由美国ACTELION PHARMS公司研制的治疗由葡萄糖酶脑苷脂酶出现功能性缺陷所引起的Ⅰ型高雪病的首例药物美格鲁特(Miglustat)胶囊剂以商品名zavesca，于2003年7月获得美国FDA批准

戈谢氏病为一种罕见遗传病，由于葡萄糖酶脑苷脂酶活性降低所致。此酶在人体内参与鞘糖脂葡萄糖鞘脑苷鞘氨醇的降解过程，当鞘糖脂葡萄糖鞘脑苷鞘氨醇的降解受到阻碍时，会使富含此种物质的巨嗜细胞的溶酶体在体内蓄积，发生广泛的病理反应，包括严重贫血、血小板减少、肝脾肿大、骨坏死和骨质减少。在治疗上常采用酶替代方法，美格鲁特用于无法以酶替代治疗的成年患者。

药理药效：美格鲁特可降低鞘内糖脂的生物合成率，将葡萄糖苷鞘酶在人体内的浓度降至一个低水平，有助于改善Ⅰ型戈谢氏病患者的肝、脾脏肿大，血色素、血小板计数低下的水平。

使用方法：推荐剂量为1次100mg，1日3次，若患者出现腹泻和震颤等不良反应，剂量可减少为1日1～2次；对轻度肾脏功能受损者(肌酐清除率为50～70ml/min  /1.73m2)推荐剂量为1次100mg，1日2次；对轻度肾脏功能受损者(肌酐清除率为50～70ml/min  /1.73m2)推荐剂量为1次100mg，1日2次；对中度肾脏功能受损者(肌酐清除率为30～50ml/min /1.73m2)推荐剂量为1次100mg，1日1次；对重度肾脏功能受损者不宜应用。

副作用：服药初始的第1个月，常见有震颤、腹泻、胃肠道不适、视力损害、体重减轻、麻木、疼痛、背痛、疲乏、手足烧灼感、肢体沉重、血小板减少等不良反应；对男性有可能影响精子的质量，因此在用药期间尽可能地采取避孕措施，对女性患者在服用期间建议不要怀孕。美格鲁特胶囊剂的规格为每粒100mg，每盒20粒。

治疗高雪病的首例药物-zavesca(Miglustat)

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原产地英文商品名:
ZAVESCA 100mg/cap 90caps/box
原产地英文药品名:
MIGLUSTAT
原产地英文化合物名称:
1,5-(butylimino)-1,5-dideoxy-D-glucitol
中文参考商品译名:
ZAVESCA 100毫克/胶囊 90胶囊/盒
中文参考药品译名:
美格鲁特
生产厂家中文参考译名:
ACTELION PHARMS LTD
生产厂家英文名:
ACTELION PHARMS LTD

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Zavesca®
(miglustat) Capsules, 100mg

ZAVESCA® (miglustat capsules, 100 mg) is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. ZAVESCA® is an N-alkylated imino sugar, a synthetic analogue of D-glucose.

The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula C10H21NO4 and a molecular weight of 219.28.

Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water ( > 1000 mg/mL as a free base).

ZAVESCA® is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each ZAVESCA® 100 mg capsule also contains sodium starch glycolate, povidone (K30), and magnesium stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide and shellac.

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INDICATIONS
ZAVESCA® is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to constraints such as allergy, hypersensitivity, or poor venous access).

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DOSAGE AND ADMINISTRATION
Instructions for Administration
Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease. The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals.

It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients for adverse effects, such as diarrhea or tremor.

Patients with Renal Insufficiency
In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m²), ZAVESCA® administration should commence at a dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clearance of 30-50 mL/min/1.73 m²), ZAVESCA® administration should commence at a dose of one 100 mg capsule per day. Use of ZAVESCA® in patients with severe renal impairment (creatinine clearance of < 30 mL/min/1.73 m²) is not recommended.

STORAGE
Store at 20° C to 25° C (68° F to 77° F). Brief exposure to 15° C to 30° C (59° F to 86° F) permitted (see USP Controlled Room Temperature).

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HOW SUPPLIED
ZAVESCA® is supplied in hard gelatin capsules containing 100 mg miglustat. ZAVESCA® 100 mg capsules are white opaque with “OGT 918” printed in black on the cap and “100” printed in black on the body.

ZAVESCA® 100 mg capsules are packed in blister cards. Five blister cards of 18 capsules are supplied in each carton.

NDC 66215-201-90: carton containing 90 capsules
NDC 66215-201-18: blister card containing 18 capsules

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SIDE EFFECTS
The most common serious adverse reaction reported with Zavesca treatment in clinical studies was peripheral neuropathy (see WARNINGS: Peripheral Neuropathy).

The most common treatment-emergent adverse events reported in clinical studies with Zavesca were weight loss, diarrhea, and tremor (see PRECAUTIONS: Tremor, and Diarrhea and Weight Loss). Other common adverse reactions were flatulence, abdominal pain, headache, and influenza-like symptoms.

The most common adverse reaction requiring intervention was diarrhea (see PRECAUTIONS: Diarrhea and Weight Loss). Most episodes of diarrhea were ameliorated by the use of anti-diarrheal medications, and/or the avoidance of high-carbohydrate-content foods, or were noted to decrease over time with continued Zavesca treatment. The next most common adverse reaction requiring intervention was tremor (see PRECAUTIONS: Tremor). In many cases, tremor resolved despite continued Zavesca treatment. Dose reduction of Zavesca may ameliorate tremor, but discontinuation of Zavesca was required in some patients.

The data described below reflect exposure of 80 adult type 1 Gaucher disease patients to Zavesca in two open-label, uncontrolled, monotherapy trials, and one open-label, active-controlled trial. Patients were ages 18 to 69 years at first treatment. The population was nearly evenly distributed by gender.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with ZAVESCA® at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily) for up to 12 months in 28 patients [Study 1], or at a dose of 50 mg three times daily for up to 6 months in 18 patients [Study 2]. Table 9 below enumerates adverse events that occurred during the trials in ≥ 5% of patients. Reported adverse events have been classified using standard WHOART terms.

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DRUG INTERACTIONS
While co-administration of ZAVESCA® appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with Cerezyme (imiglucerase) and ZAVESCA® is not indicated (see CLINICAL PHARMACOLOGY: Drug Interactions).

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WARNINGS
Peripheral Neuropathy
Cases of peripheral neuropathy have been reported in patients treated with ZAVESCA®. All patients receiving ZAVESCA® treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of the risk/benefit of ZAVESCA® therapy, and cessation of treatment may be considered.

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PRECAUTIONS
General
Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease.

Tremor
Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved within 1 to 3 months during treatment. Dose reduction may ameliorate the tremor, usually within days, but discontinuation with treatment may sometimes be required.

Diarrhea and Weight Loss
Diarrhea and weight loss were common in clinical studies of patients treated with ZAVESCA®, with approximately 85% and up to 65% of treated patients, respectively, reporting these conditions. Diarrhea appears to be the result of the disaccharidase inhibitory activity of ZAVESCA®, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. The incidence of diarrhea was noted to decrease over time with continued ZAVESCA® treatment, and was noted to result in an increase in the use of anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high-carbohydrate-content foods during treatment with ZAVESCA® if they present with diarrhea.

Patients with persistent gastrointestinal events that continue during treatment with Zavesca, and who do not respond to usual interventions (e.g., diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with Zavesca has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with Zavesca should occur only after consideration of the risks and benefits of continued treatment.

Male Fertility
Male patients should maintain reliable contraceptive methods while taking ZAVESCA®. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, thereby reducing fertility. Until further information is available, it is advised that before seeking to conceive, male patients should cease ZAVESCA® and maintain reliable contraceptive methods for 3 months thereafter (see Carcinogenesis, Mutagenesis, and Impairment of Fertility).

Information for Patients
Patients should be informed of the potential risks and benefits of ZAVESCA® and of alternative modes of therapy. Patients should be advised that diarrhea, gastrointestinal complaints, and weight loss are common side effects of ZAVESCA® therapy, and to adhere to dietary instructions. Patients should also be advised to promptly report any numbness, pain, or burning in the hands and feet, and the development of tremor or worsening in an existing tremor.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
Two-year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420, and 500 mg/kg/day (about 3, 6, and 7 times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about 6 and 7 times the recommended human dose, respectively, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60, and 180 mg/kg/day (about 1, 2, and 5 times the recommended human dose, respectively, based on the body surface area).

Miglustat was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays.

Male rats, given 20 mg/kg/day miglustat by (systemic exposure less than the human therapeutic systemic exposure based on body surface area comparisons, mg/m²) oral gavage 14 days prior to mating, had decreased spermatogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible following 6 weeks of drug withdrawal. A higher dose of 60 mg/kg/day (2 times the human therapeutic systemic exposure based on body surface area comparison, mg/m²) resulted in seminiferous tubule and testicular atrophy/degeneration.

Female rats were given oral gavage doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation. Effects observed at 20 mg/kg/day (systemic exposure less than the human therapeutic systemic exposure, based on body surface area comparisons) included decreased corpora lutea, increased postimplantation loss, and decreased live births.

Pregnancy Category X. See CONTRAINDICATIONS section.

There are no adequate and well-controlled studies of miglustat in pregnant women. ZAVESCA® should not be used during pregnancy.

Labor and Delivery
Studies in pregnant rats exposed to ZAVESCA® during gestation through lactation are associated with dystocia and delayed parturition at systemic exposure 2 times the human therapeutic systemic exposure, based on body surface area comparisons.

Nursing Mothers
It is not known whether miglustat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from miglustat, ZAVESCA® should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.

Pediatric Use
The safety and effectiveness of ZAVESCA® have not been evaluated in patients under the age of 18. Treatment with ZAVESCA® is associated with diarrhea and weight loss in approximately 85% and up to 65%, respectively, of adult patients. The effects of ZAVESCA® on growth and development in children have not been evaluated.

Geriatric Use
Clinical studies of ZAVESCA® did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy.

Renal Impairment
Miglustat is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. The clearance of miglustat is decreased by 40 to 60% in patients with mild to moderate renal impairment, and up to 70% in patients with severe renal impairment. As a result of this, dose reductions are recommended for those patients with mild to moderate renal impairment, the reduction being dependent upon the level of their creatinine clearance adjustment. For those patients with severe renal impairment, treatment with miglustat is not recommended. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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OVERDOSE
In the clinical development program for ZAVESCA®, no patient experienced an overdose of study drug. However, ZAVESCA® has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.

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CONTRAINDICATIONS
ZAVESCA® is contraindicated in patients who have demonstrated hypersensitivity to the active substance or any of the excipients.

Pregnancy Category X
Miglustat may cause fetal harm when administered to a pregnant woman. In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17 (organogenesis), decreased live births including complete litter loss and decreased fetal weight was observed in the mid- and high-dose groups (systemic exposures ≥ 2 times the human therapeutic systemic exposure based on body surface area comparison). In pregnant rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20), dystocia and delayed parturition were observed in the mid- and high-dose groups (systemic exposures ≥ 2 times the human therapeutic systemic exposure, based on body surface area comparison); in addition decreased live births and pup body weights were observed at > 20 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body surface area comparison).

In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation days 6-18 (organogenesis), maternal death and decreased body weight gain were observed at 15 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body surface area comparisons).

ZAVESCA® is contraindicated in women who are or may become pregnant. If this drug is administered to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus.

瑞士的Actelion生技公司今日藉由海报方式，在美国人类基因协会上，发表了他们针对罹患尼曼匹克症C型─一种与多处神经表现相关的罕见基因疾病──病友们，使用一年的miglustat (Zavesca reg; )后，针对其安全性与药效所做的随机对照研究成果。

29位接受研究的对象，在眼球急速振动 [2] (藉由电生理评估) ，以及吞嚥与听力方面(藉由临床评估) ，实验组(服用miglustat)与对照组(一般标準照料)相比，虽然没有具统计意义的明显差别，但有趋向进步与稳定。

29位接受研究的对象，在眼球急速振动 [2] (藉由电生理评估) ，以及吞咽与听力方面(藉由临床评估) ，实验组(服用miglustat)与对照组(一般标准照料)相比，虽然没有具统计意义的明显差别，但有趋向进步与稳定。

这项研究将会如计画般继续进行一年，这段期间，所有病人都将服用miglustat 。
这项研究将会如计画般继续进行一年，这段期间，所有病人都将服用miglustat 。 关於现有研究发现的完整讨论内容被收录在会议海报 [3] 。
关于现有研究发现的完整讨论内容被收录在会议海报 [3] 。
美国纽约哥伦比亚大学小儿神经科教授，马克·派特森 [4] 解释道：「我们现在已经知道miglustat可通过血脑屏障抵达大脑。这是我们第一次观察到药物在尼曼匹克C型患者身上可能有一些助益的效果存在。令人鼓舞的是，这些研究观察也可能暗示著某些原本被疾病进程所改变的神经元，有可能恢復其正常功能。就研究本身而言，我们更朝著一直以来的目标──试图瞭解并治疗这项复杂疾病，向前跨出另一步。」
美国纽约哥伦比亚大学小儿神经科教授，马克·派特森 [4] 解释道：「我们现在已经知道miglustat可通过血脑屏障抵达大脑。这是我们第一次观察到药物在尼曼匹克C型患者身上可能有一些助益的效果存在。令人鼓舞的是，这些研究观察也可能暗示着某些原本被疾病进程所改变的神经元，有可能恢复其正常功能。就研究本身而言，我们更朝着一直以来的目标──试图了解并治疗这项复杂疾病，向前跨出另一步。」

这项研究的安全资料评估，一天三次，使用miglustat 200毫克与先前评估，一天三次使用100毫克的安全资料相符合。
这项研究的安全资料评估，一天三次，使用miglustat 200毫克与先前评估，一天三次使用100毫克的安全资料相符合。
关於尼曼匹克症C型 关于尼曼匹克症C型
尼曼匹克症C型是一种致命的、退化性基因问题，主要影响小孩子与青少年，但任何年龄都可能发病。
尼曼匹克症C型是一种致命的、退化性基因问题，主要影响小孩子与青少年，但任何年龄都可能发病。
导致其症状的原因为某些糖化磷脂质不正常地储存在身体内的某些细胞，包括大脑。
导致其症状的原因为某些糖化磷脂质不正常地储存在身体内的某些细胞，包括大脑。 此疾病进程快速，大部分的病人在经诊断后的五到十年间离开人世。
此疾病进程快速，大部分的病人在经诊断后的五到十年间离开人世。
神经退化是这项疾病的主要特点，其表现为身体运动迟缓、平衡感发生问题、说话缓慢、含糊不清、吞嚥困难、眼睛移动障碍与癲癇发作。
神经退化是这项疾病的主要特点，其表现为身体运动迟缓、平衡感发生问题、说话缓慢、含糊不清、吞咽困难、眼睛移动障碍与癫痫发作。 一般而言，智力会下降。
一般而言，智力会下降。 在疾病末期，小孩或青少年时常需卧床、不太能控制自己的肌肉活动、且智力受损。
在疾病末期，小孩或青少年时常需卧床、不太能控制自己的肌肉活动、且智力受损。 此病目前无治疗方法。 此病目前无治疗方法。
关於研究及成果的细节 关于研究及成果的细节
这项研究目前由美国哥伦比亚大学与英国皇家曼彻斯特儿童医院共同执行。 这项研究目前由美国哥伦比亚大学与英国皇家曼彻斯特儿童医院共同执行。
罹患尼曼匹克C型的29位病人，均大於12岁，被随机分派为： 罹患尼曼匹克C型的29位病人，均大于12岁，被随机分派为：
1. 1.      实验组： 20位病人，一天三次，服用200毫克miglustat ； 实验组： 20位病人，一天三次，服用200毫克miglustat ；
2. 2.      对照组： 9位病人，接受一般标準照顾。 对照组： 9位病人，接受一般标准照顾。
 为期12个月，并定期接受一系列关於临床、电生理及生活品质的评估。 为期12个月，并定期接受一系列关于临床、电生理及生活品质的评估。
实验用了第一型高雪氏症 [5] 建议剂量的双倍用量，以增加大脑对miglustat的暴露程度。 实验用了第一型高雪氏症 [5] 建议剂量的双倍用量，以增加大脑对miglustat的暴露程度。
25位病人已完成第一阶段为期12个月的研究，另外4位并未持续接受治疗(其中有3位属於实验组， 1位属於对照组) 。
25位病人已完成第一阶段为期12个月的研究，另外4位并未持续接受治疗(其中有3位属于实验组， 1位属于对照组) 。 由这12个月的资料，经分析 [6] 显示，在水平方向的眼球急速振动及吞嚥方面，皆有改善，但这些改善并没有统计上的意义。 由这12个月的资料，经分析 [6] 显示，在水平方向的眼球急速振动及吞咽方面，皆有改善，但这些改善并没有统计上的意义。
分析并指出病人在听力上，接受治疗组趋於稳定，而未接受治疗组，有恶化的情形。
分析并指出病人在听力上，接受治疗组趋于稳定，而未接受治疗组，有恶化的情形。
在这份研究中所观察的miglustat安全资料与罹患第一型高雪氏症患者一天服用三次100毫克的结果一致，特别是在体重减轻与肠胃道不适这两方面。
在这份研究中所观察的miglustat安全资料与罹患第一型高雪氏症患者一天服用三次100毫克的结果一致，特别是在体重减轻与肠胃道不适这两方面。
根据这些结果，这份研究还会持续12个月，在这段期间所有病人将会开始服用miglustat且将同样接受一系列的检查。
根据这些结果，这份研究还会持续12个月，在这段期间所有病人将会开始服用miglustat且将同样接受一系列的检查。
关於基质减量治疗[7]合併miglustat 关于基质减量治疗[7]合并miglustat miglustat是一种小分子，其药物分佈能遍佈许多组织，服用方式为口服。
miglustat是一种小分子，其药物分布能遍布许多组织，服用方式为口服。 miglustat在基质减量治疗的原则下能有效发挥作用。
miglustat在基质减量治疗的原则下能有效发挥作用。 而所谓基质减量治疗目的就是要减少葡萄糖神经醯胺 [8] 的合成速率，因为葡萄糖神经醯胺是糖化磷脂质的前驱物质，而糖化磷脂质不正常地储存导致尼曼匹克症C型之发生。
而所谓基质减量治疗目的就是要减少葡萄糖神经醯胺 [8] 的合成速率，因为葡萄糖神经醯胺是糖化磷脂质的前驱物质，而糖化磷脂质不正常地储存导致尼曼匹克症C型之发生。
也正是因为糖化磷脂质不正常地储存使神经元功能受损，最终导致在中枢神经系统各区域的神经元死亡。
也正是因为糖化磷脂质不正常地储存使神经元功能受损，最终导致在中枢神经系统各区域的神经元死亡。
高雪氏症第一型现在为miglustat的适应症，其成人患者，若不能或不愿接受酵素替代疗法者，可使用miglustat 。
高雪氏症第一型现在为miglustat的适应症，其成人患者，若不能或不愿接受酵素替代疗法者，可使用miglustat 。

尼曼匹克症C型 尼曼匹克症C型
尼曼匹克症是一种罕见的基因异常疾病，有三种表现形式，分别为A 、 B 、 C型，各自由特定专一基因突变引起，并影响身体的新陈代谢途径。
尼曼匹克症是一种罕见的基因异常疾病，有三种表现形式，分别为A 、 B 、 C型，各自由特定专一基因突变引起，并影响身体的新陈代谢途径。
尼曼匹克症C型与其他两型在生化层级上不同，且往往是致命的。 尼曼匹克症C型与其他两型在生化层级上不同，且往往是致命的。
尼曼匹克症C型是由NPC-1或NPC -2两种基因其中之一突变(其中NPC-1较为常见) ，以及其他超过180种不同的基因突变也已被确认。
尼曼匹克症C型是由NPC-1或NPC -2两种基因其中之一突变(其中NPC-1较为常见) ，以及其他超过180种不同的基因突变也已被确认。
一般认为这两种基因与细胞内脂质运输有关，而脂质运输在细胞的维持上是关键的过程。
一般认为这两种基因与细胞内脂质运输有关，而脂质运输在细胞的维持上是关键的过程。 然而，关於这个复杂疾病的详细病理机转仍在研究中。
然而，关于这个复杂疾病的详细病理机转仍在研究中。
尼曼匹克症C型的症状，传统上以细胞内胆固醇的囤积解释，但现在有愈来愈多的证据显示有许多其他种类的脂质(如糖化磷脂质)堆积在大脑细胞中，引起病人日益衰弱的神经退化表现。
 尼曼匹克症C型的症状，传统上以细胞内胆固醇的囤积解释，但现在有愈来愈多的证据显示有许多其他种类的脂质(如糖化磷脂质)堆积在大脑细胞中，引起病人日益衰弱的神经退化表现。
尼曼匹克症C型因为其变化多端的症状及年龄分佈而使诊断困难。 尼曼匹克症C型因为其变化多端的症状及年龄分布而使诊断困难。

关於Zavesca reg;在第一型的高雪氏症 关于Zavesca reg;在第一型的高雪氏症
对高雪氏症第一型成人病患而言，若无法採用酵素替代疗法， Zavesca reg; (miglustat)是第一种口服治疗选择。
对高雪氏症第一型成人病患而言，若无法采用酵素替代疗法， Zavesca reg; (miglustat)是第一种口服治疗选择。 Zavescareg;是新一代「基质减量治疗」药物中的第一种药。 Zavesca &reg;是新一代「基质减量治疗」药物中的第一种药。 Zavescareg;藉由降低葡萄糖神经醯胺(一种会堆积在高雪氏症患者体内的糖化磷脂质)的製造速率到一定的程度，让体内剩餘的酵素还能将之清除。 Zavescareg;藉由降低葡萄糖神经醯胺(一种会堆积在高雪氏症患者体内的糖化磷脂质)的制造速率到一定的程度，让体内剩余的酵素还能将之清除。
如此可预防过剩的葡萄糖神经醯胺在吞噬细胞中累积。 如此可预防过剩的葡萄糖神经醯胺在吞噬细胞中累积。 Zavescareg;已被核准，且在欧盟会员国、美国、加拿大、以色列及瑞士皆已上市。 Zavesca reg;已被核准，且在欧盟会员国、美国、加拿大、以色列及瑞士皆已上市。
关於Zavescareg;的安全资料 关于Zavescareg;的安全资料报导指出，有高雪氏症第一型病患服用Zavesca reg;后出现週边神经病变。 报导指出，有高雪氏症第一型病患服用Zavesca reg;后出现周边神经病变。
患者应於服药后开始定期接受神经检查。 患者应于服药后开始定期接受神经检查。 对於出现週边神经病变症状的患者们，应重新评估Zavesca &reg;之使用。
对于出现周边神经病变症状的患者们，应重新评估Zavesca reg;之使用。
对孕妇而言， Zavesca reg;会对胎儿造成伤害，因此禁止使用在怀孕或即将怀孕的妇女身上，且患者应被告知此药物对胎儿的潜在危险性。 对孕妇而言，
Zavesca reg;会对胎儿造成伤害，因此禁止使用在怀孕或即将怀孕的妇女身上，且患者应被告知此药物对胎儿的潜在危险性。
此药物对男性而言有不孕的风险性。 此药物对男性而言有不孕的风险性。 男性病患应保持可信赖的生殖受孕方法，并於服药后三个月内避免怀胎。
男性病患应保持可信赖的生殖受孕方法，并于服药后三个月内避免怀胎。
关键词： C型尼曼-匹克病

瑞士Actelion制药公司日前宣布，Zavesca(miglustat)在欧盟获得批准，用于治疗成年和儿童C型尼曼-匹克病患者［Niemann-Pick type C disease (NPC)］的进行性神经系统症状。Zavesc是首个获批用于治疗C型尼曼-匹克病的药物，C型尼曼-匹克病是一种影响成人和儿童的非常罕见的、进行性并最终导致致命性神经退化的遗传疾病。
Zavesca(100 mgmiglustat)此前已被获批用于治疗轻度和中度I型戈谢病。Zavesca仅适用于酶替代疗法无效的I型戈谢病患者。
 Miglustat用于欧盟以外地区的C型尼曼-匹克病患者治疗的临床研究正在进行中。C型尼曼-匹克是一种按单纯孟德尔隐性遗传规律遗传的疾病。患者的胆固醇在细胞中积累，导致大脑损伤和死亡。主要有关酶缺乏引起神经髓鞘磷脂、胆固醇及其他磷脂在肝、脾的内皮细胞及脑部沉积引起。临床表现有肝、脾肿大，神经系统症状，聋、盲及智力低下。视网膜黄斑部有磷脂沉积者亦可见樱红斑。本病呈进行性，多在发病数年后死亡。
      
囊性纤维化
一种遗传性外分泌腺疾病,主要影响胃肠道和呼吸系统,通常具有慢性梗阻性肺部病变,胰腺外分泌功能不足和汗液电解质异常升高的特征.
发病率和病因学
囊性纤维化(CF)是白人中最常见的致寿命缩短的遗传性疾病,美国的发病率约为1/3300白人婴儿,1/15300黑人婴儿,1/32000亚裔美国人；30%的患者是成人.
 CF是常染色体隐性遗传,白人中基因携带者占3%.相关基因位于染色体7q(长臂)基因组DNA的250000对碱基对上.它编码膜相关蛋白,该蛋白称为囊性纤维化跨膜调节基子(CFTR).最常见的基因突变,△F508,导致CFTR蛋白508位置上的苯丙氨酸残基缺失,并且发生在约70%的等位基因中；另有30%有600种以上较少见的基因突变.CFTR的功能尚未明确,但显然是cAMP调节的氯离子通道的一部分,并且调节着氯,钠跨细胞膜的转运.杂合子无异常的临床症状,但存在上皮细胞膜转运的轻度异常.
有先天性双侧输精管缺失的患者,或其他原因造成的阻塞性无精症,一个或二个CFTR基因的突变几率增加,或者在CFTR非编码部位有一个不完全的点状突变(5T).这些患者一般没有呼吸道或胰腺疾病的证据,并且汗液氯离子的浓度处于正常,边缘或升高.

病理学和病理生理学
病人的外分泌腺几乎都受影响,但在分布和严重程度上差异很大.受侵犯的腺体可分为三类：腺体被管腔内粘稠的和固体状的嗜酸性物质堵塞(如胰腺,小肠腺,肝内胆管,胆囊,颌下腺)；组织学正常,但产生过量分泌物的腺体,如气管支气管腺和十二指肠腺；组织学正常,但分泌过量的钠和氯离子的腺体(汗腺,腮腺,小的唾液腺).十二指肠分泌物粘稠,含有异常的粘多糖.98%的成年男性患者由于输精管发育不良或其他形式的阻塞性无精,造成不育；成年女性患者由于子宫颈分泌物粘稠,生育力降低,但许多患囊性纤维化的妇女仍能妊娠到分娩期,然而母亲并发症的发生率很高.
有证据表明患儿出生时肺部组织结构正常.以后由于稠厚的粘性分泌物广泛阻塞小气道而导致肺部损害.梗阻和感染继发于毛细支气管炎和粘液脓性栓子阻塞气道.支气管的变化比肺实质更常见.肺气肿表现不突出.随着肺部病变进展,支气管壁增厚,气道内充满着脓性,粘稠的分泌物,肺不张区域扩大,以及肺门淋巴结肿大.慢性低氧血症导致肺动脉肌层肥厚,肺动脉高压和右心室肥大.许多肺部损害可能是由继发于呼吸道嗜中性粒细胞释放蛋白酶导致的免疫介导的炎症反应.即使在出生早期,气管肺泡冲洗液内含有大量的嗜中性粒细胞；游离中性弹性蛋白酶,DNA和细胞因子8的浓度增加.
在病程早期,从气道中分离的病原菌最常见的是金黄色葡萄球菌,但随着疾病进展,最多分离到的是假单胞菌.假单胞菌的粘液样变种是唯一与囊性纤维化有关的病菌.洋葱假单胞菌的移殖发生于7%以上的成年患者并且常与肺功能的迅速恶化有关.

症状,体征和并发症
由粘稠的胎粪引起的胎粪性肠梗阻可能是最早的征象(参见第261节胃肠道缺陷)并且出现于15%~20%受累的新生儿中.常伴肠扭转,肠穿孔或闭琐,很少有例外,随后总是出现囊性纤维化的其他特征.囊性纤维化也可与新生儿胎粪排出延迟和胎粪梗阻综合征相关(一种暂时的末端肠梗阻,由一个或几个浓缩的胎粪栓子塞在肛门或结肠引起).
在无胎粪性肠梗阻的婴儿中,疾病的开始症状常由出生后体重恢复缓慢和在生后4~6周内体重增加不足所预示.
患囊性纤维化的婴儿由于蛋白质吸收不良,即使喂大豆蛋白配方乳或母乳,患儿仍会继发性的出现低蛋白血症,导致水肿和贫血.
50%的患者有肺部受累表现,常常是慢性咳嗽和喘鸣,与反复的或慢性的肺部感染有关.咳嗽是最令人烦恼的症状,常伴有痰,恶心,呕吐,并干扰睡眠.随着病情的发展,辅助呼吸肌参与呼吸运动产生吸气性肋间凹陷,桶状胸,杵状指(趾)和发绀.上呼吸道受侵害包括有鼻息肉和慢性复发性鼻窦炎.青春期病人可有生长迟缓,青春期发育延迟和活动耐力下降.青春期和成年病人的肺部并发症包括有气胸,咯血,肺动脉高压引起的右心衰竭.
临床上85%~90%的病儿有胰腺功能不足,通常在出生早期出现,以后逐渐加重.临床表现包括大便次数频繁,恶臭,油状便,腹部膨隆,尽管食欲正常或旺盛,但生长发育欠佳,皮下组织和肌肉组织减少.20%的未治疗婴儿和学步儿童发生直肠脱落.临床上还可见有脂溶性维生素缺乏的相关症状.
热天和发热时过量出汗可引起低渗性脱水和循环衰竭.气候干燥的情况下,婴儿可表现为慢性代谢性碱中毒,皮肤有盐结晶及有咸味都明显表示患有囊性纤维化.
10%的成年病人发展成胰岛素依赖型糖尿病,4%~5%的青春期和成年病人发生结节性胆汁性肝硬化伴静脉曲张和门脉高压.慢性和/或反复的腹痛与肠套叠,消化性溃疡,阑尾周围脓肿,胰腺炎,胃食管反流,食管炎,胆囊病变或粪便异常粘稠导致的部分肠梗阻等相关.

炎性并发症包括脉管炎和关节炎.
疾病概述
囊性纤维化（cysticfibrosis，CF）是一种侵犯多脏器的遗传性疾病。主要表现为外分泌腺的功能紊乱，粘液腺增生，分泌液粘稠，汗液氯化钠含量增高。临床上有肺脏、气道、胰腺、肠道、胆道、输精管、子宫颈等的腺管被粘稠分泌物堵塞所引起一系列症状，而以呼吸系统损害最为突出。

病因病理
病因病理【病因】
囊性纤维化是由于位于第7对染色体CF基因突变引起的常染色体隐性遗传病，病人是纯合子，其双亲是杂合子。病人的同胞中半数可带有隐性基因，而1／4可得病。一般带有隐性基因的杂合子占出生新生儿的2％～5％，约在2000～2500个新生儿中有一个可得病。囊肿性纤维化外分泌腺机能障碍的发病机理尚不清楚。据研究提示患者的上皮细胞氯离子通道调节有缺陷；呼吸道粘膜上皮的水、电解质跨膜转运有障碍；粘液腺分泌物中酸性糖蛋白含量增加，改变了粘液流变学的特性，可能为分泌物变粘稠的原因。

本病主要发生在白种人，北欧、美国发病率较高，黑种人较少，亚洲人极少见。各地区患病率不一致，病人与新生儿的比例约为1∶500至1∶3500。婴幼儿时期发病，主要发生于儿童，约3％在成年后作出诊断，死亡率高。近年来由于早期诊断与合理、积极治疗，病人存活率已有所提高，至少有25％患者可活到成年，9％年龄超过30岁。
【病理说明】
肺和消化道为主要的受累脏器。粘稠分泌物堵塞支气管以及继发性感染，是呼吸系统的主要病理基础。患者于出生时呼吸道无病变发现，发病早期出现支气管腺体肥大，杯状细胞变性，以后支气管粘液腺分泌出粘稠分泌物，使粘膜上皮纤毛活动受到抑制，粘液引流不畅。支气管堵塞引起肺不张和继发性感染；反复发作，产生广泛支气管炎、肺炎、支气管扩张、细支气管扩张、肺脓肿，逐渐引起肺部广泛纤维化和阻塞性肺气肿。在以上病理基础上导致阻塞性和限制性混合的呼吸功能损害，表现为肺通气不足，吸入气体分布不均，通气与血流比例失调以及弥散功能障碍，出现缺氧和二氧化碳潴留症状，最后导致呼吸衰竭；同时肺循环阻力增加，引起肺动脉高压和肺源性心脏病。鼻息肉、慢性鼻窦炎也是常见的并发症。

粘稠分泌物阻塞胰腺外分泌管，早期出现胰管扩张、腺泡扩大形成囊肿，继以广泛纤维化伴细胞浸润、萎缩，引起糖尿病。外胰腺管阻塞，胰腺酶包括胰蛋白酶、脂肪酶和淀粉酶的分泌不足或缺乏，导致消化、特别是脂肪吸收不良。

肝脏内小胆管被粘液堵塞，引起多小叶性肝硬化、门静脉高压和肝功能损害，并可并发脾功能亢进。胆道阻塞可引起黄疸。胆汁缺乏对脂类的消化、脂溶性维生素的吸收、胰液和肠液的消化作用以及肠蠕动都有不良影响。粘液可使肠道上皮剥脱，结构破坏。新生儿在回肠末端发生胎粪梗阻，为早期常见表现。汗腺分泌中氯化钠含量明显增高。输精管发生纤维化阻塞，失去生育能力。女性生殖能力减退。

临床表现
呼吸系统主要表现为反复支气管感染和气道阻塞症状。新生儿出生后数日内即可出现症状。早期可有轻度咳嗽，伴发肺炎、肺不张后咳嗽加剧，粘痰不易咳出，呼吸急促。患者若咳出大量脓性痰或伴咯血时，提示有支气管扩张和肺脓肿的可能。体格检查常见杵状指（趾）。肺部感染的致病菌大多是金葡菌、绿脓杆菌或其他革兰阴性杆菌。肺部产生广泛性纤维化和肺气肿后，有喘鸣，活动后气急，常并发自发性气胸或纵隔气肿。出现缺氧和二氧化碳潴留症状时，气急加剧，紫绀，最后导致呼吸衰竭和肺源性心脏病。

新生儿由于肠粘液分泌和粘度增加，以及因缺乏胰酶等影响蛋白质消化，故约10％有胎粪阻塞；儿童也可发生肠梗阻和直肠脱垂。胰腺分泌不足则出现腹胀、腹部隆起、排出大量泡沫恶臭粪便等消化不良症状，甚至发生脂肪泻和氮溢（azotorrhea）。维生素缺乏，特别是维生素A缺乏可发生干眼病。病儿虽食欲旺盛，饮食量足够，但仍有营养不良和生长发育迟缓。胆道阻塞可出现黄疸，并发肝硬化时，可出现门静脉高压、脾机能亢进。婴儿若出汗过多，失去大量电解质和水份，容易引起虚脱。

化验检查
不同病期可在X线上表现为两肺支气管纹理增深或分散的圈形、小片状模糊炎症影。也可呈局限性萎陷（肺不张）、支气管扩张、肺脓肿及肺源性心脏病的征象。
汗液内氯化钠含量增加是本病的特征。正常儿童汗液内氯含量平均为30～40mmol/L，钠为60mmol／L。病儿汗内氯含量可高达105～125mmol/L，钠为120mmol/L。如汗内氯含量高于60mmol/L（成人高于70mmol／L），钠高于80mmol/L，且能排除肾上腺皮质功能不全症，即具有重要诊断意义。可用0．2％硝酸毛果芸香硷电游子透入法刺激皮肤出汗测定电解质。但正常成年人汗液内氯化钠含量可超出上述范围，不适宜作出汗试验，可抽取十二指肠液体检查，如粘稠度增加，各种胰酶特别是胰蛋白酶减少或缺乏，即为诊断依据。其他如直肠粘膜活检见腺管充满粘液而扩张形成粘液层；空肠粘膜活检发现肠粘膜绒毛消失；尿内5-羟吲哚乙酸（5hydroxyindole acetic acid）增加等，对诊断也有参考价值。

诊断和鉴别
由于CF基因突变变化多端，因而目前尚不能依赖于基因诊断，而根据临床症状可以拟诊，结合实验室检查可作出诊断。必要时作肠粘膜活组织检查。若能提高警惕，注意诊断要点，则与其他小儿腹腔疾病或成人慢性支气管炎等的鉴别并不困难。

治疗
反复慢性呼吸道感染和呼吸功能衰竭是病儿死亡的主要原因。控制呼吸道感染应针对痰菌和药物敏感情况，采用抗菌药物联合治疗至关重要。根据病情可较长时期或间歇用药。用蒸气或粘液溶解剂雾化吸入可液化粘痰，加用抗生素和支气管扩张药作超声雾化吸入效果更好。鼓励成年人作体位引流以利排痰。　对婴幼儿除作麻疹、百日咳疫苗接种外，冬季应给予多价流感疫苗接种，并及早根治慢性鼻窦炎，防止下呼吸道感染。　饮食疗法有利于食物的吸收和促进生长发育，应给予高热量、高蛋白和低脂肪饮食，补充各种维生素特别是维生素A。胰腺酶如胰酶肠溶片，口服1～3g/d，增强消化能力。　婴儿发生胎粪肠梗阻时可施行手术治疗。天热出汗过多，必须及时补充食盐和足够的水分，以防止虚脱。　迄今虽尚无可靠方法识别带有隐性基因的杂合子，但由于遗传基因研究的进展，今后将有望能发现杂合子患者，并能对本病的预防采取有效措施。

预后预防
预后取决于早期诊断和治疗。约半数儿童因感染或心肺功能衰竭等严重并发症于10岁前死亡，活至成年者较少。如能早期诊断，控制呼吸道感染，注意饮食疗法，儿童期间病死率可下降，并可存活至成年。