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It is also known as ursodeoxycholic acid (UDCA).
It is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.
The ursodeoxycholic acid in Ursobilane is an epimer of chenodeoxycholic acid (DB06777). It is an apparent precursor of bile acid or chenodeoxycholate product.
Its administration modifies the composition of the bile and can dissolve gallstones. It is used as a cholagogue and choleretic.
Chemical structure and characteristics
Bile acids are acid steroids that are synthesized from cholesterol within hepatocytes. Ursodeoxycholic acid represents a hydrophilic dihydroxy (i.e., 3a, 7b-dihydroxy-5b-cholan24-oic acid) bile acid.
The solubility of its protonated for ursodeoxycholic acid represents up to 4% of the bile acid pool. Because it is not synthesized in the liver, it probably originates in the colon by bacterial epimerization of the primary chenodeoxycholic.
After its formation, ursodeoxycholic acid is passively absorbed by the colonic mucosa to enter the portal circulation and subsequently into the bile acid pool.
Uses of ursobilane
Ursobilane has been used to treat cholestatic and other liver diseases. We review the major studies conducted for these liver disorders and discuss the use of ursobilane in clinical practice.
Primary biliary cirrhosis
Ursobilane therapy for two years leads to a reduction of clinically manifest disease and improvement of liver blood tests. It delays the rate of progression of primary biliary cirrhosis, resulting in less need for liver transplantation.
Furthermore, a combined multicenter analysis revealed that long-term ursobilane therapy (13 ± 15 mg/kg per day) improved liver transplant-free survival in patients with primary biliary cirrhosis with moderate or severe disease.
Patients with primary biliary cirrhosis who take ursobilane have a lower incidence of significant complications and lower medical costs.
Primary sclerosing cholangitis (PSC)
Initially, uncontrolled and controlled studies revealed promising effects of ursobilane in patients with primary sclerosing cholangitis.
However, the most extensive study, with primary sclerosing cholangitis and the use of ursobilane (13 ± 15 mg/kg per day) for a median follow-up of 2.2 years, did not reveal clinically beneficial results.
Although treatment with ursobilane improved the biochemical profile of the patients at 1 and 2 years, there were no significant differences.
The lack of a notable clinical effect of ursobilane in patients with primary sclerosing cholangitis may be related to the stage of the disease, the duration of treatment, and probably other factors relevant to the disease process itself.
They recently reported that treating patients with primary sclerosing cholangitis with high-dose ursobilane (25 ± 30 mg/kg/day) for one year led to improved biochemistry.
Therefore, the therapy of patients with primary sclerosing cholangitis with high doses of ursobilane (25 ± 30 mg/kg per day) is promising.
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy is a rare cholestatic entity of unknown etiology that affects pregnant women during the third trimester.
Intrahepatic cholestasis of pregnancy is characterized by severe pruritus, a cholestatic pattern of liver enzymes, and an increased rate of fetal distress, preterm delivery, and perinatal mortality.
Although the maternal prognosis is excellent after delivery, the potential adverse effect on fetal health dictates medical intervention.
In the first study, ursobilane improved itching and cholestasis and appeared safe for both mothers and babies before and after delivery.
Subsequently, in a study of patients with intrahepatic cholestasis of pregnancy, ursobilane (16 mg/kg per day) for three weeks improved pruritus and liver biochemistry in the treatment group.
Furthermore, three months after delivery, no adverse effects were observed in mothers or babies.
Ursobilane has been postulated to have a stimulatory effect on biliary excretion of 3a-sulfonated and sulfated steroids in intrahepatic cholestasis of pregnancy and facilitate bile acid excretion.
Recently, they reported that high doses of ursobilane (1.5 ± 2.0 g / d) could be even more effective in treating intrahepatic cholestasis of pregnancy without presenting toxic effects to mothers and babies.
Therefore, treatment of intrahepatic cholestasis of pregnancy with ursobilane may be justifiable.
Cystic fibrosis (CF)
Cystic fibrosis causes thick bile secretions that result in plugging and bile duct obstruction. Over time, the lesions lead to focal biliary fibrosis and subsequently to focal/multilobular cirrhosis.
Given the currently extended survival of patients with cystic fibrosis, the prevalence of hepatobiliary disease in these patients is expected to increase. Therefore, therapy that attenuates liver disease progression in cystic fibrosis would be beneficial.
The studies observed improved liver function and nutritional status in cystic fibrosis patients after ursobilane therapy. Ursobilane (15 mg/kg per day) improved cystic fibrosis’s biochemical and clinical parameters.
Recently, treatment of cystic fibrosis patients with ursobilane (10 ± 15 mg/kg/day) for two years improved liver histology.
The ideal dose of ursobilane in cystic fibrosis has been the focus of two studies, which showed that the amount of 20 mg/kg per day provides a more significant improvement in liver biochemistry than the lower doses.
In general, ursobilane should be considered potentially effective in patients with cystic fibrosis.
Whether ursobilane affects disease progression and survival in cystic fibrosis patients is unknown, and future studies should address these issues.
Progressive familial intrahepatic cholestasis (PFIC)
Progressive familial intrahepatic cholestasis or Byler’s disease, a recessive inherited disorder, is characterized by pruritus, intrahepatic cholestasis with eventual progression to cirrhosis, and hepatocellular failure that ultimately causes death before adolescence.
Using ursobilane at 20 ± 30 mg/kg per day for 2 to 4 years improves liver function and clinical status in these patients, suggesting that ursobilane should be considered in children with progressive familial intrahepatic cholestasis.
Bile duct insufficiency syndromes
These syndromes include biliary atresia, Alagille syndrome, and other syndromes of the disappearance of the bile ducts.
Ursobilane therapy should be beneficial to patients in improving / stabilizing cholestasis before liver transplantation.
Dissolution of gallstones
Ursobilane can dissolve cholesterol stones given its chemical and structural relationship with chenodeoxycholic acid; an agent studied extensively in the 1970s for this purpose.
In a pivotal study, Makino et al. first reported dissolution of the gallstone with ursobilane. Since then, ursobilane has treated gallbladder stones as an alternative to cholecystectomy.
The proposed mechanism of action involves the unsaturation of the bile by ursobilane, which leads to the dissolution of gallstones through the solubilization of cholesterol from the stone’s surface.
Candidates for ursobilane therapy should have less than 20 mm radiolucent gallstones and a patent cystic duct.
The recommended dose of ursobilane for gallbladder stones is eight ± 10 mg/kg per day, with higher doses providing no additional benefit in the outcome.
A dissolution rate of 30 to 60% has been reported. The absence or minimal change in gallstone diameter within 6 to 12 months of treatment with ursobilane represents a poor prognostic sign for dissolution.
After complete dissolution, ursobilane should be continued for three months to confirm the decomposition of microscopic stones that may escape ultrasonography.
Gallstone recurrence was reported to be 50 to 70% 12 years after successful treatment-limiting enthusiasm for this type of therapy.
Low-dose ursobilane (300 mg/day) as maintenance therapy decreased the gallstone recurrence rate over 90 years by nearly 50% compared to a control group.
Today, ursobilane may help treat gallstones in patients at high risk for surgical interventions.
Bile sludge
Today’s widespread use of ultrasound has led to the frequent description of bile sludge in many patients.
Sludge formation in the biliary system can be precipitated by rapid weight loss, pregnancy, total parenteral nutrition, ceftriaxone or octreotide therapy, and bone marrow or solid organ transplantation.
Ursobilane at 10 mg/kg per day clears gallbladder ‘microlithiasis’ within 3-6 months.
In addition, maintenance therapy with ursobilane (300 mg/day) prevents the recurrence of gallstones and further episodes of pancreatitis.
Therefore, ursobilane may play a role in selected patients with bile sludge, especially when surgical approaches are prohibited and therapy is necessary.
Graft versus host disease, which affects the liver
Graft versus host disease after allogeneic bone marrow transplantation can involve the liver and cause a cholestatic picture and venous-occlusive disease.
Studies have improved cholestasis in liver graft-versus-host disease after short-term treatment with ursobilane.
Prophylactic use of ursobilane (600 ± 900 mg/day) was reported to lead to a lower incidence of venous-occlusive disease in the treatment group.
While these findings are promising, further studies are required to define the long-term benefit of ursobilane in patients with liver graft versus host disease.
Liver allograft rejection
Given its proposed immunomodulatory properties, ursobilane was suggested to treat acute cellular rejection and was supported by promising data from uncontrolled studies.
Subsequently, randomized trials tested ursobilane as a prophylactic regimen to reduce the incidence of acute cellular rejection after liver transplantation.
In one study, the addition of ursobilane to the immunosuppression regimen resulted in fewer episodes of acute cellular rejection, a shorter hospital stay, and better survival of 90 days and one year.
The prophylactic use of ursobilane in acute cellular rejection after liver transplantation has yet to be established.
Drug-induced cholestasis
Published case reports have shown the beneficial effect of ursobilane in drug-induced cholestasis. Therefore, ursobilane in prolonged drug-induced cholestasis is reasonable.
Cholestasis is induced by total parenteral nutrition.
Although the pathogenesis of total parenteral nutrition-induced cholestasis remains obscure, it represents a clinical challenge, particularly in premature infants and adults with a history of Crohn’s disease that requires long-term bowel rest.
Successful improvement of hyperbilirubinemia was reported in one jaundiced patient during total parenteral nutrition. Subsequently, it was shown that ursobilane at 30 mg/kg per day causes the disappearance of biochemical profiles and clinical signs of cholestasis.
Benign recurrent intrahepatic cholestasis
This rare familial syndrome is characterized by recurrent episodes of cholestasis associated with jaundice, pruritus, fatigue, anorexia, and weight loss that persist for 3 to 4 months with subsequent full recovery.
Although experience with ursobilane in benign recurrent intrahepatic cholestasis is limited, a controversial empirical treatment with ursobilane should be considered.
Nonalcoholic steatohepatitis
Nonalcoholic steatohepatitis is characterized by histopathological findings of alcohol damage on liver biopsy despite the lack of alcohol abuse.
The recent increase in frequency in the diagnosis of nonalcoholic steatohepatitis and its possible progression to cirrhosis has led researchers to a study reporting that ursobilane (13 ± 15 mg/kg/day) but not the lipid-lowering agent clofibrate improved the profile—biochemical and hepatic steatosis of patients with nonalcoholic steatohepatitis.
Alcoholic liver disease
Ursobilane protected ethanol-induced damage in a human hepatocyte cell line and rat liver mitochondria.
In a study of patients with alcoholic cirrhosis, ursobilane (15 mg/kg per day) for four weeks caused an improvement in liver tests.
Pharmacokinetics
When administered orally, ursobilane is absorbed and extracted by the liver, where it is conjugated with glycerin and taurine.
These complexes are then secreted into the bile and undergo enterohepatic circulation in the same way as endogenous bile acids.
Because the ursodeoxycholic acid in ursobilane is confined within the enterohepatic circulation system in patients with normal liver function, serum ursodeoxycholic acid concentrations are deficient, and the drug is excreted in the feces as unchanged drug or bacterial metabolites.
However, in patients with primary biliary cirrhosis, ursodeoxycholic acid is efficiently absorbed, but its liver uptake and biliary secretion are impaired.
This leads to high serum ursodeoxycholic acid concentrations and reduces bile enrichment.
This could potentially result in decreased efficacy in patients with more advanced diseases.
In addition, renal clearance of ursodeoxycholic acid may be necessary for patients with severe bile duct obstruction. This is facilitated by sulfation or conjugation with glucose and N-acetylglucosamine.
Ursobilane is typically a bile acid that is used to treat gallstone problems. Gallstones can lead to symptoms such as jaundice, pain, and inflammation of the pancreas and gallbladder.
The gallbladder creates stones when the bile (usually a liquid) hardens. Calcium deposits in the gallbladder can also lead to stone formation. This can cause severe pain.
While doctors generally recommend surgery for patients with a severe gallstone problem, smaller stones can be treated with ursobilane (ursodeoxycholic acid).
Those stones that form from cholesterol are usually treated with ursobilane (ursodeoxycholic acid), as the drug can easily dissolve them. The drug can also be used in the treatment of primary biliary cholangitis.
Ursobilane administration
Before starting ursobilane (ursodeoxycholic acid), discuss your medical history with your doctor and inform him of any allergies or health problems you have. Also, please give him a list of the medications he is currently taking.
Tell your doctor if you are pregnant or trying to conceive. Nursing mothers should also discuss the pros and cons of taking the drug before starting the course with their doctor.
Ursobilane should be taken exactly as directed by your doctor. Your dose will depend on the severity of your condition. The doctor will usually advise you to take medicine at bedtime daily.
The medicine works best when taken directly after a meal or with a light snack. The mixture should be kept away from children and stored in a cool, dry place.
Mechanism of action
The ursodeoxycholic acid in ursobilane reduces elevated levels of liver enzymes by facilitating the flow of bile through the liver and protecting liver cells. The primary mechanism is antichollinic.
Although the exact process of ursodiol’s anticholnamic action is not fully understood, it is believed that the drug concentrates in the bile and lowers bile cholesterol by suppressing hepatic synthesis and cholesterol secretion and inhibiting its intestinal absorption.
The reduction of cholesterol saturation allows the gradual solubilization of cholesterol from gallstones, resulting in their final dissolution.
After oral administration, approximately 30 to 60% of ursobilane is absorbed from the intestine. Absorption occurs throughout the small intestine (~ 80%) and less in the colon (~ 20%).
Oral absorption of ursobilane is enhanced by the solubilization of bile acids, suggesting that it should be taken with meals.
After intestinal absorption, ursobilane enters the portal circulation and is then taken up by hepatocytes through specific bile acid transporters in their sinusoidal domain.
Namely, sodium taurocholate transporter polypeptide and organic anion transporter polypeptide.
Ursodeoxycholic acid is conjugated with glycine (mainly) or taurine within the hepatocyte. Subsequently, it is transported through its canalicular domain to the bile ducts through another bile acid carrier molecule called the bile salt export pump.
After secretion in the biliary system, ursodeoxycholic acid reaches the small intestine and then enters the enterohepatic circulation together with the other bile acids.
Ursobilane has a high first-pass metabolism approaching 70%, leading to its low blood level in the systemic circulation.
The ursodeoxycholic acid concentration peaks at one ± three h after administration in bile. After chronic ingestion, the degree of enrichment of ursodeoxycholic acid in bile correlates with its daily dose.
Ursobilane administered at eight ± 10 mg/kg per day produces an expected enrichment of approximately 40% in bile acids.
Ursobilane doses above ten ± 12 mg/kg per day do not further increase its proportion in bile due to its epimerization to chenodeoxycholic acid and the inability to inhibit hepatic synthesis of primary bile acids.
In humans, the half-life of ursobilane is 3.5 to 5.8 days, and the predominant route of elimination from the body is through the feces.
In the colon, unabsorbed ursobilane undergoes primarily microbial conversion to lithocholic acid, which probably remains insoluble in the colon contents and is subsequently excreted in the feces.
However, in studies of healthy individuals and cholestatic patients treated with ursobilane, ursodeoxycholic acid conjugates were increased in the latter group’s urine compared to normal subjects.
Increased renal clearance of ursodeoxycholic acid conjugates in cholestatic patients represents an essential pathway for ursodeoxycholic acid elimination.
Side effects
Gallstones commonly contain lumps of fatty material (similar to cholesterol) that have solidified and hardened.
Ursodeoxycholic acid is a bile acid that the body produces naturally, so the drug is generally well tolerated.
Drug absorption interactions with anion exchange resins deserve consideration. Metabolic interactions with compounds metabolized by cytochrome P4503A are expected.
Side effects occur when you take any type of medicine. Similarly, ursodeoxycholic acid can cause common side effects like diarrhea, skin rashes that can be very itchy, and a sick feeling.
If any of these symptoms become more complicated, it is best to see a doctor.
Effects with other medications
In contrast, the simultaneous use of other medications such as activated charcoal, aluminum-containing antacids, cholestyramine, and colestipol may decrease intestinal uptake of ursobilane due to intraluminal binding.
Therefore, it is recommended that it be administered 5 hours apart from those agents such as cholestyramine that can interfere with its intestinal absorption. Notably, the absorption and bioavailability of ursobilane may decrease in advanced cholestasis.
Side effects in clinical trials
No serious adverse effects of ursodeoxycholic acid administration were reported in early controlled clinical trials in patients with the biliary disease or long-term, large-scale placebo-controlled trials in patients with cholestatic liver disease.
A recent Cochrane review of ursodeoxycholic acid in primary biliary cirrhosis revealed no significant increase in total adverse events or serious adverse events in 10 controlled clinical trials.
The Cochrane group identified a single adverse severe effect among 990 patients with primary biliary cirrhosis. This patient was withdrawn from ursodeoxycholic acid treatment due to a recurrent episode of hemolytic anemia.
However, positive Coombs hemolytic anemia had already been diagnosed and treated in this patient five years before inclusion in the ursodeoxycholic acid trial.
After six months of treatment with ursodeoxycholic acid, a new episode of hemolytic anemia was diagnosed, treatment with ursodeoxycholic acid was discontinued, and steroids were administered for four months.
Ursodeoxycholic acid treatment was reintroduced the following year, and the patient did not experience ursodeoxycholic acid side effects until her death after another 12 years.
According to the clinical investigator, this serious adverse event was unrelated to the study drug.
Gastrointestinal disorders
The diarrhea was the most common adverse event in ursodeoxycholic acid in patients with gallstone disease and has been reported at 2 to 9%.
In patients with primary biliary cirrhosis, diarrhea was rarely observed and only incidentally reported in three of five large-scale trials.
An increased incidence of ursodeoxycholic acid diarrhea can be expected to treat patients with primary sclerosing cholangitis and inflammatory bowel disease.
Two studies reported severe diarrhea in one of six and two of 18 patients with inflammatory bowel disease during ursodeoxycholic acid treatment.
Diarrhea stopped immediately after the cessation of ursodeoxycholic acid in these patients.
Diarrhea was not documented in the largest randomized, placebo-controlled trial of ursodeoxycholic acid treatment of primary sclerosing cholangitis involving 102 patients.
The origin of diarrhea after the administration of ursodeoxycholic acid is unclear.
However, the bacterial conversion of ursodeoxycholic acid to chenodeoxycholic acid, which, unlike ursodeoxycholic acid, is a potent secretagogue in the colon, may contribute to this side effect.
Right upper quadrant abdominal pain was reported in two patients with primary biliary cirrhosis after ursodeoxycholic acid administration. Symptoms reappeared after re-exposure.
Abdominal pain and diarrhea were also reported in a ursodeoxycholic acid-treated patient with primary biliary cirrhosis who participated in a Canadian trial.
Abdominal pain, flatulence, and diarrhea were observed in nine of 99 patients who received ursodeoxycholic acid and six of 93 patients who received a placebo in a Spanish multicenter trial.
Nausea and vomiting were recorded in three of 111 ursodeoxycholic acid-treated patients and one of 111 placebo controls in the Canadian primary biliary cirrhosis trial.
Hepatobiliary disorders
Liver toxicity has not been demonstrated for ursodeoxycholic acid in controlled clinical trials.
This is in contrast to the well-described hepatotoxic effects of the hydrophobic 7α-epimer of ursodeoxycholic acid, chenodeoxycholic acid, which has been administered for medical treatment of gallstone disease in the past.
Hepatic levels of chenodeoxycholic acid in experimental cholestasis correlate with liver damage.
In animal studies, ursodeoxycholic acid has been shown to reverse liver cell damage induced by chenodeoxycholic acid.
Decompensation of liver cirrhosis has been observed in single cases during ursodeoxycholic acid treatment of late-stage primary biliary cirrhosis.
The causal relationship between ursodeoxycholic acid treatment and acute impairment of impaired liver function remains unclassified in most cases but is likely in at least one report.
Therefore, ursodeoxycholic acid treatment should be started at a low dose in jaundiced patients with stage IV primary biliary cirrhosis. The dose should be increased with regular monitoring of serum bilirubin levels.
An increase in serum bilirubin after initiation of ursodeoxycholic acid treatment may require discontinuation of ursodeoxycholic acid therapy.
Neoplasias
There is no evidence of a mutagenic or carcinogenic potential for ursodeoxycholic acid in humans.
In contrast, in patients with primary sclerosing cholangitis and concomitant ulcerative colitis, who are at increased risk of developing colon carcinoma, treatment with ursodeoxycholic acid may even decrease the risk of colon neoplasia, dysplasia, or cancer.
Although these exciting findings still require confirmation by large-scale prospective trials, they are supported by experimental studies.
In a model of colon carcinogenesis induced by intrarectal administration of N-methyl nitrosourea in rats, ursodeoxycholic acid feeding was associated with lower development of colon carcinomas.
So far, it is not clear whether treating primary sclerosing cholangitis with ursodeoxycholic acid can decrease the risk of developing cholangiocarcinoma by reducing inflammation around the bile ducts and ducts.
However, a diet enriched with ursodeoxycholic acid stimulated hepatocyte proliferation and tumor growth in hepatitis B virus transgenic mice.
Nervous system disorders
Neurological disorders have not been reported after the administration of ursodeoxycholic acid.
Although this has not been proven, ursodeoxycholic acid is membrane permeable and can pass through the human blood-brain barrier.
The distribution of radiolabeled ursodeoxycholic acid in rats was limited to the enterohepatic circulation.
The pregnancy
The embryotoxicity of ursodeoxycholic acid has not been reported in humans.
However, ursodeoxycholic acid is not approved for use during early pregnancy because there is insufficient data on the risk of ursodeoxycholic acid to the fetus in the first trimester of pregnancy.
Ursodeoxycholic acid is considered safe for the fetus and the mother in intrahepatic cholestasis of pregnancy at moderate and high daily doses27 (20–25 mg/kg).
In intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is given during the (second and) trimesters of pregnancy only when typical symptoms, such as pruritus, appear.
Unfortunately, the number of pregnant patients treated with ursodeoxycholic acid with carefully documented follow-up is limited.
Three reports on ursodeoxycholic acid treatment during the entire period of pregnancy describe ursodeoxycholic acid as a well-tolerated substance with no teratogenic effects.
In pregnant rats, no significant fetal adverse effects were observed when ursodeoxycholic acid was administered at a daily dose of up to 2000 mg/kg, except for tail malformation in the highest dose group.
Treatment with ursodeoxycholic acid during breast milk feeding is not approved. It is not known whether ursodeoxycholic acid is excreted in milk during lactation.
The substance was not detected in the breast milk of a patient with primary biliary cirrhosis during treatment with ursodeoxycholic acid.
Skin disorders
Exacerbation of pruritus has been described in patients with primary biliary cirrhosis at different stages. However, in some trials, ursodeoxycholic acid improved itching in approximately 40% of patients with pruritic primary biliary cirrhosis.
The anticholinestatic effect of ursodeoxycholic acid has been proposed to be responsible for the amelioration of pruritus in cholestatic patients. Still, the pathophysiological mechanism underlying ursodeoxycholic acid exacerbation of pruritus in single cholestatic patients during the initial treatment phase has not yet been known. Known.
In patients with distinctive pruritus, treatment with ursodeoxycholic acid should be started at low doses and increased slowly to the optimal amount.
Allergic rash and related skin reactions may be due to drug adjuvants rather than ursodeoxycholic acid.
A skin rash initially attributed to ursodeoxycholic acid was caused by an allergy to a co-ingredient, as evidenced by lymphocyte stimulation tests.
A lichenoid skin rash has been reported in an infant with neonatal hepatitis treated with ursodeoxycholic acid. Still, the ursodeoxycholic acid preparation component responsible for the skin reaction is not yet clear.
History and commercialization
Ursodeoxycholic acid (ursobilane, ursodeoxycholic, Urso®, Ursolvan®) is a naturally occurring hydrophilic bile acid present in small amounts in human bile.
Ursodeoxycholic acid in treating liver diseases originates from ancient Chinese folk medicine.
In fact, for centuries, the Chinese drug ‘Yutan,’ a powdered preparation derived from the dried bile of adult bears, was used to alleviate hepatobiliary disorders.
In 1902, Hammarsten first reported the presence of unknown bile acid in polar bear bile, which he called “ursocoleinic acid.”
At the time, given the lack of knowledge about steroid compounds, Hammarsten could not describe the chemical structure of this new bile acid.
In 1927, Shoda was the first to define the chemical form of ursodeoxycholic acid from the bile of the Chinese black bear.
Shoda named this bile acid ursodeoxycholic acid because of its initial discovery in bear bile (called “Ursus” in Latin) and his belief that it was a chemical isomer of deoxycholic acid.
In 1936, Iwasaki defined the chemical structure of ursodeoxycholic acid, which led to its synthesis sufficient for its use in clinical research.
It was first synthesized in Japan in the 1950s for its cholesterol antagonistic properties and has since been used to treat cholesterol gallstone disease.
In 1975, Makino reported on the first prospective study of gallbladder stone patients treated with ursodeoxycholic acid that demonstrated dissolution of gallstones.
In 1985, Leuschner observed for the first time improved liver tests in patients with chronic active hepatitis treated with ursodeoxycholic acid for dissolution of gallstones.
In 1987, Poupon suggested that long-term use of ursodeoxycholic acid is safe and effective in patients with primary biliary cirrhosis (PBC).
It is marketed in Japan as Urso® by Tokyo Tanabe, a significant supplier of ursodeoxycholic acid for Axcan.
Since then, various studies have shown the beneficial effect of ursodeoxycholic acid in liver disorders.
Ursodeoxycholic acid (Urso®) has had orphan drug status in the US, where Axcan Pharma has released it to treat primary biliary cirrhosis.
Axcan Schwarz has had exclusive marketing rights for Urso® for treating primary biliary cirrhosis for seven years, starting at the end of 1997.
A phase II trial is underway in North America to treat hypercholesterolemia.
Ursodeoxycholic acid has already been launched in Canada for primary biliary cirrhosis, and it has also been found in Canada and the United States (as Actigall®; Novartis) for gallstone dissolution.
It was marketed as Ursofalk® in Canada by Juvenal. Still, this license agreement has been terminated since Parke-Davis acquired Jouveinal, and Axcan Pharma now sells the drug as Urso®.
Ursodeoxycholic acid is also launched in Spain as Ursochol® (Zambon), Ursobilane® (Estedi), and Ursolite® (Vita) for the dissolution of gallstones.
Ursodeoxycholic acid is also undergoing phase II clinical trials at the Mayo Clinic, USA, for the prevention of colorectal cancer and the treatment of hepatitis C.
The phase II trial for hepatitis C evaluated Urso® in combination with interferon-α. Ursodeoxycholic acid is in phase II multicenter trial for nonalcoholic steatohepatitis and primary sclerosing cholangitis.
Ursodeoxycholic acid has demonstrated immunomodulatory properties, and the ability of Sanofi-Synthélabo’s Ursolvan® to prevent acute liver transplant rejection has been tested in clinical trials in France.
Axcan has renewed two agreements with Sanofi-Synthélabo to use, manufacture, and sale of Urso® due to the expiration in 2000 of a previous 10-year agreement.
The new license for the US is valid until the patents expire in 2008, while for Canada, Axcan has acquired all rights to the patent related to primary biliary cirrhosis.
Alfa Farmaceutici is developing soluble formulations of ursodeoxycholic acid to treat liver diseases and gallstones.
The formulations allow for the targeted administration of the drug in the first portion of the gastrointestinal tract, where absorption is optimal. Alfa’s product is in preclinical development in Italy.
In current clinical practice, ursodeoxycholic acid has a defined role in treating patients with cholestatic liver diseases.
