A Multicenter, Randomized, Open-label, Two-arm, Phase 4 Study to Evaluate the Effect of Add-on Pioglitazone or Dapagliflozin in Subjects With Type 2 Diabetes Mellitus Inadequately Controlled by Dipeptidyl Peptidase-4 Inhibitor and Metformin Therapy

The purpose of this study is to assess the pioglitazone plus alogliptin plus metformin is non-inferior to dapagliflozin plus alogliptin plus metformin on glycosylated haemoglobin (HbA1c) change from baseline at Week 26.

开始日期2020-02-11

申办/合作机构

Celltrion Pharm Inc.

NCT03501277

/ Completed临床1期

A Randomized, Open-Label, Single-Dose, 4-Period Crossover Study to Determine the Bioequivalence of Alogliptin (25 mg) and Pioglitazone (15 and 30 mg) When Administered as Individual Tablets and as Fixed-Dose Combination Tablets to Healthy Russian Subjects

The purpose of this study is to assess the relative bioavailability and bioequivalence of 2 strengths of the FDC tablet product SYR-322-4833 BL compared to the individual alogliptin and pioglitazone tablets in healthy Russian participants.

开始日期2018-05-26

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

NCT02763007

/ Terminated临床4期IIT

An Extension Study of Protocol ALO-IIT(PEAK Study) to Examine the Long-term Efficacy and Safety of Metformin + Alogliptin + Pioglitazone Triple Combination Therapy in the Korean Type 2 Diabetes Patients

Double blind, three arm, comparative intervention trial for 24 weeks(PEAK study) with open label extension trial for 28 weeks followed by 2 year observational study.

开始日期2016-05-18

申办/合作机构

The Catholic University of Korea Seoul St. Marys Hospital

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100 项与苯甲酸阿格列汀/盐酸吡格列酮相关的临床结果

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100 项与苯甲酸阿格列汀/盐酸吡格列酮相关的转化医学

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100 项与苯甲酸阿格列汀/盐酸吡格列酮相关的专利（医药）

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项与苯甲酸阿格列汀/盐酸吡格列酮相关的文献（医药）

2023-11-01·Journal of affective disorders

Low-dose lithium adjunct to quetiapine improves cognitive task performance in mice with MK801-induced long-term cognitive impairment: Evidence from a pilot study

Article

作者: Zhu, Jingjing ; Wang, Lina ; Tian, Hongjun ; Cheng, Langlang ; Zhuo, Chuanjun ; Chen, Chunmian ; Sun, Yun ; Ping, Jing ; Fang, Tao ; Chen, Guangdong

BACKGROUND:

Low-dose lithium (LD-Li) has been shown to rescue cognitive impairment in mouse models of short-term mild cognitive impairment, dementia, and schizophrenia. However, few studies have characterized the effects of LD-Li, alone or in conjunction with anti-psychotics, in the mouse model of MK801-induced long term cognitive impairment.

METHODS:

The present study used in vivo Ca²⁺ imaging and a battery of cognitive function assessments to investigate the long-term effects of LD-Li on cognition in mice exposed to repeated injections of MK801. Prefrontal Ca²⁺ activity was visualized to estimate alterations in neural activity in the model mice. Pre-pulse inhibition (PPI), novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FC) tasks were used to characterize cognitive performance; open field activity (OFA) testing was used to observe psychotic symptoms. Two treatment strategies were tested: LD-Li [250 mg/d human equivalent dose (HED)] adjunct to quetiapine (QTP; 600 mg/d HED); and QTP-monotherapy (mt; 600 mg/d HED).

RESULTS:

Compared to the QTP-mt group, the LD-Li + QTP group showed greatly improved cognitive performance on all measures between experimental days 29 and 85. QTP-mt improved behavioral measures compared to untreated controls, but the effects persisted only from day 29 to day 43. These data suggest that LD-Li + QTP is superior to QTP-mt for improving long-term cognitive impairments in the MK801 mouse model.

LIMITATIONS:

There is no medical consensus regarding lithium use in patients with schizophrenia.

CONCLUSION:

More pre-clinical and clinical studies are needed to further investigate effective treatment strategies for patients with long-term cognitive impairments, such as chronic schizophrenia.

2023-10-03·Journal of chromatographic science

An Effective Chromatographic Method for Simultaneous Quantification of Antidiabetic Drugs Alogliptin Benzoate and Pioglitazone HCl in Their Tablet Dosage Form: Implementation toIn vitroDissolution Studies and Uniformity of Dosage Unit

Article

作者: Mohamed, Mahmoud A

Abstract:

In patients with Type 2 diabetes, a combination of Alogliptin and Pioglitazone medications, together with diet and physical activity, are used to improve glycemic control. Eco-friendly, cost-effective, and precise stability-indicating RP-HPLC method was developed and validated for the identification and quantification of Alogliptin and Pioglitazone in their tablet dosage form, as well as implementation to in vitro dissolution studies and uniformity of dosage unit. Isocratic separation is conducted at ambient temperature on the InertSustain C18 Analytical Column (150 × 4.6 mm, 5 μm) using mobile phase comprising 50 mM of ammonium dihydrogen phosphate and 5.0 mM of heptane sulfonic acid:acetonitrile (45:55, v/v) at a flow rate of 1.3 mL/minute. Calibration curves are conducted in the linearity range of 1–40 μg/mL of Alogliptin and 2.5–75 μg/mL of Pioglitazone with a correlation value >0.9995 and satisfactory recovery findings between 99 and 100%. The degraded samples are analyzed under relevant stress conditions as acidity, alkalinity, thermal and oxidation. The active components in finished products were subjected to a content uniformity test, which showed that they achieved the declared claim’s acceptance standards (85–115%). Comparative in vitro dissolution studies are performed for generic products Inhibazone 12.5/30 mg FCT and Inhibazone 25/15 mg FCT against innovator products Oseni 12.5/30 mg FCT and Oseni 25/15 mg FCT at suitable FDA dissolution medium and different USP dissolution media and the results are similar. The metrics of the designed method were assessed according to ICH requirements, and all metrics, such as system suitability, linearity, recovery, robustness, LOD, LOQ, specificity and precision, were found to be within required tolerances and no overlapping was found for degradation peaks. Thence, the method can be used in quality control for the analysis of raw material, bulk, finish and stability.

2019-11-01·Journal of chromatography. B, Analytical technologies in the biomedical and life sciences3区 · 医学

Determination of pioglitazone, its metabolite and alogliptin in human plasma by a novel LC-MS/MS method; application to a pharmacokinetic study

3区 · 医学

Article

作者: Elghobashy, Mohamed R ; Kelani, Khadiga M ; Badran, Osama M ; Rezk, Mamdouh R

A novel, high throughput and sensitive LC-MS/MS assay method was developed and fully validated for quantitative determination of pioglitazone, its hydroxyl metabolite and alogliptin in human plasma. A simple and rapid sample preparation procedure based on protein precipitation technique with acetonitrile was utilized. Chromatographic separation was achieved on C₈ (50 × 4.6 mm, 5 μm) Kinetex® analytical column using methanol and 0.1% formic acid in a gradient elution mode at a flow rate of 0.7 mL/min with injection volume of 8 μL. Detection was performed on a triple quadrupole mass spectrometer accompanied with electrospray ionization (ESI) technique in positive mode, operating in multiple reaction monitoring, with the transitions of 357.2 → 119.1, 373.1 → 150.1, 340.3 → 116.1, 361.1 → 138.1 and 343.2 → 116.1 m/z for pioglitazone, its hydroxyl metabolite, alogliptin, pioglitazone-d4 (IS-1) and alogliptin-d3 (IS-2), in order. Analysis was achieved within 4 min over a linear concentration range of 10-3000 ng/mL, 5-2000 ng/mL and 3-300 ng/mL, for pioglitazone, hydroxyl pioglitazone and alogliptin, in order. The method was fully validated according to FDA guidelines. The developed method was used for estimation of the three studied analytes in human plasma and pharmacokinetic parameters were demonstrated after oral dose administration of Oseni® tablets to Egyptian healthy volunteers.

项与苯甲酸阿格列汀/盐酸吡格列酮相关的新闻（医药）

2022-09-29

·生物制品圈

新研究发现接种流感疫苗可降低罹患阿尔茨海默病、抑郁症等多种疾病风险

▍摘要流行性感冒，简称流感，是由流感病毒引起的急性呼吸道传染病，通过空气飞沫传播，是传播速度最快的传染病之一。流感在全球每年可导致300万~ 500万的重症和29万~ 65万呼吸道疾病相关死亡。每年流感流行季节，儿童流感罹患率约为20% ~ 30%，在某些高流行季节，甚至高达50%。接种流感疫苗仍然是预防流感的最有效方式，然而我国流感疫苗接种率不足3%，与欧美相差甚远。近日，国际顶级期刊《Nature》发文，一项对卡塔尔3万多名卫生保健工作者的研究发现，接种流感疫苗可降低新冠感染风险，其对重症防护效力高达90%。新的研究表明，接种流感疫苗还可以有效降低罹患阿尔茨海默病（AD）、抑郁症等神经系统疾病的风险，降低慢性阻塞性肺病、心血管等疾病的影响。▍最新研究表明接种流感疫苗可预防阿尔茨海默病阿尔茨海默病（Alzheimer Disease，AD），俗称老年痴呆。据WHO估计，目前全球有超过5500万人患有痴呆症，超过25%来自中国。在中国，每100个60岁以上的老人中就有5个痴呆症患者。阿尔茨海默病每年所致的社会总经济负担高达11406亿元，是癌症经济负担的5倍。近期，一项发表在《阿尔茨海默病杂志》（Journal of Alzheimer's Disease）的研究指出，与未接种流感疫苗的同龄人相比，接种至少一种流感疫苗的人在四年内患阿尔茨海默病的可能性降低40%[1]。为了探讨接种流感疫苗对罹患阿尔茨海默病风险的影响，来自德克萨斯大学休斯顿健康科学中心（UT Health）的研究人员从数据库中纳入了935887名、平均年龄为73.7岁且接种了流感疫苗的老年人与935887名未接种流感疫苗的65岁以上老年人进行队列分析[1]。结果显示，接种过流感疫苗的老年人中，有5.1%（n =47889）的人发展为了AD；在没接种流感疫苗的老年人中共有8.5%（n =79630）的人发展为了AD，见图1。与未接种过流感疫苗的老年人相比，接种流感疫苗后老年人发生AD的风险降低40%（RR=0.6，95% CI：0.59–0.61）[1][2]。图1. 接种流感疫苗或未接种流感疫苗患AD人数该研究发现，每年坚持接种流感疫苗的人患阿尔茨海默病的比率最低。然而，这一保护机制需要进一步研究[2]。图2. 按流感疫苗接种次数估算的偶发性AD的CIF曲线AD的两个核心病理特征是淀粉样斑块和神经纤维缠结[3][4]。淀粉样蛋白级联假说表明，淀粉样蛋白β（Aβ）的沉积触发了大脑中的神经元功能障碍和死亡。越来越多的证据表明，系统性免疫反应可以对大脑产生持久的影响，并影响AD的风险和/或进展。老年人感染各种病原微生物都会增加其认知能力下降的风险和/或比率，包括流感呼吸道感染、肺炎、疱疹感染、慢性牙周炎、尿道感染、胃肠道感染、败血症，以及最近的COVID-19。因此，预防或减少病原微生物感染可能是延迟或降低神经退行性疾病风险的合理策略[4][1]。该研究进一步分析了接种流感疫苗对降低罹患AD风险的相关机制：❶流感特异性免疫机制，包括减轻继发于流感感染引起的损害和/或流感与AD病理学之间的相似性；❷接种流感疫苗引发的固有免疫系统反应，可对其它病原微生物产生非特异性保护作用,即免疫训练；❸通过适应性免疫系统的淋巴细胞介导的交叉反应，接种流感疫苗产生的特异性免疫对其他病原微生物的非特异性保护作用[1]。无论确切机制如何，越来越多的文献支持先天免疫训练的相关性，即疫苗与降低AD风险有关。▍接种流感疫苗可降低罹患抑郁症风险与流感疫苗显著降低阿尔茨海默病的患病风险类似的机理，流感疫苗还能降低罹患其它神经系统疾病的风险。来自英国的一项研究[5]。纳入了103307名在2000年至2013年期间诊断为抑郁症的80岁以下患者，分析了与以往流感感染相关的抑郁症的相对风险估计，按此类事件的数量、时间和严重程度分级，并根据各种共病、吸烟状况、酒精摄入、体重指数、口服皮质类固醇和苯二氮卓类药物进行了对比分析。与未接种流感疫苗的患者相比，接种流感疫苗患抑郁症风险降低了6.6%（OR 1.29，95%CI 1.19–1.39）。表1. 接种流感疫苗与抑郁症风险之间的关系类型Cases(n=103307)n(%)Controls(n=103307)n(%)Crude OR(95%CI)Adjusted a OR(95%CI)未接种流感疫苗8566（8.3）6746（6.5）1.33(1.28-1.37)1.30(1.25-1.35)接种流感疫苗1742（1.7）1345（1.3）1.39(1.29-1.49)1.29(1.19-1.39)▍接种流感疫苗能有效减少慢性阻塞性肺病、心血管疾病等影响与同龄健康成年人相比，慢性基础疾病患者感染流感病毒后，更易出现严重疾病或死亡，其流感相关住院率和超额死亡率更高。我国成都开展的一项队列研究表明，接种三价流感疫苗（IIV3）可以减少慢性阻塞性肺病（COPD）和慢性支气管炎的急性感染和住院[6][7]。研究发现，与未接种疫苗的对照组相比，IIV3接种3个月、6个月后COPD急性加重的住院天数分别减少3.3天、7.1天[6]。此外，还有研究发现流感疫苗对儿童和成人哮喘患者有较好免疫原性[8]；哮喘患者接种流感疫苗能够有效减少流感感染和哮喘发作[9]。英国的一项研究表明：流感疫苗在心血管疾病患者中免疫原性良好，能够保护心血管病患减少流感感染。冠心病患者接种流感疫苗后，可以减少急性冠脉综合征（ACS）患者的心血管不良事件发生率，降低其住院风险和与心脏病相关的死亡率[10]。流感疫苗还可降低心衰患者的死亡风险。丹麦的一项队列研究提示，在随访期间（中位随访时间为3.7年），接种≥1剂次流感疫苗可使心力衰竭（HeartFailure,HF）患者的全因死亡风险降低18%（风险比（HR）=0.82,95％CI:0.81-0.84），心血管死亡风险降低18%(风险比=0.82,95％CI:0.81-0.84）。此外，一些研究显示，接种流感疫苗可减少糖尿病患者、免疫功能受损患者的住院时间，降低住院率及死亡率[11]。18-64岁的糖尿病患者接种流感疫苗对住院的保护效果是58%；老年人糖尿病患者接种流感疫苗，对住院的保护效果为23%，对全死因死亡的保护效果为38-56%[12]。另外，研究提示接种流感疫苗可以减少免疫功能受损的流感住院儿童并发症的发生风险，缩短住院时间[11]。▍鼻喷流感减毒活疫苗可产生更全面的免疫反应灭活流感疫苗主要以体液免疫发挥作用，鼻喷流感减毒活疫苗可诱导更为全面的三重免疫，即：粘膜免疫、细胞免疫、体液免疫。一项对儿童的试验表明，疫苗株亚型与流行株不匹配的流行季，接种1剂鼻喷流感减毒活疫苗的保护效力为86%（交叉免疫，即：可预防所含流感病毒流行株之外的其他亚型流感病毒）。据《中国流感疫苗预防接种技术指南》指出，除对实验室确诊流感有保护效果外，有试验表明，鼻喷流感减毒活疫苗可减少21%的发热性疾病，也可减少30%的中耳炎，对6-8月龄儿童实验室确诊流感合并急性中耳炎的保护效果为85%[13]。流感减毒活疫苗经鼻腔注射后可诱导体液和鼻粘膜均产生抗体，同时也可诱导细胞介导的免疫反应，且当疫苗株亚型与循环株不匹配的流行季，也有很高的保护率。▍小结接种流感疫苗可以有效预防阿尔茨海默病（AD）等神经系统疾病，预防慢性阻塞性肺病、心血管等疾病，减少感染新型冠状病毒风险，降低罹患抑郁症风险。这可能一方面与流感疫苗激发了人体先天免疫训练有关，另一方面与接种流感疫苗降低了流感并发症有关。与灭活流感疫苗相比，鼻喷流感减毒活疫苗可更加全面的激发人体免疫，产生更为持久的抗体保护，对疫苗株之外的流感病毒具有更为广泛的预防效果，可有效降低多种疾病以及并发症的罹患风险。参考文献：[1]Bukhbinder AS, Ling Y, Hasan O, et al. Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. J Alzheimers Dis. 2022;10.3233/JAD-220361. doi:10.3233/JAD-220361[2]Avram S. Bukhbinder, Yaobin Ling, Omar Hasan, Xiaoqian Jiang, Yejin Kim, Kamal N. Phelps, Rosemarie E. Schmandt, Albert Amran, Ryan Coburn, Srivathsan Ramesh, Qian Xiao, Paul E. Schulz. Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. Journal of Alzheimer's Disease, 2022; 1 DOI: 10.3233/JAD-220361[3]Bondi MW, Edmonds EC, Salmon DP. Alzheimer's Disease: Past, Present, and Future. J Int Neuropsychol Soc. 2017;23(9-10):818-831. doi:10.1017/S135561771700100X[4]Webers A, Heneka MT, Gleeson PA. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer's disease. Immunol Cell Biol. 2020;98(1):28-41. doi:10.1111/imcb.12301[5]Bornand D, Toovey S, Jick S S, et al. The risk of new onset depression in association with influenza–A population-based observational study[J]. Brain, behavior, and immunity, 2016, 53: 131-137. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.bbi.2015.12.005[6]黄远东, 赵晓平, 万涛, 等. 慢性阻塞性肺病人群流感疫苗接种的效果观察[J]. 海南医学, 2011, (04): 29-31. doi: 10.3969/j.issn.1003-6350.2011.04.011.[7]高忠翠,李江涛,展胜.卡舒宁联合流感疫苗对老年性慢性支气管炎合并急性感染的防治效果[J].中国生物制品学杂志,2011,24(10):1214-1216. doi: CNKI:SUN:SWZP.0.2011-10-030.[8]Schwarze J, Openshaw P, Jha A, et al. Influenza burden, prevention, and treatment in asthma-A scoping review by the EAACI Influenza in asthma task force. Allergy. 2018;73(6):1151-1181. doi:10.1111/all.13333[9]Vasileiou E, Sheikh A, Butler C, et al. Effectiveness of Influenza Vaccines in Asthma: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2017;65(8):1388-1395. doi:10.1093/cid/cix524.[10]Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M, et al. Influenza vaccines for preventing cardiovascular disease. Cochrane Database Syst Rev. 2015;2015(5):CD005050. Published 2015 May 5. doi:10.1002/14651858.CD005050.pub3.[11]Collins JP, Campbell AP, Openo K, et al. Clinical Features and Outcomes of Immunocompromised Children Hospitalized With Laboratory-Confirmed Influenza in the United States, 2011-2015. J Pediatric Infect Dis Soc. 2019;8(6):539-549. doi:10.1093/jpids/piy101.[12] Remschmidt C, Wichmann O, Harder T. Vaccines for the prevention of seasonal influenza in patients with diabetes: systematic review and meta-analysis. BMC Med. 2015 Mar 17;13:53. doi: 10.1186/s12916-015-0295-6. PMID: 25857236; PMCID: PMC4373029.[13]国家免疫规划技术工作组流感疫苗工作组.中国流感疫苗预防接种技术指南(2021—2022)[J].中华医学杂志,2021,101(40):3287-3312. doi: 10.3760/cma.j.issn.0253-9624.2020.01.007.识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

疫苗抗体信使RNA免疫疗法

2021-03-31

·SYNAPSE

Takeda Completes Sale of Four Diabetes Products in Japan to Teijin Pharma Limited

Osaka, Japan, April 1, 2021 --- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that it has completed the asset transfer associated with a portfolio of select non-core products in Japan to Teijin Pharma Limited (“Teijin Pharma”) for JPY 133.0 billion. This asset transfer agreement was announced in February 2021. The portfolio divested to Teijin Pharma was comprised of four non-core type 2 diabetes products (Nesina®, Liovel®, Inisync® and Zafatek®) sold in Japan, which generated total sales of approximately JPY 30.8 billion in FY2019. While the products included in the asset transfer continue to play important roles in meeting patient needs in the country, they were outside of Takeda’s chosen business areas – Gastroenterology (GI), Rare Diseases, Plasma-Derived Therapies, Oncology, and Neuroscience – core to its global long-term growth strategy. The transaction continues Takeda’s strong momentum toward optimizing its portfolio for growth by discovering and delivering life-transforming treatments in its focused key business areas. Takeda and Teijin Pharma have entered into a manufacturing and supply agreement and distribution agreement, under which Takeda will continue to manufacture the products, supply them and provide the distribution channel to Teijin Pharma. Takeda will, for the time being, continue holding the marketing authorizations of the transferred brands, and the timing of the transfer of the marketing authorizations will be determined later. Takeda intends to use the proceeds from the sale to reduce its debt and accelerate deleveraging towards its target of 2x net debt/adjusted EBITDA within FY2021 – FY2023. Takeda has sustained momentum in its divestiture strategy and has exceeded its $10 billion non-core asset divestiture target. Including this transaction, Takeda has announced 12 deals since January 2019, for a total aggregate value of up to approximately $12.9 billion. As the asset transfer was completed on April 1, 2021, this transaction will be reflected in Takeda’s results for the first quarter of the Fiscal Year 2021. Takeda anticipates the sales price to have a positive impact on Reported Profit before income taxes and Net Profit attributable to owners of the Company of approximately JPY 130.0 billion and JPY 90.0 billion, respectively. Since the gain relates to the divestiture of non-core assets, there will be no impact on Core Operating Profit or Core Net Profit. Takeda will announce its Forecast for the Full Year Consolidated Financials for the Fiscal Year 2021 at the Fiscal Year 2020 financial results announcement scheduled in May 2021.

财报并购

2021-02-25

·SYNAPSE

Japan's Takeda sells four diabetes products to Teijin Pharma for $1.25 bln

Japan's Takeda Pharmaceutical Co said on Friday it would sell its over-the-counter (OTC) and prescription pharmaceutical assets in Japan to Teijin Pharma, part of Teijin Group, for 133 billion yen ($1.25 billion). The deal includes Takeda's diabetes treatments Nesina, Liovel, and other products, as well as its manufacturing facility in Hikari, Yamaguchi Prefecture. The sale is part of Takeda's strategy to focus on five key business areas: gastroenterology, rare diseases, plasma-derived therapies, oncology, and neuroscience. The transaction is expected to close by March 31, 2022, and will not have a major impact on Takeda's financial results for the fiscal year ending March 31, 2022.

100 项与苯甲酸阿格列汀/盐酸吡格列酮相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	-	A10BD09	-

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适应症	国家/地区	公司	日期
2型糖尿病	美国	Takeda Pharmaceuticals U.S.A., Inc.	2013-01-25

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01395797 (CTgov)	临床1/2期	海洛因依赖 \| 尼古丁依赖	82	Placebo (Placebo - Heroin)	夢築糧襯襯遞鬱餘餘餘(選壓網夢衊襯壓願艱鹹) = 鏇襯觸艱餘範憲窪廠遞憲簾襯構鬱餘顧壓簾構 (選齋鬱鑰鏇築選艱繭鏇, 鬱壓簾觸選製壓鹽構網 ~ 選壓顧衊鑰醖憲糧積遞) 更多	-	2017-07-13
				PIO (Pio High Dose - Heroin)	夢築糧襯襯遞鬱餘餘餘(選壓網夢衊襯壓願艱鹹) = 顧糧觸遞壓製鹽鑰範選憲簾襯構鬱餘顧壓簾構 (選齋鬱鑰鏇築選艱繭鏇, 齋築築襯願鹽築網鹹構 ~ 願築壓願齋鹹糧範繭醖) 更多