TWI630912B - Methods of treating overweight and obesity - Google Patents

Methods of treating overweight and obesity Download PDF

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TWI630912B
TWI630912B TW102144268A TW102144268A TWI630912B TW I630912 B TWI630912 B TW I630912B TW 102144268 A TW102144268 A TW 102144268A TW 102144268 A TW102144268 A TW 102144268A TW I630912 B TWI630912 B TW I630912B
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naltrexone
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TW201446247A (en
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裴斯頓 克雷森
克里斯丁 泰勒
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美商歐瑞根治療有限公司
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Abstract

本發明係關於使用那曲酮(naltrexone)加丁胺苯丙酮(bupropion)治療過重及肥胖之組合物、套組、用途、系統及方法，較佳與基於網路及/或基於電話之綜合重量管理計畫組合，且較佳用於具有增加不良心血管結果之風險的個體。 The present invention relates to compositions, kits, uses, systems and methods for treating overweight and obesity using naltrexone plus bupropion, preferably with network-based and/or telephone-based integrated weight management The combination is planned and preferably used for individuals with increased risk of adverse cardiovascular outcomes.

Description

治療過重及肥胖之方法 Method of treating overweight and obesity 相關申請案Related application

本申請案為2012年6月6日申請之美國臨時專利申請案第61/656,451號的非臨時申請案且主張其優先權，在允許時該案以全文引用的方式併入本文中。 The present application is a non-provisional application of the U.S. Provisional Patent Application Serial No. 61/656,451, filed on Jun. 6, 2012, which is hereby incorporated by reference.

本發明係關於使用那曲酮(naltrexone)加上丁胺苯丙酮(bupropion)、較佳與基於網路及/或基於電話之綜合重量管理計畫組合且治療視情況具有高不良心血管結果之風險的個體的過重及肥胖的組合物、套組、用途、系統及方法。 The present invention relates to the use of naltrexone plus bupropion, preferably in combination with a network-based and/or telephone-based integrated weight management program, and the risk of treating adverse cardiovascular outcomes as appropriate. Compositions, kits, uses, systems and methods for overweight and obesity of an individual.

肥胖已根據身體質量指數(BMI)定義。BMI係以重量(kg)/[高度(m)]2形式計算。根據美國疾病控制及預防中心(U.S.Centers for Disease Control and Prevention，CDC)及世界衛生組織(World Health Organization，WHO)的準則，對於超過20歲之成人，BMI如下分類：低於18.5視為過輕，18.5-24.9視為正常，25.0-29.9視為過重，且30.0及30.0以上視為肥胖(世界衛生組織.Physical status：The use and interpretation of anthropometry.Geneva,Switzerland：世界衛生組織1995.世界衛生組織技術報告叢書(WHO Technical Report Series))。 Obesity has been defined in terms of body mass index (BMI). The BMI is calculated in the form of weight (kg) / [height (m)] 2 . According to the guidelines of the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), for adults over 20 years of age, the BMI is classified as follows: below 18.5 is considered too light, 18.5-24.9 is considered normal, 25.0-29.9 is considered overweight, and 30.0 and 30.0 or more are considered obese. (Physical status: The use and interpretation of anthropometry. Geneva, Switzerland: World Health Organization 1995. World Health Organization technology Reporting Series (WHO Technical Report Series).

在過去三十年中，肥胖流行率顯著增加，有32%男性及36%女性被視為肥胖。此等個體之與肥胖有關之各種慢性病狀的風險增高，該 等病狀包括2型糖尿病、冠心病、高血壓、中風、血脂異常、膽囊病、睡眠呼吸暫停、某些類型之癌症及骨關節炎，並且因所有病因而死亡之風險增高(NHLBI Clinical Guidelines,1998)。過重及肥胖亦與所有病因之死亡率增高有關。 In the past three decades, the prevalence of obesity has increased significantly, with 32% of men and 36% of women being considered obese. The risk of various chronic conditions associated with obesity in these individuals is increased, Such conditions include type 2 diabetes, coronary heart disease, hypertension, stroke, dyslipidemia, gallbladder disease, sleep apnea, certain types of cancer and osteoarthritis, and the risk of death from all diseases is increased (NHLBI Clinical Guidelines, 1998). Excessive weight and obesity are also associated with increased mortality from all causes.

基於膳食及運動之行為改良是重量管理療法之支柱。然而，該介入通常具有有限有效性且個體難以堅持。因此，已採用藥物療法作為膳食及運動之輔助。奧利司他(Orlistat)、氯卡色林(lorcaserin)及苯丁胺(phentermine)/托吡酯(topiramate)為當前美國批准用於長期治療肥胖的僅有的三種藥物。已確定5-10%重量減輕可產生重大醫學益處。儘管奧利司他具有有利安全型態，但其可引起軟便及大便失禁，從而使患者難以接受。減肥手術(Bariatric surgery)(尤其束胃帶)現適用於BMI30kg/m2且患有至少一種肥胖相關共病之個體。儘管在大多數情形下有效，但其仍具有侵襲性，且可能的併發症包括感染、死亡、低血糖、重量減輕失敗、胃腸症狀、營養不足、抑鬱、性及關係問題以及不順應行為建議。 Behavioral and exercise-based behavioral improvement is the backbone of weight management therapy. However, this intervention typically has limited effectiveness and is difficult for individuals to adhere to. Therefore, drug therapy has been used as an aid to diet and exercise. Orlistat, lorcaserin, and phentermine/topiramate are the only three drugs currently approved for long-term treatment of obesity in the United States. It has been determined that a 5-10% weight loss can have significant medical benefits. Although orlistat has a favorable safety profile, it can cause soft stools and fecal incontinence, making it difficult for patients to accept. Bariatric surgery (especially the gastric band) is now available for BMI An individual having 30 kg/m 2 and having at least one obesity-related comorbidity. Although effective in most cases, it is still aggressive and possible complications include infection, death, hypoglycemia, weight loss failure, gastrointestinal symptoms, undernutrition, depression, sexual and relationship problems, and recommendations for non-compliance.

美國專利第7,375,111號及第7,462,626號揭示那曲酮與丁胺苯丙酮之組合(NB)用於重量減輕療法。Wadden等人揭示那曲酮與丁胺苯丙酮之組合作為用於重量減輕之密集行為改變(BMOD)計畫之輔助。Obesity(2011)19：110-120。Wadden等人描述之BMOD計畫親自傳達至10-20人之群組。群組會議持續90min，且在最初16週每週舉行，隨後的12週每隔一週舉行，且之後每月舉行(總共產生28次會議)。群組會議通常以回顧參加者之進食及活動記錄及其他家庭任務開始。隨後，組長介紹重量控制之新主題，在最初16週期間，其包括餐食計劃、刺激控制、緩慢進食、問題解決、社會支持及處理高風險情形。後續會議涵蓋維持重量減輕所要之技能。 U.S. Patent Nos. 7,375,111 and 7,462,626 disclose the use of a combination of naltrexone and acetophenone (NB) for weight loss therapy. Wadden et al. disclose the combination of naltrexone and acetophenone as an aid to the intensive behavioral change (BMOD) program for weight loss. Obesity (2011) 19 : 110-120. The BMOD program described by Wadden et al. personally communicates to groups of 10-20 people. Group meetings lasted 90 minutes and were held weekly for the first 16 weeks, every other week for the next 12 weeks, and then monthly (total of 28 meetings). Group meetings usually begin with a review of the participants' eating and activity records and other family tasks. Subsequently, the team leader introduced a new theme of weight control, which included meal planning, stimulus control, slow eating, problem solving, social support, and handling high-risk situations during the first 16 weeks. Subsequent meetings cover the skills needed to maintain weight reduction.

儘管已知那曲酮與丁胺苯丙酮之組合單獨或與密集BMOD計畫組 合可有效用於一些患者群體之重量管理，但仍需要對具有高不良心血管結果之風險的個體的過重或肥胖的有效療法。另外，需要與那曲酮及丁胺苯丙酮組合使用之重量管理計畫，其相較於現有BMOD計畫患者較易於遵守，但仍有效、尤其在具有高不良心血管結果之風險的個體中。 Although the combination of naltrexone and acetophenone is known alone or in combination with the intensive BMOD program group The combination is effective for weight management in some patient populations, but still requires effective treatment for overweight or obesity in individuals at high risk of adverse cardiovascular outcomes. In addition, a weight management program in combination with naltrexone and acetophenone is required, which is easier to follow than existing BMOD plan patients, but is still effective, especially in individuals at high risk of adverse cardiovascular outcomes.

本發明之一實施例包括一種治療具有高不良心血管結果之風險的個體的過重或肥胖的方法，其包含：鑑別具有高不良心血管結果之風險的過重或肥胖個體；及投與該個體治療有效量之持續釋放那曲酮或其醫藥學上可接受之鹽及持續釋放丁胺苯丙酮或其醫藥學上可接受之鹽。在一些實施例中，輔助過重或肥胖個體在如下情形下鑑別為具有高不良心血管結果之風險：若該個體a.)診斷為患有具有至少一種選自由以下組成之群的風險因素的心血管疾病：鑑別前>3個月之記錄之心肌梗塞史；冠狀動脈血管再形成史，該冠狀動脈血管再形成包括冠狀動脈繞道移植手術、支架置入術、經皮經管腔冠狀動脈血管成形術或雷射粥樣斑塊切除術；頸動脈或外周血管再形成史，該頸動脈或外周血管再形成包括頸動脈內膜切除術、下肢動脈粥樣硬化病粥樣斑塊切除術、腹部主動脈動脈瘤修復、股或膕動脈繞道；分級運動測試時具有局部缺血性變化、ECG變化或心臟成像研究陽性之絞痛；鑑別前2年內藉由簡單觸診評定之踝肱指數<0.9；及鑑別前2年內冠狀動脈、頸動脈或下肢動脈50%狹窄；及/或b.)診斷為患有具有至少2種選自由以下組成之群的風險因素的2型糖尿病：用或不用藥物療法控制在<145/95mm Hg之高血壓；需要藥物療法之血脂異常；鑑別前12個月內記錄之低HDL膽固醇，在女性中<50mg/dL或在男性中<40mg/dL；及當前吸菸者。 An embodiment of the invention includes a method of treating overweight or obesity in an individual at risk of having a high adverse cardiovascular outcome, comprising: identifying an overweight or obese individual at risk of having a high adverse cardiovascular outcome; and administering to the individual An effective amount of sustained release of naltrexone or a pharmaceutically acceptable salt thereof and sustained release of bupropion or a pharmaceutically acceptable salt thereof. In some embodiments, an assisted overweight or obese individual is identified as having a risk of having a high adverse cardiovascular outcome if the individual a.) is diagnosed as having a cardiovascular condition having at least one risk factor selected from the group consisting of Disease: history of myocardial infarction recorded >3 months prior to differentiation; history of coronary revascularization, coronary artery revascularization including coronary bypass grafting, stenting, percutaneous transluminal coronary angioplasty Or laser atherectomy: a history of carotid or peripheral vascular remodeling, including carotid endarterectomy, lower extremity atherosclerotic atherectomy, abdominal abdomen Arterial aneurysm repair, femoral or radial artery bypass; graded exercise test with ischemic changes, ECG changes or positive coronal studies of cardiac imaging studies; 踝肱 index <0.9 with simple palpation assessment within 2 years prior to identification And identify the coronary, carotid or lower extremity arteries within the first 2 years 50% stenosis; and/or b.) diagnosed as having type 2 diabetes with at least 2 risk factors selected from the group consisting of: controlling hypertension at <145/95 mm Hg with or without drug therapy; requiring drug therapy Dyslipidemia; low HDL cholesterol recorded during the first 12 months of identification, <50 mg/dL in women or <40 mg/dL in men; and current smokers.

在一些實施例中，方法進一步包含2週導入期，在此期間，個體 根據如下兩種順序之一接受處理：1週包含持續釋放那曲酮或其醫藥學上可接受之鹽及持續釋放丁胺苯丙酮或其醫藥學上可接受之鹽的活性研究藥物，一天一次，繼而1週安慰劑，一天一次；或1週安慰劑，繼而1週包含持續釋放那曲酮或其醫藥學上可接受之鹽及持續釋放丁胺苯丙酮或其醫藥學上可接受之鹽的活性研究藥物。 In some embodiments, the method further comprises a 2-week lead-in period during which the individual The treatment is carried out according to one of two sequences: one week containing an active study drug that continuously releases naltrexone or a pharmaceutically acceptable salt thereof and sustained release of bupropion or a pharmaceutically acceptable salt thereof, once a day, Then 1 week placebo, once a day; or 1 week placebo, followed by 1 week containing sustained release of naltrexone or its pharmaceutically acceptable salt and sustained release of bupropion or its pharmaceutically acceptable salt Research drugs.

在一些實施例中，個體不具有一或多種選自由以下組成之群的特徵：鑑別前3個月內患有心肌梗塞；根據加拿大心血管協會(Canadian Cardiovascular Society)分級方案的III級或IV級心絞痛；包括中風之腦血管疾病臨床病史；除竇性心動過速以外之快速性心律失常史；血壓145/95mm Hg，不管是否用抗高血壓藥劑治療；鑑別前3個月內重量不穩定；有計劃之減肥手術、心臟手術或冠狀動脈血管成形術；由估算之GFR<30mL/min定義的重度腎臟損傷；肝衰竭臨床病史或記錄之ALT或AST大於正常值上限3倍；已知感染HIV或肝炎；長期使用類鴉片或類鴉片篩選陽性；鑑別前6個月內除菸鹼依賴以外之新近藥物或酒精濫用或依賴；包括熱性癲癇之癲癇、顱側創傷或使個體預先有癲癇傾向之其他病狀史；躁狂史或當前診斷為活性精神病、活性貪食症或神經性厭食症而非暴食症；具有自殺企圖之風險；急性抑鬱病，包括抑鬱新發作或症狀急劇惡化，而非長期抑鬱治療時之穩定個體；預計預期壽命少於4年之任何病狀，包括充血性心臟衰竭NYHA第3類或第4類；前5年內惡性腫瘤史，不包括非黑色素瘤皮膚癌或手術治癒之子宮頸癌；當前使用其他含丁胺苯丙酮或那曲酮產品；那曲酮或丁胺苯丙酮過敏或不耐史；鑑別前14天內使用單胺氧化酶抑制劑；鑑別前30天內使用任何研究藥物、裝置或程序；懷孕或哺乳女性，或當前試圖受孕，或具有生小孩之可能性，包括一年內有過經期之近停經女性及不願實施生育控制；及不能不斷存取寬頻帶網際網路。 In some embodiments, the individual does not have one or more characteristics selected from the group consisting of: myocardial infarction within 3 months prior to identification; grade III or IV according to the Canadian Cardiovascular Society classification protocol Angina pectoris; clinical history of cerebrovascular disease including stroke; history of tachyarrhythmia other than sinus tachycardia; blood pressure 145/95mm Hg, whether or not treated with antihypertensive agents; weight instability within 3 months prior to identification; planned bariatric surgery, cardiac surgery or coronary angioplasty; severely defined by estimated GFR <30 mL/min Kidney damage; clinical history of liver failure or recorded ALT or AST greater than 3 times the upper limit of normal; known to be infected with HIV or hepatitis; long-term use of opioid or opioid screening positive; newly identified in addition to nicotine dependence within 6 months prior to identification Drug or alcohol abuse or dependence; epilepsy including febrile epilepsy, cranial trauma or other history of predisposition to epilepsy; history of mania or current diagnosis of active psychosis, bulimia nervosa or anorexia nervosa rather than overeating Symptoms; risk of suicide attempts; acute depression, including new episodes of depression or rapid deterioration of symptoms, rather than stable individuals with long-term depression; any condition expected to have a life expectancy of less than 4 years, including NYHA for congestive heart failure Category 3 or Category 4; history of malignancy in the first 5 years, excluding non-melanoma skin cancer or surgically cured cervical cancer; current use of other butylamine-containing benzene Acetone or naltrexone product; allergic or intolerant history of naltrexone or butyl ketone; use of monoamine oxidase inhibitors within 14 days prior to identification; use of any study drug, device or procedure within 30 days prior to identification; pregnant or lactating women, or current Attempts to conceive, or have the possibility of having a child, including near-menopausal women who have had menstruation within a year and are reluctant to implement birth control; and cannot continuously access the broadband Internet.

在一些實施例中，方法進一步包含向個體提供基於網路之重量管理計畫、基於電話之重量管理計畫或其組合。 In some embodiments, the method further includes providing the individual with a network based weight management plan, a phone based weight management plan, or a combination thereof.

本發明之一實施例包括一種治療個體之過重或肥胖的方法，其包含：鑑別過重或肥胖個體；及投與個體治療有效量之持續釋放那曲酮或其醫藥學上可接受之鹽及持續釋放丁胺苯丙酮或其醫藥學上可接受之鹽與基於網路之重量管理計畫、基於電話之重量管理計畫或其組合的組合。 An embodiment of the invention comprises a method of treating overweight or obesity in an individual comprising: identifying an overweight or obese individual; and administering to the individual a therapeutically effective amount of sustained release naltrexone or a pharmaceutically acceptable salt thereof and sustained release A combination of acetophenone or a pharmaceutically acceptable salt thereof with a network based weight management program, a telephone based weight management program, or a combination thereof.

在一些實施例中，所鑑別個體之BMI30且45kg/m2，其患有無併發症之肥胖。在一些實施例中，所鑑別個體之BMI27且45kg/m2，其患有血脂異常及/或受控之高血壓。在一些實施例中，治療個體至少26週。在一些實施例中，基於電話之重量管理計畫包含對個體進行一或多次教練電話。在一些實施例中，基於電話之重量管理計畫視情況包含一或多種網路教練工具。在一些實施例中，基於網路或基於電話之重量管理計畫向個體提供行為、營養或健身教育中之一或多者。 In some embodiments, the BMI of the identified individual 30 and 45 kg/m 2 with uncomplicated obesity. In some embodiments, the BMI of the identified individual 27 and 45 kg/m 2 with dyslipidemia and/or controlled hypertension. In some embodiments, the individual is treated for at least 26 weeks. In some embodiments, the phone based weight management plan includes one or more coaching calls to the individual. In some embodiments, the phone based weight management plan includes one or more web coaching tools as appropriate. In some embodiments, one or more of behavioral, nutritional, or fitness education is provided to an individual based on a network or phone-based weight management program.

在一些實施例中，教育由經培訓之保健或健身教練及/或已註冊之營養師傳達。在一些實施例中，經培訓之保健或健身教練及/或已註冊之營養師經由電話或經由個體之網站指導個體，且提供一或多種選自由以下組成之群的主題：秘訣(tips)及激勵性訊息；經由問與答進行教練；用於經由網站對個體之詢問作出即時反應的每週辦公時間；每週教育材料；視訊課程；進行徽章獎勵之重量、運動或膳食追蹤；目標設定；進展追蹤；及鼓勵個體參加重量管理計畫之交流。 In some embodiments, the education is communicated by a trained health or fitness instructor and/or a registered dietitian. In some embodiments, a trained health or fitness instructor and/or a registered dietitian directs the individual via telephone or via an individual's website, and provides one or more subjects selected from the group consisting of: tips and Incentive messages; coaching via Q&A; weekly office hours for immediate response to individual inquiries via the website; weekly educational materials; video lessons; weights for badge rewards, sports or meal tracking; goal setting; Tracking progress; and encouraging individuals to participate in the exchange of weight management programs.

在一些實施例中，投與個體每天32mg持續釋放那曲酮或其醫藥學上可接受之鹽及每天360mg持續釋放丁胺苯丙酮或其醫藥學上可接受之鹽。在一些實施例中，投與個體呈錠劑形式之持續釋放那曲酮或其醫藥學上可接受之鹽及持續釋放丁胺苯丙酮或其醫藥學上可接受之 鹽，其中該錠劑含有8mg持續釋放那曲酮及90mg持續釋放丁胺苯丙酮。 In some embodiments, the individual is administered 32 mg per day of sustained release of naltrexone or a pharmaceutically acceptable salt thereof and 360 mg of sustained release bupropion or a pharmaceutically acceptable salt thereof per day. In some embodiments, the individual is administered a sustained release of naltrexone or a pharmaceutically acceptable salt thereof in the form of a tablet and sustained release of bupropion or a pharmaceutically acceptable A salt wherein the tablet contains 8 mg of sustained release of naltrexone and 90 mg of sustained release of bupropion.

在一些實施例中，用那曲酮及丁胺苯丙酮治療不增加個體不良心血管結果之風險。在一些實施例中，用那曲酮及丁胺苯丙酮治療降低個體不良心血管結果之風險。在一些實施例中，不良心血管結果為心血管性死亡、非致命性心肌梗塞或非致命性中風。在一些實施例中，個體達成至少5%、至少10%或至少15%之重量減輕百分比。在一些實施例中，重量管理計畫之時間為至少52週或至少78週。 In some embodiments, treatment with naltrexone and butyl ketone does not increase the risk of adverse cardiovascular outcomes in the individual. In some embodiments, treatment with naltrexone and butyl ketone reduces the risk of adverse cardiovascular outcomes in an individual. In some embodiments, the adverse cardiovascular outcome is cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. In some embodiments, the individual achieves a weight loss percentage of at least 5%, at least 10%, or at least 15%. In some embodiments, the weight management schedule is for at least 52 weeks or at least 78 weeks.

在一些實施例中，個體不接受作為重量管理計畫之一部分的親自指導。在一些實施例中，個體不接受超過5次作為重量管理計畫之一部分的親自指導會議。在一些實施例中，個體不接受重量減輕之密集行為改變(BMOD)計畫。 In some embodiments, the individual does not accept personal guidance as part of a weight management program. In some embodiments, the individual does not accept more than 5 personally directed sessions as part of a weight management program. In some embodiments, the individual does not accept a weight loss behavioral change (BMOD) program.

本發明係關於使用那曲酮加上丁胺苯丙酮、較佳與綜合生活方式介入(CLI)計畫組合治療過重及肥胖的組合物、套組、用途、系統及方法，該綜合生活方式介入計畫包括基於網路之重量管理計畫、基於電話之重量管理計畫及其組合。在一些實施例中，治療過重及肥胖之個體為具有高不良心血管結果之風險的個體。在一較佳實施例中，用那曲酮加上丁胺苯丙酮與基於網路及/或基於電話之綜合重量管理計畫組合治療具有高不良心血管結果之風險的個體相較於用基於網路及/或基於電話之重量管理計畫單獨治療不再產生嚴重不良心血管結果。在一些實施例中，用那曲酮加上丁胺苯丙酮與基於網路及/或基於電話之綜合重量管理計畫組合治療具有高不良心血管結果之風險的個體相較於用基於網路及/或基於電話之重量管理計畫單獨治療令人 驚訝地產生較少嚴重不良心血管結果。嚴重不良心血管結果為心血管性死亡(包括致命性心肌梗塞及致命性中風)、非致命性心肌梗塞、非致命性中風或需要住院治療之非致命性不穩定絞痛。 The present invention relates to a composition, a kit, a use, a system and a method for treating overweight and obesity using a combination of naltrexone plus bupropion, preferably in combination with a comprehensive lifestyle intervention (CLI) program, the integrated lifestyle intervention The painting includes a network-based weight management plan, a phone-based weight management plan, and a combination thereof. In some embodiments, the individual who treats overweight and obesity is an individual at risk of having a high adverse cardiovascular outcome. In a preferred embodiment, the combination of naltrexone plus bupropion and a network-based and/or telephone-based integrated weight management program to treat individuals at risk for high adverse cardiovascular outcomes is compared to Road and/or telephone-based weight management programs alone do not produce serious adverse cardiovascular outcomes. In some embodiments, the combination of naltrexone plus bupropion and a network-based and/or telephone-based integrated weight management program to treat individuals at high risk of adverse cardiovascular outcomes is compared to using a web-based / or a separate treatment based on the weight management program of the phone Surprisingly produced less severe adverse cardiovascular outcomes. Serious adverse cardiovascular outcomes are cardiovascular death (including fatal myocardial infarction and fatal stroke), non-fatal myocardial infarction, non-fatal stroke, or non-fatal unstable colic requiring hospitalization.

在一些實施例中，由本文所揭示之方法治療的個體具有高不良心血管結果之風險。具有高不良心血管結果之風險的個體包括患有如下疾病之個體：a.)具有至少一種以下情況之心血管疾病(確診或具有高心血管疾病可能性)：篩選前>3個月之記錄之心肌梗塞史；冠狀動脈血管再形成(亦即冠狀動脈繞道移植手術、支架置入術、經皮經管腔冠狀動脈血管成形術或雷射粥樣斑塊切除術)史；頸動脈或外周血管再形成(亦即頸動脈內膜切除術、下肢動脈粥樣硬化病粥樣斑塊切除術、腹部主動脈動脈瘤修復、股或膕動脈繞道)史；分級運動測試(GXT)時具有局部缺血性變化(靜態ECG)、ECG變化或心臟成像研究陽性之絞痛；前2年內(藉由簡單觸診)踝肱指數<0.9；前2年內冠狀動脈、頸動脈或下肢動脈50%狹窄；及/或b.具有至少2種以下情況之2型糖尿病：高血壓(用或不用藥物療法控制在<145/95mm Hg)；需要藥物療法之血脂異常；前12個月內記錄之低HDL膽固醇(在女性中<50mg/dL或在男性中<40mg/dL)；當前吸菸者。 In some embodiments, an individual treated by the methods disclosed herein is at risk of high adverse cardiovascular outcomes. Individuals at high risk of adverse cardiovascular outcomes include individuals with the following conditions: a.) Cardiovascular disease with at least one of the following conditions (diagnosed or with high cardiovascular risk): a record of >3 months prior to screening History of myocardial infarction; history of coronary revascularization (ie, coronary bypass grafting, stenting, percutaneous transluminal coronary angioplasty, or laser atherectomy); carotid or peripheral Revascularization (ie, carotid endarterectomy, lower extremity atherosclerotic atherectomy, abdominal aortic aneurysm repair, femoral or radial artery bypass); graded motion test (GXT) with local Ischemic changes (static ECG), ECG changes, or colic with positive cardiac imaging studies; sputum index <0.9 in the first 2 years (with simple palpation); coronary, carotid or lower extremity arteries in the first 2 years 50% stenosis; and/or b. Type 2 diabetes with at least 2 following conditions: hypertension (controlled at <145/95 mm Hg with or without drug therapy); dyslipidemia requiring drug therapy; recorded within the first 12 months Low HDL cholesterol (<50 mg/dL in women or <40 mg/dL in men); current smokers.

在一些該等實施例中，所治療個體患有無併發症之肥胖。在一些其他實施例中，所治療個體過重且患有血脂異常及/或受控之高血壓。在一些實施例中，由本文所揭示之方法治療的個體不具有高不良心血管結果之風險。 In some of these embodiments, the treated individual has uncomplicated obesity. In some other embodiments, the treated individual is overweight and has dyslipidemia and/or controlled hypertension. In some embodiments, an individual treated by the methods disclosed herein does not have a high risk of adverse cardiovascular outcomes.

在一些實施例中，用那曲酮及丁胺苯丙酮治療與重量管理計畫組合。在一些實施例中，重量管理計畫為基於網路之計畫。在一些其他實施例中，重量管理計畫為基於電話之計畫。在一些其他實施例中，重量管理計畫為基於網路之計畫與基於電話之計畫的組合。在一些實施例中，個體不接受超過15、10、5、4、3、2或1次作為重量管 理計畫之一部分的親自指導會議。在一些實施例中，個體不接受任何作為重量管理計畫之一部分的親自指導會議。 In some embodiments, the combination of naltrexone and acetophenone treatment with a weight management program. In some embodiments, the weight management program is a web-based plan. In some other embodiments, the weight management program is a phone based plan. In some other embodiments, the weight management program is a combination of a web-based plan and a phone-based plan. In some embodiments, the individual does not accept more than 15, 10, 5, 4, 3, 2, or 1 times as a weight tube Personally guide the meeting in one part of the plan. In some embodiments, the individual does not accept any personal guidance sessions as part of a weight management program.

基於網路之重量管理計畫Network-based weight management program

較佳地，基於網路之計畫提供具有目標設定及追蹤工具之進行性營養及運動計畫。將各個體分配至保健及健身專業人員，其經由該計畫線上指導該等個體。其他教育工具包括由定期提供之視訊課程(表1)補充的每週基於網路之資訊、教育及激勵性資源。計畫內容由以下組成：每週電子郵件，其宣佈該週之目標，提供激勵及鼓勵繼續參與；與各週專題(表1)結合之每週目標(來自電子郵件)以及置於MyWeightMate.com個體頁面之詳細說明及達成此等目標之策略；張貼至使用者頁面以輔助個體達成其每週目標之三篇其他每週內容(技巧及教育資訊)；張貼在參與者頁面之該週的激勵性訊息；基於行為(亦即缺席計畫活動、成功記錄)發送至使用者的觸發事件電子郵件；提供於MyWeightMate.com網站上以供參與者觀看且存檔以供將來存取的視訊課程：最初16週每週一次，隨後12週兩週一次，研究之剩餘持續時間每月一次，及兩次復習活動，其包括試驗第三及第四年期間每年4次週會議。視訊課程集中於相應主題且由論題專家開發。 Preferably, the web-based program provides progressive nutrition and exercise programs with goal setting and tracking tools. Individuals are assigned to health and fitness professionals who direct the individuals via the program line. Other educational tools include weekly web-based information, education and incentive resources supplemented by regularly provided video lessons (Table 1). The program consists of a weekly email that announces the goals of the week, provides incentives and encourages continued participation; weekly goals (from email) combined with weekly topics (Table 1) and individuals placed on MyWeightMate.com Detailed description of the page and strategies for achieving these goals; posting to the user page to assist the individual in achieving three other weekly content (skills and educational information) for their weekly goals; motivation for posting this week on the participant page Message; a trigger event email sent to the user based on behavior (ie, absence plan activity, successful record); video course available on the MyWeightMate.com website for participants to view and archive for future access: Initial 16 Weekly once a week, followed by 12 weeks and two weeks, the remaining duration of the study is monthly, and two review activities, including four weekly meetings during the third and fourth years of the trial. Video lessons are focused on the subject and developed by the topic experts.

基於網路之重量管理計畫提供行為、營養及健身教育，其由經培訓之保健及健身教練傳達。該網站提供「WeightMate教練」，其經由參與者之個別網頁指導個體且提供以下中之一或多者：秘訣及激勵性訊息；經由Q&A進行教練；經由網站作出即時反應的每週辦公時間；每週教育材料；由主題專家開發之內容；補充每週專題之視訊課程；進行徽章獎勵之重量、運動及膳食追蹤；建議之活動及教練技巧；鼓勵個體參加之交流；及有趣且直觀之同期網站。 The web-based weight management program provides behavioral, nutritional, and fitness education delivered by trained health and fitness coaches. The website provides "WeightMate Coach", which guides individuals through individual pages of participants and provides one or more of the following: tips and motivational messages; coaching via Q&A; weekly office hours for immediate response via the website; Weekly educational materials; content developed by subject matter experts; video lessons supplemented with weekly topics; weight, sports and meal tracking for badge rewards; recommended activities and coaching skills; encouragement of individual participation; and interesting and intuitive simultaneous website .

在一個實施例中，每週一介紹新專題及目標，其中提供該週之2-3個目標、相應內容及/或視訊課程(表1)，且在該週之一或多天提供激勵性訊息。視情況，在該週期間之一或多天提供其他技巧。在一些實施例中，視訊課程補充每週教育專題。所製作之視訊內容確保向個體提供之訊息的品質及一致性，且Q&A功能使患者可詢問問題且在24小時內得到回復。 In one embodiment, new topics and goals are introduced on a weekly basis, providing 2-3 goals, corresponding content, and/or video lessons for the week (Table 1), and providing incentives for one or more days of the week. message. Other techniques may be provided during one or more days of the week, as appropriate. In some embodiments, the video lessons complement the weekly education topic. The video content produced ensures the quality and consistency of the information provided to the individual, and the Q&A function allows the patient to ask questions and get a response within 24 hours.

在一些實施例中，由教練提供基於網路之個別指導；較佳地，個體可對教練進行無限存取。教練較佳向個體提供時間表，其包括作出即時Q&A反應之每週『辦公時間』。該計畫強調在每天食品及活動追蹤的情況下進行每週稱重輸入。較佳地，網站可使用特定食品及/或餐食之熱量的電腦資料庫追蹤每餐之熱量且保存最喜愛之食品及餐食。基於熱量要求及食品偏好提供四份參考菜單。在一些實施例中，個體因達到特定目標(例如因記錄7天活動；因記錄7天食品；因記錄3週重量；因減少最初15磅(pound)；因參與12週計畫；因參與26週計畫；因參與52週計畫；因參與78週計畫；因重量減輕5%；因重量減輕10%；因重量減輕15%)而受到徽章獎勵。在一較佳實施例中，個體 週期性確定重量減輕目標，其作為計畫之一部分而記錄。可經由個體之網頁向個體提供個體朝向個體目標之進展。重量減輕目標可為一週、兩週、一個月、兩個月、六個月、一年或一年以上時間之目標。計畫提供選擇以使參與個體可在計畫開始時設定特定重量減輕目標。計畫亦提供選擇以在每天或每週基礎上追蹤及記錄重量減輕及朝向達成特定目標之進展。視情況，經由個體之網頁向個體提供重量減輕進展之圖示。可提供週期性鼓勵訊息(例如徽章及獎勵註釋)。較佳地，提供來自培訓者之基於行為之自動訊息以提高積極性及參與。 In some embodiments, individual guidance based on the network is provided by the instructor; preferably, the individual can have unlimited access to the instructor. The coach preferably provides the individual with a timeline that includes weekly "office hours" for an immediate Q&A response. The program emphasizes weekly weighing input for daily food and activity tracking. Preferably, the website can use a computer database of specific food and/or calories of meals to track the calories of each meal and preserve the favorite foods and meals. Four reference menus are available based on thermal requirements and food preferences. In some embodiments, the individual achieves a specific goal (eg, due to recording 7 days of activity; due to recording 7 days of food; due to recording 3 weeks of weight; due to a reduction of the first 15 pounds; due to participation in the 12 week program; due to participation 26 Weekly plan; due to participation in the 52-week plan; due to participation in the 78-week plan; 5% weight reduction; 10% weight reduction; 15% weight reduction) and was awarded a badge. In a preferred embodiment, the individual The weight reduction goal is periodically determined and recorded as part of the plan. The progress of the individual toward the individual goal can be provided to the individual via the individual's web page. The weight reduction goal can be a goal of one week, two weeks, one month, two months, six months, one year or more. The plan provides a choice to enable the participating individuals to set a specific weight reduction goal at the beginning of the program. The program also provides the option to track and record weight reduction and progress towards a specific goal on a daily or weekly basis. Depending on the situation, the individual is provided with a graphical representation of the weight reduction progression via the individual's web page. Periodic encouragement messages (such as badges and bonus notes) are available. Preferably, behavior-based automated messages from the trainer are provided to increase motivation and participation.

在一些實施例中，基於網路之重量管理計畫的運動部分鼓勵5天活動且2天(較佳在不連續之日，例如週一及週五)休息。在一些實施例中，運動計畫提供關於伸展、行走及其他輕鬆有氧活動(light cardio activity)之說明。視訊剪輯可針對伸展及運動動作提供教育展示。網站可經由運動及活動記錄追蹤個體燃燒之熱量。 In some embodiments, the mobile portion of the network-based weight management program encourages 5 days of activity and rests for 2 days (preferably on discrete days, such as Monday and Friday). In some embodiments, the exercise program provides an illustration of stretching, walking, and other light cardio activities. Video clips provide educational presentations for stretching and movement. The website tracks the calories burned by individuals through sports and activity records.

在一較佳實施例中，基於網路之重量管理計畫不涉及任何親自療法或群組會議。 In a preferred embodiment, the network based weight management plan does not involve any personal therapy or group meetings.

基於電話之重量管理計畫Phone-based weight management program

在一些實施例中，基於電話之計畫包含經由一或多次電話拜訪進行個人教練。在一個實施例中，由指定教練向接受治療之個體進行電話拜訪。在另一實施例中，由註冊營養師向接受治療之個體進行電話拜訪。在一些該等實施例中，在最初3至8個月、較佳6個月治療中，基於電話之計畫包括6至15次、較佳12次預定拜訪。該等預定拜訪之主題可包括認知行為教練及營養教練(參見例如表2)。在一些該等實施例中，在隨後3至8個月、較佳6個月治療中，基於電話之計畫包括6至15次、較佳12次額外拜訪。 In some embodiments, the phone based plan includes personal coaching via one or more phone calls. In one embodiment, a telephone call is made to the individual receiving treatment by the designated coach. In another embodiment, a telephone visit is made to the individual receiving treatment by a registered dietitian. In some of these embodiments, the phone based plan includes 6 to 15 times, preferably 12 scheduled visits, during the first 3 to 8 months, preferably 6 months of treatment. The subject matter of such scheduled visits may include cognitive behavioral coaches and nutrition coaches (see, eg, Table 2). In some of these embodiments, the telephone based plan includes 6 to 15 times, preferably 12 additional visits, in the subsequent 3 to 8 months, preferably 6 months of treatment.

在一些實施例中，基於電話之計畫視情況包含線上教練工具，諸如用於網路教練之整合網路支持，包括上述基於網路之計畫。網路 教練可包括用於重量減輕及維持重量減輕、進展追蹤及/或虛擬教練之基本實踐。基本實踐之非限制性實例可包括E-課程、視訊及播客，關於諸如健康烹飪、設定實際目標及控制壓力之主題的文章及遊戲。進展追蹤器可追蹤之項目的非限制性實例包括重量、營養攝入、活動、壓力、生物統計、教練電話等。虛擬教練之非限制性實例可包括產生及更新個體參與計畫、發送電子郵件等之待辦清單。 In some embodiments, the telephony-based device includes online coaching tools, such as integrated network support for web coaches, including the web-based programs described above. network Coaches may include basic practices for weight reduction and maintenance of weight reduction, progress tracking, and/or virtual coaching. Non-limiting examples of basic practices may include E-courses, video and podcasts, articles and games on topics such as healthy cooking, setting actual goals, and controlling stress. Non-limiting examples of items tracked by the progress tracker include weight, nutrient intake, activity, stress, biometrics, coaching, and the like. Non-limiting examples of virtual coaching may include generating and updating a to-do list of individual participation plans, emails, and the like.

在一些實施例中，基於電話之計畫亦可視情況包括一或多種用於進行無線活動監視之電子裝置。該電子裝置之非限制性實例為與USB存取點結合用於追蹤步驟、距離、熱量及活動時間之FitLinxx®ActiPed。該(該等)電子裝置可與網路支持無線同步。在一個實施例中，基於電話之計畫為可購自AlereTM之Weight Talk®計畫。 In some embodiments, the telephony based plan may also include one or more electronic devices for wireless activity monitoring, as appropriate. A non-limiting example of such an electronic device is FitLinxx® ActiPed for tracking steps, distances, heat, and activity time in conjunction with a USB access point. The (these) electronic devices can be wirelessly synchronized with the network support. In one embodiment, the program is based on the telephone may be available from the Alere TM Weight Talk ® program.

接受那曲酮及丁胺苯丙酮治療之個體可經由各種方法加入基於電話之計畫，包括網路加入與電話加入。在一些實施例中，基於電話之計畫亦包括一線支持以鑑別有資格進行臨床研究之患者，討論基於電話之計畫的益處，設定實際期望，輔助加入及向教練提出特定問題。 Individuals receiving treatment with naltrexone and bupropion can be added to a phone-based program via a variety of methods, including network joining and phone joining. In some embodiments, the telephone-based program also includes first-line support to identify patients eligible for clinical research, discuss the benefits of a phone-based program, set actual expectations, assist in joining, and present specific questions to the instructor.

在一較佳實施例中，用持續釋放(SR)那曲酮/SR丁胺苯丙酮之組 合(NB)單獨或與基於網路及/或基於電話之重量管理計畫結合治療與安慰劑或基於網路及/或基於電話之重量管理計畫單獨治療相比不增加或更佳減少過重及肥胖個體之嚴重不良心臟事件之發生，該等嚴重不良心臟事件定義為心血管性死亡、非致命性心肌梗塞或非致命性中風。在一些實施例中，用NB單獨或與基於網路及/或基於電話之重量管理計畫結合治療與安慰劑或基於網路及/或基於電話之重量管理計畫單獨治療相比不增加或更佳減少過重及肥胖個體之以下中之一或多者的發生：心血管性死亡、非致命性心肌梗塞、非致命性中風或需要住院治療之非致命性不穩定絞痛。在一些實施例中，用NB單獨或與基於網路及/或基於電話之重量管理計畫結合治療與安慰劑或基於網路及/或基於電話之重量管理計畫單獨治療相比不增加或更佳減少以下中之一或多者：所有病因死亡之發生；需要住院治療之不穩定絞痛之發生；及冠狀動脈血管再形成程序之發生。在一些實施例中，用NB單獨或與基於網路及/或基於電話之重量管理計畫結合治療與安慰劑或基於網路及/或基於電話之重量管理計畫單獨治療相比降低體重或改良收縮及/或舒張血壓。在一些實施例中，所治療個體為過重或肥胖個體且具有高不良心血管結果之風險。 In a preferred embodiment, a group of sustained release (SR) naltrexone/SR butyl acetophenone is used. NB alone or in combination with web-based and/or phone-based weight management programs does not increase or better reduce overweight than placebo or web-based and/or phone-based weight management programs alone And the occurrence of severe adverse cardiac events in obese individuals defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. In some embodiments, the combination of NB alone or with a web-based and/or phone-based weight management program does not increase or is compared to a placebo or network-based and/or phone-based weight management program alone treatment. Better to reduce the occurrence of one or more of the following overweight and obese individuals: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or non-fatal unstable colic requiring hospitalization. In some embodiments, the combination of NB alone or with a web-based and/or phone-based weight management program does not increase or is compared to a placebo or network-based and/or phone-based weight management program alone treatment. It is preferable to reduce one or more of the following: the occurrence of all causes of death; the occurrence of unstable colic which requires hospitalization; and the occurrence of coronary revascularization procedures. In some embodiments, using NB alone or in combination with a web-based and/or phone-based weight management program to reduce body weight or a placebo or network-based and/or phone-based weight management program alone Improve contraction and/or diastolic blood pressure. In some embodiments, the individual being treated is an overweight or obese individual and has a high risk of adverse cardiovascular outcomes.

在一些實施例中，用持續釋放(SR)那曲酮/SR丁胺苯丙酮之組合(NB)單獨或與基於網路及/或基於電話之重量管理計畫結合治療與日常護理(無研究藥物及最少生活方式介入計畫)相比提高以下中之一或多者：體重相對於基線之變化百分比；達成基線體重減輕至少5%、10%及15%之個體的百分比；及體重相對於基線之絕對變化。在一些實施例中，用NB單獨或與基於網路及/或基於電話之重量管理計畫結合治療與日常護理(無研究藥物及最少生活方式介入計畫)相比改良以下中之一或多者：心血管風險因素(腰圍、空腹三酸甘油酯、空腹LDL膽固醇及空腹HDL膽固醇中之一或多者)；生命徵象(收縮及/或舒 張血壓及心率中之一或多者)；葡萄糖代謝之量測結果(空腹葡萄糖、空腹胰島素及HOMA-IR中之一或多者)；源自患者報導之結果的量測結果(進食行為(例如BES)、性功能(例如ASEX量表)及重量相關生活品質(例如IWQOL-Lite)中之一或多者)。在一些實施例中，在治療第26週與基線相比量測上述提高或改良，在一些實施例中，在治療第52週或第78週與基線相比進行量測。在一些實施例中，所治療個體為女性或男性，18至60歲(包括18歲及60歲)，對於患有無併發症之肥胖的個體，BMI30且45kg/m2，且對於過重或肥胖且患有血脂異常及/或受控之高血壓的個體，BMI27且45kg/m2。在一些實施例中，所治療個體過重或肥胖且具有高不良心血管結果之風險。在一些實施例中，所治療個體不過重或肥胖且具有高不良心血管結果之風險。 In some embodiments, the combination of sustained release (SR) naltrexone/SR butyl acetophenone (NB) alone or in combination with a web-based and/or telephone-based weight management program for treatment and daily care (no research drug) And the least lifestyle intervention plan) compared to one or more of the following: percentage change in body weight relative to baseline; percentage of individuals achieving baseline weight loss of at least 5%, 10%, and 15%; and body weight relative to baseline Absolute change. In some embodiments, one or more of the following improvements are improved with NB alone or in combination with a web-based and/or telephone-based weight management program for treatment versus daily care (no study drug and minimal lifestyle intervention program) Cardiovascular risk factors (one or more of waist circumference, fasting triglyceride, fasting LDL cholesterol, and fasting HDL cholesterol); signs of life (one or more of contractile and/or diastolic blood pressure and heart rate); glucose Metabolic measurements (one or more of fasting glucose, fasting insulin, and HOMA-IR); measurements derived from patient-reported results (feed behavior (eg, BES), sexual function (eg, ASEX scale), and One or more of weight-related quality of life (eg IWQOL-Lite). In some embodiments, the increase or improvement is measured as compared to baseline at week 26 of treatment, and in some embodiments, at baseline 52 or 78 of the treatment compared to baseline. In some embodiments, the individual being treated is female or male, 18 to 60 years old (including 18 and 60 years old), for individuals with uncomplicated obesity, BMI 30 and 45 kg/m 2 and for individuals who are overweight or obese and have dyslipidemia and/or controlled hypertension, BMI 27 and 45kg/m 2 . In some embodiments, the treated individual is overweight or obese and has a high risk of adverse cardiovascular outcomes. In some embodiments, the individual being treated is not overweight or obese and has a high risk of adverse cardiovascular outcomes.

在一些實施例中，用持續釋放(SR)那曲酮/SR丁胺苯丙酮之組合(NB)與基於網路及/或基於電話之重量管理計畫結合治療與NB與用於親自傳達之重量減輕的密集行為改變(BMOD)計畫結合治療相比為相同的或提高以下中之一或多者：體重相對於基線之變化百分比；達成基線體重減輕至少5%、10%及15%之個體的百分比；及體重相對於基線之絕對變化。在一些實施例中，用NB單獨或與基於網路及/或基於電話之重量管理計畫結合與NB與用於親自傳達之重量減輕的密集行為改變(BMOD)計畫結合相比為相同的或改良以下中之一或多者：心血管風險因素(腰圍、空腹三酸甘油酯、空腹LDL膽固醇及空腹HDL膽固醇中之一或多者)；生命徵象(收縮及/或舒張血壓及心率中之一或多者)；葡萄糖代謝之量測結果(空腹葡萄糖、空腹胰島素及HOMA-IR中之一或多者)；源自患者報導之結果的量測結果(進食行為(例如BES)、性功能(例如ASEX量表)及重量相關生活品質(例如IWQOL-Lite)中之一或多者)。在一些實施例中，在治療第26週與基線相比量測上述提高或改良，在一些實施例中，在治療第52週或第78週與基線 相比進行量測。在一些實施例中，所治療個體為女性或男性，18至60歲(包括18歲及60歲)，對於患有無併發症之肥胖的個體，BMI30且45kg/m2，且對於過重或肥胖且患有血脂異常及/或受控之高血壓的個體，BMI27且45kg/m2。在一些實施例中，所治療個體過重或肥胖且具有高不良心血管結果之風險。在一些實施例中，所治療個體不過重或肥胖且具有高不良心血管結果之風險。 In some embodiments, the combination of sustained release (SR) naltrexone/SR butyl acetophenone (NB) is combined with a web-based and/or telephone-based weight management program to treat NB with weight for personal communication. The Reduced Intensive Behavioral Change (BMOD) program is the same as or increases one or more of the following: the percentage change in body weight relative to baseline; individuals achieving baseline weight loss of at least 5%, 10%, and 15% Percentage; and absolute change in body weight relative to baseline. In some embodiments, the use of NB alone or in combination with a network-based and/or phone-based weight management program is the same as the NB combined with a dense behavioral change (BMOD) plan for weight loss for personal communication. Or improve one or more of the following: cardiovascular risk factors (waist circumference, fasting triglyceride, fasting LDL cholesterol, and one or more of fasting HDL cholesterol); signs of life (systolic and/or diastolic blood pressure and heart rate) One or more); measurements of glucose metabolism (one or more of fasting glucose, fasting insulin, and HOMA-IR); measurements derived from patient-reported results (feed behavior (eg, BES), sex) Function (such as the ASEX scale) and weight-related quality of life (such as one or more of IWQOL-Lite). In some embodiments, the increase or improvement is measured as compared to baseline at week 26 of treatment, and in some embodiments, at baseline 52 or 78 of the treatment compared to baseline. In some embodiments, the individual being treated is female or male, 18 to 60 years old (including 18 and 60 years old), for individuals with uncomplicated obesity, BMI 30 and 45 kg/m 2 and for individuals who are overweight or obese and have dyslipidemia and/or controlled hypertension, BMI 27 and 45kg/m 2 . In some embodiments, the treated individual is overweight or obese and has a high risk of adverse cardiovascular outcomes. In some embodiments, the individual being treated is not overweight or obese and has a high risk of adverse cardiovascular outcomes.

在一些實施例中，個體之身體質量指數(BMI)為至少25kg/m2。在一些實施例中，個體之BMI為至少30kg/m2。在一些實施例中，個體之BMI為至少40kg/m2。在一些實施例中，個體之BMI小於25kg/m2，或在投與那曲酮及丁胺苯丙酮之過程期間產生小於25kg/m2之BMI。在此等實施例中，為健康或美化目的，可能有益為緩和後續重量增加或促進重量減輕，從而使BMI甚至進一步減小。在一些實施例中，個體已由醫師診斷為過重或肥胖。在一些實施例中，個體經鑑別(包括自身鑑別)為過重或肥胖，或經鑑別為已診斷為過重或肥胖。在一些實施例中，除過重以外，或除肥胖以外，個體罹患血脂異常及/或受控之高血壓。 In some embodiments, the individual has a body mass index (BMI) of at least 25 kg/m 2 . In some embodiments, the individual has a BMI of at least 30 kg/m 2 . In some embodiments, the individual has a BMI of at least 40 kg/m 2 . In some embodiments, the individual BMI less than 25kg / m 2, or generating BMI less than 25kg / m 2 during the course of administration of naltrexone and bupropion it. In such embodiments, for health or beautification purposes, it may be beneficial to mitigate subsequent weight gain or promote weight loss, thereby further reducing the BMI. In some embodiments, the individual has been diagnosed by the physician as being overweight or obese. In some embodiments, the individual is identified (including self-identification) as being overweight or obese, or identified as having been diagnosed as being overweight or obese. In some embodiments, the individual is suffering from dyslipidemia and/or controlled hypertension in addition to or in addition to obesity.

在一些實施例中，重量減輕之促進係由基線體重之變化百分比測量。在一些此等實施例中，重量減輕之量為、為約、為至少、為至少約初始體重之0.5%、1%、1.5%、2%、2.5%、3%、4%、5%、6%、7%、8%、9%、10%、12%、15%或15%以上，或前述值中之任何兩者所界定之範圍。在一些實施例中，重量減輕之促進係以重量增加相對於相關對照所經歷之重量增加量的降低測量，且重量增加之降低量為、為約、為至少、為至少約2%、5%、10%、15%、20%、25%、30%、40%、50%、60%、70%、80%、90%、100%、105%、110%、115%、120%或120%以上，或前述值中之任何兩者所界定之範圍。 In some embodiments, the weight loss promotion is measured as a percentage change in baseline body weight. In some such embodiments, the amount of weight loss is, about, at least, at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5% of the initial body weight, 6%, 7%, 8%, 9%, 10%, 12%, 15% or more, or a range defined by any two of the foregoing values. In some embodiments, the weight loss promotion is measured as a decrease in weight relative to the decrease in weight gain experienced by the relevant control, and the weight gain reduction is, about, at least, at least about 2%, 5%. , 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 105%, 110%, 115%, 120% or 120 % or more, or a range defined by any two of the foregoing values.

在一些實施例中，劑量經調節以使患者以每六個月基線體重之 約3%的速率減輕重量。然而，患者之重量減輕速率可由治療醫師基於患者之特定要求調節。 In some embodiments, the dose is adjusted to allow the patient to have a baseline weight every six months. A weight reduction of about 3%. However, the rate of weight loss of the patient can be adjusted by the treating physician based on the particular requirements of the patient.

在一些實施例中，緩和重量增加或促進重量減輕係藉由增加個體之飽腹感進行。在一些實施例中，緩和重量增加或促進重量減輕係藉由抑制個體之食慾進行。在一些實施例中，治療包含制定膳食方案及/或增加活動。 In some embodiments, mitigating weight gain or promoting weight loss is performed by increasing the satiety of the individual. In some embodiments, alleviating weight gain or promoting weight loss is performed by inhibiting the appetite of the individual. In some embodiments, the treatment comprises formulating a meal plan and/or increasing the activity.

在一些實施例中，那曲酮或組合療法(包括那曲酮與丁胺苯丙酮或氟西汀(fluoxetine)組合)之量足以影響重量減輕，降低心血管風險因素，提高胰島素敏感性，降低食品渴望，治療內臟脂肪病狀，在吸菸停止期間緩和重量增加或促進重量減輕，或向患有嚴重抑鬱之患者提供重量減輕療法。該等治療方法之非限制性實例揭示於以下專利中：美國專利第7,375,111號及第7,462,626號；美國專利公開案第2007/0275970號、第2007/0270450號、第2007/0117827號、第2007/0179168號、第2008/0214592號、第2007/0128298號及第2007/0129283號；美國專利申請案第12/751970號、第61/167486號及第61/293844號；及WO 2009/158114，其各自以全文引用的方式且出於所有目的併入本文中，包括(但不限於)出於以下之目的：描述影響重量減輕、降低心血管風險因素、提高胰島素敏感性、降低食品渴望、治療內臟脂肪病狀、在吸菸停止期間緩和重量增加或促進重量減輕及向患有嚴重抑鬱之患者提供重量減輕療法之方法。在一些實施例中，心血管風險因素包括以下中之一或多者：總膽固醇水準、LDL膽固醇水準、HDL膽固醇水準、三酸甘油酯水準、葡萄糖水準及胰島素水準。在一些實施例中，心血管風險因素包括以下中之一或多者：總膽固醇水準、HDL膽固醇水準及三酸甘油酯水準。 In some embodiments, the amount of naltrexone or combination therapy (including naltrexone in combination with bupropion or fluoxetine) is sufficient to affect weight loss, reduce cardiovascular risk factors, increase insulin sensitivity, and reduce food cravings To treat visceral fat conditions, to alleviate weight gain or to promote weight loss during smoking cessation, or to provide weight loss therapy to patients with severe depression. Non-limiting examples of such treatments are disclosed in U.S. Patent Nos. 7,375,111 and 7,462,626; U.S. Patent Publication Nos. 2007/0275970, 2007/0270450, 2007/0117827, 2007/ U.S. Patent Application Serial Nos. 12/751,970, 61/167,486 and 61/293,844; and WO 2009/158114, the disclosure of which is incorporated herein by reference. Each is hereby incorporated by reference in its entirety for all purposes, including but not limited to the following purposes: describing effects on weight loss, lowering cardiovascular risk factors, increasing insulin sensitivity, reducing food cravings, treating viscera A fatty condition, a method of alleviating weight gain or promoting weight loss during smoking cessation and providing weight loss therapy to patients suffering from severe depression. In some embodiments, the cardiovascular risk factor comprises one or more of the following: total cholesterol level, LDL cholesterol level, HDL cholesterol level, triglyceride level, glucose level, and insulin level. In some embodiments, the cardiovascular risk factor comprises one or more of the following: total cholesterol level, HDL cholesterol level, and triglyceride level.

在一些實施例中，本文所述之重量減輕療法之提高之功效包含結果量測之改良。舉例而言，在一些實施例中，提高之功效提高重量 減輕之量。在一些實施例中，功效提高降低不良事件之頻率或嚴重性，該等不良事件包括(但不限於)噁心、便秘、嘔吐、頭暈、口乾、頭痛及失眠。在一些實施例中，提高之功效改良另一次要終點，包括(但不限於)腰圍、高敏感性C-反應蛋白(hs-CRP)水準、三酸甘油酯水準、HDL膽固醇水準或LDL/HDL膽固醇水準比率。如熟習此項技術者所認可，在一些情況下，需要降低腰圍、hs-CRP水準、三酸甘油酯水準及LDL/HDL膽固醇水準比率及提高HDL膽固醇水準。在一些實施例中，與基線或相關對照相比，結果量測之改良為、為約、為至少或為至少約1、2、3、4、5、7、10、12、15、20、30、40、50、60、70、80、90或100%或在由此等值中之任何兩者所界定之範圍內。 In some embodiments, the improved efficacy of the weight loss therapy described herein includes an improvement in the result measurement. For example, in some embodiments, the improved efficacy increases weight Reduce the amount. In some embodiments, increased efficacy reduces the frequency or severity of adverse events including, but not limited to, nausea, constipation, vomiting, dizziness, dry mouth, headache, and insomnia. In some embodiments, the improved efficacy improves another secondary endpoint including, but not limited to, waist circumference, high sensitivity C-reactive protein (hs-CRP) levels, triglyceride levels, HDL cholesterol levels, or LDL/HDL Cholesterol level ratio. As recognized by those skilled in the art, in some cases, it is desirable to reduce waist circumference, hs-CRP levels, triglyceride levels, and LDL/HDL cholesterol levels and increase HDL cholesterol levels. In some embodiments, the improvement in the resulting measurement is about, at least, or at least about 1, 2, 3, 4, 5, 7, 10, 12, 15, 20, as compared to the baseline or related controls. 30, 40, 50, 60, 70, 80, 90 or 100% or within the range defined by any two of these equivalents.

在一些實施例中，那曲酮或那曲酮與丁胺苯丙酮每天各投與一次。在一些實施例中，將那曲酮及丁胺苯丙酮各分成相等劑量且每天投與超過一次。在一些實施例中，將那曲酮及丁胺苯丙酮各分成不相等劑量且每天投與超過一次。在一些實施例中，將那曲酮及丁胺苯丙酮分成不同劑量數且每天投與不同次數。在一個該實施例中，劃分那曲酮或丁胺苯丙酮中之一者的劑量，而不劃分另一者之劑量。 In some embodiments, naltrexone or naltrexone and butyl ketone are each administered once a day. In some embodiments, naltrexone and butyl ketone are each divided into equal doses and administered more than once a day. In some embodiments, naltrexone and butyl ketone are each divided into unequal doses and administered more than once a day. In some embodiments, naltrexone and butyl ketone are divided into different dosage numbers and administered different times per day. In one such embodiment, the dose of one of naltrexone or butyl ketone is divided without dividing the dose of the other.

在一些實施例中，每天一次、兩次、三次、四次或四次以上投與那曲酮及丁胺苯丙酮中之一者或兩者。任一或兩種化合物可每天投與少於一次，例如每2、3、4、5、6、7、8、9、10、11、12、13或14天或每1或2週或由前述值中之任何兩者所界定之範圍投與一次。在一些實施例中，每天投與次數恆定(例如每天一次)。在其他實施例中，投與次數可變。投與次數可視以下因素而變化：劑型有效性、所觀察到之副作用、外部因素(例如另一藥物之變化)或劑型已投與之時間長度。 In some embodiments, one or both of naltrexone and butyl ketone are administered once, twice, three times, four times, or more than once a day. Any one or two compounds may be administered less than once a day, for example every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days or every 1 or 2 weeks or by The range defined by any two of the foregoing values is applied once. In some embodiments, the number of administrations per day is constant (eg, once a day). In other embodiments, the number of appointments is variable. The number of administrations may vary depending on factors such as the effectiveness of the dosage form, the side effects observed, external factors (such as changes in another drug), or the length of time the dosage form has been administered.

在一些實施例中，那曲酮之日劑量可在約4mg至約50mg，或約4mg至約32mg，或約8mg至約32mg，或約8mg至約16mg範圍內。 在一些實施例中，日劑量為約4mg、約8mg、約12mg、約16mg、約32mg或約48mg那曲酮或由前述值中之任何兩者所界定之範圍。可基於患者之重量選擇特定劑量。可基於另一共投與化合物之特性、劑量及/或給藥時程選擇特定劑量。然而，在一些實施例中，可能需要使用此等範圍以外之劑量。在一些實施例中，以單一口服劑型投與日劑量。在一些實施例中，那曲酮之日劑量相同，且在一些實施例中，日劑量不同。 In some embodiments, the daily dose of naltrexone can range from about 4 mg to about 50 mg, or from about 4 mg to about 32 mg, or from about 8 mg to about 32 mg, or from about 8 mg to about 16 mg. In some embodiments, the daily dose is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg, or about 48 mg of naltrexone or a range defined by any of the foregoing values. A particular dose can be selected based on the weight of the patient. A particular dose can be selected based on the characteristics, dosage, and/or schedule of administration of another co-administered compound. However, in some embodiments, it may be desirable to use doses outside of these ranges. In some embodiments, the daily dose is administered in a single oral dosage form. In some embodiments, the daily dose of naltrexone is the same, and in some embodiments, the daily dose is different.

在一些實施例中，丁胺苯丙酮之日劑量可在約30mg至約500mg，或約30mg至約360mg，或約90mg至約360mg範圍內。在一些實施例中，日劑量為約30mg、約90mg、約180mg、約360mg或約450mg丁胺苯丙酮或由前述值中之任何兩者所界定之範圍。可基於患者之重量選擇特定劑量。可基於另一共投與化合物之特性、劑量及/或給藥時程選擇特定劑量。然而，在一些實施例中，可能需要使用此等範圍以外之劑量。在一些實施例中，以單一口服劑型投與日劑量。在一些實施例中，丁胺苯丙酮之日劑量相同，且在一些實施例中，日劑量不同。 In some embodiments, the daily dose of bupropion can range from about 30 mg to about 500 mg, or from about 30 mg to about 360 mg, or from about 90 mg to about 360 mg. In some embodiments, the daily dose is about 30 mg, about 90 mg, about 180 mg, about 360 mg, or about 450 mg of butyl ketone or a range defined by any of the foregoing values. A particular dose can be selected based on the weight of the patient. A particular dose can be selected based on the characteristics, dosage, and/or schedule of administration of another co-administered compound. However, in some embodiments, it may be desirable to use doses outside of these ranges. In some embodiments, the daily dose is administered in a single oral dosage form. In some embodiments, the daily dose of butanone is the same, and in some embodiments, the daily dose is different.

本文所述之組合物可分配、提供至患者以自身投與或投與個體。在一些實施例中，那曲酮/丁胺苯丙酮組合療法包括第三化合物。 The compositions described herein can be dispensed, provided to a patient for their own administration or administered to an individual. In some embodiments, the naltrexone / butyl ketone combination therapy comprises a third compound.

在一些實施例中，那曲酮及/或丁胺苯丙酮以口服劑型提供或投與。在一些實施例中，口服劑型呈丸劑、錠劑、核心、膠囊、囊片、鬆散粉末、溶液或懸浮液形式。在一較佳實施例中，口服劑型呈丸劑、錠劑或膠囊形式。在一些實施例中，那曲酮/丁胺苯丙酮組合療法以單一口服劑型提供。在一些實施例中，口服劑型呈如美國專利公開案第2008/0113026號中所述之三層錠劑形式，該案以全文引用的方式且出於所有目的併入本文中，包括(但不限於)出於以下之目的：描 述三層錠劑、製備及調配三層錠劑之方法及其投與方法。 In some embodiments, naltrexone and/or butyl ketone is provided or administered in an oral dosage form. In some embodiments, the oral dosage form is in the form of a pill, lozenge, core, capsule, caplet, loose powder, solution or suspension. In a preferred embodiment, the oral dosage form is in the form of a pill, lozenge or capsule. In some embodiments, the naltrexone/bupropion combination therapy is provided in a single oral dosage form. In some embodiments, the oral dosage form is in the form of a three-layer tablet as described in U.S. Patent Publication No. 2008/0113026, which is hereby incorporated by reference in its entirety herein in Limited to) for the following purposes: The invention relates to a three-layer tablet, a method for preparing and formulating a three-layer tablet, and a method for administering the same.

在一些實施例中，在治療期間那曲酮及丁胺苯丙酮中之至少一者以變化之頻率投與。在一些此等實施例中，變化之頻率包含隨時間降低之頻率。舉例而言，可最初每天投與那曲酮及丁胺苯丙酮中之一者或兩者超過一次，繼而在治療之後續時間每天僅投與一次。在一些實施例中，那曲酮及丁胺苯丙酮中之至少一者的日劑量一致但投與頻率變化。舉例而言，在一些實施例中，最初每天兩次投與那曲酮及丁胺苯丙酮各兩錠，而在治療後續時間每天一次投與那曲酮及丁胺苯丙酮各四錠。或者，在一些實施例中，在治療後續時間投與那曲酮及丁胺苯丙酮各一或兩錠，其中該一或兩錠與最初每天兩次投與那曲酮及丁胺苯丙酮各兩錠具有相等總日劑量。 In some embodiments, at least one of naltrexone and acetophenone is administered at a varying frequency during the treatment period. In some such embodiments, the frequency of the change comprises a frequency that decreases over time. For example, one or both of naltrexone and butyl ketone may be initially administered more than once per day, and then only once per day during the subsequent treatment period. In some embodiments, the daily dose of at least one of naltrexone and butyl ketone is consistent but the frequency of administration varies. For example, in some embodiments, two ingots of each of naltrexone and butyl ketone are initially administered twice daily, and four ingots of each of naltrexone and butyl ketone are administered once daily at a subsequent time of treatment. Alternatively, in some embodiments, one or two ingots of each of naltrexone and acetophenone are administered at a subsequent time of treatment, wherein the one or two ingots are administered with two doses of naltrexone and acetophenone twice daily. Have an equal total daily dose.

在那曲酮及丁胺苯丙酮中之一者或兩者以控制釋放或持續釋放(SR)調配物形式每天投與少於一次的一些實施例中，選擇劑量以使得患者接受與本文所述之日劑量大致相同的日劑量。 In some embodiments in which one or both of naltrexone and butyl ketone are administered less than once a day in a controlled release or sustained release (SR) formulation, the dosage is selected such that the patient is accepted as described herein. The daily dose is approximately the same daily dose.

在一些實施例中，單獨或組合療法中之那曲酮不為那曲酮之螯合形式。舉例而言，在一些實施例中，那曲酮呈非螯合控制釋放調配物形式。在一些實施例中，那曲酮為非螯合持續釋放調配物。在較佳實施例中，至少50%那曲酮在投藥24小時內釋放。 In some embodiments, the naltrexone in the combination therapy alone or in combination is not a chelated form of naltrexone. For example, in some embodiments, naltrexone is in the form of a non-chelating controlled release formulation. In some embodiments, the naltrexone is a non-chelating sustained release formulation. In a preferred embodiment, at least 50% of naltrexone is released within 24 hours of administration.

在一些實施例中，那曲酮或丁胺苯丙酮中之至少一者在整個治療期間以一致日劑量投與。在一些實施例中，那曲酮或丁胺苯丙酮中之至少一者在治療期間以變化之日劑量投與。在一些此等實施例中，日劑量包含隨時間增加之日劑量。在一些此等實施例中，日劑量包含隨時間降低之日劑量。 In some embodiments, at least one of naltrexone or butyl ketone is administered at a consistent daily dose throughout the treatment period. In some embodiments, at least one of naltrexone or butyl ketone is administered at a varying daily dose during treatment. In some such embodiments, the daily dose comprises a daily dose that increases over time. In some such embodiments, the daily dose comprises a daily dose that decreases over time.

在一些實施例中，個別地投與那曲酮及丁胺苯丙酮。在一些實施例中，以包含那曲酮及丁胺苯丙酮之單一醫藥組合物形式投與那曲酮及丁胺苯丙酮。在一些實施例中，那曲酮或丁胺苯丙酮中之至少一 者呈持續釋放或控制釋放調配物形式。舉例而言，那曲酮之持續釋放形式描述於美國專利公開案第2007/0281021號中，該案以全文引用的方式且出於所有目的併入本文中，包括(但不限於)出於以下之目的：描述那曲酮及丁胺苯丙酮之持續釋放形式、其製備及調配為適合劑型之方法及其投與方法。在一些實施例中，那曲酮或丁胺苯丙酮中之至少一者與生理學上可接受之載劑、稀釋劑或賦形劑或其組合一起投與。那曲酮/丁胺苯丙酮組合、其調配物及其投與方法之非限制性實例揭示於美國專利第7,375,111號及第7,462,626號中，該兩者均以全文引用的方式且出於所有目的併入本文中，包括(但不限於)出於以下之目的：描述那曲酮與丁胺苯丙酮之組合、其製備及調配為適合劑型之方法及其投與方法。本文提及使用或投與那曲酮及那曲酮/丁胺苯丙酮組合應理解為包括本文所揭示或提及之所有投藥模式，包括(但不限於)各別投藥、以單一劑型投藥、以鹽及/或代謝物形式投藥及/或以持續釋放形式投藥。本申請案化合物之調配及投與技術可見於「Remington's Pharmaceutical Sciences,」Mack Publishing Co.,Easton,PA，第18版，1990，其以全文引用的方式併入本文中。 In some embodiments, naltrexone and butyl ketone are administered separately. In some embodiments, naltrexone and butyl ketone are administered as a single pharmaceutical composition comprising naltrexone and butyl ketone. In some embodiments, at least one of naltrexone or acetophenone The person is in the form of a sustained release or controlled release formulation. For example, the sustained release form of naltrexone is described in U.S. Patent Publication No. 2007/0281021, which is hereby incorporated by reference in its entirety in its entirety for all its purposes in OBJECTIVE: To describe the sustained release form of naltrexone and acetophenone, the preparation thereof and the method of formulating it into a suitable dosage form, and the method of administration thereof. In some embodiments, at least one of naltrexone or butyl ketone is administered with a physiologically acceptable carrier, diluent or excipient, or a combination thereof. Non-limiting examples of naltrexone/butyl ketone combination, formulations thereof, and methods of administration thereof are disclosed in U.S. Patent Nos. 7,375,111 and 7,462,626 each incorporated by reference in entirety in As used herein, including, but not limited to, the following: a combination of naltrexone and acetophenone, a process for its preparation and formulation into a suitable dosage form, and methods of administration thereof. Reference herein to the use or administration of a combination of naltrexone and naltrexone / butyl ketone should be understood to include all modes of administration disclosed or referred to herein, including but not limited to, separate administration, administration in a single dosage form, salt administration And/or metabolite form administration and/or administration in sustained release form. Techniques for formulation and administration of the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th Edition, 1990, which is incorporated herein by reference in its entirety.

在一些實施例中，那曲酮在丁胺苯丙酮前投與。在一些實施例中，那曲酮在丁胺苯丙酮後投與。在一些實施例中，共投與那曲酮與丁胺苯丙酮。如本文中所用之共投與包括以單一劑型投與或同時或幾乎同時投與各別劑型。 In some embodiments, the naltrexone is administered prior to bupropion. In some embodiments, the naltrexone is administered after bupropion. In some embodiments, naltrexone and acetophenone are co-administered. Co-administration as used herein includes administration in a single dosage form or simultaneous or nearly simultaneous administration of separate dosage forms.

在一些實施例中，持續投與那曲酮及丁胺苯丙酮1、2、3、4、6、8、10、12、16、20、24、36、48或52週或由前述值中之任何兩者所界定之範圍或約1、2、3、4、6、8、10、12、16、20、24、36、48或52週或由前述值中之任何兩者所界定之範圍。在一些實施例中，持續投與那曲酮及丁胺苯丙酮直至疾病、病症或病狀之症狀減輕穩定1、2、3、4、5、6週或6週以上或由前述值中之任何兩者所界定之範 圍或約1、2、3、4、5、6週或6週以上或由前述值中之任何兩者所界定之範圍。舉例而言，在一些實施例中，持續施以那曲酮/丁胺苯丙酮組合療法直至個體之重量增加的緩和或重量減輕的促進穩定1、2、3、4、5、6週或6週以上或由前述值中之任何兩者所界定之範圍或約1、2、3、4、5、6週或6週以上或由前述值中之任何兩者所界定之範圍。在一些實施例中，持續投與那曲酮或那曲酮與丁胺苯丙酮直至個體不再需要治療。 In some embodiments, continuous administration of naltrexone and acetophenone 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, or 52 weeks or from the foregoing values Any range defined by either, or a range of about 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, or 52 weeks or defined by any of the foregoing values . In some embodiments, naltrexone and butyl ketone are continuously administered until the symptoms of the disease, disorder, or condition are alleviated for 1, 2, 3, 4, 5, 6 weeks, or 6 weeks or more, or by any of the foregoing values The two defined by the two A range of about 1, 2, 3, 4, 5, 6 weeks, or more than 6 weeks or defined by any of the foregoing values. For example, in some embodiments, continuous administration of naltrexone/bupropion combination therapy until the weight gain of the individual is promoted or the weight loss promotes stability for 1, 2, 3, 4, 5, 6 weeks or 6 weeks. The above or a range defined by any two of the foregoing values or a range defined by or by any of the foregoing values of 1, 2, 3, 4, 5, 6 weeks or more. In some embodiments, naltrexone or naltrexone and butyl ketone are continuously administered until the individual no longer needs treatment.

在一些實施例中，「投與」藥物包括個體自身獲得且攝入藥物。舉例而言，在一些實施例中，個體自藥房獲得藥物且根據本文所提供之方法自投與該藥物。 In some embodiments, "administering" a drug includes the individual's own acquisition and ingestion of the drug. For example, in some embodiments, an individual obtains a drug from a pharmacy and self-administers the drug according to the methods provided herein.

在一些實施例中，本發明係關於一種套組。該套組可包括一或多種單位劑型，其包含那曲酮、丁胺苯丙酮或那曲酮與丁胺苯丙酮。單位劑型可屬於口服調配物。舉例而言，單位劑型可包含丸劑、錠劑或膠囊。套組可包括複數種單位劑型。在一些實施例中，單位劑型處於容器中。在一些實施例中，劑型為單一口服劑型，其包含那曲酮及丁胺苯丙酮或其醫藥學上可接受之鹽。 In some embodiments, the present invention is directed to a kit. The kit may include one or more unit dosage forms comprising naltrexone, butyl ketone or naltrexone and butyl ketone. The unit dosage form can be an oral formulation. For example, unit dosage forms can contain pills, troches, or capsules. The kit can include a plurality of unit dosage forms. In some embodiments, the unit dosage form is in a container. In some embodiments, the dosage form is a single oral dosage form comprising naltrexone and acetophenone or a pharmaceutically acceptable salt thereof.

本文所揭示之方法、組合物及套組可包括資訊。資訊可呈由調節藥物製造、使用或銷售之政府機構所規定之形式，該注意事項反映該機構對用於人類或獸醫投與之藥物形式的批准。資訊例如可為美國食品及藥物管理局(U.S.Food and Drug Administration)關於處方藥物所批准之標籤或經批准之產品插頁。資訊可包括關於劑量及劑型、投藥時程及投藥途徑、不良事件、禁忌、警告及預防措施、藥物相互作用及在特定群體中使用所要求的資訊(參見例如21 C.FR.§201.57，其以全文引用的方式併入本文中)，且在一些實施例中要求呈現於藥物上或與藥物關聯以進行藥物銷售。包含在相容醫藥載劑中調配的本發明之持續釋放那曲酮調配物的劑型亦可經製備、置於適當容器中且經 標記以治療指定病狀。在一些實施例中，套組係用於銷售需要政府機構(諸如美國食品及藥物管理局)批准且經受其調節之處方藥物。在一些實施例中，套組包含該機構(諸如FDA)要求之標籤或產品插頁以例如在美國向消費者銷售該套組。 The methods, compositions, and kits disclosed herein can include information. Information may be in the form prescribed by a government agency that regulates the manufacture, use, or sale of a drug, which reflects the agency's approval of the form of the drug for human or veterinary administration. The information may be, for example, a label approved by the US Food and Drug Administration for prescription drugs or an approved product insert. Information may include information about dosage and dosage form, time course of administration and route of administration, adverse events, contraindications, warnings and precautions, drug interactions, and use in specific populations (see, for example, 21 C.FR. §201.57 , Incorporated herein by reference in its entirety, and in some embodiments it is claimed that it is presented on or in connection with a drug for drug sales. A dosage form comprising a sustained release naltrexone formulation of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled to treat the indicated condition. In some embodiments, the kit is used to sell a prescription drug that requires approval by a government agency, such as the U.S. Food and Drug Administration, and is subject to its conditioning. In some embodiments, the kit includes a label or product insert required by the institution (such as the FDA) to, for example, sell the kit to a consumer in the United States.

資訊可包含以約4mg、約8mg、約12mg、約16mg、約32mg或約48mg那曲酮或其醫藥學上可接受之鹽的劑量投與單位劑型之說明。資訊可包含以約30mg、約90mg、約180mg、約360mg或約450mg丁胺苯丙酮或其醫藥學上可接受之鹽的劑量投與單位劑型之說明。此等說明可以各種方式提供。資訊可包含關於何時投與單位劑型之說明。舉例而言，資訊可包含關於相對於投與另一藥物或食品何時投與單位劑型之說明。在較佳實施例中，資訊指導個體將那曲酮或那曲酮與丁胺苯丙酮與食品、較佳餐食一起攝入。 The information can include instructions for administering the unit dosage form at a dose of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg, or about 48 mg of naltrexone or a pharmaceutically acceptable salt thereof. The information can include instructions for administering the unit dosage form at a dose of about 30 mg, about 90 mg, about 180 mg, about 360 mg, or about 450 mg of butyl ketone or a pharmaceutically acceptable salt thereof. These instructions can be provided in a variety of ways. The information may include instructions on when to inject the unit dosage form. For example, the information can include instructions regarding when to administer a unit dosage form relative to the administration of another drug or food. In a preferred embodiment, the information directs the individual to ingest naltrexone or naltrexone with butanone and the food, preferably a meal.

一些實施例包括如下較佳經印刷之資訊：相較於攝入相同量之那曲酮或其醫藥學上可接受之鹽而不攝入食品，將那曲酮或其醫藥學上可接受之鹽與食品一起攝入使那曲酮或其醫藥學上可接受之鹽之生物利用率增加。一些實施例包括如下較佳經印刷之資訊：相較於攝入相同量之丁胺苯丙酮或其醫藥學上可接受之鹽而不攝入食品，將丁胺苯丙酮或其醫藥學上可接受之鹽與食品一起攝入使丁胺苯丙酮或其醫藥學上可接受之鹽之生物利用率增加。一些實施例包括如下較佳經印刷之資訊：相較於攝入相同量之那曲酮與丁胺苯丙酮或其醫藥學上可接受之鹽而不攝入食品，將那曲酮與丁胺苯丙酮或其醫藥學上可接受之鹽與食品一起攝入使那曲酮及/或丁胺苯丙酮或其醫藥學上可接受之鹽之生物利用率增加。一些實施例包括如下較佳經印刷之資訊：相較於攝入相同量之那曲酮與丁胺苯丙酮或其醫藥學上可接受之鹽而不攝入食品，將那曲酮及/或丁胺苯丙酮或其醫藥學上可接受之鹽與食品一起攝入產生較少或較不嚴重之藥物相關不良事件。在一些實施例 中，不良事件為胃腸事件。在一些實施例中，向個體提供關於生物利用率、不良事件之資訊或關於投藥方案之說明，向個體提供包含資訊中所述之藥物的劑型，且根據該資訊投與該劑型。在一些實施例中，個體為需要該藥物之患者。在一些實施例中，投與該藥物作為本文所述疾病之療法。 Some embodiments include the preferred printed information that naltrexone or a pharmaceutically acceptable salt thereof is compared to the ingestion of the same amount of naltrexone or a pharmaceutically acceptable salt thereof without ingesting the food. The ingestion of food together increases the bioavailability of naltrexone or its pharmaceutically acceptable salt. Some embodiments include information that is preferably printed as follows: butyl mercapto or pharmaceutically acceptable compared to the intake of the same amount of acetophenone or a pharmaceutically acceptable salt thereof without ingesting the food The intake of the salt with the food increases the bioavailability of the acetophenone or its pharmaceutically acceptable salt. Some embodiments include information that is preferably printed as follows: naltrexone and acetophenone are compared to the intake of the same amount of naltrexone and acetophenone or a pharmaceutically acceptable salt thereof without ingesting food. The ingestion of the pharmaceutically acceptable salt thereof with the food increases the bioavailability of naltrexone and/or acetophenone or a pharmaceutically acceptable salt thereof. Some embodiments include the following preferably printed information: naltrexone and/or butylamine compared to the intake of the same amount of naltrexone and acetophenone or a pharmaceutically acceptable salt thereof without ingesting the food Ingestion of propiophenone or a pharmaceutically acceptable salt thereof with the food produces less or less severe drug-related adverse events. In some embodiments Among them, the adverse event was a gastrointestinal event. In some embodiments, the individual is provided with information regarding bioavailability, adverse events, or instructions regarding a dosing regimen, the dosage form comprising the drug described in the information is provided to the individual, and the dosage form is administered based on the information. In some embodiments, the individual is a patient in need of the drug. In some embodiments, the drug is administered as a therapy for the diseases described herein.

在一些實施例中，本文所揭示之方法、組合物及套組可包括關於加入及/或存取基於網路及/或基於電話之重量管理計畫的資訊。在一些實施例中，加入基於網路及/或基於電話之重量管理計畫為獲得治療藥物之要求。在一些實施例中，僅在獲得治療藥物之處方或實際藥物後才允許加入基於網路及/或基於電話之重量管理計畫。在一些實施例中，治療方法包含在接受治療藥物前加入基於網路及/或基於電話之重量管理計畫及/或包含加入基於網路及/或基於電話之重量管理計畫作為接受治療藥物之條件。在一些實施例中，資訊包括用於加入及/或存取基於網路及/或基於電話之重量管理計畫之獨特登錄或加入密鑰。 In some embodiments, the methods, compositions, and kits disclosed herein can include information regarding joining and/or accessing network-based and/or phone-based weight management programs. In some embodiments, a network-based and/or telephone-based weight management program is added to obtain a therapeutic drug. In some embodiments, network-based and/or phone-based weight management programs are allowed to be added only after the treatment drug is obtained or after the actual drug. In some embodiments, the method of treatment comprises adding a web-based and/or phone-based weight management plan prior to receiving the therapeutic agent and/or including adding a network-based and/or phone-based weight management program as a therapeutic drug The conditions. In some embodiments, the information includes a unique login or join key for joining and/or accessing a network-based and/or phone-based weight management plan.

說明及/或資訊可以各種形式呈現，包括於適合媒體或基板上印刷之資訊(例如上面印刷資訊之一張或多張紙)、電腦可讀媒體(例如上面已記錄資訊之磁片、CD等)或可經由網際網路存取之網址。印刷資訊可例如提供於與藥品關聯之標籤、藥品之容器上，與藥品一起包裝或除藥品以外各別地給與患者，或以患者可獨立獲得資訊之方式(例如網站)提供。印刷資訊亦可向參與患者治療之醫療照護者提供。在一些實施例中，以口述方式向個人提供資訊。 The description and/or information may be presented in various forms, including information suitable for printing on a medium or substrate (eg, one or more sheets of printed information), computer readable media (eg, magnetic sheets, CDs, etc. on which information has been recorded) ) or a web address accessible via the Internet. The printed information can be provided, for example, on a label associated with the drug, on a container of the drug, packaged with or separately from the drug, or provided in a manner that the patient can obtain information independently (eg, a website). Printed information can also be provided to medical caregivers who are involved in patient care. In some embodiments, information is provided to the individual in an oral manner.

一些實施例包含適用於商業銷售之治療包裝。一些實施例包含容器。容器可呈如此項技術中已知由醫藥學上可接受之材料製成之任何習知形狀或形式，例如紙或紙板盒、玻璃或塑膠瓶或罐、可再密封袋(例如用於容納錠劑之「再填充物」以置於不同容器中)或具有根據 治療時程自包裝壓出之個別劑量的發泡包裝。所用容器可取決於所涉及之精確劑型，例如習知紙板盒通常不用於容納液體懸浮液。可將超過一個容器於單一包裝中一起用以出售單一劑型。舉例而言，錠劑可容納於小瓶中，而該小瓶又容納於盒中。包裝及施配器以及口服劑型之非限制性實例揭示於美國專利公開案第2008/0110792號及第2008/0113026號中，該兩者均以全文引用的方式且出於所有目的併入本文中，包括(但不限於)出於以下之目的：描述那曲酮與丁胺苯丙酮之組合、其製備及調配為適合劑型之方法、其包裝及施配方法及其投與方法。 Some embodiments comprise a therapeutic package suitable for commercial sale. Some embodiments comprise a container. The container may be in any conventional shape or form known in the art from pharmaceutically acceptable materials, such as paper or cardboard boxes, glass or plastic bottles or cans, resealable bags (eg for holding ingots) "refill" of the agent to be placed in a different container) or have a basis The treatment schedule consists of individual doses of blister packs that are extruded from the package. The container used may depend on the precise dosage form involved, for example, conventional cartons are typically not used to hold a liquid suspension. More than one container can be used together in a single package to sell a single dosage form. For example, the tablet can be contained in a vial that is in turn contained in the cartridge. Non-limiting examples of packaging and dispensers, as well as oral dosage forms, are disclosed in U.S. Patent Publication Nos. 2008/0110792 and 2008/0113026, both of which are incorporated herein by reference in their entirety, These include, but are not limited to, the following: a combination of naltrexone and acetophenone, a method of preparing and formulating the same as a suitable dosage form, a method of packaging and dispensing thereof, and a method of administration thereof.

資訊可藉由如下方式與容器關聯，例如：書寫於黏著於容納本文所述劑型之瓶的標籤(例如處方標籤或各別標籤)上；以書寫之包裝插頁形式包括在容器內部，諸如在容納單位劑量包裝之盒內部；直接塗覆於容器上，諸如印刷於盒壁上；或藉由繫栓或膠黏附著，例如以經由帶子、繩索或其他線、繫索或繫鏈型裝置附著於瓶頸之說明卡片形式。資訊可直接印刷於單位劑量包裝或發泡包裝或發泡卡片上。 Information may be associated with the container by, for example, writing on a label (e.g., a prescription label or a separate label) that is adhered to a bottle containing the dosage form described herein; in the form of a written package insert, included in the interior of the container, such as in The interior of the box containing the unit dose package; applied directly to the container, such as printed on the wall of the box; or attached by tethering or gluing, for example to attach via a strap, rope or other thread, lanyard or tethered device In the form of a description of the bottleneck. Information can be printed directly on a unit dose package or a blister pack or foam card.

術語「丁胺苯丙酮」在本文中可以一般方式用於指丁胺苯丙酮之游離鹼、醫藥學上可接受之丁胺苯丙酮鹽(包括無水形式，例如無水丁胺苯丙酮)、丁胺苯丙酮代謝物(例如羥基丁胺苯丙酮、蘇型氫丁胺苯丙酮(threohydrobupropion)及赤型氫丁胺苯丙酮(erythrohydrobupropion))、丁胺苯丙酮異構體或其混合物。 The term "ampicanilide" is used herein in a generic manner to mean the free base of butyl ketone, a pharmaceutically acceptable butanide (including anhydrous forms such as anhydrous butanone), butylamine. a propiophenone metabolite (eg, hydroxybutanol, threohydrobupropion, and erythrohydrobupropion), butylbutazone isomer, or a mixture thereof.

術語「那曲酮」在本文中可以一般方式用於指那曲酮之游離鹼、醫藥學上可接受之那曲酮鹽(包括水合物及無水形式，例如那曲酮鹽酸鹽二水合物及無水那曲酮鹽酸鹽)、那曲酮代謝物、那曲酮異構體或其混合物。 The term "naltrexone" is used herein in a generic manner to mean the free base of naltrexone, a pharmaceutically acceptable naltrexone salt (including hydrates and anhydrous forms such as naltrexone hydrochloride dihydrate and anhydrous naltrexone). Hydrochloride), a naltrexone metabolite, a naltrexone isomer or a mixture thereof.

如本文所用之術語「醫藥學上可接受之鹽」係指化合物之調配物，其不對其所投與之生物體造成嚴重刺激且不去除化合物之生物活 性及特性。可藉由常規實驗獲得醫藥鹽。醫藥學上可接受之鹽的非限制性實例包括丁胺苯丙酮鹽酸鹽、雷達法辛(radafaxine)鹽酸鹽、那曲酮鹽酸鹽及6-β那曲醇(naltrexol)鹽酸鹽。 The term "pharmaceutically acceptable salt" as used herein refers to a formulation of a compound that does not cause severe irritation to the organism to which it is administered and does not remove the biological activity of the compound. Sex and characteristics. Pharmaceutical salts can be obtained by routine experimentation. Non-limiting examples of pharmaceutically acceptable salts include butyl ketone hydrochloride, radafaxine hydrochloride, naltrexone hydrochloride, and 6-beta naltrexol hydrochloride.

在本發明通篇中，當藉由名稱提及特定化合物(例如丁胺苯丙酮或那曲酮)時，應瞭解本發明之範疇涵蓋此名稱化合物之醫藥學上可接受之鹽、酯、醯胺或代謝物。舉例而言，在本文之任何實施例中，那曲酮之活性代謝物(例如6-β那曲醇)可與那曲酮組合或替代其使用。在本文之任何實施例中，丁胺苯丙酮之活性代謝物(包括S,S-羥基丁胺苯丙酮，亦即雷達法辛)可與丁胺苯丙酮組合或替代其使用。 Throughout the present invention, when reference is made to a particular compound by name (eg, acetophenone or naltrexone), it is understood that the scope of the invention encompasses pharmaceutically acceptable salts, esters, and guanamines of the name compound. Or metabolites. For example, in any of the embodiments herein, the active metabolite of naltrexone (eg, 6-beta natriureol) can be used in combination with or in place of naltrexone. In any of the embodiments herein, the active metabolite of bupropion (including S,S-hydroxybutylaminopropiophenone, ie, radar fasin) can be used in combination with or in place of butyl ketone.

本文所用之術語「持續釋放」具有如熟習此項技術者所理解之普通含義，且由此以非限制性實例方式包括藥物自一種劑型經長時間控制釋放。舉例而言，在一些實施例中，持續釋放劑型為釋放速率比可相比之立即釋放形式慢(例如小於80%之立即釋放劑型之釋放速率)之劑型。 The term "sustained release" as used herein has the ordinary meaning as understood by those skilled in the art, and thus includes, by way of non-limiting example, the release of the drug from a dosage form over a prolonged period of time. For example, in some embodiments, the sustained release dosage form is a dosage form that has a slower release rate than a comparable immediate release form (eg, a release rate of less than 80% immediate release dosage form).

適合用作參考標準之立即釋放那曲酮調配物為可以REVIA®牌那曲酮鹽酸鹽廣泛購得之立即釋放那曲酮調配物或其相等物。適合用作參考標準之立即釋放丁胺苯丙酮調配物為可以WELLBUTRIN®牌丁胺苯丙酮廣泛購得之立即釋放丁胺苯丙酮調配物或其相等物。美國政府規定可用以標記處方藥物之方式，且由此本文提及REVIA®牌那曲酮鹽酸鹽及WELLBUTRIN®牌丁胺苯丙酮對於熟習此項技術者具有熟知、固定及明確含義。 An immediate release naltrexone formulation suitable for use as a reference standard is an immediate release naltrexone formulation or equivalent thereof which is widely available from REVIA® brand naltrexone hydrochloride. An immediate release butylamine ketone formulation suitable for use as a reference standard is an immediate release butylamine ketone formulation or equivalent thereof which is widely available from WELLBUTRIN® brand acetophenone. U.S. government regulations may be used to label prescription drugs, and thus reference herein to REVIA® brand naltrexone hydrochloride and WELLBUTRIN® acetophenone is well known, fixed, and well defined by those skilled in the art.

本文所用之術語「口服劑型」具有如熟習此項技術者所理解之普通含義，且由此以非限制性實例方式包括藥物之調配物呈可投與人類之形式，包括丸劑、錠劑、核心、膠囊、囊片(caplets)、鬆散粉末、溶液及懸浮液。 The term "oral dosage form" as used herein has the ordinary meaning as understood by those skilled in the art, and thus, by way of non-limiting example, includes a pharmaceutical formulation in a form that can be administered to humans, including pills, lozenges, cores. Capsules, caplets, loose powders, solutions and suspensions.

本文所用之術語「緩和」重量增加包括阻止或降低有關之重量 增加之量，例如由投與藥物或改變生活活動。在一些實施例中，緩和重量增加係相對於僅投與那曲酮或丁胺苯丙酮中之一者或兩者均未投與時通常所經歷之重量增加量測量。 The term "moderate" weight gain as used herein includes preventing or reducing the weight associated. Increase the amount, for example by administering drugs or changing living activities. In some embodiments, the moderation weight gain is measured relative to the weight gain typically experienced when one or both of naltrexone or acetophenone is administered.

本文所用之術語「促進」重量減輕包括於至少一部分治療期相對於基線重量引起重量減輕。此包括個體最初增加一些重量，但在治療過程期間相對於開始治療前之基線減輕重量，以及個體在治療期結束時恢復一部分或全部所減輕之重量。在一個較佳實施例中，在治療期結束時，個體相對於基線已減輕重量。在一個較佳實施例中，在投與那曲酮及丁胺苯丙酮之患者中，重量增加之緩和或重量減輕之促進大於那曲酮或丁胺苯丙酮皆不投與或僅投與兩者中之一者，且更佳達成投與兩種化合物的至少相加效應或優於相加效應或協同效應。 As used herein, the term "promoting" weight loss includes causing weight loss relative to baseline weight for at least a portion of the treatment period. This includes the individual initially adding some weight, but during the course of the treatment, the weight is reduced relative to the baseline before the start of treatment, and the individual recovers some or all of the reduced weight at the end of the treatment period. In a preferred embodiment, the individual has lost weight relative to the baseline at the end of the treatment period. In a preferred embodiment, in patients who are administered naltrexone and acetophenone, the increase in weight gain or weight loss is greater than either naltrexone or acetophenone is not administered or only administered. One, and more preferably, achieves at least an additive effect or an additive effect or a synergistic effect on the two compounds.

在任何本文所述之實施例中，治療方法可替代地必須包括用途技術方案，諸如瑞士型用途技術方案(Swiss-type use claim)。舉例而言，用組合物治療過重或肥胖之方法可替代地必須包括組合物在製造用於治療過重或肥胖之藥物中之用途或組合物用於治療過重或肥胖之用途。 In any of the embodiments described herein, the method of treatment may alternatively include a technical solution of use, such as a Swiss-type use claim. For example, a method of treating overweight or obesity with a composition may alternatively include the use of the composition or composition for the manufacture of a medicament for treating overweight or obesity for the treatment of overweight or obesity.

熟習此項技術者應瞭解，可在不背離本發明之精神的情況下進行多種及各種修改。因此，顯然應瞭解，本文所揭示之本發明實施例僅為說明性的且不欲限制本發明之範疇。本文中所提及之任何參考文獻均關於本文中所論述之物質以全文引用的方式併入本文中。 It will be appreciated by those skilled in the art that various and various modifications can be made without departing from the spirit of the invention. Therefore, it is apparent that the embodiments of the invention disclosed herein are merely illustrative and are not intended to limit the scope of the invention. Any reference to any of the references herein is hereby incorporated by reference in its entirety in its entirety herein.

實例 Instance

以下實例為非限制性的，且僅代表本發明之各種態樣。 The following examples are non-limiting and represent only a variety of aspects of the invention.

實例1概述如下臨床研究之方案，其展示用SR那曲酮/SR丁胺苯丙酮治療不增加或減少具有心血管風險因素之過重及肥胖個體的嚴重不良心血管事件(MACE)的發生。 Example 1 outlines a protocol for a clinical study demonstrating that treatment with SR naltrexone/SR butyl acetonide does not increase or decrease the incidence of severe adverse cardiovascular events (MACE) in overweight and obese individuals with cardiovascular risk factors.

附錄1Appendix 1

實例2概述展示與最少生活方式介入計畫相比SR那曲酮/SR丁胺苯丙酮與綜合生活方式介入(CLI)計畫結合對過重及肥胖個體之體重及心血管風險因素的有益作用的臨床研究之方案。 Example 2 summarizes the clinical effects of SR-naltrexone/SR butylidene acetonide combined with a comprehensive lifestyle intervention (CLI) program on the weight and cardiovascular risk factors of overweight and obese individuals compared to the minimal lifestyle intervention program. Research program.

附錄2：實例2之研究程序的時程Appendix 2: Timeline of the study procedure for Example 2

Claims (14)

一種持續釋放那曲酮(naltrexone)或其醫藥學上可接受之鹽及持續釋放丁胺苯丙酮(bupropion)或其醫藥學上可接受之鹽之用途，其係用於製備在過重或肥胖個體治療過重或肥胖的藥物，其中該個體具有增加嚴重不良心血管事件(MACE)之風險，且其中若該過重或肥胖個體具有至少一種選自由以下組成之群的風險因素的心血管疾病，該個體具有增加嚴重不良心血管事件之風險：該鑑別前>3個月記錄之心肌梗塞史；冠狀動脈血管再形成史，包括冠狀動脈繞道移植手術、支架置入術、經皮經管腔冠狀動脈血管成形術或雷射粥樣斑塊切除術；頸動脈或外周血管再形成史，包括頸動脈內膜切除術、下肢動脈粥樣硬化病粥樣斑塊切除術、腹部主動脈動脈瘤修復、股或膕動脈繞道；分級運動測試時具有局部缺血性變化、ECG變化或心臟成像研究陽性之絞痛；該鑑別前2年內藉由簡單觸診評定之踝肱指數<0.9；及該鑑別前2年內冠狀動脈、頸動脈或下肢動脈50%狹窄；且其中該藥物不增加但減少該個體之嚴重不良心血管事件之風險。 A sustained release naltrexone or a pharmaceutically acceptable salt thereof and the sustained release of bupropion or a pharmaceutically acceptable salt thereof for use in the treatment of an overweight or obese individual An overweight or obese drug, wherein the individual has a risk of increasing a severe adverse cardiovascular event (MACE), and wherein if the overweight or obese individual has at least one cardiovascular disease selected from the group consisting of risk factors, the individual has Increased risk of serious adverse cardiovascular events: history of myocardial infarction >3 months prior to identification; history of coronary revascularization, including coronary bypass grafting, stenting, percutaneous transluminal coronary angioplasty Surgery or laser atherectomy: history of carotid or peripheral vascular remodeling, including carotid endarterectomy, lower extremity atherosclerotic atherectomy, abdominal aortic aneurysm repair, femoral or Brachial artery bypass; graded exercise test with ischemic changes, ECG changes, or coronal studies positive for cardiac imaging studies; Single palpation assessment of the ankle-brachial index <0.9; and 2 years prior to the identification of the coronary arteries, carotid arteries or leg 50% stenosis; and wherein the drug does not increase but reduces the risk of serious adverse cardiovascular events in the individual. 如請求項1之用途，其中該過重或肥胖個體不具有至少2種選自由以下組成之群的風險因素的2型糖尿病：用或不用藥物療法控制在<145/95mm Hg之高血壓；需要藥物療法之血脂異常； 該鑑別前12個月內記錄之低HDL膽固醇，女性<50mg/dL或男性<40mg/dL；及當前吸菸者。 The use of claim 1, wherein the overweight or obese individual does not have at least 2 types of diabetes selected from the group consisting of: a risk factor of <145/95 mm Hg with or without drug therapy; a drug is required Abnormal blood lipids in therapy; Low HDL cholesterol recorded during the first 12 months of identification, <50 mg/dL for women or <40 mg/dL for men; and current smokers. 如請求項1或2之用途，其中該個體不具有一或多個選自由以下組成之群的特徵：該鑑別前3個月內患有心肌梗塞；根據加拿大心血管協會(Canadian Cardiovascular Society)分級方案的III級或IV級心絞痛；包括中風之腦血管疾病臨床病史；竇性心動過速以外之快速性心律失常史；血壓145/95mm Hg，無論是否用抗高血壓藥劑治療；該鑑別前3個月內重量不穩定；有計劃之減肥手術、心臟手術或冠狀動脈血管成形術；由估算之GFR<30mL/min定義的重度腎臟損傷；肝衰竭臨床病史或記錄之ALT或AST大於正常值上限3倍；已知感染HIV或肝炎；類鴉片之長期使用或篩檢陽性；在該鑑別前6個月內，除菸鹼依賴以外之新近藥物或酒精濫用或依賴；癲癇(seizures)，包括熱性癲癇，顱創傷，或使該個體有癲癇傾向之其他病狀史；躁狂史，或當前診斷為活性精神病、活性貪食症或神經性厭食症，而非暴食症；具有自殺企圖之風險；急性抑鬱病，包括抑鬱新發作或症狀急性惡化，而非長期抑鬱治療之穩定個體；預期壽命預計少於4年之任何病狀，包括充血性心臟衰竭NYHA第3類或第4類；前5年內惡性腫瘤史，不包括非黑色素瘤皮膚癌或手術治癒之子宮頸癌；當前使用其他含丁胺苯丙酮或那曲酮之產品；那曲酮或丁胺苯丙酮過敏或不耐史；該鑑別前14天內使用單胺氧化酶抑制劑；該鑑別前30天內使用任何研究藥物、裝置或程序；懷孕或哺乳女性，或當前試圖受孕，或具有生育可能性，包括一年內有過經期之更年期(peri-menopausal)女性，及不願實施節育；及不能持續不 斷存取寬頻帶網際網路。 The use of claim 1 or 2, wherein the individual does not have one or more characteristics selected from the group consisting of: myocardial infarction within 3 months prior to the identification; grading according to the Canadian Cardiovascular Society Grade III or IV angina pectoris; clinical history of cerebrovascular disease including stroke; history of tachyarrhythmia other than sinus tachycardia; blood pressure 145/95mm Hg, whether or not treated with antihypertensive agents; weight instability within 3 months prior to identification; planned bariatric surgery, cardiac surgery or coronary angioplasty; defined by estimated GFR <30 mL/min Severe renal injury; clinical history of liver failure or recorded ALT or AST greater than 3 times the upper limit of normal; known to be infected with HIV or hepatitis; long-term use or screening of opioids positive; within 6 months before the identification, in addition to nicotine Abuse or dependence on new drugs or alcohols other than dependence; seizures, including thermal epilepsy, cranial trauma, or other history of epilepsy that causes the individual to have epilepsy; history of mania, or current diagnosis of active psychosis, active bulimia Or anorexia nervosa, not bulimia nervosa; risk of suicide attempts; acute depression, including new episodes of depression or acute exacerbations of symptoms, rather than stable individuals with long-term depression treatment; any condition with life expectancy estimated to be less than 4 years , including congestive heart failure NYHA class 3 or 4; history of malignancy within the first 5 years, excluding non-melanoma skin cancer or surgically cured cervical cancer; current use He is a product containing butyl acetonide or naltrexone; a history of allergic or intolerance of naltrexone or butyl ketone; a monoamine oxidase inhibitor used within 14 days prior to identification; any study drug, device or procedure used within 30 days prior to the identification Pregnant or breastfeeding women, or currently attempting to conceive, or have the possibility of childbirth, including peri-menopausal women who have had menstruation within a year, and are reluctant to implement birth control; and cannot continuously access the broadband Internet . 如請求項1或2之用途，其中該過重或肥胖個體之BMI30且45kg/m2。 The use of claim 1 or 2, wherein the BMI of the overweight or obese individual 30 and 45kg/m 2 . 如請求項1或2之用途，其中該過重或肥胖個體之BMI27且45kg/m2。 The use of claim 1 or 2, wherein the BMI of the overweight or obese individual 27 and 45kg/m 2 . 如請求項1或2之用途，其中該藥物係用於至少16週之治療。 The use of claim 1 or 2, wherein the medicament is for at least 16 weeks of treatment. 如請求項1或2之用途，其中該藥物係用於與基於網路之重量管理計畫、基於電話之重量管理計畫或其組合併用。 The use of claim 1 or 2, wherein the medicament is for use with a network based weight management program, a telephone based weight management program, or a combination thereof. 如請求項7之用途，其中該重量管理計畫之期間為至少26週。 The use of claim 7, wherein the weight management plan period is at least 26 weeks. 如請求項1或2之用途，其中該藥物包含每天32mg持續釋放那曲酮或其醫藥學上可接受之鹽及每天360mg持續釋放丁胺苯丙酮或其醫藥學上可接受之鹽。 The use of claim 1 or 2, wherein the medicament comprises 32 mg of sustained release of naltrexone or a pharmaceutically acceptable salt thereof per day and 360 mg of sustained release of bupropion or a pharmaceutically acceptable salt thereof per day. 如請求項1或2之用途，其中該藥物為含有8mg持續釋放那曲酮及90mg持續釋放丁胺苯丙酮之錠劑。 The use of claim 1 or 2, wherein the medicament is a lozenge containing 8 mg of sustained release of naltrexone and 90 mg of sustained release of bupropion. 如請求項1或2之用途，其中該嚴重不良心血管事件係選自心血管性死亡、非致命性心肌梗塞或非致命性中風。 The use of claim 1 or 2, wherein the severe adverse cardiovascular event is selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. 如請求項11之用途，其中該嚴重不良心血管事件係心血管性死亡。 The use of claim 11, wherein the severe adverse cardiovascular event is cardiovascular death. 如請求項1或2之用途，其中該個體達成至少5%之重量減輕百分比。 The use of claim 1 or 2, wherein the individual achieves a weight reduction percentage of at least 5%. 如請求項1或2之用途，其中該個體未接受用於重量減輕之密集行為改變(BMOD)計畫。 The use of claim 1 or 2, wherein the individual does not receive a Bulk Behavior Change (BMOD) program for weight loss.
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