1. Can you please describe the hypothetical mechanism by which a high (20-30 mg/kg) Urso dose works to slow the progression of PSC in those patients who experience this benefit? Is it "merely" that the drug "thins the bile" and eases its passage through the ducts, or is there more to it than that? In your view, why do some patients taking the high dose fail to benefit much, or at least as much, as other patients taking the same dose who are in the same stage of the disease?

A: The mechanism of efficacy of high dose urso is not known. It is known that children with cystic fibrosis need higher dose for efficacy, it may be that it is a more effective choleretic ie encouraging bile flow but we don't know. The paper from my group showing that the higher dose is more effecive is to be published soon in Gastroenterology.

2. Would you be able to estimate for us what the approximate half-life of Urso is in the body? We ask because people taking large doses (in one case, for example, sixteen 300 mg capsules daily) may find it more convenient to take 6 or 7 capsules at, say, 8 am, and another 7 or 8 capsules at, say, 8 pm. Does such a schedule pose the risk that: (A) some of the Urso may not be well absorbed by the body?; or (B) there may be sub-optimal levels of the drug in the body during the 12 hour interval between administrations?

A: A dutch group have shown that urso once a day is as effective as twice daily. The drug is recycling throughout and a 12 hour interval would be fine.

3. Do you think it likely that the high dose Urso program would yield benefits for a PSC patient's Ulcerative Colitis or Crohns? Alternatively, could the program exacerbate the symptoms (i.e., cause flareups) or hasten the progression of other digestive/intestinal conditions?

A: An interesting Question! High dose urso has not caused any problems with UC or Crohns. I believe that there may be theoretical benefits but there is no evidence yet.

4. Would there be any potential benefit from taking higher dosages of Urso (i.e., 40 or 50 mg/kg)? Or are the potential adverse effects too great to warrant this dosage?

A: we are studying 30mg/kg if it looks a better dose than 20mg/kg we may study 40mg/kg.

5. For patients in Stage II or III of their PSC progression, do you recommend a somewhat different dosage or protocol of Urso/Actigall therapy?

A: I do not advise a different dose regimen at different disease stages. There is no evidence to justify diff dosages.

6. For patients with variants of PSC-such as Small Duct PSC-do you recommend a different dosage level of Urso; or are there other differences in your recommended treatment?

A: Good question, but we don't know. We are about to publish our experience with small duct PSC, anecdotally they seem to respond well to high dose urso.

7. Short of ERCP or biopsy, how can we tell if the high dose is working for us (if we are likely to be among the group that benefits from it)? For example, if pruritus is significantly reduced after commencing the high dose regimen, does this suggest that the high dose will slow progression? Along these lines, what meaning is there to lowered LFTs? Is the only real indicator a biopsy or ERCP, and how long does one have to wait to see the results of the high dose in those tests?

A: The markers of reponse are indirect ie LFT's, gold standard remains liver biosy and or ERCP. I dont believe that MRCP is good enough yet, and other surrogate markers of fibrosis are being developed but not yet on stream.

9. Are you aware of reports regarding any medium- or long-term negative side effects of the high Actigall dose?

A: I am unaware of any long term negative side effects of urso.

10. Do you think that taking Urso within, say, 1-2 hours, of taking SAM-e; Vitamins B and E; or Milk Thistle or N Acetyl Cysteine (these are all supplements that many of our members are currently taking) poses a risk for sub-optimal bioavailability of Urso? Conversely, would administration of Urso at the same time as these nutrients pose a significant chance of diminishing the bioavailability of these nutrients? How about taking Urso at the same time as other drugs (for example, Asacol or other medications for Ulcerative Colitis)? We ask this because, given the need to avoid taking Urso within as many as five hours of taking Cholestyramine/ Questran, it may be difficult for some people to arrange to take Urso at a different time from when they take other drugs.

A: as you say urso should be taken 2 hrs away from Questran, there is no data but no reason to suppose that the other agents you mention would interfere with the absorption of urso

11. Speaking of various nutrientional supplements, what are your thoughts regarding the likely or possible benefits of taking Milk Thistle, SAM-e, Glutathione and NAC (that is, for slowing the progression of PSC or mitigating some of its symptoms)? Many of our members take some or all of these and other nutrients, but we recognize that authoritative scientific evidence in support of a benefit for chronic liver disease (or PSC in particular) has yet to be advanced. In the absence of authoritative scientific evidence, it would be valuable for us to hear your insights or even your speculative thoughts about which nutrients/non-drug supplements might plausibly be used to try to slow the progression of PSC.

A: There is really no evidence to support the use of these agents ie milk thistle, in PSC, but they appear to do no harm!

12. Would you please discuss the prospects for finding the cause and the cure for PSC in the next, say, ten years? Are there particular scientists, research projects, or subspecialties of research (genetic research or canalicular research, etc) that you feel hold particular promise?

A: I cannot forsee a cure for PSC in 10 years. I think we will better understand the molecular basis of the disease and relationship with colitis ,and it is possible that anti cyokines may offer a lot of benefit, but a cure is unlikely.

13. What are your thoughts regarding how PSC patients and their families can assist in the search for the etiology and cure of the disease? For example, would it help if our members offered to enroll in a large, multi-center (country) trial of your high-dose Urso/Actigall protocol? Are there significant potential benefits to be derived from a relatively large genetic study that seeks to identify the Single Nucleotide Polymorphism(s) implicated in PSC? Would you be willing to help us to plan such a project?

A: I'm sure that your suggestion of large multi center trials is absolutely correct, the logistics of a Brit organising a US trial would are considerable however although I would be very happy to be involved in helping to design the study. I know that Dr Keith Lindor at the Mayo Clinic in Minnesota is currently thinking about such a trial. Again the idea of a large US data base is exciting and important but prob requires a US investigator such as Dr Lindor to coordinate it. The other person would be Dr Jenny Heathcote in Toronto, Canada.

I'm sorry to have taken so long to reply but I will try and be prompter in future!
Please keep in touch,

best wishes
Roger Chapman

www psc-literature.org