A Phase i Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C

Phytotherapy Research

Volumn 30, Issue 1, 2016, Pages 160-168

  Lu, Nu T ^a   Crespi, Catherine M ^b,c   Liu, Natalie M ^a   Vu, James Q ^a   Ahmadieh, Yasaman ^d   Wu, Sheng ^b   Lin, Sherry ^e   McClune, Amy ^f   Durazo, Francisco ^a   Saab, Sammy ^a   Han, Steven ^a   Neiman, David C ^g   Beaven, Simon ^a   French, Samuel W ^a,c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d Touro University California   (United States)

^e Boston Scientific   (United States)

^f KAISER PERMANENTE   (United States)

^g APPALACHIAN STATE UNIVERSITY   (United States)

Author keywords

bioflavonoids; dose escalation; hepatitis C; phase I; phytomedicine; quercetin

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; QUERCETIN; ANTIVIRUS AGENT;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTIVIRAL ACTIVITY; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CHRONIC HEPATITIS C; CLINICAL ARTICLE; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; FOLLOW UP; HUMAN; LIVER INJURY; MALE; MAXIMUM TOLERATED DOSE; MILD HEPATIC IMPAIRMENT; OUTCOME ASSESSMENT; PATIENT COMPLIANCE; PHASE 1 CLINICAL TRIAL; STOMACH DISCOMFORT; TREATMENT DURATION; UNSPECIFIED SIDE EFFECT; VIRUS LOAD; BLOOD; CLINICAL TRIAL; DOSE RESPONSE; HEPACIVIRUS; HEPATITIS C, CHRONIC; MIDDLE AGED;

ADULT; AGED; ALANINE TRANSAMINASE; ANTIVIRAL AGENTS; ASPARTATE AMINOTRANSFERASES; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HEPACIVIRUS; HEPATITIS C, CHRONIC; HUMANS; MALE; MIDDLE AGED; QUERCETIN; VIRAL LOAD;

EID: 84954068490     PISSN: 0951418X     EISSN: 10991573     Source Type: Journal    
DOI: 10.1002/ptr.5518     Document Type: Article

References (43)

1. Ader P, Block M, Pietzsch S, Wolffram S,. 2001. Interaction of quercetin glucosides with the intestinal sodium/glucose co-transporter (SGLT-1). Cancer Lett 162 (2): 175-180.
2. Afdhal N, Reddy KR, Nelson DR, et al., 2014a. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 370 (16): 1483-1493.
3. Afdhal N, Zeuzem S, Kwo P, et al., 2014b. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 370 (20): 1889-1898.
4. Alter MJ,. 1997. Epidemiology of hepatitis C. Hepatology 26 (3 Suppl 1): 62S-65S.
5. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ,. 2006. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 144 (10): 705-714.
6. Bachmetov L, Gal-Tanamy M, Shapira A, et al., 2012. Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity. J Viral Hepat 19 (2): e81-e88.
7. Bala S, Petrasek J, Mundkur S, et al., 2012. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 56 (5): 1946-1957.
8. Bhattacharya D, Ansari IH, Mehle A, Striker R,. 2012. Fluorescence resonance energy transfer-based intracellular assay for the conformation of hepatitis C virus drug target NS5A. J Virol 86 (15): 8277-8286.
9. Bieger J, Cermak R, Blank R, et al., 2008. Tissue distribution of quercetin in pigs after long-term dietary supplementation. J Nutr 138 (8): 1417-1420.
10. Bobe G, Weinstein SJ, Albanes D, et al., 2008. Flavonoid intake and risk of pancreatic cancer in male smokers (Finland). Cancer Epidemiol Biomarkers Prev 17 (3): 553-562.
11. Boulton DW, Walle UK, Walle T,. 1999. Fate of the flavonoid quercetin in human cell lines: chemical instability and metabolism. J Pharm Pharmacol 51 (3): 353-359.
12. Cleveland WS,. 1979. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 74 (368): 829-836.
13. Day AJ, Bao Y, Morgan MR, Williamson G,. 2000. Conjugation position of quercetin glucuronides and effect on biological activity. Free Radic Biol Med 29 (12): 1234-1243.
14. Falck-Ytter Y, Kale H, Mullen KD, Sarbah SA, Sorescu L, McCullough AJ,. 2002. Surprisingly small effect of antiviral treatment in patients with hepatitis C. Ann Intern Med 136 (4): 288-292.
15. Fanning MJ, Macander P, Drzewiecki G, Middleton E Jr,. 1983. Quercetin inhibits anaphylactic contraction of guinea pig ileum smooth muscle. Int Arch Allergy Appl Immunol 71 (4): 371-373.
16. Fried MW, Buti M, Dore GJ, et al., 2013. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 58 (6): 1918-1929.
17. Gee JM, DuPont MS, Day AJ, Plumb GW, Williamson G, Johnson IT,. 2000. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. J Nutr 130 (11): 2765-2771.
18. Gonzalez O, Fontanes V, Raychaudhuri S, et al., 2009. The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology 50 (6): 1756-1764.
19. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC,. 2007. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45 (11): 2179-2205.
20. Heinz SA, Henson DA, Austin MD, Jin F, Nieman DC,. 2010a. Quercetin supplementation and upper respiratory tract infection: a randomized community clinical trial. Pharmacol Res 62 (3): 237-242.
21. Heinz SA, Henson DA, Nieman DC, Austin MD, Jin F,. 2010b. A 12-week supplementation with quercetin does not affect natural killer cell activity, granulocyte oxidative burst activity or granulocyte phagocytosis in female human subjects. Br J Nutr 104 (6): 849-857.
22. Hoofnagle JH,. 2002. Course and outcome of hepatitis C. Hepatology 36 (5 Suppl 1): S21-S29.
23. Ishisaka A, Kawabata K, Miki S, et al., 2013. Mitochondrial dysfunction leads to deconjugation of quercetin glucuronides in inflammatory macrophages. PLoS One 8 (11): e80843.
24. Kowdley KV, Lawitz E, Crespo I, et al., 2013. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 381 (9883): 2100-2107.
25. Kowdley KV, Gordon SC, Reddy KR, et al., 2014. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 370 (20): 1879-1888.
26. McAnulty SR, McAnulty LS, Nieman DC, et al., 2008. Chronic quercetin ingestion and exercise-induced oxidative damage and inflammation. Appl Physiol Nutr Metab 33 (2): 254-262.
27. McHutchison JG, Lawitz EJ, Shiffman ML, et al., 2009. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 361 (6): 580-593.
28. Nieman DC, Henson DA, Davis JM, et al., 2007a. Quercetin's influence on exercise-induced changes in plasma cytokines and muscle and leukocyte cytokine mRNA. J Appl Physiol 103 (5): 1728-1735.
29. Nieman DC, Henson DA, Gross SJ, et al., 2007b. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc 39 (9): 1561-1569.
30. Prussia A, Thepchatri P, Snyder JP, Plemper RK,. 2011. Systematic approaches towards the development of host-directed antiviral therapeutics. Int J Mol Sci 12 (6): 4027-4052.
31. Rogatko A, Xu TM,. 2005. EWOC User's Guide Version 2.0. Available from http://www.sph.emory.edu/BRI-WCI/ewoc.html.
32. Romano B, Pagano E, Montanaro V, Fortunato AL, Milic N, Borrelli F,. 2013. Novel insights into the pharmacology of flavonoids. Phytother Res 27 (11): 1588-1596.
33. Sesink AL, Arts IC, Faassen-Peters M, Hollman PC,. 2003. Intestinal uptake of quercetin-3-glucoside in rats involves hydrolysis by lactase phlorizin hydrolase. J Nutr 133 (3): 773-776.
34. Shanely RA, Knab AM, Nieman DC, Jin F, McAnulty SR, Landram MJ,. 2010. Quercetin supplementation does not alter antioxidant status in humans. Free Radic Res 44 (2): 224-231.
35. Shoskes D, Lapierre C, Cruz-Correa M, et al., 2005. Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial. Transplantation 80 (11): 1556-1559.
36. Srinivas NR,. 2015. Recent trends in preclinical drug-drug interaction studies of flavonoids-review of case studies, issues and perspectives. Phytother Res 29 (11): 1679-1691.
37. Sterling RK, Lissen E, Clumeck N, et al., 2006. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 43 (6): 1317-1325.
38. Terrault NA, Pawlotsky JM, McHutchison J, et al., 2005. Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy. J Viral Hepat 12 (5): 465-472.
39. Tighiouart M, Rogatko A, Babb JS,. 2005. Flexible Bayesian methods for cancer phase I clinical trials. Dose escalation with overdose control. Stat Med 24 (14): 2183-2196.
40. Valentova K, Stejskal D, Bednar P, et al., 2007. Biosafety, antioxidant status, and metabolites in urine after consumption of dried cranberry juice in healthy women: a pilot double-blind placebo-controlled trial. J Agric Food Chem 55 (8): 3217-3224.
41. Walle T, Walle UK, Halushka PV,. 2001. Carbon dioxide is the major metabolite of quercetin in humans. J Nutr 131 (10): 2648-2652.
42. Wasley A, Grytdal S, Gallagher K, Centers for Disease and Prevention. 2008. Surveillance for acute viral hepatitis-United States, 2006. MMWR Surveill Summ 57 (2): 1-24.
43. Younossi ZM, Park H, Saab S, Ahmed A, Dieterich D, Gordon SC,. 2015. Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection. Aliment Pharmacol Ther 41 (6): 544-563.