, the so-called "white matter" of the brain). IDB has shown dramatic protective effects against glutamate toxicity.

Idebenone - The summary
With all these powers, IDB should now rightfully take its place in the first rank of anti-aging/ nootropic/ energizer drugs, along with Hydergine, Piracetam, Vinpocetine, and GH3. So who can benefit from Idebenone? The answers are:
1. Healthy people wishing cognitive enhancement and brain energizer effects (it synergizes well with Piracetam, Vinpocetine, Pyritinol and Picamilon).
2. Stroke victims wishing to improve memory, emotional or speech disturbances.
3. Alzheimer's and cerebrovascular dementia patients.
4. Those preparing for major surgery, especially brain, heart, liver or kidney.
5. People with heart energetics problems, cardiomyopathy, ischemic heart disease, and congestive heart failure.
6. People with myelination problems, multiple sclerosis or "white matter" stroke injury.
7. Those seeking to increase their general energy and vitality levels.
8. People with especially high endurance energy needs, e.g. cross country skiers, long distance runners, cyclists, and swimmers.
9. Those at risk of EAA brain damage, e.g. people who routinely consume large amounts of aspartame sweetened foods/ drinks, or those who routinely eat MSG or "hydrolyzed vegetable protein" containing restaurant or prepared foods.
10. People wishing to enhance the serotonin boosting benefits of tryptophan or 5-HTP supplements or SSRI drugs, such as Prozac, Paxil, and Zoloft.
11. Those suffering acute or chronic liver damage from toxic chemicals or hepatitis.
12. People desiring a "long haul" broad-spectrum anti-aging drug. Synergizes well with Hydergine, Acetyl-Carnitine, NADH, and GH3.

Because of its synergy with other life extension drugs, those also taking any or all of Acetyl-Carnitine, Piracetam, Vinpocetine, Pyritinol, and GH3 may benefit from even just one 45mg tablet a day, especially if taken regularly on a long-term basis. Because idebenone is fat soluble, it is best taken with a fat rich meal, or with lipid absorption enhancing agents such as lecithin or phosphatidyl choline. Numerous studies have shown that idebenone is well distributed through-out the body after absorption, accumulating in cellular and organelle membranes, as well as in the electron transport chain, exactly where it does the most good!


Source: www.smart-drugs.com

Edited by LifeMirage, 17 October 2003 - 11:05 AM.

[LifeMirage]

Idebenone: A Drug with Antiaging Benefits
By Robert Mason Ph.D.

When Coenzyme Q10 was found to produce heart and energy improvement, it soon became apparent that it was a most important supplement. Now there is also a synthetic variant available called Idebenone, it has all the qualities of CoQ10 but with an even greater range and depth of protection. It protects the precious tiny mitochondria (the energy producing cells) and even has brain-enhancing qualities. It is, if you like, the "ultimate" CoQ10 and as such qualifies as an important anti-aging supplement.

Mitochondria, Oxygen and Energy Production
There are literally thousands of mitochondria in every cell of our body. Their primary role is to produce pregnenolone- the precursor to the steroids and to produce ATP (adenosine triphosphate)- the "raw energy" that powers every activity of our bodies.
In the process of producing ATP, the mitochondria utilize oxygen and CoQ10 in a process of energy production called the "electron transport chain" or ETC. Unfortunately oxygen can also be a potent free radical (unstable out of control molecules). As a result of the amount of oxygen used inside the mitochondria (in fact most of the oxygen we breathe is used inside the ETC to produce ATP), a lot of free-radical damage can occur.

Free radicals therefore have to be "mopped up" by free radical scavengers and protected from occurring by anti-oxidants. If left "unchecked" free radical damage inside the mitochondria will eventually lead to its malfunction and eventually cessation. As cells cannot "borrow" energy from one another, in the end, the organ they " provide" for becomes damaged and ultimately this will lead to organ failure and possibly death.

Whilst under "normal" circumstances CoQ10 provides protection and free radical scavenging, this can change under the condition of ischemia (poor blood flow). This can take happen during a heart attack, stroke, trauma or shock, it can even be affected by general poor blood supply due to "aging" affecting the condition of the heart's pumping capabilities. As a result of poor blood supply the oxygen levels drop and this causes CoQ10 to oxidize itself, effectively turning itself into another free radical! Under more extreme conditions a large presence of free radicals can cease ATP production and therefore create a life threatening condition.

This is one key-area where idebenone has been shown to be much more effective than CoQ10. Under the same hypoxic (low oxygen) conditions that cause CoQ10 to become oxidized- idebenone prevents free radical damage and maintains relatively normal ATP production. Idebenone should therefore be the supplement of choice for those concerned with stroke, heart conditions, shock, trauma and mitochondrial failure/conditions.

Slowing Aging
The mitochondria are key life-preserving cells producing over 90% of ATP bio-energy. As we've seen their vast use of oxygen exposes them to free radicals and therefore over a lifetime they become ever more damaged and therefore inefficient. The mitochondria most at risk from aging- free radical damage are those in the heart, brain and skeletal muscles. Therefore a key aspect of current anti-aging thinking is to slow down/ prevent damage from occurring to mitochondrial function. According to the research, idebenone is the current- most effective drug capable of performing this task.

Dementia, Memory and Cognition
Nerve Growth Factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system (CNS). In dementias such as Alzheimer's, it is known that learning and memory are impaired by the loss of neurons in an area of the brain called the magnocellular cholinergic neuronal system.
Nerve Growth Factor cannot cross the blood brain barrier and in scientific experiments, it has only been able to be utilized when it is injected directly into the brain. However, animal experiments have shown that oral use of idebenone can induce an increase in NGF and improve choline- acetyltransferase activity. One rat study demonstrated that idebenone stimulated NGF synthesis and recovered reduced NGF content in aged rat brains. After 21 days of successive idebenone supplementation the NGF brain quantity of aged rats was increased to an amount similar to young rats.

As a result of these studies, idebenone is being used in the treatment of senile dementias, particularly Alzheimer's disease. In a German clinical study, 90mg of idebenone was administered for 6 months; Alzheimer patients thereafter showed statistically significant improvement. Treatment with idebenone was found effective on memory, attention and orientation. Perhaps most importantly of all, idebenone slowed down the natural progression of the disease. Furthermore, there were so few (and minor) side effects that the study ended with "... results demonstrate the efficacy and safety of idebenone in the treatment of Alzheimer's disease patients." Once again, as with most nootropics, clinical trials indicate that patients with mild dementia seem more likely to respond, than those with greater functional decline.

Comparing CoQ10 and Idebenone
1. Idebenone is so much more potent than CoQ10 in its anti-oxidant abilities. In fact, studies indicate that idebenone is 30-100 times more effective than Vitamin E or Vinpocetine as a free radical quencher.
2. Idebenone protects under hypoxic conditions, a situation where CoQ10 can become quite the reverse.
3. Idebenone (unlike CoQ10) has been shown to increase Nerve Growth Factor and enhance cholinergic activity, thereby showing it to have cognitive enhancement abilities.
4. Idebenone is a superb anti-oxidant for protecting the all important mitochondria, by both "mopping up" free radical activity and protecting the unique mitochondrial DNA (mtDNA)- unique because it is only derived from our mother's genes.
However, rather than switching from CoQ10 to idebenone, some studies have suggested that adding idebenone to a CoQ10 supplement is the best way to "cover all the bases."

Side Effects and Contraindications
Side effects have been rare and usually of mild intensity when they do occur. There are no known contraindications, but it is known that concurrent use of anti-convulsants will affect/ impede its pharmacokinetics.

Doses and Uses
Idebenone may be useful in the treatment and prevention of all the following:
1. Stroke
2. Alzheimer's disease
3. Liver, kidneys, heart or brain disturbances
4. Multiple Sclerosis
5. Chronic fatigue
6. Persons in need of "high-energy" quotas
7. Anti-aging protection

Normal anti-aging doses may be considered at 45mg to 90mg daily, (normally one or two tablets). For specific treatment purposes dosages of 45-90mg three times a day may be required. It is suggested that late evening use by avoided in order to help prevent insomnia. CoQ10 was one of the "earth-shattering" discoveries in recent years and as such has become a well-known and demanded supplement. Idebenone with its even greater and broader range of uses is (we feel), also likely to impact onto the general public's attention. This is going to occur as soon as the word spreads and the momentum has reached a certain point.


Above Article from www.smart-drugs.com

[LifeMirage]

Imre Nagy: Anti-Aging Pioneer Key developer of Idebenone
By Ward Dean, MD

Professor Imre Zs.-Nagy, Ph.D., D.Sc., is a world-renowned gerontologist. He is the Director of the Fritz Verzar International Laboratory for Experimental Gerontology, University Medical School in Debrecen, Hungary, and is the founding editor of the internationally acclaimed scientific journal, Archives of Gerontology and Geriatrics. In addition to training under the venerable Professor Verzar himself at his Laboratory for Experimental Gerontology in Basel, Switzerland, Zs.-Nagy has also been a distinguished invited scientist at the Laboratory for Experimental Gerontology in Ancona, Italy, and the Tokyo Metropolitan Institute of Gerontology in Japan. A key focus of his research has been to develop his free radical-related Membrane Theory of Aging. Another objective was to identify anti-aging substances for use in humans, based on his theory.

We are proud that Prof. Zs.-Nagy accepted our invitation to be a featured speaker at the Anti-Aging Conference in Monaco last June, and he has been invited for a return visit to the Second Monaco Conference to be held in June 2001.
Through a combination of diplomacy and science, Zs.-Nagy also played a key role in developing a highly effective life extension substance—Idebenone.

Idebenone
Idebenone is an analog of CoQ10. I learned about it at the meeting in Acapulco at a conference sponsored by Takeda Chemical Industries, Ltd. Takeda had been marketing Idebenone in Japan, under the trade name Avan since 1986. John Morgenthaler and I included a chapter about it in our book, Smart Drugs & Nutrients. Although we rated Idebenone quite highly at that time, we reluctantly reported that it was available only in Japan (by prescription) and that it was prohibitively expensive.
Prior to 1990, the majority of the world literature on Idebenone had been published in Japanese—largely unavailable to scientists in the West. Zs.-Nagy, through his contacts in the Japanese research community, encouraged the translation of many of these studies, and was an active participant in much of the research. He published three special issues of his journal, each of which focused entirely on Idebenone.
The first two (May 1989 & November/December) 1990—contained articles on the in vivo and in vitro effects of Idebenone on experimental animals. Zs.-Nagy himself authored or co-authored twelve of the articles.

While in Italy at the Laboratory for Experimental Gerontology, Zs.-Nagy encouraged his colleagues there to investigate the clinical effects of Idebenone. These studies resulted in his third special issue, which was devoted exclusively to human clinical trials.

Idebenone’s numerous benefits were attributed to its antioxidant properties and protective effect against damage to mitochondrial membranes. This results in an enhanced formation of ATP (the body’s principal energy molecule), increased glucose metabolism, and reduced tissue oxygen requirements. These properties are the basis for Idebenone’s powerful effects on cellular energy metabolism and utilization.

Protection Against Hypertension and Strokes
Idebenone was found to (1) protect experimental animals against neurological damage caused by [induced] strokes; (2) prevent the development of hypertension and strokes in a breed of rat that typically develops hypertension, resulting in strokes (Spontaneously Hypertensive Stroke Prone rats—SHRsp); and (3) prolong survival of mice subjected to hypoxia (reduced oxygen). Idebenone protects against brain damage by improving cerebral energy metabolism in both normal rats and SHRsp. Idebenone also enhances the formation of cyclic AMP, and increases serotonin (5-HT) turnover.

Chronic Cerebrovascular Disease
Idebenone also protects experimental animals and humans from the devastating effects on memory and cognition caused by hypoxia and other causes. One of the first human studies outside Japan was performed in Italy at the University of Pavia.13 This study involved a total of 75 hospitalized men and women who suffered from mild to moderate cognitive impairment. Idebenone was administered in doses of 90 or 180 mg daily. The patients treated with Idebenone improved significantly—particularly in cognitive performance and general behavior.

Zs.-Nagy’s third special issue on Idebenone reported on further human studies conducted in Italy. Combined, the studies reported on 422 patients with dementia of varying causes, half of whom were given placebo. Patients in all studies were given 45 mg of Idebenone twice daily for periods varying from three to six months. The results were overwhelmingly positive in most of the standard rating scales used. In particular, the authors consistently reported overall improvements in memory, attention, cognition, and behavior. Measurable improvement was frequently noted after one month, with continued improvement as the treatment lengthened, up to about six months (the maximum duration of the study). In addition, benefits tended to persist for at least a month after cessation of treatment. There were no side effects that could be attributed to Idebenone in any study.

A Safe Effective Anti-Depressant?
Scientists induced low serotonin levels in rats by feeding them tryptophan-free diets (tryptophan is a precursor of the neurotransmitter serotonin). When these rats were given Idebenone, the serotonin-deficient rats performed as well on a discrimination test as did rats with normal serotonin levels.

Low serotonin levels in humans are associated with impulsiveness, bad temper and violent behavior. Some studies of violent people have found low levels of serotonin metabolites, indicating low serotonin levels. Because of this ability to stimulate the release of serotonin and norepinephrine, Idebenone has been shown to be a very safe, effective anti-depressant.

Conclusion
Idebenone appears to be another in the growing armamentarium of safe, effective anti-aging substances. The major limitations to its use—availability and affordability—have now been largely resolved. Thanks to the Dietary Supplement Health Education Act (DSHEA), Idebenone qualifies as a dietary supplement. Also, although not cheap by any means, it is now within the price range of many consumers. Hopefully, as demand increases, the increased supply will further reduce the price.

One question will certainly be: In view of the similarity of Idebenone to CoQ10, is one better than the other? Or should we take both? Unfortunately, there are no definitive answers. One reason to consider taking both is that the substances may have slightly varying effects. For example, niacin and niacinamide (both forms of vitamin B3) have very different effects when taken in pharmaceutical doses. Consequently, many people take high doses of both substances. Another example of synergistic action of similar substances is the various forms of vitamin E (i.e., alpha, beta, delta and gamma tocopherols). Also, while there are many studies demonstrating effectiveness of Idebenone in dementing illnesses, there are no such studies of CoQ10 in this regard (likewise, there are no studies that I know of showing benefits of Idebenone in cardiac conditions). I believe that taking various forms of substances can be synergistic, because of slightly different sites and mechanisms of action.
The optimum dosage of Idebenone appears to be 45 mg, twice daily. Improvements in cognition, mood and behavior can usually be noted in about one month, with progressively continuing improvement up to about six months.


Above Article from www.vrp.com

[LifeMirage]

Idebenone Monograph

Introduction

Idebenone [2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone] is a synthetic analogue of coenzyme Q10 (CoQ10), the vital cell membrane antioxidant and essential constituent of the ATP-producing mitochondrial electron transport chain (ETC). Idebenone is a potent antioxidant, with the ability to operate under low oxygen tension situations. Because of its ability to inhibit lipid peroxidation, idebenone protects cell membranes and mitochondria from oxidative damage. Its antioxidant properties protect against cerebral ischemia and nerve damage in the central nervous system. Idebenone also interacts with the ETC, preserving ATP formation in ischemic states. This compound has also been shown to stimulate nerve growth factor, a characteristic that is important in the treatment of Alzheimer's and other neurodegenerative diseases.

Biochemistry and Pharmacokinetics

Idebenone is rapidly absorbed and reaches peak concentrations in the brain comparable to those in plasma. Animal studies showed a peak plasma level 15 minutes after oral administration, with a half-life of 2.2-15.4 hours. Idebenone was well distributed in tissues, with higher concentrations in the gut, liver, and kidney. Excretion was via both urine and feces, mostly as metabolites. A human pharmacokinetic and safety study found a half-life of 18 hours, with biphasic elimination. Researchers found no long-term tissue accumulation in humans or rats.

Mechanisms of Action

As with other antioxidants, idebenone exists in a reduced and an oxidized state. In a study of idebenone's effect on astroglial cells, idebenone, in either redox state, significantly inhibited the enzymatic metabolism of arachidonic acid by cyclooxygenase and lipoxygenase. This effect was stronger with the reduced form, and showed potential central nervous system anti-inflammatory activity.

Introduction of iron and ascorbate to a cell mixture or a group of isolated cells can establish experimental cellular oxidant injury. Synaptosomes isolated from rat brain cortex were treated with iron and ascorbate. Idebenone prevented both the formation of reactive oxygen species in the cytosol and mitochondria, as well as a decrease in protein-sulfhydryl content (an indicator of protein oxidation), compared to controls.

It appears that, in addition to functioning as an antioxidant, idebenone functions as an electron carrier in the ETC, similar to CoQ10. To illustrate, researchers in Japan introduced idebenone into a canine CoQ10-depleted brain mitochondrial preparation, which prevented the loss of ETC activity normally seen with CoQ10 depletion. Idebenone also inhibited mitochondrial lipid peroxidation, which can be interpreted as protecting against mitochondrial membrane damage. Other animal studies confirm the mitochondrial membrane protective effects of idebenone.

Idebenone treatment of rats with experimental cerebral ischemia inhibited the loss of acetylcholine in forebrain regions, prevented increases in lactate and free fatty acids, and preserved ATP content in the cerebral cortex. These results indicate idebenone protects against ischemic damage and promotes ATP production in the brain.

Clinical Indications:

Alzheimer's Disease: Nerve growth factor plays an important role in the growth, survival, and preservation of cholinergic neurons in the central nervous system. In Alzheimer's disease, cholinergic neurons can become damaged and die. In a rat study, oral administration of idebenone stimulated increases in nerve growth factor protein, mRNA, and choline acetyltransferase activity in basal forebrain lesioned rats. Idebenone also improved behavioral deficits in habituation, water maze, and passive avoidance tasks, which suggests idebenone might stimulate nerve growth factor synthesis in vivo. Similar results were found in aged rats.

Amyloid beta-peptide (ABP), the major constituent of senile plaques in Alzheimer's disease, is neurotoxic, possibly via an oxidative stress mechanism. Rats given an intracerebroventricular infusion of ABP demonstrated significant impairment of memory and behavior, which was prevented when idebenone and alpha tocopherol were given orally before and during ABP infusion. In a double-blind, placebo-controlled multi-center human study, 450 patients were given either placebo for 12 months, followed by idebenone 90 mg three times per day for another 12 months; 90 mg three times per day for 24 months; or 120 mg three times per day for 24 months. Significant dose-dependent improvements were seen in measurements of clinical status and in neuropsychiatric tests compared to placebo. These improvements continued over the two-year study.

300 patients with mild-to-moderate Alzheimer's disease were randomized to receive either placebo, idebenone 30 mg 3 times per day, or 90 mg 3 times per day for six months. Statistically significant improvement was noted in the total score of the Alzheimer's Disease Assessment Scale (ADAS-total), and in one cognitive parameter (ADAS-cog). An analysis of therapy responders revealed significant improvement in three outcome measures (clinical global response, ADAS-Cog, and non-cognitive scores) in the idebenone 90 mg 3 times per day group, compared to placebo. Other studies have confirmed these findings.

Liver Disease: Oxidative stress has been implicated in a number of hepatic diseases, including bile acid-induced liver injury in hepatic cholestasis, which was evaluated in an in vitro study. Treatment with idebenone protected against bile acid-induced rat hepatocellular injury and lipid peroxidation, and prevented hydroperoxide production in hepatic mitochondria.

Cerebrovascular Disease: In a small human study of nine patients with cerebrovascular disease, 90 mg idebenone was given daily, and electroencephalograms and clinical symptoms were monitored. The results suggested that idebenone supplementation produced improvements in EEG and clinical symptoms in these patients.

Friedreich's Ataxia: Friedreich's ataxia (FA), an autosomal recessive spinal ataxia, is characterized by unsteady gait, weakness, sensory loss, upper extremity ataxia, mental decline, and progressive cardiomyopathy. The pathophysiology of FA is due to a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content, which causes oxidative damage from mitochondrial iron overload. This leads to a deficiency in mitochondrial enzymes, reduced energy output, and mitochondrial damage. Idebenone dosing (5 mg/kg daily for 8 weeks) in FA patients significantly decreased a marker of oxidative DNA damage. Idebenone prevented iron-induced lipoperoxidation and cardiac muscle injury in three patients given 5 mg/kg daily for 4-9 months, resulting in a reduction of left ventricular enlargement in these patients.

Dosage and Safety
Two hundred Alzheimer's disease patients received either 90 mg or 270 mg idebenone per day for six months. No significant adverse events or changes in vital signs, ECG or clinical laboratory parameters were noted. Barkworth et al gave 10 healthy male volunteers 300 mg per day for 35 days. No changes were seen in blood and urine lab values, and the dose was well tolerated.3 Safety and tolerability of idebenone were good and similar to placebo during a two-year study utilizing doses up to 360 mg per day. A 900 mg per day dose was given to 17 men for four weeks, with no adverse effects seen on electroretinography, auditory evoked potentials, or visual analogue scales. Idebenone has been found to inhibit platelet aggregation in vitro, by inhibition of phospholipase B2 production, which might contraindicate its use in patients already on anti-clotting therapy or in those with a history of or at risk for hemorrhagic stroke.


Source: www.thorne.com

Edited by LifeMirage, 28 October 2003 - 09:16 AM.

[LifeMirage]

Idebenone In Dementia

Pharmacopsychiatry 2002 Jan;35(1):12-8
Safety and Efficacy of Idebenone versus Tacrine in Patients with Alzheimer's Disease: Results of a Randomized, Double-Blind, Parallel-Group Multicenter Study.

Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Wilhelm Griesinger Hospital, Department of Gerontopsychiatry, Berlin, Germany.

This study evaluated the safety and efficacy of idebenone vs. tacrine in a prospective, randomized, double-blind, parallel-group multicenter study in patients suffering from dementia of the Alzheimer type (DAT) of mild to moderate degree. Diagnosis was based on DSM-III-R (primary degenerative dementia) and NINCDS-ADRDA criteria (probable Alzheimer's disease). A total of 203 patients of both sexes aged between 40 and 90 years were randomized to either idebenone 360 mg/day (n = 104) or tacrine up to 160 mg/day (n = 99) and treated for 60 weeks. The primary outcome measure was the Efficacy Index Score (EIS). The EIS combines dropout as well as the relevant improvements individually across the three levels of assessment (cognitive function, activities of daily living, global function). Secondary outcome measures were the ADAS-Cog score, the NOSGER-IADL score and the clinical global response (CGI-Improvement). After 60 weeks of treatment, 28.8 % of the patients randomized to idebenone, but only 9.1 % of the patients randomized to tacrine were still on the drug. In the LOCF analysis, 50 % of the patients randomized to idebenone but only 39.4 % of the patients randomized to tacrine showed an improvement in the Efficacy Index Score or at least one of the secondary outcome variables. The primary efficacy measurement was the change of the Efficacy Index Score from baseline to the assessment after 60 weeks treatment. The analysis was done on intention-to-treat (ITT) in a before-and-after test design. Patients randomized to idebenone showed a higher benefit from treatment than patients randomized to tacrine. We conclude that the benefit-risk ratio is favorable for idebenone compared to tacrine, and furthermore, that this ratio is likely to be similar when comparing idebenone to other cholinesterase inhibitors.

J Neural Transm Suppl 1998;54:301-10
Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double blind multicentre study.

Gutzmann H, Hadler D. Krankenhaus Hellersdorf, o.B. Wilhelm-Griesinger-Krankenhaus, Abteilung fur Gerontopsychiatrie, Berlin, Federal Republic of Germany.

The 2-year efficacy and safety of idebenone were studied in a prospective, randomized, double-blind multicentre study in 3 parallel groups of patients with dementia of the Alzheimer type (DAT) of mild to moderate degree. A total of 450 patients were randomized to either placebo for 12 months, followed by idebenone 90 mg tid for another 12 months (n = 153) or idebenone 90 mg tid for 24 months (n = 148) or 120 mg tid for 24 months (n = 149). The primary outcome measure was the total score of the Alzheimer's Disease Assessment Scale (ADAS-Total) at month 6. Secondary outcome measures were the ADAS cognitive (ADAS-Cog) and noncognitive score (ADAS-Noncog), the clinical global response (CGI-Improvement), the SKT neuropsychological test battery, and the Nurses' Observation Scale for Geriatric Patients (NOSGER-Total and IADL subscale). Safety parameters were adverse events, vital signs, ECG and clinical laboratory parameters. During the placebo-controlled period (the first year of treatment), idebenone showed statistically significant dose-dependent improvement in the primary efficacy variable ADAS-Total and in all the secondary efficacy variables. There was no evidence for a loss of efficacy during the second year of treatment, as a further improvement of most efficacy variables was found in the second year in comparison to the results at the 12 months visit. Also, a clear dose effect relationship (placebo/90 mg < idebenone 90 mg < idebenone 120 mg) was maintained throughout the second year of treatment. This suggests that idebenone exerts its beneficial therapeutic effects on the course of the disease by slowing down its progression. Safety and tolerability of idebenone were good and similar to placebo during the first year of treatment and did not change during the second year.

Neuropsychobiology 1997;36(2):73-82
A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease.

Weyer G, Babej-Dolle RM, Hadler D, Hofmann S, Herrmann WM. Institute of Psychology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany.

Two doses of idebenone were studied in a prospective, randomized, double-blind, placebo-controlled multicentre study in patients suffering from dementia of the Alzheimer type (DAT) of mild to moderate degree. Diagnosis was based on DSM-III-R (primary degenerative dementia) and NINCDS-ADRDA criteria (probable Alzheimer's disease). A total of 300 patients were randomized to either placebo, idebenone 30 mg t.i.d. or 90 mg t.i.d. (n = 100, each) and treated for 6 months. The primary outcome measure was the total score of the Alzheimer's Disease Assessment Scale (ADAS-Total) at month 6. Secondary outcome measures were the ADAS cognitive (ADAS-Cog) and noncognitive scores (ADAS-Noncog), the clinical global response (CGI-Improvement), the MMSE, the Digit Symbol Substitution test (DSS) and several scales for the assessment of daily activities (the self- and observer-rating scales NAA and NAB of the Nuremberg Age Inventory NAI and Greene's Assessment). Safety parameters were adverse events, vital signs, ECG and clinical laboratory parameters. Clinical and psychometric evaluations were performed at baseline, and after 1, 3 and 6 months of treatment. After month 6 idebenone 90 mg t.i.d. showed statistically significant improvement in the primary efficacy variable ADAS-Total and in ADAS-Cog. An analysis of therapy responders performed for 3 outcome measures (CGI-global improvement, ADAS-Cog, ADAS-Noncog), selected to represent different domains of assessment, revealed significant superiority of idebenone 90 mg t.i.d. with respect to placebo in each of the 3 variables and in the concordance of responses across the 3 measures. Exploratory results for a subgroup of patients (ADAS-Total > or = 20) showed dose-related superiority of idebenone additionally on ADAS-Noncog and the CGI-Improvement scale. Safety results were inconspicuous for all assessments. The study results demonstrate the efficacy & safety of idebenone in the treatment of DAT patients.

Drugs Aging 1994 Aug;5(2):133-52
Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders.

Gillis JC, Benefield P, McTavish D. Adis International Limited, Auckland, New Zealand.

Idebenone is a benzoquinone compound, which has been investigated, in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective & subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients & good tolerability.

Funct Neurol 1994 May-Jun;9(3):161-8
Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type.

Bergamasco B, Scarzella L, La Commare P. III Neurological Clinic, University of Turin, Italy.

Alzheimer's disease (AD) is a central nervous system disorder characterized by the presence of neurofibrillary tangles, neuritic plaques and dystrophic neurones in susceptible areas of the brain. Few options for treatment of AD symptomatology are available. We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel trial consisting of a 90 day treatment period followed by a 30 day single blind placebo administration and by an optional long term period of treatment up to a year with idebenone in open fashion. 92 patients entered the study and 9 of them dropped out before the first control. Treatment with idebenone was found effective on memory, attention, and orientation and in slowing down the natural progressive worsening of the disease. The most common side effects associated with this treatment were insomnia, gastralgia, nausea, and anxiety. However, all adverse effects were of mild intensity and did not require specific therapies.

Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):271-8.
Idebenone in the treatment of multi-infarct dementia: a randomised, double-blind, placebo controlled multicentre trial.

Bergamasco B, Villardita C, Coppi R.

III Neurologic Clinic, University of Turin, Italy.

A controlled double blind randomised open multicentre study was carried out on 104 patients with multi-infarct dementia (MID) from a mild to a moderate degree. The patients were randomly assigned to balanced blocks in each center and treated for 90 days either with idebenone (CV-2619) 90 mg/daily or placebo, after a 2-week turn-in period. The Gottfries Rating Scale, SCAG, Rey's A Figure Test, Rey's 15 Words Test, Token Test, Verbal Fluidity Test and the Blessed Dementia Test were used for assessment. The data were statistically analyzed using parametric and non-parametric tests. Seven patients were excluded (5 idebenone + 2 placebo) after a few days treatment, for reasons not related to drug administration; therefore, 97 patients were assessed for efficacy and 104 for tolerability. A certain placebo effect was found in the examination results but it never achieved the efficacy levels of idebenone. The latter is particularly effective for improving recent and remote memory, attention, orientation, vigilance and verbal comprehension and the effects continued even after a month of placebo treatment. There were no important adverse reactions and neither laboratory parameters nor clinical vital signs were significantly altered.

Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):249-60.
Idebenone in senile dementia of Alzheimer type: a multicentre study.

Senin U, Parnetti L, Barbagallo-Sangiorgi G, Bartorelli L, Bocola V, Capurso A, Cuzzupoli M, Denaro M, Marigliano V, Tammaro AE, Fioravanti M.

Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.

Idebenone is a new cerebro-active drug, effective in dementia disorders, particularly indicated in primary degenerative dementias, i.e. Alzheimer's disease. This new molecule acts as an electron trapper and a free radical scavenger protecting mitochondrial membranes from lipid peroxidation. A multicentric, double-blind trial of idebenone (45 mg twice daily orally) vs. placebo was carried out on 102 elderly patients affected by Alzheimer-type dementia of mild or moderate severity. Idebenone was administered for 4 consecutive months, 45 mg twice daily. Clinical evaluations were performed at the time of enrollment (t0) and monthly thereafter (t30, t60, t90 and t120) and at follow-up (t150 ). Tolerability to idebenone treatment was good and was associated with a statistically significant improvement of memory, attention and behaviour. It is worthwhile noting that these cognitive and behavioral findings were observed after the first month of treatment with enhancement evident in the following period.

Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):239-48.
Randomized, double-blind, placebo controlled, multicentre study of idebenone in patients suffering from multi-infarct dementia.

Marigliano V, Abate G, Barbagallo-Sangiorgi G, Bartorelli L, Capurso A, Cucinotta D, Cuzzupoli M, Senin U, Tammaro AE, Fioravanti M.

University of Rome La Sapienza, Rome, Italy.

In this randomized double-blind, placebo controlled, multicentre study on 108 elderly patients with mild to moderate mental deterioration of vascular origin, idebenone - a benzoquinone derivative with a hydroxyalkyl side chain - proved to be therapeutically effective in the treatment of multi-infarct dementia. The oral administration of idebenone 45 mg/day b.i.d. for 120 days significantly improved the scores of the following test in comparison with placebo: Mini Mental State, Randt Memory Test, Gottfries Rating Scale, Token Test, Toulouse Pieron Test, indicating improvements in memory attention and cognitivity. The drug was well tolerated and effective in patients with multi-infarct dementia. No changes in laboratory parameters were observed either before or after treatment.


Source: Medline

Edited by LifeMirage, 15 March 2005 - 08:43 AM.

[LifeMirage]

Idebenone In CerebroVascular Disorders

Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):225-37.
Evaluation of the clinical efficacy of idebenone in patients affected by chronic cerebrovascular disorders.

Lingetti M, Porfido FA, Ciarimboli M, Oliviero U, Cocozza M, Coto V, Policicchio D, Carifi S, Piermatteo E, Lombardi R, Tranfaglia E, Di Grazia F.

Division of Geriatrics and Rehabilitation, U.S.L. 04, Avellino, Italy.

This study evaluated the efficacy and tolerability of idebenone, a new neuroactive drug, in 33 patients aged from 50 to 80 years. They were affected by chronic cerebrovascular disease (CCVD) and their last cerebrovascular accident had taken place at least 3 months prior to enrollment. All these subjects presented a score within the range of the following psychometric scales: Hamilton Scale for Depression <24; Hachinski Dementia Score >/=18 and < 25; Mini Mental State >/=16 and During the study, the following evaluation scales were administered: Sandoz Clinical Assessment of Geriatrics (SCAG), Gottfries-Brane-Steen (GBS), Instrumental Activity of Daily Living (IADL), Greene Relatives' Stress Scale (GRSS), Toulouse Pieron, Randt Memory Test. The results show that idebenone is effective both in improving the sense of psycho-physical wellbeing and in improving cognitive, attentive and behavioural efficiency. The tolerability of the treatment was very good.

Arch Gerontol Geriatr 1989 May;8(3):355-66
Effects of idebenone on electroencephalograms of patients with cerebrovascular disorders.

Nakano T, Miyasaka M, Mori K, Ohtaka T, Kifune Y. Department of Psychiatry, Dokkyo University School of Medicine, Tochigi, Japan.

A daily dose of 90 mg of idebenone was given to 9 patients with cerebrovascular disorders to investigate its effects on clinical symptoms and electroencephalograms (EEG). Changes in EEG before and after the administration were compared quantitatively by computer analysis using the wave-form recognition method. Significant increase in frequency in the alpha band (O1) and trends of increased appearance of beta waves, decreased appearance of alpha 1 bands, and lowered amplitude in the alpha 1 and alpha 2 bands were observed after administration of idebenone. The theta waves of 30 microV and over had a significantly diminished maximum amplitude (C3) and a tendency to appear less often. Mean frequency of the EEG and appearance of fast waves apparently increased in the patients showing improvement of the clinical symptoms as compared with those not showing improvement. The results suggested that idebenone improved the EEG in the patients with cerebrovascular disorders, causing changes in EEG similar to those observed with psychostimulants.

Arch Gerontol Geriatr 1989 May;8(3):343-53
Effects of idebenone on monoamine metabolites in cerebrospinal fluid of patients with cerebrovascular dementia.

Kawakami M, Itoh T. 3rd Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Monoamine metabolites and norepinephrine (NE) in the cerebrospinal fluid of patients with cerebrovascular dementia were measured to study the effects of administration of idebenone. 6 patients with cerebral infarction and one with cerebral hemorrhage (mean age 65.4 years) were enrolled as subjects. All the patients had mental and intelligence impairment which was evaluated by the Hasegawa's Dementia Rating (DR) Scale. The patients were medicated with a 90 mg/day dose of idebenone for 1 to 2 months, and homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and NE in the cerebrospinal fluid were determined by high-performance liquid chromatography before and after the medication of idebenone. Before the medication, the level of HVA was 21.7 +/- 1.4 ng/ml (mean +/- SE), which was significantly lower (p less than 0.01) as compared with that in control subjects of similar age. The level of 5-HIAA was 18.5 +/- 2.7 ng/ml, and that of MHPG 9.5 +/- 0.7 ng/ml, both of which were lower than those of the controls, though statistically not significant. NE was similar to the control value. After administration of idebenone, HVA measured was 27.1 +/- 3.2 ng/ml, showing a tendency to increase. The levels of 5-HIAA and MHPG were 26.7 +/- 2.3 ng/ml and 10.7 +/- 0.6 ng/ml, respectively, which were significantly (p less than 0.05) higher than the premedication values. The percentages of the change were 12.8 +/- 8.0 for HVA, 58.2 +/- 18.5 for 5-HIAA and 14.2 +/- 5.0 for MHPG. The score of the DR scale was improved by 5 or less after the idebenone medication in most subjects. HVA and 5-HIAA increased markedly in the patients who showed a tendency of improvement of mental impairment as evaluated by the DR scale. The results suggested that idebenone would improve abnormalities in neurotransmitters of patients with cerebrovascular dementia, especially promoting serotonin turnover.


Source: Medline

Edited by LifeMirage, 15 March 2005 - 08:46 AM.

[LifeMirage]

Idebenone In Friedreich Ataxia

Orv Hetil. 2003 Jun 22;144(25):1241-4.
Successful idebenone therapy of hypertrophic cardiomyopathy in Friedreich ataxia

Kadar K. Gottsegen Gyorgy Orszagos Kardiologiai Intezet, Gyermeksziv Kozpont.

Severe hypertrophic cardiomyopathy in a 15 years old child with Friedreich ataxia was treated with idebenone on the basis of a preliminary study reported in the literature. After 3 months of treatment the muscle thickness and mass and idices of diastolic function on echocardiogram and ischaemic signs on ECG changed significantly. IN CONCLUSION: Our data proves the preliminary results, so idebenobe treatment is very effective in the disease, where a deficiency of frataxin is involved in the regulation of mitochondral iron content which is responsible for myocardial injury. We suggest the widespread use of idebenone to treat patients with Friedreich ataxia and hypertrophic cardiomyopathy to improve the fatal prognosis of this type of cardiomyopathy.

Neurology. 2003 May 27;60(10):1679-1681.
Idebenone treatment in Friedreich's ataxia: Neurological, cardiac, and biochemical monitoring.

Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B, Goossens W, Goemans N, Sutherland GR, Van Hove JL. Departments of Pediatric Neurology (Drs. Buyse, Matthijs, and Goemans), Pediatric Cardiology (Drs. Mertens and Eyskens), Cardiology (Drs. Di Salvo, Weidemann, and Sutherland), Laboratory Medicine (Dr. Goossens), and Pediatric Metabolic Diseases (Dr. Van Hove), University Hospitals Leuven, Belgium.

The authors report 1-year prospective data on eight patients with Friedreich ataxia. Idebenone did not halt the progression of ataxia. At the end of therapy, cardiac ultrasound demonstrated significant reduction of cardiac hypertrophy in six of eight patients. Cardiac strain and strain rate imaging showed that the reduction of hypertrophy is preceded by an early and linear improvement in cardiac function. Idebenone reduced erythrocyte protoporphyrin IX levels in five of six patients with elevated baseline levels; however, changes did not consistently relate to cardiac improvement.

Neurology. 2003 May 27;60(10):1676-9.
Idebenone treatment in Friedreich patients: One-year-long randomized placebo-controlled trial.

Mariotti C, Solari A, Torta D, Marano L, Fiorentini C, Di Donato S. Division of Biochemistry and Genetics (Drs. Mariotti and Di Donato) and Unit of Neuro-Epidemiology (Dr. Solari), Carlo Besta National Neurological Institute-IRCCS, Milan.

The authors carried out a 1-year, randomized, placebo-controlled trial of idebenone in 29 patients with Friedreich ataxia. They found significant reductions of interventricular septal thickness and left ventricular mass in the idebenone group vs the placebo group, with no improvement in other heart ultrasound measures or neurologic condition. The absolute cardiac changes were modest, but the findings suggest that larger trials should assess whether idebenone reduces ventricular hypertrophy in patients with Friedreich ataxia.

Neuropediatrics. 2002 Aug;33(4):190-3.
Friedreich's ataxia: idebenone treatment in early stage patients.

Artuch R, Aracil A, Mas A, Colome C, Rissech M, Monros E, Pineda M. Biochemistry Department, Hospital Sant Joan de Deu, University of Barcelona, Spain. rartuch@hsjdbcn.org

BACKGROUND: Antioxidant therapy has been applied to Friedreich's ataxia patients. We assessed the effect of idebenone treatment in patients with Friedreich's ataxia. METHODS: Design: open-label trial. Nine Friedreich's ataxia patients (age range 11 - 19 years) were treated with idebenone (5 mg/kg/day). Patients were evaluated before the start of the therapy and throughout one year of treatment by International Cooperative Ataxia Rating Scales (ICARS) scores, neurophysiological investigations and echocardiographic measurements. Serum idebenone concentrations were measured by HPLC with electrochemical detection. The number of GAA repeats at the frataxin gene was analyzed by PCR. RESULTS: Serum idebenone concentrations ranged between 0.04 - 0.37 micro mol/L. Significantly positive correlation was observed between idebenone values and the percentage of difference between the ICARS scores before and 12 months after the start of the therapy (r = 0.883; p = 0.002). Significant reduction was observed comparing the ICARS scores in baseline conditions and after 3 months of treatment (p = 0.017). No differences were observed in echocardiographic measurements after the start of the therapy. CONCLUSIONS: Cerebellar improvement was notable in mild patients after the first 3 months of therapy. Idebenone treatment at early stages of the disease seems to reduce the progression of cerebellar manifestations. Further blind trials with a greater number of patients and higher doses are needed to fully assess the therapeutic potential of idebenone in Friedreich's ataxia.

Neuropediatrics 2002 Aug;33(4):190-3
Friedreich's Ataxia: Idebenone Treatment in Early Stage Patients.

Artuch R, Aracil A, Mas A, Colome C, Rissech M, Monros E, Pineda M. Biochemistry Department, Hospital Sant Joan de Deu, University of Barcelona, Spain.

Background. Antioxidant therapy has been applied to Friedreich's ataxia patients. We assessed the effect of idebenone treatment in patients with Friedreich's ataxia. Methods. Design: open-label trial. Nine Friedreich's ataxia patients (age range 11 - 19 years) were treated with idebenone (5 mg/kg/day). Patients were evaluated before the start of the therapy and throughout one year of treatment by International Cooperative Ataxia Rating Scales (ICARS) scores, neurophysiological investigations and echocardiographic measurements. Serum idebenone concentrations were measured by HPLC with electrochemical detection. The number of GAA repeats at the frataxin gene was analyzed by PCR. Results. Serum idebenone concentrations ranged between 0.04 - 0.37 micro mol/L. Significantly positive correlation was observed between idebenone values and the percentage of difference between the ICARS scores before and 12 months after the start of the therapy (r = 0.883; p = 0.002). Significant reduction was observed comparing the ICARS scores in baseline conditions and after 3 months of treatment (p = 0.017). No differences were observed in echocardiographic measurements after the start of the therapy. Conclusions. Cerebellar improvement was notable in mild patients after the first 3 months of therapy. Idebenone treatment at early stages of the disease seems to reduce the progression of cerebellar manifestations. Further blind trials with a greater number of patients and higher doses are needed to fully assess the therapeutic potential of idebenone in Friedreich's ataxia.

Free Radic Res 2002 Apr;36(4):467-9
Heart hypertrophy and function are improved by idebenone in Friedreich's ataxia.

Rustin P, Rotig A, Munnich A, Sidi D. Unite de Recherches sur les Handicaps Genetiques de l'Enfant (INSERM U393), Hjpital Necker-Enfants Malades, Paris, France.

Friedreich's ataxia (FRDA) is a neuro-degenerative disease causing limb and gait ataxia and hypertrophic cardiomyopathy. It results from a triplet expansion in the first intron of the frataxin gene encoding a mitochondrial protein of yet unknown function. Cells with low frataxin content display generalized deficiency of mitochondrial iron-sulfur cluster-containing proteins, which presumably denotes overproduction of superoxide radicals in these organelles. Idebenone, a short-chain quinone, may act as a potent free radical scavenger protecting mitochondria against oxidative stress. We therefore carried out an open trial of idebenone (oral supplementation; 5mg/kg/day) in a large series of FRDA patients and followed their left ventricular mass and function. Consistent and definitive worsening being observed in the natural course of the disease and cardiac hypertrophy having no chance of spontaneous reversal and to be subject to a placebo effect, the patient's heart status before and after the treatment was used to unambiguously establish the effect of the drug. After six months, heart ultrasound revealed more than 20% reduction of left ventricular mass in about half of the patients (p < 0.001) and no significant change in the other half. Since any measurable reversion of this pathogenic trait is highly significant, this demonstrates the efficiency of idebenone in controlling heart hypertrophy in FRDA. Owing to the absence of side effects of the drug, idebenone (up to 15mg/kg/day) should be prescribed for FRDA patients continuously as early as possible.

Heart 2002 Apr;87(4):346-9
Idebenone and reduced cardiac hypertrophy in Friedreich's ataxia.

Hausse AO, Aggoun Y, Bonnet D, Sidi D, Munnich A, Rotig A, Rustin P. Service de Cardiologie Pediatrique, Hopital Necker-Enfants Malades, 149 rue de Sevres, Paris, France.

BACKGROUND: Friedreich's ataxia encodes a protein of unknown function, frataxin. The loss of frataxin is caused by a large GAA trinucleotide expansion in the first intron of the gene, resulting in deficiency of a Krebs cycle enzyme, aconitase, and of three mitochondrial respiratory chain complexes (I-III). This causes oxidative stress. Idebenone, a short chain quinone acting as an antioxidant, has been shown to protect heart muscle against oxidative stress in some patients. OBJECTIVE: To assess the efficiency of idebenone on cardiac hypertrophy in Friedreich's ataxia. DESIGN: Prospective, open trial. SETTING: Tertiary care centre. METHODS: Idebenone (5 mg/kg/day) was given orally to 38 patients with Friedreich's ataxia aged 4-22 years (20 males, 18 females). Cardiac ultrasound indices were recorded before and after idebenone treatment. RESULTS: After six months, cardiac ultrasound indicated a reduction in left ventricular mass of more than 20% in about half the patients (p < 0.001). The shortening fraction was initially reduced in six of the 38 patients (by between 11-26%) and it improved in five of these. In one patient, the shortening fraction only responded to 10 mg/kg/day of idebenone. No correlation was found between responsiveness to idebenone and age, sex, initial ultrasound indices, or the number of GAA repeats in the frataxin gene. CONCLUSIONS: Idebenone is effective at controlling cardiac hypertrophy in Friedreich's ataxia. As the drug has no serious side effects, there is a good case for giving it continuously in a dose of 5-10 mg/kg/day in patients with Friedreich's ataxia at the onset of hypertrophic cardiomyopathy.

J Inherit Metab Dis 2001 Feb;24(1):28-34
Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone.

Lerman-Sagie T, Rustin P, Lev D, Yanoov M, Leshinsky-Silver E, Sagie A, Ben-Gal T, Munnich A. Mitochondrial Disease Clinic, Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel.

Idebenone, a synthetic analogue of coenzyme Q10, has been shown to improve cardiac function in patients with Friedreich ataxia and a deficiency of respiratory chain complexes I-III. We describe a woman with severe combined right and left heart failure due to a mitochondrial cardiomyopathy. The patient underwent an endomyocardial biopsy as part of an evaluation for cardiac transplantation. It showed severely decreased respiratory complex activities dependent on CoQ, pointing to CoQ depletion. Following idebenone treatment there was a dramatic improvement in her clinical status with resolution of the heart failure.


Source: Medline

Edited by LifeMirage, 28 October 2003 - 09:17 AM.

[LifeMirage]

Idebenone In Leber's Hereditary Optic Neuropathy & MELAS

J Neurol Sci 1997 May 1;148(1):25-31
Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study.

Cortelli P, Montagna P, Pierangeli G, Lodi R, Barboni P, Liguori R, Carelli V, Iotti S, Zaniol P, Lugaresi E, Barbiroli B. Institute of Neurology, University of Bologna, Italy.

We used phosphorus magnetic resonance spectroscopy (31P-MRS) to study in vivo brain and muscle bioenergetics in a male patient with Leber's hereditary optic neuropathy (LHON) and mtDNA mutation at 11,778 bp who developed spastic paraparesis with white matter lesions on brain MR imaging. The study was performed before and during treatment with idebenone (135 mg t.i.d.) and after withdrawal. Clinical amelioration and worsening were associated with parallel changes in brain and skeletal muscle bioenergetics following the administration or withdrawal of idebenone. Reversal of paraparesis by idebenone was paralleled by normalization of 31P-MRS, serum lactate and central motor conduction. Extra-ocular neurological dysfunction in LHON may be amenable to treatment by appropriate quinones.

Neurol Sci 2000;21(5 Suppl):S981-2
Long-term treatment with idebenone and riboflavin in a patient with MELAS.

Napolitano A, Salvetti S, Vista M, Lombardi V, Siciliano G, Giraldi C. Division of Neurology, Campo di Marte Hospital, I-55100 Lucca, Italy.

We report a patient with MELAS treated for 24 months with idebenone and riboflavin, during which no stroke-like episodes occurred. Moreover neurological symptoms clearly improved, and a recovery of brain MRI and EEG abnormalities was observed. We conclude that the combined treatment with idebenone and riboflavin may restore the metabolic impairment in MELAS, possibly improving the long-term prognosis in these patients.

J Neuroophthalmol 2000 Sep;20(3):166-70
Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?

Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

OBJECTIVES: The authors investigated the effectiveness of idebenone combined with vitamins B2 & C in the treatment of patients with Leber hereditary optic neuropathy (LHON) in an early stage as compared with untreated patients with LHON. These agents may stimulate the formation of ATP. MATERIALS AND METHODS: For this retrospective study, the authors selected 28 outpatients with LHON from the Keio University Hospital. These patients were followed for 2 to 19 years from disease onset. They were divided into two groups: 14 untreated patients (11778 mutation in 10 patients, 3460 mutation in 2 patients, and 14484 mutation in 2 two patients); and 14 treated patients (11778 mutation in 11 patients, 3460 mutation in 1 patient, and 14484 mutation in 2 patients). The treated patients were administered medical treatment with idebenone, vitamin B2, and vitamin C for at least 1 year. The current study evaluated the following: 1) number of eyes with visual recovery > or = 0.3; 2) interval between the onset of LHON and the beginning of visual recovery; 3) interval between the onset of LHON and visual recovery to 0.3; and 4) interval between the beginning of medical treatment and the beginning of visual recovery in the treated subjects. RESULTS: There was no significant difference in the number of eyes with visual recovery > or = 0.3 in the two groups with the 3460, 11778, or 14484 mutation. Patients with visual recovery showed a fenestrated scotoma or a clearing of central vision. The mean interval between the onset of LHON and the beginning of visual recovery was significantly shorter in the treated group (11.1 months) than in the untreated group (17.4 months) (P = 0.03). The mean interval between the onset of LHON and visual recovery to 0.3 was significantly shorter in the treated group (17.6 months) than in the untreated group (34.4 months) (P = 0.01). The mean interval between the initiation of medical treatment to the beginning of visual recovery was 5.4 months. CONCLUSIONS: Results suggest that the administration of idebenone & vitamins B2 & C sped the recovery of vision in patients with LHON.

Neurology 1996 Aug;47(2):583-5
Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS.

Ikejiri Y, Mori E, Ishii K, Nishimoto K, Yasuda M, Sasaki M. Division of Clinical Neurosciences, Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan.

We report a 36-year-old man with MELAS in whom a 5-month course of high-dose oral idebenone, a derivative of coenzyme Q10, increased markedly cerebral metabolic ratio of oxygen and oxygen extraction fraction without increased cerebral blood flow with PET. The results indicate that idebenone improves mitochondrial oxidative metabolism in the brain and suggest a therapeutic potential of idebenone for MELAS.


Source: Medline

Edited by LifeMirage, 28 October 2003 - 09:17 AM.

[LifeMirage]

6 newly published studies have been added. Including the following:


Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):279-86.
Effects of idebenone in elderly subjects with cognitive decline. Results of a multicentre clinical trial.

Bergamasco B, Villardita C, Coppi R.

III Neurologic Clinic, University of Turin, Italy.

A randomized, multicentre study on idebenone vs. oxiracetam was carried out in order to evaluate the therapeutic efficacy of idebenone in subjects with senile cognitive decline. Seventy-nine patients were enrolled: 39 treated with idebenone 45 mg twice daily p.o. and 40 treated with oxiracetam 800 mg twice daily p.o. Idebenone proved to be more effective and was shown to be statistically significant in the following test: SCAG, Rey's 15 Words, Gottfries Rating Scale. The greater efficacy of idebenone was confirmed by the efficacy judgement given by the investigators. The tolerability of both treatments can be said to be most satisfactory: none of the patients left the study because of side-effects. No significant variations were observed in the vital signs.


Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):261-9.
Long-term idebenone treatment of vascular and degenerative brain disorders of the elderly.

Nappi G, Bono G, Merlo P, Denaro A, Proietti R, Martucci N, Fioravanti M.

Department of Neurology, C. Mondino Foundation, University of Pavia, Pavia, Italy.

A multicentre study with an open experimental design was carried out on 118 patients suffering from mild to moderate cognitive decline due to cerebrovascular and degenerative disorders (chronic cerebrovascular disorders, CCVD; multi-infarct dementia, MID; aging brain, AB; dementia of Alzheimer's type, DAT). All patients, after a wash-out period of 3 weeks, were treated with idebenone (45 mg twice daily by oral route) for a period of 6 months. Behavioral and cognitive measures (Sandoz Clinical Assessment of Geriatrics, SCAG; Serial Learning Test) were applied to evaluate the long term therapeutical aspects. The results, analyzed by multivariate analysis of variance and chi2 test, showed a significant improvement of the cognitive profile in all patients, more evident in CCVD and AB groups. No remarkable side-effects were found in all groups of patients, thus confirming good tolerability of idebenone.