None listed
Conditions
Brief summary
There is no medical treatment that has been shown to have clinical benefit in primary sclerosing cholangitis (PSC); a condition affecting the liver and bile ducts. Mesalazine (5-ASA) is a first-line medication used for treatment for ulcerative colitis. Ulcerative colitis has a strong association with PSC. 5-ASA is rapidly metabolised before reaching the liver and bile ducts which may restrict its potential benefit in PSC. This study investigates whether a naturally occurring flavonoid, quercetin, may inhibit metabolism of 5-ASA and lead to improved drug delivery to the liver and bile ducts. This study will also explore the impact of quercetin on the bacterial population in the faeces.
Interventions
Pharmacokinetic Pilot Study
Mesalazine (5-ASA) is an effective first-line therapy for patients with UC however there are no reports, positive or negative, of efficacy in PSC. 5-ASA is known to be rapidly N-acetylated once it is absorbed in the colon and released into the blood. N-acetylation inactivates 5-ASA, likely negating its effect before it reaches the biliary duct. Some 5-ASA escapes the intestine without being metabolized and is subsequently acetylated in the liver. The enzyme responsib
Pharmacokinetic Pilot Study Mesalazine (5-ASA) is an effective first-line therapy for patients with UC however there are no reports, positive or negative, of efficacy in PSC. 5-ASA is known to be rapidly N-acetylated once it is absorbed in the colon and released into the blood. N-acetylation inactivates 5-ASA, likely negating its effect before it reaches the biliary duct. Some 5-ASA escapes the intestine without being metabolized and is subsequently acetylated in the liver. The enzyme responsible for the N-acetylation is N- acetyltransferase 1, or NAT-1. NAT-1 is present in the lining of the intestine as well as in the liver. Quercetin is a flavonoid found in fruits and vegetables that has been shown to inhibit NAT-1. Quercetin was reviewed by the Food and Drug Administration (FDA) in 2010 and was given “generally recognised as safe” (GRAS) designation at a dose of 1500mg/d. We propose that 5-ASA may be an effective therapy for primary sclerosing cholangitis (PSC). However, 5-ASA is metabolized to an inactive form preventing active 5-ASA to be able exert a therapeutic effect on the liver and biliary tree in PSC. Quercetin has been shown to inhibit N-acetyl transferase 1, the enzyme that metabolizes 5-ASA. Quercetin may also be therapeutic in PSC based on its anti-inflammatory properties. This pilot study aims to test if quercetin has a therapeutic potential in PSC by inhibiting NAT-1 and delivering active 5-ASA at a higher concentration to the liver. If successful, subsequent studies will examine its therapeutic potential in PSC. Participants already taking 5-ASA (4g daily, oral tablets or granules) will be enrolled. After the initial visit for screening and consent, participants will be instructed to continue their oral 5-ASA 4g tablets or granules, once a day in the morning before food. For baseline results without quercetin supplmentation, participants will return to the study centre on day 7 after continuing their prescribed 5-ASA regimen to complete two questionnaires (disease activity & quality of life) and have blood tests & stool tests collected. During the intervention period, participants will continue their oral 5-ASA 4g daily and in addition, take oral quercetin 1500mg daily for 7 days (split dosing 1000mg in the morning 1 hour after 5-ASA and 500mg in the evening, formulated as encapsulated powder). For post-intervention results, participants will return to the study centre on day 14 of the study after having taken 7 days of 5-ASA and quercetin to complete two questionnaires (disease activity & quality of life) and have blood tests & stool tests collected. Adherence to 5-ASA & quercetin during the study will be monitored through the use of a medication diary. A food diary will be maintained to account for unexpected significant variations in quercetin levels. Participants do not need to modify their usual diet for this study. The intervention involves adding quercetin supplement to the usual medication regimen. There is no washout period.
Sponsors
IBD Clinical Trials Unit, Mater Research Ltd.
Study design
Allocation
Non-randomised trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1) Age>18 2) A diagnosis of UC 3) Disease in remission (SCCAI < 3 which is accepted as correlating with remission and has been confirmed in prospective validation cohorts, no specific duration of remission mandated) 4) On 5-ASA therapy, ideally on Mezavant at 4.8 g/day or Pentasa at 4 g/day.
Exclusion criteria
1) Chronic renal impairment (eGFR< 60) 2) Significant liver disease defined as PSC or elevated liver function tests > 1.5 x upper limit of normal 3) Evidence of decompensated liver disease such as recurrent variceal bleeding, refractory ascites, or spontaneous hepatic encephalopathy 4) Findings highly suggestive of liver disease of an alternative or concomitant aetiology, including but not limited to chronic alcoholic liver disease, chronic hepatitis B or C infection, haemochromatosis, Wilson’s disease, a1-antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or secondary sclerosing cholangitis 5) Pregnancy or lactation (due to unknown risk profile of quercetin in pregnancy) 6) Active illicit drug or alcohol abuse 7) Need for chronic use of antibiotics 8) History of cholangiocarcinoma, colon cancer 9) History of a colectomy with > 1/3 bowel resected 10) Taking a polyphenol supplement chronically including resveratrol, curcumin, green tea extract, quercetin 11) Taking an immunosuppressant or biologic for IBD 12) Hypersensitivity to quercetin
Outcome results
None listed