WO2007016771A1 - Regime de dosage pour perte de poids - Google Patents

Regime de dosage pour perte de poids Download PDF

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Publication number
WO2007016771A1
WO2007016771A1 PCT/CA2006/001284 CA2006001284W WO2007016771A1 WO 2007016771 A1 WO2007016771 A1 WO 2007016771A1 CA 2006001284 W CA2006001284 W CA 2006001284W WO 2007016771 A1 WO2007016771 A1 WO 2007016771A1
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WIPO (PCT)
Prior art keywords
receptor antagonist
alkyl
hydrogen
days
weekly
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PCT/CA2006/001284
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English (en)
Inventor
Henry Sjoerd Koopmans
Keith Alexander Sharkey
Adam Paul Chambers
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Uti Limited Partnership
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Priority claimed from CA002518579A external-priority patent/CA2518579A1/fr
Application filed by Uti Limited Partnership filed Critical Uti Limited Partnership
Priority to US12/063,024 priority Critical patent/US20090170900A1/en
Publication of WO2007016771A1 publication Critical patent/WO2007016771A1/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to dosing regimens and methods for the treatment of obesity, overweight and/or overeating in mammals comprising administering to the mammal a pharmaceutically effective amount of a CB 1 receptor antagonist as a unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, thrice-weekly dosing, biweekly dosing and bimonthly dosing.
  • the present invention relates to a method for reducing food intake and/or body weight in a mammal comprising administering to said mammal a pharmaceutically effective amount of a CBi receptor antagonist once every 2 to 14 day or, in the alternative, on two or three consecutive days every 7 to 14 days, preferably prior to or during a period of increased caloric intake.
  • Obesity is widely recognized as a serious health problem that is increasing in prevalence across the United States and the world. According to the 1998 National Institute of Health (NIH) Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults, an estimated 97 million people in the US are classified as either overweight or obese. The medical and other costs related to obesity have risen considerably in the last two decades (K. M. Flegal et al. 2005, "Excess deaths associated with underweight, overweight and obesity.” JAMA 293: 1861 -7). In addition, many pets or companion animals, such as dogs or cats, have become obese and their owners may seek veterinary treatment to cure their obesity and associated medical problems.
  • the endocannabinoid system comprises endogenous ligands commonly referred to as cannabinoids (anandamide, 2-arachidonoyl glycerol, 2-arachidonyl glyceryl ether (noladin ether), virodhamine), and two cannabinoid receptor subtypes (CB 1 and CB 2 ).
  • cannabinoids anandamide, 2-arachidonoyl glycerol, 2-arachidonyl glyceryl ether (noladin ether), virodhamine
  • CB 1 and CB 2 cannabinoid receptor subtypes
  • the cannabinoid CB 1 receptor has received the greatest attention with respect to appetite and body weight regulation, leading to the development of a new class of appetite suppressants and/or weight regulating drugs that appear to work by selectively blocking the CBi receptors.
  • the discovery of the first selective CB 1 receptor antagonist was reported several years ago. See M. Rinaldi-Carmona et al., 1994, "SR141716A, a Potent and Selective Antagonist of the Brain Cannabinoid Receptor", FEBS Letters 350: 240-244.
  • SR141716A This antagonist compound, ⁇ /-(piperidin-1 - yl)-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 /-/-pyrazole-3-carboxamide (SR141716A or rimonabant), has been shown to have anorectic efficacy and produce a sustained reduction in body weight.
  • SR141716A is the hydrochloride of SR 141716. See G. Columbo et al., 1998, "Appetite Suppression and Weight Loss After Cannabinoid Antagonist SR 141716", Life Sci 63:PL 1 13-7 and U.S. Patent No. 6,344,474, incorporated herein by reference.
  • SR141716A binds to CB 1 receptors and competitively antagonizes many of the CB 1 receptor-mediated effects of cannabinoids.
  • synthesis of an antagonist such a SR141716A that selectively binds to CB 1 receptors without producing cannabimimetic activity in vivo suggests that recognition and activation of cannabinoid receptors are separable events. See D.R. Compton et al., 1996, "In Vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A): Inhibition of delta 9-tetrahydrocannabinol-induced Responses and Apparent Agonist Activity", J Pharmacol Exp Ther. 277: 586-594.
  • a CB 1 receptor antagonist according to a continuous schedule having a dosing interval of once-weekly dosing, twice-weekly dosing, or thrice-weekly dosing, many of the adverse effects observed with daily doses of CB 1 receptor inhibitors can be minimized.
  • a dosing regimen reduces the development of tolerance or desensitization to the suppressant effect of the CB 1 receptor antagonist.
  • administration of the antagonist at a relatively low dosage at a relatively low dosing frequency is less likely to cause significant rebound-hyperphagia.
  • weekly or twice- or thrice-weekly dosing or biweekly dosing or bimonthly dosing could minimize other unwanted side effects observed with CBi receptor antagonists.
  • the methods of the present invention would also be more convenient than daily regimens and would result in greater patient compliance.
  • the patient could focus on a particular time of the week when the medicine would be taken most effectively.
  • dosing regimens could be commenced on the day before periods of rest and socialization (such as week-ends and the like), which have been shown to be a period of time when people overeat by about 8-13 %. See ST. St. Jeor et al. 1983 "Variability in Nutrient Intake in a 28-day Period.” J. Amer Diet Assoc 83:155-62; J. M.
  • a patient can commence the weekly regimen on a Friday, before the Saturday/Sunday weekend that is enjoyed as a period of rest and socialization by much of the Western world.
  • the invention herein relates to the surprising finding that the weight loss effect of CB 1 receptor antagonists continues far longer than 1 -2 days after administration. A reasonable concentration of the drug might be expected to remain within the brain for 1 -2 days. In the present invention, it is found that reductions in body weight and/or food intake can occur for a period of at least 3-6 days after administration of the CBi receptor antagonist and may continue even longer. This surprising result would not have been predicted based on the known pharmacokinetics of CB 1 antagonists.
  • the anorectic and/or weight loss effect of the present invention also exceeded the predicted half-life for rimonabant or AM-251 of 22 hours, as determined from behavioral tests. See P.J. McLaughlin, et al., 2003, 'The cannabinoid CB1 antagonists SR 171416A and AM-251 suppress food intake and food re-inforced behavior in a variety of tasks in rats.” Behav Pharmacol 14: 583-8.
  • the reduction in weight loss may be accompanied by a reduction in food intake in a dose dependent manner.
  • the duration of weight loss the most important measure, exceeded the duration of reduced food intake.
  • the termination of the delivery of CBi receptor antagonists has been shown to lead to significant hyperphagia and a rapid return in body weight when treatment is stopped. Therefore, continued infrequent use of the drug is an effective way to prevent the regain of lost body weight.
  • the invention herein relates to methods for the treatment of obesity, overweight and/or overeating in a mammal in need thereof, comprising administering to said mammal a pharmaceutically effective amount of a CBi receptor antagonist as a unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, thrice-weekly dosing, biweekly dosing and bimonthly dosing, wherein said continuous schedule is maintained until the desired therapeutic effect is achieved for said mammal.
  • the invention relates to methods comprising a continuous dosing periodicity ranging from about once every 2 days to about once every 14 days.
  • the invention relates to methods for reducing food intake and/or body weight in a mammal in need of such treatment. More particularly, the invention relates to methods for reducing food intake and/or body weight in a mammal in need of such treatment comprising administering a single dose of a pharmaceutically effective amount of a CB 1 receptor antagonist prior to an anticipated period of higher food intake (e.g., higher caloric intake). In one embodiment, the invention relates to methods for reducing food intake and/or body weight in a mammal in need of such treatment comprising administering a pharmaceutically effective amount of a CB 1 receptor antagonist for two or three consecutive days every 7 to 14 days, preferably prior to or during a period of increased caloric intake. In other embodiments, the invention herein relates to such methods useful in humans.
  • the invention herein relates to such methods useful in companion animals, such as dogs or cats.
  • the present invention may result in one or more of the following effects: (1 ) a lowering of the overall dosage of the CB 1 receptor antagonist drug needed to cause a fixed amount of weight loss;
  • Figure 1 is a bar graph showing cumulative food intake over 3 h after injection of either vehicle or CBi receptor antagonist AM-251.
  • Figure 2 shows the changes in daily food intake starting 2 days before and finishing 7 days after administration of a single dose of either vehicle or 5.0 mg/kg CB 1 receptor antagonist AM-251.
  • Figure 3 shows the dose-dependent changes in daily food intake (g) starting 2 days before and finishing 7 days after administration of a single dose of either vehicle or CB 1 receptor antagonist AM-251 (1.25 mg/kg or 2.5 mg/kg).
  • Figure 4 shows the changes in weight gain or loss (g) starting 2 days before and finishing 8 days after administration of a single dose of either vehicle or CB 1 receptor antagonist AM-251 (1.25 mg/kg or 2.5 mg/kg).
  • Figure 5 shows the daily food intake (mean ⁇ SEM; g) expressed in g whereby one gram equals 1.41 kcal for vehicle treated rats (filled triangles) and rats treated every 5 days with AM-251 (5 mg/kg) (hollow circles). Hash marks on the x- axis indicate where 5 mg/kg treatments were given. Significant differences in food intake between vehicle- and AM-251 - treated rats are shown by the bars, p ⁇ .05, unpaired f-test.
  • Figure 6 shows the changes in body weight (mean ⁇ SEM; g) starting the day before treatment with either vehicle (filled triangles), or AM-251 (5 mg/kg every 5days, hollow circles). Hash marks on the x-axis indicate where 5 mg/kg treatments were given.
  • Figure 7 shows the average daily body weight of male rats given daily or twice-weekly injections of the cannabinoid antagonist, AM-251.
  • Figure 8 shows the average daily body weight of male rats given daily or twice-weekly injections of the cannabinoid antagonist, rimonabant.
  • the present invention relates to a method, preferably an oral method, for treating disorders of feeding behavior or energy balance, such as obesity, overweight and/or overeating, comprising administering to a subject in need thereof a therapeutically effective amount of a CBi receptor antagonist.
  • CB 1 receptor antagonists of the present invention are broadly defined as those compounds that selectively bind to CB 1 receptors without producing cannabimimetic activity in vivo.
  • W 2 , W 3 , W 4 , W 5 and W 6 are identical or different and are independently hydrogen, a chlorine, bromine or iodine atom, a (C 1 -C 3 )BlKyI, a (C 1 - C 3 )alkoxy, a trifluoromethyl or a nitro group and g 4 can also be a phenyl group;
  • R 1 is a (C r C 6 )alkyl or a hydrogen
  • R 2 is - + NR 3 R 5 R 6 or -NR 5 R 6 ;
  • R 3 is a (C r C 6 )alkyl or R 3 forms a bridge with one of the atoms of the heterocyclic radical formed by NR 5 R 6 ;
  • R 4 is hydrogen or a (CrC 5 )alkyl;
  • R 5 is hydrogen or a (C r C 6 )alkyl and R 6 is hydrogen, a (C r C 6 )alkyl, a phenyl or a (C 3 -C 8 )cycloalkyl, or R 5 and R 6 , together with the nitrogen atom to which they are bonded, form a 5- to 10-membered saturated or unsaturated heterocyclic radical which is unsubstituted or monosubstituted or polysubstituted by a (CrC ⁇ alkyl, a benzyl, a phenyl, a hydroxyl, a (Ci-C 6 )alkoxy or a halogen, with the proviso that if R 2 is NR 5 R 6 , R 5 and Re, together with the nitrogen atom to which they are bonded, form a heterocyclic radical other than a 5- to 8-membered saturated radical which is unsubstituted or substituted by a (Ci-C 3 )al
  • (Ci-C 3 )alkyl, (d-C 5 )alkyl and (C r C 6 )alkyl are understood as meaning C 1 -C 3 , CrC 5 and CrC 6 linear or branched alkyls.
  • the preferred alkyl groups are methyl, ethyl, propyl and isopropyl groups.
  • 5- or 10-membered saturated or unsaturated heterocyclic radical is understood as meaning a fused or bridged, mono-, di- or tri-cyclic, non-aromatic heterocyclic radical which can contain a second heteroatom such as nitrogen, oxygen or sulfur.
  • These radicals include the following radicals in particular: pyrrolidin-1 -yl, piperidin-1 -yl, hexahydroazepin-1 -yl, morpholin-4-yl, thiomorpholin-4- yl, 2-azabicyclo [2.2.2]oct-5-en-2-yl, 2-methyl-2-azoniabicyclo[2.2.2]oct-5-2-yl, 2- azaadamant-2-yl, 1 ,2,3,6-tetrahydropyridin-1 -yl, 2-azabicyclo[2.2.1]heptan-2-yl, 2- azabicyclo[2.2.2]octan-2-yl and 1 -azoniabicyclo[2.2.2]
  • the salts of the compound of formula (I) include the pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methylsulfate, maleate, oxalate, fumarate, naphthalene-2-sulfonate, glyconate, gluconate, citrate, isethionate, paratoluenesulfonate and mesitylenesulfonate salt.
  • the pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methylsulfate, maleate, oxalate, fumarate, naphthalene-2-sulfonate, glyconate, gluconate, citrate, isethionate, paratoluenesulfonate and me
  • CB 1 receptor antagonists are 5-(4-bromophenyl)-1 -(2,4-dichlorophenyl)-4-ethyl-N-(1 - piperidinyl)-1 H-pyrazole-3-carboxamide; 3-(4-chlorophenyl-N'-(4- chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamide; the compounds described in U.S. Patent No. 5,462,960, to Barth et al., issued October 31 , 1995; the compounds described in U.S. Patent No.
  • PCT/GB2004/001831 published November 11 , 2004 as WO 2004/096763; the azetidine-1-carboxamides described in International Application No. PCT/GB2004/001812, published November 1 1 , 2004 as WO 2004/096209; the bi-heteroaryl compounds described in International Application No. PCT/IB2003/00441 1 , published April 29, 2004 as WO 2004/035566; tetrahydroquinoline containing compounds described in International Application No. PCT/US2004/022408, published January 27, 2005 as WO 2005/007628; and substituted pyrazolopyridazine and imidazopyridazine compounds described in U.S. Patent Appl. No. 10/853,993, published December 9, 2004 as US 2004/0248881 , all of which are incorporated herein by reference.
  • Compounds of the present invention include pharmaceutically acceptable salts of the compounds and hydrates or solvates of the compounds.
  • pharmaceutically effective amount means that amount of the CBi receptor antagonist that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen.
  • a preferred pharmaceutically effective amount of the CBi receptor antagonist is an appetite-suppressing amount and/or an amount that results in weight loss.
  • once-weekly dosing is meant that a unit dosage of the CB 1 receptor antagonist is administered once a week, i.e., one time during a seven-day period, preferably on the same day of each week.
  • the unit dosage is generally administered about every seven days.
  • a non-limiting example of a once-weekly dosing regimen would entail the administration of a unit dosage of the CB 1 receptor antagonist every Friday.
  • a unit dosage of the CB 1 receptor antagonist is administered twice a week, i.e., two times during a seven-day period, preferably on the same two days of each weekly period.
  • each unit dosage may be either administered every three to four days or delivered on two consecutive days followed by a rest period of four to five days.
  • a non-limiting example of a twice-weekly dosing regimen would entail the administration of a unit dosage of the CB 1 receptor antagonist every Friday and Tuesday.
  • Another non-limiting example would entail the administration of the CB 1 receptor antagonist on two consecutive days, preferably either prior to or during a period of increased caloric intake, for example, prior to a "weekend".
  • biweekly dosing is meant that a unit dosage of the CB 1 receptor antagonist is administered once during a two-week period, i.e., one time during a fourteen-day period, preferably on the same day during each two-week period. In the twice-weekly dosing regimen, each unit dosage is generally administered about every fourteen days.
  • a non-limiting example of a biweekly dosing regimen would entail the administration of a unit dosage of the CB 1 receptor antagonist every other Friday.
  • twin-monthly dosing is meant that a unit dosage of the CB 1 receptor antagonist is administered twice, i.e., two times, during a monthly calendar period.
  • compositions of the present invention comprise a pharmaceutically effective amount of a CBi receptor antagonist compound.
  • the CBi receptor antagonist compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which will depend upon the route of administration.
  • These pharmaceutical compositions can be prepared by conventional methods, using compatible, pharmaceutically acceptable excipients or vehicles.
  • compositions include capsules, tablets, transdermal patches, lozenges, troches, sprays, syrups, powders, granulates, gels, elixirs, suppositories, and the like, for the preparation of extemporaneous solutions, injectable preparations, rectal, nasal, ocular, vaginal etc.
  • a preferred route of administration is the oral route.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes.
  • Solid compositions of similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the dosage form can be designed for immediate release, controlled release, extended release, delayed release or targeted delayed release. The definitions of these terms are known to those skilled in the art.
  • the dosage form release profile can be effected by a polymeric mixture composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition.
  • a polymeric mixture composition effected by a polymeric mixture composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition.
  • the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange, osmosis or combinations thereof.
  • a solution of a CBi receptor antagonist compound in either sesame or peanut oil or in aqueous propylene glycol can be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic.
  • the aqueous solutions are suitable for intravenous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the precise dosage of the CB 1 receptor antagonist may vary with the dosing schedule, the oral potency of the particular CB 1 receptor antagonist chosen, the age, size, sex and condition of the mammal or human, and other relevant medical and physical factors.
  • the CB 1 receptor antagonists is administered in dosages ranging from about 0.5 to about 100 mg, advantageously from 1 to 40 mg and preferably from 2 to 35 mg per dosage unit, for weekly or twice- or thrice-weekly administration.
  • the dosages may be moderately higher and preferably 5 to 50 mg per dosage unit.
  • Ensure Plus Vanilla-flavoured Ensure Plus (Ross Laboratories, Saint-Laurent, Quebec, Canada) was used as food on account of its palatability, and to reduce the risk of spillage.
  • a milky-sweet liquid, Ensure Plus is composed of 53.3% carbohydrate, 29% fat, 16.7% protein (1.41 kcal/g), which includes daily minerals and vitamins typical of a Western diet.
  • Food was available from 1600 to 1700 (prefeed) and 1800-0900 h daily; water was freely available at all times. Food and water were presented in inverted glass bottles that attached to the outside of the cage. Animals were habituated to handling and testing procedures 3 weeks prior to testing on liquid diet.
  • AM-251 ( ⁇ /-(piperidin-1 -yl)-5-(4-iodophenyl)-1 -(2,4-dichlorophenyl)-4-methyl- 1 /-/-pyrazole-3-carboxamide) was purchased from Tocris Cookson and resuspended in a vehicle (2% dimethyl sulfoxide, 1% Tween 80 and 97% physiological saline). Drugs were aliquoted and placed in a freezer at -7O 0 C until use.
  • Figure 2 is a plot of the changes in daily food intake (g), measured starting 2 days prior to administration and finishing 7 days after administration, of either vehicle or AM-251 (5 mg/kg). It can be seen from Figure 2 that there was a prolonged reduction in food intake after a single administration of AM-251 .
  • Figure 3 shows the dose-dependent changes in daily food intake (g) starting 2 days prior to administration of the drug or vehicle and finishing 7 days after administration of either vehicle or AM-251 (1.25 mg/kg or 2.5 mg/kg).
  • AM-251 1.25 mg/kg or 2.5 mg/kg.
  • Reductions in food intake using 2.5 mg/kg of AM-251 were significant starting the day of administration and for the next 4 days p ⁇ .001.
  • Figure 4 shows the changes in weight gain or loss (g) starting 2 days before and finishing 8 days after the administration of either vehicle or AM-251 (1.25 mg/kg or 2.5 mg/kg). It can be seen from Figure 4 that a single dose of drug resulted in significant reductions in weight gain. On average, rats gained weight during vehicle conditions (7.3 ⁇ 1.4 g over 10 days) and lost weight or failed to gain weight during the 1.25 mg/kg AM-251 (2.5+2.0 g) and 2.5 mg/kg (-5.1 ⁇ 2.1 g) conditions. Interestingly, in animals given the lowest dose of AM-251 (1 .25 mg/kg), the duration of weight loss exceeded the duration of reduced food intake.
  • FIG. 6 shows that differences in weight change between vehicle and AM- 251 treated rats were significant from day 1 to day 24, p ⁇ .05, Newman-Keuls multiple comparison test.
  • the present study was undertaken to examine the effects of infrequent doses of two CB 1 cannabinoid antagonists, rimonabant and AM-251 , on the change in body weight when compared with daily delivery, which is common practice for the delivery of most pharmaceutical products.
  • the total weekly dose for a 2-day delivery would be less than half the dose for the rats receiving daily doses. This reduction in dose would not only expose the body to less of the drug but would also provide the drug infrequently so that long-term adaptation to the drug would be less likely to occur.
  • Another objective was to determine whether the animals were responding negatively to the drug as determined by the use of a two-flavored conditioned aversion test in which the drug was repeatedly paired with one flavor of liquid diet while the vehicle injection was paired with the other flavor.
  • This test procedure involved giving the rats two bottles, containing the liquid diets flavored with chocolate and strawberry, and determining the individual rat's preference for one or the other of the flavors.
  • a conditioned aversion was established if the rat chose against the flavor associated with the drug injections.
  • the doses of drugs used in these experiments were chosen to be the approximate rat equivalent of the doses used in human clinical trials.
  • a purse string suture held the tube tight within the stomach and a small piece of hernia mesh allowed the stomach, the tube and abdominal wall to seal strongly together and to prevent any leakage of gastric contents into the abdomen or under the skin.
  • the inner bore of the tube was sealed with a hooked stainless-steel wire plug that could be removed before injection of the drug or vehicle was to be performed. Injection of the drug was followed by the insertion of a small amount of saline to deliver the full dose of drug and to keep the tube filled and open between injections.
  • the main period of feeding was during the night as is appropriate for nocturnal animals. Once the rats were fully recovered from surgery and adapted to this feeding schedule, the first baseline period of the experiment began. The rats weighed approximately 430 gm at the beginning of the experiment. All the rats were presented with the powdered laboratory chow every day at 4 pm and with the liquid diet, vanilla Ensure Plus (Ross Labs), on two "weekend” days to closely mimic the eating habits of many Western societies wherein the "weekend” diet may comprise more variety and/or an intake of higher caloric foods. During this time the rats were familiarized with the experimental procedure by injections of appropriate volumes of saline. This procedure continued for 14 days until intragastric drug delivery began.
  • the 32 male Lewis rats were assigned to one of five groups of rats based on their body weight and rate of weight gain. These assignments were made when the rats approached the time for the beginning of drug injections and were assigned in such a way as to have matched groups during the baseline period.
  • This conditioning procedure was done for 10 exposures before the actual conditioned aversion test was done on day 33.
  • This aversion test was done by allowing each rat exposure for 17 hrs to two bottles, one containing chocolate- flavored and the other containing strawberry-flavored liquid diet. No drugs or vehicles were injected on this day.
  • the rats were allowed to drink the diets for 15 min and the position of the nozzle was balanced across rats within each group to control for possible side preferences.
  • the rats were forced to taste both flavors for three or four licks before the diets were made freely available to them so the rats were fully aware that two flavors were present. Readings of the amount of food eaten were determined at 15 min (short-term) and at 17 hr (daily).
  • the short- term data showed the rat's immediate response to taste with minimal internal signals from the ingestion of the diets that were the same in calories and composition.
  • the 17-hour tests allowed repeated association between the internal consequences of the drug and the taste of the drug associated primary flavor.
  • the CB 1 cannabinoid antagonist drugs used in these experiments were AM-
  • rimonabant (Sanofi-Aventis product synthesized by the NIMH repository program). These drugs are fat-soluble and readily cross cell membranes.
  • the appropriate amount of drug was dissolved DMSO (5% by weight) which was later mixed with Tween 80 (2% as an emulsifier) and made up to full weight (100%) with saline.
  • the drug-solvent mixture was sonicated to obtain an even distribution of drug within the injection solution.
  • the initial concentration of the daily dose of AM- 251 was 0.80 mg/kg/day and of Rimonabant was 0.67 mg/kg/day. These daily doses were increased by 1.5X for the "weekend" dose. Both daily and weekend doses were increased again by 1.5X for the second 14 day period of drug injection.
  • the amount of drug delivered was adjusted to the weight of each rat by changing the volume of the drug solution delivered.
  • the rats were weighed every day at 3:30 pm when they had been deprived of food for more than 6 hours and their weights would have been most stable. After the rats became familiar with the experimental procedures, their body weights were measured for a total of 42 days that were divided into 3 sets of 14 days each. During the first 14 days, the rats continued to adapt to the conditions of the experiment as well as having a daily intragastric injection of saline equal in volume/kg to their subsequent daily injection of drug. The drugs were injected 1 -2 min before their daily food was presented to the rats. During the next 14 days, the rats were injected with the low dose of each of the cannabinoid drugs, and for the last 14 days, with the 50% higher dose.
  • Figure 7 illustrates the average daily body weight of male rats given daily or twice-weekly injections of the cannabinoid antagonist, AM-251.
  • the rats were adapted to the conditions of the experiment which included daily 17-hour access to powdered laboratory chow, twice-weekly 17-hr access ("weekend days") to the vanilla-flavored liquid diet, Ensure Plus, and ad lib access to water.
  • weekend days daily 17-hour access to powdered laboratory chow
  • twice-weekly 17-hr access to the vanilla-flavored liquid diet
  • Ensure Plus twice-weekly 17-hr access
  • ad lib access to water.
  • the rats had injections of saline just before eating to allow them to get used to the injection procedure.
  • Rats also had a randomly assigned flavor of liquid diet, either chocolate or strawberry, fed to them for the first two days of injection.
  • the dose of AM-251 for both daily and weekend injections was increased by 50%, but otherwise the same procedures were followed.
  • Figure 8 illustrates the average daily body weight of male rats given daily or twice-weekly injections of the cannabinoid antagonist, rimonabant.
  • F 8.2, p ⁇ 0.002
  • the conditioned taste aversion paradigm showed that the rats did not develop an aversion to the flavor paired with the drug injection despite the fact that the rats had 10 pairings of the flavor with the drug over a full 17 hours before the one-day preference test was done on day 33. There were no significant differences in flavor preference noted at 15 minutes or at 17 hrs.
  • the failure to obtain a conditioned taste aversion after 10 repeated full-day pairings of the drug with the primary flavor suggests that the side effects of these drugs at the doses given were relatively minor and insufficiently strong to lead to an avoidance of the flavors associated with the delivery of the drugs.
  • the rats did not appear to distinguish between the two drugs or the dosing procedures on the conditioned aversion test.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne des régimes de dosage et des méthodes de traitement de l'obésité, du surpoids et/ou de l'hyperphagie chez des mammaliens. Ces régimes et méthodes consistent à administrer au mammalien une quantité efficace pharmaceutiquement d'un antagoniste du récepteur CB1 en tant que dosage unitaire en fonction d'un programme continu présentant un intervalle de dosage sélectionné parmi le groupe englobant un dosage hebdomadaire, bi-hebdomadaire, tri-hebdomadaire, deux fois par semaine et bimensuel.
PCT/CA2006/001284 2005-08-05 2006-08-04 Regime de dosage pour perte de poids WO2007016771A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2042175A1 (fr) * 2007-09-21 2009-04-01 Laboratorios del Dr. Esteve S.A. Ligands du récepteur CB1 au traitement de l'obésité

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5462960A (en) * 1993-12-17 1995-10-31 Sanofi Pyrazole-3-carboxamide derivatives, process for their preparation and pharmaceutical compositions in which they are present

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5462960A (en) * 1993-12-17 1995-10-31 Sanofi Pyrazole-3-carboxamide derivatives, process for their preparation and pharmaceutical compositions in which they are present

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CHAMBERS A.P. ET AL.: "AM 251 produces sustained reductions in food intake and body weight that are resistant to tolerance and conditioned taste aversion", BRITISH JOURNAL OF PHARMACOLOGY, vol. 147, 2006, pages 109 - 116, XP003008572 *
CHAMBERS A.P. ET AL.: "Cannabinoid (CB)1 receptor antagonist, AM 251, causes a sustained reduction of daily food intake in the rat", PHYSIOLOGY AND BEHAVIOR, vol. 82, 2004, pages 863 - 869, XP004586363 *
COLOMBO G. ET AL.: "Appetite suppression and weight loss after the cannabinoid antagonist SR 141716", LIFE SCIENCES, vol. 63, 1998, pages PL113 - PL117, XP003008574 *
HILDEBRANDT A.L. ET AL.: "Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 462, 2003, pages 125 - 132, XP002273842 *
JARBE T.U. ET AL.: "Delta-9-THC induced hyperphagia and tolerance assessment: interactions between the CB1 receptor agonist delta 9-THC and the CB1 receptor antagonist SR 141716 (rimonabant) in rats", BEHAVIOURAL PHARMACOLOGY, vol. 16, 2005, pages 373 - 380 *
LANGE J.H.M. ET AL.: "Keynote review: Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists", DRUG DISCOVERY TODAY, vol. 10, May 2005 (2005-05-01), pages 693 - 702, XP004894759 *
MCLAUGHLIN P.J. ET AL.: "The cannabinoid CB1 antagonists SR141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats", BEHAVIOURAL PHARMACOLOGY, vol. 14, 2003, pages 583 - 588 *
ROWLAND N.E. ET AL.: "Effects of the cannabinoid receptor antagonist SR 141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats", PSYCHOPHARMACOLOGY, vol. 159, 2001, pages 111 - 116, XP003008573 *
WILEY J.L. ET AL.: "CB1 cannabinoid receptor-mediated modulation of food intake in mice", BRITISH JOURNAL OF PHARMACOLOGY, vol. 145, March 2005 (2005-03-01), pages 292 - 300, XP003008571 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2042175A1 (fr) * 2007-09-21 2009-04-01 Laboratorios del Dr. Esteve S.A. Ligands du récepteur CB1 au traitement de l'obésité
ES2347400A1 (es) * 2007-09-21 2010-10-28 Laboratorios Del Dr. Esteve, S.A. Procedimiento de tratamiento que usa un compuesto receptor de cb1 en ciertas pautas de dosificacion.

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