美国Sankyo Pharma公司宣布Colesevelam（商品名WelChol）作为一种新的降低胆固醇的药物已在全美国上市。
WelChol不但可以单独使用降低LDL胆固醇，而且还是唯一的经FDA批准的可与他汀类药物联合使用的降脂药。对以胆固醇升高为主的高脂血症，当饮食和锻炼不能很好达到效果时， WelChol单独使用或与他汀类合用可有效的降低血浆胆固醇。
WelChol的一个优点是它与其他常用的降低胆固醇的药物不同，它不被吸收入血而散布全身。美国芝加哥临床研究中心主席Michael Davidson教授在评价这种新药时说：“对于血浆胆固醇较高而正在服用其他降脂药的病人来说，WelChol是他们的福音，因为它不被吸收的特性决定了它无全身副作用，这些副作用在其他降脂药中很常见。这使得已经服药很久的病人可以在加服WelChol的同时继续服用其他降脂药。”
此外，WelChol与其他药之间的交叉反应也很小。在药物交叉反应研究中，WelChol没有明显的影响地高辛、洛伐他汀、奎尼丁和华法令等药的吸收，而这些药却与其他降脂药之间却有显著的反应。尽管如此，病人还是应该在服用WelChol之前将他们正在服用的药物告诉他们的医生。
一项调查显示，尽管国家胆固醇教育计划（NCEP）中列出了降低胆固醇的指导方针，但仅有54％的患有高胆固醇血症的被调查者知晓他们的降脂目标。
另一项称为血脂治疗评估计划（L-TAP）的研究指出，在患有高胆固醇血症的被调查者中，仅有38％接受降脂治疗的病人达到了NCEP要求的胆固醇降低的目标水平。为此，Sankyo Pharma的负责人William L. Bailey说：“L-TAP研究表明对于难以达到降脂目标水平的病人来说，的确需要在现有药物治疗之上找到更好的辅助药物。我们临床试验表明，在降低LDL-c方面WelChol是有效的和安全的。特别是当WelChol与他汀类药物（如洛伐他汀、辛伐他汀等）联合使用时，WelChol能够很好的达到降低胆固醇的作用，且这种效果是单用其中一种药物所达不到的。”美国贝勒医学院的Peter H. Jones教授指出：“WelChol与他汀类药物合用可显著改善病人的血脂水平，以达到NCEP的目标水平。此外如果病人不能耐受他汀类药物，单独使用WelChol也能有很不错的效果。”

分类名称
一级分类：循环系统药物 二级分类：调整血脂及抗动脉粥样硬化药物 三级分类：胆汁酸结合树脂 
 
药品英文名
Colesevelam
 
药品别名
Welchol
 
药物剂型
片剂：每片含本品625mg。
 
药理作用
本品是新型的降低胆固醇的药物，能与胆酸及其主要成分甘氨胆酸相结合，加速其排清，阻断其重吸收，造成胆酸耗竭，肝脏胆固醇7-α-羟化酶上调，从而增加胆固醇向胆酸的转化。 本品可以降低原发性高胆固醇血症(primary hypercholesterolemia)患者体内的低密度脂蛋白胆固醇(LDLcholesterol，LDL-ch)浓度。临床试验结果显示，本品可以有效降低LDL-ch及总胆固醇浓度。 本品是以其非吸收性聚合体技术(non-absorbed polymer technology)为基础开发的新药，具有亲水性，为不溶于水的聚合物，而且不被消化酶水解，不被人体吸收，仅是通过人体，而后被排泄。
 
药动学
本品与其他常用的降低胆固醇的药物不同，该药物不被吸收进入血液而散布全身，不会导致全身性副作用，药动学性质简单。
 
适应证
本品可以单独使用以降低低密度脂蛋白胆固醇水平，用作原发性高胆固醇血症病人饮食和运动的辅佐治疗；另外，该药物还是惟一经FDA批准的可与他汀类药物联合使用的降脂药。对以胆固醇升高为主的高脂血症，当饮食和锻炼不能很好达到效果时，本品单独使用或与他汀类合用可有效的降低血浆胆固醇浓度。
 
禁忌证
本品禁用于肠功能紊乱者，以及对药物中任一组分过敏者。
 
注意事项
当患者总胆固醇水平高于7.8mmol/L时，一般不使用本品，如需使用应谨慎。非临床安全性研究显示，大鼠给予本品人体用药剂量的30倍可因维生素K缺乏而引起出血。

不良反应
本品可引起头痛、疼痛和无力等中枢神经系统不良反应；耳鼻喉方面常见有咽炎、鼻炎、鼻窦炎等不良反应；胃肠方面可引起腹痛、便秘、腹泻、消化不良、胃肠胀气和恶心等不良反应；骨骼肌肉系统的不良反应有肌痛和背痛；呼吸系统有咳嗽；皮肤方面可引起损伤、感染及感染综合征等。 本品因不被吸收而无全身副作用，本品与其他药之间的交叉反应也很小。
 
用法用量
口服，推荐起始剂量为3片/次，2次/d，或6片/次，1次/d。根据需要剂量可调整为7片/d。和HMG-COA还原酶抑制剂合用时，以4～6片/次较为安全和合适。
 
药物相应作用
本品与其他药物同服时，未见本品对地高辛、洛伐他汀、美托洛尔、奎尼丁、丙戊酸和华法林生物利用度有明显影响。本品可使丙戊酸缓释剂(Calan SR)的Cmax和AUC分别降低31%和11%。尽管临床丙戊酸的生物利用度具有较大的可变性，但原因目前尚不清楚。
本品与阿托伐他汀、洛伐他汀或辛伐他汀同服不会影响他汀类药物的降脂作用。但尚未在其他药物中进行有关研究。当与可能干扰药物血浓度的其他药物同服时，药物的安全性和有效性可能受到影响，用药时应考虑进行药物浓度监测。
 本品在与其他药物联用时虽不易产生副作用，但患者还是应该在服用本品前告诉医生是否正在服用的其他药物。 如果患者不能耐受他汀类药物，单独使用本品也可以达到很好的效果。本品由于不被吸收，使用时的安全性将比目前被广泛使用的其他降血脂药物如他汀类药物显著增高。
 
专家点评
临床试验表明，在降低LDL胆固醇方面本品是有效的和安全的。特别是当本品与他汀类药物联合使用时，能够很好的达到降低胆固醇的作用。 临床研究显示，对于原发性高胆固醇血症患者，本品无论单用或与他汀类药物(如洛伐他汀、辛伐他汀等)合用均可降低其总胆固醇、LDL-ch和载脂蛋白B(Apo B)水平，同时升高HDL胆固醇水平，且这种效果是单用其中任一种药物所达不到的。约有1400例患者参与为期分别为4～50周的8项研究，其中除1项长程研究外，其余均为多中心随机双盲安慰剂对照研究。研究显示，本品用药后2周可达最大疗效，且这1疗效在整个长程研究中始终保持。 LDL-ch水平在3.38～5.72mmol/L(平均4.12mmol/L)的患者中进行的研究显示，在早餐和晚餐分别给予本品3.8g和4.5g，用药24周可使LDL-ch平均降低15%和18%；总胆固醇平均分别降低7%和10%；而Apo B两组均平均降低12%。本品2种剂量均使HDL胆固醇升高3%，两组甘油三酯轻度升高，与安慰剂组相比未见有统计学意义的明显差异。 98例LDL-ch在3.77～6.50mmol/L(平均4.39mmol/L)的患者中进行的研究显示，本品3.8g分别与早餐、晚餐同服或与早餐或晚餐分开服用，治疗6周后3种给药方案分别使平均LDL-ch降低18%，15%和18%，三组间无明显差异 本品与他汀类药物如阿托伐他汀(atorvastin)、洛伐他汀(lovastatin)或辛伐他汀(simvastatin)联合使用的3项临床研究显示，联合用药可使LDL-ch进一步降低。

Welchol (colesevelam hydrochloride)

Company: Daiichi Sankyo
Approval Status: Approved January 2008
Treatment for: glycemic control in type 2 diabetes mellitus
Areas: Endocrinology
General Information
Welchol contains colesevelam hydrochloride, a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent. It works by binding bile acids, including the major bile acid in humans known as glycocholic acid. However, the exact mechanism by which Welchol improves glycemic control is unknown.
Welchol is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Welchol is supplied as a 625 mg tablet designed for oral administration. The recommended initial dose of the drug is 6 tablets once daily or 3 tablets twice daily. Welchol should be taken with a meal and liquid.
Clinical Results
FDA Approval
The FDA approval of Welchol for this indication was based on the results of three clinical trials. These double-blind, placebo-controlled add-on therapy trials enrolled a total of 1,018 subjects with baseline A1C 7.5-9.5%. The subjects received Welchol, in combination with metformin, sulfonylureas or insulin or placebo administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.
Add-on Combination Therapy with Metformin:
Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 subjects already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). The combination of Welchol plus metformin resulted in statistically significant placebo-corrected reductions in A1C with a -0.6 treatment difference (p<0.001) and FPG with a -14 treatment difference (p=0.10). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with Welchol compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for Welchol and -0.3 kg for placebo.
Add-on Combination Therapy with Sulfonylurea:
Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). In combination with a sulfonylurea, Welchol resulted in statistically significant placebo corrected reductions in A1C and FPG. Welchol also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 11). The mean percent change in serum LDLC levels with Welchol compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with Welchol compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for Welchol and -0.4 kg for placebo.
Add-on Combination Therapy with Insulin:
Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the Welchol group and 65 units in the placebo group. In combination with insulin, Welchol resulted in a statistically significant placebo-corrected reduction in A1C (Table 12). Welchol also reduced LDL-C and Apo B, but increased serum TG (Table 13). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with Welchol compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for Welchol and 0.2 kg for placebo.
Ongoing Study Commitments
Daiichi Sankyp has agreed to study WelChol as monotherapy treatment for type 2 diabetes mellitus:
Protocol Submission: by July 31, 2008
Study Start: by January 31, 2009
Final Report Submission: by July 31, 2011
Daiichi Sankyo has agreed to study WelChol in combination with thiazolidinediones as treatment for type 2 diabetes mellitus:
Protocol Submission: by October 31, 2008
Study Start: by April 30, 2009
Final Report Submission: by October 31, 2011
Daiichi Sankyo has agreed to the following time lines for in Vivo Studies for an ARB, glimepiride, glipizide ER, and phenytoin:
Protocol Submission: by June 30, 2008
Study Start: by September 30, 2008
Final Report Submission: by September 30, 2009
Side Effects
Adverse events associated with the use of Welchol may include, but are not limited to, the following:
Constipation
Nasopharyngitis
Dyspepsia
Hypoglycemia
Nausea
Hypertension
Mechanism of Action
Colesevelam hydrochloride, the active pharmaceutical ingredient in Welchol, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. However, the exact mechanism by which Welchol improves glycemic control is unknown.
Literature References
Staels B, Kuipers F Bile acid sequestrants and the treatment of type 2 diabetes mellitus. Drugs 2007;67(10):1383-92
Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL Results of the glucose-lowering effect of WelChol study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clinical therapeutics 2007 Jan;29(1):74-83
Zema MJ Colesevelam HCl and ezetimibe combination therapy provides effective lipid-lowering in difficult-to-treat patients with hypercholesterolemia. American Journal of Therapeutics 2005 Jul-Aug;12(4):306-10
Additional Information
For additional information regarding Welchol or glycemic control, please visit the Welchol web page.

【-原产地英文商品名-】WELCHOL TABLET 625mg/tab 180tabs/bottle
【-原产地英文药品名-】COLESEVELAM HCL
【-原产地英文化合物名称-】1-Hexanaminium, N,N,N-trimethyl-6-(2-propenylamino)-, chloride, polymer with (chloromethyl)oxirane, 2-propen-1-amine and N-2-propenyl-1-decanamine, hydrochloride
【-中文参考商品名-】WELCHOL片剂 625毫克/片 180片/瓶
【-中文参考药品名-】盐酸考来维仑
【-临床试验期】完成-】
【-中文适应病症参考-】降血脂
【-中文适应病症参考-】降低胆固醇
【-中文适应病症参考-】降脂
【-生产厂家中文参考-】第一三共
【-生产厂家英文名-】DAIICHI SANKYO