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WO1997034605A1 - Utilisation de nicotine pour traiter une hepatopathie - Google Patents

Utilisation de nicotine pour traiter une hepatopathie Download PDF

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Publication number
WO1997034605A1
WO1997034605A1 PCT/US1997/004601 US9704601W WO9734605A1 WO 1997034605 A1 WO1997034605 A1 WO 1997034605A1 US 9704601 W US9704601 W US 9704601W WO 9734605 A1 WO9734605 A1 WO 9734605A1
Authority
WO
WIPO (PCT)
Prior art keywords
nicotine
hepatitis
dosage form
liver disease
unit dosage
Prior art date
Application number
PCT/US1997/004601
Other languages
English (en)
Inventor
William J. Sandborn
Keith D. Lindor
Original Assignee
Mayo Foundation For Medical Education And Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mayo Foundation For Medical Education And Research filed Critical Mayo Foundation For Medical Education And Research
Priority to AU23403/97A priority Critical patent/AU2340397A/en
Publication of WO1997034605A1 publication Critical patent/WO1997034605A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • PSC Primary sclerosing cholangitis
  • IBD chronic inflammatory bowel disease
  • 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.
  • administration of corticosteroids may be prescribed in association with azathioprine to suppress inflammation.
  • 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.
  • Treatment is limited to addressing the complications of cirrhosis rather than the condition itself.
  • 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.
  • the liver disease is primary sclerosing cholangitis.
  • 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.
  • nicotine is administered to treat and/or reduce the symptoms of a liver disease.
  • the liver disease is primary sclerosing cholangitis (PSC).
  • PG-PS peptidoglycan-polysaccharide
  • 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
  • the nicotine base liquid at room temperature
  • the nicotine salts crystalline at room temperature
  • 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.
  • 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.
  • 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.
  • a unit dosage form such as a pill, tablet or capsule
  • 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.
  • 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.
  • 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.
  • 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.
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • 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.
  • 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.
  • 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.
  • 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.
  • hydrophilic polymer matrices e.g., comprising natural gels, synthetic polymer gels or mixtures thereof.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • Cmax maximum serum nicotine concentration
  • Tmax time to reach Cmax
  • 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
  • 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 ' ⁇ 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 bili
  • a complete history and physical examination 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de nicotine pour traiter une hépatopathie, des compositions pharmaceutiques contenant de la nicotine et un matériel de traitement d'une hépatopathie, comprenant une quantité prête à l'emploi de nicotine et des instructions indiquant que ladite nicotine doit être administrée à un patient atteint d'une hépatopathie.
PCT/US1997/004601 1996-03-21 1997-03-21 Utilisation de nicotine pour traiter une hepatopathie WO1997034605A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU23403/97A AU2340397A (en) 1996-03-21 1997-03-21 Use of nicotine to treat liver disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US63251396A 1996-03-21 1996-03-21
US08/632,513 1996-03-21

Publications (1)

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WO1997034605A1 true WO1997034605A1 (fr) 1997-09-25

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Cited By (16)

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Publication number Priority date Publication date Assignee Title
EP1202736A1 (fr) * 1999-07-28 2002-05-08 The Board Of Trustees Of The Leland Stanford Junior University Utilisation de nicotine dans l'angiogenese et la vasculogenese therapeutiques
EP1207879A1 (fr) * 1999-07-28 2002-05-29 The Board Of Trustees Of The Leland Stanford Junior University Agoniste du recepteur de la nicotine, present dans une cellule souche, et mobilisation de cellules souches
WO2008029145A1 (fr) * 2006-09-07 2008-03-13 Ucl Business Plc biomarqueurs pour évaluer la fonction hépatique
US7598275B2 (en) 1999-07-28 2009-10-06 The Board Of Trustees Of The Leland Stanford Junior University Nicotine in therapeutic angiogenesis and vasculogenesis
US7718677B2 (en) 2007-04-02 2010-05-18 Parkinson's Institute Methods and compositions for reduction of side effects of therapeutic treatments
US7838539B2 (en) 1999-07-28 2010-11-23 The Board Of Trustees Of The Leland Stanford Junior University Nicotine receptor agonists in stem cell and progenitor cell recruitment
GB2468424B (en) * 2007-04-02 2011-11-09 Parkinson S Inst Methods and compositions for reduction of side effects of therapeutic treatments
US10213586B2 (en) 2015-01-28 2019-02-26 Chrono Therapeutics Inc. Drug delivery methods and systems
US10258778B2 (en) 2004-09-13 2019-04-16 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US10653686B2 (en) 2011-07-06 2020-05-19 Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
US10679516B2 (en) 2015-03-12 2020-06-09 Morningside Venture Investments Limited Craving input and support system
US10716764B2 (en) 2003-10-27 2020-07-21 Morningside Venture Investments Limited Transdermal drug delivery method and system
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US11434471B2 (en) 2012-02-10 2022-09-06 Orbsen Therapeutics Limited Stromal stem cells
CN115581697A (zh) * 2022-10-19 2023-01-10 云南中烟工业有限责任公司 尼古丁及衍生物作为FXR-meglin/cublin调节剂在制备利胆产品中的应用
US11596779B2 (en) 2018-05-29 2023-03-07 Morningside Venture Investments Limited Drug delivery methods and systems

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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160904B2 (en) 1999-07-28 2007-01-09 The Board Of Trustees Of The Leland Stanford Junior University Nicotine in therapeutic angiogenesis and vasculogenesis
EP1207879A1 (fr) * 1999-07-28 2002-05-29 The Board Of Trustees Of The Leland Stanford Junior University Agoniste du recepteur de la nicotine, present dans une cellule souche, et mobilisation de cellules souches
EP1207879A4 (fr) * 1999-07-28 2004-05-12 Univ Leland Stanford Junior Agoniste du recepteur de la nicotine, present dans une cellule souche, et mobilisation de cellules souches
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