WO1997034605A1

WO1997034605A1 - Use of nicotine to treat liver disease

Info

Publication number: WO1997034605A1
Application number: PCT/US1997/004601
Authority: WO
Inventors: William J. Sandborn; Keith D. Lindor
Original assignee: Mayo Foundation for Medical Education and Research; Mayo Clinic in Florida
Current assignee: Mayo Foundation for Medical Education and Research; Mayo Clinic in Florida
Priority date: 1996-03-21
Filing date: 1997-03-21
Publication date: 1997-09-25
Anticipated expiration: 1998-09-21
Also published as: AU2340397A

Abstract

The use of nicotine to treat liver disease is disclosed as well as pharmaceutical compositions comprising nicotine and a kit for the treatment of liver disease comprising a packaged amount of nicotine and instruction means indicating that said nicotine is to be administered to a patient with liver disease.

Description

USE OF NICOTINE TO TREAT LIVER DISEASE

Background ofthe Invention

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by obliterative inflarrimatory fibrosis ofthe extrahepatic and intrahepatic bile ducts. The disease often follows a progressive course generally leading to cirrhosis, portal hypertension and death from liver failure in many patients. Obstruction ofthe bile ducts produces symptoms such as jaundice, abdominal pain, fever and chills, itching, and fatigue. Genetic predisposition, immunologic mechanisms, abnormalities in fibrogenesis and damage related to the accumulation of toxic bile acids have all been considered possible mechanisms. Frequently, sclerosing cholangitis is associated with underlying chronic inflammatory bowel disease (IBD). Current management consists of symptomatic relief, dilatation of complicating strictures, and liver transplantation for end-stage disease.

Although the liver is capable of regeneration, it suffers from many other diseases, especially inflammatory conditions that can threaten its functioning and the health of its host. Hepatitis is an inflammation ofthe liver caused by a virus, or less commonly, by certain medications or toxins. The main ^' types of viral hepatitis identified to date include hepatitis A, B, C, D, E, and F. The symptoms include jaundice, fatigue, lack of appetite, nausea and vomiting, alterations in senses of taste and smell and low-grade fever. The only specific treatment for viral hepatitis is interferon alpha. For autoimmune chronic active hepatitis, administration of corticosteroids may be prescribed in association with azathioprine to suppress inflammation. However, corticosteroids may not prevent progression to cirrhosis.

Cirrhosis is a condition in which liver tissue has been irreversibly and progressively destroyed as a result of infection, toxins or some other disease. The normal liver tissue is replaced by scarring and areas of regenerating liver cells. Types of cirrhosis include alcohol-induced cirrhosis, viblar, cryptogenic cirrhosis, and primary and secondary biliary cirrhosis. Symptoms may include loss of appetite, weight loss, nausea and vomiting, jaundice, abdominal pain, intestinal bleeding, impotence, itching and swelling in the abdomen and legs. Extreme cases may include vomiting or passing of blood, and mental confusion. Currently, treatment is limited to addressing the complications of cirrhosis rather than the condition itself.

Thus, a continuing need exists for a safe and effective method of treating liver diseases.

Summary ofthe Invention The present invention provides a therapeutic method of treating and/or reducing the symptoms of a liver disease comprising administering to the stomach, duodenum and or proximal jejunum of a patient in need of such treatment, an amount of nicotine or a pharmaceutically acceptable salt thereof, effective to reduce the symptoms ofthe liver disease. Liver diseases that can be treated with the method of the invention include cirrhosis, including primary and secondary biliary cirrhosis, alcohol-induced and cryptogenic cirrhosis; and hepatitis, including steatohepatitis, alcoholic hepatitis, hepatitis A, B, C, D, E and F. In a preferred method ofthe invention, the liver disease is primary sclerosing cholangitis. Preferably, the nicotine is administered by means of an orally ingested unit dosage form comprising an effective amount of nicotine. The dosage form may be solid such as a pill, tablet or capsule or may be a liquid form. Detailed Description ofthe Invention According to the present invention, nicotine is administered to treat and/or reduce the symptoms of a liver disease. In a preferred embodiment ofthe method, the liver disease is primary sclerosing cholangitis (PSC).

A negative association between smoking and PSC was observed in a case-control study of 178 patients with PSC, associated with ulcerative colitis in 80% of cases (Loftus et al., Gastroentero 106:A722 (1994)). The results of the study indicated that smoking might decrease the chance of having PSC. The treatment of PSC with nicotine is not disclosed. Speculations concerning possible mechanisms by which nicotine might be effective in patients with PSC include the effects of nicotine on immunity, the hypothalamo- pituitary-adrenal axis and intestinal mucosal function. For example, data suggest that nicotine inhibits NK cell activity, which may play an important role in the pathogenesis of PSC.

Although the role played by B cells and humoral immunity in the pathogenesis of PSC is unknown, nicotine may cause alterations in humoral immunity such as increased serum IgE production to occupational antigens and decreased IgG and IgA responses to inhaled antigens. Defective hypothalamo-pituitary-adrenal responsiveness to inflammatory mediators causes inflammatory arthritis in rats treated with a bacterial cell-wall product, peptidoglycan-polysaccharide (PG-PS). PG-PS has also been implicated in the hepatobiliary abnormalities observed in a rat model of PSC. Since nicotine increases ACTΗ and consequently cortisol secretion by selectively stimulating brainstem catecholaminergic regions, it is plausible that this effect accounts for the negative association between nicotine and ulcerative colitis/PSC. The steroid-induced transient improvement in liver tests in patients with PSC supports this hypothesis.

Nicotine reduces the mucosal production of inflammatory mediators such as eicosanoids and alters colonic mucous production.

Restoration of mucosal permeability to normal by nicotine may prevent the absorption of pro-inflammatory polypeptides, such as PG-PS into the portal circulation.

Nicotine is an organic compound which can be derived from tobacco leaves, and comprises a pyridine (hydrophilic) and a pyrrolidine

(hydrophobic) ring which enable it to be dispersed or dissolved in many liquid vehicles such as water, alcohol, ether, chloroform and oils. The nicotine base (liquid at room temperature) is quite volatile and readily absorbed through mucous membranes and intact skin. The nicotine salts (crystalline at room temperature) on the contrary are very stable and not absorbed through the skin. The nicotine tartrate salt consists of a single nicotine base in conjunction with two tartrate molecules and a single water molecule.

Any pharmacologically acceptable derivative or metabolite of nicotine which exhibits pharmacotherapeutic properties similar to nicotine may be used in practicing the invention. Such derivatives and metabolites are known in the art (Glenn et al. J. Org. Chem., 43:2860-2870 (1978); Dominiak et al., Klin Woehenschr, 63:90-92 (1985)) and include nicotine oxide, norcotinine and cotinine.

Any pharmaceutically acceptable acid or metal salt of nicotine may also be used in practicing the present invention. A particular characteristic property of this molecule is its ability to form salts with almost any acid and double salts with many metals and acids. The acids that may be used to prepare the pharmaceutically acceptable acid salts of nicotine are those that form non- toxic acid salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluene sulfonate, camphorate and pamoate salts, and the like. Although the compounds described herein and/or their salts may be administered as the pure chemicals, it is preferable to present the active ingredient as a pharmaceutical composition. The invention thus further provides the use of a pharmaceutical composition comprising one or more compounds and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients ofthe composition and not deleterious to the recipient thereof.

Pharmaceutical compositions include those suitable for oral or parenteral (including intramuscular, subcutaneous and intravenous) administration. The compositions may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any ofthe methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combination thereof, and then, if necessary, shaping the product into the desired delivery system.

The effective amount of nicotine can be locally administered to the liver ofthe patient by oral ingestion of a unit dosage form such as a pill, tablet or capsule, comprising an effective amount of nicotine. Orally administered nicotine is absorbed by the upper small bowel (e.g., stomach, duodenum and/or proximal jejunum), enters the portal blood, and proceeds directly to the liver where it is metabolized. Thus, oral administration of nicotine can reduce systemic bioavailability consequently decreasing side effects and improving patient tolerance of nicotine treatment. The nicotine may also be enterically coated so as to be released from the unit dosage form in the upper intestinal tract, e.g., in the duodenum and jejunum of the patient. Enteric coatings remain intact in the stomach, but will dissolve and release the contents ofthe dosage form once it reaches the region where the pH is optimal for dissolution ofthe coating used. This prevents exposure to the more acidic environment ofthe stomach which can result in a positively charged molecule which is not absorbed. The neutral nicotine resulting from a more basic environment may then be absorbed through the small intestine and passed to the liver via the superior mesenteric and portal veins.

Pharmaceutical compositions suitable for oral administration may be presented as discrete unit dosage forms such as hard or soft gelatin capsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art., e.g., with enteric coatings. Aqueous film-coating technology is employed for the enteric coating of pharmaceutical dosage forms. Delayed-released oral nicotine dosage forms have the potential advantage of delivering nearly all the nicotine to the proximal small intestine in an easily administered form. In addition, enterically coated nicotine will not have the dermatologic side effects directly related to patch delivery.

Thus, a useful enteric coating is one that remains intact in the low pH environment ofthe stomach, but readily dissolves when the optimum dissolution pH ofthe particular coating is reached. This can vary between pH 3 to 7.5 depending upon the chemical composition ofthe enteric coating. The thickness ofthe coating will depend upon the solubility characteristics ofthe coating material and the site to be treated.

The most extensively used polymer for enteric coating is cellulose acetate phthalate (CAP). CAP has an optimum dissolution pH greater than 6. Another useful polymer is polyvinyl acetate phthalate (PVAP) which is less permeable to moisture and gastric fluid, more stable to hydrolysis and able to dissolve at a lower pH, which allows release of nicotine in the duodenum. Another available polymer is hydroxypropyl methylcellulose phthalate. This has similar stability to PVAP and dissociates in the same pH range. Microparticles of nicotine may be individually coated with a pharmaceutically acceptable polymeric coating such as cellulose ethers or acrylic acids polymers, and delivered as a suspension in a liquid vehicle; may be encapsulated as a powder; or may be compressed into a pill or tablet and swallowed. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservative. The compounds may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small bolus infusion containers or in multi-does containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds may be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch. Suitable transdermal delivery systems are disclosed, for example, in Fisher et al. (U.S. Patent No. 4,788,603) or Bawas et al. (U.S. Patent No. 4,931,279, 4,668,504 and 4,713,224). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122, 4,383,529, or 4,051,842.

When desired, the above-described compositions can be adapted to provide sustained release ofthe active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic polymer gels or mixtures thereof. It will be appreciated that the amount of nicotine, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition ofthe patient and will be ultimately at the discretion ofthe attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.001 to about 1.5 mg/kg, preferably in the range of 0.01 to 0.20 mg/kg, most preferably in the range of 0.04 to 0.10 mg/kg, calculated as nicotine in the free base form. Preferably, nicotine is administered 1 to 4 times daily, more preferably 3-4 times daily, although more frequent dosing is contemplated where hourly dosing is desired. The compound is conveniently administered orally in unit dosage form; for example, containing 0.10 to 20 mg, conveniently 0.5 to 10 mg, most conveniently, 2 to 6 mg of active ingredient per unit dosage form.

The invention will be further described by reference to the following detailed examples. EXAMPLES

EXAMPLE I - Bioavailability of Orally Administered Nicotine

Intravenous nicotine was prepared using a nicotine base, supplied as the tartrate salt (Fisher Scientific/Eastman Kodak Company, Rochester, NY). Solutions for injection were made up by combining 1.5 mg nicotine base (4.44 mg tartrate salt) in 100 ml of 0.9% sterile normal saline to form a 15 mcg/mL solution. The intravenous solution was filtered through a 0.22 micron filter into a sterile container and under sterile conditions. The solution was then cultured for organisms, assayed for endotoxin, and chemically analyzed prior to infusion to assure stable nicotine concentration. These samples were then be stored in sealed vials until the time of administration.

The oral preparation was formed by dissolving 45 micrograms nicotine base/kg body weight (133.3 micrograms tartrate salt/kg body weight) in 30 ml purified water. This dosage (approximately 3 mg nicotine base for a 70 kg subject) has been well-tolerated in a previous study in which oral nicotine was administered (Benowitz et al., Clin. Pharmacol. Ther. 49:270-7 (1991)).

Subjects were given a 15-30 minute infusion ofthe IV nicotine solution (15 mcg/kg dose). During the non-IV visit subjects were given a 45 mcg/kg dose of nicotine base via oral administration.

On each study day, venous blood samples were drawn from an IV catheter into standard chemistry vacutainer tubes. Samples were obtained before nicotine administration and at the following time points (time = 0 was defined as the point at which the nicotine infusion was started or the non-IV dose was administered): 5, 10, 15, 30, 60, 90 minutes, and 2, 3, 4, 5, 6, and 8 hours. Whole blood samples were centrifuged and serum samples were then stored at - 20 degrees Celsius until analysis. Serum concentrations of nicotine were determined by gas chromatography/mass spectrometry as described by Baskin et al. (Clin. Chem., 31:76-80 (1991)).

For this study, the maximum serum nicotine concentration (Cmax) and the time to reach Cmax (Tmax) were defined as the highest measured serum concentrations and the time ofthe sample, respectively. The following pharmacokinetics parameters were calculated using standard equations (Gibaldi (ed.) Pharmcokinetics 2nd ed, Marcel Dekker Inc., New York 409-17 (1982)): area under the serum nicotine concentration versus time curve (AUC), bioavailability (F), blood elimination half-life (Tl/2), volume of distribution (Vdss), and blood nicotine clearance (CLb). Nicotine was first detected in the serum at 30 minutes with oral administration. The mean values for the pharmacokinetics parameters and statistical probability by analysis of covariance for nicotine administered orally is shown in Table 1. The mean bioavailability for the oral routes of administration was 20%. Table 1

Subjects (n) AUC⁺ F T ^■' max c

(ng)(h)/mL % hr ng/mL

Oral 6 9 ± 5 20 ± 10 1.1 ± 0.1 3 ± 1

* Analysis of covariance adjusting for baseline.

⁺ Analyzed on the natural log scale.

IV nicotine studies (n=30) (mean±SD): AUC=12±5 (ng)(hr)/mL; C max 9 ' —+3 ng/mL; T_m!lx = 0.3±0.1 h.

Intraindividual side effects occurred during each study, as determined by a questionnaire filled out every 30 minutes, closely correlated with serum nicotine concentrations. However, the threshold above which symptoms appeared varied from individual to individual with the nicotine concentration at which side effects first appeared ranging from 2.4 ng/mL to 9.9 ng/mL (although some subjects had nicotine concentrations of > 11 ng/mL without symptoms). When side effects occurred, they consisted of nausea, lightheadedness, and diaphoresis with variable frequency.

The pharmacokinetics parameters Tl/2, Vdss, and CLb calculated for IV dosing in the current study are somewhat different from those previously reported by in the literature (see, e.g., Benowitz et al., Clin. Pharmacol. Ther. 49:270-7 (1991)). A shorter Tl/2 (53 (27 min.) vs. 203 (61 min.)), smaller Vdss (1.8 (0.5 L/Kg) vs 3.0 (0.7 L/Kg)), and faster CLb (106 (46 L/hr) vs. 66 (8 L/hr)) was observed in the current study. The observed differences are most likely due to the different population of subjects studied (non-smokers in the current study vs. heavy smokers in the Benowitz study), as well as the different dose of nicotine administered (0.5 meg/Kg in the current study vs. 2 meg/Kg in the Benowitz study). Additionally, a lower mean bioavailability was observed for the oral dose in the current study 20 (10%) as compared to that observed by Benowitz et al. (44 (9%)).

In conclusion, oral administration of nicotine had low or negligible bioavailability and was well tolerated.

EXAMPLE II - Evaluation of Nicotine in Treatment of PSC The safety profile and effects of oral nicotine treatment in patients with PSC is based on the following parameters: (1) symptoms: pruritus and fatigue; and (2) liver biochemistries: aspartate aminotransferase, alkaline phosphatase, bilirubin, albumin, and immunoglobulin M & prothrombin time. Serum cotinine levels are correlated with the degree of improvement in symptoms and biochemical parameters in patients with PSC.

Primary sclerosing cholangitis is defined as present in a subject when all the following criteria are met: (1) chronic cholestatic disease of at least six month's duration; (2) serum alkaline phosphatase at least 1 'Λ times the upper limits of normal; (3) retrograde, operative, or percutaneous cholangiography demonstrating intra and/or extrahepatic biliary duct obstruction, beading, or narrowing consistent with PSC; and (4) liver biopsy in the previous six months compatible with the diagnosis of PSC.

The exclusion criteria for the study evaluation include (1) treatment with pentoxifylline, ursodeoxycholic acid, corticosteroids, cyclosporin, colchicine, azathioprine, methotrexate, or D-penicillamine in the preceding three months; (2) anticipated need for transplantation in one year, Cox model estimate of < 50% one year survival, recurrent variceal bleeds, spontaneous uncontrolled encephalopathy, or resistant ascites that suggest that anticipated survival will be less than one year; (3) pregnancy or a nursing mother; (4) less than 18 years of age or greater than 70 years of age; (5) findings highly suggestive of liver disease of other etiology such as chronic alcoholic liver disease, chronic hepatitis B infection, hepatitis C, autoimmune hepatitis, primary biliary cirrhosis, or cholangiocarcinoma; (6) previous intraductal stones or operations on the biliary tree (other than cholecystectomy) such as biliary drainage procedures; (7) recurrent ascending cholangitis requiring hospitalization occurring more than two times per year; (8) renal insufficiency (serum creatinine > 1.8 mg% in males, 1.5 mg% in females); (9) history of atherosclerotic heart disease, cardiac arrhythmias, accelerated hypertension, peripheral vascular disease, Buerger's disease, Prinzmetal's angina, diabetes mellitus, hyperthyroidism, or active peptic ' ulcer disease; or (10) patients who have consistently smoked or used other tobacco or nicotine products in the past 3 months.

Prior to study entry, a complete history and physical examination, complete blood count, chemistry group, ALT, prothrombin time, immunoglobulin levels, and pANCA determination is performed. Abdominal ultrasonograpy is performed to assess liver parenchyma, the biliary tree, vascular patency, and the presence of ascites or portal hypertension. Flexible proctosigmoidoscopy or colonoscopy, if not previously performed to assess for colitis, is performed. A liver biopsy is performed or, in patients who have undergone a liver biopsy within the previous one year, the slides reviewed. Liver tests (AST, alkaline phosphatase, total and direct bilirubin) are repeated at six weeks, and subsequently at three-month intervals during the study. A blood sample for serum nicotine and cotinine levels is drawn concurrently, 90 minutes after administration ofthe nicotine capsule and stored for analysis. Patients are re-evaluated at one year with complete history and physical examinations, CBC, chemistry panel, and ALT. A general quality of life questionnaire, the SF-36 survey, is administered at entry and at one year.

The oral dosage forms are prepared in a capsule form and contain 2, 4 and 6 mg of nicotine base as the tartrate salt (Fisher Scientific/Eastman Kodak Company, Rochester, NY). Nicotine tartrate contains 32.8% nicotine base (based on M.W. of 498 for the dihydrate product). To make 100 capsules containing 2 mg of nicotine base, each capsule weighing 0.300 g, combine 0.610 g of nicotine tartrate with 29.390 g of lactose. Similarly, the 4 mg base capsules are made by combining 1.220 g of nicotine tartrate with 28.780 g of lactose. For the 6 mg base capsules, combine 1.830 g nicotine tartrate with 28.170 g lactose. Capsules are then filled using the Minicap capsule filling machine per instruction manual (Dott Bonapace and Co., Via Canova 12, Milao, Italy).

Based on previous studies, significant gastrointestinal side effects are not anticipated using 6 mg dose of oral nicotine in patients with PSC. For patients who cannot tolerate 6 mg of oral nicotine, the dose or frequency will be adjusted with reassessment 2 weeks and one month thereafter. In Stage 1, 16 patients with PSC will receive 2 mg q.i.d. for two weeks increasing as tolerated in 2 mg q.i.d. increments at two week intervals to a maximum dose of 6 mg q.i.d., maintained for one year. Patients who are intolerant ofthe 2 mg q.i.d. dose receive 2 mg b.i.d. for four weeks, after which the dose is increased to 2 mg q.i.d. Patients who fail to tolerate the 2 mg q.i.d. dose at this stage are classified as study failures. If the 4 mg q.i.d. or 6 mg q.i.d. doses are poorly tolerated, the dose is temporarily reduced to 2 mg q.i.d. or 4 mg q.i.d. respectively for 4 weeks. Another attempt to titrate the dose upward is made in four weeks. If this second attempt is unsuccessful, the highest tolerated dose is maintained for one year. The data are analyzed after all 16 patients have completed treatment for one year. Patients who meet the criteria for treatment success (as defined below) may be continued on the medication thereafter, on a compassionate use basis, only after obtaining approval from the IRB.

Monitoring with hematology and chemistry group is performed every six weeks to monitor for possible toxicity. Pronounced worsening of liver biochemistries sustained over a three-month period (quadrupling of AST, alkaline phosphatase or bilirubin, or, absolute AST > 400 U/L, elevation in alkaline phosphatase by 1000 U/L, absolute total bilirubin > 10 mg%) results in discontinuation of therapy. Unless a dominant stricture or obstruction from a common duct stone is present to explain the liver biochemical changes, these patients are regarded as failures, in the intent to treat analysis. Lesser abnormalities will lead to a temporary reduction ofthe dose of oral nicotine by 2 mg q.i.d. for worsening liver biochemistries or pruritus. Repeat values are obtained at two weeks and one month with the dosage adjusted accordingly. If patients have significant gastrointestinal side-effects (nausea, abdominal cramping or diarrhea), the dose of nicotine is reduced by 2 mg four times daily for four weeks. Thereafter, the dose is adjusted upward to the maximum tolerated dose, up to 6 mg for the remaining treatment period. Treatment is stopped if liver transplantation is to be undertaken.

The effect of treatment on biochemical liver tests and symptoms is assessed using the following scores.

SYMPTOM SCORES

PRURITUS FATIGUE

Grade Grade

0 - none 0 - none

1 - mild 1 - mild, does not interfere with activity or require extra rest

2 - moderate some interference 2 - requires extra rest, limits with sleep activity, able to work

3 - severe excoriations, substantial 3 - unable to work full day, sleep disturbance activity severely limited

Treatment success in an individual patient is defined as an improvement in AST, alkaline phosphatase, or bilirubin by ≥ 50% or to normal without an increase of > 25% in other values.

If the overall response to nicotine is > 30%, nicotine is considered efficacious. If the overall rate of treatment success with nicotine exceeds 40% (≥ 12 of 28 [if both phases conducted]), nicotine is considered as potentially efficacious.

The one-year data on symptoms and liver tests is summarized as changes from initial values (% with improvement in symptoms and actual deltas for biochemistries). The 95% Cls for these changes is also estimated. The changes are correlated with serum cotinine levels (Spearman rank correlation or logistic regression for symptom improvement).

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope ofthe invention.

Claims

WHAT IS CLAIMED IS:

1. The use of nicotine, or a pharmaceutically acceptable salt thereof, to prepare a medicament effective for the treatment of liver disease.

2. The use of claim 1 wherein the liver disease is primary sclerosing cholangitis.

3. The use of claim 1 wherein the liver disease is cirrhosis.

4. The use of claim 3 wherein the cirrhosis is primary or secondary biliary cirrhosis.

5. The use of claim 3 wherein the cirrhosis is alcohol-induced cirrhosis or cryptogenic cirrhosis.

6. The use of claim 1 wherein the liver disease is hepatitis.

7. The use of claim 6 wherein the hepatitis is steatohepatitis.

8. The use of claim 6 wherein the hepatitis is alcoholic hepatitis.

9. The use of claim 6 wherein the hepatitis is hepatitis A.

10. The use of claim 6 wherein the hepatitis is hepatitis B.

11. The use of claim 6 wherein the hepatitis is hepatitis C, D, E or F.

12. The use of claim 6 wherein the hepatitis is autoimmune chronic active hepatitis.

13. A pharmaceutical unit dosage form comprising an amount of nicotine effective to treat liver disease and a pharmaceutically acceptable carrier wherein the unit dosage form is adapted for oral ingestion.

14. A pharmaceutical unit dosage form of claim 13 that is a solid dosage form.

15. The pharmaceutical unit dosage form of claim 14 wherein the solid dosage form is a pill, tablet or capsule.

16. The pharmaceutical unit dosage form of claim 15 wherein the solid dosage form is enterically coated.

17. A pharmaceutical unit dosage form of claim 13 that is a liquid dosage form.

18. The pharmaceutical unit dosage form of claim 13 containing about 0.1 mg to about 20 mg of nicotine or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical unit dosage form of claim 18 containing about 2 mg to about 6 mg of nicotine or a pharmaceutically acceptable salt thereof.