Re: still confused about urso dosage

June 10, 2006

Hi Clint;

I might recommend reading this article:

Harnois DM, Angulo P, nsen RA, Larusso NF, Lindor KD 2001 High-

dose ursodeoxycholic acid as a therapy for patients with primary

sclerosing cholangitis. Am. J. Gastroenterol. 96: 1558-1562.

which is in the " Files " folder: " High Dose Urso Harnois.pdf "

It explains in the Introduction that .... " UDCA at a dose of 10–15

mg/kg per day has consistently improved liver biochemistries in PSC

patients in several trials (7–10). UDCA at a dose of 13–15 mg/kg per

day led to a significant biochemical improvement, but did not improve

other outcomes in the largest randomized, controlled trial after as

much as 6 yr of follow-up (7). This contrasts with the long-term

effects of UDCA in primary biliary cirrhosis (PBC), another chronic

cholestatic liver disease with a less erratic course than PSC. The dose

of 13–15 mg/kg per day has shown to improve long-term survival in

patients with PBC (11) Thus, it seemed feasible to hypothesize that in

PSC, a dosage of UDCA higher than 15 mg/kg per day would be necessary

to see a beneficial effect on clinically relevant endpoints such as

disease progression and long-term survival. On the other hand, although

UDCA at a dose of 13–15 mg/kg per day is safe, a doubling of the dose

may, in theory, be associated with adverse events. To deal with these

issues we conducted an open-label pilot study aimed at assessing the

safety and efficacy of high-dose UDCA (25–30 mg/kg per day) in the

treatment of patients with PSC. "

While we don't still know whether high-dose UDCA will delay disease

progression and increase survival (trials are still in progress), this

preliminary trial did show:

" This expected survival at 4 yr was significantly different between

placebo and the dose of 25–30 mg/kg per day (p 5 0.04), but not between

placebo and the dose of 13–15 mg/kg per day (p 5 0.4). High-dose

UDCA was well tolerated. "

As the dose of ursodiol goes up, so does the biliary enrichment:

Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A 2004 Effect of high-

dose ursodeoxycholic acid on its biliary enrichment in primary

sclerosing cholangitis. Hepatology 40: 693-698.

also in the " Files " folder: " High Dose Urso RostD2004.pdf "

" At a UDCA dose of 10-13 mg/kg/d (n = 18) biliary UDCA represented

43.1% + 0.3% (mean + SD) of total bile acids; at a UDCA dose of 14-17

mg/kg (n = 14), its biliary content increased to 46.9% + 0.3%, at 18-21

mg/kg (n = 34) to 55.9% + 0.2%, at 22-25 mg/kg (n = 12) to 58.6% +

2.3%, and at 26-32 mg/kg (n = 8) to 57.7% + 0.4%. During UDCA

treatment, the biliary content of all other bile acids was unchanged or

decreased. In conclusion, biliary enrichment of UDCA increases with

increasing dose and reaches a plateau at 22-25 mg/kg. There was no

increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA

represents the decisive factor for its clinical effect, it seems likely

that UDCA doses of up to 22-25 mg/kg may be more effective than lower

doses. "

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)

>

> My question is why would I want to up the dosage with such an

improvement in my labs..Is the improvement just a coincidence?

June 10, 2006

> >

> > My question is why would I want to up the dosage with such an

> improvement in my labs..Is the improvement just a coincidence?

>

June 10, 2006

> >

> > My question is why would I want to up the dosage with such an

> improvement in my labs..Is the improvement just a coincidence?

>

June 10, 2006

> >

> > My question is why would I want to up the dosage with such an

> improvement in my labs..Is the improvement just a coincidence?

>

June 10, 2006

--- In , " relaytech1960 " > >

> So basically the article is saying that it may improve the labs but

> not the progression of the disease? thanks clint

That's correct Clint ... the low-dose of ursodiol seems to improve

liver biochemisty, but only the high-dose of ursodiol has been found

to improve liver biochemistry AND give results expected to translate

into prolonged survival. However, the evidence that it actually does

increase survival in long-term trials has not been obtained yet.

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)

June 10, 2006

> >

> So basically the article is saying that it may improve the labs but

> not the progressionof the disease?

> thanks

> clint

>

> > >

> > > My question is why would I want to up the dosage with such an

> > improvement in my labs..Is the improvement just a coincidence?

> >

>

What the articles are basically saying is that although there is

improvement in labs at 13-15 mg/kg, it is pretty well accepted that

this does not result in improvement in progression.

The jury is still out in higher doses currently being studied at a

level of 25-30 mg/kg. As with studies at lower doses there is an

improvement in lab results and some initial studies have shown some

potential improvement in progression but there is not enough data to

support a conclusion one way or the other.

Several of us are currently enrolled in a multi-center study with

Urso doses at the higher levels of 25-30 mg/kg. This is a 4 year

study. I enrolled fairly early on and will reach the 4 year mark at

the end of this year. I have heard there is a high probability that

this study will be extended beyond that because there has not yet

been enough data collected. Because Urso is generally well tolerated

with little or no side effects for most, most doctors prescribe the

high dose. Even though you have seen an improvement in labs at a

lower dose I would encourage you to push for the higher dose since it

is fairly well known the lower dose will not have much long term

impact.

in Seattle

UC 1991, PSC 2001

June 10, 2006