Contraindications:

Ursodeoxycholic acid is contraindicated in acute inflammation of the gall bladder and bile ducts; and obstruction of the biliary tract (common bile duct)

Adverse-Reactions:

Gastrointestinal: Diarrhoea, nausea, digestive tract disorders, etc.

Miscellaneous: Elevated creatinine, elevated blood glucose, leukopenia, skin rash etc.

Therapeutic Uses:

Ursodeoxycholic acid (UDCA) is currently used for the treatment of acute and chronic cholestatic liver disease and for cholesterol gallstone dissolution

Dose and Dosage Regimen

. Gallstone Prevention

600 mg/day (300mg twice daily )

Gallstone Dissolution

8 to 10 mg/kg/day given in 2 or 3 divided dose

Primary biliary cirrhosis

15 mg/kg/day given in 2 or 3 divided dose

Gallstone Prevention and Dissolution:

Ursodeoxycholic aid sustained-release formulation is indicated for the prevention and treatment of gallstone. It may be used alone or in combination with other bile acid agents.

Gallstone or cholelithiasis:^{9, 10}

Gallstones are small, pebble-like substances that develop in the gallbladder. Gallstones form when bile stored in the gallbladder hardens into pieces of stone-like material, if the liquid bile contains too much cholesterol, bile salts, or bilirubin, it can harden into gallstones. The two types of gallstones are cholesterol stones and pigment stones. Cholesterol stones are usually yellow-green and are made primarily of hardened cholesterol Pigment stones are small, dark stones made of bilirubin. Bile trapped in bile ducts can cause inflammation in the gallbladder, the ducts, or in rare cases, the liver. Sometimes gallstones passing through the common bile duct provoke inflammation in the pancreas called gallstone pancreatitis an extremely painful and potentially dangerous condition.

Gallstone is treated by two way , first is Cholesterol gallstones can sometimes be dissolved by oral ursodeoxycholic acid, but it may be required that the patient takes this medication for up to two years. Gallstones may recur however; once the drug is stopped and second one is surgically gallbladder removal has a 99% chance of eliminating the recurrence of cholelithiasis. Only symptomatic patients must be indicated to surgery.

Figure: Gallstones in the bile duct.

Indications for ursodeoxycholic acid¹¹

Ursodeoxycholic acid has been tested in various liver diseases. Primary biliary cirrhosis and primary sclerosing cholangitis are two diseases in which ursodeoxycholic acid has been used most extensively.

Ursodeoxycholic acid: potential indications

Acute liver diseases

· cholestasis of acute viral hepatitis

· acute alcoholic hepatitis

· recurrent cholestasis of pregnancy

· acute graft-versus-host disease

· acute rejection following livertransplant

chronic liver diseases

* cholestatic: primary biliary

cirrhosis, primary sclerosing

Cholangitis

* noncholestatic: chronic active

hepatitis, cirrhosis of the liver with activity

PRIMARY BILIARY CIRRHOSIS

This is a progressive cholestatic disease characterized by bile ductular destruction. The interlobular and septal bile duct injury is associated with accumulation of toxic hydrophobic bile salts. There is also an aberrant expression of HLA class I and class II molecules on hepatocytes and bile duct epithelial cells. There have been several uncontrolled (table 1) and randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis (table 2), most of which have yielded promising results. Because of the small number of patients in each report a meta-analysis would be the preferable method to examine these results. Unfortunately, the methodological variations, differences in inclusion and exclusion criteria, and the different stages at which the patients were included in these studies, preclude a meta-analysis of the existing data. The studies published to date show an improvement in the clinical and laboratory parameters of cholestasis and inflammation. Significant improvement in the post-treatment values compared with pretreatment values have been reported for serum alkaline phosphatase, alanine transaminase and yglutamyl transferase. Improvement in the laboratory parameters occurs within the first few months, reaching a plateau after three to six months of therapy. The effects of ursodeoxycholic acid on laboratory parameters seem to be consistently better than those on clinical manifestations. A beneficial effect on survival free of transplant (time to transplant or death without transplant) has been reported in a single randomised controlled trial.

Ursodeoxycholic acid in

primary biliary cirrhosis

* clinical improvement

* improvement in liver function tests

* improvement in histology and

survival not established

* improvement not seen in advanced

Disease

* beneficial effect not sustained

Table 1 Ursodeoxycholic acid in primary biliary cirrhosis (non randomized trials). All studies showed beneficial response to therapy

No of patients	Daily dose
7	600 mg
14	10-12 mg/kg
10	1800 mg
17	7-9 mg/kg
10	500 mg
29	10-15 mg/kg
12	600 mg
19	10-15 mg/kg
11	10-15 mg/kg

Table 2 Ursodeoxycholic acid therapy in primary biliary cirrhosis (controlled trials). No deterioration in symptoms was observed in any study.

patients	(months)	response*	response*	response
0 20	0 9	Y	Y	no change
088	12	Y	Y	no change
045	12	Y	Y	no change
145	24	Y	Y	improved
222	24	N	Y	no change**
180	48	N	Y	no change
064	24	N	Y	no change**
012	03	Y	Y	no change
045	6	N	Y	no change

*Y = significantly improved; N = not improved; **A trend towards improvement was observed even though no objective improvement was documented.

Heathcote et al have combined raw data from three large, randomized controlled trials (French, American and Canadian) and followed up these patients subsequently. It has been shown that not only was survival free of transplantation extended with ursodeoxycholic acid (mean of 3.66 vs 3.45years, p=0.014) but the risk of dying or being transplanted was reduced by 32% (11%) in the ursodeoxycholate group. It has also been shown thatursodeoxycholic acid improved survival over that expected from a validated, adjusted model natural history. A trend towards histological improvement has been reported in three controlled trials. Portal inflammation and piecemeal necrosis have reportedly decreased. In an uncontrolled trial, improvement has also been observed in established fibrosis.

The results of therapy with ursodeoxycholic acid showed a lower efficacy in patients with advanced stages of disease. The improvement in clinical and laboratory parameters is not sustained in these patients, and deterioration has been observed within three or four weeks of discontinuation of therapy, as well as after a year of uninterrupted therapy. Finally, data have been presented showing histological deterioration accompanied by improvement of clinical and biochemical parameters on ursodeoxycholic acid therapy. Thus, it seems that ursodeoxycholic acid may be useful as an adjuvant for primary biliary cirrhosis rather than as a primary treatment.

PRIMARY SCLEROSING CHOLANGITIS:

Primary sclerosing cholangitis is a chronic cholestatic liver disease with inflammation, fibrosis and destruction of the large intra- and extra-hepatic bile ducts. The bile acid profile in patients with primary sclerosing cholangitis has been shown to be similar to that of patients with primary sclerosing cholangitis with increased levels of hydrophobic bile acids. Three uncontrolled and placebo-controlled trials of treatment with ursodeoxycholic acid in primary sclerosing cholangitis have been reported. An inconsistent improvement in symptoms has been accompanied by consistent improvement in laboratory parameters of cholestasis and necro-inflammatory activity. Withdrawal of ursodeoxycholic acid results in deterioration within four weeks. Improvement in parenchymal and portal inflammation and hepatocyte necrosis was observed in a small number of patients. The effect of ursodeoxycholic acid on survival has not been assessed because of the small number of patients. In primary sclerosing cholangitis the role of ursodeoxycholic acid is at best adjunctive to therapy with other agents.

ACUTE VIRAL HEPATIS:

The majority of patients with acute viral hepatitis have a self-limiting illness with a complete resolution and no long-term squeal. A subgroup of patients with acute viral hepatitis develop a prolonged cholestatic course with intolerable pruritus. Such patients may benefit from ursodeoxycholic acid therapy.

A prospective, randomised, double-blind trial has recently demonstrated that ursodeoxycholic acid may prevent the development of chronic hepatitis B by enhanced clearance of hepatitis B virus.

CHRONIC LIVER DISEASE:

The first report of the role of ursodeoxycholic acid in hepatic diseases arose from the serendipitous observation of improvement in levels of transaminases in patients with gallstone disease and coexistent chronic hepatitis.59 Several randomised double-blind trials of patients with chronic hepatitis have subsequently shown improvement in biochemical parameters (table 3).6064 In three of these studies, the duration of treatment was short and, following discontinuation, enzyme values returned to pretreatment levels within four weeks in the majority of patients. The mechanism of action of Ursodeoxycholic acid in chronic hepatitis may be related to its membrane stabilizing, choleretic or immunomodulatory action. The major limitation of this therapy is the lack of antiviral effect. A recent study from Germany has shown that Ursodeoxycholic acid has no positive impact on HCV RNA titers or HCV IgM in patients with chronic hepatitis C and the major mechanism for improvement in liver enzymes is the choleretic effect of ursodeoxycholic acid. An Italian study has shown that ursodeoxycholic acid might induce alanine transaminase normalisation in patients with chronic hepatitis C not responding to interferon treatment. In autoimmune hepatitis type 1 ursodeoxycholic acid has been shown to induce a significant fall in IgG and y-globulins and an improvement in intra hepatic inflammation but not fibrosis.

Table 3 Ursodeoxycholic acid in chronic liver disease. All studies were randomized controlled studies. All showed a benefit of therapy.

Disease	No of patients	Daily dose (mg)	Duration of therapy
chronic actve hepatits	14	10	1year
chronic persistent hepatitis	7
cirrhosis	82
chronic active hepatitis	36	300	6 months
increased transaminases	30	600
chronic active hepatitis	26	450	12 weeks
cirrhosis	27	450	6 months

In combination with vitamin K1, ursodeoxycholic acid has been shown to reduce the haemorrhagic tendency in patients with decompensated cirrhosis of the liver.68 On the basis of the existing data, however, no definite recommendation can be made for the dose, duration or efficacy of ursodeoxycholic acid in chronic hepatitis or liver cirrhosis.

INTRAHEPATIC CHOLESTASIS OF PREGNANCY:

Ursodeoxycholic acid has been tried in an open-label trial in eight patients with cholestasis of pregnancy. Significant improvement was reported in pruritus and serum alanine transaminase levels, No adverse effects were reported in the mother or child. All patients had received ursodeoxycholic acid in the second half of the pregnancy, ie, after organogenesis. Randomised double-blind trials are required before ursodeoxycholic acid can be considered as a therapeutic option for intrahepatic cholestasis of pregnancy. Amniotic fluid and umbilical cord bile acid content in patients with intrahepatic cholestasis of pregnancy may pose a threat to foetal well being. Ursodeoxycholic acid may also help in normalizing the bile acid profile in umbilical cord blood and in amniotic fluid, thus protecting the fetus from the adverse effects of abnormal amounts of bile acids.

GRAFT-VERSUS-HOST DISEASE:

Graft-versus-host disease occurs when an immune competent donor T cell recognizes the recipient's antigens as foreign, resulting in an immune-mediated injury. Chronic cholestasis results in up to 80% of patients. The similarity between chronic graft-versus-host disease and primary biliary cirrhosis led to an uncontrolled trial of ursodeoxycholic acid in which 13 patients with chronic refractory graft-versus-host disease were treated with 10- 15 mg/kg of ursodeoxycholic acid daily for six weeks. There was symptomatic improvement and biochemical parameters of cholestasis also showed improvement during therapy, although enzyme values returned to pretreatment levels following its discontinuation.

ACUTE REJECTION OF LIVER TRANSPLANT:

Acute rejection of liver transplant has been treated with cyclosporine, corticosteroids, antilymphocyte globulin and FK-506.Adjuvant therapy with ursodeoxycholic acid after orthotopic liver transplant may be beneficial (table 4). Patients treated prospectively with ursodeoxycholic acid had fewer episodes of acute rejection than historical controls. Ursodeoxycholic acid appears to have a role in preventing recurrent and/or steroid-resistant rejection following orthotopic liver transplant, but the mechanism of action is not known.

CONCLUSIONS:

Ursodeoxycholic acid is a hydrophilic bile acid with membrane-stabilizing, cytoprotective, and imunomodulatory effects on liver cells. It has been shown to exert beneficial effects in various liver diseases, especially those with cholestatic features. The majority of data on the use of ursodeoxycholic acid in cholestasis have been derived from uncontrolled trials. It is reported to have a beneficial effect in primary biliary cirrhosis, primary sclerosing cholangitis and chronic graft-versus-host disease. Potential uses of ursodeoxycholic acid that exploit its cytoprotective properties include fulminant and subacute hepatic failure. Controlled trials are required before definite recommendations can be made.

Table 4 Effect of addition of ursodeoxycholic acid to the immunosuppressive regime following orthotopic liver transplantation.

Parameter assessed one month	Control	Ursodeoxycholic acidacid
after transplantation	(n=8)	(n=41)
Recipients with acute rejection	75%	17%*
Aspartate transaminase (IU/1)	78.1 + 18.0	42+6*
Alanine transaminase (IU/1)	114.1+24.0	54 + 12*
Alkaline phosphatase (IU/1)	762 + 180	366 + 42**
Bilirubin (,umol/l)	86 + 34	40 + 9

*p<0.05; **p<0.01

Example of marketed product:¹²

URSOFALK:^®

DESCRIPTION:

Ursodeoxycholic acid (UDCA) is a white or almost white powder. It is practically insoluble in water, readily soluble in alcohol, sparingly soluble in acetone, in chloroform and in ether. It melts at 200 - 204°C. The IUPAC chemical name of UDCA is 3a, 7β-dihydroxy-5-cholan-24-oic acid. Its CAS number is 128-13-2. Ursofalk Capsule contains ursodeoxycholic acid 250 mg, maize starch, colloidal silicon dioxide, magnesium stearate, gelatin and titanium dioxide.

PHARMACOLOGY:

In patients with severe liver disease, renal excretion becomes a major route for elimination of bile

Clinical Trials:

Primary Biliary Cirrhosis:

Five pivotal randomised, double-blind control studies examined the efficacy of ursodeoxycholic acid in the treatment of primary biliary cirrhosis. All 5 trials were of at least 2 years follow-up. Four of the five studies used a dosage in the range of 10 - 15 mg/kg/day; the fifth trial used a significantly lower dose of 7.7 ± 0.2 mg/kg/day. Significant improvement in some or all biochemical tests of liver function was shown in subjects given UDCA during the treatment period. Symptom improvement or improvement in histology was not consistently reported with UDCA but longer survival without liver transplantation was reported in two long term studies. One of the studies reported that the efficacy of UDCA in patients with primary biliary cirrhosis was greater in patients with less advanced disease (entry bilirubin < 2mg/dL; histological stage I or II) compared to patients with more advanced disease.

Primary Sclerosing Cholangitis:

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation, fibrosis, and destruction of the large intra- and extra-hepatic bile ducts. One pivotal randomized, double-blind placebo-controlled study examines the efficacy of UDCA in the treatment of PSC in 105 patients over 2 years. The dosage used was in the range of 13 - 15 mg/kg/day. Irrespective of initial histological stage, UDCA had no effect on time to treatment failure and survival, without liver transplantation. Serum bilirubin, ALP and AST improved, but UDCA was not associated with a significant improvement in symptoms or histological score. In three smaller randomised, double-blind, placebo-controlled studies, UDCA similarly showed significant improvement in liver biochemistry (in 2 of the studies) when compared to placebo, but did not significantly improve symptom scores. One study found significant improvement in some liver histological features in the patients treated with UDCA. These trials used UDCA doses ranging from 10 - 15 mg/kg/day.

Cystic fibrosis-related cholestasis:

Cystic fibrosis (CF) is a hereditary disease with multi organ involvement. Clinical liver disease is rare although many patients may have biochemical evidence of cirrhosis. One double-blind, placebo-controlled, study randomised 55 patients with CF to UDCA 900 mg/day or placebo for one year. In addition, taurine supplements or placebo were randomly assigned. Efficacy was assessed by improvements in clinically relevant and nutritional parameters, and liver biochemistry. After one year, the UDCA group had significant improvement in GGT and 5'-nucleosidase but not AST or ALT. However, there was a deterioration of overall clinical condition, as measured by the Shwachman-Kulcycki score in those receiving placebo compared to the UDCA group.

In a dose comparison study, UDCA 20 mg/kg/day for 12 months resulted in a more pronounced improvement in GGT and ALT compared to UDCA 10 mg/kg/day. Improvements in AST and ALP were comparable. Although this study suggested a possible benefit with higher drug doses in resolving liver biochemistry, whether UDCA improves quality of life, histology, or survival is unknown.

INDICATIONS:

URSOFALK is indicated in the treatment of chronic cholestatic liver diseases.

CONTRAINDICATIONS:

URSOFALK must not be used in the presence of acute inflammation of the gall bladder and bile ducts; and obstruction of the biliary tract (common bile duct).

PRECAUTIONS:

During the first three months of therapy, it is advisable to monitor the liver parameters of AST (SGOT), ALT (SGPT), and GGT every 4 weeks, subsequently every 3 months.

Pre-existing radiolucent gallstones may occasionally become calcified. The clinical significance of this observation is unclear.

The effect of URSOFALK in patients with renal impairment has not been studied.

Carcinogenicity/mutagenicity and Impairment of Fertility:

In two 24-month oral carcinogenicity studies in mice, ursodeoxycholic acid at doses up to 1000 mg/kg/day was not tumourigenic. Based on body surface area (BSA), this dose represents 5 times the recommended maximum clinical dose of 16 mg/kg/day. In two 2-year oral carcinogenicity studies in rats, ursodeoxycholic acid at doses up to 300 mg/kg/day (3 times the recommended maximum human dose based on BSA) was not tumourigenic.

In 103-week oral carcinogenicity studies of lithocholic acid, a metabolite of ursodeoxycholic acid, doses up to 250 mg/kg/day in mice and 500 mg/kg/day in rats did not produce any tumours.

URSOFALK was not genotoxic in the following studies: gene mutation assays (in vitro Ames test, gene mutation assay at the TK locus in mouse lymphoma L5178Y cells), assays of chromosome aberrations (analysis of chromosome aberrations in Chinese hamster bone marrow and in spermatogonia of mice, and micronucleus test in hamsters) and assay of sister chromatid exchanges in cultured human lymphocytes.]

In a fertility study in Sprague-Dawley rats at oral doses up to 2700 mg/kg/day (27 times the maximum recommended human dose based on BSA), no adverse effect on male or female fertility or pregnancy outcome were observed. However, in an oral fertility study in Wistar rats, there was evidence of a reduction in female mating behavior at doses ≥ 250 mg/kg/day (2.5 times the maximum recommended human dose based on BSA) and of embryolethality (resulting in a reduction in number of live fetuses) at doses ≥ 1000 mg/kg/day.

Use in pregnancy (Category B3)

URSOFALK has been shown to cross the placenta in rats. There was no evidence of a teratogenic effect of URSOFALK following oral administration to rats, mice or rabbits at doses of up to 4000, 1500 and 300 mg/kg/day, respectively. In one of two studies in rats, there was evidence of embryolethality, with a reduction in number of live fetuses and live births at oral doses of 2000 mg/kg/day.

There are no adequate or well-controlled studies in pregnant women. URSOFALK should not be used during the first three months of pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with URSOFALK.

Use in lactation:

It is not known whether URSOFALK is excreted in human milk but small amounts of UDCA or its metabolites were excreted in milk of lactating rats following oral administration of 30 mg/kg. In an oral peri-postnatal study in rats, there was a slight transient reduction in postnatal body weight gain of pups at 2000 mg/kg/day. The possibility of adverse reactions on the infant should be considered if URSOFALK is administered to a nursing mother. Alternatively, nursing can be discontinued.

Interactions with other drugs:

Some drugs, such as cholestyramine, charcoal, colestipol and certain antacids (e.g. aluminium hydroxide) bind bile acids in vitro. They could therefore have a similar effect in vivo and may interfere with the absorption of URSOFALK.

UDCA may increase the absorption of cyclosporin in transplantation and non-transplant patients. Therefore, monitoring cyclosporin plasma concentrations are recommended.

UDCA has been reported to decrease the absorption of ciprofloxacin in a few cases.

ADVERSE REACTIONS:

UDCA is generally well tolerated with few side effects. Diarrhoea is the main reported side effect. The incidence of diarrhoea in controlled studies was up to 3%.

Some patients may experience increased pruritus in the early weeks of treatment. In such cases a dose reduction, and thereafter a slow (weekly) increase of dose to the recommended dose, may help.

Allergic reactions have been reported in some patients.

Other adverse reactions reported include increased cholestasis, nausea, and vomiting and sleep disturbance.

DOSAGE AND ADMINISTRATION:

Adults and the elderly:

10 - 15mg UDCA per kg per day in two to four divided doses are recommended for PBC (primary biliary cirrhosis) and chronic cholestic liver diseases other than CF (cystic fibrosis). This dose can be approximated as follows:

For the capsule:

body weight (kg)	daily dose	Number of capsules
body weight (kg)	(capsules)	morning	noon	evening
34 - 50	2	1	-	1
51 - 65	3	1	1	1
66 - 85	4	1	1	2
86 - 110	5	1	2	2
Over 110	6	2	2	2

For CF, the general recommended dose is up to 20 mg/kg/day. This dose has been shown to improve histology in PSC patients.

Children:

Data on use in children are very limited. In the few available studies, dosages used have generally been up to 15 - 20 mg/kg/day.

In patients with primary biliary cirrhosis, there may, in rare cases, be an initial deterioration in symptoms, e.g. itching. If this is the case, therapy can be continued with 1 capsule of URSOFALK daily, and the daily dose gradually increased until the recommended daily dose has been reached.

OVERDOSAGE:

Serious adverse effects are unlikely to occur in over dosage. However, liver function should be monitored. If necessary, ion-exchange resins may be used to bind bile acids in the intestines.

PRESENTATION:

Ursofalk Capsules are presented as white, opaque, hard gelatin capsules. It is supplied in clear PVC blister strips of aluminium foil backing packed in cardboard cartons. Each carton contains 100 capsules.

Storage Condition:

Store below 25°C

Date of Preparation:

3 September 2007

Provisional consent for distribution of Ursofalk Capsules under section 23 of the Medicines Act has been granted. This approval was gazetted in the New Zealand Gazette notice on 28 October 2004.

REFERENCES:

1) Arch Intern Med. 1999;159:2647-2658.

2) http://www.patient.co.uk/

3) http://www.drugbank.ca/

4) Merk index,8 ^thEdn. ,P.1098

5) Physician desk refrence -61,2007,P.710-71

6) Martin dale,35^th Edn., vol.I,P.No.2057,2182

7) European pharmacopoeia, 9 ^thEdn.,vol.I,P.416

8) British pharmacopeia 2005,vol. III, p..5856-2858

9) Wikipedia, the free encyclopedia.mht

10) Digestive Diseases A-Z List of Topics and Titles : Gallstones, www.google.com

11) Postgrad Med J 1997; 73: 75 – 80

12) Medisafe newz eland medicines and medical devices safty authority a business unit of ministry of health.

Received on 24.05.2010

Accepted on 12.06.2010

Research J. Pharmacology and Pharmacodynamics. 2(6): Nov. –Dec. 2010, 355-362

Molecular Structure
IUPAC Name	3α,7β-dihydroxy-5β-cholan-24-oic acid
Molecular Formula	(C24H40O4)
Molecular Weight	392.56
Melting Range	203-206 ºC
Bioavailability	Approximately 40 %
pKa	9.6
Log P	4.1300011444
pH	7.0 to 7.6 (of 2 % aqueous solution)
Plasma protein binding	Approximately 96-98 %
Plasma half life	3.5-5.8 days.
Stability	Stable molecule
Solubility	Freely soluble in ethanol, methanol and glacial acetic acid; sparingly soluble in chloroform, slightly soluble in ether and insoluble in water.
Description	White odourless crystalline powder and bitter in test.
Category	treatment of chronic cholestatic liver diseases..
Standards	Contains 95.0 - 110.0 % of (C₂₄H₄₀O₄) calculated on the dried basis
Moisture content	Less than 0.5 %
Storage	Preserve in tight containers at controlled room temperature
Pharmacology^4,5,6,7,8	Ursodeoxycholic acid is a secondary bile acid formed in the intestine. It involved in the emulsification of fats in intestine. it is choleretic and decreases the concentration of cholesterol in the bile. The pharmaceutical preparation of ursodeoxycholic acid, is used to treat biliary diseases by dissolving radiolucent and noncalcifying gallstones.