Dr. Ron’s Research Review – August 19, 2015

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This week’s research review focuses on P5P and Parkinson's disease.

Carbidopa (Lodosyn) is prescribed in Parkinson's to inhibit peripheral metabolism of levodopa. Carbidopa and benserazide are indicated for the management of L-dopa)-induced nausea.
Both carbidopa and benserazide irreversibly bind to and permanently deactivate P5P, the active form of vitamin B6. (Hinz et al., 2014a) (Hinz et al., 2014b)
During the first 15 years of prescribing L-dopa, a decreasing Parkinson's disease death rate was observed. Then, in 1976, 1 year after US FDA approved the original L-dopa/carbidopa combination, the PD death rate started increasing. This trend has continued to the present, for 38 years and counting. (Hinz et al., 2014a)

A study published in Neurology examined 40 individuals diagnosed with idiopathic PD who were being treated as outpatients at the Boston University Medical Center Neurology Clinic. Twenty of the patients were on L-dopa therapy (treatment group) and 20 were L-dopa-naive (control group). (Miller et al., 2003)
The mean plasma homocysteine concentration was higher in the treatment group than in the controls (p = 0.018) and was correlated with plasma folate, vitamin B(12), and PLP concentrations. L-Dopa can cause hyperhomocysteinemia, and the B-vitamin requirements necessary to maintain normal plasma homocysteine concentrations are higher in L-dopa-treated patients than in those not on L-dopa therapy.   

Dr. Ron


 

Articles

The Parkinson's disease death rate: carbidopa and vitamin B6.
            (Hinz et al., 2014a) Download
The only indication for carbidopa and benserazide is the management of L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson's disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson's disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson's disease death rate and to the classification of Parkinson's as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis.

Parkinson's disease: carbidopa, nausea, and dyskinesia.
            (Hinz et al., 2014b) Download
When l-dopa use began in the early 1960s for the treatment of Parkinson's disease, nausea and reversible dyskinesias were experienced as continuing side effects. Carbidopa or benserazide was added to l-dopa in 1975 solely to control nausea. Subsequent to the increasing use of carbidopa has been the recognition of irreversible dyskinesias, which have automatically been attributed to l-dopa. The research into the etiology of these phenomena has identified the causative agent of the irreversible dyskinesias as carbidopa, not l-dopa. The mechanism of action of the carbidopa and benserazide causes irreversible binding and inactivation of vitamin B6 throughout the body. The consequences of this action are enormous, interfering with over 300 enzyme and protein functions. This has the ability to induce previously undocumented profound antihistamine dyskinesias, which have been wrongly attributed to l-dopa and may be perceived as irreversible if proper corrective action is not taken.


 

Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status.
            (Miller et al., 2003) Download
BACKGROUND: The antiparkinsonian drug L-dopa causes increased cellular synthesis of homocysteine and consequent hyperhomocysteinemia in rats. This effect of L-dopa on plasma homocysteine is accentuated under conditions of impaired homocysteine metabolism such as folate deficiency. OBJECTIVE: To investigate the effect of L-dopa administration and B-vitamin status on plasma homocysteine concentrations in humans with PD. METHODS: Plasma homocysteine, folate, vitamin B(12), and pyridoxal-5'-phosphate (PLP) concentrations were determined in 40 individuals diagnosed with idiopathic PD who were being treated as outpatients at the Boston University Medical Center Neurology Clinic. Twenty of the patients were on L-dopa therapy (treatment group) and 20 were L-dopa-naive (control group). RESULTS: The mean plasma homocysteine concentration was higher in the treatment group than in the controls (p = 0.018). Plasma homocysteine was correlated with plasma folate, vitamin B(12), and PLP concentrations in the treatment group (p <or= 0.007) but not in the controls. CONCLUSION: L-Dopa can cause hyperhomocysteinemia in PD patients, the extent of which is influenced by B-vitamin status. The B-vitamin requirements necessary to maintain normal plasma homocysteine concentrations are higher in L-dopa-treated patients than in those not on L-dopa therapy. B-Vitamin supplements may be warranted for PD patients on L-dopa therapy.

 

References

Hinz, M, A Stein, and T Cole (2014a), ‘The Parkinson’s disease death rate: carbidopa and vitamin B6.’, Clin Pharmacol, 6 161-69. PubMedID: 25364278
——— (2014b), ‘Parkinson’s disease: carbidopa, nausea, and dyskinesia.’, Clin Pharmacol, 6 189-94. PubMedID: 25484598
Miller, JW, et al. (2003), ‘Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status.’, Neurology, 60 (7), 1125-29. PubMedID: 12682318