TWI461192B - 降低血脂異常病患之糖化血色素的醫藥組成物 - Google Patents
降低血脂異常病患之糖化血色素的醫藥組成物 Download PDFInfo
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- TWI461192B TWI461192B TW101125701A TW101125701A TWI461192B TW I461192 B TWI461192 B TW I461192B TW 101125701 A TW101125701 A TW 101125701A TW 101125701 A TW101125701 A TW 101125701A TW I461192 B TWI461192 B TW I461192B
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- Prior art keywords
- dyslipidemia
- patients
- diacerein
- drug
- glycosylated hemoglobin
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- 230000003442 weekly effect Effects 0.000 description 1
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Description
本發明係關於一種用於治療具血脂異常之糖尿病患者之糖化血色素異常的醫藥組成物，對有需求之個體投與有效治療劑量之IL-1β
調控藥物，可讓血脂異常患者降低其糖化血色素趨向標準值。
血脂異常症是指患者血液中的脂質含量異常，大部份血脂異常患者為高血脂群，包括高膽固醇、高三酸甘油脂、高脂蛋白與高血脂。血脂異常者血液中的總膽固醇、低密度脂蛋白膽固醇和三酸甘油脂的濃度會較正常者增加，而高密度脂蛋白膽固醇的濃度則會降低。
血脂異常是導致糖尿病的主要危險因子之一，它會影響beta細胞的功能和存活，其對beta細胞影響的程度取決於血脂異常病患的血脂變化。游離脂肪酸和脂蛋白會造成beta細胞進入凋亡前期，脂蛋白也會影響beta細胞的功能和存活，非常低密度脂蛋白(VLDL)和低密度脂蛋白(LDL)會造成細胞凋亡前期，但高密度脂蛋白則會保護beta細胞。
血脂異常也是造成糖尿病患者得到心血管疾病的主要危險因子之一。糖尿病患者中，約有13%男性和24%女性的血中總膽固醇含量有異常增加；19%男性和17%女性的血中三酸甘油脂含量有異常增加；9%男性和15%女性的血中低密度脂蛋白膽固醇含量較正常人增加；以及21%男性和25%女性的血中高密度脂蛋白膽固醇含量較正常人偏低。在美國有90%的人其總膽固醇、低密度脂蛋白膽固醇和三酸甘油脂是偏高的，在英國也有類似的血脂異常情形。
成人糖尿病患者血液中的總膽固醇含量應小於200 mg/dL(5.0 mmol/L)，而且每年應測量低密度脂蛋白膽固醇、高密度脂蛋白膽固醇和三酸甘油脂的含量。成人糖尿病患者最理想的低密度脂蛋白膽固醇需小於100 mg/dL(2.60 mmol/L)；男性糖尿病患者的高密度脂蛋白膽固醇需等於或大於40 mg/dL(1.0 mmol/L)、女性則是等於或大於50 mg/dL(1.02 mmol/L)；三酸甘油脂則需小於150 mg/dL(1.7 mmol/L)。
對大部分的糖尿病患者而言，常見治療血脂異常的方法包括1)飲食和生活作息的調整；2)羥甲基戊二酰基Co-A還原酶抑制劑(hydroxymethylglutaryl coenzyme A)，包含阿托伐他汀(Atorvastatin)，薛利伐史達丁(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、匹伐他汀(Pitavastatin)、普伐他汀(Pravastatin)、瑞舒伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)；3)菸鹼酸及其衍生物，包含菸鹼酸(Niacin)、煙酸戊四醇酯(Niceritrol)、煙呋糖酯(Nicofuranose)、煙酸鋁(Aluminium nicotinate)、煙酰醇(Nicotinyl alcohol)、阿西莫司(Acipimox)；4)苯氧芳酸類(Fibrates)，包含苯扎貝特(Bezafibrate)、氯貝酸鋁(Aluminium clofibrate)、苯氧戊酸(Gemfibrozil)、非諾貝特(Fenofibrate)、雙貝特(Simfibrate)、氯煙貝特(Ronifibrate)、環丙貝特(Ciprofibrate)、依托泊甙(Etofibrate)、氯貝胺(Clofibride)和克利貝特(Clinofibrate)；5)膽固醇吸收抑制劑，包含伊折麥布(ezetimibe)；6)膽酸結合物，包含考來烯胺(Cholestyramine)、考來替泊(Colestipol)、考來替蘭(Colestilan)、考來糖酐(Colextran)和考來維倫(Colesevelam)；7)Omega-3脂肪酸；8)膽固醇酯轉移蛋白抑制劑(cholesterylester transfer protein inhibitors)，包含Anacetrapib、Dalcetrapib和Torcetrapib。
Interleukin-1β(IL-1β)是一種前發炎細胞激素，與血脂異常和糖尿病發生有關。慢性血脂異常病患的IL-1β表現量會升高，進而引起化學激素和其他細胞激素的分泌、黏著分子的表現量增加、內皮細胞的活化和平滑肌的增生、巨噬細胞的活化、增加血管通透性。
IL-1β亦會抑制beta細胞的功能和強化透過轉錄因子nuclear factor-B進而活化Fas而導致細胞凋亡。將非糖尿病患者的胰島細胞暴露在高糖環境下會造成IL-1β的生成與釋放，進而活化nuclear factor-B、調控Fas、造成DNA斷裂和使beta細胞的分泌功能受損；IL-1受體拮抗劑(IL-1 receptor antagonist)則可以保護人類胰島細胞。胰島中的Beta細胞經由葡萄糖誘導後會產生IL-1β，在第二型糖尿病病人的胰臟也發現會產生IL-1β的beta細胞，但非糖尿病病人則未發現。這些發現指出第二型糖尿病所造成的發炎反應和IL-1β有關。
IL-1β調控藥物，如IL-1受體拮抗劑(IL-1 receptor antagonist)、IL-1 TRAP、人類IL-1β單株抗體和IL-1β抑制劑在先前研究中皆可有效的治療或預防第二型糖尿病。但並沒有文獻指出IL-1β調控藥物可以改善或控制血脂異常病人的糖化血色素異常。
本發明係關於治療病人的糖化血色素異常之方法，該糖化血紅素異常病人可能有第二型糖尿病和血脂異常，尤其適用於對現有抗糖尿病藥物反應不佳之患者。利用有效劑量之IL-1β調控藥物，如IL-1受體拮抗劑(IL-1 receptor antagonist)、IL-1 TRAP、人類IL-1β單株抗體和IL-1β抑制劑、及其有效劑量之藥物包含其鹽類化合物、類似物、前趨藥物或其活性代謝產物，治療病人的糖化血色素異常，其降低糖化血色素的效果對於血脂異常之患者有預期外的好處，且效果優於血脂正常的糖尿病患者。
本發明提供的治療方法包含選擇性給予抗糖尿病藥物，例如磺醯脲(sulfonylurea)、雙胍(biguanides)、α-葡糖苷酶抑制劑(alpha-glucosidase inhibitors)、噻唑烷二酮(thiazolidinediones,TZD)、二肽基肽酶-4抑制劑(dipeptidyl peptidase-4 inhibitors)、非磺醯脲胰島素促泌素(nonsulfonylurea insulin secretagogues)、升糖素樣肽-1類似物(glucagon-like peptide-1 analogs)、鈉葡萄糖轉運蛋白亞型2抑製劑(sodium-glucose transport proteins subtype 2 inhibitors)及胰島素。
此發明提供一種輔助治療血脂異常之第二型糖尿病患者之異常糖化血色素的醫藥組成物，此醫藥組成物其中包含至少一種抗糖尿病藥物和有效劑量之IL-1β調控藥物。
IL-1β調控藥物，包括anakinra、利洛納塞(rilonacept)、canakinumab、gevokizumab、雙醋瑞因，以及醫藥上可接受之鹽類化合物、類似物、前趨藥物或其活性代謝產物。
更具體來說，IL-1β調控藥物係雙醋瑞因或醫藥上可接受之鹽類化合物、類似物、前趨藥物或其活性代謝產物，其有效劑量係介於每日25至200毫克。
雙醋瑞因之活性代謝產物為單乙醯基大黃酸或大黃酸。
如本文所用，糖化血色素異常是指人體血液中糖化血色素高於7.0%。
此發明為治療具糖化血色素異常患者的醫藥組成物，包括至少一種血脂調節劑、有效劑量的IL-1β調控藥物。
於一實施例中，血脂調節劑包含羥甲基戊二酰基Co-A還原酶抑制劑、菸鹼酸及其衍生物、苯氧芳酸類、膽固醇吸收抑制劑、膽酸結合物、Omega-3脂肪酸、膽固醇酯轉移蛋白抑制劑和上述組合物。
此發明為治療具糖化血色素異常的醫藥組成物，包括至少一種血脂調節劑和IL-1β調控藥物。
有效劑量之IL-1β調控藥物，例如IL-1受體拮抗劑(IL-1 receptor antagonist)、IL-1 TRAP如利洛納塞(rilonacept)、人類IL-1β的單株抗體如canakinumab和gevokizumab、IL-1β的抑制劑如雙醋瑞因和大黃酸、及其有效劑量之藥物包含其鹽類化合物、類似物、前趨藥物或其活性代謝產物，其降低糖化血色素的效果對於血脂異常之患者有預期外的好處，且其效果優於血脂正常的糖尿病患者。
IL-1β調控藥物如雙醋瑞因，可以抑制IL-1β的生成及調控IL-1β所引起的相關活性。雙醋瑞因已在骨關節炎的動物模式、及有關節炎、指關節炎和膝關節炎的病人顯示療效，因此可知IL-1β在骨關節炎和軟骨破壞的病理中的確佔有重要的角色。IL-1β可誘導一氧化氮的產生、增加前列腺素E2、IL-6、IL-8在軟骨細胞中釋放，且血脂異常糖尿病患者比血脂正常糖尿病患者有較高的前發炎因子(IL-1β和IL-6)。雙醋瑞因或IL-1β調控藥物可以降低上述前發炎因子的過度表現與調控beta細胞的功能和存活，因此，IL-1β調控藥物如雙醋瑞因可用來控制血脂異常患者之糖化血色素，且其效果優於血脂正常的糖尿病患者。
再者，IL-1β調控藥物如雙醋瑞因可以降低致少接受一種抗糖尿病藥物的第二型糖尿病和血脂異常患者的前發炎因子表現，尤其針對使用抗糖尿病藥物控制不當的糖尿病患者有效，該糖尿病患者可能合併血脂異常症狀。
此發明亦提供一種輔助治療血脂異常之第二型糖尿病患者之糖化血色素異常的醫藥組合物，其中包含至少一種抗糖尿病藥物和有效劑量之IL-1β調控藥物。
雙醋瑞因，(4,5-雙(乙醯氧基)-9,10-二氧代-2-蒽羧酸或1,8-二乙醯氧基-3-羰基蒽醌)，是一種IL-1β調控藥物，具有以下結構式：
雙醋瑞因之醫藥上可接受之鹽類化合物、類似物、前趨藥物及其活性代謝產物亦用於本發明中，其醫藥上可接受之鹽類化合物包括酸基或鹼基鹽。
大黃酸(9,10-二氫-4,5-二羥基-9,10-二側氧基-2-蒽羧酸)及單乙醯基大黃酸係已知為雙醋瑞因之活性代謝產物。
前趨藥物係指活性藥物經設計後衍生之無活性藥物，可透過活體生理作用如水解、代謝及類似者將其轉變成活性藥物。
如本文所用，糖化血色素異常是指人體血液中糖化血色素高於7.0%。
雙醋瑞因之有效劑量係隨個體年齡差異、體重、糖尿病程度及患者病況而改變，任何熟悉本技術領域之人士皆可輕易以各種方法確定劑量範圍。本發明之較佳實施例，雙醋瑞因之每日有效劑量係介於25至200毫克。於一實施例中，雙醋瑞因或其衍生物包括，但不限於雙醋瑞因之醫藥上可接受之鹽類化合物、類似物、前趨藥物及其活性代謝產物，可每日投與一次或兩次。雙醋瑞因的較佳有效劑量為每日25至200毫克之雙醋瑞因鹼。”每日25至200毫克之雙醋瑞因鹼”係指醫藥上可接受之鹽類化合物、類似物、前趨藥物及其活性代謝產物之含量具有和服用25至200毫克雙醋瑞因相同的作用。
本發明中之「抗糖尿病藥物」係指藉由降低血液中之葡萄糖濃度而用於治療糖尿病之藥物。現有抗糖尿病藥物包括但不限於，磺醯脲(sulfonylurea)、雙胍(biguanides)、α-葡糖苷酶抑制劑(alpha-glucosidase inhibitors)、噻唑烷二酮(thiazolidinediones,TZD)、二肽基肽酶-4抑制劑(dipeptidyl peptidase-4 inhibitors)、非磺醯脲胰島素促泌素(nonsulfonylurea insulin secretagogues)、升糖素樣肽-1類似物(glucagon-like peptide-1 analogs)、鈉葡萄糖轉運蛋白亞型2抑製劑(sodium-glucose transport proteins subtype 2 inhibitors)及胰島素。更具體言之，抗糖尿病藥物包括，但不限於，二甲雙胍、格列本脲(glyburide)、格列美脲(glimepiride)、格列吡脲(glipyride)、格列吡嗪(glipizide)、氯磺丙脲
(chlorpropamide)、格列齊特(gliclazide)、醣祿(acarbose)、米格列醇(miglitol)、吡格列酮(pioglitazone)、曲格列酮(troglitazone)、羅格列酮(rosiglitazone)、伊沙列酮(isaglitazone)、莫格列扎(muraglitizar)、皮裡列扎(peliglitazar)、西他列汀(sitagliptin)、沙西列汀(saxagliptin)、維格列汀(vildagliptin)、阿格列汀(alogliptin)、利納列汀(linagliptin)、杜格列汀(dutogliptin)、瑞格列萘(repaglinide)、那替格列(nateglinide)、米替林汀(mitiglindine)、艾塞那肽(exenatide)、利戈魯泰(liraglutide)、阿比泰德(albiglutide)及胰島素。此等藥物可單獨或以組合方式投與。
於另一實施例中，此發明為治療具血脂異常患者之糖化血色素異常的醫藥組成物，包括至少一種血脂調節劑、有效劑量的雙醋瑞因或醫藥上可接受之鹽類化合物、類似物、前趨藥物及其活性代謝產物。
如本文所使用，”血脂調節劑”包括羥甲基戊二酰基Co-A還原酶抑制劑、菸鹼酸及其衍生物、苯氧芳酸類、膽固醇吸收抑制劑、膽酸結合物、Omega-3脂肪酸和膽固醇酯轉移蛋白抑制劑或是其組合物。
羥甲基戊二酰基Co-A還原酶抑制劑，包含但不限於阿托伐他汀(Atorvastatin)，薛利伐史達丁(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、匹伐他汀(Pitavastatin)、普伐他汀(Pravastatin)、瑞舒伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)；菸鹼酸及其衍生物，包含但不限於菸鹼酸(Niacin)、煙酸戊四醇酯(Niceritrol)、煙呋糖酯(Nicofuranose)、煙酸鋁(Aluminium nicotinate)、煙酰醇(Nicotinyl alcohol)、阿西莫司(Acipimox)；苯氧芳酸類，包含但不限於苯扎貝特(Bezafibrate)、氯貝酸鋁(Aluminium clofibrate)、苯氧戊酸(Gemfibrozil)、非諾貝特(Fenofibrate)、雙貝特(Simfibrate)、氯煙貝特(Ronifibrate)、環丙貝特(Ciprofibrate)、依托泊甙(Etofibrate)、氯貝胺(Clofibride)和克利貝特(Clinofibrate)；膽固醇吸收抑制劑，包含但不限於伊折麥布(ezetimibe)；膽酸結合物，包含但不限於考來烯胺(Cholestyramine)、考來替泊(Colestipol)、考來替蘭(Colestilan)、考來糖酐(Colextran)和考來維倫(Colesevelam)；Omega-3脂肪酸；膽固醇酯轉移蛋白抑制劑，包含但不限Anacetrapib、Dalcetrapib和Torcetrapib。
雙醋瑞因或其醫藥上可接受之鹽類化合物、類似物、前趨藥物及其活性代謝產物，皆可用於製備醫藥組成物。用於本發明之醫藥組成物可呈固體、溶液、乳液、懸浮液、顆粒小球、微脂粒及類似之形式。該組成物可利用已知的任何方式投與，如經口、鼻、局部、皮膚或直腸，以口服為佳。例如，可將藥物與適宜賦形劑混合，以製備錠劑、膠囊、球粒、糖錠、含錠、溶液、粉末或顆粒、懸浮液、硬或軟膠囊及適宜使用之任何其他形式。發明中所指之醫藥組成物可利用任何文獻中常見方法製造。
雙醋瑞因包括其醫藥上可接受之鹽類化合物、類似物、前趨藥物及其活性代謝產物的醫藥組成物，還可以加入其他活性成份，如：1)羥甲基戊二酰基Co-A還原酶抑制劑；2)菸鹼酸及其衍生物；3)苯氧芳酸類；4)膽固醇吸收抑制劑；5)膽酸結合物；6)Omega-3脂肪酸；7)膽固醇酯轉移蛋白抑制劑。
更具體來說，本發明提供一種治療糖化血色素異常之醫藥組成物，包含雙醋瑞因或至少一種以下活性成份：羥甲基戊二酰基Co-A還原酶抑制劑、菸鹼酸及其衍生物、苯氧芳酸類、膽固醇吸收抑制劑、膽酸結合物、Omega-3脂肪酸和膽固醇酯轉移蛋白抑制劑。
羥甲基戊二酰基Co-A還原酶抑制劑，包含但不限於阿托伐他汀(Atorvastatin)，薛利伐史達丁(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、匹伐他汀(Pitavastatin)、普伐他汀(Pravastatin)、瑞舒伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)；菸鹼酸及其衍生物，包含但不限於菸鹼酸(Niacin)、煙酸戊四醇酯(Niceritrol)、煙呋糖酯(Nicofuranose)、煙酸鋁(Aluminium nicotinate)、煙酰醇(Nicotinyl alcohol)、阿西莫司(Acipimox)；苯氧芳酸類，包含但不限於苯扎貝特(Bezafibrate)、氯貝酸鋁(Aluminium clofibrate)、苯氧戊酸(Gemfibrozil)、非諾貝特(Fenofibrate)、雙貝特(Simfibrate)、氯煙貝特(Ronifibrate)、環丙貝特(Ciprofibrate)、依托泊甙(Etofibrate)、氯貝胺(Clofibride)和克利貝特(Clinofibrate)；膽固醇吸收抑制劑，包含但不限於伊折麥布(ezetimibe)；膽酸結合物，包含但不限於考來烯胺(Cholestyramine)、考來替泊(Colestipol)、考來替蘭(Colestilan)、考來糖酐(Colextran)和考來維倫(Colesevelam)；Omega-3脂肪酸；膽固醇酯轉移蛋白抑制劑，包含但
不限Anacetrapib、Dalcetrapib和Torcetrapib。
第二種活性成份可為控制釋放劑型或是速放劑型。
下列實例係在於闡明本發明，並不侷限發明範圍。
目的：雙醋瑞因對治療第2型糖尿病之療效及安全性評估。
試驗指標：現有糖尿病藥物反應不佳之第二型糖尿病患者經過24週治療後，比較併用雙醋瑞因與安慰劑之療效。
受試者：由接受口服降血糖藥至少3個月的男性或女性第二型糖尿病患者(BMI35 kg/m2
)中篩選，篩選時糖化血色素測定值需介於7%與12%之間。參與研究之患者接受一或多種口服降血糖藥，包括磺醯脲、雙胍、α-葡糖苷酶抑制劑、噻唑烷二酮(TZD)及非磺醯脲胰島素促泌素。
試驗設計：比較雙醋瑞因與安慰劑在現有糖尿病藥物反應不佳之第二型糖尿病患者的隨機、雙盲和平行之研究。雙醋瑞因起始劑量係每日早上50 mg，連續4週，然後調整至每日二次50 mg(早晨及夜晚)。在一開始的4週篩選期間內，受試者持續現有抗糖尿病療法、維持膳食及其他生活習慣，在這4週篩選期後隨機分組，受試者應不具有低血糖症且兩次空腹血糖(FPG)測定結果均應在135至250 mg/dL之間，隨機分組之受試者在第0週至第4週接受每日一次50mg的雙醋瑞因或安慰劑，於第5週至第24週接受每日兩次的雙醋瑞因50 mg或安慰劑。連續觀察24週，並於治療/觀察期間，持續現有抗糖尿病療法，包括其類型及劑量，在試驗期間要求患者在八個時間點(篩選、基線、第4、8、12、16、20及24週)回診，總研究時間(包含篩選期)為28週。於完成治療/觀察後有兩週追蹤期追蹤患者之不良反應事件。
療效/安全性評估之統計方法：以基線值為共變量，藉由ANCOVA來分析兩治療組間之糖化血色素下降之差異(雙醋瑞因組值減去安慰劑組值)，計算95%之信賴區間，亦藉由t-test來評估各治療組與基線的差異。
就療效參數而言，藉由訪查獲得敘述性統計。統計分析為自基線之平均變化。以濃度-時間曲線下面積(AUC)來評估口服葡萄糖之耐受性。
不良事件是根據調節活動之醫學辭典(Medical Dictionary for Regulatory Activities (MedDRA))所規範。表格內容包含不良事件之患者數量，及每種器官出現至少一種不良事件之患者總數。兩種治療組中各組之不良事件發生率是用費雪精確性檢定(Fisher's Exact test)去計算。
血脂異常組試驗評估：血脂異常組之受試者選取須具備以下其中一個條件：a)血中的膽固醇濃度大於200 mg/dL或；b)血中的三酸甘油脂濃度大於150 mg/dL或；c)血中的低密度脂蛋白濃度大於100 mg/dL，再經由paired t-test分析其組之糖化血色素與安慰劑組之結果。
結果顯示於表一。76位受試者隨機以1比1的比例投與4週每日一次之雙醋瑞因或安慰劑及長達20週每日兩次之雙醋瑞因(一次為50 mg,n=38)或安慰劑(n=38)。有26位投與雙醋瑞因的受試者完成此試驗。在這26位受試者中，有16位具有血中膽固醇濃度大於200 mg/dL或血中的三酸甘油脂濃度大於150 mg/dL或血中的低密度脂蛋白濃度大於100 mg/dL，有10位則是正常血脂，所以血脂異常組共有16位受試者。
治療24週後，雙醋瑞因組比安慰劑組降低0.63%的糖化血色素(p<0.05).相較於基準，雙醋瑞因之血脂異常組可降低0.82%的糖化血色素，但在血脂正常組只降低糖化血色素0.30%(表一)。
[050]雙醋瑞因組在24週治療過後，總人數26位受試者中，有13位受試者(50%)降低其糖化血色素大於或等於0.5%。在血脂異常組總人數為16位受試者中，有10位受試者(62.5%)降低其糖化血色素大於或等於0.5%。在高三酸甘油脂或高膽固醇組總人數為14位受試者中，有10位受試者(71.4%)降低其糖化血色素大於或等於0.5%。在高三酸甘油脂組總人數為11位受試者中，有7位受試者(63.6%)降低其糖化血色素大於或等於0.5%。在高膽固醇組總人數為7位受試者中，有4位受試者(57.1%)降低其糖化血色素大於或等於0.5%，與血脂異常組截然不同的是，在血脂正常組總人數為10位受試者中只有4位受試者(40%)降低其糖化血色素大於或等於0.5%(第一圖)。
在此試驗中，使用雙醋瑞因的患者相較於安慰劑組，其體重和血脂沒有顯著差異性。
此研究結果顯示雙醋瑞因可以顯著的降低血脂異常糖尿病患者的糖化血色素，但是不會影響其血脂。
第一圖為血脂異常病患和血脂正常病患的糖化血色素。
Claims (2)
- 一種使用至少一種抗糖尿病藥物和有效劑量之IL-1β調控藥物於製造供輔助治療有血脂異常之第二型糖尿病患者的糖化血色素異常之醫藥組合物的用途，其中該抗糖尿病藥物係選自至少一種下列藥物，包含磺醯脲(sulfonylurea)、雙胍(biguanides)、α-葡糖苷酶抑制劑(alpha-glucosidase inhibitors)、噻唑烷二酮(TZD)、及非磺醯脲胰島素促泌素(nonsulfonylurea insulin secretagogues)；且其中該IL-1β調控藥物係選自雙醋瑞因、其醫藥上可接受之鹽類化合物、其活性代謝產物單乙醯基大黃酸或大黃酸、及上述之組合。
- 如請求項1所述之用途，其中該IL-1β調控藥物之每日有效劑量係介於25至200毫克。
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