Peter H. Proctor, PhD, MD is an American pharmacologist, toxicologist, biophysicist and physician.[1] He has worked in neuroscience and biological psychiatry, organic electronics, pharmacology/toxicology, as well as free radical and oxidative stress research. He pioneered aspects of redox signaling, which is the concept that reactive oxygen species, other electronically activated molecules, and solid-state electronic processes are involved in cell signaling.
Education and professional career
Dr Proctor graduated from Rice University and received his Master and PhD degrees from the University of Texas Health Science Center at Houston. He received his medical degree from University of Texas Medical Branch at Galveston.
Research
Dr Proctor is the author of research publications, book chapters, and presentations. He also holds pharmaceutical patents, e.g., for the use of nitrone and nitroxide drugs in the treatment of radiation dermatitis and alopecia, as well as (among other indications)fibrocystic disease of breast and neuropathic pain.[2] Some of his drugs are currently in clinical trials.[3]
Psychiatry and neuroscience
Beginning in 1970, Peter Proctor and his coworkers proposed a fundamental role for electron-transfer processes (including free radicals, redox signaling and oxidative stress) in a variety of neuropsychiatric disorders, including schizophrenia. For example, they noted the common association of oxidative stress with specific clusters of symptoms in humans diseases These symptoms include psychosis, dyskinesia, pigmentation abnormalities, and deafness. This association was later extended to include, e.g., diabetes, inflammation, and fibrosis. Likewise, they postulated an underlying common etiology involving electronically activated processes in such symptomology.[4][5][6][7][8][9][10] Oxidative stress and redox signaling are now an important area of research in psychiatry and neuroscience, as well as general disease pathogenesis[11]
Proctor has also published in the area of stroke concerning oxidative stress in ischemic injury and its application to neuroprotection, an area pioneered by his co-worker Harry Demopoulos.[12] For example, NXY-059 or Cerovive is the disulfonyl derivative of Proctor's patented drug PBN (phenylbutylnitrone). After showing significant efficacy in the first wing of its phase-3 clinical trial for the treatment of stroke, Cerovive failed the second wing. The failure of this trial wiped several billion dollars off the net asset value of the drug company AstraZeneca. Proctor and Tamborello suggested that the effective agent in the first stroke-treatment trial was a pharmacologically active breakdown product of NXY-059, MNP or "methylnitrosopropane", to which he also holds patent claims.[13] They further propose that stabilization of Cerovive to prevent such breakdown was responsible for the failure of the second trial.[14][15][16][17]
Similarly, Proctor has explained the puzzling repeated failure in human trials of neuroprotective agents and antioxidants effective in animals by noting the uniquely high endogenous levels of the antioxidant neuroprotectant uric acid in humans[18][19] In summary, high levels of uric acid leave little "therapeutic room" for analogous extracellular neuroprotectants to work in humans. Following up, Proctor suggested[20] the use of birds, which also have high urate levels, in the future screening of agents to prevent and treat ischemic injury.
Likewise, by studying its semiconductor properties, Proctor and his associates helped clarify the function of neuromelanin in the human brain. Melanized neuronal tracts such as in the substantia nigra and locus caeruleus figure in the etiology of most Axis-I psychiatric disorders. This includes schizophrenia, bipolar disorder, depression, and drug dependency. Concerning Proctor's work with melanin, Hill's review[21] notes: “...Aside from camouflage, its other roles can be brought together by a unifying hypothesis as first proposed by Proctor and McGinness nearly 20 years ago...”
Uric acid
Uric acid is a strong reducing substance present in uniquely high levels in human blood. In a 1970 paper in the journal Nature[22] Proctor suggested that in primates uric acid partially substitutes for another strong reducing substance, ascorbic acid (vitamin-C), e.g., as an antioxidant and enzyme cofactor. Uric acid is now thought to be the major blood antioxidant. Similarly, in 1972, Proctor reported the conditional pro-oxidant properties of uric acid and further proposed that oxidative stress figures in the pathogenesis of hyperuricemic syndromes in general.[23][24] Subsequent researchers have confirmed the putative role of urate-induced oxidative stress in many human diseases. These include stroke and atherosclerosis,[25] as well as gout, metabolic syndrome,[26] diabetes,[27] and hypertension.[28] Similarly, the antioxidant role of uric acid is thought to figure in Parkinsonism,[29] stroke[30] and multiple sclerosis.[31] A clinical trial is now underway using uric acid as an antioxidant neuroprotectant in acute ischemic stroke [32]
Redox signaling
Redox signaling is the concept that electronic processes figure in cell signalling. With respect to "solid state" electronic processes in biomaterials, the concept of redox signaling is generally credited to Albert Szent-Gyorgyi.[33] In his review of molecular electronics, Hush[34] credits Proctor's research group [35] with the first experimental confirmation of Szent-Gyorgyi's conjectures concerning semiconductor mechanisms in cellular signaling, noting “Also in 1974 came the first experimental demonstration of an operating molecular electronic device that functions along the lines of the biopolymer conduction ideas of Szent-Gyorgi.” Bettinger et al.[36] reiterates their priority in the development of biopolymer-based organic electronic devices.
Expanding on Szent-Gyorgi, Proctor and coworkers further proposed that not only semiconductor processes, but electronically activated molecules in general function in redox cell signaling, e.g., in neurotransmission and inflammation. One example is the neurotransmitter action of dopamine.[6] Such species include reactive oxygen species and their derivatives. While this proposal met with initial scepticism, scientists now generally believe that redox signaling figures widely in normal cellular function and in human diseases.
Organic semiconductors and conductive polymers
While working with melanin and related organic semiconductors, McGinness, Corry, and Proctor materially contributed to the modern field of organic electronics and conductive polymers. For example, they reported the first-known organic-polymer electronic device, a voltage-controlled switch.[37, 38] Organic electronics is now generally considered part of nanotechnology and nanoelectronics. This apparatus is now in the Smithsonian Chip collection of pioneering and historic electronic devices.[39] Proctor and his associates were also one of several groups reporting[40][41][42][43] highly conductive linear backbone organic polymers well before their 1977 investigation by Shirakawa et al.[44]
Nitrone and nitroxide drugs
Proctor holds multiple patents on the pharmaceutical use of nitrone and nitroxide spin traps and spin labels. These agents show promise in the treatment and prevention of a variety of human disease conditions[45] Potential applications include hair losss treatment, treatment and prevention of cancer, neurological diseases such as stroke, senile dementia, and Parkinson's disease, as well as a variety of inflammatory and degenerative conditions. Such agents are also useful in the treatment of hair loss or alopecia. One such agent, TEMPOL, is currently in clinical trials for radiation-induced hair loss [3]. Other clinical trials with TEMPOL and its derivatives include treatment of macular degeneration and hypertension. Also see:..[46][47] for media reports on Dr Proctor's work in hair loss and hair loss treatment. In a new patent[2] Dr Proctor claims other pharmaceutical uses for these compounds in the treatment of human diseases. These include treatment of fibrocystic disease of breast, menstrual cramps and their associated symptoms, migraine, hemorrhoids, neuropathic pain, cyclic vomiting syndrome, and peridontitis. The patent also claims treatment of the symptoms of influenza, herpes zoster and herpes simplex.
References
[1] UTMB Alumni Directory, p236 (2007)
[2] Proctor, Peter, "Nitrone, Nitroso, and Nitroxide Spintraps and Spin Labels and Their Hydroxylamines" (http://appft1.uspto.gov/netacgi/ nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=/netahtml/PTO/search-adv.html&r=1&f=G&l=50&d=PG01&p=1&S1=20120115905. PGNR.&OS=DN/20120115905&RS=DN/20120115905)
[3] http://www.mitospharma.com/
[4] Proctor, P. (1970). "Relationship between alkaptonuria and parkinsonism" (http://www.sciencedirect.com/science/article/pii/ S0140673670921665). Lancet 296 (7680): 984. .
[5] Proctor, Peter (1971). "Psychosis, dyskinesia, and hyperpigmentation" (http://www.lancet.com/journals/lancet/article/ PIIS0140-6736(71)91630-8/fulltext). Lancet 297 (7708): 1069. .
[6] Proctor, Peter (1970). "Concerning the mechanism of action of L-DOPA in Parkinsonism" (http://www.ncbi.nlm.nih.gov/pubmed/ 5524076). Biochem Med. 4 (3): 357– 379. .
[7] Proctor, P.; McGinness, J.E. (1970). "Levodopa side-effects and the Lesch-Nyhan syndrome" (http://www.sciencedirect.com/science/ article/pii/S0140673670923998). Lancet 296: 1367. .
[8] Proctor, Peter (1976). "The role of melanin in human neurological disorders". Pigment Cell 3: 378– 382.
[9] Proctor, Peter; Reynolds, Edward.S. (1984). "Free radicals and disease in man". Physiol. Chem. Phys. 16: 175– 195.
[10] Proctor, Peter H., 1989 Free Radical Mechanisms in Human Disease, CRC Handbook of Free Radicals and Antioxidants in Biomedicine, Vol 1. CRC Press, Boca Raton, pp. 209-221.
[11] Asevedo E, Cunha GR, Zugman A, Mansur RB, Brietzke E. N-acetylcysteine as a potentially useful medication to prevent conversion to schizophrenia in at-risk individuals. Rev Neurosci. 2012;23(4):353-62. doi:10.1515/revneuro-2012-0039. Review. PubMed PubMed (http:// www.ncbi.nlm.nih.gov/pubmed/22944654).
[12] D. Al. Nita, et al., "Oxidative damage following cerebral ischemia depends on reperfusion" (http://www.jcmm.org/en/pdf/5/2/ jcmm005.002.05.pdf)
[13] "SAINT-I worked, but the neuroprotectant is not NXY-059". Stroke 38 (10): e109; author reply e110. October 2007. doi:10.1161/STROKEAHA.107.489161. PMID 17717310.
[14] ABC News: “Once Promising Stroke Drug Fails in Clinical Trial” http://abcnews.go.com/Health/Healthday/story?id=4508232&page=1 [15] Healthday http://healthlibrary.epnet.com/GetContent.aspx?token=1b9310cd-caa8-432e-8056-25c0fb118e50&chunkiid=220911
[16] cafepharma http://www.cafepharma.com/boards/showthread.php?t=219799
[17] Palm Beach Post. http://www.palmbeachpost.com/health/content/shared-auto/healthnews/drug/607150.html.
[18] Proctor, Peter H., (May 2008) Uric Acid: Neuroprotective or Neurotoxic? Stroke Volume 39(5) p e88 (http://stroke.ahajournals.org/ content/39/5/e88.full.pdf+html)
[19] Proctor, Peter H. Uric Acid and Neuroprotection (http://stroke.ahajournals.org/content/39/8/e126.full)
[20] Proctor, Peter, Birds as Potential Models in Ischemic Injury, Experimental & Translational Stroke Medicine 2009, 1:7 doi:10.1186/2040-7378-1-7 (http://www.etsmjournal.com/content/1/1/7/comments)
[21] Hill HZ. The function of melanin or six blind people examine an elephant. Bioessays. 1992 Jan;14(1):49-56. http://www.ncbi.nlm.nih. gov/pubmed/1546980
[22] Proctor P, Similar Functions of Uric Acid and Ascorbate in Man ?. Nature 228:868; 1970. http://www.nature.com/nature/journal/v228/ n5274/abs/228868a0.html
[23] Proctor, P. H. Electron-transfer factors in psychosis and dyskinesia, Phvsiol. Chem. Phvs. 4:349-360; 1972.
[24] Proctor, P, Kirkpatrick DS, and McGinness JE, Superoxide dismutase therapy in hyperuricaemic syndromes. Lancet, 2:95; 1978.
[25] Hashemi M, Yavari M, Amiri N, Taheri H, Shaigannia I, Moghadas L, Shirzadi E, Talaee Z, Shams H, Ketabi OL, Soleimani B. Uric acid: a risk factor for coronary atherosclerosis? Cardiovasc J S Afr. 2007 Jan-Feb;18(1):16-9. PubMed PMID 17392990.
[26] Johnson RJ, Lanaspa MA, Gaucher EA. Uric acid: a danger signal from the RNAworld that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Semin Nephrol. 2011 Sep;31(5):394-9. doi: 10.1016/j.semnephrol.2011.08.002. PubMed PMID 22000645; PubMed Central PMCID: PMC3203212.
[27] Katsiki N, Papanas N, Fonseca VA, Maltezos E, Mikhailidis DP. Uric acid and diabetes: is there a link? Curr Pharm Des. 2012 Dec 26. [Epub ahead of print] PubMed PMID 23278493.
[28] Richard J. Johnson,et al,Brief Review:Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease?
Hypertension. 2003; 41: 1183-1190
[29] Chen X, Wu G, Schwarzschild MA. Urate in Parkinson's disease: more than a biomarker? Curr Neurol Neurosci Rep. 2012 Aug;12(4):367-75. doi:10.1007/s11910-012-0282-7. Review. PubMed PubMed (http://www.ncbi.nlm.nih.gov/pubmed/22580741).
[30] Proctor PH. Uric acid: neuroprotective or neurotoxic? Stroke. 2008 May;39(5):e88; author reply e89. doi:10.1161/STROKEAHA.107.513242. Epub 2008 Mar 27. PubMed PMID 18369163. (http://stroke.ahajournals.org/content/39/5/e88. full.pdf+html)
[31] Koch M, De Keyser J. Uric acid in multiple sclerosis. Neurol Res. 2006 Apr;28(3):316-9. Review. PubMed PubMed (http://www.ncbi. nlm.nih.gov/pubmed/16687059)
[32] http://www.strokecenter.org/trials/clinicalstudies/
efficacy-study-of-combined-treatment-with-uric-acid-and-rtpa-in-acute-ischemic-stroke/description [33] Forman, H.J. Signal transduction and reactive species. Free Radic. Biol. Med. 47:1237-1238; 2009
[34] Hush, N.S. An Overview of the First Half-Century of Molecular Electronics. Ann. N.Y. Acad. Sci. 1006:1– 20; 2003.
[35] McGinness, J.E., Corry, P.M., and Proctor, P. (1974). "Amorphous semiconductor switching in melanins" (http://www.organicmetals. com/amorphous.htm). Science 183 (4127): 853– 855. Bibcode 1974Sci...183..853M. doi:10.1126/science.183.4127.853. PMID 4359339. .
[36] "Biomaterials-Based Organic Electronic Devices". Polym Int 59 (5): 563– 567. May 2010. doi:10.1002/pi.2827. PMC 2895275.
PMID 20607127.
[37] http://smithsonianchips.si.edu/proctor/index.htm
[38] "Semiconductors in the human body?". Nature 248: 475. April 5, 1974.
[39] The Chip Collection - Proctor-McGinnes Introduction, Smithsonian Institution (http://smithsonianchips.si.edu/proctor/index.htm)
[40] McGinness, J.E., Corry, P.M., and Proctor, P. (1974). "[[Amorphous semiconductor (http://www.organicmetals.com/amorphous.htm)] switching in melanins"]. Science 183 (4127): 853– 855. Bibcode 1974Sci...183..853M. doi:10.1126/science.183.4127.853. PMID 4359339. .
[41] "Semiconductor Switching in Melanins" (http://www.organicsemiconductors.com/amorphous.htm). Organicsemiconductors.com. 14 December 1973. . Retrieved 18 October 2009.
[42] Hush, NS (2003). "An overview of the first half-century of molecular electronics". Annals of the New York Academy of Sciences 1006: 1– 20.
Bibcode 2003NYASA1006....1H. doi:10.1196/annals.1292.016. PMID 14976006.
[43] Historical Background (or there is nothing new under the Sun), Inzelt,G. "Conducting Polymers", (2008), chapter 8, pp. 265– 269
[44] Shirakawa H, Louis EJ, MacDiarmid AG, Chiang CK, and Heeger AJ, Synthesis of electrically conducting organic polymers: halogen derivatives of polyacetylene, (CH)x, J. Chem. Soc., Chem. Commun., 1977, 578-580 doi:10.1039/C3977000057 (http://pubs.rsc.org/en/ Content/ArticleLanding/1977/C3/c39770000578)
[45] Wilcox CS. Effects of tempol and redox-cycling nitroxides in models ofoxidative stress. Pharmacol Ther. 2010 May;126(2):119-45. doi:10.1016/j.pharmthera.2010.01.003. Epub 2010 Feb 11. Review. PubMed PubMed (http://www.ncbi.nlm.nih.gov/pubmed/20153367); PubMed Central PMCID: PMC2854323.
[46] "Hair About it", Newsweek. May 28, 1995.
[47] "Gone Today, Hair Tomorrow", Newsweek. Nov 23, 1997.
Also see
CRC Review on Free radicals and Human Disease (http://www.drproctor.com/crcpap2.htm)
Redox Signaling Homepage (http://www.redoxsignaling.com/)
Organic Semiconductors Homepage (http://www.organicsemiconductors.com/)