Abstracts
Results
Results
Forty patients have been treated so far. All of them exhibited a pronounced drop of their disability score. The patients' ages ranged from 48 to 85, duration of the disease ranged from 2 to 20 years. The overall improvement of the disability of all patients was 46.25%. A very good response was exhibited in 65% of the patients: more than 30% improvement of disability, 35% of the patients a moderate benefit of up to 30%.
Walking and pushing ability improved considerably as did posture, speech, and mimics. The action of NADH lasted between 1 and 4 days, depending on the severity of the symptoms. Withdrawal of NADH led to a relapse with worsening of disability. About one-fifth of the patients did well on NADH alone, and LD-therapy could be omitted. In the other patients the LD dosage could be reduced materially. Fifteen patients have been examined with regard to the duration of the daily pattern of phases. The daily 'on' phases could be increased by 6 to 10 hr. In a number of patients so examined, the urine level of the dopamine metabolite HVA was markedly increased. Such HVA increase is also observed after treatment with LD. As NADH is not a precursor of LD, it seems most likely that it stimulates endogenous LD biosynthesis.
Discussion
Discussion
The beneficial clinical effect of NADH on the disability of Parkinsonian patients has been demonstrated. A possible mechanism by which this may occur is shown in the simplified pathway of LD biosynthesis. L-Dopa is formed from tyrosine by the enzyme TH. This is an iron-containing enzyme with H4Biopterin as coenzyme. H4Biopterin provides electrons to reduce molecular oxygen and is in turn oxidized to the quinonoid-H2-pterin. The dihydropteridine reductase (DHPR) regenerates H4biopterin. The cofactor of this enzyme is NADH.13 H4Biopterin in brain and in cerebrospinal fluid of PD patients is reduced.6 This H4biopterin deficiency could be due either to a decreased biosynthesis or to a lack in the biologically active form of H4biopterin. It could well be that H4biopterin is exhausted in Parkinsonian patients because of an enormous consumption, perhaps caused by a toxic agent.
The idea is derived from the observation that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that can induce Parkinsonism in men and animals, inhibits DHPR, the enzyme which regenerates tetrahydrobiopterin, the coenzyme required for endogenous dopamine formation.14 MPTP seems to be a competitive inhibitor of DHPR with respect to NADH. If this is so, NADH should be able to neutralize the toxic effect of MPTP or other free radical-inducing agents. There are two arguments in favor of our hypothesis. First, the clinical effect of NADH closely resembles that of LD, indicating that this coenzyme stimulates the endogenous LD biosynthesis. Second, the improvement in the clinical symptoms parallels an increase in the urine level of HVA, which also has been found with the standard LD therapy.
Birkmayer: The Clinical Benefit Of NADH as Stimulator of Endogenous L-Dopa Biosynthesis in Parkinsonian Patients. In: Streifler, M.B., A.D. Korczyn, E. Melamed, and M.B.H. Youdim (Eds): Advances in Neurology, Vol. 53: Parkinson's Disease:Anatomy, Pathology, and Therapy, edited by, Raven Press, New York 1990.
NADH was used as medication in an open label trial with Parkinsonian patients (#885). A beneficial effect occurred in 80%.
20% Very good
60% Moderate
20% non responders
A shorter duration of disease correlated with more marked improvements.
The oral form was comparable to the parenterally applied version.
Birkmayer JGD, et al., Nicotinamide adenine dinucleotide (NADH) - a new therapeutic approach to Parkinson's disease. Comparison of oral and parenteral application. Acta Neurol. Scand. 1993 146S:32-35.
Parkinson's Disease
Parkinson's Disease
Treatment of "Parkinson's disease" with L-"dopa" (LD) in combination with decarboxylase and "monoamine oxidase inhibitors" is a pure substitutional therapy designed to correct the lack of "dopamine" in the "brain". The dopamine deficit is caused by the diminished "tyrosine" hydroxylase (TH) in the substantia nigra. However, catecholamines such as dopamine and its precursor LD inhibit TH via a feedback mechanism. This suggests that application of LD to PD patients may further decrease the already reduced TH activity. Therefore, therapeutic strategies other than substitution have to be considered, e.g., stimulation of endogenous dopamine production in the brain.
This may be achieved by activating the LD producing "enzyme". As shown by Nagatsu et al., this enzyme is an "iron"-containing "protein" with tetrahydrobiopterin (H4biopterin) as coenzyme. H4biopterin is reduced in the brain of PD patients and has therefore been used in clinical trials, but with only partial success. On the other hand, it has been shown that the special iron compound oxyferriscorbone is able to improve the symptoms of Parkinsonian patients suggesting production of endogenous LD in the brain of Parkinsonians.
The stimulation of LD biosynthesis is reflected by an increase in the "urine" level of homovanillic acid (HVA).8 We believe that this occurs by TH activation by the iron compound oxyferriscorbone, because there is no other enzyme except TH which catalyzes LD formation, and it also has been shown that this enzyme can be markedly activated "in vitro" by iron. Our findings have already been confirmed.
After long-term iron medication, however, its effectiveness subsides in some patients. This prompted us to look for other therapeutic modalities. Our choice was "nicotinamide adenine dinucleotide" (NADH), which promotes the formation of H4 biopterin, the active coenzyme of tyrosine hydroxylase.
Materials and Methods
Diagnosis and disability scores of the Parkinsonian patients were established according to the method of Birkmayer and Neumayr.
Nicotinamideadeninedinucleotide, reduced form disodium "salt" (synonyms: beta-NADH, reduced DPN, beta-DPNH), was purchased from Sigma Diagnostics (St. Louis, Missouri). Twenty-five mg of NADH were dissolved in 100 ml of 0.9% sterile "sodium" "chloride", pH 7.4, and infused intravenously in 30 min. NADH solutions were always prepared fresh immediately prior to use. Disability scores were determined before, 1 hr after, and 4 hrs. after the NADH infusion.
Genotypes in Parkinson's Disease
Genotypes in Parkinson's Disease
Genotype confers increased susceptibility to Parkinson's disease.
Kosel, S. et al., NADH dehydrogenase and CYP2D6 genotypes in Parkinson's disease. 2nd workshop Neurogenetics, Munich, Germany, October 19-21, 1995.
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