URSO - Ursodiol

Pharmacology: Ursodiol, a naturally occurring bile acid, is present as a minor fraction of the total human bile acids. Oral administration of ursodiol increases this fraction in a dose related manner, to become the major biliary acid.

The cholesterol-lowering effect observed following the administration of ursodiol in patients with primary biliary cirrhosis could be related to an improvement of cholestatis, modifications in cholesterol metabolism, or both. Changes in the endogenous bile acid composition induced by ursodiol might be the common denominator of these two mechanisms.

Indications: For the management of cholestatic liver diseases, such as primary biliary cirrhosis (PBC) and PSC.

Cholestatic liver diseases are characterised by a decrease in bile secretion and bile flow.

The diagnosis of cholestatic liver diseases is based on the biochemical signs of cholestasis (such as an increase in alkaline phosphatase, ÿ-GT, bilirubin), and also an increase in IgM levels and the presence of antimitochondrial antibodies in PBC.

The monitoring of the efficacy of ursodiol in the management of cholestatic liver diseases should be based on the biochemical parameters of cholestasis, as described above, as well as on signs of hepatic cytolysis (such as AST, ALT) which are very often associated with cholestasis during the progression of the disease.

Therefore, liver function tests (ÿ-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored every month for 3 months after start of therapy, and every 6 months thereafter. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase.

Ursodiol is not indicated for the treatment of decompensated cirrhosis.

The long-term effect of ursodiol treatment for chronic cholestatic liver disease conditions has not been fully established. Results from clinical trials indicate that ursodiol treatment improves certain laboratory parameters, such as bilirubin level, and serum levels of alkaline phosphatase, AST, and ALT and IgM. Ursodiol may be effective in slowing down the progression of the disease.

Contraindications: In patients who are hypersensitive or intolerant to ursodiol or any of the components of the formulation.

Warnings: None.

Precautions: Patients with variceal bleeding, hepatic encephalopathy, ascites, or in need of an urgent liver transplant, should receive appropriate specific treatment.

Patient Monitoring: Lithocholic acid, the metabolite of ursodeoxycholic acid (ursodiol), is hepatotoxic unless it is effectively detoxified in the liver. Therefore, the following tests are important for patient monitoring: Liver function tests (ÿ-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored every month for 3 months after start of therapy, and every 6 months thereafter. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase.

Drug Interactions: Bile acid sequestrants such as cholestyramine or colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum based antacids have been shown to absorb bile acid in vitro and may be expected to interfere with ursodiol in the same manner as the sequestering agents.

Carcinogenesis, Mutagenesis and Fertility Impairment: Ursodiol has no carcinogenic, mutagenic or teratogenic effects in laboratory animals treated at higher doses than those intended for therapy in human and after long-term treatment.

Pregnancy: Teratogenic Effects: There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ursodiol should not be used in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus.

Lactation: It is not known whether ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ursodiol is administered to a nursing mother.

Children: The safety and effectiveness of ursodiol in children have not been established.

Geriatrics: Appropriate studies with ursodiol have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of ursodiol in the elderly are not expected.

Adverse Effects: The adverse reactions presented in Table I were observed in clinical trials in primary biliary cirrhosis with 180 patients (89 randomized to Urso treatment, 91 to placebo treatment). Adverse reactions occurring at a rate of 1% or higher in the Urso group and that are higher than placebo are included in Table I. Diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other toxicity are not included because they occurred at the same rate or a lower rate than placebo.

Overdose: Symptoms and Treatment: Accidental or intentional overdosage with ursodiol has not been reported. The most severe manifestation of overdosage would likely consist of diarrhea which should be treated symptomatically.

Symptoms of acute toxicity in animal studies were salivation and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters.

Dosage: The recommended adult dosage for ursodiol in the treatment of PBC is 13 to 15 mg/kg/day administered in 2 to 4 divided doses with food. See Table II.

Patient Monitoring: Liver function tests (ÿ-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored every month for 3 months after start of therapy, and then every 6 months. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase.

Capsule contains: ursodiol USP 250 mg. Nonmedicinal ingredients: carnauba wax, dibutyl sebacate, ethylcellulose aqueous, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and sodium starch glycolate. High density polyethylene bottles of 100. Store at controlled room temperature (15 to 30°C) in a closed container.

Comment
Urso does various good things. It alters the bile acid, which means that it reduces the amount of toxic bile acids. It also increases bile flow. It also has an effect on the immune system. What it does is make the immune system less active in damaging the liver cells. There are three reasons why it should work in these types of conditions where you have bile duct blockage.

A study published by the Mayo Clinic, in the New England Journal of Medicine looked at 90 patients of PSC. They had quite low doses of urso, doses which have been shown to be effective in PBC (Primary Biliary Cirrhosis). Unfortunately in this trial, over a 5 year period, there was no improvement at all with this low dosage.

Dr Chapman from Oxford collaborating with Royal Free hospital put patients on to high dose (20 mg/kilogram) trial of urso; doubled the dose of urso in a small study of 26 patients, giving either a high dose or a placebo for two years. There were some encouraging trends toward improvement in this quite small group of patients.

Improvement in liver biopsy appearance for the first time occured; improvement in the ERCP changes and by and large the treatment was very well tolerated. It has very little side effects but is expensive. It was also used to dissolve gall stones which is originally how it came about.

In Sweden they are about to start a trial of their 300 patients with high dose urso. It will take 2 to 5 years before the results are known. URSO seems to improves liver function tests as well as general well being in some people.

The clinical features of ulcerative colitis associated with PSC are:

• young onset of colitis at less than 20 years of age.
• male predominance
• colitis is symptomically mild where PSC is also present
• the outcome of colitis is unrelated to the outcome of PSC
• PSC may precede colitis symptoms
• there is some indication that colitis may get worse after transplant.

PSC can recur in transplanted livers. At 5 years after transplant, approximately 30% have a recurrence of PSC. However, the PSC is usually milder. The nature of PSC is long term and liver transplants are a relatively recent treatment (last 10-15 years). As a result, long term statistics are still not available on this.

If you are a long time sufferer of both PSC and UC, you have a greater risk of getting colon cancer. The risk level increases the longer you have these illness, being a 10% higher risk after 10 years, 35% higher risk at 20 years and a 45% risk at 30 years. If you have had both conditions for a long time, you should discuss the risk element with your GP/consultant and make sure that appropriate screening is carried out. Additionally, if you have had a liver transplant, you are at a higher risk of development colon cancer and extra surveillance for this condition is needed.

Questran

Questran will help with the itching - it doesn't affect jaundice. Questran is certainly the main drug used for itching. Urso doesn't have much effect on itching. It has some effect, but not a lot . But that will improve other factors. It will improve jaundice, probably. It certainly improves liver function tests and encourages bile flow. They work well together except that you can't give them together. The Questran sits in the bile. It is not absorbed into the body. It leeches out into it, in the salts which cause the itching and then is passed out in the motions and takes the itching with it. Urso is absorbed into the body, taken into the liver and becomes part of what is called the bile acid pool which circulates through the body.

If you are taking urso, it is important to take it 3 or 4 hours away from the Questran. The Questran will help the itching but will also take onto itself the Urso so that the Urso can't be absorbed.

Take your Questran or Calestipal before or after breakfast when it will do the most good and then take your urso later on in the day. An hour is a bit too soon - I would leave it longer than that. I would say three or four hours. Before and after breakfast is a good time for Questran and take urso at a different time. The idea being that if you take it before or after breakfast you have the maximum amount of bile in the gall bladder. You have your breakfast, and the bile comes out the gall bladder and it is then taken onto the Questran and passed out of your body which helps the itching.