近日，美国FDA批准批准3种剂量：290微克用于便秘型肠易激综合征（IBS-C）成人患者的治疗，145微克和72微克用于慢性特发性便秘（CIC）成人患者的治疗。
linaclotide是一种鸟苷酸环化酶‐C（GC-C）激动剂，能够结合并局部作用于小肠上皮管腔表面的GC-C受体。GC-C的激活导致细胞内和细胞外环磷酸鸟苷（cGMP）浓度均升高。细胞内cGMP升高刺激氯离子和碳酸氢根离子分泌进入肠腔，导致小肠分泌液增加和加速通过。动物模型中，linaclotide还表现出减轻小肠疼痛的作用，而这被认为是细胞外cGMP增加所介导，降低了肠道疼痛感应神经的活动，从而诱导内脏疼痛减轻。
FDA的药物评价和研究中心药物评价第III室副主任Victoria Kusiak，M.D.说：“没有一种药物对所有被这些胃肠道疾病对患这些病的所有患者，没有一个药物有效” “新治疗的可供利用性,患者和它们的医生可对其情况最适宜治疗。”
批准日期：2012年8月30日；公司：Ironwood Pharmaceuticals，Inc.和Forest Laboratories，Inc.
LINZESS(利那洛肽[linaclotide])胶囊，为口服使用
美国初次批准：2012
作用机制
利那洛肽是一种鸟苷酸环化酶-C(GC-C)激动剂。Both 利那洛肽及其活性代谢物与GCC结合和局部作用于小肠上皮管腔表面上。GC-C的激活导致细胞内和细胞外环磷酸鸟苷(cGMP)浓度都增高。细胞内cGMP升高刺激氯离子和碳酸氢根的分泌进入肠腔，主要是通过激活的囊性纤维化跨膜电导调节器(CFTR)离子通道，导致小肠液体增加和加速通过。在动物模型中，利那洛肽曾显示to both 加速GI通过和减低小肠疼痛。利那洛肽在动物中诱导内脏疼痛减轻被认为是细胞外cGMP增加所介导，被证明是减低痛觉神经的活动。
适应证和用途
LINZESS是一种鸟苷酸环化酶-C 激动剂适用于在成年中为治疗：
（1）有便秘肠易激综合征(IBS-C)
（2）慢性特发性便秘(CIC)
剂量和给药方法
（1）IBS-C：290 μg口服每天1次
（2）CIC：145 μg 口服每天1次
（3）空胃服用首次餐至少30分前。
剂型和规格
胶囊：72μg，145μg和290μg
禁忌证
（1）患儿至6岁。
（2）患者有已知或怀疑 机械性胃肠道梗阻
黑框警告和注意事项
（1）腹泻:患者可能经受严重腹泻。不用或停止LINZESS。
不良反应
在IBS-C或CIC患者中报道的最常见不良反应(发生率至少2%)是腹泻，腹痛，胀气和腹胀.
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产地国家：美国 
原产地英文商品名:
LINZESS 72mμg/cap 30caps/box
原产地英文药品名:
linaclotide
中文参考商品译名:
LINZESS 72微克/胶囊 30胶囊/瓶 
中文参考药品译名:
利那洛肽
生产厂家中文参考译名:
ForestLaboratories
生产厂家英文名:
ForestLaboratories

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产地国家：美国 
原产地英文商品名:
LINZESS 145mμg/cap 30caps/box
原产地英文药品名:
linaclotide
中文参考商品译名:
LINZESS 145微克/胶囊 30胶囊/瓶 
中文参考药品译名:
利那洛肽
生产厂家中文参考译名:
ForestLaboratories
生产厂家英文名:
ForestLaboratories

---------------------------------------
产地国家：美国 
原产地英文商品名:
LINZESS 290mμg/cap 30caps/box
原产地英文药品名:
linaclotide
中文参考商品译名:
LINZESS 290微克/胶囊 30胶囊/瓶 
中文参考药品译名:
利那洛肽
生产厂家中文参考译名:
ForestLaboratories
生产厂家英文名:
ForestLaboratories

Linzess (linaclotide), a medication for irritable bowel syndrome (IBS) with constipation or chronic idiopathic constipation is now available in American pharmacies, Ironwood Pharmaceuticals Inc. and Forest Laboratories Inc announced.
The FDA (Food and Drug Administration) recently approved the once-daily oral capsule, Linzess, for adults of either sex who suffer from IBS-C (IBS with constipation) or CIC (chronic idiopathic constipation).
Linaclotide is the only FDA-approved GC-C (guanylate cyclase-C) agonist that acts locally in the gut. Ironwood Pharmaceuticals says this is the first new prescription option for adults with these disorders in over six years.
About Linzess (linaclotide)Linzess (linaclotide) is the "first and only guanylate cyclase‐C (GC‐C) agonist approved by the FDA for the treatment of both irritable bowel syndrome with constipation (IBS‐C) and chronic idiopathic constipation (CIC) in adults", according to Ironwood Pharmaceuticals.
Linzess is taken orally, in capsule form, once a day. It helps relieve the pain and constipation linked to IBS-C and constipation and hard stools experienced by patients with CIC.
The recommended doses are:
■290 mcg for IBS‐C patients
■145 mcg for CIC patients
You should take Linzess at least thirty minutes before breakfast (or your first meal of the day).
Scientists believe Linzess works in two ways "Linzess binds to the GC‐C receptor locally, within the intestinal epithelium. Activation of GC‐C results in increased intestinal fluid secretion and transit and a reduction in visceral pain, which is thought to be mediated by decreased activity of pain‐sensing nerves. The clinical relevance of the effect on pain fibers in nonclinical studies has not been established."
In randomized, placebo-controlled Phase III human studies involving over 2,800 adults, Linzess was shown to alleviate abdominal pain in patients with IBS-C, as well as increasing bowel movement frequency among those with CIC and IBS-C.
Abdominal pain relief was reported during the first week of treatment and was maintained during the whole of the 12-week treatment period. Maximum effect on constipation was seen during week two, and on abdominal pain at weeks 6 to 9.
A subset of patients who had been on Linzess were switched over to placebo during the trial. They reported that their symptoms went back to pretreatment levels within seven days. Some placebo patients were switched over to Linzess and reported improvements soon after taking the medication.
Linzess should not be taken by patients up to the age of six years. The medication should be avoided in patients aged from 6 to 17 years. Animal studies showed that a clinically relevant adult dose of linaclotide caused deaths in juvenile mice. No trials have been carried out on children. The most commonly reported side effect associated with Linzess treatment was diarrhea.
Linzess is being co-promoted by Ironwood and Forest in the USA.
Linaclotide, which was also approved in the European Union, will be marketed under the brand name Constella through a licence agreement between Ironwood and Almirall S.A. The development and commercialization in Japan and other Asian markets will be done via agreements between Ironwood and Astellas Pharma Inc. and AstraZeneca.
Irritable Bowel Syndrome with ConstipationUp to 13 million people are thought to have irritable bowel syndrome with constipation (IBS‐C) in the USA.
It is a chronic functional gastrointestinal disorder. IBS‐C symptoms can be severe enough to seriously undermine a patient's ability to properly carry out daily living duties.
Patients typically suffer recurring abdominal discomfort or pain, constipation, hard or lumpy stools in over 25% of their bowel movements, and soft/watery stools in less than 25%.
Ironwood says there are very few approved therapies for IBS‐C available today.
Chronic Idiopathic ConstipationCIC (chronic idiopathic constipation) is thought to affect up to 35 million Americans today. It is a functional gastrointestinal disorder in which the sufferer has fewer than three bowel movements each week for at least three months.
CIC patients may also have a sensation of incomplete evacuation after going to the toilet, as well as hard stools.

利那洛肽Linzess(linaclotide)是首个具有此种作用机制的便秘治疗药物
利那洛肽在IBS-C患者中应用的安全性和有效性在两项随机双盲研究中得到了肯定，这两项研究纳入了1604例受试者。试验中，患者随机分入290μg利那洛肽治疗组和安慰剂组，治疗至少12周。结果显示，与安慰剂相比，利那洛肽在患者患者腹痛和增加完全自发排便次数（CSBMs）方面较安慰剂更有效。这两项IBS-C研究计划在10月份《美国胃肠病学杂志》发表。
进一步开展的两项双盲、多中心临床试验确定了利那洛肽在慢性特发性便秘患者中的安全性和有效性，研究纳入了1272例慢性便秘患者。这两项研究去年发表在新英格兰医学杂志，医景医疗新闻（Medscape Medical News）曾对此做过报道。在这两项研究中，患者随机分入安慰剂组、利那洛肽145μg/d组或利那洛肽290μg/d组。治疗12周后，达到主要终点（每周完全自发的排便（CSBM）≥ 3 次，以及在12 周中的至少有9周CSBM 比基线增加 ≥ 1 次），利那洛肽145 μg治疗组达到终点的患者数显著性高于安慰剂组。FDA只批准了145μg剂量，原因在于患者服用290μg并不比145μg更有效。
据称，药物作用迅速，24小时内即可观察到效果，并且作用可维持16周。
据在新英格兰医学杂志发文的作者推测，导致患者病情改善的因素包括肠腔液体增加以及小肠蠕动加快。“尽管利那洛肽治疗引发的肠道功能改善极有可能是肠液增加和肠道移行加快的结果，但是改善腹部症状的可能另有原因，”。
医学博士Brennan M.R. Spiegel与本次研究无关，他告诉医景医疗新闻说，利那洛肽改善CSBMs的作用令人印象深刻。“对便秘而言，自主排便频率大概是最重要的一件事件了，所以药物可以改善此功能这一点非常重要，”Spiege博士说。Spiege博士是美国退伍军人事务部洛杉矶医疗保健系统和洛杉矶加州大学大卫格芬医学院的副教授。Spiegel博士还指出，除了增加肠液外，利那洛肽还有一个独一无二的作用机理，令其卓尔不群。“所有通过某种方法增加肠液分泌的药物，例如Miralax [MSD Consumer Care]可以促进肠液分泌，但却是通过渗透压被动的发挥作用，而利那洛肽则是主动发挥作用，通过囊性纤维化跨膜传导调节蛋白通道主动的将氯离子泵入肠腔，随后将水主动泵入肠腔，”Spiegel博士说。“有意思的是，药物作用于鸟甘酸环化酶，而这是一个独一无二的作用机制。但是净效果没到独一无二那种程度，”他继续说道。Spiegel博士说他对利那鲁肽治疗IBS-C的研究满心期望，这一项研究正在进行之中。“现在我们已经获得了几个慢性便秘治疗药物，并且，通常情况下，药物疗效良好，但对面对IBS时，就是另一码事了。”Spiege博士说。“在这方面，现在看起来，很有希望获得一种不但可以治疗便秘还可以治疗腹胀、腹痛和其它许多临床症状的治疗药物，现在治疗这些症状的有效药物并不多。”但是，“如果它的零售价与现有药物相当，那么利那洛肽就被真正的证明是难治性慢性便秘的一线药物。”他继续说道。
利那洛肽每日空腹服用一次，在一天当中的第一餐前至少30分钟口服。利那洛肽最常见的不良反应是腹泻，FDA批准的药品事项中有一项加框警告，提醒患者和医务人员不应将该药用于16岁及以下年龄患者。
完整处方附件：Download the Linzess Full Prescribing Information, including Boxed Warning.