Pharmacokinetics and Efficacy
Lee HA, Moon SJ, Yoo H, Kim MK, Jang SB, Lee S, Kim S, Lee H. YH12852, a Potent and Selective Receptor Agonist of 5-hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation. Clin Transl Sci. 2020 Nov 17. doi: 10.1111/cts.12924. Epub ahead of print. PMID: 33202093.

Jung HK, Choung RS, Locke GR 3rd, Schleck CD, Zinsmeister AR, Szarka LA, Mullan B, Talley NJ. The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006. Gastroenterology. 2009 Apr;136(4):1225-33. doi: 10.1053/j.gastro.2008.12.047. Epub 2008 Dec 24. PMID: 19249393; PMCID: PMC2705939.

Syed AR, Wolfe MM, Calles-Escandon J. Epidemiology and Diagnosis of Gastroparesis in the United States: A Population-based Study. J Clin Gastroenterol. 2020 Jan;54(1):50-54. doi: 10.1097/MCG.0000000000001231. PMID: 31135630; PMCID: PMC6903337.

Camilleri, M Gastroparesis: Etiology, clinical manifestations, and diagnosis. UpToDate Sep 2020!

Krishnasamy S, Abell TL. Diabetic Gastroparesis: Principles and Current Trends in Management. Diabetes Ther. 2018 Jul;9(Suppl 1):1-42. doi: 10.1007/s13300-018-0454-9. Epub 2018 Jun 22. PMID: 29934758; PMCID: PMC6028327.

Parkman HP. Idiopathic gastroparesis. Gastroenterol Clin North Am. 2015 Mar;44(1):59-68. doi: 10.1016/j.gtc.2014.11.015. Epub 2014 Dec 24. PMID: 25667023; PMCID: PMC4324534.

Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Müller-Lissner S, Quigley EM, Schuurkes J, De Maeyer JH, Stanghellini V. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012 Apr;35(7):745-67. doi: 10.1111/j.1365-2036.2012.05011.x. Epub 2012 Feb 22. PMID: 22356640; PMCID: PMC3491670.

Camilleri M. Treatment of gastroparesis. UpToDate Apr 2020.!

Lee A, Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev Endocrinol Metab. 2010;5(5):653-662. doi: 10.1586/eem.10.41. PMID: 21278804; PMCID: PMC3027056

Clinical Efficacy
Braman V, Graham P, Cheng C, Turnquist D, Harnett M, Sabounjian L, Shipley J. A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy. Clin Pharmacol Drug Dev. 2013 Jan;2(1):53-66. doi: 10.1002/cpdd.3. Epub 2013 Feb 21. PMID: 27121560

Sabounjian L, Graham P, Wu L, Braman V, Cheng C, Liu J, Shipley J, Neutel J, Dao M. A First-in-Patient, Multicenter, Double-Blind, 2-Arm, Placebo-Controlled, Randomized Safety and Tolerability Study of a Novel Oral Drug Candidate, CTP-499, in Chronic Kidney Disease. Clin Pharmacol Drug Dev. 2016 Jul;5(4):314-25. doi: 10.1002/cpdd.241. Epub 2016 Feb 11. PMID: 27310332.

Tang X, Bridson G, Ke J, Wu L, Erol H, Graham P, Lin CH, Braman V, Zhao H, Liu JF, Lin ZJ, Cheng C. Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jul 15;963:1-9. doi: 10.1016/j.jchromb.2014.05.043. Epub 2014 May 28. PMID: 24927417.

Overview of NL
Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol. 1966 Mar;93(3):272-81. doi: 10.1001/archderm.93.3.272. PMID: 5910868.

Wanat K, Rosenbach M. Necrobiosis Lipoidica. UpToDate Nov 2020

Antiinflammatory activities of PCS499
Fantin M, Quintieri L, Kúsz E, Kis E, Glavinas H, Floreani M, Padrini R, Duda E, Vizler C. Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties. Eur J Pharmacol. 2006 Mar 27;535(1-3):301-9. doi: 10.1016/j.ejphar.2006.02.017. Epub 2006 Mar 20. PMID: 16545799.

Semmler J, Gebert U, Eisenhut T, Moeller J, Schönharting MM, Alléra A, Endres S. Xanthine derivatives: comparison between suppression of tumour necrosis factor-alpha production and inhibition of cAMP phosphodiesterase activity. Immunology. 1993 Apr;78(4):520-5. PMID: 8388363; PMCID: PMC1421886.

Sullivan GW, Carper HT, Mandell GL. Pentoxifylline modulates activation of human neutrophils by amphotericin B in vitro. Antimicrob Agents Chemother. 1992 Feb;36(2):408-16. doi: 10.1128/aac.36.2.408. PMID: 1318681; PMCID: PMC188449.

Hemorrheological Effects of PCS499
Ambrus JL, Stadler S, Kulaylat M. Hemorrheologic effects of metabolites of pentoxifylline (Trental). J Med. 1995;26(1-2):65-75. PMID: 7561532.

Metabolic Pathway
Lillibridge JA, Kalhorn TF, Slattery JT. Metabolism of lisofylline and pentoxifylline in human liver microsomes and cytosol. Drug Metab Dispos. 1996 Nov;24(11):1174-9. PMID: 8937849.

Epidemiology/ Clinical Course of NL
Erfurt-Berge C, Dissemond J, Schwede K, Seitz AT, Al Ghazal P, Wollina U, Renner R. Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicentre study. Eur J Dermatol. 2015 Nov-Dec;25(6):595-601. doi: 10.1684/ejd.2015.2636. PMID: 26575980.

Jockenhöfer F, Kröger K, Klode J, Renner R, Erfurt-Berge C, Dissemond J. Cofactors and comorbidities of necrobiosis lipoidica: analysis of the German DRG data from 2012. J Dtsch Dermatol Ges. 2016 Mar;14(3):277-84. doi: 10.1111/ddg.12749. PMID: 26972191.

Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol. 1966 Mar;93(3):272-81. doi: 10.1001/archderm.93.3.272. PMID: 5910868.

Treatment of NL
Feily A, Mehraban S. Treatment Modalities of Necrobiosis Lipoidica: A Concise Systematic Review. Dermatol Reports. 2015 Jun 8;7(2):5749. doi: 10.4081/dr.2015.5749. PMID: 26236446; PMCID: PMC4500868.

Reid SD, Ladizinski B, Lee K, Baibergenova A, Alavi A. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol. 2013 Nov;69(5):783-791. doi: 10.1016/j.jaad.2013.05.034. Epub 2013 Aug 19. PMID: 23969033.

Case reports of Treatment with Pentoxifylline
Basaria S, Braga-Basaria M. Necrobiosis lipoidica diabeticorum: response to pentoxiphylline. J Endocrinol Invest. 2003 Oct;26(10):1037-40. doi: 10.1007/BF03348204. PMID: 14759079.

Littler CM, Tschen EH. Pentoxifylline for necrobiosis lipoidica diabeticorum. J Am Acad Dermatol. 1987 Aug;17(2 Pt 1):314-6. doi: 10.1016/s0190-9622(87)80338-9. PMID: 3624574.

Noz KC, Korstanje MJ, Vermeer BJ. Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline. Clin Exp Dermatol. 1993 Jan;18(1):78-9. doi: 10.1111/j.1365-2230.1993.tb00977.x. PMID: 8440063.

Wee E, Kelly R. Pentoxifylline: An effective therapy for necrobiosis lipoidica. Australas J Dermatol. 2017 Feb;58(1):65-68. doi: 10.1111/ajd.12420. Epub 2015 Nov 12. PMID: 26559761.

Cadoo KA, Gajria D, Suh E, Patil S, Theodoulou M, Norton L, Hudis CA, Traina TA. Decreased gastrointestinal toxicity associated with a novel capecitabine schedule (7 days on and 7 days off): a systematic review. NPJ Breast Cancer. 2016 Mar 30;2:16006. doi: 10.1038/npjbcancer.2016.6. PMID: 28721374; PMCID: PMC5515341.

Chang AY, Most C, Pandya KJ. Continuous intravenous infusion of 5-fluorouracil in the treatment of refractory breast cancer. American Journal of Clinical Oncology. 1989 Oct;12(5):453-455. DOI: 10.1097/00000421-198910000-00019.

Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res. 1993 Nov 15;53(22):5433-8. PMID: 8221682.

Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs. 2000 Nov;18(4):299-313. doi: 10.1023/a:1006416410198. PMID: 11081567.

Grem JL, Harold N, Shapiro J, Bi DQ, Quinn MG, Zentko S, Keith B, Hamilton JM, Monahan BP, Donavan S, Grollman F, Morrison G, Takimoto CH. Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. J Clin Oncol. 2000 Dec 1;18(23):3952-63. doi: 10.1200/JCO.2000.18.23.3952. PMID: 11099325.

Guo XD, Harold N, Saif MW, Schuler B, Szabo E, Hamilton JM, Monahan BP, Quinn MG, Cliatt J, Nguyen D, Grollman F, Thomas RR, McQuigan EA, Wilson R, Takimoto CH, Grem JL. Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule. Cancer Chemother Pharmacol. 2003 Jul;52(1):79-85. doi: 10.1007/s00280-003-0613-0. Epub 2003 Apr 18. PMID: 12707718.

Hansen R, Quebbeman E, Ausman R, Frick J, Ritch P, Schulte W, Haas C, Beatty P, Anderson T. Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: results in 91 patients. J Surg Oncol. 1989 Mar;40(3):177-81. doi: 10.1002/jso.2930400309. PMID: 2645464.

Keith B, Guo XD, Zentko S, Harold N, Schuler B, Quinn M, Shapiro J, Grem JL. Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition. Clin Cancer Res. 2002 May;8(5):1045-50. PMID: 12006517.

Milano G, Etienne MC, Renée N, Thyss A, Schneider M, Ramaioli A, Demard F. Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol. 1994 Jun;12(6):1291-5. doi: 10.1200/JCO.1994.12.6.1291. PMID: 8201391

Milano G, Etienne MC. Individualizing therapy with 5-fluorouracil related to dihydropyrimidine dehydrogenase: theory and limits. Ther Drug Monit. 1996 Aug;18(4):335-40. doi: 10.1097/00007691-199608000-00004. PMID: 8857547

Paff MT, Baccanari DP, Davis ST, Cao S, Tansik RL, Rustum YM, Spector T. Preclinical development of eniluracil: enhancing the therapeutic index and dosing convenience of 5-fluorouracil. Invest New Drugs. 2000 Nov;18(4):365-71. doi: 10.1023/a:1006401432488. PMID: 11081572.

Rivera E, Chang JC, Semiglazov V, Burdaeva O, Kirby MG, Spector T. Eniluracil plus 5-fluorouracil and leucovorin: treatment for metastatic breast cancer patients in whom capecitabine treatment rapidly failed. Clin Breast Cancer. 2014 Feb;14(1):26-30. doi: 10.1016/j.clbc.2013.08.018. Epub 2013 Nov 1. PMID: 24183612.

Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. doi: 10.1200/JCO.2002.20.6.1519. PMID: 11896100.

Schilsky RL, Bukowski R, Burris H 3rd, Hochster H, O'Rourke M, Wall JG, Mani S, Bonny T, Levin J, Hohneker J. A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer. Ann Oncol. 2000 Apr;11(4):415-20. doi: 10.1023/a:1008356522080. PMID: 10847459.

Spector T, Cao S. A possible cause and remedy for the clinical failure of 5-fluorouracil plus eniluracil. Clin Colorectal Cancer. 2010 Jan;9(1):52-4. doi: 10.3816/CCC.2010.n.007. PMID: 20100689.

Mechanism of Action of PCS6422
Baccanari DP, Davis ST, Knick VC, Spector T. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci U S A. 1993;90(23):11064-11068. doi:10.1073/pnas.90.23.11064

Baker SD, Diasio RB, O'Reilly S, Lucas VS, Khor SP, Sartorius SE, Donehower RC, Grochow LB, Spector T, Hohneker JA, Rowinsky EK. Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil. J Clin Oncol. 2000 Feb;18(4):915-26. doi: 10.1200/JCO.2000.18.4.915. PMID: 10673535.

Baker SD. Pharmacology of fluorinated pyrimidines: eniluracil. Invest New Drugs. 2000 Nov;18(4):373-81. doi: 10.1023/a:1006453500629. PMID: 11081573.

Cao D, Pizzorno G. Uridine phosophorylase: an important enzyme in pyrimidine metabolism and fluoropyrimidine activation. Drugs Today (Barc). 2004 May;40(5):431-43. doi: 10.1358/dot.2004.40.5.850491. PMID: 15319798.