Nicotinamide adenine dinucleotide (NADH)--a new therapeutic approach to Parkinson's disease. Comparison of oral and parenteral application.

The reduced coenzyme nicotinamide adenine dinucleotide (NADH) has been used as medication in 885 parkinsonian patients in an open label trial. About half of the patients received NADH by intravenous infusion, the other part orally by capsules. In about 80% of the patients a beneficial clinical effect was observed: 19.3% of the patients showed a very good (30-50%) improvement of disability, 58.8% a moderate (10-30%) improvement. 21.8% did not respond to NADH. Statistical analysis of the improvement in correlation with the disability prior to treatment, the duration of the disease and the age of the patients revealed the following results: All these 3 parameters have a significant although weak influence on the improvement. The disability before the treatment has a positive regression coefficient (t value < 0.01). The duration of the disease has a negative regression coefficient (< 0.01) and so has the age a negative regression coefficient (t value < 0.05). In other words younger patients and patients with a shorter duration of disease have a better chance to gain a marked improvement than older patients and patients with longer duration of the disease. The orally applied form of NADH yielded an overall improvement in the disability which was comparable to that of the parenterally applied form.

The coenzyme nicotinamide adenine dinucleotide (NADH) improves the disability of parkinsonian patients.

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used in an open label trial as novel medication in 34 patients with Parkinson's disease, using an intravenous administration technique. In all patients a beneficial clinical effect was observed. 21 patients (61.7%) showed a very good (better than 30%) improvement of disability, 13 patients (38.3%) a moderate (up to 30%) improvement. Concomitant with the improvement of the disability the urine level of homovanillic acid (HVA) increased significantly in all patients (in some patients by more than a 100%). The daily "on phases" of the patients could be increased from 2 up to 9 hours in the individual patients by NADH administration.

Strategy and tactic of modern Parkinson therapy.

The aim of modern Parkinson therapy is to overcome the dopamine deficit in the brain of parkinsonian patients which is the cause of their motor disability. This can be achieved in two ways: (a) substitution of the lacking dopamine by l-dopa, or (b) stimulation of the endogenous biosynthesis by activating the enzyme tyrosine hydroxylase. The latter approach is possible by the iron compound oxyferriscorbone or by the coenzyme nicotinamide adenine dinucleotide (NADH). In addition to these two major medications the essential therapeutic additives such as the decarboxylase inhibitor benserazide, the monoamineoxidase B inhibitor deprenyl and the dopamine receptor agonist lisuride should be used for the fine adjustment of the individual patient.

Nicotinamidadenindinucleotide (NADH): the new approach in the therapy of Parkinson's disease.

The coenzyme Nicotinamidadenindinucleotide (NADH) has been used as novel medication in 34 Parkinson patients in an open label trial. In all patients, a beneficial clinical effect was observed. Twenty-one patients (61.7 percent) showed a very good (better than 30 percent) improvement of disability and 13 patients (38.3 percent) a moderate (up to 30 percent) improvement. The effect of NADH was dependent on the dosage and the severity of the case. The best therapeutic dose was in the range of 25 to 50 mg per day. The clinical improvement was more pronounced after i.v. and less after i.m. administration. Concomitant with improvement of the disability, the urine level of homovanillinic acid (HVA) increased significantly in all patients (in some patients by more than a 100 percent), indicating a stimulation of the endogenous L-DOPA biosynthesis. The daily "on phases" of the patients could be increased from two up to nine hours in the individual patients by NADH administration.

Stimulation of endogenous L-dopa biosynthesis--a new principle for the therapy of Parkinson's disease. The clinical effect of nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotidephosphate (NADPH).

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used as a novel medication in 161 Parkinson patients in an open label trial. In all but 18 patients (11.2%) an improvement in their disability was observed. 115 patients (71.4%) showed a very good (better than 30%) response, and 28 patients (17.4%) a moderate response up to 30%. The best results were obtained with a dose of 25 to 50 mg every second day by i.v. administration. Concomitantly with the improvement in disability, the urine HVA level increased significantly, indicating a stimulation of endogenous L-DOPA biosynthesis. 8 patients have been treated with nicotinamide adenine dinucleotidephosphate (NADPH), 5 of whom exhibited an improvement in their disability from 35 to 55%. The other 3 showed a moderate response of 20 to 25%. In all these patients an increase in the urine level of HVA was detected, reflecting elevated endogenous L-DOPA production.

Improvement of disability and akinesia of patients with Parkinson's disease by intravenous iron substitution.

Akinetic crises are one of the problems arising in patients with Parkinson's disease in particular after long term treatment with levo-dihydroxyphenylalanine (L-DOPA). They are characterized by severe disability to move. Increasing dosages of L-DOPA and decarboxylase or monoaminooxidase inhibitors do not improve these symptoms. Intravenously applied iron in the form of a ferri-ferro-complex exhibits a considerable benefit for all patients treated so far. They regained a remarkable mobility. Their disability score dropped from up to 90 percent down to 30 percent. The effect is dosage-dependent, and withdrawal of iron will lead again to akinetic crises.

Dopamine action and disorders of neurotransmitter balance.

Disorders of neurotransmitter balance are observed in Parkinson's disease, pharmacotoxic psychosis and depression. The dopamine-serotonin ratio is reduced to about 20% in Parkinson and pharmacotoxic patients in the caudate nucleus and in the substantia nigra. The serotonin content in these brain areas is lowered only to about 50% in comparison to that of the control, whereas the dopamine level is reduced to 85% in Parkinson patients. This dopamine deficiency has been substituted by exogenous supply of L-dopa in combination with decarboxylase and monoaminooxydase inhibitors. First evidence is presented that L-dopa can be replaced, at least partially, by iron in form of a ferriascorbate complex. This iron compound improves the symptoms of Parkinson's disease to almost the same extent as L-dopa.

[Clinical picture of Parkinson disease]. / Das klinische Bild der Parkinson-Krankheit.

The clinical pattern of symptoms consists of motor disorders (akinesia, tremor, rigor), emotional disorders (depression, abnormal behaviour), autonomic disorders (sweating, salivation, seborrhoea, constipation) and intellectual disorders (bradyphrenia, Alzheimer's dementia)

[Therapeutic strategies and tactics in parkinsonism]. / Therapeutische Strategie und Taktik.

The main medication is Madopar and Sinemet; various additives are able to reduce the Dopa dose in order to avoid various side effects. Additives: Deprenil (Jumex), Amantadin derivatives) Symmetrell, PK Merz, Hofkomant). Furthermore Dopamin agonists (Umprel, Dopergin). Delpral for dyskinesias. Driving antidepressive in the morning (Noveril, Dixeran, Tofranil). In the evening tranquillizing antidepressive like Tryptizol, Saroten, Sinequan, Ludiomil, Tolvon. Anticholinergica for Salivation, L-Tryptophan in hot environment.

Effect of (-)deprenyl in long-term treatment of Parkinson's disease. A 10-years experience.

The effect of (-)deprenyl as additive to a Madopar treatment of parkinsonian patients has been investigated in a retrospective study over the past ten years. 941 patients have been evaluated. Addition of (-)deprenyl to the standard Madopar treatment resulted in an improvement of the disability, in a prolongation of life expectancy, in a reduction of side effects caused by Madopar and a leveling down of the fluctuations in the clinical improvement. In addition the time from the onset of Parkinson's disease to significantly longer in the group of patients which were treated with Madopar and (-)deprenyl in combination.

Iron, a new aid in the treatment of Parkinson patients.

One of the problems in treating Parkinson patients is the so called "off-effect" which occurs after long term treatment with L-DOPA. Off-effects are characterized by severe rigor and akinesia. Increasing dosages of L-DOPA and decarboxylase- or monoaminooxidase-inhibitors do not improve these symptoms. Intravenously applied iron--in form of a ferri-ferro-complex--exhibited a considerable benefit for all patients treated so far. They regained a remarkable mobility. Their disability score dropped from up to 90% down to 30%. The effect of iron is dosage-dependent and lasts 24 to 48 hours.

Biological aspects of depression in Parkinson's disease.

A clinical survey indicates a similar incidence of depression in old age and Parkinson's disease. Divergences, therefore, are apparent, when the biochemical basis of depression is related to the pathobiology of Parkinson's disease (PD) and endogenous depression. However, a common biological concept for endogenous depression and depression in PD is possible by assuming that neurotransmission can operate at various levels of homeostasis. Then depression is the behavioral correlate rather of regional changes that disturb this homeostasis. Therefore, the incidence of depression in old age and PD is similar.

Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study.

In an open, uncontrolled study the longterm (9 years) effect of treatment with Madopar alone (n = 377) or in combination with l-deprenyl (selegiline, selective monoamine oxidase type B inhibitor) (n = 564) have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of l-deprenyl resulted in a significant recouping of levodopa effect. The survival analysis revealed a significant increase of life expectancy in Madopar--l-deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account. Although the mechanism underlying this action of l-deprenyl is not known, the results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons. l-Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not far fetched since l-deprenyl selectively prevents the degeneration of striatal dopaminergic neurons induced in animals by the illicit drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since latter compound is known to cause Parkinsonism in man and primates or Parkinson-like neurochemical and pathological changes in other animals the implications of the present study involving monoamine oxidase activity and l-deprenyl are apparent.

L-deprenyl plus L-phenylalanine in the treatment of depression.

The antidepressive efficacy of 1-deprenyl (5-10 mg daily) plus 1-phenylalanine (250 mg/day) has been evaluated in 155 unipolar depressed patients. Both oral and intravenous administration showed beneficial effects in 90% of outpatients and 80.5% of inpatients. It is concluded that this combined treatment has a potent antidepressive action based on the accumulation of 1-phenylethylamine in the brain.