English:
[0001] This application claims benefit of International Patent Application No. PCT/US2006/012601, filed March 31, 2006, the entire contents of which is incorporated herein for all purposes.
[0002] This disclosure is in the medical field and in particular to the fields of psychology and psychiatry, as well as health, diet and nutrition.
[0003] Psychiatric diseases and disorders (also referred to as mental illnesses or disorders) are described in resources such as the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, or DSM-W. Broad categories of mental disorders include, but are not limited to, mood disorders, anxiety disorders, schizophrenia and other psychotic disorders, substance-related disorders, sleep disorders, somatoform disorders, and eating disorders. Examples of mood disorders include bipolar and depression. Other conditions falling within the broader category of disorders described above can be found in the DSM-IV, which is incorporated by reference in its entirety. These are debilitating illnesses that affect millions of people and involve astronomical costs, in terms of treatment, lost productivity, and emotional toll.
[0004] In 2001, the National Institute of Mental Health published a summary of statistics describing the prevalence of mental disorders in America. In the report, it estimated that 22.1% of Americans ages 18 and older suffer from a diagnosable mental disorder in a given year (Reiger et al. (1993) Archives of General Psychiatry 50:85-94). When applied to the 1998 U.S. Census, the number of people affected was 44.3 million.
[0005] Depressive disorders can encompass, among others illnesses, major depressive disorder, dysthymic disorder and bipolar disorder. About 9 to 9.5 percent of the U.S. population ages 18 and older have a depressive condition. It has been reported that the direct _ ^ Λ cost olMprls-iivk di'slilfes is aϋoύt $80 billion, with two-thirds of it being borne by businesses. The indirect costs associated with depressive disorders, such as lost productivity, are harder to calculate because of events such as "presenteeism," described as people at work but limited in their ability to produce or participate (Durso, Employee Benefit News, Dec 2004).
[0007] Another common psychiatric condition is eating disorders. There are three main types, anorexia nervosa, bulimia nervosa, and binge-eating disorders. These are psychiatric conditions are often linked to perceived notions about body image and are usually independent of actual body weight or body mass index. The mortality of people with anorexia has been estimated at 0.56 percent per year, or approximately 5.6 percent per decade, which is about 12 times higher than the annual death rate due to all causes of death among females ages 15-24 in the general population (Sullivan (1995) American Journal of Psychiatry 152:1073-1074). It should be noted that psychiatric illnesses usually present with elements of other psychiatric disorders.
[0010] Psychiatric diseases and disorders can be found in any age group. Accordingly, these disorders can be found in young adults and adults (defined herein as those aged 65 or under) as well as infants, children, adolescents, and the elderly (defined herein as over the age of 65). In fact, certain segments of the population may be particularly prone to having a condition, such as eating disorders in adolescents and young adults. The elderly may be particularly susceptible to conditions such as depression.
[0026] Figs. 7A and 7B are graphs depicting effects of clozapine on weight. The graph in Fig. 7A depicts the effect of clozapine alone on weight and the graph in Fig. 7B depicts the effect of the combination of clozapine and amylin on weight.
[0029] In exploring new medical treatments, it was noted that a number of metabolic pathologies (e.g., diabetes, obesity) are associated with behavioral dysfunction (e.g., major depression, schizophrenia). Although these diseases are generally believed to be co-morbid, there is recent evidence suggesting that the behavioral and metabolic alterations are physiologically linked in many cases (Laugero et al. (2001) Endocrinology 142:2796-2804; Laugero et al. (2002) Endocrinology 143:4552-4562; Dallman et al. (2003) Proc. Natl. Acad. ScL USA 100:11696-11701; Laugero (2004) Vitamins and Hormones, Volume 68, Litwack (ed.)). A common link between these seemingly disparate disease states may be chronic stress and the associated changes in brain CRF and the adrenocortical steroid hormones, GC.
[0030] The CRF and GC molecules play a critical role in modulating behavioral, neuroendocrine, autonomic, and metabolic function under normal and stressful conditions. Chronic stress and the induction of expression and activity of these molecules are highly associated with behavioral diseases like anxiety and depression, and also with some obesities and diabetes. There is evidence that links CRF and adrenocortical abnormalities to the metabolic syndrome, autoimmune inflammatory disorders, acute and chronic neurodegeneration, sleep disorders, chronic pain, eating disorders, chronic anxiety disorder, and major depression (Wong et al. (2000) Proc. Natl. Acad. Sci. USA 97:325-330; Sarnyai et al. (2001) Pharmacol. Rev. 53:209-243; Heinrichs et al. (1999) Baillieres Best Pract. Res. Clin. Endocrinol. Metab. 13:541-554; Chrousos (2000) Int. J. Obes. Relat. Metab. Disord. 24:S50-S55; Peek et al. (1995) Ann. N.Y. Acad. ScL 771:665-676; Grammatopoulos et al. (1999) Lancet 354:1546-1549; Dallman et al (2003) Proc. Natl. Acad. ScL USA 100:11696-11701).
[0032] More particular types of the above named disorders can be found in the DSM-IV. The following are only examples of disorders that may be treated by the methods disclosed herein. Examples include mood disorders that may include depressive disorders and bipolar disorders. They can further be characterized as major depressive disorders, dysthymic disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder not otherwise specified, mood disorders due to a medical condition, substance-induced mood disorder, or mood disorder not otherwise specified. Anxiety disorders can include panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a medical condition, substance induced anxiety disorder and anxiety disorder not otherwise specified.
[0038] In some embodiments, methods provided can be used to treat subjects experiencing intermittent excessive behaviors (IEB). EEB characterize a variety of disorders including, binge eating, substance abuse, alcoholism, aberrant sexual conduct, and compulsive gambling. IEB occur when occasional normal behavioral excess is transformed into repetitive, intermittent, maladaptive behavioral excess. Corwin (2006) Appetite 46: 11-15.
[0039] In certain embodiments, methods provided may not include the treatment of somatoform disorders. In certain embodiments, methods provided may include somatoform disorders but do not include the treatment of physical pain. In still other embodiments, methods provided may include the treatment of the psychiatric illness associated with pain.
[0047] As used herein, a "subject" may include any mammal, including humans. A "subject" may also include pets (e.g., dogs, cats, horses), as well as other animals. Subjects may have at least one ###0003### 1ISIHI)S- herein. -Subjects who may benefit from the methods disclosed herein may be overweight or obese; however, they may also be lean. They may have a metabolic disorder or condition in addition to a psychiatric disorder. Exemplary metabolic disorders include diabetes, metabolic syndrome, insulin-resistance, and dyslipidemia. Subjects can be of any age. Accordingly, these disorders can be found in young adults and adults (defined herein as those aged 65 or under) as well as infants, children, adolescents, and the elderly (defined herein as over the age of 65). In fact, certain segments of the population may be particularly prone to having a particular condition, such as eating disorders in adolescents and young adults. The elderly may be particularly susceptible to conditions such as depression.
[0048] As used herein, and as well-understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. "Treating" or "palliating" a disease, disorder, or condition means that the extent, undesirable clinical manifestations of a condition, or both, of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder. For purposes of the methods disclosed herein, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disorder, stabilized (i.e., not worsening) state of disorder, delay or slowing of disorder progression, amelioration or palliation of the disorder, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Further, treating does not necessarily occur by administration of one dose, but often occurs upon administration of a series of doses. Thus, a therapeutically effective amount, an amount sufficient to palliate, or an amount sufficient to treat a disease, disorder, or condition may be administered in one or more administrations.
[0051] Stress, GC, and CRF seem to have an intricate and complicated relationship in psychological and metabolic function. Stress has profound effects on neuroendocrine (e.g., hypothalamic-pituitary-adrenal (HPA) axis), autonomic, behavioral (e.g., anxiety, depression, substance abuse, feeding), and metabolic (e.g., fat deposition, energy utilization) function in man and animals (Dallman et al. (2002) Hormones, Brain, and Behavior pp 571-631, San Diego, CA USA: Academic Press.). All of these effects are modulated by GCs. The neuropeptide CRF mediates many of the stress-induced responses, including acute inhibition of food intake and anxiety (Krahn et al. (1986) Brain Research Bulletin 17:285-289; Dunn et al. (1990) Brain Res. Brain Res. Rev. 15:71-100; Smagin et al. (1999) Am. J. Physiol. 276:R1461-1468; Koob (1999) Biol. Psychiatry 46:1167-1180). GC and CRF activity are tightly interdependent and, together, make up a functional and well-described physiological system that controls behavioral, autonomic, neuroendocrine, and metabolic function (Dallman et al. (2003) Proc. Natl. Acad. ScL USA 100:11696-11701).
[0052] Disruptions in the GC and CRF relationship, such as those caused by stress, can have profound effects on health. Through the central actions of chronically elevated glucocorticoid hormones (Cortisol in man, corticosterone in rodents), chronic stress promotes palatable feeding (e.g., simple sugar, fat). When palatable food is available, as it abundantly is in modern societies, chronic stress increases the proportion of palatable calories consumed (Pecoraro et al. (2004) Endocrinology 145:3754-3762; Laugero (2004) Vitamins and Hormones, Volume 68. Ed. Gerald Litwack; Laugero et al. (2002) Endocrinology 143:4552-4562). The significance of this response, under the background of elevated GCs, is increased fat deposition in the abdominal or truncal region (Dallman et al (2003) Proc. Natl. Acad. ScL USA 100:11696-11701), which is a significant and independent risk factor for the development of cardiovascular disease (Bjorntorp (1993) Obesity Research 1:206; Carr et al. (2004) Diabetes 53:2087-2094). In fact, endogenous GC elevation, as in Cushing's patients, or through exogenous administration, as in Lupus patients, cause metabolic syndrome (truncal obesity, insulin resistance, hypertension, hypertriglyceridemia) (Stewart (2003) The Adrenal Cortex, Williams Textbook of Endocrinology, 10th edition, Saunders Publishing, U.S.). Furthermore, truncal obesity is characterized by increased glucocorticoid activity, and it has been hypothesized that, through the activation of adrenocortical synthesis and secretion of GCs, chronic stress plays a significant role in the development of truncal obesity and the metabolic syndrome (Bjorntorp (2001) Obes. Rev. 2:73-86; Rosmond et al. (2000) Obes. Res. S:445M&j&Qt$)§ψ $$miMMMSι:795-803; Dallman et al. (2002) Hormones, Brain, and Behavior pp 571-631, San Diego, CA USA: Academic Press.; Dallman et al. (2003) Proc. Natl Acad. ScL USA 100:11696-11701).
[0053] Hyper- and hypo-cortisolemia are also well-documented features of psychiatric disease, and patients suffering from the metabolic syndrome show signs of abnormal Cortisol secretion and are more likely to present with a psychiatric disease such as major depression. Chronic stress and the associated increase in central CRF activity are believed to play a critical role in the development of clinical depression, anxiety disorders, substance abuse, eating disorders, and metabolic syndrome (Chrousos et al. (2000) Int. J. Obes. Relat. Metab. Disord. 24:S50-S55; Koob (1999) Biol. Psychiatry 46:1167-1180). In fact, small molecule CRF antagonists are currently being investigated for their therapeutic actions in patients with major depression, general anxiety disorder, eating disorders, and other stress related pathologies.
[0063] The C-terminal portion can be amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy, aralkyloxy or carboxyl. Suitable side chains for X and Y include groups derived from alkyl sulfhydryls which may form disulfide bonds; alkyl acids and alkyl amines which may form cyclic lactams; alkyl aldehydes or alkyl halides and alkylamines which may condense and be reduced to form an alkyl amine bridge; or side chains which may be connected to form an alkyl, alkenyl, alkynyl, ether or thioether bond. Preferred alkyl chains include lower alkyl groups having from about 1 to about 6 carbon atoms.
[0064] An additional aspect, compositions and methods of use provided herein are directed to agonist analogues of SEQ ID NO:3 which are not bridged, and wherein X and Y are independently selected from Ala, Ser, Cys, VaI, Leu and lie or alkyl, aryl, or aralkyl esters and ethers of Ser or Cys.
[0069] Amino acid sequences of exemplary AFP-6 analogs for use in the disclosed methods include:
[0073] Alkyl chains may include lower alkyl groups having from about 1 to about 6 carbon atoms. In certain embodiments, the intramolecular linkage may be a disulfide, amide, imine, amine, alkyl or alkene bond. In certain embodiments, X and Y are independently selected from Ser, Asp, GIu, Lys, Orn, or Cys. In certain embodiments, X and Y are Cys and Cys. In other embodiments, X and Y are Ser and Ser. In still other embodiments, X and Y are Asp and Lys or Lys and Asp.
[0077] In a general aspect, the sequence of formula V, VI, VII, or VIII further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more modifications of substitutions, insertions, deletions, elongations and/or derivatizations. In certain embodiments, the sequence of formula V, VI, VII, or VTH comprises a deletion at position 24. In certain embodiments, the sequence of formula V, VI, or VH comprises a VaI inserted between amino acids at positions 22 and 23. In other embodiments, the sequence of formula V, VI, or VDL comprises a GIn inserted between positions 22 and 23. In still other embodiments, the sequence of formula V, VI, or VII comprises a sequence of Gln-Thr-Tyr between positions 22 and 23. In yet other embodiments, the sequence of formula V, VI, or VH comprises a sequence of Leu-Gln-Thr-Tyr (SEQ ID NO: 84) between positions 22 and 23. In another general aspect, the modifications of formula V, VI, or VQ may be at the N-terminal end. In certain embodiments, the N-terminal portion of formula V, VI, or VII has an added octylglycine. In other embodiments, the N-terminal portion of formula V, VI, or VII has an added isocap. Other embodiments are described in PCT Application No. PCT/US2005/004631 and incorporated by reference.
[0095] In a particular embodiment, a pharmaceutical formulation may contain a range of concentrations of the compound, e.g., between about 0.01% to about 98% (w/v), or between about 1 to about 98% (w/v), or between 80% and 90% (w/v), or between about 0.01% to about 50% (w/v), or between about 10% to about 25% (w/v) in this embodiment. A sufficient amount of water for injection may be used to obtain the desired concentration of solution.
[00101] A stabilizer may be included in the present formulation but, and importantly, is not necessarily needed. If included, however, a stabilizer useful in the practice of the present foimuliffiti Is 4 darfebfe'yitafe-iϊ'i' polyhfdric alcohol: A suitable stabilizer useful in the practice of the present methods is approximately 1.0 to 10% (w/v) of a carbohydrate or polyhydric alcohol. The polyhydric alcohols and carbohydrates share the same feature in their backbones, i.e., -CHOH- CHOH-, which is responsible for stabilizing the proteins. The polyhydric alcohols include such compounds as sorbitol, mannitol, glycerol, and polyethylene glycols (PEGs). These compounds are straight-chain molecules. The carbohydrates, such as mannose, ribose, sucrose, fructose, trehalose, maltose, inositol, and lactose, on the other hand, are cyclic molecules that may contain a keto or aldehyde group. These two classes of compounds have been demonstrated to be effective in stabilizing protein against denaturation caused by elevated temperature and by freeze-thaw or freeze-drying processes. In embodiments in which the subjects have diabetes, suitable carbohydrates include: galactose, arabinose, lactose or any other carbohydrate which does not have an adverse affect on a diabetic patient, i.e., the carbohydrate is not metabolized to form unacceptably large concentrations of glucose in the blood. Such carbohydrates are well known in the art as suitable for diabetics. Sucrose and fructose are suitable for use with the compound in non-diabetic subjects.
[00103] The United States Pharmacopeia (USP) states that anti-microbial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple dose containers. They must be present in adequate concentration at the time of use to prevent the multiplication of microorganisms inadvertently introduced into the preparation while withdrawing a portion of the contents with a hypodermic needle and syringe, or using other invasive means for delivery, such as pen injectors. Anti-microbial agents should be evaluated to ensure compatibility with all other components of the formula, and their activity should be evaluated in the total formula to ensure that a particular agent that is effective in one formulation is not ineffective in another. It is not uncommon to find that a particular anti-microbial agent will be effective in one formulation but not effective in another formulation.
[00109] It is possible that other ingredients may be present in the pharmaceutical formulations. Such additional ingredients may include, e.g., wetting agents, emulsifiers, oils, antioxidants, bulking agents, tonicity modifiers, chelating agents, metal ions, oleaginous vehicles, proteins (e.g., human serum albumin, gelatin or proteins) and a zwitterion (e.g., an amino acid such as betaine, taurinl?'lp^iΩ'e!4^n^l^sϊil;lnilisidine). Additionally, polymer solutions, or mixtures with polymers provide the opportunity for controlled release of the peptide. Such additional ingredients, of course, should not adversely affect the overall stability of the pharmaceutical formulation provided herein.
[00110] Containers are also an integral part of the formulation of an injection and may be considered a component, for there is no container that is totally inert, or does not in some way affect the liquid it contains, particularly if the liquid is aqueous. Therefore, the selection of a container for a particular injection must be based on a consideration of the composition of the container, as well as of the solution, and the treatment to which it will be subjected. Adsorption of the peptide to the glass surface of the vial can also be minimized, if necessary, by use of borosilicate glass, for example, Wheaton Type I borosilicate glass #33 (Wheaton Type 1-33) or its equivalent (Wheaton Glass Co.). Other vendors of similar borosilicate glass vials and cartridges acceptable for manufacture include Kimbel Glass Co., West Co., Bunder Glas GMBH and Forma Vitrum. The biological and chemical properties of the compound may be stabilized by formulation and lyophilization in a Wheaton Type 1-33 borosilicate serum vial to a final concentration of 0.1 mg/ml and 10 mg/ml of the compound in the presence of 5% mannitol, and 0.02% Tween 80.
[00112] Each of the components of the pharmaceutical formulation described above is known in the art and is described in Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 1, 2nd ed., Avis et al. Ed., Mercel Dekker, New York, N. Y. 1992, which is incorporated by reference in its entirety herein.
[00115] In one embodiment, the liquid pharmaceutical formulations are intended for parenteral administration. Suitable routes of administration include intramuscular, intravenous, subcutaneous, intradermal, intraarticular, intrathecal and the like. The subcutaneous route of administration is one particular route. Mucosal delivery is also particularly suitable. These mucosal routes include, but are not limited to, oral, nasal, sublingual, pulmonary and buccal routes which may include administration of the peptide in liquid, semi-solid or solid form. Administration via these routes requires substantially more peptide to obtain the desired biological effects due to decreased bioavailability compared to parenteral delivery. In addition, parenteral controlled release delivery can be achieved by forming polymeric microcapsules, matrices, solutions, implants and devices and administering them parenterally or by surgical means. Examples of controlled release formulations are described in U.S. Patent Nos. 6,368,630, 6,379,704, and 5,766,627, which are incorporated herein by reference. These dosage forms may have a lower bioavailability due to entrapment of some of the peptide in the polymer matrix or device. See e.g., U.S. Pat. Nos. 6,379,704, 6,379,703, and 6,296,842.
[00117] However, typical doses may contain from a lower limit of about 1 μg, 5 μg, 10 μg, 50 μg to 100 μg to an upper limit of about 100 μg, 500 μg, 1 mg, 5 mg, 10 mg, 50 mg or 100 mg of the pharmaceutical compound per day. Also contemplated are other dose ranges such as 0.1 μg to 1 mg of the compound per dose. Thus, exemplary doses may be 30, 60, 120, 240, or 360 μg of the compound per dose. The doses per day may be delivered in discrete unit doses or provided continϋfeSslf "iri"I..KUl!3ili'pέiiI#o? apportion of that 24 hour period. The number of doses per day may be from 1 to about 4 doses per day, although it could be more. Continuous delivery can be in the form of continuous infusions. Exemplary doses and infusion rates include from 0.005 nmol/kg to about 20 nmol/kg per discrete dose or from about 0.01/pmol/kg/min to about 10 pmol/kg/min in a continuous infusion. These doses and infusions can be delivered by intravenous administration (i.v.) or subcutaneous administration (s.c). Exemplary total dose/delivery of the pharmaceutical composition given i.v. may be about 2 μg to about 8 mg per day, whereas total dose/delivery of the pharmaceutical composition given s.c may be about 6 μg to about 16 or 24 mg per day.
[00118] The following Examples are provided to illustrate, but not limit, the invention.
[00127] The prepulse inhibition (PPI) test measures the reflex response to externally applied auditory stimulation (acoustic startle response) and is related to the deficiency in sensory-motor gating capacity seen in schizophrenia. The acoustic startle reflex is a very basic response to strong exteroceptive stimuli and is widely used to assess sensorimotor reactivity in animals and humans. A weak auditory stimulus (prepulse, 74 - 82 dB) given prior to the strong acoustic stimulus (120 dB) blunts the startle response. This blunting of the startle response is refered to as prepulse inhibition. See, for example, Conti et al. (2005) Behavioral Neuroscience 119:1052-1060. Antipsychotics increase the ability of the prepulse stimulus to blunt the startle response to the strong stimulus. Some psychotomimetic agents, such as phencyclidine (PCP) and ketamine, can actually reduce the percent prepulse inhibition and stimulate a psychotic-like state in animals, which can be antagonized by antipsychotic agents.

中文:
[0001]本申请要求2006年3月31日提交的国际专利申请PCT/US2006/012601的权益,在此其全部内容被引入,用于所有目的。
[0002]本公开属于医学领域,并且特别涉及心理学和精神病学领域,以及健康、饮食和营养学领域。
[0003]在资料如American Psychiatric Association(美国精神病协会)的Diagnostic and Statistical Manual of Mental Disorders或DSM-IV中描述了精神疾病和病症(也称为精神疾病或病症)。精神疾病的宽泛类别包括但不限于,心境障碍、焦虑症、精神分裂症和其它精神病病症、物质相关疾病、睡眠障碍、躯体病样精神障碍、进食障碍疾患。心境障碍的例子包括双相抑郁和抑郁。落入上述病症的较宽范畴内的其它症状可以在DSM-IV中见到,引入其全部作为参考。这些是影响数百万人的衰弱疾病,并且在治疗、失去生产力和情感服务方面包括巨大花费。
[0004]在2001年,National Institute of Mental Health公布了描述美国精神疾病患病率的统计总结。在该报告中,在给定年度估计有22.1%的18岁和以上的美国人患有可诊断的精神病症(Reiger等,(1993)Archieves of General Psychiatry 50:85094)。当应用到1998年的美国人口普查时,受到影响的人数是4.43千万。
[0005]抑郁症可以包括,严重抑郁症、情绪恶劣性障碍和双相抑郁以及其它抑郁症。美国18岁和以上年龄的人口中有大约9%至9.5%具有抑郁症状。已经报道,抑郁症的直接花费是大约800亿美元,其三分之二由商业承担。与抑郁症有关的非直接花费,如失去生产力,更加难以计算,原因在于诸如“赖工(presenteeism)”这样的情况,其被描述为在工作但是他们生产或参与的能力有限的人(Durso,Employee BenefitNews,Dec 2004)。
[0007]另一个常见的精神病症状是进食障碍病患。有三种主要类型,神经性厌食症、神经性贪食症和暴食症。这些精神病症状经常与关于身体形象的感知观念有关,并且通常不依赖于实际的体重或体重指数。据估计患有厌食症的人的死亡率每年在0.56%,或每十年大约5.6%,其比总人口中年龄在15-24岁的女性由于所有死亡原因的年死亡率高大约12倍(Sullivan(1995)American Journal of Psychiatry 152:1073-1074)。应该指出,精神疾病通常与其它的精神病症的因素一同存在。
[0010]可以在任何年龄组中见到精神疾病和病症。因此,可以在年轻人和成年人(此处被定义为那些65岁或以下的人)以及婴儿、儿童、青少年和老年人(此处被定义为超过65岁的人)中见到这些病症。实际上,人群的某些年龄段可能特别倾向于具有某一病症,如在青少年和年轻人中的饮食障碍病患。老年人可能特别易患诸如抑郁症的病症。
[0026]图7A和7B是描述氯氮平对体重的影响的图。图7A中的图描述单独的氯氮平对体重的影响,图7B中的图描述氯氮平和支链淀粉联合对体重的影响。
[0029]在探索新的医学治疗中,指出:许多代谢病理(如糖尿病、肥胖)与行为功能障碍(如,严重抑郁症、精神分裂症)有关。虽然这些疾病一般被认为是合并症,但是最近有证据表明,在许多情况下行为和代谢改变是生理相关的(Laugero等,(2001)Endocrinology 142:2796-2804;Laugero等,(2002)Endocrinology 143:4552-4562;Dallman等,(2003)Proc.Natl.Acad.Sci.USA 100:11696-11701;Laugero(2004)Vitamins and Hormones,Volume 68,Litwack(编辑))。这些似乎不相干的疾病状态之间的共同联系可以是慢性应激和脑CRF以及肾上腺皮质类固醇激素GC中的相关变化。
[0030]CRF和GC分子在正常和应激状态下调节行为的、神经内分泌的、自主的以及代谢的功能中发挥关键作用。慢性应激和这些分子的表达与活性的诱导与行为疾病如焦虑症和抑郁症高度相关,以及也与一些肥胖和糖尿病高度相关。存在这样的证据,其将CRF和肾上腺皮质异常与代谢综合征、自身免疫性炎症疾病、急性和慢性神经退行性变、睡眠障碍、慢性疼痛、进食障碍疾患、慢性焦虑症和严重抑郁症联系起来(Wong等,(2000)Proc.Natl.Acad. Sci.USA 97:325-330;Sarnyai等,(2001)Pharmacol.Rev.53:209-243;Heinrichs等,(1999)Baillieres Best Pract.Res.Clin.Endocrinol.Metab.13:541-554;Chrousos(2000)Int.J.Obes.Relat.Metab.Disord.24:S50-S55;Peek等,(1995)Ann.N.Y.Acad.Sci.771:665-676;Grammatopoulos等,(1999)Lancet 354:1546-1549;Dallman等,(2003)Proc.Natl.Acad.Sci.USA100:11696-11701)。
[0032]可以在DSM-IV中见到上述病症的更多具体类型。下述仅仅是可以通过本文公开的方法治疗的病症的例子。例子包括可以包含抑郁症和双相精神障碍的心境障碍。它们可以进一步被表征为严重抑郁症、情绪恶劣性障碍、I型双相精神障碍、II型双相精神障碍、循环情感性精神障碍、没有另外具体列出的双相精神障碍、由于医疗条件引起的心境障碍、物质诱导的心境障碍、或没有另外具体列出的心境障碍。焦虑症可以包括急性焦虑症、特定恐怖症、社交恐怖症、强迫性精神障碍、创伤后应激障碍、急性应激障碍、广泛性焦虑症、由于医疗条件引起的焦虑症、物质诱导的焦虑症和没有另外具体列出的焦虑症。
[0038]在一些实施方式中,所提供的方法可以被用于治疗遭受间歇性超常行为(IEB)的对象。IEB表现为各种病症,包括:暴食、物质滥用、酒精中毒、异常性行为和强迫性赌博。IEB在偶尔的正常行为过度转变为反复的、间歇的、不良适应的行为过度时发生。Corwin(2006)Appetite 46:11-15。
[0039]在某些实施方式中,所提供的方法可以不包括治疗躯体病样精神障碍。在某些实施方式中,所提供的方法可以包括躯体病样精神障碍但不包括身体疼痛的治疗。仍在其它实施方式中,所提供的方法可以包括与疼痛有关的精神疾病的治疗。
[0047]如本文所用的,“对象”可以包括任何哺乳动物,包括人。“对象”也可以包括宠物(如狗、猫、马)以及其它动物。对象可以具有本文所述的精神病症的至少一种。从本文所公开的方法受益的对象可以是超重或肥胖的;然而,它们也可以是瘦的。它们可以具有除精神病症以外的代谢紊乱或症状。示例性的代谢紊乱包括糖尿病、代谢综合征、胰岛素抵抗和血脂障碍。对象可以是任何年龄。因此,这些病症可以在年轻人和成年人(此处被定义为65岁或以下的那些)以及婴儿、儿童、青少年和老年人(此处被定义为超过65岁)中发现。实际上,人群中的某些年龄段可能特别倾向于具有特定的症状,如在青少年和年轻人中的进食障碍。老年人可能特别容易患如抑郁症的疾病。
[0048]如本文所用的,并且在本领域是熟知的,“治疗”是获得有益的或期望的结果——包括临床结果的方法。“治疗”或“减轻”疾病、病症或症状表示,与未治疗病症的相比,病症或疾病状态的病况程度、不期望临床表现或二者得以减少,和/或进程的时程得以减缓或延长。为了本文公开的方法的目的,有益的或期望的临床结果包括但不限于,一种或多种症状的缓和或改善、病症程度的降低、病症状态的稳定(即,不恶化)、病症进展的延缓或减缓、病症的改善或减轻以及好转(无论部分或全部),不管是可检测的还是无法检测的。“治疗”也可以表示与如果不接受治疗的预期生存期相比,延长了生存期。此外,治疗不一定通过施用一种剂量发生,而是常常在施用一系列剂量时发生。因此,治疗有效量,足以减轻疾病的量,或足以治疗疾病、病症或症状的量可以在一次或多次给药中被施用。
[0051]应激、GC和CRF在心理和代谢功能中似乎具有错综复杂的关系。应激对人和动物中的神经内分泌(如下丘脑-垂体-肾上腺(HPA)轴)、自主的、行为的(如焦虑、抑郁、物质滥用、进食)以及代谢(如脂肪沉积、能量利用)功能具有显著的作用(Dallman等(2002)Hormones,Brain,and Behavior pp 571-631,San Diego,CA USA:Academic Press)。所有这些作用由GC调节。神经肽CRF介导许多应激诱导的反应,包括食物摄取和焦虑的急性抑制(Krahn等(1986)Brain Research Bulletin17:285-289;Dunn等(1990)Brain Res.Brain Res.Rev.15:71-100;Smagin等(1999)Am.J.Physiol.276:R1461-1468;Koob(1999)Biol.Psychiatry46:1167-1180)。GC和CRF是紧密地相互依赖的,并且共同构成功能性的以及清楚描述的生理系统,该系统控制行为的、自主的、神经内分泌和代谢的功能(Dallman等(2003)Proc.Natl.Acad.Sci.USA100:11696-11701)。
[0052]GC和CRF的关系的破坏,如由应激引起的那些破坏,可以对健康具有显著的影响。通过慢性升高的糖皮质激素(人类中的皮质醇、啮齿动物中的皮质脂酮)的中枢作用,慢性应激促进适口摄食(如单糖、脂肪)。当适口食物可得时,由于其在现代社会中丰富存在,慢性应激增加了所消费适口卡路里的比例(Pecoraro等(2004)Endocrinology145:3754-3762;Laugero(2004)Vitamins and Hormones,Volume 68.Ed.Gerald Litwack;Laugero等(2002)Endocrinology 143:4552-4562)。在升高GC的情况下,这种反应的意义是,在腹部或躯干区域增加了脂肪沉积((Dallman等(2003)Proc.Natl.Acad.Sci.USA 100:11696-11701),其是心血管疾病发展的重要和独立的风险因子(Bjorntorp(1993)ObesityResearch 1:206;Carr等(2004)Diabetes 53:2087-2094)。事实上,内源性GC升高,如在库欣氏病患者中,或通过外源性施用,如在患有狼疮的患者中,引起代谢综合征(躯干肥胖、胰岛素抵抗、高血压、高甘油三酯血症)(Stewart(2003)The Adrenal Cortex,Williams Textbook ofEndocrinology,第10版,Saunders Publishing,U.S.)。而且,躯干肥胖以升高的糖皮质激素活性为特征,并且已假定,通过肾上腺皮质合成和GC分泌的活化作用,慢性应激在躯干肥胖和代谢综合征的发展中发挥了重要作用(Bjorntorp(2001)Obes.Rev.2:73-86;Rosmond等(2000)Obes.Res.8:445-450;Bjorntorp(1997)Nutrition 13:795-803;(Dallman M.F.,2002)。
[0053]皮质醇过多或皮质醇过少也是被很好地描述的精神病的特征,并且患有代谢综合征的患者显示异常的皮质醇分泌迹象并且更可能与精神病如严重抑郁症一起出现。慢性应激和相关的中枢CRF活性的升高被认为在临床抑郁、焦虑症、物质滥用、进食障碍和代谢综合征的发展中起着关键作用(Chrousos等,(2000)Int.J.Obes.Relat.Metab.Disord.24:S50-S55;Koob(1999)Biol.Psychiatry 46:1167-1180)。事实上,现在正在对小分子CRF拮抗剂在患有严重抑郁症、一般焦虑症、进食障碍以及其它应激相关病状的患者中的治疗作用进行研究。
[0063]C-末端部分可以是氨基、烷基氨基、二烷基氨基、环烷基氨基、芳基烷基、芳烷基氨基、烷氧基、芳氧基或芳烷氧基或羧基。用于X和Y的合适的侧链包括来源于下述的基团:可以形成二硫键的烷基巯基;可以形成环内酰胺的烷基酸和烷基胺;可以缩合并且被还原形成烷基胺桥的烷基醛或烷基卤化物和烷基胺;或可以被连接形成烷基、链烯基、炔基、醚或硫醚键的侧链;优选的烷基链包括具有大约1个至大约6个碳原子的低碳烷基。
[0064]本文所提供的应用的另外的方面、组合物和方法涉及没有被桥连的SEQ ID NO:3的激动剂类似物,并且其中X和Y独立地选自Ala、Ser、Cys、Val、Leu和Ile或烷基、芳基、或芳烷基酯以及Ser或Cys的醚。
[0069]在本公开的方法中使用的示例性AFP-6类似物的氨基酸序列包括:
[0073]烷基链可以包括具有大约1个至大约6个碳原子的低碳烷基。在某些实施方式中,分子内连接可以是二硫键、酰胺键、亚胺键、胺键、烷基键或烯键。在某些实施方式中,X和Y独立地选自Ser、Asp、Glu、Lys、Orn、或Cys。在某些实施方式中,X和Y是Cys和Cys。在其它实施方式中,X和Y是Ser和Ser.。仍在其它实施方式中,X和Y是Asp和Lys或Lys和Asp。
[0077]在一个总的方面,式V、VI、VII、或VIII的序列进一步包括1、2、3、4、5、6、7、8、9、10、11、12或更多个置换、插入、缺失、延伸和/或衍生修饰。在某些实施方式中,式V、VI、VII、或VIII的序列包括在24位的缺失。在某些实施方式中,式V、VI、或VII的序列包括22位和23位氨基酸之间插入的Val。在其它实施方式中,式V、VI、或VII的序列包括22位和23位氨基酸之间插入的Gln。仍在其它实施方式中,式V、VI、或VII的序列包括22位和23位之间的Gln-Thr-Tyr序列。而在另外的实施方式中,式V、VI、或VII的序列包括22位和23位之间的Leu-Gln-Thr-Tyr序列(SEQ ID NO:84)。在另一个总的方面,式V、VI、或VII的修饰可以在N-末端。在某些实施方式中,式V、VI、或VII的N-末端部分具有添加的辛基甘氨酸。在其它实施方式中,式V、VI、或VII的N-末端部分具有添加的异构帽。其它的实施方式在PCT申请第PCT/US2005/004631中被描述并且引入作为参考。
[0095]在具体的实施方式中,药物制剂可以包含化合物的一系列浓度,如,在此实施方式中,在大约0.01%至大约98%(w/v)之间、或大约1至大约98%(w/v)之间、或80%和90%(w/v)之间、或大约0.01%至大约50%(w/v)之间、或大约10%至大约25%(w/v)之间。用于注射的足量的水可以被用于获得期望的溶液浓度。
[00101]稳定剂可以包含在本制剂中,但是,并且重要地,其不是必需的。然而,如果被包含,在本制剂的实践中有用的稳定剂是碳水化合物或多元醇。在本方法的实践中有用的合适稳定剂是大约1.0至10%(w/v)的碳水化合物或多元醇。多元醇和碳水化合物在它们的主链中共有相同的特征,即-CHOH-CHOH-,其负责稳定蛋白质。多元醇包括这样的化合物,如山梨醇、甘露醇、甘油以及聚乙二醇(PEG)。这些化合物是直链分子。碳水化合物,如甘露糖、核糖、蔗糖、果糖、海藻糖、麦芽糖、肌醇和乳糖,在另一方面,是可含有酮基或醛基的环状分子。已经显示这两类化合物在稳定蛋白质、抵抗由温度升高和由冻融或冷冻干燥过程引起的变性方面是有效的。在对象患有糖尿病的实施方式中,合适的碳水化合物包括:半乳糖、阿拉伯糖、乳糖或对糖尿病患者没有不利影响的任何其它碳水化合物,即,碳水化合物在血液中不代谢形成不可接受的高浓度葡萄糖。对于适合于糖尿病,这样的碳水化合物在本领域是熟知的。蔗糖和果糖适合在非-糖尿病对象中与化合物一起使用。
[00103]美国药典(USP)规定必须以抑菌或抑真菌浓度将抗菌剂加入到包含在多剂量容器中的制备物中。它们必须以使用时足以抑制微生物繁殖的浓度存在,所述微生物是在用皮下注射针和注射器取出部分内容物,或使用其它用于输送的侵入性途径如笔注射器时被无意引入到制备物中的。应该评价抗菌剂以确保其与制剂的所有其它组分的相容性,并且应在全部配方中评价它们的活性以保证在一种制剂中有效的具体试剂在另一种制剂中不是无效的。很少见到一种具体的抗菌剂在一种制剂中有效但在另一种制剂中无效。
[00109]其它的成分可能在药物制剂中存在。这种额外的成分可以包括,如润湿剂、乳化剂、油、抗氧化剂、填充剂、张度改性剂、螯合剂、金属离子、油质载体、蛋白质(如人血清白蛋白、明胶或蛋白质)以及两性离子(如氨基酸,例如甜菜碱、牛磺酸、精氨酸、甘氨酸、赖氨酸和组氨酸)。另外,聚合物溶液,或具有聚合物的混合物为肽的控释提供了机会。这种额外的成分,当然,不应对本文提供的药物制剂的整体稳定性产生不利影响。
[00110]容器也是注射制剂的完整部分并且可以被认为是一个组分,因为不存在完全惰性的容器,或者没有容器不以某种方式影响其包含的液体,特别是所述液体为水性时。因此,用于具体注射的容器的选择必须基于这样的考虑:容器的组成以及溶液的组成和其要经受的处理。如果必要,通过使用硼硅玻璃,例如,Wheaton I型硼硅玻璃#33(Wheaton类型I-33)或其等效物(Wheaton Glass Co),也可以使肽对瓶子玻璃表面的吸附最小化。可接受用于制造的类似硼硅玻璃小瓶和药筒的其它供应商包括Kimbel Glass Co.、West Co.、Bünder Glas GMBH和Forma Vitrum。可以通过在5%甘露醇和0.02%吐温80存在下,在Wheaton Type I-33硼硅酸盐血清瓶中,配制和冻干化合物至0.1mg/ml和10mg/ml的终浓度,使化合物的生物和化学性质稳定。
[00112]上述药物制剂的每一种组分在本领域是已知的并且描述在Pharmaceutical Dosage Forms:Parenteral Medications,第1卷,第2版,Avis等编辑,Mercel Dekker,New York,N.Y.1992中,在此引入其全部作为参考。
[00115]在一个实施方式中,液体药物制剂拟用于肠胃外施用。合适的施用途径包括肌内、静脉内、皮下、真皮内、关节内、鞘内等。皮下施用途径是一种具体的途径。粘膜输送也特别合适。这些粘膜途径包括但不限于,口、鼻、舌下、肺和颊的途径,其可以包括液体、半固体或固体形式的肽的施用。经由这些途径的施用需要更多的肽以获得期望的生物学效果,原因在于,与肠胃外输送相比,生物可利用率降低。此外,可以通过形成聚合物微胶囊、基质、溶液、植入物和装置并且肠胃外施用它们或通过外科方法,实现肠胃外控释输送。在美国专利6,368,630、6,379,704和5,766,627中描述了控释制剂的例子,其被引入作为参考。由于一些肽被包埋聚合物基质或装置中,这些剂量形式可能具有较低的生物可利用率。见,例如美国专利第6,379,704、6,379,703和6,296,842号。
[00117]然而,典型的剂量可以包括每天大约1μg、5μg、10μg、50μg至100μg的下限到大约100μg、500μg、1mg、5mg、10mg、50mg和100mg的上限的药物化合物。也考虑的是其它剂量范围如每剂量0.1μg至1mg化合物。因此,示例性的剂量可以是每剂量30、60、120、140或360μg的化合物。每天剂量可以离散单位剂量输送或在24小时期间或在该24小时期间的任何时间持续提供。每天的剂量数目可以每天1到大约4剂量,但可以更多。可以以持续输注的形式持续输送。示例性的剂量和输注速率包括每离散剂量0.005nmol/kg至大约20nmol/kg,或在持续输注中大约0.01/pmol/kg/min至  大约  10pmol/kg/min。可以通过静脉内施用(i.v.)或皮下施用(s.c.)输送这些剂量和输注液。静脉内施用的药物组合物的示例性总剂量/输送可以是每天大约2μg至大约8mg,而皮下施用的药物组合物的总剂量/输送可以是每天大约6μg至大约16或24mg。
[00118]提供下列实施例用以说明,但不是限制本发明。
[00127]前脉冲抑制(PPI)试验测定对外部施加的听觉刺激的反射性响应(听觉惊恐反应),并且与精神分裂症中所见的感觉-运动门控能力缺乏相关。听觉惊恐反应是对强外感受性刺激的非常基本的反应,并被广泛用于评价动物和人的感觉运动反应性。在强听觉刺激(120dB)前给予的弱听觉刺激(前脉冲,74-82dB)削弱了惊恐反应。这种惊恐反应的削弱称为前脉冲抑制。参见,例如,Conti等(2005)Behavioral Neuroscience119:1052-1060。抗精神病剂提高了前脉冲刺激削弱对强刺激的惊恐反应的能力。一些拟精神病剂,如苯环利定(PCP)和氯胺酮可实际上降低前脉冲抑制百分数,并且刺激动物的可以被抗精神病剂拮抗的精神病样状态。