WO2009152152A1 - Traitement de l'obésité par un interféron - Google Patents

Traitement de l'obésité par un interféron Download PDF

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WO2009152152A1
WO2009152152A1 PCT/US2009/046748 US2009046748W WO2009152152A1 WO 2009152152 A1 WO2009152152 A1 WO 2009152152A1 US 2009046748 W US2009046748 W US 2009046748W WO 2009152152 A1 WO2009152152 A1 WO 2009152152A1
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interferon
alpha
composition
administered
human
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Joseph Mont Cummins
Martin Joseph Cummins
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Ainos Inc
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Amarillo Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta

Definitions

  • Obesity is a world wide pandemic. In Mexico, Egypt, and South Africa more than half of adults are overweight or obese (Popkin, Scientific American, 2007,
  • Obesity Trends 1985-2005 available at http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/; Ogden & Carroll, JAMA, 2006, 295, 13, 1549).
  • a number of health problems are linked to obesity including heart disease, metabolic syndrome, diabetes, hypertension, stroke, cancer, dyslipidemia, gallbladder disease, sleep apnea, respiratory problems, reduced fertility, osteoarthritis, and increased overall mortality.
  • a method for inducing weight loss is provided by administering low dose interferon to an individual desirous of losing weight.
  • the interferon administered is interferon- alpha (IFN- ⁇ ), and the interferon is administered orally including for example in a saliva soluble dosage form.
  • interferon- alpha is administered at a dose range from about 50 to about 2000 IU per day.
  • interferon- alpha is administered from about 400 to about 1000 IU per day, to induce or maintain weight.
  • a method is provided for treating patients that are overweight or obese and help promote weight loss. Alternatively, in one embodiment a method is provided to prevent weight gain.
  • the term "pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents. The term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
  • the term “treating” includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
  • treating obesity will refer in general to inducing weight loss or preventing weight gain or reducing complications associated with obesity including vascular disease (coronary artery disease, stroke, peripheral vascular disease, ischemia reperfusion, etc.), hypertension, onset of diabetes type II, hyperlipidemia and musculoskeletal diseases.
  • vascular disease coronary artery disease, stroke, peripheral vascular disease, ischemia reperfusion, etc.
  • hypertension onset of diabetes type II
  • hyperlipidemia hyperlipidemia and musculoskeletal diseases.
  • an "effective" amount or a “therapeutically effective amount” of an anti-obesity composition comprising interferon refers to a composition comprising a nontoxic but sufficient amount of an interferon to provide the desired effect.
  • one desired effect would be the reduction or maintenance of body weight.
  • the amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
  • purified and like terms relate to the isolation of a molecule or compound in a form that is substantially free of contaminants normally associated with the molecule or compound in a native or natural environment.
  • purified does not require absolute purity; rather, it is intended as a relative definition.
  • isolated requires that the referenced material be removed from its original environment (e.g., the natural environment if it is naturally occurring).
  • a naturally-occurring polypeptide present in a living animal is not isolated, but the same polypeptide, separated from some or all of the coexisting materials in the natural system, is isolated.
  • "Obese” is defined as having a body mass index (BMI) > 30.
  • Body mass index is calculated as an individual's weight (in kilograms) divided the individual's height (in meters squared).
  • Interferon is a term generally describing a group of cytokines exhibiting pleiotropic activity categorized as antiviral, antiproliferative and immunomodulatory.
  • interferon a factor must be a protein which exerts virus non-specific, antiviral activity at least in homologous cells through cellular metabolic process involving synthesis of both RNA and protein
  • Interferon as used herein in describing in the present invention shall be deemed to have that definition and shall contemplate proteins and glycoproteins, including for example, the subtypes: interferon- alpha, interferon-beta, interferon-delta, interferon-epsilon, interferon-gamma, interferon-kappa, interferon-lambda, interferon-omega and interferon-tau, regardless of their source or method of preparation or isolation.
  • Interferons can be small, inducible, about 20 to about 25 KD, usually glycosylated proteins that are produced by vertebrate cells in response to various biological stimuli. Interferons mediate their biological activities by binding to receptors present on the surface of target cells. Specific ligand-receptor interactions trigger intracellular signaling cascades downstream, resulting in the synthesis of proteins that mediate biological activity.
  • Interferons are classified into two groups: type I or type II, based on their structure, physicochemical properties and biological activities. Type I and type II interferons exert their biological effects through different cellular receptors. In mammals, eight families of type I interferon have been described. These families include interferon- alpha, interferon-beta, interferon-delta, interferon-epsilon, interferon- kappa, interferon-lambda, interferon-omega and interferon-tau.
  • Interferon-tau also known as interferon trophoblast
  • Interferon-tau is not inducible by viruses, and is found only in ruminant ungulates where it is produced in the embryonic trophoectoderm at a specific time early during pregnancy. Its major function is to facilitate conditions for the completion of pregnancy.
  • Interferon-delta a polypeptide of about 149 amino acids, has been described only in pigs. This interferon is physiologically expressed by trophoblast during the period of implantation in uterus.
  • Interferon-gamma is the sole representative of type II interferon in mammals.
  • Interferons have generally been named in terms of the species of animal cells producing the substance, the type of cell involved (e.g., leukocyte/lymphoblastoid or fibroblast) and, occasionally, the type of inducing material responsible for the interferon production.
  • the designations alpha ( ⁇ ), beta ( ⁇ ) and gamma ( ⁇ ) have been used to correspond to the previous designations of leucocyte, fibroblast, and immune interferons, respectively.
  • Alpha and beta interferons are usually acid-stable and correspond to what have been called Type I interferons;
  • gamma interferons are usually acid-labile and correspond to what have been called Type II interferons.
  • interferon tau has been described as an interferon- alpha related Type I interferon produced by bovine and ovine trophoblasts.
  • Interferon of human and murine origin is quantified in the art in terms of International Units (IU). Note that interferons of other than human or murine origin can also be used in accordance with the methods disclosed herein. In that certain practices may not extend the use of "International Units" to quantify non-human and non-murine interferons, it shall be understood that administration of amounts of non-human/non- murine interferons having the same efficacy as the quantities (IU) of human interferon specified in this description for treatment of overweight and obese patients is within the scope of the present disclosure. EMBODIMENTS
  • a method of reducing weight gain or inducing weight loss comprises administering a composition comprising an interferon to a patient in need of weight reduction or weight maintenance.
  • the patient is a human, however the methods disclosed herein are not limited to humans but also may include the treatment of animals including for example domesticated animals such as cats and dogs.
  • a method for inducing weight loss in a human patient comprises orally administering low-dose interferon- alpha.
  • the method comprises administering to a patient, such as a human, about 1 to about 1500 IU of interferon per day.
  • the interferon is administered at a dosage of about 0.01 to about 5 IU/lb (from about 0.02 to about 11 IU/kg), or from about 0.25 to about 1.5 IU/lb (from about 0.55 to about 3.3 IU/kg) of patient body weight.
  • the interferon may be administered buccally, sublingually, or by oral ingestion.
  • the administered interferon is a type I interferon and in a further embodiment the type I interferon is selected from the group of interferon-alpha, interferon-beta, interferon-delta, interferon-epsilon, interferon-kappa, interferon-lambda, interferon-omega and interferon-tau.
  • the administered composition comprises a type I interferon selected from the group consisting of interferon-alpha, interferon-beta and interferon-tau, and in one embodiment the interferon is interferon-alpha.
  • the composition comprising interferon may be administered in unit dose forms once, twice or three times a day.
  • the interferon is administered as a daily single unit dose form, comprising about 50 to about 2000 IU of interferon.
  • the interferon is administered as a daily single unit dose form, comprising about 400 to about 1000 IU of interferon.
  • the treatment can be continued indefinitely or until the desired weight loss is obtained.
  • the interferon is administered for at least one to two weeks and in an alternative embodiment the treatment is continued for 1 to 6 months.
  • a method for treating overweight and obese patients to produce a therapeutic response is provided. The method comprises the step of administering to a patient from about 1 to about 1500 IU of interferon per day.
  • a pharmaceutical composition comprising interferon is administered orally.
  • Such methods are expected to be useful in reducing body weight, preventing weight gain, or treating obesity of various causes, including drug-induced obesity.
  • a further benefit of such treatment is the expected reduction in complications associated with obesity, including vascular disease (coronary artery disease, stroke, peripheral vascular disease, ischemia reperfusion, etc.), hypertension, onset of diabetes type II, hyperlipidemia and musculoskeletal diseases.
  • the interferon compositions may be administered alone or in combination with other anti-obesity agents. When used in combination with known anti-obesity agents, the interferon can be administered either simultaneously or concurrently with the administration of the known anti-obesity agent.
  • a single composition comprising an isolated interferon, a known anti-obesity agent and a pharmaceutically acceptable carrier.
  • two separate pharmaceutical compositions are administered to a patient, the first comprising an isolated interferon and the second comprising a known anti-obesity agent.
  • the separate interferon and anti-obesity compositions are administered within 0.5, 1, 2, 3, 4, 5, 6, 8, 12, or 24 hours of one another.
  • the separate interferon and anti-obesity compositions are administered within 15 to 60 minutes of one another.
  • the interferon composition comprises two or more interferon isotypes.
  • Anti-obesity agents known in the art or under investigation include appetite suppressants, including phenethylamine type stimulants, phentermine (optionally with fenfluramine or dexfenfluramine), diethylpropion (Tenuate®), phendimetrazine (Prelu-2®, Bontril®), benzphetamine (Didrex®), sibutramine (Meridia®, Reductil®); rimonabant (Acomplia®), other cannabinoid receptor antagonists; fluoxetine hydrochloride (Prozac); Qnexa (topiramate and phentermine), Excalia (bupropion and zonisamide) or Contrave (bupropion and naltrexone); or lipase inhibitors, similar to xenical (Orlistat) or Cetilistat (also known as ATL-962), or GT 389-255.
  • Another compound that induces weight loss is oxyntomodulin, a naturally occurring 37 amino
  • a method for treating overweight and obese patients to produce a therapeutic response comprises the step of administering to a patient a composition comprising from about 1 to about 1500 IU of interferon per day.
  • the interferon may be administered using standard pharmaceutically acceptable carriers and routes of administration known to those skilled in the art, including parenterally, such as intravenously, intraperitoneally, subcutaneously or intramuscularly, intrathecally, transdermally, rectally, orally, nasally or by inhalation.
  • the composition is administered buccally, sublingually, or by oral ingestion.
  • “Therapeutic response” as used herein refers to a patient response characterized by a reduction in weight or improvement of other clinical symptoms associated with obesity and being overweight.
  • Buccal and sublingual administration comprises contacting the oral and pharyngeal mucosa of the patient with the dose of interferon.
  • the interferon may be contained in either a pharmaceutically acceptable liquid dosage form or a saliva soluble dosage form, which is held in the patient's mouth to form a saliva solution of the dose of interferon in contact with the oral and pharyngeal mucosa.
  • Interferons useful in accordance with the presently disclosed composition and methods include both Type I and Type II interferons of either heterologous or homologous origin.
  • the interferon is a Type I interferon selected from interferon- alpha, interferon-beta and interferon-tau.
  • the interferons can be of human or non-human origin.
  • the clinical agent useful for the treatment of overweight and obesity is human leucocyte interferon (human interferon- alpha) produced by art recognized procedures.
  • Interferon-alpha can be mass produced by collection and purification of quantities of human buffy-coat leucocytes, induction of interferon production with a virus, and isolation from culture media; or interferon-alpha can be produced, for example, in accordance with the procedures described in U.S.
  • interferon-alpha is commercially available. Also acceptable for use in accordance with the methods disclosed herein are human interferon-alpha compositions produced by recombinant DNA technology.
  • a method for treating overweight or obese patients comprises the step of orally administering to a patient about 50 to about 2000 IU of interferon-alpha per day.
  • interferon-alpha is administered from about 450 to about 1000 IU per day.
  • the interferon-alpha can be of heterologous (non-human) or homologous (human) origin and can be formulated in a liquid or solid dosage form.
  • the interferon composition is administered by oral ingestion or by buccal or sublingual administration.
  • the interferon intended for buccal or sublingual administration is administered to the patient in a dosage form adapted to promote contact of the interferon with the oral and pharyngeal mucosa.
  • the dosage form can be in the form of an interferon containing solution or syrup to be administered and used by the patient in a manner that promotes contact of the interferon component with oral mucosal tissues, for example, by holding the interferon solution in the mouth for up to about one minute.
  • the interferon is formulated into a solid dosage form comprising a low dose of interferon, for example, interferon-alpha, and a saliva soluble carrier. Excipients, such as buffers or tableting aids, are optional.
  • the solid dosage form is formulated to dissolve when held in an individual's mouth to form a saliva solution of the dose of interferon and promote contact of the interferon with the oral and pharyngeal mucosa.
  • the solid dosage form is in the form of a lozenge adapted to be dissolved upon contact with saliva in the mouth, with or without the assistance of chewing, to form a saliva solution of the interferon.
  • a lozenge is formulated to provide from about 0.01 to about 5 IU/lb (from about 0.02 to about 11 IU/kg), or from about 0.25 to about 1.5 IU/lb (from about 0.55 to about 3.3 IU/kg) of patient body weight of interferon- alpha in solution upon dissolution of the dosage form in saliva in the mouth.
  • Lozenges for use in accordance with the methods disclosed herein can be prepared, for example, by art-recognized techniques for forming compressed tablets where the interferon is dispersed on a compressible solid carrier, optionally combined with any appropriate tableting aids such as a lubricant (e.g., sodium-stearate) and compressed into tablets.
  • a lubricant e.g., sodium-stearate
  • the solid carrier component for such tableting formulations can be a saliva soluble solid, such as cold-water-soluble starch or a monosaccharide or disaccharide, so that the lozenge will readily dissolve in the mouth to release the contained interferon in saliva solution for contact with and absorption by the oral/pharyngeal mucosa when the lozenge is held in the mouth.
  • an interferon pharmaceutical composition is formulated to provide a therapeutic response in the treatment of overweight or obese patients.
  • the pharmaceutical composition comprises from about 1 to about 1500 IU of interferon-alpha in combination with a saliva soluble carrier.
  • the pharmaceutical composition may comprise from about 5 to about 1000 IU of interferon-alpha in combination with a saliva soluble carrier.
  • the pharmaceutical composition comprises about 15 to about 150 IU of interferon-alpha in combination with a saliva soluble carrier.
  • Interferon can be administered in either a liquid (solution) or solid dosage form.
  • interferon can be administered dissolved in a buffered aqueous solution typically containing a stabilizing amount (about 1-5% by weight) of albumin or blood serum.
  • a buffered solution suitable as a carrier of interferon is phosphate buffered saline prepared as follows:
  • a concentrated (2Ox) solution of phosphate buffered saline may be prepared by dissolving the following reagents in sufficient water to make 1,000 ml of solution: sodium chloride, 160 grams; potassium chloride, 4 grams; sodium hydrogen phosphate, 23 grams; potassium dihydrogen phosphate, 4 grams; and optionally phenol red powder, 0.4 grams.
  • the solution is sterilized by autoclaving at 15 pounds pressure for 15 minutes and then diluted with additional water to a single strength concentration prior to use.
  • the interferon for use in a composition administered by buccal, sublingual or oral ingestion routes can be formulated into flavored or unflavored solutions or syrups using a buffered aqueous solution of interferon as a base with added caloric or non-caloric sweeteners, flavor oils and pharmaceutically acceptable surfactant/dispersants.
  • Solid dosage forms for oral ingestion administration can be prepared using standard tableting protocols and excipients to provide interferon- containing tablets, capsules, caplets, or gel seals.
  • Interferon in a solid dosage form can also be in the form of a lozenge adapted to be dissolved upon contact with saliva in the mouth with or without the assistance of chewing.
  • Such a unitary dosage form is formulated to release from about 1 to about 1500 IU of interferon upon dissolution in the mouth for contact with the oral and pharyngeal mucosa.
  • a unitary dosage form of interferon can be prepared by art recognized techniques for forming compressed tablets such as chewable vitamins.
  • interferon can be incorporated into starch-based gel formulations to form a lozenge which will dissolve and release interferon for contact with the oral mucosa when held in the mouth.
  • Solid unitary dosage forms of interferon can be prepared utilizing art recognized dosage formulation techniques. The pH of such formulations can range from about 4 to about 8.5. In processing such unitary dosage forms, one should avoid heating a formulation after addition of interferon above about 50 0 C.
  • the daily doses of interferon- alpha can be administered as single doses, or they can be divided and administered as a multiple-dose daily regimen.
  • a staggered regimen for example, one to three days of buccal/sublingual interferon treatments per week, can be used as an alternative to daily treatment.
  • intermittent or staggered regimens are considered to be equivalents of every day treatment and are within the scope of this invention.
  • Antiviral activity of low dose IFN- ⁇ is effective against human diseases caused by DNA virus classes such as herpes virus, papilloma virus, or poxvirus (molluscum contagiosum).
  • DNA virus classes such as herpes virus, papilloma virus, or poxvirus (molluscum contagiosum).
  • adenovirus Another DNA virus, adenovirus, has been implicated as a contributing factor to obesity in a subset of obese human and animals.
  • adenovirus infections are common causes of acute respiratory tract infections, enteritis, or conjunctivitis.
  • the presence of antibodies to adenoviruses is common in the general population.
  • Adenoviral DNA is detected in asymptomatic adult human lymphocytes and the number of positive cells increases with age. There are 6 subgroups (A-F) among 50 human adenoviruses.
  • Ad-36 belongs to subgroup D, serotype 36.
  • Ad-36 was first isolated from a fecal sample obtained from a diabetic girl with enteritis.
  • Ad-36 is serologically distinct from 48 types of human adenovirus but has a weak cross-reaction with Ad-29 (Pasarica et al., 2006, Obesity, 14, 11, pp. 1905-13).
  • Ad-36 Human adenovirus-36 increases adiposity in chickens, mice, and nonhuman primates and is associated with human obesity.
  • Ad-36 increases adipocyte differentiation and triglyceride accumulation in 3T3-L1 preadipocyte cells in vitro, but, paradoxically, Ad-36 reduces serum cholesterol and triglycerides in animal models.
  • Ad-31, Ad-36, and Ad-37 In 3T3-L1 cells in vitro, Ad-31, Ad-36, and Ad-37, but not Ad-2, increased adipocyte differentiation and triglycerides accumulation.
  • Ad-37 increased adiposity and reduced serum triglycerides in an animal model.
  • serum cholesterol to Ad-37 is opposite that of Ad-36 (Whigham et al., 2006, Am J Regul Integr Comp Physiol, 290, 1, pp. R190-94).
  • Further effects of human adenovirus Ad- 36 infection Experimental infection of rats with Ad-36 improves insulin sensitivity and promotes adipogenesis.
  • the E4 open reading frame (orf)-l gene of the virus was found to be necessary and sufficient for Ad-36-induced adipogenesis.
  • Selective knockdown of E4 orf-1 by RNAi abrogated Ad-36-induced adipogenic signaling cascade in 3T3-L1 cells and hASC.
  • selective expression of Ad-36 E4 orf-1 in 3T3- Ll induced adipogenesis which was abrogated when the PDZ-binding domain of the protein was deleted.
  • Ad-36 E4 orf-1 is an inducer of rodent and human adipocyte differentiation processes (Rogers et al., 2008, Int J Obes, 32, 3, pp. 397-406).
  • Ad-36 causes adiposity in animal models and enhances differentiation and lipid accumulation in human and 3T3-L1 preadipocytes, which may, in part, explain the adipogenic effect of Ad-36.
  • Preadipocytes (3T3-L1) were used to determine the effect of infection by human adenoviruses Ad-36, Ad-2, Ad-9 and Ad-37 on leptin secretion and lipid accumulation.
  • Rat primary adipocytes were used to determine the effect of Ad-36 infection on leptin secretion and glucose uptake in vitro.
  • the effect of Ad-36 on the expression of leptin and selected genes of de novo lipogenesis pathway of visceral adipose tissue were compared ex vivo between Ad-36 infected and uninfected control rats.
  • Ad-36 suppressed the expression of leptin mRNA in 3T3-L1 cells by approximately 58% and 52% on days 3 and 5 post-infection, respectively.
  • Leptin release normalized to cellular lipid content, was 51% lower (p ⁇ 0.002) in the Ad-36 infected 3T3-L1 cells. Lipid accumulation was significantly greater and leptin secretion was lower for the 3T3-L1 cells infected with other human adenoviruses, Ad-9, Ad-36, or Ad-37.
  • Human adenovirus Ad-2 did not influence cellular lipid accumulation or the leptin release.
  • Ad- 36 reduced leptin release by about 40% in the presence of 0.48 nM (p ⁇ 0.01) or 1.6 nM insulin (p ⁇ 0.05).
  • Ad-36 infection increased glucose uptake by 93% (p ⁇ 0.001) or 18% (p ⁇ 0.05) in the presence of 0 nM or 0.48 nM insulin, respectively.
  • the adipose tissue of Ad-36 infected rats showed 2- to 5-fold lower leptin mRNA expression.
  • the expression of Acetyl Co-A carboxylase- 1 and fatty acid synthase, key genes of de novo lipogenesis, were also measured.
  • Ad-36 infected rats showed 1.6- to 21-fold greater expression of acetyl Co-A carboxylase-1 mRNA, and 1.2- to 6.3- fold greater expression of fatty acid synthase mRNA compared to uninfected controls matched for weight and adiposity.
  • the in vitro and ex vivo studies show that Ad-36 modulates adipocyte differentiation, leptin production, and glucose metabolism (Vangipuram et al., 2007, Int J Obes, 31, 1, pp. 87-96).
  • Ad-36 antibodies Adenovirus association with human obesity
  • body mass index BMI
  • Ad-36 was associated with increased body weight and lower serum lipids in humans (Atkinson et al., 2005, Int J Obes, 29, 3, pp. 281-86).
  • the adiposity promoting effect of a human adenovirus (Ad-36) was investigated in two different animal models. The findings were replicated in experiments using a chicken model (three times) and a mammalian model (once).
  • Ad-36 Animals inoculated with Ad-36 developed a syndrome of increased adipose tissue, but low levels of serum cholesterol and triglycerides. This syndrome was not seen in chickens inoculated with CELO virus. Sections of the brain and hypothalamus of Ad-36 inoculated animals did not show any overt histopathological changes. Ad-36 DNA could be detected in adipose tissue, but not skeletal muscles, of randomly selected animals for as long as 16 weeks after Ad-36 inoculation. Data from these animal models further supports the role of viral disease in the etiology of human obesity (Dhurandhar et al., 2000, Int J Obes Relat Metab Disord, 24, 8, pp. 989-96).
  • Ad-36 a human adenovirus
  • SMAM-I an avian adenovirus
  • Ad-36 a human adenovirus
  • Nonhuman primates were used to investigate the potential of Ad-36 to promote adiposity.
  • spontaneously occurring Ad-36 antibodies in 15 male rhesus monkeys were found. The monkeys were observed for 18 months after appearance of the antibodies was detected, and a significant longitudinal association of positive antibody status with weight gain and plasma cholesterol lowering was found.
  • Ad-36 was examined to determine if it enhanced differentiation of preadipocytes. Immunofluorescence studies showed adenoviral attachment to 3T3-L1 cells, and reverse transcriptase-polymerase chain reaction (RTPCR) showed expression of the Ad-36 ElA gene in the infected cells.
  • RTPCR reverse transcriptase-polymerase chain reaction
  • Ad-36, but not Ad-2 increased the number of differentiated adipocytes, glycerol 3-phosphate dehydrogenase (GPDH) enzyme levels, and total cellular lipid content. Also, Ad-36, but not Ad-2, increased GPDH levels in human preadipocytes.
  • Ad-36 enhanced differentiation of preadipocytes, which may be a contributory mechanism to its adipogenic effect in vivo.
  • the lack of effect of Ad-2 on differentiation demonstrated that the observed findings were not a common characteristic of all adenoviruses.
  • Future understanding of the molecular interactions of cellular and viral genes responsible for enhanced differentiation may reveal signaling pathways and controls of preadipocyte differentiation (Vangipuram et al., 2004, Int J Obes, 31, 1, pp. 87-96).
  • the serum of 52 humans with obesity in Bombay, India was screened for antibodies against SMAM-I virus using the agar gel precipitation test (AGPT) method.
  • AGPT agar gel precipitation test
  • Body weights and serum cholesterol and triglyceride levels were compared in SMAM-I- positive (P-AGPT) and SMAM- 1-negative (N-AGPT) groups. Ten subjects were positive for antibodies to SMAM-I, and 42 subjects tested negative for SMAM-I antibodies.
  • the P-AGPT group had a significantly higher bodyweight (p ⁇ 0.02) and body mass index (p ⁇ 0.001) (95.1 +/- 2.1 kg and 35.3 +/- 1.5 kg/m 2 , respectively) compared with the N-AGPT group (80.1 +/- 0.6 kg and 30.7 +/- 0.6 kg/m 2 , respectively).
  • the P-AGPT group had significantly lower serum cholesterol (p ⁇ 0.02) and triglyceride (p ⁇ 0.001) values (4.65 mmol/L and 1.45 mmol/L, respectively) compared with the N-AGPT group (5.51 mmol/L and 2.44 mmol/L, respectively).
  • p ⁇ 0.02 and triglyceride (p ⁇ 0.001) values (4.65 mmol/L and 1.45 mmol/L, respectively) compared with the N-AGPT group (5.51 mmol/L and 2.44 mmol/L, respectively).
  • Ad-36 increases adiposity and reduces serum lipids in chicken, mouse, and non-human primate models, and it is linked to obesity in sero-epidemiological studies in humans. Involvement of the central nervous system (CNS) or adipose tissue in the mechanism of Ad-36-induced adiposity is unknown.
  • CNS central nervous system
  • Ad-36 adipose tissue in the mechanism of Ad-36-induced adiposity is unknown.
  • Epididymal-inguinal, retroperitoneal, and visceral fat pad weights of the infected group were greater by 60%, 46%, and 86%, respectively (p ⁇ 0.00001).
  • the fasting serum insulin level and homeostasis model assessment index indicated greater insulin sensitivity in the infected group.
  • Visceral adipose tissue expression of GPDH, peroxisome proliferator-activated receptor gamma (PPAR- ⁇ ), and CCAAT/enhancer-binding protein alpha and beta was markedly increased in the infected animals compared with controls.
  • Ad-36 also decreased norepinephrine levels significantly in the paraventricular nucleus in infected vs.
  • Ad-36 decreased serum corticosterone in infected vs. control rats (mean ⁇ standard error, 97 ⁇ 41.0 vs. 221 + 111 ng/mL; p ⁇ 0.005).
  • the male Wistar rat may be a good model for the elucidation of metabolic and molecular mechanisms of Ad-36-induced adiposity (Pasarica et al., 2006, Obesity, 14, 11, pp. 1905-13).
  • SMAM-I an avian adenovirus from India, acts directly on adipocytes and is an animal virus that is associated with human obesity.
  • Ad-36 has been studied further and has been linked with human obesity.
  • Ad-36 which causes obesity in chickens, mice, rats, and monkeys, was present in 30% of obese humans and 11% of non-obese humans.
  • Recombinant human interferon- alpha or placebo was given orally to 264 veal calves in Indiana. Interferon or placebo was placed in the milk replacer once daily for 5 consecutive days. Calves were observed for respiratory tract infections, nasal discharge, ear infections, diarrhea and fever through their 11th week in the veal barn. Calves given interferon had a significantly (p ⁇ 0.05) shorter duration of diarrhea, fewer ear infections (otitis media), and lower incidence of nasal secretions. The incidence of mild or severe diarrhea was reduced significantly (p ⁇ 0.0001 and p ⁇ 0.004, respectively).
  • Calves given interferon gained an average of 13.1 pounds more per calf than calves given placebo (Cummins et al., 1993, Arch Immunol Ther Exp, 41, 3-4, pp. 199-203).
  • 112 feeder calves were given a single oral dose of human interferon- alpha or placebo upon arrival at the feed yard.
  • Calves given 48 IU/calf had significantly (p ⁇ 0.05) improved average daily weight gain and had better feed efficiency 14 and 28 days after treatment (Chirase and Greene, 2000, Proc West Sect Am Soc Animal Sci, 51, pp. 411-14).
  • the effect of natural human interferon-alpha on rotavirus diarrhea was studied in 99 calves in Japan.
  • the oral treatment was given once daily at 0.5 IU/kg body weight for 5 consecutive days.
  • Calves given interferon had significantly (p ⁇ 0.05) greater weight gain, less virus excretion, and fewer days of diarrhea.
  • ISG interferon stimulated genes
  • Table 1 shows weight gain in piglets administered placebo or human interferon in their feed for 21 days at 0.014, 0.022, 0.135, or 0.319 IU of interferon/kg body weight.
  • the average daily weight gain was higher in all interferon treatment groups, ranging from 222 grams to 376.5 grams, compared to an average weight gain of 211 grams in controls.
  • Table 2 demonstrates the percentage of female clinical trial participants losing at least 5% of total body weight after administration of interferon-alpha (0-2000 IU per day) over 3-6 months. As compared to controls, a statistically significant percentage of participants were found to have greater than 5% weight loss at interferon-alpha doses of 450 and 1000 IU per day
  • Table 3 shows the percentage of the heaviest 50% of female clinical trial participants losing at least 5% of total bodyweight after administration of interferon-alpha (0-2000 IU per day) over 3-6 months. As compared to controls, a statistically significant percentage of participants were found to have greater than 5% weight loss at interferon- alpha doses of 450 and 1000 IU per day.
  • Table 4 Interferon Induced Weight Loss in Heaviest 33% of Females from Controlled
  • Table 4 shows the percentage of the heaviest 33% of female clinical trial participants in three controlled studies losing at least 5% of total bodyweight after administration of interferon- alpha (0-2000 IU per day) over 3-6 months. As compared to controls, a statistically significant percentage of participants were found to have greater than 5% weight loss at an interferon-alpha dose of 1000 IU per day.
  • Table 5 shows the percentage of the heaviest 25% of female clinical trial participants in three controlled studies losing at least 5% of total bodyweight after administration of interferon-alpha (0-2000 IU per day) over 3-6 months. As compared to controls, a statistically significant percentage of participants were found to have greater than 5% weight loss at an interferon-alpha dose of 1000 IU per day.
  • Low dose orally administered interferon-alpha produced weight loss in females without the adverse side effects observed in patients treated with high dose injectable interferon.
  • Common gastrointestinal disorders attributed to high dose injectable interferon include diarrhea, anorexia, nausea, and taste alteration, which occur in up to 24-69% of subjects (Physician's Desk Reference, 2008).
  • Table 6 the adverse effects of diarrhea, nausea, taste alteration and abdominal pain occurred no more often in oral interferon-treated subjects than in placebo-treated subjects.
  • Table 6 shows the incidence of gastrointestinal adverse events of female patients administered IFN-alpha compared to placebo. No statistically significant differences were found.

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Abstract

L'invention concerne l'utilisation d'un interféron alpha pour traiter des individus en surpoids ou obèses. Dans un mode de réalisation, on administre aux patients des pastilles comprenant une faible dose d'interféron-alpha pour obtenir une perte de poids. Un traitement par interféron alpha dans la plage d'environ 50 à environ 2 000 unités internationales par jour pendant 3-6 mois produit une perte de poids souhaitée sans les effets secondaires couramment associés à l'interféron-alpha injectable à dose élevée.
PCT/US2009/046748 2008-06-09 2009-06-09 Traitement de l'obésité par un interféron Ceased WO2009152152A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3375452A1 (fr) * 2017-03-16 2018-09-19 Evangelos Andreakos Utilisation d'interférons lambda dans le traitement de troubles et de maladies apparentées

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Publication number Priority date Publication date Assignee Title
US6270756B1 (en) * 1999-08-30 2001-08-07 Rx/Ibr Corporation Weight loss induced by alpha interferon and gamma interferon
WO2005049068A1 (fr) * 2003-11-17 2005-06-02 Pepgen Corporation Utilisation de l'interferon tau pour traiter l'obesite et favoriser la perte de poids
US20060009514A1 (en) * 2002-05-17 2006-01-12 Gadde Kishore M Method for treating obesity
US20070129400A1 (en) * 2005-06-14 2007-06-07 Jingwu Duan Modulators of glucocorticoid receptor, AP-1, and/or NF-kB activity, and use thereof
US20070190041A1 (en) * 2004-02-27 2007-08-16 Ashai Kasei Pharama Corporation Novel benzothiazepine and bensothiepine compounds

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Publication number Priority date Publication date Assignee Title
US6270756B1 (en) * 1999-08-30 2001-08-07 Rx/Ibr Corporation Weight loss induced by alpha interferon and gamma interferon
US20060009514A1 (en) * 2002-05-17 2006-01-12 Gadde Kishore M Method for treating obesity
WO2005049068A1 (fr) * 2003-11-17 2005-06-02 Pepgen Corporation Utilisation de l'interferon tau pour traiter l'obesite et favoriser la perte de poids
US20050147588A1 (en) * 2003-11-17 2005-07-07 Chih-Ping Liu Methods for treatment of obesity and for promotion of weight loss
US20070190041A1 (en) * 2004-02-27 2007-08-16 Ashai Kasei Pharama Corporation Novel benzothiazepine and bensothiepine compounds
US20070129400A1 (en) * 2005-06-14 2007-06-07 Jingwu Duan Modulators of glucocorticoid receptor, AP-1, and/or NF-kB activity, and use thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3375452A1 (fr) * 2017-03-16 2018-09-19 Evangelos Andreakos Utilisation d'interférons lambda dans le traitement de troubles et de maladies apparentées
WO2018167287A1 (fr) * 2017-03-16 2018-09-20 Biomedical Research Foundation Of The Academy Of Athens Utilisation d'interférons lambda dans le traitement de troubles liés à l'obésité et de maladies associées
GB2574747A (en) * 2017-03-16 2019-12-18 Salagianni Maria Use of lambda interferons in the treatment of obesity-related disorders and related diseases
GB2574747B (en) * 2017-03-16 2023-01-18 Biomedical Res Foundation Of The Academy Of Athens Use of lambda interferons in the treatment of obesity-related disorders and related diseases
US12121564B2 (en) 2017-03-16 2024-10-22 Biomedical Research Foundation Of The Academy Of Athens Use of lambda interferons in the treatment of obesity-related disorders and related diseases

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