CN101511381A - Methods of treating obesity using satiety factors - Google Patents

Methods of treating obesity using satiety factors Download PDF

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Publication number
CN101511381A
CN101511381A CNA2007800327134A CN200780032713A CN101511381A CN 101511381 A CN101511381 A CN 101511381A CN A2007800327134 A CNA2007800327134 A CN A2007800327134A CN 200780032713 A CN200780032713 A CN 200780032713A CN 101511381 A CN101511381 A CN 101511381A
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peptide
individuality
satiety factors
satiety
factors
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拜伦·鲁宾
彼得·C.M.·麦克威廉姆斯
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Harkness Pharmaceuticals Inc
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Harkness Pharmaceuticals Inc
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Abstract

The present invention provides methods of treating or preventing disorders or conditions associated with an undesirable level of a satiety factor by administering to a subject in need thereof an effective amount of an agonist or antagonist of a satiety factor. The present invention also provides methods of selecting a subject for therapy with an agonist or antagonist of a satiety factor. Exemplary disorders or conditions associated with an undesirable level of a satiety factor include overweight, obesity, metabolic disorders, hypertension, lipid related disorders, anorexia and type II diabetes.

Description

Use the fat method of satiety factors treatment
1. the cross reference of related application
The application advocates the priority of U.S. Provisional Application 60/830,410 that on July 11st, 2006 submitted to and the U.S. Provisional Application of submitting on February 2nd, 2,007 60/899,223 according to 35 U.S.C. § 119 (e).
2. technical field
The invention provides by use the agonist or the antagonist of the satiety factors (satietyfactors) of effective dose, the disorder that the undesirable level of treatment or prevention and satiety factors (for example, intestinal peptide) is relevant or the method for disease to individuality that these needs are arranged.The present invention also provides the method for the individuality of selecting to use the treatment that satiety factors agonist or antagonist carry out.The agonist of the satiety factors by using effective dose to the patient or antagonist for treating patient group's (patient who for example, has the satiety factors undesirable level) method have been the present invention further provides.That exemplary disorder relevant with the satiety factors undesirable level or disease comprise is overweight, fat, metabolism disorder, hypertension, disorder, anorexia and type ii diabetes that lipid is relevant.
3. background technology
Obesity is the complicated disease that influences whole world population day by day.According to World Health Organization's data, nineteen ninety-five the whole world estimate at 200,000,000 overweight peoples that grow up, other has 1,000 8 hundred ten thousand child below five years old to be considered to overweight.By 2000, the overweight people's that grows up quantity surpassed 300,000,000 to rise to.Referring to people such as Formiguera, 2004, Best Practice ﹠amp; Research Clinical Gastroenterology, 18:6,1125-1146.
The risk of multiple disease of overweight according to the show or fat increase and health disease, comprise hypertension, dyslipidemia (high T-CHOL or high triglyceride level), type ii diabetes, coronary heart disease, apoplexy, gallbladder disease, osteoarthritis, sleep apnea and breathing problem and certain cancers (for example, carcinoma of endometrium, breast carcinoma and colon cancer).For example, referring to prevention of American National chronic disease and health promotion center (U.S.NationalCenter for Chronic Disease Prevention and Health Promotion).Its consequence scope aspect healthy from the risk of the premature dead that increases to the severe chronic disease that reduces the life oeverall quality.
People have proposed or have checked the multiple therapy that is used to regulate the physiological process of diseases such as may causing for example overweight or obesity.Referring to people such as Orzano, 2004, J.Am.Board Fam.Pract.17 (5): 359-69.Multiple according to the show satiety factors (for example synthetic and excretory intestinal peptide by the human gastrointestinal tract) can be regulated food intake and full sense signal.Therefore, some endogenous intestinal peptide has been used as the potential material standed for of Bariatric and has studied.Exemplary intestinal peptide comprises, for example, and ghrelin, cholecystokinin (CCK), pancreas peptide (PP), peptide-YY (PYY), glucagon-like peptide 1 (GLP-1) etc.
Yet, the research (comprising clinical trial) of most satiety factors has been obtained fuzzy, the result of contradiction mutually usually.Therefore, in this area the effective ways for the treatment of fat and relevant disease are existed demand.The invention solves this kind demand and the method for the treatment of this kind disease is provided.
4. summary of the invention
The present invention part is based on following discovery: () level for example, the intestinal peptide, treatment has the crowd that bigger response maybe can produce bigger response to satiety factors might to identify statistically relatively other crowd by estimating satiety factors.
On the one hand, the invention provides treatment or prevention and have the disorder in the individuality of satiety factors undesirable level or the method for disease.Depend on individuality, described peptide and disorder or disease, this undesirable level can be too low or too high.This method comprises agonist from the amount of effective treatment or prevention disorder or disease to individuality or the antagonist of using satiety factors with.As is known to the person skilled in the art, agonist or antagonist adopt the pharmacy acceptable forms to use by the acceptable route of administration of pharmacy.
Do not wish to be subject to any specific theory of operation, believe that the most effectual way of treatment as diseases such as overweight or obesity is that specific therapy is applied to specific patient crowd.Advantageously, in some embodiments, the invention provides and select to be suitable for using the satiety factors agonist of effective dose or the method for the population of individuals (for example, subpopulation) that antagonist is treated according to method as herein described.In some embodiments, method of the present invention strengthens or even forms the treatment or the prophylactic activity of satiety factors agonist or antagonist.In some embodiments, method of the present invention is tested and appraised the potential side effect that the individuality that is unsuitable for using this satiety factors agonist or antagonist reduces or avoid satiety factors agonist or antagonist.
Exemplary disorder or the disease relevant with the satiety factors undesirable level include, but are not limited to: overweight, fat, metabolism disorder, hypertension, disorder, anorexia and type ii diabetes that lipid is relevant.
On the other hand, the invention provides the method for treatment satiety factors undesirable level in this individuality that needs is arranged.This method comprises agonist or the antagonist to the described satiety factors of this individuality administering therapeutic effective dose.
On the other hand, the invention provides the method for the individuality that select to use the treatment that satiety factors agonist or antagonist carry out.In some embodiments, this method comprises the amount of mensuration from the satiety factors in the individual specimen.When the quantity of the described satiety factors in this individual specimen is lower than normal value, select this individuality to treat.Hereinafter specifically described normal satiety factors value.
On the other hand, the invention provides treatment or the prevention disorder relevant or the method for disease with the satiety factors undesirable level.This method comprises the individuality that will treat of selecting to have the satiety factors undesirable level and with treatment or prevent the effective dose of this disorder or disease to use the agonist and the antagonist of described satiety factors to this individuality.This paper has described the method for selecting to have the individual of satiety factors undesirable level and using satiety factors agonist and antagonist.In some embodiments, use a kind of agonist or the antagonist of described satiety factors.In some embodiments, use the multiple agonist or the antagonist of described satiety factors.In some embodiments, use the multiple agonist or the antagonist of one or more satiety factors.In some embodiments, the agonist of satiety factors or antagonist and can be used for treating or prevent second reagent of this disorder or disease co-administered.
Satiety factors of the present invention can be to be generated or should be generated by endogenous by individual endogenous, and can modulation of appetite, food intake, energy is taken in or consume or any molecule of full sense signal.Satiety factors of the present invention comprises peptide and non-peptide satiety factors.The peptide satiety factors can be the intestinal peptide, promptly generate or should generate by endogenous by gastrointestinal tract (for example, stomach, pancreas, intestinal or colon) endogenous, and can modulation of appetite, food intake, energy is taken in or consume or the peptide of full sense signal.In some embodiments, the intestinal peptide also can be generated by another organ (for example, brain).In some embodiments, the intestinal peptide is selected from dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, insulin, Proglucagon derived peptide (as glucagon, glucagon-like peptide 1 or oxyntomodulin), fat inhibin, pancreatic polypeptide and peptide YY.In some embodiments, the intestinal peptide is an enterostatin.In some embodiments, the intestinal peptide is not an enterostatin.
The peptide satiety factors can be non-intestinal peptide, promptly generate or should generate by endogenous by organ or tissue's (for example, brain, liver or the fatty tissue) endogenous beyond the gastrointestinal tract, and can modulation of appetite, food intake, energy is taken in or consume or the peptide of full sense signal.
Satiety factors of the present invention includes, but are not limited to: adiponectin, agouti associated protein (AGRP), dextrin, apolipoprotein A-1 V, beacon, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, enterostatin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), melanotroph hormone (MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide (comprises for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2) and oxyntomodulin, enteroglucagon, relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRFP 43 (RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
The agonist of satiety factors can be this satiety factors biological activity of simulation, induce the similar physiological action of this satiety factors, increase this satiety factors action time, strengthen the biological activity of this satiety factors or strengthen the optionally any agent of this satiety factors.In some embodiments, the agonist of satiety factors is this satiety factors itself.In other embodiments, the agonist of satiety factors is active fragment, analog or the derivant of this satiety factors.
The antagonist of satiety factors can be to suppress the biological activity of satiety factors or any agent of physiological action.In some embodiments, the antagonist of satiety factors is the antibody of this satiety factors.In some embodiments, the antagonist of satiety factors is the inhibitor of this satiety factors.In some embodiments, the antagonist of satiety factors is the acceptor inhibitor of this satiety factors.
The agonist of described satiety factors or antagonist can be used by any approach well known by persons skilled in the art, include but not limited in oral, intranasal, the lung, intravenous, subcutaneous, transdermal, gastric, intraperitoneal, Intraventricular or rectal administration.
Whether individuality has the satiety factors undesirable level can be measured by ability any means known to the skilled.This paper has described exemplary method.In some embodiments, when the individuality comparison was expressed according to individuality or secreted the satiety factors of less amount, this individuality had the satiety factors undesirable level.In some embodiments, when the individuality comparison was expressed according to individuality or secreted more substantial satiety factors, this individuality had the satiety factors undesirable level.When this individuality comparison was expressed according to individuality or secreted the satiety factors of less amount, the satiety factors agonist was useful.When the individuality comparison was expressed according to individuality or secreted more substantial satiety factors, the satiety factors antagonist was useful.
Advantageously, the people who implements method of the present invention need not to measure normal satiety factors value.Replace, this normal satiety factors value can be by determining with reference to retrievable knowledge of those skilled in the art or data.These data can be obtained from the available any source of those skilled in the art, comprise for example medical records, clinical testing data etc.In some embodiments, can use by those skilled in the art and develop the source according to the satiety factors amount of methods described herein collection.
In some embodiments, normal satiety factors amount comes from the contrast individuality of the symptom that does not show any disorder relevant with one or more satiety factors undesirable levels or disease.In some embodiments, this contrast is individual for having the healthy individual of normal type.In some embodiments, the individual thin partially individuality of this contrast for having normal type.
The amount of the satiety factors in the individuality can be without restriction measured with reference to any technology known to those skilled in the art.In some embodiments, the technology of measuring satiety factors is unimportant for the purpose of the present invention, implements the personnel of this paper method even need not to implement this technology.In some embodiments, the satiety factors amount in the individual sample can be passed through technical measurement described herein, should measure then with normal satiety factors value to compare, to determine whether the selecting agonist of this body and function satiety factors or antagonist to treat.In some embodiments, the satiety factors amount in the individual specimen can be by hereinafter specifically described spectrometry, chromatography, immunoassay or electrophoresis method are measured.Some preferred embodiment in, the amount of satiety factors detects by immunoassay.In a preferred embodiment, immunoassay are ELISA.
The amount of this satiety factors can be measured in any sample of individuality as provided herein.Sample can be body fluid as herein described or tissue samples.This paper has described the technology of preparation body fluid or tissue, for example, and the technology of extraction or purification satiety factors.The amount of the satiety factors technical staff that can obtain employment in this area thinks that the useful time measures.In some embodiments, after food intake, measure this amount.In some embodiments, before food intake, measure this amount.The ratio of the amount after the amount when in some embodiments, measuring individuality by fasting is taken food with individuality.Concrete detection method hereinafter is provided.
In some embodiments, can measure the amount of individual multiple satiety factors.When individuality has one of the satiety factors of bad quantity, can use the agonist or the antagonist of this satiety factors to this individuality according to method as herein described.When individuality has the multiple satiety factors of bad quantity, can use the agonist or the antagonist of multiple satiety factors to this individuality according to method as herein described.In favourable embodiment, can measure the amount of one group of individual satiety factors.By these quantity, can use the combination of the agonist and the antagonist of selected satiety factors to this individuality according to method as herein described.In the specific embodiment, can organize the personalized mixture of the amount of satiety factors according to this for this individual selection agonist and antagonist.
On the other hand, the invention provides and be used to select use satiety factors agonist or antagonist to treat the test kit of fat individuality.In some embodiments, test kit has comprised the device that can comprise this individuality body fluid, and the reagent that can detect satiety factors in this body fluid.In some embodiments, test kit has comprised the agonist or the antagonist of the satiety factors of the reagent that can detect satiety factors and effective dose.Test kit can further comprise label or the sign that use is instructed to test kit.In some embodiments, this test kit comprises label or the sign with normal satiety factors value.
5. detailed Description Of The Invention
5.1. Definition
Following term used herein has following implication:
Term " individuality " refers to animal, and as mammal, it includes but not limited to: Primate (for example, people), cattle, sheep, goat, horse, Canis familiaris L., cat, rabbit, rat, mice etc.In preferred embodiment, this individuality is the people.
Term " satiety factors " refers to be generated or should be generated by endogenous by individual endogenous, and can modulation of appetite, food intake, energy is taken in or consume or any molecule of full sense signal.Satiety factors of the present invention can be peptide or non-peptide satiety factors.Peptide satiety factors of the present invention can be hereinafter specifically described intestinal peptide or non-intestinal peptide.
Satiety factors of the present invention includes but not limited to: adiponectin, agouti associated protein (AGRP), dextrin, apolipoprotein A-1 V, beacon, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, enterostatin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), melanotroph hormone (MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide (comprises for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2) and oxyntomodulin, enteroglucagon, relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRFP43 (RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
Term " intestinal peptide " refers to anyly known in the artly be generated or should endogenous be generated by gastrointestinal tract (for example, stomach, pancreas, intestinal or colon) endogenous, and can modulation of appetite, the peptide of food intake, energy absorption, energy expenditure or full sense.In some embodiments, the intestinal peptide also can generate in another organ (for example brain).Intestinal peptide of the present invention includes but not limited to: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, Proglucagon derived peptide (comprising for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
In some embodiments, this intestinal peptide is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, Proglucagon derived peptide (comprising for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this intestinal peptide is an enterostatin.In some embodiments, this intestinal peptide is not an enterostatin.
In some embodiments, this intestinal peptide is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this intestinal peptide is a dextrin.In some embodiments, this intestinal peptide is Magainin or bombesin-like peptide.In some embodiments, this intestinal peptide is a cholecystokinin.In some embodiments, this intestinal peptide is ghrelin.In some embodiments, this intestinal peptide is the Proglucagon derived peptide, it for example comprises, glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon and main Proglucagon fragment.In some embodiments, this intestinal peptide is GLP-1.In some embodiments, this intestinal peptide is an oxyntomodulin.In some embodiments, this intestinal peptide is fat inhibin.In some embodiments, this intestinal peptide is peptide YY.In some embodiments, this intestinal peptide is the pancreas peptide.
Term " non-intestinal peptide " refer to any known in the art by the organ or tissue beyond the gastrointestinal tract (for example, brain, liver or fatty tissue) endogenous generates or should endogenous generates, and can modulation of appetite, the peptide of food intake, energy absorption, energy expenditure or full sense.
In some embodiments, this non-intestinal peptide is selected from: adiponectin, agouti associated protein (AGRP), apolipoprotein A-1 V, beacon, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, galanin, galanin sample peptide (GALP), growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), melanotroph hormone (MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), oxytocin, the Proglucagon derived peptide (comprises for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, relevant pancreas peptide of enteroglucagon and main Proglucagon fragment, enteroglucagon, the enteroglucagon pancreas peptide of being correlated with, main Proglucagon fragment), the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRFP43 (RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
Term " agonist of satiety factors " can be simulation satiety factors biological activity, induce the similar physiological action of satiety factors or increase the action time, biological activity of this satiety factors or any agent optionally.In some embodiments, the agonist of satiety factors is this satiety factors itself.In other embodiments, the agonist of satiety factors is active fragment, analog or the derivant of this satiety factors.The agonist of satiety factors also can be by indirect mode generation effect.For example, the agonist of glucagon-like peptide 1 (GLP-1) can be the inhibitor of the DPP IV (DPP IV) of deactivation GLP-1.
Term " antagonist of satiety factors " can be to suppress the biological activity of satiety factors or any reagent of physiological action.In some embodiments, the antagonist of satiety factors suppresses the biological activity or the physiological action of satiety factors fully.In other embodiments, the antagonist of satiety factors partly suppresses the biological activity or the physiological action of satiety factors.
Term " undesirable level of satiety factors " refers to express or the amount of excretory satiety factors is below or above according to those skilled in the art's the judgement individuality to this individual desired amount.In some embodiments, express or secretion still less or more during the satiety factors of volume according to individual when the individuality comparison that is in fasting state, this individuality has the undesirable level of satiety factors.In some embodiments, express or secretion still less or more during the satiety factors of volume according to individual when individual after the meal comparison just, this individuality has the undesirable level of satiety factors.
In some embodiments, express or the amount of excretory satiety factors when being lower than judgement according to those skilled in the art to this individual desired amount when individuality, this individuality has " undesirable level of satiety factors ".In some embodiments, do not express or secrete can be by the detected satiety factors amount of state of the art the time when individuality, this individuality has the undesirable level of satiety factors.In some embodiments, when individuality was not expressed or secreted any described satiety factors, this individuality had the undesirable level of satiety factors.
In some embodiments, express or the amount of excretory satiety factors when being higher than judgement according to those skilled in the art to this individual desired amount when individuality, this individuality has " undesirable level of satiety factors ".
The individual undesirable level that whether has satiety factors can be determined by technology well known by persons skilled in the art.In some embodiments, can by measure from the amount of the satiety factors in the sample of individuality and should measure and normally the satiety factors value determined after relatively.In some embodiments, when from the satiety factors amount of individual specimen less than according to the normal satiety factors amount of this area working technical staff's judgement 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2% or 1% the time, this individuality has the undesirable level of satiety factors.In other embodiments, when the satiety factors amount from individual specimen be about according to the normal satiety factors amount of this area working technical staff's judgement 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or 1500% the time, this individuality has the undesirable level of satiety factors.Normal satiety factors amount will be described at following chapters and sections.
Term " contrast is individual " is the standard according to those skilled in the art's approval, does not show the individuality of the symptom of one or more disorders relevant with the satiety factors undesirable level or disease.In some embodiments, contrast is individual has with individual similarly age, height, the race and sex of the selected treatment of accepting satiety factors agonist or antagonist is other.In some embodiments, this contrast is individual is thin partially individuality or individuality with normal type.When this individuality is a man-hour, this contrast individuality can be that Body Mass Index (" BMI ") is at 20-25kg/m 2Individuality in the scope.BMI can by with body weight (kilogram) divided by height (rice) square after obtain.The contrast individuality can be used for setting up normal satiety factors value, and this value can be used for assessing the individual undesirable level that whether has satiety factors.
" prevention " refers to reduce and obtains disease or disorderly risk (that is, making at least a clinical symptoms of disease can not develop may being exposed to this disease of this disease or easy infection but still not experiencing or show in the individuality of this disease symptoms).Preferably, prevention refer to as yet not by disease or disorderly influence do not show disease as yet or the individuality of disorderly symptom (for example not infected as yet or do not show as yet the individuality of the symptom that infects) in use chemical compound or compositions.
In one embodiment, any disease or disorderly " treatment " are referred to alleviate disease or the disorder (that is, checking or slow down the development of this disease or its at least a clinical symptoms) that exists in the individuality.In another embodiment, " treatment " refer to improve this individuality may at least a body parameter inconspicuous.In another embodiment, " treatment " refer to regulate disease or disorder from health (for example, can discern symptom stable) or physiology (for example, body parameter is stable) or from both.In another embodiment, " treatment " refer to slow down disease or disorderly outbreak.
Term " effective dose " refers to be enough to the amount that makes effective satiety factors agonist of this treatment of diseases or antagonist or comprise their compositions when using with the treatment disease to individuality.Effective dose can be along with the disease of used satiety factors, individuality to be treated and seriousness thereof and age, body weight etc. and other factors and is changed.
Term " obesity " refer to body weight especially the quality of fatty tissue be higher than the current individuality of accepting standard.In some embodiments, this individuality when having the current BMI that accepts more than the standard for fat.When individuality is a man-hour, the current standard that all can be accepted as " normally " to masculinity and femininity is 20-24.9kg/m 2BMI.In these embodiments, fat individuality has 30kg/m 2Or higher BMI.In some embodiments, Fei Pang individuality has 40kg/m 2Or higher BMI.In other embodiments, when individuality than 120% when heavier of the normal type of relatively its age and height, this individuality obesity.Normal type is different between race and individuality according to height, physique, bone structure and sex.
Term " overweight " refers to that the fat appropriateness in the individuality is excessive.In some embodiments, when individuality is a man-hour, this overweight individuality has 25kg/m 2Or higher BMI.
This paper is conventional to the aminoacid symbol of the L-aminoacid use of 20 genetic codings.In preferred embodiment, unless indicate separately, any peptide of the present invention or aminoacid are the L type.
5.2. The method of treatment or prevention
Although do not wish to be subject to any specific theory of operation, the present invention is partly based on following discovery: some colony fat or overweight individuality has the undesirable level of one or more satiety factors, and the subpopulation with fat or overweight individuality of one or more satiety factors undesirable levels produces positive response to treating fat or overweight Therapeutic Method, and this Therapeutic Method comprises agonist or the antagonist of using one or more satiety factors.Further find: the subpopulation of suffering from relevant disorderly of metabolism disorder or lipid and having an individuality of one or more satiety factors undesirable levels produces positive response to Therapeutic Method equally, and this method comprises agonist or the antagonist of using one or more satiety factors.
Correspondingly, the invention provides the method for treatment satiety factors undesirable level in this individuality that needs is arranged.In some embodiments, this method comprises agonist or the antagonist to the described satiety factors of the undesirable level effective dose of this individuality administering therapeutic satiety factors.Whether individuality has the satiety factors undesirable level can be measured by ability any means known to the skilled.This paper has described exemplary method.
The disorder relevant in treatment or the prevention individuality or the method for disease have been the present invention further provides with the satiety factors undesirable level.This method comprises to individual administering therapeutic or prevents this disorder or the agonist or the antagonist of the described satiety factors of disease effective dose.
Exemplary disorder or the disease relevant with the satiety factors undesirable level include but not limited to: overweight, fat, metabolism disorder, hypertension, disorder, anorexia and type ii diabetes that lipid is relevant.
In some embodiments, relevant with the satiety factors undesirable level disorder or disease are overweight.In another embodiment, relevant with the satiety factors undesirable level disorder or disease are fat.In some embodiments, relevant with the satiety factors undesirable level disorder or disease are metabolism disorder.In some embodiments, relevant with the satiety factors undesirable level disorder or disease are the lipid associated disorders.In some embodiments, relevant with the satiety factors undesirable level disorder or disease are type ii diabetes.In some embodiments, relevant with the satiety factors undesirable level disorder or disease are hypertension.In some embodiments, relevant with the satiety factors undesirable level disorder or disease are anorexia.
On the one hand, the invention provides the method that in having individuality that these needs are arranged of satiety factors undesirable level, reduces appetite.This method comprises to described individuality uses agonist or the antagonist that its amount can effectively reduce the described satiety factors of appetite.
On the other hand, the invention provides the method that in having individuality that these needs are arranged of satiety factors undesirable level, reduces food intake.This method comprises to described individuality uses agonist or the antagonist that its amount can effectively reduce the described satiety factors of food intake.
On the other hand, the invention provides the method that in having individuality that these needs are arranged of satiety factors undesirable level, reduces the fat absorption.This method comprises to described individuality uses agonist or the antagonist that its amount can effectively reduce the described satiety factors of fat absorption.
On the other hand, the invention provides the method that in having individuality that these needs are arranged of satiety factors undesirable level, reduces the carbohydrate absorption.This method comprises to described individuality uses agonist or the antagonist that its amount can effectively reduce the described satiety factors of carbohydrate absorption.
On the other hand, the invention provides the method that in having individuality that these needs are arranged of satiety factors undesirable level, reduces the albumen absorption.This method comprises to described individuality uses agonist or the antagonist that its amount can effectively reduce the described satiety factors of albumen absorption.
On the other hand, the invention provides the individuality with satiety factors undesirable level is lost weight or stimulates the method for weight loss.This method comprises to described individuality uses agonist or the antagonist that its amount could effectively lose weight or stimulate the described satiety factors of weight loss.Term " weight loss " refer to individual body weight relatively its in the past sometime body weight have the minimizing that can survey.
On the other hand, the invention provides the method that in having individuality that these needs are arranged of satiety factors undesirable level, reduces body fat.This method comprises to described individuality uses agonist or the antagonist that its amount can effectively reduce the described satiety factors of body fat.
Will be appreciated that, method of the present invention contained treatment to obesity, reduce the method for appetite, reduce food intake method, reduce method that fat takes in, reduce the method that albumen takes in and reduce the method that carbohydrate is taken in, these methods more likely produce the patient that replys and realize to its administering therapeutic treatment by selecting.More likely producing the patient reply can determine or select by one or more endogenous satiety factors levels that detect or otherwise know them.
5.2.1 Individual
In some embodiment of the present invention, individuality is an animal, preferred mammal, more preferably inhuman Primate.In most preferred embodiments, individuality is the people.Individuality can be male or female individuals.
Method of the present invention can be used for selecting the individuality for the treatment of with the agonist or the antagonist of the satiety factors in any individuality.Useful especially individuality comprises the individuality with satiety factors undesirable level.Whether individuality has the satiety factors undesirable level can be measured by the obtainable any method of ability technical staff.Exemplary method has hereinafter been described.
In some embodiments, the individual existence suffered from the disorder relevant with the satiety factors undesirable level or the risk of disease, and this disorder or disease include, but are not limited to: overweight, fat, metabolism disorder, hypertension, lipid associated disorders, anorexia and type ii diabetes.In some embodiments, individuality has overweight or fat risk.In some embodiments, individuality has the risk of metabolism disorder.In some embodiments, individuality has hypertensive risk.In some embodiments, individuality has the risk of lipid associated disorders.In some embodiments, individuality has the risk of anorexia.In some embodiments, individuality has the risk of type ii diabetes.
In some embodiments, individuality is unsound.In some embodiments, individuality suffers from diabetes, gastrointestinal disease and/or cardiovascular disease.In some embodiments, individuality suffers from or suffers disorder or the disease relevant with the satiety factors undesirable level, and this disorder or disease include, but are not limited to: overweight, fat, metabolism disorder, hypertension, lipid associated disorders, anorexia and type ii diabetes.In some embodiments, individuality suffers from metabolism disorder.In some embodiments, individuality suffers from hypertension.In some embodiments, individuality suffers from the lipid associated disorders.In some embodiments, individuality suffers from type ii diabetes.In some embodiments, individuality has the abnormal glucose level.In some embodiments, individuality suffers from apositia.
In some embodiments, individuality is overweight.In the specific embodiment, individuality is for the people and have 25kg/m 2Or higher BMI.In some embodiments, individuality is the people and has between 25kg/m 2And 30kg/m 2BMI.In some embodiments, individuality is fat.In some embodiments, individuality is the people and has 30kg/m 2Or higher BMI.In some embodiments, individuality is the people and has between 30kg/m 2And 35kg/m 2BMI.In some embodiments, individuality is the people and has 35kg/m 2Or higher BMI.In some embodiments, individuality is the people and has 40kg/m 2Or higher BMI.In some embodiments, 120% of the normal type of individual its age relatively and height is heavier.In some embodiments, individuality is that people and body weight surpass 96kg.
In some embodiments, individual for the people and have waistline greater than 1.02m.In some embodiments, individual for the people and have hip circumference greater than 1.06m.In some embodiments, individual for the people and have waist: the buttocks ratio greater than 0.98.In some embodiments, individuality is that people and body fat surpass 40.9%.
In some embodiments, individual in the normal type scope.In the context of the present invention, the individuality with normal type comprises: because the individuality for the treatment of with the agonist or the antagonist of satiety factors according to any reason needs of this area practitioner's judgement.In some embodiments, individuality is the people and has 25kg/m 2Or lower BMI.In some embodiments, individuality is the people and has 22kg/m 2Or lower BMI.In some embodiments, individuality is the people and has between about 20kg/m 2With about 25kg/m 2BMI.In some embodiments, individuality is the people and has 20kg/m 2Or lower BMI.Such individuality can have the undesirable level of satiety factors and his or her body weight owing to diseases such as for example polyphagia are kept.
In some embodiments, individuality is not accepted any at disorder or the treatment of conditions relevant with the satiety factors undesirable level before.In other embodiments, once accepted before this individuality or now just accepting at disorder or the treatment of conditions relevant with the satiety factors undesirable level.In some embodiments, once accepted or now just accepting the treatment that agonist or antagonist by corresponding satiety factors carry out before this individuality.In some embodiments, once accepted before this individuality or now just accepting except that the agonist of satiety factors or the treatment the antagonist.
In some embodiments, individuality has the abnormal glucose level.In the specific embodiment, individuality has the hyperglycemia level.In some embodiments, individuality suffers from diabetes.In some embodiments, individuality suffers from type ii diabetes.In other embodiments, individuality is not suffered from diabetes.
In some embodiments, individual at under-21.In some embodiments, individual below 15 years old.In other embodiments, individual more than 49 years old.In some embodiments, individual 15,25,35,40,45,50,55 or over-65s.
In some embodiments, individuality is taken exercise regularly.In other embodiments, this individuality is clocklike taken exercise.
5.2.2 Satiety factors of the present invention
Satiety factors of the present invention can be to be generated or should be generated by endogenous by individual endogenous, and can modulation of appetite, food intake, energy is taken in or consume or any molecule of full sense signal.In some embodiments, satiety factors is a peptide.In these embodiments, the peptide satiety factors can be intestinal peptide or non-intestinal peptide.In other embodiments, satiety factors is not a peptide.
Satiety factors of the present invention includes but not limited to: adiponectin, agouti associated protein (AGRP), dextrin, apolipoprotein A-1 V, beacon, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, enterostatin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), melanotroph hormone (MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide (comprises for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2) and oxyntomodulin, enteroglucagon, relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRFP 43 (RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin, specific descriptions can be referring to Bray GA, 1995, Obesity Research 3 (appendix 4): 569S-572S; Bays HE, 2004, Obesity Research12 (8): 1197-1211, Sahu A, 2004, Endocrinology 145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a peptide.In some embodiments, satiety factors is the intestinal peptide, be known in the artly to generate or should generate by endogenous by gastrointestinal tract (for example, stomach, pancreas, intestinal or colon) endogenous, and can modulation of appetite, the peptide of food intake, energy absorption, energy expenditure or full sense.The intestinal peptide that is suitable for includes but not limited to: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, Proglucagon derived peptide (comprising for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, the intestinal peptide is an enterostatin.In some embodiments, the intestinal peptide is not an enterostatin.
In some embodiments, satiety factors is a dextrin.Dextrin is also referred to as Diabetes-associated peptide, is formed and is discharged by the β cell of pancreas by 37 aminoacid.It is reported that using of dextrin and Pramlintide (pramlintide, synthetic people's dextrin analog) causes food intake that reduces and the weight loss that continues.Referring to people such as Reda, 2002, Obesity Res.10:1087-91, its content is all quoted as a reference at this.
In some embodiments, satiety factors is Magainin or bombesin-like peptide.Magainin or bombesin-like peptide (for example, gastrin releasing peptide and neuromedin B) are distributed widely in gastrointestinal tract and central nervous system.Reported that Magainin or bombesin-like peptide suppress the feed of various species (comprising the people).Referring to people such as Yamamda, 2002, Euro.J.Pharm.440:281-290, its content is incorporated by reference in this text to be examined.
In some embodiments, satiety factors is a cholecystokinin.Cholecystokinin (CCK) generates in gallbladder, pancreas stomach function regulating, and concentrates in small intestinal.It mainly responds dietary fat and is released, and is used to increase full sense and reduces appetite.Studies show that a lot of species (comprising normal type and fat human individual) periphery is being had dose-dependent inhibition to food intake after using CCK.Referring to, people such as Kissileff, 1981, Am.J.Clin.Nutr.34:154-60, its content is all quoted as a reference at this.
In some embodiments, satiety factors is an enterostatin.In some embodiments, satiety factors is not an enterostatin.Enterostatin is 5 amino acid whose peptides, and it is generated by the trypsin activation of the former colipase (procolipase) in intestinal or the stomach, to generate lipase.For example, referring to, people such as Erlanson-Albertsson, 1991, Physiol.Behav.49:1191-1194, its content is incorporated by reference in this text to be examined.Confirm as the rodent institute, it is believed that the propetide enterostatin reduces the dietary fat priority in the mammal.For example, referring to people such as Erlanson-Albertsson, 1991, Physiol.Behav.49:1191-1194; People such as Okada, 1991, Physiol.Behav.49:1185-1189; People such as Shargill, 1991, Brain Res.544:137-140, its content is all quoted as a reference at this.
In some embodiments, satiety factors is ghrelin.Ghrelin is 28 amino acid whose acylated peptides, and it is mainly generated by the endogenic ligand of harmonization of the stomach growth sercretogogue receptor (GHS-R).Referring to people such as Kojima, 1999, Nature, 402 (6762): 656660, its content is all quoted as a reference at this.The cyclical level of ghrelin can rise during the fasting and after the feed.Referring to people such as Cummings, 2001, Diabetes50:1714-19, its content is all quoted as a reference at this.Shown that in rodent and human body ghrelin can be by stimulating food intake and reducing fat oxidation and come weight increase.Referring to, people such as Druce, 2006, Intl.J.Obesity30:293-96; People such as Druce, 2005, Intl.J.Obesity29:1130-36; People such as Wren, 2001, Diabetes141:4325-28, its content is all quoted as a reference at this.
In some embodiments, satiety factors is fat inhibin.Fat inhibin derives from the peptide precursor (preproghrelin) identical with ghrelin.Referring to people such as Zhang, 2005, Science310 (5750): 985-86, its content is all quoted as a reference at this.Opposite with the appetite stimulation effect of ghrelin, can suppress food intake, suppress the jejunum contraction and reduce weight increase with fat inhibin treatment rat.Referring to above.
In some embodiments, satiety factors is selected from the Proglucagon derived peptide, for example comprise glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon and main Proglucagon fragment.
In some embodiments, satiety factors is an oxyntomodulin.Oxyntomodulin, a kind of 37 amino acid whose peptides are to take in proportional small intestinal L-cell in the Proglucagon gene outcome that discharges after the meal with calorie.It is being applied to rodent and man-hour according to the show, can regulate full sense signal and reduce the energy absorption.Referring to people such as Cohen, 2003, J.Clin.Endocrinol Metab.88:4696-4701; People such as Wynne, 2006 (distribution on April 19), Int.J.Obesity, its content is all quoted as a reference at this.
In some embodiments, satiety factors is glucagon-like peptide 1 (GLP-1).Glucagon-like-peptide-1 (7-36)-amide (GLP-1) in intestinal L-cell by the glucagon precursor before the tissue specificity translation post-treatment of Proglucagon synthesize and respond dining and discharge into circulation.Referring to people such as Varndell, 1985, J.Histochem Cytochem, 33:1080-6, its content is all quoted as a reference at this.The periphery of GLP-1 in healthy and obese individuals used and can be suppressed hungry and reduce food intake.Referring to, people such as Flint, 2001, Int.J.Obes.Relat.Metab.Disord.25 (6): 781-92; People such as Gutzwiller, 1999, Gut 44 (1): 81-86, its content is all quoted as a reference at this.
In some embodiments, satiety factors is peptide YY.Peptide YY (PYY) is the member of neuropeptide Y protein (NPY) family, and the endocrine gland cell on its small intestinal and the colon wall generates justacrine, and is proportional with the calorie content in the diet.Referring to, people such as Pedersen-Bjergarrd, 1996, Scand.J.Clin.Lab.Invest.56:497-503; People such as Adrian, 1985, Gastroenterology 89:1070-77; People such as Grandt, 1994, Regul.Pept.51:151-59, its content is all quoted as a reference at this.The principal mode of PYY in storing and circulating is PYY 3-36, it is the N-terminal clipped form of full-length peptide.PYY 3-36Mainly in the brain effect, it is considered to and can stimulates the release of hormone NPY and the release of the inhibitor α-melanotroph hormone that stimulates appetite by appetite-suppressing.PYY 3-36As if by Y2 receptor (the G-protein-coupled receptor of being discerned by NPY equally) thus directly act on hypothalamic arcuate nucleus appetite-suppressing.Referring to people such as Batterham, 2002, Nature 418 (698): 650-4, its content is all quoted as a reference at this.
Reported that obese individuals not only has the PYY endogenous level of decline, also having the inductive PYY of impaired dining increases.Referring to people such as Batterham, 2003, N Eng.J.Med.349 (10): 941-48, its content is all quoted as a reference at this.In rat and mice, adopt PYY 3-36Peripheral injection suppress food intake and reduce weight increase.Referring to people such as Batterham, 2002, Nature418 (698): 650-4, its content is all quoted as a reference at this.In addition, at intravenous with PYY 3-36The input human body can cause tangible food intake to descend, and blood plasma level and normal individual are close with regard to after the meal level.Referring to people such as Batterham, 2003, N Eng.J.Med.349 (10): 941-48, its content is all quoted as a reference at this.
In some embodiments, satiety factors is pancreas peptide (PP).Be similar to PYY, the pancreas peptide is 36 amino acid whose peptides that belong to NPY family.It generates in islets of langerhans and responds food intake and discharge.Referring to people such as Adrian, 1976, Gut 17:940-44, its content is all quoted as a reference at this.In rodent, chronic administration PP can reduce the food intake and the weight increase of heritability obesity mice.Referring to people such as Ueno, 1999, Gastroenterology 117:1427-32, its content is all quoted as a reference at this.In human body, the intravenous of PP is used the persistence that can cause appetite and food intake and is descended.Referring to people such as Batterham, 2003, J.Clin.Endocrinol Metab.88:3989-92, its content is all quoted as a reference at this.
In some embodiments, satiety factors is non-intestinal peptide, be known in the art by the organ or tissue beyond the gastrointestinal tract (for example, brain, liver or fatty tissue) endogenous generates or should endogenous generates, and can modulation of appetite, the peptide of food intake, energy absorption, energy expenditure or full sense.
In some embodiments, satiety factors is an adiponectin, and it can improve the sensitivity of hepatocyte to insulin, and for example it describes visible Saltiel AR 2001, Nat Med. (8): 887-8, and its content is all quoted as a reference at this.
In some embodiments, satiety factors is agouti associated protein (AGRP), and it is present in hypothalamus, and its level rises in the male of obesity, and for example it describes visible Sahu A, 2004, and Endocrinology 145 (6); 2613-20, people such as Katsuki, 2001, J.Clin.Endocr.Metab.86:1921-1924, its content is all quoted as a reference at this.
In some embodiments, satiety factors is apolipoprotein A-1 V, the dose dependent that it can form food intake in animal body reduces, for example it describes visible Bray GA, and 1995, Obesity Research3 (appendix 4): 569S-572S, people such as Fujimoto, 1993, J.Clin.Invest.91 (appendix 4): 1830-33, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a beacon, it is expressed also and can stimulate food intake and weight increase in dose-dependent mode in animal body at hypothalamus, for example its description can be referring to people such as Collier GR, 2000, Diabetes49:1766-1771, people such as Brailoiu GC, 2002, Neurosci Lett317 (3): 166-8, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a brain source property neural factor (BDNF), and for example it describes visible Sahu A, 2004, and Endocrinology 145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is calcitonin-gene-related peptide (CGRP), it can reduce the food intake of fat and non-obese animal according to the show, for example it describes visible Bray GA, 1995, ObesityResearch 3 (appendix 4): 569S-572S, people such as Morley 1982, Peptides 3:17-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a β cheese deltorphin delta, it is the peptide of the seven amino acid that generates in caseic trypsinization process in the intestinal, and can improve the food intake of the animal with high fat diet, reduce the food intake of the animal with low fat diet, for example it describes visible Bray GA, 1995, Obesity Research 3 (appendix 4): 569S-572S, people such as Lin, 1994, Peptides 15 (appendix 5): 849-54, its content is all quoted as a reference at this.
In some embodiments, satiety factors is ciliary neurotrophic factor (CNTF), and it can cause weight loss, and for example it describes people such as visible Lambert, 2001, and PNAS 98 (8): 4652-57, its content is all quoted as a reference at this.
In some embodiments, satiety factors is that ***e and amphetamine are regulated transcription product (CART), and for example it describes visible Sahu A, 2004, and Endocrinology 145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is corticotropin releasing hormone (CRH), and it can reduce the food intake of animal, and for example it describes people 1998 such as visible Kristensen P, Nature393 (6680): 72-6, its content is all quoted as a reference at this.
In some embodiments, satiety factors is cyclo-his-pro, it is diketopiperazine (diketopiperzaine), and can reduce food intake when maincenter or periphery are used, and for example it describes visible Bray GA, 1995, Obesity Research3 (appendix 4): 569S-572S, Bray GA, 1992, Am.J.Clin.Nutr.55:265S-271S, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a dynorphin, the food intake that it is generated and can be stimulated animal by brain, for example it describes people such as visible Olszewski, 2004, Endocrinology146 (6): 2627-2632, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a beta-endorphin, and it has been shown as the regulator of energy homeostasis, and for example it describes people 2003 such as visible Appleyard, Endocrinology 144:1753-1760, and its content is all quoted as a reference at this.
In some embodiments, satiety factors is galanin or galanin sample peptide (GALP), the food intake of their stimulation in rats, and for example it describes visible Sahu A, and 2004, Endocrinology145 (6); 2613-20, people such as Patterson, 2006.J.Neuroendocrinal18 (10): 742-747, its content is all quoted as a reference at this.
In some embodiments, satiety factors is growth hormone releasing hormone (GHRH), and it stimulates food intake and weight increase, for example it describes visible Bays HE, and 2004, Obesity Research12 (8): 1197-1211, Sahu A, 2004, Endocrinology 145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is appetite peptide/orexin (orexin-A and B), it is accredited as the part of two kinds of orphan G-protein-coupled orexin receptors-1 and-2, generation effect during it is regulated with Sleep-Wake on the feed, and the appetite and the food intake of energy stimulation in rats, for example it describes visible SahuA, and 2004, Endocrinology 145 (6); 2613-20, people such as Adam, 2002, Int.J.Obes.26 (2): 274-276, people such as Sakurai, 1998, Cell92:573-585, its content is all quoted as a reference at this.
In some embodiments, satiety factors is insulin or quasi-insulin growthing factor I and II (IGF-I and IGF-II), it is the regulator of food intake, for example it describes visible Bray GA, 1995, ObesityResearch3 (appendix 4): 569S-572S, SahuA, 2004, Endocrinology145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a leptin, and it can reduce food intake and body weight, and for example it describes visible Sahu A, 2004, and Endocrinology 145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is melanin concentration hormone (MCH), it is the ring-type neuropeptide, and generation effect in the stimulation of mammiferous feed behavior, for example it describes people such as visible Shimada, 1998, Nature 396:670-673, its content is all quoted as a reference at this.
In some embodiments, satiety factors is melanotroph hormone (MSH), it generates in hypophysis cerebri, it is the part of melanocortin receptor, and generation effect in the adjusting of energy homeostasis, for example it describes people such as visible MacNeil DJ, 2002, Eur J Pharmacol.440 (2-3): 141-57, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a motilin, and it is the polypeptide hormone by small intestinal Mo emiocytosis, and gastrointestinal motility can be provided, and for example it describes people such as visible Davidson, and 1999, Phiol.Behav.66 (2): 309-315, its content is all quoted as a reference at this.
In some embodiments, satiety factors is nesfatin, and it is generated and can be reduced in dose-dependent mode the food intake of animal by brain, for example it describes people such as visible Shinsuke, 2006,443:709-712, its content is all quoted as a reference at this.
In some embodiments, satiety factors is neuromedin B and neuromedin U, it is the neuropeptide that is distributed widely among intestinal and the central nervous system, and the maincenter that participates in feed is controlled, for example it describes people 2000 such as visible Howard, Nature406,70-75, its content is all quoted as a reference at this.
In some embodiments, satiety factors is neuropeptide B (NPB) and (NPW), it is accredited as the part of orphan G-protein-coupled receptor, and the food intake that can stimulate animal, for example it describes people 2002 such as visible Shimomura, J.Biol.Chem., 277 (39): 35826-32, its content is all quoted as a reference at this.
In some embodiments, satiety factors is neuropeptide K (NPK), and it can suppress the food intake of animal, and for example it describes people 1992 such as visible Achapu, Brain Res.Bull28 (2): 299-303, and Sahu A, 2004, Endocrinology 145 (6); 2613-20, its content is all quoted as a reference at this.
In some embodiments, satiety factors is neuropeptide tyrosine (NPY), and it can stimulate the food intake of animal after injection, and for example it describes people 1993 such as visible Myers, Regul Pept 47, and 239-245, its content is all quoted as a reference at this.
In other embodiments, satiety factors is neurotensin (NT), it is 13 amino acid whose neuropeptides, and can use the back at maincenter and reduce food intake, for example it describes people such as visible Ohinaka, 2004, Peptide 25 (12): 2135-2138, its content is all quoted as a reference at this.
In some embodiments, satiety factors is an oxytocin, and it can increase the food intake of animal, and for example it describes people 2006 such as visible Billings, Behav.Brain Res.171 (1)-134-141, and its content is all quoted as a reference at this.
In some embodiments, satiety factors is the lactotropin release peptide, it can increase the food intake of animal, for example it describes visible Bray GA, and 1995, Obesity Research3 (appendix 4): 569S-572S, people such as Gerardo-Gettens, 1989,256 (2pt2): R701-706, its content is all quoted as a reference at this.
In some embodiments, satiety factors is proopiomelanocortin (POMC), it is a mediator of regulating feed behavior, insulin level and body weight, for example it describes visible Boston BA.2001, J.PediatrEndocrinol Metab.14 appendix 6:1409-16, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a protoporphyrin, it generates in the haemachrome metabolism, and can reduce food intake and body weight when injection, and for example it describes visible Bray GA, 1995, ObesityResearch3 (appendix 4): 569S-572S, people such as Galbraith, 1991, Am.J.Physiol261:R1395-41, its content is all quoted as a reference at this.
In some embodiments, satiety factors be QRFP 43 (the RF amidated peptide, 26Rfa), it is the regulator of appetite and energy expenditure, and for example it describes visible Moriya R, waits people 2006, Endocrinology.147 (6) 2916-22, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a Somat, it can reduce the food intake of animal according to the show, for example it describes visible Bays HE, and 2004, Obesity Research 12 (8): 1197-1211, people such as Levine, 1982, Pharmacol Biochem Bahav.16:897-902, its content is all quoted as a reference at this.
In some embodiments, satiety factors is throtropin releasing hormone (TRH), and it is the regulator of food intake and energy expenditure, for example it describes people such as visible Al-Arabi, 2005, Biomedsci.Instrum.41:62-67, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a Urocortin, it is the high affinity ligand of 2 type corticotropin-releasing factors, and can behind infusion, reduce feed and the water inlet of rat, for example it describes people 2003 such as visible Inoue, J Pharmacol Exp Ther305 (1): 385-393, its content is all quoted as a reference at this.
In some embodiments, satiety factors is a vassopressin, and it can reduce the food intake of animal model according to the show, for example it describes visible Bray GA, and 1995, Obesity Research3 (appendix 4): 569S-572S, people such as Langhans, 1991, Phiol.Behav.49; 169-176, its content is all quoted as a reference at this.
5.2.3 Satiety factors agonist and antagonist
The agonist of satiety factors can be action time, biological activity or optionally any reagent of simulation satiety factors biological activity, the similar physiological action of inducing satiety factors, increase satiety factors.In some embodiments, the agonist of satiety factors is this satiety factors itself.In other embodiments, the agonist of satiety factors is the active analogue thereof of satiety factors or derivant, fragment.The active analogue thereof of satiety factors or derivant, fragment can be naturally occurring or non-natural exists, for example, and the GLP-1 analog Exenatide (exenatide) that non-natural exists.
The antagonist of satiety factors can be to suppress the biological activity of satiety factors or any reagent of physiological action.The antagonist of satiety factors can completely or partially suppress the biological activity or the physiological action of satiety factors.
In some embodiments, this satiety factors is a dextrin, and to there being this individuality that needs to use the dextrin agonist of effective dose.In some embodiments, the dextrin agonist is a dextrin.In some embodiments, the dextrin agonist is Pramlintide (pramlintide), and it describes visible United States Patent (USP) 5,175,145,5,686,411,5,814,600,5,998,367 or 6,114,2304, and its content is all quoted as a reference at this.
In some embodiments, satiety factors is Magainin or bombesin-like peptide, and to there being this individuality that needs to use the Magainin or the bombesin-like peptide of effective dose.In some embodiments, the agonist of this Magainin or bombesin-like peptide is Magainin or bombesin-like peptide.
In some embodiments, satiety factors is a cholecystokinin, and to there being this individuality that needs to use the cholecystokinin agonist of effective dose.In some embodiments, the cholecystokinin agonist is a cholecystokinin.
In some embodiments, satiety factors is an enterostatin, and to there being this individuality that needs to use the enterostatin of effective dose.In some embodiments, the enterostatin agonist is an enterostatin.
In some embodiments, satiety factors is ghrelin, and to there being this individuality that needs to use the ghrelin antagonist of effective dose.In some embodiments, the ghrelin antagonist is the antagonist that is described in U.S. Patent Publication 20050201938,20050080007,20040186181 or 20020187938, and its content is all quoted as a reference at this.
In some embodiments, satiety factors is GLP-1, and to there being this individuality that needs to use the GLP-1 agonist of effective dose.In some embodiments, the GLP-1 agonist is GLP-1.In some embodiments, the GLP-1 agonist is Exenatide (exendin) or its analog, and it describes visible United States Patent (USP) 6,872,700 or 6,989,366, and its content is all quoted as a reference at this.In some embodiments, the GLP-1 agonist is
Figure A200780032713D0042154027QIETU
In some embodiments, the GLP-1 agonist is the inhibitor of the DPP IV (DPP IV) of deactivation GLP-1.
In some embodiments, this satiety factors is fat inhibin, and to there being this individuality that needs to use the fat inhibin agonist of effective dose.In some embodiments, fat inhibin agonist is fat inhibin.
In some embodiments, satiety factors is an oxyntomodulin, and to there being this individuality that needs to use the oxyntomodulin agonist of effective dose.In some embodiments, the oxyntomodulin agonist is an oxyntomodulin.
In some embodiments, satiety factors is peptide YY, and to there being this individuality that needs to use the peptide YY agonist of effective dose.In some embodiments, peptide YY agonist is peptide YY 3-36
In some embodiments, satiety factors is the pancreas peptide, and to there being this individuality that needs to use the pancreas peptide agonists of effective dose.In some embodiments, the pancreas peptide agonists is the pancreas peptide.
The agonist of satiety factors also can be by indirect mode generation effect.For example, the agonist of glucagon-like peptide 1 (GLP-1) can be the inhibitor of the DPP IV (DPP IV) of deactivation GLP-1.
In some embodiments, use the agonist of following material: adiponectin, dextrin, apolipoprotein A-1 V, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, enterostatin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, α melanotroph hormone (α-MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide b (NPB) and (NPW), neuropeptide K (NPK), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide (comprises for example glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, relevant pancreas peptide of enteroglucagon and main Proglucagon fragment), proopiomelanocortin (POMC), protoporphyrin, QRFP43 (the RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin or vassopressin.
In some embodiments, use the antagonist of following material: agouti associated protein (AGRP), beacon, β cheese deltorphin delta, dynorphin, beta-endorphin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, melanin concentration hormone (MCH), neuropeptide tyrosine (NPY), lactotropin release peptide or QRFP43 (the RF amidated peptide, 26Rfa).
The agonist of described satiety factors or antagonist can be used by any approach well known by persons skilled in the art, include but not limited in oral, intranasal, the lung, intravenous, subcutaneous, transdermal, gastric, intraperitoneal, Intraventricular or rectal administration.
Satiety factors agonist and antagonist can as mentioned belowly prepare, prepare and be applied to individuality by the conspicuous any method of those skilled in the art.Certainly, the preferred acceptable prepared product of pharmacy, preparation and application method.
5.2.4 Therapeutic alliance
In some embodiments, method of the present invention can be united use with second therapy.Second therapy can be any disease and the disorderly any therapy of being used for well known by persons skilled in the art.In some embodiments, this disease or disorder are selected from: overweight, fat, metabolism disorder, hypertension, lipid associated disorders, anorexia and type ii diabetes.
In some embodiments, second therapy can be considered as suitable technique according to this area practitioner and uses.
In some embodiments, second therapy is using of satiety factors.Satiety factors can be any satiety factors well known by persons skilled in the art, comprises satiety factors as herein described.In some embodiments, the second therapy satiety factors can be considered as suitable technique according to this area practitioner and uses.In some embodiments, second therapy can be used according to method as herein described, that is, select the individuality treat, and use the agonist of described satiety factors of the amount that can effectively treat or prevent this disorder or disease or the method for antagonist to this individuality with satiety factors undesirable level.
In some embodiments, second therapy is the agonist or the antagonist of non-intestinal peptide satiety factors.In some embodiments, second therapy is non-intestinal peptide satiety factors.Example comprises adiponectin, agouti associated protein (AGRP), apolipoprotein A-1 V, beacon, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, galanin, galanin sample peptide (GALP), growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), melanotroph hormone (MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide b (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), oxytocin, the Proglucagon derived peptide (comprises for example glucagon, glucagon-like peptide 1 (GLP-1)), the lactotropin release peptide, proopiomelanocortin (PMOC), protoporphyrin, QRFP43 (the RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
In some embodiments, second therapy is an intestinal peptide satiety factors.Example comprises dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, Proglucagon derived peptide (comprising pancreas peptide that glucagon for example, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, enteroglucagon are relevant and main Proglucagon fragment), fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
The use of therapeutic alliance is not limited in the order that reagent or treatment are provided to individuality in the method that is provided.For example, the reagent of therapeutic alliance can be simultaneously, with any order successively or cyclical administration to individual.In some embodiments, two of therapeutic alliance kinds of compositions are applied to individuality simultaneously.
The composition of therapeutic alliance can be administered to individuality in identical pharmaceutical composition.Perhaps, the composition of therapeutic alliance can be administered to individuality in independent pharmaceutical composition, and these independent compositionss can be used by identical or different route of administration (for example comprising oral, parenteral or part).In preferred embodiment, other therapies can with reference to they separately standard or the dosage and the dosage regimen of this area approval be administered to individuality.
In some embodiments, other therapies is selected because of itself and satiety factors agonist or antagonist have an addition in the disorder relevant with the satiety factors undesirable level or treatment of conditions or prevention.
In some embodiments, other therapies is selected because of itself and satiety factors agonist or antagonist have a synergism in the disorder relevant with the satiety factors undesirable level or treatment of conditions or prevention.
The example that can be used for the therapy of method provided herein includes but not limited to: go on a diet, the bent piperazine of adjustment, sympathomimetic such as amphetamine (dexamphetamine), Duromine, benzfetamine, benzene first, mazindol, diethylpropion, phenylpropanolamine, 5-hydroxy tryptamine (5-HT) reuptake inhibitor such as sibutramine, gastrointestinal tract lipase such as the orlistat (orlistat) of motion, life style and behavior.Referring to ObesityResearch12 (8): 1197-1211, its content is all quoted as a reference at this.
5.3. Determine the method for the individuality for the treatment of with satiety factors agonist or antagonist
The present invention part is based on following discovery: with the agonist of satiety factors or antagonist to the treatment of fat and relevant disease in that treatment has in the individuality of response effectively to satiety factors, and satiety factors treated have the individuality of response to comprise individuality with the bad endogenous levels of satiety factors.
5.3.1 Determine the satiety factors level
Satiety factors endogenous level in the individuality can be determined by the obtainable any means of those skilled in the art.It can directly or indirectly be determined.In some embodiments, determine from the amount of the satiety factors in the sample of individuality by measuring.In other embodiments, measure from the activity of satiety factors precursor in the sample of individuality by measuring.For example, can be by the level of measurement from the determination of activity enterostatin of the sample Central Plains colipase (procolipase) of individuality.Except total endogenous level of satiety factors, can determine that individuality embezzles the endogenous level of sense factor active form.For example, can determine the aggregate level of ghrelin and the level of acidylate ghrelin in some embodiments.
In some embodiments of the present invention, the method for the amount of mensuration satiety factors and non-key.Correspondingly, the invention provides the method for the individuality of selecting the treatment carried out with satiety factors agonist or antagonist, this method comprises according to the amount from the satiety factors in the sample of individuality determines the single step whether individuality is suitable for treating.
The amount of satiety factors can be determined by any way by the people who implements method of the present invention.This paper has described exemplary technology.
The amount of satiety factors can be from from determining any sample of individuality, this sample can be, such as but not limited to: blood sample, plasma sample, saliva sample, serum sample, sputum sample basis, urine specimen, fecal sample, cell sample, cell extraction thing sample and tissue slice sample or can be by the arbitrary sample that well known to a person skilled in the art that technology is obtained from individuality.The definite sample that obtains from individuality is varied, but sampling preferably has minimum invasive and can implement easily by routine techniques.
According to the judgement that those skilled in the art carry out based on the type and the detection technique of for example used sample, can handle or purification sample.Useful especially treatment step is precipitation, centrifugal, filtration and/or chromatography.
5.3.2 Measure the amount of satiety factors
Can determine by any method known to those skilled in the art without restriction from the satiety factors amount in the sample of individuality.For example, can determine by spectrographic method, chromatography, immunoassay or electrophoresis method.In some embodiments, the amount of satiety factors is determined by immunoassay.Some preferred embodiment in, the amount of satiety factors is determined by ELISA.
In preferred embodiment, people such as the amount of dextrin such as Ludvik, 1991, determine described in Diabetes40 (12): the 1615-19 (its content is all quoted as a reference at this).
In preferred embodiment, the amount of enterostatin can be with reference to people such as Imamura, and 1998, Peptides, 19:8,1385-1391; People such as Bowyer, 1991, Clinica.Chimica.Acta..200:137-152; People such as Mizuma, 1995, Biochemical ﹠amp; Biophysical Research Communications1995,215 (1): people such as 227-234 or Zhao, 2001, Fresenius J.Anal.Chem.269:220-224 (its content is all quoted as a reference at this) is described to be determined.
In preferred embodiment, the amount of GLP-1 can be with reference to people such as Kreymann, and 1987, Gut2 (8571): 1300-04; People such as Verdich, 2001, people such as Int.J.Obesity 25:1206-14 or Feinle, 2002, Peptides 23:1491-95 (its content is all quoted as a reference at this) is described to be determined.
In preferred embodiment, the amount of ghrelin can be with reference to people such as Druce, and 2005, Intl.J.Obesity29:1130-36; People such as Akamizu, 2005, J.Clin.Endodrinol.Metab.90 (1): 6-9 (at acidylate and deacylated tRNA ghrelin) or
Figure A200780032713D0048154227QIETU
Deng the people, 2001, Diabetes, 50:707-09 (its content is all quoted as a reference at this) is described to be determined.
In preferred embodiment, the amount of PYY can be with reference to people such as Batterham, and 2003, N.Eng.J.Med.349 (10): 941-8; People such as Adrian TE, 1987, Surgery 101 (6): 715-19; People such as Savage, 1987, Gut 28 (2): people such as 166-70 or Fuessl, 1988, Klin Wochenschr 66 (19): 985-89 (its content is all quoted as a reference at this) is described to be determined.
In preferred embodiment, the amount of pancreatic polypeptide can be with reference to people such as Berntson, and 1993, Peptides.14 (3): 497-503; People such as Polak, 1976, Lancet.1 (7955): people such as 328-30 or Adrian, 1976, Gut17 (5): 393-94 (its content is all quoted as a reference at this) is described to be determined.
Can utilize the standard technique of the amount that is used for determining peptide that sample exists or interested peptide to determine the amount of satiety factors in the sample.For example, can adopt the standard technique of immunoassay for example to determine the amount of the protein of interest that exists in the sample, described immunoassay is the Western trace for example, and immunoprecipitation carries out SDS-PAGE (SDS-PAGE), immunocytochemistry etc. subsequently.A kind of exemplary reagent that is used to detect protein of interest be can specificity in conjunction with the antibody of interested peptide, preferably by the antibody behind the detectable label directly or indirectly.
For these detection methods, if desired, can separate simply by technology well known by persons skilled in the art from the satiety factors of sample.These class methods can be for example Harlow and Lane, 1988, the described method of Antibodies:A Laboratory Manual.Cold Spring Harbor Laboratory Press (ColdSpring Harbor, New York) (its content is all quoted as a reference at this).
In some embodiments, the method that detects the amount of satiety factors in the sample comprises the detection by carrying out with the interaction that can specificity combines the antibody of satiety factors.Antibody can obtain from commercial source, and standard technique perhaps well known by persons skilled in the art generates.In specific embodiment, antibody can be polyclonal antibody, or more preferably is monoclonal antibody.For example, can use complete antibody or antibody fragment (for example, scFv, Fab or F (ab ') 2).Exemplary immunoassay have hereinafter been described.
In some embodiments, use the protein chip experiment (for example, referring to Zhu ﹠amp; Snyder, 2003, Curr.Opin.Chem.Biol.7:55-63; Mitchell, 2002, Nature Biotechnology20:225-229) measures the amount of biomarker in the biomarker spectrum (profile).For example, also can be referring to Lin, 2004, Modern Pathology, 1-9; Li, 2004, Journal of Urology 171,1782-1787; Wadsworth, 2004, Clinical Cancer Research, 10,1625-1632; Prieto, 2003, Journal of Liquid Chromatography ﹠amp; Related Technologies26,2315-2328; Coombes, 2003, Clinical Chemistry 49,1615-1623; Mian, 2003, Proteomics 3,1725-1737; People such as Lehre, 2003, BJU International 92,223-225 and Diamond, 2003, Journal of the American Society for Mass Spectrometry 14,760-765, its content is all quoted as a reference at this.Useful especially In some embodiments of the present invention be the antibody chip being convenient to detect by MALDI or SELDI (for example,, wait the people referring to Wang, 2001, Int ' l.J.of Cancer 92:871-876; Figeys, 2002, Proteomics 2:373-382; People such as Sonksen, 1998, Anal.Chem.70:2731-6;
Figure A200780032713D0050154812QIETU
， ﹠amp; Angenendt, 2003, J.ChromatographyB, 797:229 240, its content is all quoted as a reference at this).
In some embodiments, the specific antibody of satiety factors or antibody fragment can be used to detect the amount of satiety factors in the sample.This can realize by for example immunofluorescence technique.In addition, antibody (or its fragment) can be by Histological method's in-site detecting satiety factors such as immunofluorescence or immuno-electron microscope.
Immunoassay generally includes hatches sample with the antibody of the detectable label that can discern satiety factors, and by the bonded antibody of any technology for detection in some technology well known in the art.Exemplary immunoassay is the Western blotting, carries out SDS-PAGE (SDS-PAGE) behind the immunoprecipitation, thereby immunocytochemistry etc. are determined the amount of peptide in the sample.
But one of the method that can carry out mark note to the specific antibody of satiety factors is it to be connected and to be used for enzyme immunoassay (EIA) (Voller with enzyme, 1978, " The Enzyme Linked ImmunosorbentAssay (ELISA) ", Diagnostic Horizons 2:1-7, Microbiological Associates QuarterlyPublication, Walkersville, MD; People such as Voller, 1978, J.Clin.Pathol.31:507-520; Butler, J.E., 1981, Meth.Enzymol.73:482-523; Maggio, E. (volume), 1980, EnzymeImmunoassay, CRC Press, Boca Raton, FL; Lshikawa, people such as E. (volume), 1981, EnzymeImmunoassay, its content is all quoted as a reference at this).With the enzyme of antibodies will be in some way with suitable substrate (preferred chromophoric substrate) thus reaction generates the chemical part that can pass through spectrophotometer, exometer or visible sensation method detection.Can be used for the enzyme that antagonist carries out detectable label and include but not limited to malic dehydrogenase, staphylococcal nuclease, δ-5-steroid isomerase, Alcohol Dehydrogenase from Yeast, α-glycerophosphate, dehydrogenase, triose phosphate salt isomerase, horseradish peroxidase, alkali phosphatase, asparaginase, glucoseoxidase, beta galactosidase, ribonuclease, urase, catalase, glucose-6-phosphate dehydrogenase (G6PD), glucoamylase and acetylcholinesterase.Can finish detection by colorimetry, this method is used the chromophoric substrate at enzyme.Also can realize this detection by the standard of the enzyme reaction degree of substrate and similar foundation is carried out visual comparison.
Also can be by various other immunoassays realization measurements arbitrarily.For example, carry out radioactive label by antagonist or antibody fragment, may be by (for example using radioimmunoassay (RIA) detection of biological labelling, referring to Weintraub, B., Principles of Radioimmunoassays, Seventh TrainingCourse on Radioligand Assay Techniques, The Endocrine Society, in March, 1986, it is incorporated herein by reference).Radiosiotope (for example, 125I, 131I, 35S or 3H) can detect by using as gamma counter or scintillation counter or by means such as autoradiography.
Also may use the fluorescent chemicals traget antibody.When fluorescently-labeled antibody is exposed to following time of light of suitable wavelength, rely on fluorescence can detect its existence.The most frequently used fluorescent labeling chemical compound is Fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, to phthaldialdehyde and fluorescamine.
Antibody also can adopt the fluorescent emission metal as 152Eu, or other lanthanide series carries out detectable label.These metals can be by being connected with antibody such as diethylene triamine pentacetic acid (DTPA) (DTPA) or ethylenediaminetetraacetic acid metal sequestration groups such as (EDTA).
Also can be by coming antagonist to carry out detectable label antibody and chemiluminescence compound coupling.Can measure the existence of chemiluminescent labeling antibody by detecting the luminous existence that produces in the chemical reaction process then.The example of useful especially chemiluminescent labeling chemical compound is luminol, different luminol, theromatic acridinium ester, imidazoles, acridinium salt and oxalate.
Similarly, available bioluminescent compound labelling antibody of the present invention.Bioluminescence is a class chemiluminescence that is found in the biosystem, and catalytic protein has improved the efficient of chemiluminescence reaction in this biosystem.The existence of bioluminescent protein can be determined by detecting luminous existence.The important biomolecule luminophor that can be used for labelling is luciferin, luciferase and photoprotein.
The amount of satiety factors also can for example be passed through, and one or more in the method as described below are determined.For example, method can comprise nuclear magnetic resonance, NMR (NMR) spectrum, and mass spectrography is desorbing/ionizing (DIOS) on electro-spray ionization mass spectrography (ESI-MS), ESI-MS/MS, ESI-MS/ (MS) n (n is the integer greater than zero), substance assistant laser desorpted ionized time-of-flight mass spectrometry (TOFMS) (MALDI-TOF-MS), surface-enhanced laser desorption ionization time-of-flight mass spectrometry (TOFMS) (SELDI-TOF-MS), the silicon, secondary ion mass spectrometry (SIMS), quadrupole time-of-flight method (Q-TOF), atmospheric pressure chemical ionization massspectrum method (APCI-MS), APCI-MS/MS, APCI-(MS) for example n, atmospheric pressure photoionization mass spectrography (APPI-MS), APPI-MS/MS and APPI-(MS) nOther mass spectrography comprises: four-electrode method, fourier transform mass spectrometry (FTMS) and ion trap and other.Other method that is suitable for can comprise chemical extraction distribution, column chromatography, ion-exchange chromatography, hydrophobic (anti-phase) liquid chromatography, isoelectrofocusing, the poly-propionic acid amide. gel electrophoresis (PAGE) of one dimension, the poly-propionic acid amide. gel electrophoresis (2D-PAGE) of two dimension or other chromatography, for example thin layer chromatography, gas chromatogram or liquid chromatograph, or its combination in any.In one embodiment, biological specimen can carry out fractional distillation before using separation method.
In one embodiment, laser desorption/ionizing time-of-flight mass spectrometry (TOFMS) can be used for the amount of detection of biological labelling, and wherein biomarker is the molecule that has been ionized and has been gasified from fixing holder by incidenting laser radiation.Multiple laser desorption/ionization techniques known in the art (for example, referring to, people such as Guttman, 2001, people such as Anal.Chem.73:1252-62 and Wei, 1999, Nature399:243-246, its content is incorporated herein by reference).
Laser desorption/ionizing time-of-flight mass spectrometry (TOFMS) allows to generate a large amount of information in the short relatively time.Biological specimen is added in can be in conjunction with on a kind of in the multiple holder of all biomarkers or its subclass in this sample.Passing through or do not pass through purification or isolated cells pyrolysis product or sample directly is added on these surfaces with little volume to 0.5 μ L.Pyrolysis product or sample can concentrate before being added on the support surface or dilute.Use laser desorption/ionizing being as short as the mass spectrum that generates sample in time of three hours then.
The analysis of being undertaken by LC/MS generates the quality intensity spectrum, and the various components in the sample have been represented at peak wherein, and each component has distinctive mass-to-charge ratio (m/z) and retention time (r.t.).Existence with peak of the m/z of biomarker and retention time has shown the existence of this labelling.Represent the peak of labelling can compare with corresponding peak to obtain the relative measurement value from another mass spectrum (for example, coming from check sample).When the needs quantitative measurement, can adopt any normalization technology (for example, interior mark) in this area.In addition, can use the software that deconvolutes to separate fused peaks.Retention time to a certain degree depends on the condition that is adopted when carrying out liquid chromatograph separates.
In MALDI mass spectrography (MALDI-MS), can adopt various mass-synchrometers, for example, the sectorial magnetic field of single-stage or three grades of quadrupole patterns/magnetic deflection instrument (MS/MS), Fourier transformation and flight time (TOF) comprise the quadrature flight time (O-TOF), are configured by the known configuration in mass spectrography field.For desorbing/ionization process, can use multiple substrate/laser combination.Also can adopt ion trap and reflector arrangement.
Electro-spray ionization mass spectrography (ESI-MS) is widely used in the macromole analysis of (comprising albumen, nucleic acid and carbohydrate) (people such as Fenn, 1989, Science 246:64-71; People such as Crain, 1998, Curr.Opin.Biotechnol.9:25-34; People such as Smith, 1990, Anal Chem.62:882-99; Han ﹠amp; Gross, 1994, Proc Natl Acad Sci USA91:10635 10639).The electron spray technology be used to separate and the inspection amount suc as formula the biomarker of I and formula Ia (referring to people such as Petkovic, 2001, Anal Biochem.289 (2): 202-16; Pulfer ﹠amp; Murphy, 2003, Mass Spec Rev 22:332-364; Han ﹠amp; Gross, 1995, J.Amer.Soc.Mass Spec.6:1202-1210, its content is all quoted as a reference at this).
For albumen or peptide, for example, Vorm, O. wait the people, Anal.Chem.66:3281-3287 (1994) and Vorm and Mann, J.Am.Soc.Mass.Spectrom.5:955-958 (1994) provide the extra guidance of the mass spectral analysis of these molecules and their content have all been quoted as a reference at this.The content of these publications is all quoted as a reference at this.
5.3.3 The individuality that selection is treated with satiety factors
Whether individuality has the satiety factors undesirable level can be measured by ability any means known to the skilled.Exemplary method has been described herein.
In some embodiments, selecting to have the individuality of low-level satiety factors or individuality that satiety factors lacks treats.When the amount of the satiety factors in this individual sample is lower than normal satiety factors value, select this individuality to treat.In some embodiments, select not express or do not secrete the individuality of the satiety factors of the amount that can record by state of the art.In another embodiment, select not express or do not secrete the individuality of any satiety factors.In preferred embodiment, expressing after the meal or excretory satiety factors amount is lower than contrast when individual when individuality, select this individuality.The low-level of satiety factors can be owing to any reason known in the art in the individuality.For example, it may be low expression level or secretion owing to satiety factors, perhaps because insufficient activation of satiety factors in intestinal or the stomach.It also may be the result of proteolytic activity excessive (for example the proteinase activity of hydrolyzable satiety factors is excessive).
In some embodiments, the individuality of selecting to have high-level satiety factors individual or excessive generation satiety factors is treated.When the amount of the satiety factors in the sample of individuality is higher than normal satiety factors value, select this individuality to treat.In preferred embodiment, express or the amount of excretory satiety factors is higher than contrast when individual at fasting state when individuality, select this individuality.The high level of satiety factors may be owing to any reason known in the art in the individuality.For example, may be because the high level expression or the secretion of satiety factors.
In some embodiments, selection can be based on the amount and the normal satiety factors value of satiety factors in the sample of individuality.Hereinafter specifically described normal satiety factors value in the chapters and sections.In some embodiments, if the satiety factors amount in the test individuality is lower than or is lower than substantially normal satiety factors value, then select the individual treatment of accepting to use satiety factors of this test.In some embodiments, when the amount of the satiety factors in this individual sample is lower than normal satiety factors value, select this individuality.In other embodiments, when from the satiety factors amount in the sample of individuality less than normal satiety factors value 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2% or 1% the time, select this individuality.
In other embodiments, if the satiety factors amount in the test individuality is higher than or is higher than substantially normal satiety factors value, then select this test body and function satiety factors to treat.In some embodiments, when the quantity of the satiety factors in the sample of individuality is higher than normal satiety factors value, select this individuality.In other embodiments, when be about from the satiety factors amount in the sample of individuality normal satiety factors value 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or 1500% the time, select this individuality.
In some embodiments, use the one or more samples that from individuality, obtain at single time point to select.In some embodiments, only obtain the single sample of single time point.In other embodiments, obtain a plurality of samples at different time points from this individuality.A plurality of samples can be identical or different sample types.In the specific embodiment, use is selected from blood sample and urine specimen that individuality obtains.When using a plurality of sample of same type, assessment can be based on any statistical technique well known by persons skilled in the art, for example ANOVA or Chi-square test (Chi squared test).
When using the single sample of single time point, can work as individually during by overnight fasting, when individuality take food, or take food at individuality and to obtain sample from this individuality in afterwards about 0.5,1.0,1.5,2.0,2.5,3.0,3.5 or 4.0 hour.In some embodiments, individual conventional meals, high fat diet or the high carbohydrate diet used.
In some embodiments, meals comprise carbohydrate.In some embodiments, meals comprise albumen.In some embodiments, meals comprise fat.In some embodiments, meals are the stimulation (challenge) of specific nutrition thing.In some embodiments, meals are the stimulation of carbohydrate.In some embodiments, meals are proteic stimulation.In some embodiments, meals are the stimulation of fat.
In some embodiments, use a plurality of samples that from individuality, obtain in different time points to select.This time can separate according to those skilled in the art's judgement.In some embodiments, but obtain sample from individuality every day, perhaps alternatively, can be more continually, obtained these samples from individuality in for example per 4,6,8 or 12 hours.
In some embodiments, the purpose of obtaining a plurality of samples at different time is duplicate detection.In these embodiments, assessment can be based on any statistical technique well known by persons skilled in the art, for example ANOVA or Chi-square test.Preferably, when judgement, when this individuality is in identical or similar feed condition, obtain sample from this individuality according to this area practitioner.In some embodiments, sample obtains during by overnight fasting at individuality.In some embodiments, sample obtains when individuality is taken food.In some embodiments, sample obtains at individuality feed back special time.In concrete embodiment, all samples obtained in this individuality dining back in about 0.5,1.0,1.5,2.0,2.5,3.0,3.5 or 4.0 hour.
In other embodiments, obtain a plurality of samples from individuality in different time points, and the variation of assessment satiety factors amount or do not change to select.It is reported that obese individuals not only has the satiety factors endogenous level of change, the meals that also have an impaired satiety factors level are induced and are replied.For example, referring to people such as Verdich, 2001, Int.J.Obesity 25:1206-14 (GLP-1); People such as le Roux, 2005, J.Clin.End.﹠amp; Metab.90 (2): 1068-71 (ghrelin).Correspondingly, can determine the feed of satiety factors amount: the fasting ratio, and use it for the treatment of selecting individual acceptance to use satiety factors agonist or antagonist to carry out.
In some embodiments, by overnight fasting, and all obtain sample after 1,2 or 3 hour, calculate the feed of individual satiety factors amount: the fasting ratio in individuality feed or individual feed back at individuality.In some embodiments, the satiety factors amount was continuous measurement after the meal 1,2 just or 3 hours.In some embodiments, when the fasting of individuality: the feed ratio is with respect to normal satiety factors fasting: when the feed ratio descends to some extent, select this individuality.In another embodiment, fasting when individuality: the feed ratio is less than the fasting of normal satiety factors: the feed ratio 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2% or 1% the time, select this individuality.In some embodiments, when the fasting of individuality: the feed ratio is with respect to normal satiety factors fasting: when the feed ratio rises to some extent, select this individuality.In another embodiment, when fasting: the feed ratio is about the fasting of normal satiety factors: the feed ratio 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or 1500% the time, select this individuality.The normal feed of satiety factors has hereinafter been described: the fasting ratio.
In some embodiments, determine the endogenous level of a plurality of satiety factors, and use it for the individuality that selection is treated with satiety factors agonist or antagonist.For example, measure satiety factors spectrum (profile) (including but not limited to dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY), and use it for the individuality that selection is treated with satiety factors agonist or antagonist.
Except the satiety factors level, also other parameter or variable and satiety factors horizontal combination can be made to be used for selecting the individuality for the treatment of with satiety factors agonist or antagonist.In some embodiments, use individual blood sugar level.In other embodiments, use individual body weight or BMI to select.In addition, whether select individuality to come to treat with satiety factors agonist or antagonist can be according to those skilled in the art's judgement, for example, decide in conjunction with the satiety factors level based on blood examination, electrocardiogram, fasting chemical group (fasting chemistrypanel), CBC, blood pressure, pulse rate, urine examination, the adverse events of individuality.
In some embodiments, can determine the amount of individual multiple satiety factors.As mentioned above, if one or more amount is bad, then select this individuality.Described in the method as mentioned,, can use the agonist or the antagonist of corresponding satiety factors to this individuality if an amount is bad.If more than one amount is bad, can use the combination of the agonist or the antagonist of corresponding satiety factors to this individuality.This combination can be the combination in any that those skilled in the art are considered as safety and effective agonist or antagonist.This agonist and antagonist can be used in mixture simultaneously, perhaps simultaneously but use in independent dosage, perhaps use in circulation dosage, or use according to other scheme that those skilled in the art determine.
In some embodiments, can determine the amount of one group of individual satiety factors.As mentioned above, if one or more amount is bad, then select this individuality.Advantageously, this group can be used to use agonist or antagonist to this individuality personalization.Each agonist or antagonist all can be used with reference to method known to those skilled in the art (method for example as herein described).Agonist and antagonist can be used with mixture, perhaps use with while dosage, perhaps use with circulation dosage, or use according to other scheme that those skilled in the art determine.In the specific embodiment, can according to the amount of in group, measuring the mixture of individual selection agonist or antagonist.For example,, the method according to this invention has low-level enterostatin and high-caliber ghrelin, agonist that then can co-administered enterostatin and the antagonist of ghrelin if recording this individuality.
In some embodiments, this group comprises that two or more are selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises three kinds or more kinds ofly be selected from following intestinal peptide: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises four kinds or more kinds ofly be selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises five kinds or more kinds ofly be selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises six kinds or more kinds ofly be selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises seven kinds or more kinds ofly be selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises eight kinds or more kinds ofly be selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises nine kinds or more kinds ofly be selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.In some embodiments, this group comprises and is selected from following satiety factors: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
5.3.4 Normal satiety factors value and normal satiety factors feed: fasting ratio
Normal satiety factors value can be for example, to contrast individual or a plurality of satiety factors amounts that contrast individual sample from one.The amount of satiety factors can be measured with reference to technology well known by persons skilled in the art (comprising the techniques described herein) in the contrast individuality.Advantageously, in some embodiments, in the contrast individuality in the amount of satiety factors and the test individuality amount of satiety factors obtain by identical technology.It will be appreciated by those skilled in the art that: for each concrete mensuration, every kind of sample type and every kind of acellular extract type, normal satiety factors value all may change.Those skilled in the art can understand: normal satiety factors value may change according to the different plant species or the sex of individuality to be selected.For example, the normal satiety factors value of male may be higher than female individuals in the same species.Correspondingly, in preferred embodiment, the satiety factors level of female individuals and the expection level of female individuals are compared; The satiety factors level of male and the expection level of male are compared.
Normal satiety factors value can be determined or obtains from available other source of those skilled in the art with reference to method as herein described.In some embodiments, normal satiety factors value can be determined by the value of measuring in the normal individual.Individuality should be thought normally by this area practitioner, and is for example not fat or not overweight.Preferred normal individual has comparability (for example for sex, age, height etc.) with the treatment individuality under possible situation.Satiety factors value in these individualities can be determined according to method as herein described or conspicuous other method of those skilled in the art.Normal satiety factors value also can be determined from the available source of those skilled in the art (comprising for example document, clinical trial, availability database etc.).Provide the exemplary of satiety factors value but the indefiniteness list of references comprises people such as Alevizake, 2001, Eur.J.Endocrinol.145:585-9; People such as Schou, 2005, J.Clin.Endocrinl.Metabol.90:4912-4919; People such as Peracci, 1999, Scand.J.Gastroenterol.34:25-28; People such as Teitelbaum, 1989, J.Pediatr.Surg.24:629-633; People such as Zhou, 2006, Obesity14:683-689; Batterham ﹠amp; Bloom, 2003, Ann.KY.Acad.Sci.994:162-168; Kim. wait people, 2005, J.Clin.Endocrinl.Metabol.90:6665-6671; People such as Teff, 2004, J.Clin.Endocrinl.Metabol.89:2963-2972; People such as Espelund, 2005, J.Clin.Endocrinl.Metabol.90:2741-2746; People such as le Roux, 2006, Ann.Surgery 243:108-114, its content is all quoted as a reference at this.
The contrast individuality can be the thin partially individual or individuality with normal type.When individuality is a man-hour, the contrast individuality can be that BMI is at 20-25kg/m 2Individuality in normal range.In some embodiments, normal satiety factors amount comes from a plurality of contrasts individualities of the symptom of disorder that demonstrations is not relevant with the satiety factors undesirable level or disease.Normal satiety factors amount can be calculated according to any suitable statistical method well known by persons skilled in the art.For example, normal satiety factors amount can be based on the satiety factors statistics of variables meansigma methods from the individual sample of contrast, and described contrast individuality does not show the disorder relevant with the satiety factors undesirable level or the symptom of disease.
Advantageously, need not to obtain or measure this normal satiety factors value by the people who implements the inventive method.The ground that replaces, the amount of normal satiety factors value can be by determining with reference to the available any resource of those skilled in the art, this resource comprises scientific and technical literature, public or private data storehouse or with reference to data provided herein etc.
Absolute value or numerical range that determined as those skilled in the art, normal satiety factors value can be absolute value, have the limit of error.In some embodiments, select based on the range of normal value of satiety factors amount.The scope of normal value can as described hereinly obtain, and can be obtained by the implementer of the inventive method.
In some embodiments, normal satiety factors value is the critical reference amount.The critical reference amount is the absolute value of normal satiety factors amount.The critical reference amount can determined from the basis that contrasts the individual contrast amount that obtains by using statistical technique well known by persons skilled in the art.For example, it can be based on from satiety factors statistics of variables meansigma methods in the individual sample of contrast.
Can will compare from satiety factors amount in the sample of individuality and normal satiety factors value by any suitable statistical method well known by persons skilled in the art.In preferred embodiment, use dual factors or three-factor analysis of variance (ANOVA) or Chi-square test and replication to compare.
In some embodiments, can be based on the feed of satiety factors in the individual specimen: fasting ratio and normal satiety factors feed: the fasting ratio be selected the individual treatment of using satiety factors agonist or antagonist to carry out accepted.The feed of satiety factors: the fasting ratio can be by obtaining after the amount of satiety factors in the sample of the individuality of the overnight fasting amount divided by satiety factors in the sample of about 0.5,1,1.5,2, the 2.5 or 3 hour individuality in feed or feed back.The description of above-mentioned relevant normal satiety factors value is equally applicable to normal satiety factors feed: the fasting ratio.For example, normal satiety factors is taken food: the fasting ratio can be for example, to take food from the individual normal satiety factors of the individual or a plurality of contrasts of contrast: the fasting ratio, and need not obtain by the implementer of the inventive method or measure.It all may change for each concrete mensuration, every kind of sample type and every kind of acellular extract type.It can be absolute value, have the absolute value of the limit of error, numerical range or critical reference amount.
The dosage form of satiety factors agonist or antagonist and route of administration
Satiety factors agonist that is used for the treatment of or antagonist can with the form of pharmaceutical composition, with the form of complex (co-complex) altogether or with the form of the pharmaceutical composition that comprises common complex be administered to individual itself.
The agonist of satiety factors or antagonist can be used by any approach according to those skilled in the art's judgement, include but not limited in oral, intranasal, the lung, intravenous, subcutaneous, transdermal, gastric, intraperitoneal, Intraventricular and rectal administration.
In preferred embodiment, the compositions that is used to use is pharmaceutical composition or single unit dosage forms.Pharmaceutical composition and single unit dosage forms can comprise one or more preventive or the therapeutic agent of prevention or treatment effective dose, and typically one or more pharmaceutically acceptable carriers or excipient.In the specific embodiment and context, term " medicine is acceptable " refers to be included in the universally recognized pharmacopeia by the administrative organization of federation or state government approval or by American Pharmacopeia or other and is used for animal, more specifically is used for the people's.The diluent that term " carrier " refers to use with therapeutic agent, adjuvant (for example, Fu Shi reagent (fully or not exclusively)), excipient or carrier.These pharmaceutical carriers can be sterile liquids, and for example water and oil comprise the oil from oil, animal, vegetable or synthetic source, for example Oleum Arachidis hypogaeae semen, soybean oil, mineral oil, Semen Sesami wet goods.When this pharmaceutical composition was used by intravenous, water was preferred carrier.Saline solution and dextrose aqueous solution and glycerite also can be used as liquid-carrier, are specially adapted to injection solution.The example of suitable drug carrier has been described in E.W.Martin " Remington ' s Pharmaceutical Sciences ".
Typical pharmaceutical composition and dosage form comprise one or more excipient.The excipient that is suitable for has been that the technical staff of drug world is known, and the non-limiting example that is suitable for excipient comprises starch, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, Talcum, sodium chloride, defatted milk powder, glycerol, propylene, ethylene glycol, water, ethanol etc.Concrete excipient whether is suitable for pharmaceutical composition or dosage form depends on multiple factor well known in the art, and it includes but not limited to, dosage form is concrete active component in approach that the patient uses and dosage form.If desired, compositions or single unit dosage forms also can comprise a spot of wetting agent or emulsifying agent, or the pH buffer agent.
Free from lactose compositions of the present invention can comprise excipient well known in the art and as enumerating in American Pharmacopeia (USP) SP (XXI)/NF (XVI).Generally speaking, but the free from lactose compositions comprises active component, binding agent/filler and the lubricant of the compatible and pharmacy receiving amount of pharmacy.Exemplary free from lactose dosage form comprises active component, microcrystalline Cellulose, pregelatinized Starch and magnesium stearate.
The present invention further comprises and uses anhydrous pharmaceutical composition and the dosage form that comprises satiety factors agonist or antagonist.For example, a kind of long term store of simulating that the interpolation of water (for example, 5%) is that pharmaceutical field is accepted extensively is to measure the method as shelf-life or preparation characteristics such as stability in time.For example, referring to JensT.Carstensen, Drug Stability:Principles ﹠amp; Practice, the 2nd edition, Marcel Dekker, NY, NY, 1995, the 379-80 pages or leaves.On effect, water and Re Ke quicken the decomposition of some chemical compounds.Therefore, water may be very important to the effect of preparation, because often run into moisture and/or dampness in production, processing, packing, storage, transportation and the use of preparation.
Anhydrous pharmaceutical composition of the present invention and dosage form can adopt the composition of anhydrous or low water content and prepare under low moisture or low humidity condition.If be expected in production, packing and/or the storage process with moisture and/or dampness substantive the contact arranged, the pharmaceutical composition and the dosage form that comprise lactose and at least a active component that comprises primary amine or secondary amine are preferably anhydrous.
The preparation of anhydrous pharmaceutical composition and storage should keep its no aqueous nature.Therefore, thus anhydrous composition preferably uses waterproof material known in the art to pack can be included in the appropriate formulations test kit.Suitably the example of packing includes but not limited to sealed foil, plastics, unit-dose container (for example, phial), blister package and strip packing.
The present invention further comprises and uses pharmaceutical composition and the dosage form that comprises one or more chemical compounds that can reduce the active component decomposition rate.These chemical compounds that are referred to herein as " stabilizing agent " include, but not limited to as antioxidants such as ascorbic acid, pH buffer or salt buffer.
Pharmaceutical composition and single unit dosage forms can be forms such as solution, suspending agent, Emulsion, tablet, pill, capsule, powder, slow release formulation.Peroral dosage form can comprise standard vector, for example the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate etc.These compositionss and dosage form will comprise the preventive that preferably is purified form or the therapeutic agent of prevention or treatment effective dose, comprise an amount of carrier simultaneously so that the form of correctly using to the patient to be provided.The pattern that dosage form should be fit to use.In preferred embodiment, pharmaceutical composition or single unit dosage forms are aseptic, and are in the suitable appropriate format of using to individual (being preferably animal individual, more preferably mammalian subject, most preferably human individual).
Preparation comprises the pharmaceutical composition of satiety factors agonist or antagonist to match with its target route of administration.The example of route of administration includes but not limited to parenteral, for example intravenous, skin are interior, subcutaneous, intramuscular, subcutaneous, oral, oral cavity, Sublingual, suction, intranasal, transdermal, part, wear in mucosa, the tumor, in the synovial membrane and rectal administration.In the specific embodiment, can according to conventional methods compositions be mixed with and be suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or local application to human pharmaceutical composition.In embodiment, thereby the pharmaceutical compositions subcutaneous administration is to human according to conventional methods.Typically, the compositions used of intravenous is that aseptic grade is opened the solution in the aqueous buffer solution.When in case of necessity, compositions also can comprise solubilizing agent and local anesthetic (for example lignocamne) to alleviate the pain of injection site.
The example of dosage form includes but not limited to: tablet; The capsule sheet; Capsule (as soft elastic gelatin capsule); Cachet; Lozenge; Lozenge; Dispersant; Suppository; Ointment; Paste (poultice); Unguentum; Powder; Dressing; Cream; Plaster; Solution; Patch; Aerosol (for example, nasal spray or inhaler); Gel; Be suitable for the patient and carry out liquid dosage form oral or that mucosa is used, comprise suspending agent (for example, water or on-aqueous liquid suspending agent, oil-in-water emulsion or water-in-oil type liquid emulsion), solution and elixir; Be suitable for the liquid dosage form of parenteral administration to the patient; And can be suitable for by the sterile solid (for example, crystal or amorphous solid) of parenteral administration to provide by reprovision to patient's liquid dosage form.
The composition of the agonist of satiety factors and the dosage form of antagonist, shape and type change with its purposes usually.For example, the comparable dosage form that is used for chronic treatment disease of the same race of dosage form that is used for disorderly acute treatment comprises more substantial one or more satiety factors agonist or antagonisies.Similarly, the treatment effective dose can be between cancer dissimilar and change.Similarly, parenteral dosage forms is comparable is used for the treatment of one or more its active component of being comprised that same disease or disorderly peroral dosage form comprise less amount.The present invention is contained the particular dosage form variety of way and will be differed from one another, and this point is conspicuous to those skilled in the art.For example, referring to Remington ' s Pharmaceutical Sciences, the 18th edition, MackPublishing, Easton PA (1990).
Generally speaking, the composition of compositions that comprises the agonist of satiety factors or antagonist in single unit dosage forms independently or mix and provide, for example, at the sealed container ampoule or the sachette of active agents quantity (as shown) as lyophilized powder or there is not aqueous concentrate.When compositions will be applied by infusion, it can be packed into by branch and contain aseptic pharmaceutical grade water or brinish infusion bottle.When compositions will be applied by injection, ampoule Injectable sterile water or saline can be provided, thereby can before using, mix these compositions.
The exemplary dosage form that is used for using in the methods of the invention comprises the agonist or the antagonist of satiety factors or comprises the satiety factors agonist or the common complex of antagonist or the acceptable salt of its pharmacy, solvate or hydrate, its scope every day about 0.001mg to about 1000mg or about 0.1pmol/l about 100pmol/l extremely, carry out once a day administration in every morning, but preferably in whole day with food gradation administration.
5.3.5 Peroral dosage form
Can carry out the Orally administered pharmaceutical composition that is used for the inventive method and can be used as and disperse dosage form to provide, such as but not limited to tablet (for example, chewable tablet), capsule sheet, capsule and liquid (for example, local flavor syrup).These dosage forms comprise the active component of scheduled volume, and can be by well known to a person skilled in the art the pharmaceutical methods preparation.Generally can be referring to Remington ' s Pharmaceutical Sciences, the 18th edition, Mack Publishing, Easton PA (1990).
In preferred embodiment, chapters and sections specifically describe as mentioned, and peroral dosage form is a solid, and prepare under anhydrous condition with no water constituent.Yet scope of the present invention is not limited to anhydrous, solid oral dosage form.Therefore, this paper has described other dosage form.
Typical peroral dosage form can be prepared by active component is fully mixed according to the conventional medicament preparation technique with at least a excipient.The dosage form that excipient is used according to hope is taked various ways.For example, the excipient that is applicable to liquid oral or aerosol dosage forms includes but not limited to water, ethylene glycol, oil, alcohol, flavour enhancer, antiseptic and coloring agent.The example that is applicable to the excipient (for example, powder, tablet, capsule and capsule sheet) of solid oral dosage form includes but not limited to starch, sugar, microcrystalline Cellulose, diluent, granulating agent, lubricant, binding agent and disintegrating agent.
Tablet and capsule have wherein adopted solid excipient because it is convenient to use and becomes best oral unit dosage form.If desired, can carry out coating to tablet by standard water or non-water technology.These dosage forms can be prepared by any pharmaceutical methods.Generally speaking, pharmaceutical composition and dosage form can be prepared by as required product being shaped to required form after active component and liquid-carrier, fine granular solid carrier or both are evenly fully mixed.
For example, tablet can be by compacting or molded being prepared.Compressed tablet can be prepared by the active component (randomly with mixed with excipients) of free-flowing form (as powder or granule) is suppressed in suitable machine.Molded tablet can be by powdered compounds mixture molded being prepared in the suitable machine machine with the inert liquid diluent moistening.
The example that can be used for the excipient of peroral dosage form of the present invention includes but not limited to binding agent, filler, disintegrating agent and lubricant.The binding agent that is applicable to pharmaceutical composition and dosage form (for example includes but not limited to corn starch, potato starch or other starch, gel, natural and paragutta such as Radix Acaciae senegalis, sodium alginate, alginic acid, other alginate, powdery tragacanth, melon glue, cellulose and derivant thereof, ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized Starch, hydroxypropyl emthylcellulose (for example numbering 2208,2906,2910), microcrystalline Cellulose and composition thereof.
The example that is applicable to the filler of pharmaceutical composition disclosed herein and dosage form includes but not limited to; Talcum, calcium carbonate (for example, granule or powder), microcrystalline Cellulose, powdery cellulose, glucosan, Kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized Starch and composition thereof.Binding agent in the pharmaceutical composition of the present invention or filler exist to about 99 percentage by weights with about 50 of pharmaceutical composition or dosage form usually.
Suitable microcrystalline cellulose prime form includes but not limited to, as AVICEL-PH101, AVICEL-PH103, AVICEL RC-581, AVICEL-PH-105 (can be from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA buys) material sold and composition thereof.Special adhesive is as the microcrystalline Cellulose of AVICEL RC-581 sale and the mixture of sodium carboxymethyl cellulose.Anhydrous or the low moisture excipient or the additive that are suitable for comprise AVICEL-PH-103 and starch 1500LM.
The tablet of disintegrate takes place when using disintegrating agent to be exposed to water environment to be provided in the compositions of the present invention.The tablet that contains too much disintegrating agent may disintegrate when storing, may be with the speed of hope or can't disintegrate under the condition of hope and comprise the tablet of very few disintegrating agent.Therefore, should use and both exceeded only few to form solid oral dosage form of the present invention so that change the capacity disintegrating agent that active component discharges nocuously.The amount of the disintegrating agent that uses depends on that the type of preparation and those of ordinary skill in the art can be simply definite.Typical pharmaceutical composition comprises about 0.5 disintegrating agent to about 15 percentage by weights, particularly about 1 disintegrating agent to about 5 percentage by weights.
The disintegrating agent that can be used for pharmaceutical composition of the present invention and dosage form includes but not limited to agar, alginic acid, calcium carbonate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, polacrilin potassium, sodium starch glycolate, Rhizoma Solani tuber osi or tapioca, pregelatinized Starch, other starch, clay, other Algin, other cellulose, natural gum and composition thereof.
The lubricant that can be used for pharmaceutical composition of the present invention and dosage form includes but not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, Polyethylene Glycol, other ethylene glycol, stearic acid, dodecyl sodium sulfate, Talcum, hydrogenated vegetable oil (for example, Oleum Arachidis hypogaeae semen, cotton seed oil, Oleum Helianthi, Oleum sesami, olive oil, Semen Maydis oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar and composition thereof.Other lubricant comprises, for example, syloid silica gel (AEROSIL200, by Baltimore, the W.R.Grace Co. production of MD), the aerosol that condenses of synthetic silica is (by Piano, the Degussa Co. sale of TX), CAB-O-SIL (by Boston, a kind of pyrogenic silica product that the Cabot Co. of MA sells) and composition thereof.In use, the consumption of lubricant in pharmaceutical composition that comprises it or dosage form is less than about 1 percentage by weight.
5.3.6 Transdermal, part and mucosa dosage form
Although preferred solid, anhydrous peroral dosage form, the present invention also provides transdermal, part or the satiety factors agonist of mucosa dosage form or using of antagonist.Transdermal of the present invention, part and mucosa dosage form include but not limited to ophthalmic solution, spray, aerosol, cream, lotion, ointment, gel, solution, Emulsion, suspending agent, or other form well known by persons skilled in the art.For example, referring to Remington ' sPharmaceutical Sciences, the 16th and 18 edition, Mack Publishing, Easton PA (1980﹠amp; 1990); And Introduction to Pharmaceutical Dosage Forms, the 4th edition, Lea ﹠amp; Febiger, Philadelphia (1985).Being applicable to that dosage form at the intraoral therapy mucosal tissue can be made into gargles agent or oral gel.In addition, the transdermal dosage form comprises " reservoir devices " or " matrix type " patch, and it can be applicable to skin and adhere to the regular hour penetrate with the active component that allows requirement.
The suitable excipient of transdermal, part and the mucosa dosage form that can be used for providing the present invention to contain (for example, carrier and diluent) and other raw material be that the pharmaceutical field technical staff is known, and depend on and will be applied the particular organization of given pharmaceutical composition or dosage form.Given this, typical case's excipient includes but not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, fourth-1,3-glycol, isopropyl myristate, isopropyl palmitate, mineral oil and composition thereof, thus form nontoxic and the acceptable lotion of pharmacy, tincture, cream, Emulsion, gel or ointment.If desired, also can in pharmaceutical composition and dosage form, add wetting agent or wetting agent.These examples of additional ingredients are known in this field.For example, referring to, Remington ' sPharmaceutical Sciences, the 16th and 18 edition, Mack Publishing, Easton PA (1980 ﹠amp; 1990).
According to particular organization to be treated, before treating, simultaneously or can use extra composition afterwards with active component of the present invention.For example, penetration enhancers can be used for assisting active component is passed to tissue.The penetration enhancers that is suitable for includes but not limited to: acetone; Various alcohol are as ethanol, oleyl alcohol, oxolane etc.; Alkyl sulfoxide is as dimethyl sulfoxine; Dimethyl acetylamide; Dimethyl formamide; Polyethylene Glycol; Ketopyrrolidine is as polyvinylpyrrolidone; Kollidon level (polyvidone, polyvinylpyrrolidone); Carbamide; And and various water solublity or the insoluble glycolipid of water, as Tween 80 (polysorbate80) and Span 60 (sorbitan monostearate).
Also can be to the pH of pharmaceutical composition or dosage form, or the pH of the tissue that pharmaceutical composition or dosage form are used regulates to improve the transmission of one or more active component.Similarly, polarity, its ionic strength or the opening property that can adjust solvent carrier sent with improvement.Thereby also can send with the hydrophilic or the lipotropy improvement that advantageously change one or more active component as chemical compounds such as stearate to pharmaceutical composition or dosage form interpolation.Thus, stearate can be used as the lipid carrier of preparation, as emulsifying agent or surfactant and as delivery enhancer or penetration enhancer.Different salt, hydrate or the solvate of active component also can be used for further adjusting the character of the compositions that generates.
5.3.7 Application dosage and frequency
Effectively prevention, treatment, control or improve the agonist of the satiety factors in the inventive method of disorderly or its one or more symptoms or the amount of antagonist will change along with the route of administration of the character of this disease or disease and seriousness and active component.Frequency and dosage also will be according to every patient's specific factors, according to the specific therapy that gives (for example, treatment or preventive), the seriousness of disorderly, disease or disease, is replied and passing medical history and changing at approach of using and patient's age, body weight.Effective dose can be from obtaining from dosage-response curve extrapolation external or that the animal model test macro obtains.
The exemplary dosage of satiety factors agonist or antagonist comprises that every kilogram of individuality or sample weight (for example use the agonist of milligram or Gamma Magnitude or antagonist, about 1 microgram/kilogram is to about 500 mg/kg, about 100 microgram/kilograms are to about 5 mg/kg, or about 1 microgram/kilogram is to about 50 microgram/kilograms).
Satiety factors agonist or antagonist can be used as single dosage once a day and use, perhaps preferably in one day gradation use.In some embodiments, daily dose is divided into application in two dressings every day of five equilibrium dosage.In other embodiments, daily dose divides to use for three times every day.In concrete embodiment, daily dose is divided into five equilibrium dosage and divides every day and to use for three times.In some embodiments, daily dose is divided into three dosage and divides every day and to use for three times, and each fractionated dose comprises satiety factors agonist or the antagonist of about 0.0001-100mg, about 0.001-10mg, about 0.01-1mg or about 0.001-1000pmol/1,0.01-100pmol/1 or 0.1-10pmol/1.Preferably, three of the agonist of satiety factors or antagonist fractionated doses were used before and after the breakfast, lunch and dinner in every day.In some embodiments, agonist or antagonist can as indicated abovely pass through, for example, and transdermal or infiltration or pump delivery system continuous administration.
Satiety factors agonist or antagonist can be used in the different time.In some embodiments, it can be applied to the individuality with satiety factors undesirable level during by fasting at individuality.In some embodiments, it can used before the meal.In some embodiments, it can be used in the process of having dinner.In some embodiments, it can used after the meal.
Understand as those of ordinary skills, different treatment effective doses are applicable to different diseases and disease.Similarly, above-mentioned dosage and administration frequency scheme have also comprised to be enough to prevent, control, treat or improve these disorders, but is not enough to cause or is enough to reduce with satiety factors agonist of the present invention or antagonist and use the amount of relevant side effect.In addition, when satiety factors agonist of the present invention from multiple dose to the patient that use or antagonist, be not that all dosage need identical.For example, can improve prevention or the therapeutic effect of dosage that is applied to the patient, perhaps also can reduce dosage to reduce one or more side effect that particular patient runs into to improve common complex.
In some embodiments, can repeat using of satiety factors agonist of the present invention or antagonist, and these are used and can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months.In other embodiments, can repeat using of this identical prevention or therapeutic agent, and these are used and can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months.
In some embodiments, method and composition can be used as single disposable dosage or long-term dosage is used.Refer to that for a long time method of the present invention or compositions can be more than given individuality be used once.For example, chronic administration can be with once a day, the pharmaceutical composition of the multiple dose used to individuality of twice of every day or higher or lower frequency ground, these are that those skilled in the art are conspicuous.If the judgement according to the practitioner is suitable, chronic administration can last for days, several weeks, several months or several years.
In another embodiment, method and composition is an acute administration.Acute finger is taking place in the approaching time period with incident or is using method and composition of the present invention with it simultaneously.For example, acute administration can be single dose or the multi-dose pharmaceutical compositions of using before and after having dinner.In some embodiments, meals are high calorie or high fat diet.Acute administration can also be to crave for food, particularly craving for single dose or the multi-dose pharmaceutical compositions of using before and after the fat food.Near incident take place or with it simultaneously time period can change with this incident, but can be, for example, within having dinner or craving for about 30 minutes of food.In some embodiments, acute administration is to use within an hour in the pact of having dinner or crave for food.In some embodiments, acute administration be have dinner or crave for food after used in about 2 hours, about 6 hours, about 10 hours, about 15 hours or about 24 hours.
In specific implementations, the invention provides the method for prevention, treatment, control or improvement disorder or its one or more symptoms, described method comprises per 3 days 1 time, and preferably per 4 days 1 time, per 5 days 1 time, per 6 days 1 time, per 7 days 1 time, per 8 days 1 time, per 10 days 1 time, per two weeks 1 time, per three weeks 1 time or 1 time every month are to the agonist that has this individuality that needs to use to comprise satiety factors or the compositions of antagonist.
The satiety factors agonist of effective dose as herein described or antagonist will provide the treatment benefit and not cause substantial toxicity.
The agonist of satiety factors or the toxicity of antagonist can the medicine program by standard be measured in cell culture or laboratory animal, for example measure LD 50(causing the dosage of colony's death of 50%) or LD 100(causing the dosage of colony's death of 100%).Dosage rate between toxicity and the therapeutic effect is a therapeutic index.The chemical compound that preferably has high therapeutic index.Can be used for formulating to the nontoxic dosage range of human body use from the data of cell culture assays and zooscopy acquisition.The dosage of chemical compound as herein described is in preferably that to comprise effective dose and toxicity very little or do not have in the scope of toxic circulation composition.Dosage can change in this scope according to the dosage form that adopts and the route of administration of use.Definite dosage form, route of administration and dosage can be selected according to patient's situation by doctor individual.(for example, referring to people such as Fingl, 1996, In:ThePharmacological Basis of Therapeutics, the 9th edition, the 2nd chapter, the 29th page, Elliot M.Ross).
5.4. Be used to select have the test kit of the individuality of satiety factors undesirable level
The present invention also provides and can be used for selecting the individual test kit of accepting to use the treatment that satiety factors agonist of the present invention or antagonist carry out.In some embodiments, test kit of the present invention comprises the reagent that can detect from the satiety factors in the sample of individuality or a plurality of satiety factors.Reagent can be antibody or its functional fragment or derivant (for example, Fab, the F (ab) of specificity in conjunction with one or more satiety factors 2, Fv or sc Fv fragment).In some embodiments, but antibody can be by the geodetic labelling.Reagent can be the part of array, and perhaps reagent can independently and/or individually be packed.Test kit also can comprise at least one interior mark that is used to measure one or more satiety factors quantity.
In some embodiments, test kit can comprise the agonist or the antagonist of one or more satiety factors that one or more reagent that can detect one or more satiety factors and quantity and form are suitable for application to the individuality of these needs.Useful reagent and useful agonist and antagonist are described at chapters and sections above.
Test kit of the present invention also can comprise the reagent such as the buffer that can be used to obtain from individuality sample.Guarantee prevention by comprising various antibiotic and antifungal (for example, hydroxy benzoic acid, methaform, phenol, ascorbic acid etc.) to microbial action.Also may wish to comprise isotonic agent, for example sugar, sodium chloride etc.
In some embodiments, test kit further comprises labelling or the sign that has the explanation of implementing method of the present invention.For example, labelling or sign can provide normal satiety factors value.In addition, labelling or sign can provide quoting as proof or linking the source of these reference quantities.In some embodiments, at least one positive control and at least one negative control have been comprised in the test kit.
The embodiment that below provides is used to set forth the present invention, not the scope that should be construed as limiting the invention by any way.
6. embodiment
6.1. Embodiment 1: with satiety factors agonist or antagonist for treating obesity
6.1.1 Measure the amount of satiety factors in the blood sample
Blood collection has been advanced to apply the pipe of heparin from individuality, contained the aprotinin of 5000 kallikrein-Inhibitor-Einbeits in this pipe.By centrifugal separated plasma immediately under 4 ℃, and be stored under-70 ℃ until analyzing.
Obtain from available source or by well known to a person skilled in the art that standard technique generates the antibody at satiety factors.Antibody can be polyclone or monoclonal antibody.
The blood plasma level of satiety factors can adopt radiolabeled antibody to measure by immunoassay or adopt standard technique known in the art to measure by ELISA.
6.1.2 Comprise the agonist of satiety factors or the pharmaceutical composition of antagonist
Comprising the satiety factors agonist of effective dose or the pharmaceutical composition of antagonist and one or more pharmaceutically acceptable carriers or excipient can prepare by standard method known in the art.Pharmaceutical composition is forms such as solution, suspending agent, Emulsion, tablet, pill, capsule, powder, slow release formulation.
6.1.3 With satiety factors agonist or antagonist for treating obesity
The above-mentioned pharmaceutical composition that comprises satiety factors agonist or antagonist can be used for the individual treatment obesity of these needs is arranged.Amount and normal satiety factors value based on satiety factors in the sample of individuality are selected individuality.In this embodiment, normal satiety factors value is set up on a plurality of contrast individual primaries.
From contrasting the individual normal satiety factors value of determining
According to those skilled in the art's judgement, to the age be 18-60 year, have 20kg/m 2To 25kg/m 2The male of BMI carry out physical examination, electrocardiogram, chemical group test, blood count or urine examination fully.On the basis of these detections and medical history, select ten healthy males to determine their normal satiety factors value with normal BMI.The individuality of routine administration has been got rid of in this research.
These individual overnight fastings and permission are drunk water but not drinkable calorie of beverage.Early provided conventional meals on 1st to these individualities.After meals provide one hour, gather the blood sample of 5ml.Prepare as mentioned above and handle each blood sample.Determine the satiety factors quantity of each blood sample by immunoassay.
The normal satiety factors value of fasting individuality is calculated as from the meansigma methods of the satiety factors amount of these individual samples that obtain.
Select to carry out the individuality of Bariatric with satiety factors agonist or antagonist
(BMI is by 30kg/m to 10 obesities of age in 18-60 year 2To 40kg/m 2) but in addition all healthy male screen to carry out satiety factors agonist or antagonist for treating.Individual described at contrast as mentioned, determine these individual health status by physical examination and chemical group test etc.
These obese individuals are by fasting and feed, and sample of blood, drawn as mentioned above.Determine amount, and itself and above definite normal satiety factors value are compared from the satiety factors of each blood sample.
If, select this individuality to carry out intestinal peptide agonists or antagonist for treating from the intestinal peptide amount of individual blood sample 50% o'clock less than above definite normal bowel peptide value.Preparation comprises the pharmaceutical composition of satiety factors agonist or antagonist as mentioned above, and passes through intravenous or Orally administered to selected individuality around continuing when every day, breakfast, lunch and dinner began.
Carry out the safety that electrocardiogram, the test of chemical group, complete blood count or urine examination are used with monitoring.Monitor food intake, energy absorption or consumption, appetite, sensation of fullness, body weight, BMI, body fat percentage ratio and metabolism (for example SMR, resting metabolic rate, fat oxidation and fatty balance) etc. by the practitioner, to determine this effectiveness of using and safety.
Embodiment 2: fat with the enterostatin treatment
6.2.1 Measure the amount of enterostatin in the blood sample
Enterostatin amount in the blood sample is measured by ELISA.Adopt the ELISA of anti--APGPR antibody can be with reference to people such as Imamura, 1998, Peptides, 19:8,1385-1391; People such as Bowyer, 1991, carry out described in the Clinica.Chimica.Acta.200:137-152 (it is incorporated herein by reference in full).
The collection of blood sample
Gather the 5ml blood sample, existing side by side is about to it and mixes with the 20mM zinc acetate, at room temperature condenses then 30 minutes.Then with sample centrifugal 20 minutes with 3000g.With isolating serum and isopyknic 50mM TRIS/HCl, 0.05% (w/v) casein, 3.1mM NaN of containing 3, 10mM ethylenediaminetetraacetic acid (EDTA) and 0.05% (w/v) Tween 20 pH be the ELISA immunoassay buffering liquid-phase mixing of 7.2-7.4.Sample in bathing, was suspended 10 minutes in boiling, then with 10, and centrifugal 5 minutes of 000g, and measure until carrying out enterostatin at-70 ℃ of following stored frozen supernatant.
Subsequently can be at room temperature the five equilibrium serum that stores thawed thoroughly to mix be incorporated in 10, under the 000g centrifugal five minutes.In order to extract enterostatin, supernatant is pressed volume ratio and the methanol mixed of 1:9.Mixture is stored 30-60 minute on ice, then under 4 ℃ with 11, centrifugal 10 minutes of 000g.With clarifying supernatant lyophilizing, and be suspended in the ELISA buffer and measure, or be suspended in TBS (50mM Tris.HCl, 150nM NaCl, 3.1mM NaN 3, be used for chromatography in pH7.4).In order to suppress the proteolytic degradation of enterostatin in mensuration, can add two kinds of albumen enzyme inhibitors (final concentration, 1mmol/L diprotein A and 0.1mmol/L captopril) at ELISA forward direction serum sample.
Enzyme-linked immunosorbent assay (ELISA)
Can utilize at the antibody of APGPR and well known to a person skilled in the art that standard technique generates.Antibody can be polyclone or monoclonal antibody.
The preparation of envelope antigen: (the 1ml PBS of pH7.2 USA) slowly dropwise is added among the 2ml PGS that contains 10g/l albumin rabbit serum (RSA) suberate (BS) for Pierce, Illinois, and at room temperature stirs 2 hours will to contain 5mg two (sulfo group amber uncle acid imides).On 2-20cm Sephadex G-50 post, in PBS, remove excessive BS by gel filtration.Collect in 280nm and absorb the protein peak that monitors down.It 4 ℃ of following overnight incubation, is changed dialysis buffer liquid twice.Employing Lowry method (for example, referring to people such as Markwell, 1978, Anal.Biochem.87:206-210) measuring protein content is 730 μ g/ml.It is diluted to 0.5mg/ml, and adds 3.1mmol/l NaN 3When storing until needs down for-20 ℃.
Competitive ELISA: by using the 100 μ l that contain 0.2 μ g/ml RSA-BS-CCG-APGPR and 0.8 μ g/mlRSA, the 15mmol/l Na of pH9.6 2CO 3, 35mmol/l NaHCO 3, 3.1mmol/lNaN 3Solution wraps by the micropore of PVC microtitration plate 4 ℃ of following overnight incubation.Hatching all after this at room temperature carried out on agitator.Then with plate washing three times, then with lavation buffer solution sealing (20mmol/l Tris/HCl, 75mmol/l NaCl, 3.1mmol/l NaN 3, 0.05% (w/v) Tween 20, pH7.2-7.4).Then with 100 μ l the unknowns or the synthetic APGPR peptide of standard (available from AmericanPeptide Company) solution and 50 μ l contain ELISA buffer (the 50mM TRIS/HCl of 1:2000 mouse anti-APGPR monoclonal antibody, 0.05% (w/v) casein, 3.1mM NaN 3, 10mM ethylenediaminetetraacetic acid (EDTA) and 0.05% (w/v) Tween 20 pH7.2-7.4) are hatched one hour in micropore.Between hatching, wash dull and stereotyped three times with lavation buffer solution at every turn.At first, the ELISA buffer that 100 μ l is contained 1:1000 goat anti-mouse IgG biotin conjugates was hatched in each micropore 30 minutes, and the lavation buffer solution that then 100 μ l is contained 1:500 extravidin alkaline phosphatase lipase solution was hatched in each micropore 30 minutes.The substrate buffer solution (10% (w/v) diethanolamine/HCl, the 0.49mmol/l MgCl that at last 100 μ l are contained 1mg/ml p-nitrophenyl phosphate ester 2, 3.1mmol/l NaN 3, pH9.8) in each micropore, hatch until the minimum sandards peptide concentration and when Anthos 2001 reads on the plate device to measure, reach 1.5 in the 405nm absorption maximum.Add 3mmol/l NaOH (50 μ l) cessation reaction.Read flat board then under 405nm, the drawing standard curve is to proofread and correct reading then.
It can be x axle (logarithmic scale) by the concentration with competitive synthetic antigen (APGPR) that standard under given conditions suppresses curve, obtains to be absorbed as y axle (lineal scale) drafting.Can obtain from this standard antigen-inhibition curve interpolation from the antigen in the sample of individuality (APGPR) concentration.
Chromatography analysis
In order to determine the immunoreactive size of serum APGPR, can adopt Sephadex G-25 (50 * 1.0m; 9.3ml; The segmentation limit of globulin, 1-5kDa) post carries out gel filtration chromatography.With serum reprovision in the distilled water of minimum volume of freeze dried methanol extraction, last sample is extremely with buffer A (10mmol/lNH 4HCO 3) equilibrated post.Use 10mmol/l NH 4HCO 3With segmental this post of flow velocity eluting of about 5 minutes/1ml.
6.2.2 The peroral dosage form of enterostatin
Prepare the peroral dosage form that comprises enterostatin or comprised the common complex of enterostatin.
Enterostatin is produced according to Good Manufacturing Practice and Quality Control of Drug (cGMP) by U.S. peptide company (American Peptide Company).The enterostatin purity that the HPLC analysis obtains is greater than 95%.
Enterostatin complex altogether can be prepared with reference to U.S. Provisional Application 60/750,208 (its content is incorporated by reference in this text and examines).For example, by the mixed in molar ratio with 1:1 in solvent obtains enterostatin complex altogether with cocrystallization object (guest) and enterostatin.Evaporating solvent, and the solid of collection gained is total to complex.This solvent can be a methanol, and this salt is enterostatin acetate, and this object is 1-hydroxyl-2-naphthoic acid.The solid of gained is the laminar or cullet shape of light brown.
The peroral dosage form of enterostatin can comprise 2.5,4,5,7.5,10,15,20,30,40,50,60 or the enterostatin of 70mg.They can comprise excipient or non-hygroscopic additive.The excipient that is suitable for can be starch, sugar and microcrystalline Cellulose etc.The non-hygroscopic additive that is suitable for can be calcium phosphate dibasic anhydrous, calcium sulfate, cellulose powder, dextrose and lactose etc.The peroral dosage form of enterostatin can be tablet or capsule.
The exemplary capsule that comprises chalone can comprise have 2.5% enterostatin (% weight), 42%CremphorEL, 20% Polyethylene Glycol-8-glycerol sad/filler of certain herbaceous plants with big flowers acid fat (Labrasol) and 30% labrafil M2125CS, and shell with 54% gelatin, 18% glycerol, 22% anidrisorb 35/70 and 6% water.
6.2.3 Fat with the enterostatin treatment
The peroral dosage form of above-mentioned enterostatin can be used for the individual treatment obesity of these needs is arranged.Amount and normal bowel chalone value according to enterostatin in the sample of individuality are selected individual.In this embodiment, normal bowel chalone value obtains on a plurality of contrast individual primaries.
Select the patient to accept the Bariatric that uses enterostatin to carry out
From contrasting a body measurement normal bowel chalone value
According to those skilled in the art's judgement, to the age be 18-60 year, have 20kg/m 2To 25kg/m 2The male of BMI carry out physical examination, electrocardiogram, the test of chemical group, blood count and urine examination fully.On the basis of these detections and medical history, select ten healthy males to determine normal bowel chalone value with normal BMI.The individuality at routine administration is just got rid of in this research.
These individual overnight fastings, and allow drinking-water, but not drinkable calorie of beverage.Morning on the secondth, provide high fat diet to these individualities.High fat diet comprises about 800 calories and comprise 45% fat.Provide after these meals three hours, gather the 5ml blood sample from individuality by inlying catheter.Prepare as mentioned above and handle each blood sample.Determine the enterostatin amount of each blood sample as mentioned above.
The normal bowel chalone value of fasting individuality is calculated as from the meansigma methods of the enterostatin amount of these individual samples that obtain.
The individuality of Bariatric is carried out in selection with enterostatin
(BMI is by 30kg/m to 10 obesities of age in 18-60 year 2To 40kg/m 2Thereby) but in addition all healthy male screen and accept the enterostatin treatment.As above individual described, determine these individual health status by physical examination and chemical group test etc. at contrast.
These obese individuals are by fasting and feed, and take blood sample as mentioned above.Use the definite enterostatin amount of above-mentioned ELISA, and itself and above definite normal bowel chalone value are compared from each blood sample.
If, then select this body and function enterostatin to treat from the enterostatin amount of the blood sample of individuality half less than above-mentioned definite normal bowel chalone value.Orally administered capsule that comprises the 20.0mg enterostatin such as method for preparing.Around continuing the enterostatin capsule was applied to selected individuality when every day, breakfast, lunch and dinner began.
Carry out electrocardiogram, the test of chemical group, complete blood count or urine examination to monitor the safety that oral enterostatin is used.Monitor food intake, energy absorption or consumption, appetite, sensation of fullness, body weight, BMI, body fat percentage ratio and metabolism (for example SMR, resting metabolic rate, fat oxidation and fatty balance) etc. by the practitioner, with effectiveness and the safety of determining that oral enterostatin is used.
6.3. embodiment 3: use peptide YY 3-36 (PYY 3-36 ) the treatment obesity
6.3.1 Measure peptide YY in the blood sample 3-36 Amount
PYY 3-36Blood plasma level adopt radiolabeled antibody to measure by immunoassay.Can be as people such as Batterham, 2003, New Eng.J.Med.349 (10): 941-8 (it is incorporated herein by reference in full) is described adopt radiolabeled anti--immunoassay of PYY antibody.
From individuality blood collection is put into the pipe that has applied heparin, comprise the aprotinin of 5000 kallikrein-Inhibitor-Einbeits in this pipe.By 4 ℃ of following centrifugal separated plasmas immediately, and it is stored under-70 ℃ until analyzing.
Can utilize at the antibody of PYY and well known to a person skilled in the art that standard technique generates.Antibody can be polyclone or monoclonal antibody.Antibody at PYY can generate at the synthetic pig PYY by glutaraldehyde and bovine serum albumin coupling in the rabbit body, and finally through 1:50,000 dilution is used.Antibody can detect PYY and PYY simultaneously 3-36I 125The PYY antibody of-labelling can prepare by the iodogen method, and by the high pressure liquid chromatography purification.All blood sample counterpoises are rechecked and are surveyed, and analyze the blood plasma that 200 μ l do not extract.This is determined in the 0.06M phosphate buffer (pH7.3) that 700 μ l contain 0.3% bovine serum albumin and carries out.With the no PYY blood plasma of 200 μ l with comparing.By before the goat anti-rabbit antibody separated free and labelling antibodies, sample was hatched under 4 ℃ three days.This mensuration can detect the variation of 2pmol/1PYY in the sample.
6.3.2 Comprise PYY 3-36 Pharmaceutical composition
PYY 3-36Produce according to Good Manufacturing Practice and Quality Control of Drug (cGMP) by Phoenix Pharmaceuticals company.Record PYY by the HPLC analysis 3-36Purity greater than 95%.Can comprise PYY with reference to the description preparation and the preparation of U.S. Patent application 20050009748 3-36Pharmaceutical composition.
6.3.3 Use PYY 3-36 Treatment is fat
Comprise above-mentioned PYY 3-36Pharmaceutical composition can be used for the individual treatment obesity of these needs is arranged.Amount and normal PYY value according to PYY in the individual specimen are selected individual.In this embodiment, normal PYY value obtains on a plurality of contrast individual primaries.
From contrasting the individual normal PYY value of determining
According to those skilled in the art's judgement, to the age be 18-60 year, have 20kg/m 2To 25kg/m 2The male of BMI carry out physical examination, electrocardiogram, the test of chemical group, blood count and urine examination fully.On the basis of these detections and medical history, select ten healthy males to determine normal PYY value with normal BMI.The individuality at routine administration is just got rid of in this research.
These individual overnight fastings, and allow drinking-water, but not drinkable calorie of beverage.Morning on the secondth, provide conventional meals to these individualities.After meals provide one hour, gather the blood sample of 5ml.Prepare as mentioned above and handle each blood sample.Determine the PYY amount of each blood sample as mentioned above.
The normal PYY value of fasting individuality is calculated as from the meansigma methods of the PYY amount of these individual samples that obtain.
The individuality of Bariatric is carried out in selection with PYY
(BMI is by 30kg/m to 10 obesities of age in 18-60 year 2To 40kg/m 2Thereby) but in addition all healthy male screen and use PYY 3-36Treatment.As above individual described, determine these individual health status by physical examination and chemical group test etc. at contrast.
These obese individuals are by fasting and feed, and sample of blood, drawn as mentioned above.Adopt above-mentioned method to measure PYY amount, and the normal PYY value of itself and above mensuration is compared from each blood sample.
If PYY from the individual blood sample 3-36Amount is less than above definite normal PYY 3-3670% of value then selects this individuality to use PYY 3-36Treatment.Preparation comprises PYY as mentioned above 3-36Pharmaceutical composition, and when every day, breakfast, lunch and dinner began, be applied to selected individuality around continuing by oral.Carry out electrocardiogram, the test of chemical group, complete blood count or urine examination to monitor oral PYY 3-36The safety of using.Monitor food intake, energy absorption or consumption, appetite, sensation of fullness, body weight, BMI, body fat percentage ratio and metabolism (for example SMR, resting metabolic rate, fat oxidation and fatty balance) etc. by the practitioner, to determine this oral PYY 3-36Effectiveness of using and safety.
All publications and the patent application of being quoted in this description are all quoted as a reference, and it is quoted degree and is specific independent quoting as a reference as each independent publication and patent application.Although for the clear purpose of understanding, by explaination and embodiment the present invention is described in detail, those of ordinary skill in the art should understand easily and can carry out certain change and adjustment to it under the situation of the spirit or scope that do not break away from claims according to instruction of the present invention.

Claims (87)

1. treat or prevent the disorder relevant in the individuality or the method for disease with the undesirable level of satiety factors, this method comprises to this individuality administering therapeutic or prevents this disorder or the agonist or the antagonist of the described satiety factors of disease effective dose that wherein said individuality has the undesirable level of described this satiety factors.
2. the method for claim 1, that wherein said disorder or disease are selected from is overweight, fat, metabolism disorder, hypertension, disorder, anorexia and type ii diabetes that lipid is relevant.
3. method as claimed in claim 2, wherein said disorder or disease are overweight.
4. method as claimed in claim 2, wherein said disorder or disease are fat.
5. method as claimed in claim 2, wherein said disorder or disease are type ii diabetes.
6. the method for claim 1, wherein said individuality is the people.
7. method as claimed in claim 6, wherein said individuality has 25kg/m 2Above Body Mass Index (" BMI ").
8. method as claimed in claim 6, wherein said individuality has 30kg/m 2Above Body Mass Index (" BMI ").
9. method as claimed in claim 6, wherein said individuality has 35kg/m 2Above Body Mass Index (" BMI ").
10. method as claimed in claim 6, wherein said individuality has 25kg/m 2Following Body Mass Index (" BMI ").
11. method as claimed in claim 6, wherein said individuality has 22kg/m 2Following Body Mass Index (" BMI ").
12. method as claimed in claim 6, wherein said individuality has 20kg/m 2Following Body Mass Index (" BMI ").
13. the method for claim 1, wherein said satiety factors are peptide.
14. the method for claim 1, wherein said satiety factors is selected from: adiponectin, agouti associated protein (AGRP), dextrin, apolipoprotein A-1 V, beacon, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, enterostatin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), the melanotroph hormone (α-MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide, the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRFP43 (the RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
15. method as claimed in claim 14, wherein said Proglucagon derived peptide are glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon or main Proglucagon fragment.
16. the method for claim 1, wherein said satiety factors are non-intestinal peptide.
17. the method for claim 1, wherein said satiety factors are the intestinal peptide.
18. method as claimed in claim 17, wherein said satiety factors is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
19. the method for claim 1, wherein when the amount from the described satiety factors in the sample of described individuality was lower than normal value, this individuality had the undesirable level of described satiety factors.
20. method as claimed in claim 19, wherein said satiety factors is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
21. method as claimed in claim 19 is wherein to described individual administering therapeutic or prevent this disorder or the agonist of the described satiety factors of disease effective dose.
22. the method for claim 1, wherein when the amount from the described satiety factors in the sample of described individuality was higher than normal value, this individuality had the undesirable level of described satiety factors.
23. method as claimed in claim 22 is wherein to described individual administering therapeutic or prevent this disorder or the antagonist of the described satiety factors of disease effective dose.
24. the method for claim 1, wherein said use in oral, intranasal, the lung, intravenous, subcutaneous, transdermal, gastric, intraperitoneal, Intraventricular or rectal administration.
25. the method for claim 1, the described agonist or the antagonist of wherein said satiety factors are being used before the meal.
26. the method for claim 1, the described agonist of wherein said satiety factors or antagonist at table between before and after use.
27. the method for claim 1, the described agonist of wherein said satiety factors or antagonist are by continuous administration.
28. the method for claim 1 is wherein used the agonist or the antagonist of intestinal peptide satiety factors with the agonist or the antagonist of non-intestinal peptide satiety factors.
29. select the method for the individuality for the treatment of with satiety factors agonist or antagonist, this method comprises the step of determining from the amount of the described satiety factors in this individual sample, wherein when the amount of satiety factors described in this individual sample is higher or lower than normal value, select this individuality to treat.
30. method as claimed in claim 29, wherein said individuality are the people.
31. method as claimed in claim 29, wherein said sample are selected from blood sample, plasma sample, saliva sample, serum sample, sputum sample basis, urine specimen, cell sample, cell extraction thing sample and tissue slice sample.
32. method as claimed in claim 29 wherein can be passed through spectrographic method, chromatography, immunoassay or electrophoresis method from the amount of the described satiety factors in the sample of described individuality and determine.
33. method as claimed in claim 29, the amount of wherein said satiety factors is determined during by fasting at described individuality.
34. method as claimed in claim 29, the amount of wherein said satiety factors is determined when described individuality is taken food.
35. method as claimed in claim 29, wherein said satiety factors are peptide.
36. method as claimed in claim 29, wherein said satiety factors is selected from: adiponectin, agouti associated protein (AGRP), dextrin, apolipoprotein A-1 V, beacon, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, enterostatin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), α melanotroph hormone (MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide, the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRFP43 (the RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
37. method as claimed in claim 36, wherein said Proglucagon derived peptide are glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon or main Proglucagon fragment.
38. method as claimed in claim 29, wherein said satiety factors are non-intestinal peptide.
39. method as claimed in claim 29, wherein said satiety factors are the intestinal peptide.
40. method as claimed in claim 39, wherein said satiety factors is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
41. method as claimed in claim 29, wherein when the amount of the described satiety factors in the sample of described individuality was lower than normal value, this individuality is selected treated.
42. method as claimed in claim 41, wherein said satiety factors is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
43. method as claimed in claim 29, wherein when the amount of the described satiety factors in the sample of described individuality was higher than normal value, this individuality is selected treated.
44. treat or prevent the disorder relevant with the undesirable level of satiety factors in the individuality or the method for disease, this method comprises that (a) selects the individuality with bad satiety factors level for the treatment of; (b) to this individuality administering therapeutic or prevent this disorder or the agonist or the antagonist of the described satiety factors of disease effective dose.
45. that method as claimed in claim 44, wherein said disorder or disease are selected from is overweight, fat, metabolism disorder, hypertension, disorder, anorexia and type ii diabetes that lipid is relevant.
46. method as claimed in claim 45, wherein said disorder or disease are overweight.
47. method as claimed in claim 45, wherein said disorder or disease are fat.
48. method as claimed in claim 45, wherein said disorder or disease are type ii diabetes.
49. method as claimed in claim 44, wherein said individuality are the people.
50. method as claimed in claim 49, wherein said individuality has 25kg/m 2Above Body Mass Index.
51. method as claimed in claim 49, wherein said individuality has 30kg/m 2Above Body Mass Index.
52. method as claimed in claim 49, wherein said individuality has 35kg/m 2Above Body Mass Index.
53. method as claimed in claim 49, wherein said individuality has 25kg/m 2Following Body Mass Index.
54. method as claimed in claim 49, wherein said individuality has 22kg/m 2Following Body Mass Index.
55. method as claimed in claim 49, wherein said individuality has 20kg/m 2Following Body Mass Index.
56. method as claimed in claim 49, wherein said satiety factors are peptide.
57. method as claimed in claim 56, wherein said satiety factors is selected from: adiponectin, agouti associated protein (AGRP), dextrin, apolipoprotein A-1 V, beacon, Magainin or bombesin-like peptide, brain source property neural factor (BDNF), calcitonin-gene-related peptide (CGRP), β cheese deltorphin delta, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), ***e and amphetamine are regulated transcription product (CART), corticotropin releasing hormone (CRH), cyclo-his-pro, dynorphin, beta-endorphin, enterostatin, galanin, galanin sample peptide (GALP), ghrelin, growth hormone releasing hormone (GHRH), appetite peptide/orexin, insulin, quasi-insulin growthing factor I and II (IGF-I and IGF-II), leptin, melanin concentration hormone (MCH), the melanotroph hormone (α-MSH), motilin, nesfatin, neuromedin B and neuromedin U, neuropeptide B (NPB) and (NPW), neuropeptide K (NPK), neuropeptide tyrosine (NPY), neurotensin (NT), fat inhibin, oxytocin, the pancreas peptide, peptide YY, the Proglucagon derived peptide, the lactotropin release peptide, proopiomelanocortin (POMC), protoporphyrin, QRPP43 (the RF amidated peptide, 26Rfa), Somat, throtropin releasing hormone (TRH), Urocortin and vassopressin.
58. method as claimed in claim 57, wherein said Proglucagon derived peptide are glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, enteroglucagon, the relevant pancreas peptide of enteroglucagon or main Proglucagon fragment.
59. method as claimed in claim 56, wherein said satiety factors are non-intestinal peptide.
60. method as claimed in claim 56, wherein said satiety factors are the intestinal peptide.
61. method as claimed in claim 60, wherein said satiety factors is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
62. method as claimed in claim 44, wherein said method further comprise the amount of determining from the described satiety factors in the sample of described individuality.
63. method as claimed in claim 44, wherein said sample are selected from blood sample, plasma sample, saliva sample, serum sample, sputum sample basis, urine specimen, cell sample, cell extraction thing sample and tissue slice sample.
64. method as claimed in claim 44 wherein can be passed through spectrographic method, chromatography, immunoassay or electrophoresis method from the amount of satiety factors described in the sample of described individuality and determine.
65. method as claimed in claim 44, the amount of wherein said satiety factors is determined during by fasting at described individuality.
66. method as claimed in claim 44, the quantity of wherein said satiety factors is measured when described individuality is taken food.
67. method as claimed in claim 44, wherein when the amount of satiety factors described in the sample of described individuality was lower than normal value, this individuality is selected treated.
68. as the described method of claim 67, wherein said satiety factors is selected from: dextrin, Magainin or bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
69. as the described method of claim 67, administering therapeutic or prevent this disorder or the agonist of the described satiety factors of disease effective dose wherein.
70. method as claimed in claim 44, wherein when the amount of the described satiety factors in the sample of described individuality was higher than normal value, this individuality is selected treated.
71. method as claimed in claim 44 is wherein used the agonist or the antagonist of intestinal peptide satiety factors with the agonist or the antagonist of non-intestinal peptide satiety factors.
72. reduce the method for individual food intake, this method comprises that (a) selects to have the individuality of satiety factors undesirable level; And agonist or the antagonist of (b) using the described satiety factors that reduces the food intake effective dose to this individuality.
73. as the described method of claim 72, wherein said food comprises fat.
74. as the described method of claim 72, wherein said food is fat.
75. as the described method of claim 72, wherein said food comprises carbohydrate.
76. as the described method of claim 72, wherein said food is carbohydrate.
77. as the described method of claim 72, wherein said food comprises albumen.
78. as the described method of claim 72, wherein said food is albumen.
79. select the method for the individuality for the treatment of with one or more satiety factors agonist or antagonist, this method comprises the step of determining from the amount of the satiety factors in this individual sample, wherein when the amount of one or more satiety factors in this individual sample is higher or lower than normal value independently, select this individuality to treat.
80., wherein determine amount from one group of satiety factors in the sample of described individuality as the described method of claim 79.
81. as the described method of claim 80, wherein said group has comprised from following two kinds, three kinds, four kinds, five kinds, six kinds, seven kinds, eight kinds, nine kinds or ten kinds of satiety factors: dextrin, Magainin and bombesin-like peptide, cholecystokinin, enterostatin, ghrelin, glucagon-like peptide 1, fat inhibin, oxyntomodulin, pancreatic polypeptide and peptide YY.
82. as the described method of claim 79, this method further comprises one or more agonist from the satiety factors with the normal value of being higher or lower than to described individuality or the antagonist of using.
83., wherein use multiple agonist or antagonist to described individuality as the described method of claim 82.
84., wherein the agonist or the antagonist of intestinal peptide are used with the agonist or the antagonist of non-intestinal peptide as the described method of claim 82.
85. the individual fat method of treatment, this method comprises that (a) selects to have the individuality of satiety factors undesirable level; And (b) to the agonist or the antagonist of the described satiety factors of the fat effective dose of this individuality administering therapeutic.
86. be used to select to carry out with satiety factors agonist or antagonist the test kit of the individuality of Bariatric, it comprises and can obtain the equipment of body fluid and the reagent that can detect described satiety factors this body fluid from this individuality.
87. be used for the treatment of or prevent individual fat test kit, it comprises the agonist or the antagonist of this satiety factors of the reagent that can detect the satiety factors in this individuality body fluid and effective dose.
CNA2007800327134A 2006-07-11 2007-07-10 Methods of treating obesity using satiety factors Pending CN101511381A (en)

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