The Peripheral Levodopa Project: 2017

M. Hintz has written many papers discussing his theories regarding peripheral levodopa therapy, and his views on carbidopa and novel alternative PD treatments. While his papers have caused some controversy, and even notable backlash, nevertheless I think they are worth examining. In particular, the cited references appear to point towards a deeper understanding of peripheral systems impacting PD.

Amino acid management of Parkinson’s disease: a case study
https://www.dovepress.com/amino-acid-management-of-parkinsonrsquos-disease-a-case-study-peer-reviewed-article-IJGM

Parkinson’s disease managing reversible neurodegeneration
https://www.dovepress.com/parkinsonrsquos-disease-managing-reversible-neurodegeneration-peer-reviewed-fulltext-article-NDT

Parkinson’s disease-associated melanin steal
https://www.dovepress.com/parkinsonrsquos-disease-associated-melanin-steal-peer-reviewed-fulltext-article-NDT

Relative nutritional deficiencies associated with centrally acting monoamines
https://www.dovepress.com/relative-nutritional-deficiencies-associated-with-centrally-acting-mon-peer-reviewed-article-IJGM

The discrediting of the monoamine hypothesis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282597/

APRESS: apical regulatory super system, serotonin, and dopamine interaction
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157489/

The Parkinson's disease death rate: carbidopa and vitamin B6
https://www.dovepress.com/the-parkinson39s-disease-death-rate-carbidopa-and-vitamin-b6-peer-reviewed-fulltext-article-CPAA

citations:

1.	National Parkinson Foundation [webpage on the Internet]. What is Parkinson’s disease? Miami, FL: National Parkinson Foundation; 2014. Available from: http://www.parkinson.org/parkinson-s-disease/pd-101/what-is-parkinson-s-disease. Accessed July 19, 2014.
2.	Mayo Clinic [webpage on the Internet]. Diseases and conditions: Parkinson’s disease. Rochester, MN: Mayo Clinic; 2014. Available from: http://www.mayoclinic.org/diseases-conditions/parkinsons-disease/basics/treatment/con-20028488. Accessed July 19, 2014.
3.	SINEMET CR (carbidopa and levodopa) tablet, extended release [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc.; 2014. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=69e575b9-f8a5-494f-b736-2520ef505cb0. Accessed July 1, 2014.
4.	US Food and Drug Administration [webpage on the Internet]. Drugs@FDA: FDA approved drug products. Silver Spring, MD: US Food and Drug Administration; 2014. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed July 19, 2014.
5.	Airoldi L, Watkins CJ, Wiggins JF, Wurtman RJ. Effect of pyridoxine on the depletion of tissue pyridoxal phosphate by carbidopa. Metabolism. 1978;27(7):771–779.
6.	Hoyert DL, Heron MP, Murphy SL, Kung H. National Vital Statistics Report. Deaths: Final Data for 2003. Hyattsville, MD: National Center for Health Statistics; 2006. Available from: http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_13.pdf. Accessed July 1, 2014.
7.	Daidone F, Montioli R, Paiardini A, et al. Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors. PLoS One. 2012;7(2):e31610.
8.	Andrews DW, Patrick RL, Barchas JD. The effects of 5-hydroxytryptophan and 5-hydroxytryptamine on dopamine synthesis and release in rat brain striatal synaptosomes. J Neurochem. 1978;30(2):465–470.
9.	Awazi N, Guldberg HC. On the interaction of 5-hydroxytryptophan and 5-hydroxytryptamine with dopamine metabolism in the rat striatum. Naunyn Schmiedebergs Arch Pharmacol. 1978;303(1):63–72.
10.	Hinz M. Depression. In: Kohlstadt I, editor. Food and Nutrients in Disease Management. Baton Rouge, FL: CRC Press; 2009:465–481.
11.	Hinz M, Stein A, Uncini T. The dual-gate lumen model of renal monoamine transport. Neuropsychiatr Dis Treat. 2010;6:387–392.
12.	Hinz M, Stein A, Uncini T. Amino acid management of Parkinson’s disease: a case study. Int J Gen Med. 2011;4:165–174.
13.	Hinz M, Stein A, Uncini T. Relative nutritional deficiencies associated with centrally acting monoamines. Int J Gen Med. 2012;5:413–430.
14.	Hinz M, Stein A, Uncini T. APRESS: apical regulatory super system, serotonin, and dopamine interaction. Neuropsychiatr Dis Treat. 2011;7:457–463.
15.	Stein A, Hinz M, Uncini T. Amino acid-responsive Crohn’s disease: a case study. Clin Exp Gastroenterol. 2010;3:171–177.
16.	Hinz M, Stein A, Neff R, Weinberg R, Uncini T. Treatment of attention deficit hyperactivity disorder with monoamine amino acid precursors and organic cation transporter assay interpretation. Neuropsychiatr Dis Treat. 2011;7:31–38.
17.	Hinz M, Stein A, Trachte G, Uncini T. Neurotransmitter testing of the urine: a comprehensive analysis. Open Access J Urol. 2010;2:177–183.
18.	Hinz M, Stein A, Uncini T. A pilot study differentiating recurrent major depression from bipolar disorder cycling on the depressive pole. Neuropsychiatr Dis Treat. 2010;6:741–747.
19.	Zhelyaskov DK, Levitt M, Udenfriend S. Tryptophan derivatives as inhibitors of tyrosine hydroxylase in vivo and in vitro. Mol Pharmacol. 1968;4(5):445–451.
20.	Ng LK, Chase TN, Colburn RW, Kopin IJ. Release of (3 H)dopamine by L-5-hydroxytryptophan. Brain Res. 1972;45(2):499–502.
21.	Stamford JA, Kruk ZL, Millar J. Striatal dopamine terminals release serotonin after 5-HTP pretreatment: in vivo voltammetric data. Brain Res. 1990;515(1–2):173–180.
22.	Ritvo ER, Yuwiler A, Geller E, et al. Effects of L-dopa in autism. J Autism Child Schizophr. 1971;1(2):190–205.
23.	Wuerthele SM, Moore KE. Studies on the mechanisms of L-dopa-induced depletion of 5-hydroxytryptamine in the mouse brain. Life Sci. 1977;20(10):1675–1680.
24.	Borah A, Mohanakumar KP. Long-term L-DOPA treatment causes indiscriminate increase in dopamine levels at the cost of serotonin synthesis in discrete brain regions of rats. Cell Mol Neurobiol. 2007;27(8):985–996.
25.	Karobath M, Díaz JL, Huttunen MO. The effect of L-dopa on the concentrations of tryptophan, tyrosine and serotonin in rat brain. Eur J Pharmacol. 1971;14(4):393–396.
26.	García NH, Berndt TJ, Tyce GM, Knox FG. Chronic oral L-DOPA increases dopamine and decreases serotonin excretions. Am J Physiol. 1999;277(5 Pt 2):R1476–R1480.
27.	Carta M, Carlsson T, Kirik D, Björklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain. 2007;130(Pt 7):1819–1833.
28.	Carta M, Carlsson T, Muñoz A, Kirik D, Björklund A. Serotonin–dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias. Prog Brain Res. 2008;172:465–478.
29.	Everett GM, Borcherding JW. L-dopa: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice. Science. 1970;168(3933):849–850.
30.	UniProt [webpage on the Internet]. UniProt. UniProt Consortium; 2014. Available from: http://www.uniprot.org/uniprot/?query=pyridoxal+AND+organism%3A%22Homo+sapiens+%5B9606%5D%22&sort=score. Accessed July 4, 2014.
31.	Paiardini A, Contestabile R, Buckle AM, Cellini B. PLP-dependent enzymes. Biomed Res Int. 2014;2014:856076.
32.	Nicotra A, Parvez S. Apoptotic molecules and MPTP-induced cell death. Neurotoxicol Teratol. 2002;24(5):599–605.
33.	Fangman A, O’Malley WE. L-dopa and the patient with Parkinson’s disease. Am J Nurs. 1969;69(7):1455–1457.
34.	Srimal RC, Dhawan BN. An analysis of methylphenidate induced gnawing in guinea pigs. Psychopharmacologia. 1970;18(1):99–107.
35.	Leon AS, Spiegel HE, Thomas G, Abrams WB. Pyridoxine antagonism of levodopa in parkinsonism. JAMA. 1971;218(13):1924–1927.
36.	Smythe GA, Edwards G, Graham P, Lazarus L. Biochemical diagnosis of pheochromocytoma by simultaneous measurement of urinary excretion of epinephrine and norepinephrine. Clin Chem. 1992;38(4):486–492.
37.	Verde G, Oppizzi G, Colussi G, et al. Effect of dopamine infusion on plasma levels of growth hormone in normal subjects and in agromegalic patients. Clin Endocrinol (Oxf). 1976;5(4):419–423.
38.	Weiner RI, Ganong WF. Role of brain monoamines and histamine in regulation of anterior pituitary secretion. Physiol Rev. 1978;58(4):905–976.
39.	Mason LJ, Cojocaru TT, Cole DJ. Surgical intervention and anesthetic management of the patient with Parkinson’s disease. Int Anesthesiol Clin. 1996;34(4):133–150.
40.	Volkow ND, Fowler JS, Gatley SJ, et al. PET evaluation of the dopamine system of the human brain. J Nucl Med. 1996;37(7):1242–1256.
41.	Checkley SA. Neuroendocrine tests of monoamine function in man: a review of basic theory and its application to the study of depressive illness. Psychol Med. 1980;10(1):35–53.
42.	Nishino T, Lahiri S. Effects of dopamine on chemoreflexes in breathing. J Appl Physiol Respir Environ Exerc Physiol. 1981;50(4):892–897.
43.	Pollock JD, Rowland N. Peripherally administered serotonin decreases food intake in rats. Pharmacol Biochem Behav. 1981;15(2):179–183.
44.	Greenamyre JT. Glutamate–dopamine interactions in the basal ganglia: relationship to Parkinson’s disease. J Neural Transm Gen Sect. 1993; 91(2–3):255–269.
45.	Ward DS, Bellville JW. Effect of intravenous dopamine on hypercapnic ventilatory response in humans. J Appl Physiol Respir Environ Exerc Physiol. 1983;55(5):1418–1425.
46.	Morton JJ, Connell JM, Hughes MJ, Inglis GC, Wallace EC. The role of plasma osmolality, angiotensin II and dopamine in vasopressin release in man. Clin Endocrinol (Oxf). 1985;23(2):129–138.
47.	Seri I, Tulassay T, Kiszel J, et al. Effect of low-dose dopamine infusion on prolactin and thyrotropin secretion in preterm infants with hyaline membrane disease. Biol Neonate. 1985;47(6):317–322.
48.	Al-Damluji S, Rees LH. Effects of catecholamines on secretion of adrenocorticotrophic hormone (ACTH) in man. J Clin Pathol. 1987;40(9):1098–1107.
49.	Hoffman B, Lefkowitz R. Catecholamines and sympathomimetic drugs. In: Gillman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. New York, NY: Pergamon Press; 1990.
50.	Levein NG, Thörn SE, Wattwil M. Dopamine delays gastric emptying and prolongs orocaecal transit time in volunteers. Eur J Anaesthesiol. 1999;16(4):246–250.
51.	Bell DG, McLellan TM, Sabiston CM. Effect of ingesting caffeine and ephedrine on 10-km run performance. Med Sci Sports Exerc. 2002;34(2):344–349.
52.	Bergerot A, Storer RJ, Goadsby PJ. Dopamine inhibits trigeminovascular transmission in the rat. Ann Neurol. 2007;61(3):251–262.
53.	Scanlon MF, Weightman DR, Shale DJ, et al. Dopamine is a physiological regulator of thyrotrophin (TSH) secretion in normal man. Clin Endocrinol (Oxf). 1979;10(1):7–15.
54.	Allen GF, Land JM, Heales SJ. A new perspective on the treatment of aromatic L-amino acid decarboxylase deficiency. Mol Genet Metab. 2009;97(1):6–14.
55.	Rubí B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let’s seek the balance. Endocrinology. 2010;151(12):5570–5581.
56.	Hinz M, Stein A, Uncini T. The discrediting of the monoamine hypothesis. Int J Gen Med. 2012;5:135–142.
57.	Carlsson A. A Half-Century of Neurotransmitter Research: Impact on Neurology and Psychiatry. Nobel Lecture, December 8, 2000. Available from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2000/carlsson-lecture.pdf. Accessed July 4, 2014.
58.	Kandel ER. The Molecular Biology of Memory Storage: A Dialog Between Genes and Synapses. Nobel Lecture, December 8, 2000. Available from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2000/kandel-lecture.pdf. Accessed July 4, 2014.
59.	The Royal Swedish Academy of Sciences. Advanced Information on the Nobel Prize in Chemistry 2001. Stockholm, Sweden: The Royal Swedish Academy of Sciences; 2001. Available from: http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2001/advanced-chemistryprize2001.pdf. Accessed July 4, 2014.
60.	Sweet RD, McDowell FH. Five years’ treatment of Parkinson’s disease with levodopa. Therapeutic results and survival of 100 patients. Ann Intern Med. 1975;83(4):456–463.
61.	Murphy SL, Xu JQ, Kochanek KD. Deaths: Final data for 2010. National vital statistics reports; vol 61 no 4. Hyattsville, MD: National Center for Health Statistics. 2013. Available from: http://www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf. Accessed July 1, 2014.
62.	National Parkinson Foundation. The National Parkinson Foundation’s Helpline Speaks: Lessons from the 2011 Sinemet Shortage. Miami, FL: National Parkinson Foundation; 2012. Available from: http://www.parkinson.org/Files/PDFs/NPF-Content-Documents/White-Papers/NPF466-_2011-Sinemet-Shortage_WhitePaper-_Full-art. Accessed July 1, 2014.
63.	Mones RJ, Elizan TS, Siegel GJ. Analysis of L-dopa induced dyskinesias in 51 patients with Parkinsonism. J Neurol Neurosurg Psychiatry. 1971;34(6):668–673.
64.	Chase TN. Serotonergic mechanisms in Parkinson’s disease. Arch Neurol. 1972;27(4):354–356.
65.	Busch AE, Karbach U, Miska D, et al. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998;54(2):342–352.
66.	Mayeux R, Stern Y, Williams JB, Cote L, Frantz A, Dyrenfurth I. Clinical and biochemical features of depression in Parkinson’s disease. Am J Psychiatry. 1986;143(6):756–759.
67.	Chan-Palay V, Höchli M, Jentsch B, Leonard B, Zetzsche T. Raphe serotonin neurons in the human brain stem in normal controls and patients with senile dementia of the Alzheimer type and Parkinson’s disease: relationship to monoamine oxidase enzyme localization. Dementia. 1992;3(5–6):253–269.
68.	Charlton CG, Mack J. Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain. Support for an excess methylation hypothesis for parkinsonism. Mol Neurobiol. 1994;9(1–3):149–161.
69.	Roche. Modpar [prescribing information’. Dee Why, Australia: Roche Products Pty Limited; 2010. Available from: http://www.roche-australia.com/content/dam/internet/corporate/roche/en_AU/files/central_nervous_agents/madopar-pi.pdf. Accessed July 20, 2014.
70.	Bertoldi M. Mammalian Dopa decarboxylase: structure, catalytic activity and inhibition. Arch Biochem Biophys. 2014;546:1–7.
71.	Wu F, Christen P, Gehring H. A novel approach to inhibit intracellular vitamin B6-dependent enzymes: proof of principle with human and plasmodium ornithine decarboxylase and human histidine decarboxylase. FASEB J. 2011;25(7):2109–2122.
72.	Cellini B, Montioli R, Oppici E, Voltattorni CB. Biochemical and computational approaches to improve the clinical treatment of dopa decarboxylase-related diseases: an overview. Open Biochem J. 2012;6:131–138.
73.	Bartlett MG. Biochemistry of the water soluble vitamins: a lecture for first year pharmacy students. Am J Pharm Educ. 2003; 67(2):Article 64.
74.	Palfreyman MG, Danzin C, Bey P, et al. Alpha-difluoromethyl DOPA, a new enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase. J Neurochem. 1978;31(4):927–932.
75.	DrugBank [webpage on the Internet]. Pyridoxal phosphate. DrugBank; 2013. Available from: http://www.drugbank.ca/drugs/DB00114. Accessed July 20, 2014.
76.	DrugBank [webpage on the Internet]. Carbidopa. DrugBank; 2013. Available from: http://www.drugbank.ca/drugs/DB00190. Accessed July 2014.
77.	National Institutes of Health [webpage on the Internet]. Vitamin B6: Dietary Supplement Fact Sheet. Bethesda, MD: National Institutes of Health; 2011. Available from: http://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/. Accessed July 20, 2014.
78.	Jansen MC, Bueno-de-Mesquita HB, Buzina R, et al. Dietary fiber and plant foods in relation to colorectal cancer mortality: the Seven Countries Study. Int J Cancer. 1999;81(2):174–179.
79.	Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation. 1998;97(5):437–443.
80.	Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A; Japan Collaborative Cohort Study Group. Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study. Stroke. 2010;41(6):1285–1289.
81.	Medrano MJ, Sierra MJ, Almazán J, Olalla MT, López-Abente G. The association of dietary folate, B6, and B12 with cardiovascular mortality in Spain: an ecological analysis. Am J Public Health. 2000;90(10):1636–1638.
82.	Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA. 2002;288(8):973–979.
83.	Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337(4):230–236.
84.	Centers for Disease Control and Prevention [webpage on the Internet]. Health data interactive. Atlanta, GA: Centers for Disease Control and Prevention; 2014. Available from: http://www.cdc.gov/nchs/hdi.htm. Accessed July 1, 2014.
85.	Baker AB. Treatment of paralysis agitans with vitamin B6 (pyridoxine hydrochloride). JAMA. 1941;116(22):2484–2487.
86.	Giardina G, Montioli R, Gianni S, et al. Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases. Proc Natl Acad Sci USA. 2011;108(51):20514–20519.
87.	Barbeau A. The pathogenesis of Parkinson’s disease: a new hypothesis. Can Med Assoc J. 1962;87:802–807.
88.	US Food and Drug Administration [webpage on the Internet]. Drugs@FDA: FDA approved drug products. Silver Spring, MD: US Food and Drug Administraiton; 2014. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed July 2014.
89.	Hoyert DL, Xu JQ. Deaths: Preliminary data for 2011. National vital statistics reports; vol 61 no 6. Hyattsville, MD: National Center for Health Statistics. 2012.

Parkinson's disease: carbidopa, nausea, and dyskinesia
https://www.dovepress.com/parkinson39s-disease-carbidopa-nausea-and-dyskinesia-peer-reviewed-fulltext-article-CPAA

citations:

1.	Hinz M, Stein A, Uncini T. Relative nutritional deficiencies associated with centrally acting monoamines. Int J Gen Med. 2012;5:413–430.
2.	GenomeNet. Homo sapiens (human):1644. Available from: http://www.genome.jp/dbget-bin/www_bget?hsa:1644+H01161+D00405+D00558+D01653+D03082+D08205. Accessed August 2, 2014.
3.	Mayo Clinic. Parkinson’s disease: treatments and drugs. 2014. Available from: http://www.mayoclinic.org/diseases-conditions/parkinsons-disease/basics/treatment/con-20028488. Accessed August 2, 2014.
4.	Sinemet CR^® [prescribing information]. Available from: http://packageinserts.bms.com/pi/pi_sinemet_cr.pdf. Accessed August 2, 2014.
5.	Daidone F, Montioli R, Paiardini A, et al. Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors. PLoS One. 2012;7(2):e31610.
6.	Roche Australia. Madopar^® [prescribing information]. Sydney: Roche Australia; 2010. Available from: http://www.roche-australia.com/content/dam/internet/corporate/roche/en_AU/files/central_nervous_agents/madopar-pi.pdf. Accessed August 2, 2014.
7.	Hinz M, Stein A, Uncini T. Amino acid management of Parkinson disease: a case study. Int J Gen Med. 2011;4:1–10.
8.	Hinz M, Stein A, Uncini T. Validity of urinary monoamine assay sales under the “spot baseline urinary neurotransmitter testing marketing model”. Int J Nephrol Renovasc Dis. 2011;4:101–113.
9.	Hinz M, Stein A, Uncini T. APRESS: apical regulatory super system, serotonin, and dopamine interaction. Neuropsychiatr Dis Treat. 2011;2011:7 1–7.
10.	Hinz M, Stein A, Uncini T. The dual-gate lumen model of renal monoamine transport. Neuropsychiatr Dis Treat. 2010;6:387–392.
11.	Stein A, Hinz M, Uncini T. Amino acid responsive Crohn’s disease: a case study. Clin Exp Gastroenterol. 2010;3:171–177.
12.	Hinz M, Stein A, Uncini T. Treatment of attention deficit hyperactivity disorder with monoamine amino acid precursors and organic cation transporter assay interpretation. Neuropsychiatr Dis Treat. 2011;7:31–38.
13.	Hinz M, Stein A, Uncini T. Urinary neurotransmitter testing: considerations of spot baseline norepinephrine and epinephrine. Open Access J Urol. 2011;3:19–24.
14.	Hinz M, Stein A, Uncini T. Monoamine depletion by reuptake inhibitors. Drug Healthc Patient Saf. 2011;3:69–77.
15.	Hinz M, Stein A, Uncini T. The discrediting of the monoamine hypothesis. Int J Gen Med. 2012;5:135–142.
16.	Hinz M, Stein A, Uncini T. 5-HTP efficacy and contraindications. Int J Gen Med. 2012;5:413–430.
17.	Carta M, Carlsson T, Muñoz A, Kirik D, Björklund A. Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias. Prog Brain Res. 2008;172:465–468.
18.	Mones RJ, Elizan TS, Siegel GJ. Analysis of L-dopa induced dyskinesias in 51 patients with parkinsonism. J Neurol Neurosurg Psychiatry. 1971;34:668–673.
19.	Chase TN. Serotonergic mechanisms in Parkinson’s disease. Arch Neurol. 1972;27:354–356.
20.	Busch AE, Karbach U, Miska D, et al. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998;54:342–352.
21.	Mayeux R, Stern Y, Williams JB, Cote L, Frantz A, Dyrenfurth I. Clinical and biochemical features of depression in Parkinson’s disease. Am J Psychiatry. 1986;143:756–759.
22.	Chan-Palay V, Höchli M, Jentsch B, Leonard B, Zetsche T. Raphe serotonin neurons in the human brain stem in normal controls and patients with senile dementia of the Alzheimer type and Parkinson’s disease: relation to monoamine oxidase enzyme location. Dementia. 1992;3:253–269.
23.	Charlton CG, Mack J. Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain: support for an excess methylation hypothesis for parkinsonism. Mol Neurobiol. 1994;9:149–161.
24.	UniProt. Search query results. Available from: http://www.uniprot.org/uniprot/?query=pyridoxal+AND+organism%3A%22Homo+sapiens+%5B9606%5D%22&sort=score. Accessed July 4, 2014.
25.	Andrews DW, Patrick RL, Barchas JD. The effects of 5-hydroxytryptophan and 5-hydroxytryptamine on dopamine synthesis and release in rat brain striatal synaptosomes. J Neurochem. 1978;30:465–470.
26.	Awazi N, Guldberg HC. On the interaction of 5-hydroxytryptophan and 5-hydroxytryptamine with dopamine metabolism in the rat striatum arch. Naunyn Schmiedebergs Arch Pharmacol. 1978;303:63–72.
27.	Zhelyaskov DK, Levitt M, Udenfriend S. Tryptophan derivatives as inhibitors of tyrosine hydroxylase in vivo and in vitro. Mol Pharmacol. 1968;4:445–451.
28.	Ng LK, Chase TN, Colburn RW, Kopin IJ. Research of [³H] dopamine by L-5-hydroxytryptophan. Brain Res. 1972;45:499–505.
29.	Stamford JA, Kruk ZL, Millar J. Striatal dopamine terminals release serotonin after 5-HTP pretreatment: in vivo voltammetric data. Brain Res. 1990;515:173–180.
30.	Ritvo ER, Yuwiler A, Geller E, et al. Effects of L-dopa in autism. J Autism Child Schizophr. 1971;1:190–205.
31.	Wuerthele SM, Moore KE. Studies on the mechanisms of L-dopa induced depletion of 5-hydroxytryptamine in the mouse brain. Life Sci. 1977;20:1675–1680.
32.	Borah A, Mohanakumar KP. Long-term L-DOPA treatment causes indiscriminate increase in dopamine levels at the cost of serotonin synthesis in discrete brain regions of rats. Cell Mol Neurobiol. 2007;27:985–996.
33.	Karobath M, Díaz JL, Huttunen MO. The effect of L-dopa on the concentrations of tryptophan, tyrosine, and serotonin in rat brain. Eur J Pharmacol. 1971;14:393–396.
34.	García NH, Berndt TJ, Tyce GM, Knox FG. Chronic oral L-DOPA increases dopamine and decreases serotonin excretions. Am J Physiol. 1999;277:R1476–R1480.
35.	Carta M, Carlsson T, Kirik D, Björklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain. 2007;130:1819–1833.
36.	Everett GM, Borcherding JW. L-DOPA: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice. Science. 1970;168:847–850.
37.	Hinz M, Stein A, Cole T. Management of L-dopa overdose in the competitive inhibition state. Drug Healthc Patient Saf. 2014;6:93–99.
38.	US Department of Agriculture. Mucuna chochinchinensis (Lour) A Chev Available from: http://www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?70451. Accessed August 3, 2014.
39.	US Food and Drug Administration. FDA approved drug products. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed September 22, 2014.
40.	Google. Dyskinesia definition. Available from: https://www.google.com/search?sourceid=navclient&ie=UTF-8&rlz=1T4GGHP_enUS590US590&q=dyskinesia+definition. Accessed August 2, 2014.
41.	Barbeau A. L-dopa therapy in Parkinson’s disease: a critical review of nine years’ experience. Canada Med Assoc J. 1969;101:59–68.
42.	Krack P, Pollak P, Limousin P, et al. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain. 1998;121:451–457.
43.	Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG. Levodopa-induced dyskinesias. Mov Disord. 2007;22:1379–1389; quiz 1523.
44.	Caparros-Lefebvre D, Blond S, Vermersch P, Pécheux N, Guieu JD, Petit H. Chronic thalamic stimulation improves tremor and levodopa induced dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1993;56:268–273.
45.	Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368–376.
46.	Fahn S. Levodopa in the treatment of Parkinson’s disease. J Neural Transm Suppl. 2006:1–15.
47.	Del Sorbo F, Albanese A. Levodopa-induced dyskinesias and their management. J Neurol. 2008;255 Suppl 4:32–41.
48.	Lewitt PA, Hauser RA, Lu M, et al. Randomized clinical trial of fipamezole for dyskinesia in Parkinson disease (FJORD study). Neurology. 2012;79:164–169.
49.	Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med. 2000;342;1484–1491.
50.	Paiardini A, Contestabile R, Buckle AM, Cellini B. PLP-dependent enzymes. Biomed Res Int. 2014;2014;856076.
51.	Giardinia G, Montioli R, Gianni S, et al. Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to group II decarboxylases. Proc Natl Acad Sci U S A. 2011;108:20514–20519.
52.	Google Scholar. Search: [parkinson’s irreversible dyskinesias “l-dopa or levodopa”] with query prior to 1977. Accessed August 2, 2014.
53.	Schreck J, Kelsberg G, Rich J, Ward R. Clinical inquiries. What is the best initial treatment of Parkinson’s disease? J Fam Pract. 2003;52:897–899.
54.	Weiss JL, Ng LK, Chase TN. Long-lasting dyskinesia induced by L-dopa. Lancet. 1971;1:1016–1017.
55.	Greener M. New Hope for patients with Parkinson’s disease. Inpharma. 1999:3–4.
56.	Landers M. Exercise-Induced Neuroprotection in a Hemiparkinsonian 6-Hydroxydopamine Rat Model [doctoral thesis]. Las Vegas: University of Nevada; 2012.
57.	Oxford Dictionaries. Definition of antihistamine. Available from: http://www.oxforddictionaries.com/us/definition/american_english/antihistamine. Accessed August 2, 2014.
58.	Kemp SF, Lockey RF, Simons FE. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy. 2008;63:1061–1070.
59.	Wu F, Christen P, Gehring H. A novel approach to inhibit intracellular vitamin B6-dependent enzymes: proof with human and plasmodium ornithine decarboxylase and human histidine decarboxylase. FASEB J. 2011;25:2109–2122.
60.	Olson K. Poisoning and Drug Overdose. 4th ed. New York: McGraw-Hilll; 2003.
61.	Edriss H, Pfarr M. Acute respiratory distress syndrome, metabolic acidosis, and respiratory acidosis associated with citalopram overdose. 2014. Available from: http://pulmonarychronicles.com/ojs/index.php?journal=pulmonarychronicles&page=article&op=view&path%5B%5D=102&path%5B%5D=213. Accessed August 2, 2014.
62.	Scharman EJ1, Erdman AR, Wax PM, et al. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44:205–223.
63.	DrugBank. Pyridoxal phosphate. Available from: http://www.drugbank.ca/drugs/DB00114. Accessed July 20, 2014.
64.	DrugBank. Carbidopa. Available from: http://www.drugbank.ca/drugs/DB00190. Accessed July 20, 2014.
65.	Pitkin R. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin, and Choline. Washington: National Academies; 1998.
66.	Hinz M, Stein A, Cole T. Parkinson’s disease death rate: carbidopa and vitamin B6 (PLP). Clinical Pharmacology: Advances and Applications. 2014;6:161–169.

The Peripheral Levodopa Project

Powerful Food And A Walk In The Sun

Wednesday, December 27, 2017

How Does Carbidopa work?

Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase

Friday, December 22, 2017

Eisenhofer et al on mesenteric dopamine

Substantial Production of Dopamine in the Human Gastrointestinal Tract

Thursday, December 21, 2017

Metabolism of Levodopa, Liver

Preliminary Communications
LEVODOPA IN HEPATIC COMA

Altered systemic iron metabolism in Parkinson's disease

Understanding Catecholamine Metabolism as a Guide to the Biochemical Diagnosis of Pheochromocytoma

Sunday, December 17, 2017

Papers By M. Hintz (Considered By Some As Controversial)

On Catecholamine Production in General

Saturday, December 16, 2017

On B6, Peripheral Levodopa, Carbidopa, AADC

Levodopa and Decarboxylase Inhibitors: A Review of their Clinical Pharmacology and Use in the Treatment of Parkinsonism

Pyridoxine Antagonism of Levodopa in Parkinsonism

Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase.

Identification by Virtual Screening and In Vitro Testing of Human DOPA Decarboxylase Inhibitors

Effect of pyridoxine on the depletion of tissue pyridoxal phosphate by carbidopa☆