A New Therapeutic Approach for Improving Dementia of the ALZHEIMER TYPE

TWO MAIN STRATEGIES:
For the time being, two main strategies are followed in the treatment of dementia. One approach is to increase the concentration of the neurotransmitter acetylcholine, a substance which is assumed to play an important role in cognitive processes and which is reduced in certain brain areas of dementia patients. As acetylcholine is degraded by the enzyme acetylcholinesterase, it is assumed that inhibitors of these enzymes may lead to an increase in acetylcholine concentration in the brain.

All acetylcholinesterase inhibitors in therapeutic trials, such as Tacrine, follow this strategy. However, as the enzyme itself is reduced in the brain of Alzheimer patients ( ¹² ), the question is whether or not a further inhibition may have a beneficial effect. As already outlined, not only acetylcholine but also other neurotransmitters, such as dopamine and noradrenaline, are considerably reduced in the brain of dementia patients. Therefore, only the inhibition of acetylcholine degradation may not be sufficient to alleviate the symptoms of dementia.

A different therapeutic approach is to stabilize the membrane of nerve cells in order to prevent its breakdown and, owing to this, the degeneration of certain brain areas. This concept seems reasonable in terms of preserving certain brain regions and may stop the progression of the dementia. Substances used in that direction are the phospholipids phosphatidylcholine and phosphatidylserine. Phospholipids are involved in the transport of biological information across membranes as well as in the production and release of locally acting messenger molecules ( ³¹ ).

The concept of using NADH as an anti-dementia agent follows a strategy which differs from the approaches mentioned previously. The NADH seems to act in two ways. One is the stimulation of the endogenous biosynthesis of dopamine and noradrenaline ( ²⁶ ). The other is an increase in energy production of cells in the brain and in the periphery. This effect may lead to higher capacity in the metabolic performance. In addition, NADH can be regarded as an energy substitute. It is itself a very energy rich compound. One mol of NADH will form 3 moles of adenosine triphosphate (ATP) which is equivalent to energy of 36 kilocalories. In order to provide the cell with additional energy, NADH has to enter the cell and the mitochondria to reach the target of its actions. Preliminary experiment with radio-labeled NADH indicates that this seems to be the case. It should be noted that NADH, known also as Coenzyme I, in its reduced form is a physiological substance which not only occurs in all cells of the human body but in all living cells whatsoever.

For example, human red blood cells contain 3.5 micro-gram/ gram skeletal muscles and brain tissue contain 50 micro-gram/gram of tissue. Our patients were treated with 10 mg of NADH daily. This is only a very low percentage of the total NADH content of the body. Nevertheless, safety of NADH should be considered with priority. In this regard, extensive toxicology studies performed at the Corning Hazelton laboratories in England before starting this clinical pilot study revealed that the maximum tolerated dosage of NADH is 500 mg/Kg body weight per day. Dogs were treated with a intravenous dose of 500 mg/kg for 14 days. There were no deaths. Some of the treated animals were frequently subdued and had pale gums. Some of them had warm ears and dry noses. In some animals the blood pressure was lower than before dosing which indicated that at this high dose level the cardiovascular system is influenced.

DOSAGE:
The dosage given to our patient is 10 mg per patient per day. With an average weight of 70 kg per patient, a dosage level of 0.14 mg NADH per kg of body weight is obtained, which is our therapeutic dosage. Hence, the maximum tolerated dose in dogs is a more than 7,000 times higher than the dose being given to our patients. In a further subacute toxicity study, beagle dogs received 150 mg NADH per kg body weight in oral form. In other words, a 10 kg heavy beagle dog received 1500 mg of the oral form of NADH or 300 tablets containing 5 mg NADH. The results of this study showed there were no deaths. Body weight and food consumption were considered to be unaffected by the treatment with NADH. The electrocardiography traces did not show any treatment-related changes. The hematology and the clinical chemistry parameters measured were not affected by the treatment, and there were no gross or microscopic findings suggestive of toxicity in the organs or tissues examined.

In a further study, rats received 1 tablet of 5 mg NADH per dose every day for six months. This corresponds to 25 mg/kg body weight, an amount which is about 180 times higher than the therapeutic dose used in our patients.

All parameter examined, such as food uptake, body weight, and laboratory parameters, were not affected by the NADH treatment. There were no microscopic findings suggestive of organ or tissue toxicity.

The number of patients evaluated in our study make up a rather low number, and no definitive conclusion may be drawn. This first trial can be regarded as pilot study without placebo controls. Pharmacokinetic and other pre-clinical data are now being collected in order to fulfill the requirements for a double blind placebo controlled study by the United States government..

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