Kuvan于2008年获欧盟和FDA批准，该药是一种口服制剂，治疗由苯丙酮尿症（PKU）或四氢生物蝶呤（BH4）缺乏症引发的高苯丙氨酸血症（HPA）。Kuvan是首个也是唯一一个与饮食调整相结合的药物，用于降低苯丙酮尿症（PKU）患者血液和大脑中的苯丙氨酸浓度，以防止PKU的破坏性影响。Kuvan适用于所有年龄段的四氢生物蝶呤（BH4）缺乏症患者，以及对Kuvan有响应且年龄大于4岁的PKU患者。 此前，FDA和欧盟均已授予Kuvan孤儿药地位 适应症 kuvan表示，以减少由于呤（BH4的）响应苯丙酮尿症（PKU）高苯丙氨酸血症（HPA）的血苯丙氨酸（Phe）患者中的水平。 kuvan是在与苯丙氨酸限制饮食结合使用。 剂量和用法 Kuvan推荐起始剂量是10毫克/公斤/天每天服用一次。 在5至20毫克/千克，每天一次采取的范围内进行调整的Kuvan剂量可能。血Phe必须定期监测。 应采取与粮食口头kuvan以增加吸收。 kuvan片应溶解在4至8盎司。 （120-240毫升）水或苹果汁，并采取在15分钟内。 Kuvan 100mg soluble tablets 1. Name of the medicinal product Kuvan 100 mg soluble tablets 2. Qualitative and quantitative composition Each soluble tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 77 mg of sapropterin). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Soluble tablet Off-white to light yellow soluble tablet with “177” imprinted on one face. 4. Clinical particulars 4.1 Therapeutic indications Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of 4 years of age and over with phenylketonuria (PKU) who have been shown to be responsive to such treatment (see section 4.2). Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment (see section 4.2). 4.2 Posology and method of administration Treatment with Kuvan must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency. Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine levels and nutritional balance. As HPA due to either PKU or BH4 deficiency is a chronic condition, once responsiveness is demonstrated, Kuvan is intended for long-term use. However, there are limited data regarding the long-term use of Kuvan. Posology Kuvan is provided as 100 mg tablets. The calculated daily dose based on body weight should be rounded to the nearest multiple of 100. For instance, a calculated dose of 401 to 450 mg should be rounded down to 400 mg corresponding to 4 tablets. A calculated dose of 451 mg to 499 mg should be rounded up to 500 mg corresponding to 5 tablets. PKU The starting dose of Kuvan in adult and paediatric patients with PKU is 10 mg/kg body weight once daily. The dose is adjusted, usually between 5 and 20 mg/kg/day, to achieve and maintain adequate blood phenylalanine levels as defined by the physician. BH4 deficiency The starting dose of Kuvan in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/kg body weight once daily. Doses may be adjusted up to 20 mg/kg/day. It may be necessary to divide the total daily dose into 2 or 3 administrations, distributed over the day, to optimise the therapeutic effect. Paediatric population The safety and efficacy of Kuvan in children under 4 years of age has not been established. Currently available data are described in section 5.1, but no recommendation on posology can be made. Elderly patients Safety and efficacy of Kuvan in patients above 65 years of age have not been established. Caution must be exercised when prescribing to elderly patients. Patients with renal or hepatic impairment Safety and efficacy of Kuvan in patients with renal or hepatic insufficiency have not been established. Caution must be exercised when prescribing to such patients. Determination of response It is of primary importance to initiate Kuvan treatment as early as possible to avoid the appearance of non-reversible clinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of blood phenylalanine. Response to treatment is determined by a decrease in blood phenylalanine following treatment with Kuvan. Blood phenylalanine levels should be checked before initiating treatment and after 1 week of treatment with Kuvan at the recommended starting dose. If an unsatisfactory reduction in blood phenylalanine levels is observed, then the dose of Kuvan can be increased weekly to a maximum of 20 mg/kg/day, with continued weekly monitoring of blood phenylalanine levels over a one month period. The dietary phenylalanine intake should be maintained at a constant level during this period. A satisfactory response is defined as a ≥30 percent reduction in blood phenylalanine levels or attainment of the therapeutic blood phenylalanine goals defined for an individual patient by the treating physician. Patients who fail to achieve this level of response within the described one month test period should be considered non-responsive and should not receive treatment with Kuvan. Once responsiveness to Kuvan has been established, the dose may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy. It is recommended that blood phenylalanine and tyrosine levels be tested one or two weeks after each dose adjustment and monitored frequently thereafter under the direction of the treating physician. Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho-motor development). Dose adjustment Treatment with Kuvan may decrease blood phenylalanine levels below the desired therapeutic level. Adjustment of the sapropterin dose or modification of dietary phenylalanine intake may be required to achieve and maintain blood phenylalanine levels within the desired therapeutic range. Blood phenylalanine and tyrosine levels should be tested, particularly in children, one to two weeks after each dose adjustment and monitored frequently thereafter, under the direction of the treating physician. If inadequate control of blood phenylalanine levels is observed during treatment with Kuvan, the patient's adherence to the prescribed treatment, and diet, should be reviewed before considering an adjustment of the dose of Kuvan. Discontinuation of Kuvan treatment should be done only under the supervision of a physician. More frequent monitoring may be required, as blood phenylalanine levels may increase. Dietary modification may be necessary to maintain blood phenylalanine levels within the desired therapeutic range. Method of administration The tablets should be administered with a meal as a single daily dose, to increase the absorption, and at the same time each day preferably in the morning. Patients should be advised not to swallow the desiccant capsule found in the bottle. The prescribed number of tablets should be placed in a glass or cup of water and stirred until dissolved. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster they can be crushed. Small particles may be visible in the solution and will not affect the effectiveness of the medicinal product. The solution should be drunk within 15 to 20 minutes. For doses below 100 mg, one tablet should be dissolved in 100 ml of water and only a certain volume of solution should be administered, corresponding to the prescribed dose, e.g. use 50 ml of solution for 50 mg of the medicine. An accurate measuring device with suitable graduations should be used for this purpose. Adults The prescribed number of tablets should be placed in a glass or cup with 120 to 240 ml of water and stirred until dissolved. Paediatric population The prescribed number of tablets should be placed in a glass or cup with up to 120 ml of water and stirred until dissolved. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Dietary intake Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho-motor development). Low blood phenylalanine and tyrosine levels Sustained or recurrent dysfunction in the phenylalanine-tyrosine-dihydroxy-L-phenylalanine (DOPA) metabolic pathway can result in deficient body protein and neurotransmitter synthesis. Prolonged exposure to low blood phenylalanine and tyrosine levels during infancy has been associated with impaired neurodevelopmental outcome. Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance. Health disturbances Consultation with a physician is recommended during illness as blood phenylalanine levels may increase. Convulsions disorders Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients (see section 4.5). Discontinuation of treatment Rebound, as defined by an increase in blood phenylalanine levels above pre-treatment levels, may occur upon cessation of treatment. There are limited data regarding the long-term use of Kuvan. Sodium content This medicine contains less than 1 mmol (23 mg) sodium per tablet, i.e. essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Although concomitant administration of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) has not been studied, such medicinal products may interfere with BH4 metabolism. Caution is recommended when using such medicinal products while taking Kuvan. BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvan with all medicinal products that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil. Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients. 4.6 Fertility, pregnancy and lactation Pregnancy No clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Maternal blood phenylalanine levels must be strictly controlled before and during pregnancy. If maternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be harmful to the mother and the foetus. Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group. The use of Kuvan should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels. Caution must be exercised when prescribing to pregnant women. Breast-feeding It is not known whether sapropterin or its metabolites are excreted in human breast milk. Kuvan should not be used during breast-feeding. Fertility In preclinical studies, no effects of sapropterin on male and female fertility were observed. 4.7 Effects on ability to drive and use machines Kuvan has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Approximately 35% of the 579 patients who received treatment with sapropterin dihydrochloride (5 to 20 mg/kg/day) in the clinical trials for Kuvan experienced adverse reactions. The most commonly reported adverse reactions are headache and rhinorrhoea. Tabulated list of adverse reactions In the pivotal clinical trials for Kuvan, the following adverse reactions have been identified. The following definitions apply to the frequency terminology used hereafter: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Frequency not known (cannot be estimated from available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Immune system disorders Not known: Hypersensitivity reactions (including serious allergic reactions) and rash Metabolism and nutrition disorders: Common: Hypophenylalaninaemia Nervous system disorders: Very common: Headache Respiratory, thoracic and mediastinal disorders: Very common: Rhinorrhoea Common: Pharyngolaryngeal pain, nasal congestion, cough Gastrointestinal disorders: Common: Diarrhoea, vomiting, abdominal pain Paediatric population Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. United Kingdom Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard Ireland Healthcare professionals are asked to report any suspected adverse reactions via the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via 'freepost' (see details below). Alternatively, the traditional post-paid 'yellow card' option may also be used. FREEPOST Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace Dblin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie 4.9 Overdose Headache and dizziness have been reported after the administration of sapropterin dihydrochloride above the recommended maximum dose of 20 mg/kg/day. Treatment of overdose should be directed to symptoms. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16AX07 Mechanism of action Hyperphenylalaninaemia (HPA) is diagnosed as an abnormal elevation in blood phenylalanine levels and is usually caused by autosomal recessive mutations in the genes encoding for phenylalanine hydroxylase enzyme (in the case of phenylketonuria, PKU) or for the enzymes involved in 6R-tetrahydrobiopterin (6R-BH4) biosynthesis or regeneration (in the case of BH4 deficiency). BH4 deficiency is a group of disorders arising from mutations or deletions in the genes encoding for one of the five enzymes involved in the biosynthesis or recycling of BH4. In both cases, phenylalanine cannot be effectively transformed into the amino acid tyrosine, leading to increased phenylalanine levels in the blood. Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan. The rationale for administration of Kuvan in patients with BH4-responsive PKU is to enhance the activity of the defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism of phenylalanine sufficient to reduce or maintain blood phenylalanine levels, prevent or decrease further phenylalanine accumulation, and increase tolerance to phenylalanine intake in the diet. The rationale for administration of Kuvan in patients with BH4 Deficiency is to replace the deficient levels of BH4, thereby restoring the activity of phenylalanine hydroxylase. Clinical efficacy The Phase III clinical development program for Kuvan included 2, randomised placebo-controlled studies in patients with PKU. The results of these studies demonstrate the efficacy of Kuvan to reduce blood phenylalanine levels and to increase dietary phenylalanine tolerance. In 88 subjects with poorly controlled PKU who had elevated blood phenylalanine levels at screening, sapropterin dihydrochloride 10 mg/kg/day significantly reduced blood phenylalanine levels as compared to placebo. The baseline blood phenylalanine levels for the Kuvan-treated group and the placebo group were similar, with mean ± SD baseline blood phenylalanine levels of 843 ± 300 μmol/l and 888 ± 323 μmol/l, respectively. The mean ± SD decrease from baseline in blood phenylalanine levels at the end of the 6 week study period was 236 ± 257 μmol/l for the sapropterin treated group (n=41) as compared to an increase of 2.9 ± 240 μmol/l for the placebo group (n=47) (p<0.001). For patients with baseline blood phenylalanine levels ≥600 µmol/l, 41.9% (13/31) of those treated with sapropterin and 13.2% (5/38) of those treated with placebo had blood phenylalanine levels < 600 µmol/l at the end of the 6-week study period (p=0.012). In a separate 10-week, placebo-controlled study, 45 PKU patients with blood phenylalanine levels controlled on a stable phenylalanine-restricted diet (blood phenylalanine ≤480 μmol/l on enrolment) were randomized 3:1 to treatment with sapropterin dihydrochloride 20 mg/kg/day (n=33) or placebo (n=12). After 3 weeks of treatment with sapropterin dihydrochloride 20 mg/kg/day, blood phenylalanine levels were significantly reduced; the mean ± SD decrease from baseline in blood phenylalanine level within this group was 149 ±134 μmol/l (p<0.001). After 3 weeks, subjects in both the sapropterin and placebo treatment groups were continued on their phenylalanine-restricted diets and dietary phenylalanine intake was increased or decreased using standardized phenylalanine supplements with a goal to maintain blood phenylalanine levels at <360 μmol/l. There was a significant difference in dietary phenylalanine tolerance in the sapropterin treatment group as compared to the placebo group. The mean ± SD increase in dietary phenylalanine tolerance was 17.5 ±13.3 mg/kg/day for the group treated with sapropterin dihydrochloride 20 mg/kg/day, compared to 3.3 ± 5.3 mg/kg/day for the placebo group (p=0.006). For the sapropterin treatment group, the mean ± SD total dietary phenylalanine tolerance was 38.4 ± 21.6 mg/kg/day during treatment with sapropterin dihydrochloride 20 mg/kg/day compared to 15.7 ± 7.2 mg/kg/day before treatment. Paediatric population Kuvan has not been specifically studied in children under 4 years of age, although the published literature indicates that more than 600 children of 0 to 4 years old with PKU, have been exposed to treatment with an un-registered preparation of BH4, including at least 35 who received therapy ≥2 months. The maximum daily dose used was 20 mg/kg body weight. Limited studies have been conducted in patients under 4 years of age with BH4 deficiency using another formulation of the same active substance (sapropterin) or an un-registered preparation of BH4. e5.2 Pharmacokinetic properties Absorption Sapropterin is absorbed after oral administration of the dissolved tablet, and the maximum blood concentration (Cmax) is achieved 3 to 4 hours after dosing in the fasted state. The rate and extent of absorption of sapropterin is influenced by food. The absorption of sapropterin is higher after a high-fat, high-calorie meal as compared to fasting, resulting, in average, in 40-85% higher maximum blood concentrations achieved 4 to 5 hours after administration. Absolute bioavailability or bioavailability for humans after oral administration is not known. Distribution In non-clinical studies, sapropterin was primarily distributed to the kidneys, adrenal glands, and liver as assessed by levels of total and reduced biopterin concentrations. In rats, following intravenous radiolabeled sapropterin administration, radioactivity was found to distribute in foetuses. Excretion of total biopterin in milk was demonstrated in rats by intravenous route. No increase in total biopterin concentrations in either foetuses or milk was observed in rats after oral administration of 10 mg/kg sapropterin dihydrochloride. Biotransformation Sapropterin dihydrochloride is primarily metabolised in the liver to dihydrobiopterin and biopterin. Since sapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, it can be reasonably anticipated to undergo the same metabolism, including 6R-BH4 regeneration. Elimination Following intravenous administration in rats, sapropterin dihydrochloride is mainly excreted in the urine. Following oral administration it is mainly eliminated through faeces while a small proportion is excreted in urine. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology (CNS, respiratory, cardiovascular, genitourinary), and toxicity to reproduction. An increased incidence of altered renal microscopic morphology (collecting tubule basophilia) was observed in rats following chronic oral administration of sapropterin dihydrochloride at exposures at or slightly above the maximal recommended human dose. Sapropterin was found to be weakly mutagenic in bacterial cells and an increase in chromosome aberrations was detected in Chinese hamster lung and ovary cells. However, sapropterin has not been shown to be genotoxic in the in vitro test with human lymphocytes as well as in in vivo micronucleus mouse tests. No tumorigenic activity was observed in an oral carcinogenicity study in mice at doses of up to 250 mg/kg/day (12.5 to 50 times the human therapeutic dose range). Emesis has been observed in both the safety pharmacology and the repeated-dose toxicity studies. Emesis is considered to be related to the pH of the solution containing sapropterin. No clear evidence of teratogenic activity was found in rats and in rabbits at doses of approximately 3 and 10 times the maximum recommended human dose, based on body surface area. 6. Pharmaceutical particulars 6.1 List of excipients Mannitol (E421) Calcium hydrogen phosphate, anhydrous Crospovidone type A Ascorbic acid (E300) Sodium stearyl fumarate Riboflavin (E101) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store below 25°C. Keep the bottle tightly closed in order to protect from moisture. 6.5 Nature and contents of container High-density polyethylene (HDPE) bottle with child-resistant closure. The bottles are sealed with an aluminium seal. Each bottle contains a small plastic tube of desiccant (silica gel). Each bottle contains 30, 120 or 240 tablets. 1 bottle per carton. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Disposal No special requirements Handling Patients should be advised not to swallow the desiccant capsule found in the bottle. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Merck Serono Europe Limited 56, Marsh Wall London E14 9TP United Kingdom 8. Marketing authorisation number(s) EU/1/08/481/001 EU/1/08/481/002 EU/1/08/481/003 9. Date of first authorisation/renewal of the authorisation Date of the first authorisation: 02 December 2008 Date of latest renewal: 09/2013 10. Date of revision of the text Date of revision of the text: 09/2013 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Kuvan/Phenoptin-治疗PKU的BH4口服活性制剂 PKU和轻度高苯丙氨酸血症是由于苯丙氨酸羟化酶缺陷而导致的遗传病。如果在饮食中不限制苯丙氨酸的摄入将导致智力的损害。Kuvan是一种口服的制剂，一种在BH4（苯丙氨酸羟化酶的辅助因子，辅酶）基础上人工合成的，它已经获得了治疗PKU的罕用药身份和快通道指定。临床二期和三期实验数据证明Kuvan对于所选患者的治疗是安全和有效的，这些患者对BH4负荷反应的高苯丙氨酸血症和轻到适度的PKU患者。根据这些临床数据分析，BioMarin制药公司估计对于大约5万患者中30-50%的人来说Kuvan是一种潜在的治疗选择. 首个苯丙酮尿症新药二盐酸沙丙蝶呤上市 二盐酸沙丙蝶呤—首个高苯丙氨酸血症治疗药，二盐酸沙丙蝶呤是首个获准用于治疗四氢生物蝶呤(BH4)缺乏症或苯丙酮尿症(PKU)患者的高苯丙氨酸血症(HPA)的罕用药，于2008年12月9日获得欧盟上市批准，预计于2009年上半年在欧洲开始上市。 2008年12月9日，MerckKGaA公司及其分公司MerckSerono宣布欧盟委员会已批准二盐酸沙丙蝶呤(Kuvan)上市，用于治疗四氢生物蝶呤(BH4)缺乏症或苯丙酮尿症(PKU)患者的高苯丙氨酸血症(HPA)。 二盐酸沙丙蝶呤是首个获准用于治疗HPA的罕用药，本品在欧盟将获得为期10年的专利保护。预计本品将于2009年上半年在欧洲开始上市。 二盐酸沙丙蝶呤最常见的不良反应有头痛、流涕、鼻塞、腹泻、呕吐、咽痛、咳嗽、腹痛、苯丙氨酸血浓度低。这些不良反应的严重程度一般为轻微至中等程度，且为一过性的。 药动学 在健康受试者中进行的研究比较了二盐酸沙丙蝶呤片在溶于水或橙汁以及禁食条件下服用的吸收情况。结果显示，受试者进食高脂或高热量食物后服用溶于水的Kuvan，Cmax增加84％，AUC增加87％。在对Kuvan进行的临床实验中，受试者均于清晨服用溶解后的片剂，而不考虑其饮食情况。该药在PKU患者体内的平均半衰期为6．7h，而在健康受试者中则为3．0—5．3h。 临床研究 有4项临床研究考察了苯丙酮尿症(PKU)患者服用二盐酸沙丙蝶呤的有效性和安全性。第1项研究为对489名8—48岁的PKU患者进行的多中心、开标记、非对照试验。试验前，PKU患者的血清Phe水平高于450μmol／L，且不禁食含Phe的食物，所有受试患者连续8天服用Kuvan[10mg／(kg·d)]；与给药前相比，血清Phe水平降低30％以上视为对该治疗有响应。结果，第8天时，有96名患者的Phe水平达到响应值，响应率为20％。 在经过停药间隔期后，进行了为期6周的第2项研究，该多中心、双盲、安慰剂对照研究选取了第1项研究中对Kuvan治疗有响应的88名患者，并将其随机分为两组：Kuvan[10mg／(kg·d)]组(n=41)和安慰剂组(n=47)。治疗前，两组患的血清Phe水平分别为(843±300)和(888±323)μmol／L；在治疗的第6周，Kuvan组血清Phe水平降为(607±377)μmol／L，而安慰剂组反升至(891±348)tmaol／L，两组平均变化值分别为-239和6μmol／L，有显著性差异。 第3项研究则是前两项研究的扩展试验，为期6周。该试验选取了在第1项研究中对Kuvan治疗有响应并完成第2项研究的8o名患者，对Kuvan的3个剂量进行调整，即前两周的剂量为5mg／(kg·d)，第3、4周为20mg／(kg·d)，第5,6周则为10mg／(kg·d)。每2周测定1次血清Phe值。治疗前，受试患者血清Phe水平为(844±398)μmol／L，而每个剂量组治疗2周后患者血清Phe水平分别为(744±384)、(640±382)和(581±399)μmol／L。 第4项研究为对90名年龄为4-12岁的PKU儿童患者进行的多中心、开标记试验，这些患者均禁食含Phe的食物，且血清Phe水平低于480tmaol／L，连续8天给予Kuvan[20mg／(kg·d)]治疗。与给药前相比，血清Phe水平降低30％以上视为对该治疗有响应。结果，第8天有5O名患者的Phe水平达到响应值，响应率为56％。 苯丙酮尿症 中文名称：苯丙酮尿症 英文名称：phenylketonuria;PKU 定义：由于缺乏苯丙氨酸羟化酶不能生成酪氨酸，大量苯丙氨酸脱氨后生成苯丙酮酸，随尿排出而患病，儿童患者可出现先天性痴呆。 苯丙酮尿症（phenylketonurics; PKU）是一种常见的氨基酸代谢病，是由于苯丙氨酸代谢途径中的酶缺陷，使得苯丙氨酸不能转变成为酪氨酸，导致苯丙氨酸及其酮酸蓄积并从尿中大量排出。临床主要表现为智能低下，惊厥发作和色素减少。本病属常染色体隐性遗传。其发病率随种族而异，美国约为1/14000，日本1/60000，我国1/16500。 苯丙酮尿症疾病描述 苯丙酮尿症是先天代谢性疾病的一种，为常染色体隐性遗传，由于染色体基因突变导致肝脏中苯丙氨酸羟化酶(PAH)缺陷从而引起苯丙氨酸(PA)代谢障碍所致，引起中枢神经系统的损伤。神经系统异常体征不多见，可有脑小畸形，肌张力增高，步态异常，腱反射亢进，手部细微震颤，肢体重复动作等。由于黑色素缺乏，患儿常表现为头发黄、皮肤和虹膜色浅黑色素的缺乏使患者更容易受到太阳光中紫外线的伤害，因此患者应尽量减少阳光照射的机会，减少白天的户外活动。患儿尿液中常有令人不快的鼠尿味。同时，患儿易合并有湿疹、呕吐、腹泻等。低苯丙氨酸饮食疗法是目前治疗经典型PKU的惟一方法，治疗的目的是预防脑损伤。对于非典型苯丙酮尿症的治疗除了饮食治疗以外，还应补充多种神经介质，如BH4、多巴、5-羟色胺、叶酸等。 苯丙酮尿症症状体征 出生时患儿正常，随着进奶以后，一般在3—6个月时，即可出现症状，1岁时症状明显。 　　 1、神经系统 　　 早期可有神经行为异常，如兴奋不安、多动或嗜睡、萎靡、少数呈现肌张力增高，腱反射亢进，出现惊厥（约25％），继之智能发育落后日渐明显，80％有脑电图异常。BH4缺乏型的神经系统症状出现较早且较严重，常见肌张力减低、嗜睡、惊厥，如不经治疗，常在幼儿期死亡。　　 2、外貌 　　 因黑色素合成不足，在生后数月毛发、皮肤和虹膜色泽变浅。皮肤干燥，有的常伴湿疹。 　　 3、其他 　　 由于尿和汗液中排出苯乙酸，呈特殊的鼠尿臭味。 苯丙酮尿症疾病病因 苯丙氨酸（PA）是人体必需的氨基酸之一。正常小儿每日需要的摄入量约为200-500mg，其中1/3供合成蛋白，2/3则通过肝细胞中苯丙氨酸羟化酶（PAH）的转化为酪氨酸，以合成甲状腺素、肾上腺素和黑色素等。苯丙氨酸转化为酪氨酸的过程中，除需PAH外，还必须有四氢生物蝶呤（BH4）作为辅酶参与。人体内的BH4是由鸟苷三磷酸（GTP），经过鸟苷三磷酸环化水合酶（GTP—CH）、6—丙酮酸四氢蝶呤合成酶（PTPS）和二氢生物蝶呤还原酶（DHPR）等一系列酶的催化而合成，PAH、GTP—CH、DHPR三种酶的编码基因分别定位于12q24.1、14q11，4p15.1—p16.1；而对PTPS编码基因的研究尚在进行中，上述任一编码基因的突变都有可能造成相关酶的活性缺陷，致使苯氨酸发生异常累积。 苯丙酮尿症病理生理 本病分为典型和BH4缺乏型两类： 　　 ①典型PKU是由于患儿肝细胞缺乏PAH，部分将苯丙氨酸转化为酪氨酸，因此苯丙氨酸在血、脑脊液、各种组织和尿液中的浓度极度增高，同时经旁路代谢产生大量的苯丙酮酸、苯乙酸、苯乳酸和对羟基苯乙酸，并从尿中排出。由于酪氨酸生成减少，致使甲状腺素、肾上腺素和黑色素等合成不足，而蓄积的高浓度的苯丙氨酸及其旁路代谢产物导致细胞受损。　　 ②BH4缺乏型是由于GTP—CH、PTPS或DHPR等任何一种酶缺乏所导致，BH4是苯丙氨酸、酪氨酸和色氨酸等芳香氨基酸在羟化过程中所必须的共同的辅酶，BH4的缺乏不仅苯丙氨酸不能转变成酪氨酸，而且造成酪氨酸不能转变成多巴胺，色氨酸不能转变成5—羟色胺、5—羟色胺均匀为重要的神经递质，其缺乏可加重神经系统的损害，故BH4缺乏型PKU的临床症状更重，治疗亦不易。　　本病绝大多数为典型PKU，约10％~15%左右为BH4缺乏型，国内目前全为PTPS缺乏类型。 苯丙酮尿症诊断检查 本病为少数可治性遗传性代谢病之一，上述症状经饮食控制治疗后可逆转，但智能发育落后难以转变，应力求早期诊断治疗，以避免神经系统的不可逆损伤。 由于患儿早期无症状不典型，必须借助实验室检测。 　　 1、新生儿期筛查 　　 新生儿喂奶3日后，采集足根末梢血，吸收再生厚滤纸上，晾干后邮寄到筛查中心，采用Guthrie细菌生长抑制试验半定量测定，其原理是苯丙氨酸能促进已被抑制的枯草杆菌重新生长，以生长圈的范围测定血中苯病氨酸的含量，亦可在苯丙氨酸脱氢酶的作用下进行比色定量测定，其假阳性率较低。当苯丙氨酸含量＞0.24mmol/L（4mg/dl）即两倍于正常参考值时，应复查或采静脉血定量测定苯丙氨酸和酪氨酸。正常人苯丙氨酸浓度为0.06—0.18mmol/L（1—3mg/dl）而无患儿血浆苯丙氨酸可高达1.2mmol/L（20mg/dl）以上，且血中酪氨酸正常或稍低。　 2、尿三氯化铁试验 　　 用于较大婴儿和儿童的筛查。将三氯化铁滴入尿液，如立即出现绿色反应，则为阳性，表明尿中苯丙氨酸浓度增高。此外，二硝基苯肼试验也可以测尿中苯丙氨酸，黄色沉淀为阳性。　　 3、血浆氨基酸分析和尿液有机酸分析 　　 可为本病提供生化诊断依据，同时，也可鉴别其他的氨基酸、有机酸代谢病。 4、尿蝶呤分析 　　 应用高压液相层析（PHLC）测定尿液中新蝶呤和生物蝶呤的含量，用以鉴别各型PKU。典型PKU患儿尿中蝶呤总排出量增高，新蝶呤与生物蝶呤比值正常。DHPR缺乏的患儿蝶呤总排出量增加，四氢生物蝶呤减少，6—PTS缺乏的患儿则新蝶呤排出量增加，其与生物蝶呤的比值增高，GTP—CH缺乏的患儿其蝶呤总排出量减少。 5、酶学诊断 　　 PAH仅存在于肝细胞、需经肝活检测定，不适用于临床诊断。其他3种酶的活性可采用外周血中红、白细胞或皮肤成纤维细胞测定。　　 6、DNA分析 　　 改变技术近年来广泛用于PKU诊断，杂合子检出的产前诊断。但由于基因的多态性、分析结果务须谨慎。 苯丙酮尿症检查化验 1.尿苯丙酮酸试验由于患儿尿中排出苯丙酮酸增多，可作定性试验。 方法有： 　　 (1)三氯化铁试验：将5%三氯化铁滴入5ml尿中立即出现绿色反应则为阳性。新生儿尚未喂食，此试验呈阴性。枫糖尿病者尿也可呈阳性，故此试验特异性较差。= (2)2，4-硝基苯肼试验：如果产生黄色混浊沉淀则为阳性。 　　 2.血苯丙氨酸测定正常人血中苯丙氨酸为60～180μmol/L，PKU患者可高达600～3600μmol/L。如果以258μmol/L为正常人与PKU病人的分界点，则有高达4%的假阳性。用色层析法则在生后几天的新生儿中可出现假阴性。MS/MS法可减少假阳性率，此方法可同时测定血苯丙氨酸和酪氨酸，并可计算苯丙氨酸/酷氨酸比值。如果以比值2.5为正常儿童与患PKU者的分界点，则可将假阳性减少到1%。 故目前多用此方法来筛选新生儿苯丙酮尿症。此方法还可用来筛选半乳糖血症、枫糖尿病、同型胱氨酸尿症和先天性甲状腺功能减低症，一次检查可以筛选多种先天性疾病。　　 1.脑电图(EEG)：主要是棘慢波，偶见高波幅节律紊乱。EEG随访研究显示，随年龄增长，EEG异常表现逐渐增多，至12岁后EEG异常才逐渐减少。　　 2.产前检查：由于绒毛及羊水细胞测不出苯丙氨酸羟化酶活性，所以产前诊断问题长期不能解决。目前我国已鉴定出25种中国人PKU致病基因突变型，约占我国苯丙氨酸羟化酶突变基因的80%，已成功用于PKU患者家系突变检测和产前诊断。　 3.X线检查：可见小头畸形，CT和MRI可发现弥漫性脑皮质萎缩等非特异性改变。 苯丙酮尿症治疗方案 诊断一旦明确，应尽早给予积极治疗，主要是饮食疗法。开始治疗的年龄愈小，效果愈好。 1、低苯丙氨酸饮食 　　 主要适用于典型PKU以及血苯丙氨酸持续高于1.22mmol/L（20mg/dl）的患者。由于苯丙氨酸是合成蛋白质的必需氨基酸，完全缺乏时亦可导致神经系统损害，因此对婴儿可喂给特制的低苯丙氨酸奶粉，到幼儿期添加辅食时应以淀粉类、蔬菜、水果等低蛋白食物为主。苯丙氨酸需要量，2个月以内约需50—70mg/（kg.d）3—6个月约40mg/（kg.d），2岁均约为25—30mg/（kg.d），4岁以上约10—30mg/（kg..d），以能维持血中苯丙氨酸浓度在0.12—0.6mmol/L（2—10mg/dl）为宜。饮食控制至少需持续到青春期以后。　　 2、BH4、5—羟色胺和L—DOPA 　　主要用于BH4缺乏型PKU，除饮食控制外，需给予此类药物。 二盐酸沙丙蝶呤片（sapropterin dihydrochloride,商品名：Kuvan）完整处方 [附件:/uploadfile/article/uploadfile/201010/20101002085413649.pdf] https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=AF38711E-8873-4790-A92D-4D583E23FB89 ------------------------------------------------- 注：以下产品不同规格不同价格，购买以咨询为准！ ------------------------------------------------- 产地国家: 德国 原产地英文商品名: KUVAN 100mg/tab 30tabs/bottle 原产地英文药品名: SAPROPTERIN DIHYDROCHLORIDE 中文参考商品译名: 科望 100毫克/瓶 30片/瓶 中文参考药品译名: 盐酸沙丙蝶呤 生产厂家中文参考译名: 默克 生产厂家英文名: Merck Serono GmbH. -------------------------------------------------------------- 产地国家: 德国 原产地英文商品名: KUVAN 100mg/tab 120tabs/bottle 原产地英文药品名: SAPROPTERIN DIHYDROCHLORIDE 中文参考商品译名: 科望 100毫克/瓶 120片/瓶 中文参考药品译名: 盐酸沙丙蝶呤 生产厂家中文参考译名: 默克 生产厂家英文名: Merck Serono GmbH. -------------------------------------------------------------- 产地国家:美国 原产地英文商品名: KUVAN 100mg/tab 120tabs/bottle 原产地英文药品名: SAPROPTERIN DIHYDROCHLORIDE 中文参考商品译名: 科望 100毫克/瓶 120片/瓶 中文参考药品译名: 盐酸沙丙蝶呤 生产厂家中文参考译名: 雪兰诺 生产厂家英文名: BIOMARIN PHARM