英文药名：ALDURAZYME(laronidase solution for infusion) 中文药名：拉罗尼酶注射溶液（别名：α-艾杜糖醛酸酶注射液） 生产厂家：健赞公司 药品介绍 拉罗尼酶（Aldurazyme）用于治疗粘多糖贮积症―静脉注射； 美国FDA已批准用于治疗Ⅰ型黏多糖病 (MDSI)的一种罕用 (orphan)药—α艾杜糖醛酸酶 (α Liduronidase ,通用名laronidase ,商品名Aldurazyme)。MDSI(Hurler综合征 )是一种溶酶体贮积障碍 ,因该酶短缺所致。 ALDURAZYME（laronidase）静脉滴注 中文药名：美国药名：α-艾杜糖醛酸酶  欧洲药名：拉罗尼酶 最初美国批准：2003年 适应症 ALDURAZYME表示粘多​​糖投掷者和投掷者，Scheie形式和与Scheie形式的患者有中度至重度症状的患者。尚未建立的与Scheie形式处理轻度影响患者的风险和利益。 ALDURAZYME已被证明可以改善肺功能和行走能力。 ALDURAZYME尚未评估上的障碍中央神经系统表现的影响。 剂量和用法 0.58毫克/公斤体重为静脉输液每周一次 Aldurazyme 100 U/ml concentrate for solution for infusion Genzyme Therapeutics contact details Active ingredient laronidase Legal Category POM: Prescription only medicine 1. Name of the medicinal product Aldurazyme 100 U/ml concentrate for solution for infusion 2. Qualitative and quantitative composition 1 ml contains 100 U (approximately 0.58 mg) of laronidase. Each vial of 5 ml contains 500 U of laronidase. The activity unit (U) is defined as the hydrolysis of one micromole of substrate (4-MUI) per minute. Laronidase is a recombinant form of human α-L-iduronidase and is produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture. Excipient(s) with known effect: Each vial of 5 ml contains 1.29 mmol sodium. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Concentrate for solution for infusion. A clear to slightly opalescent, and colourless to pale yellow solution. 4. Clinical particulars 4.1 Therapeutic indications Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency) to treat the non-neurological manifestations of the disease (see section 5.1). 4.2 Posology and method of administration Aldurazyme treatment should be supervised by a physician experienced in the management of patients with MPS I or other inherited metabolic diseases. Administration of Aldurazyme should be carried out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available. Posology The recommended dosage regimen of Aldurazyme is 100 U/kg body weight administered once every week. Paediatric population No dose adjustment is necessary for the paediatric population. Elderly The safety and efficacy of Aldurazyme in patients older than 65 years have not been established and no dosage regimen can be recommended in these patients. Renal and hepatic impairment The safety and efficacy of Aldurazyme in patients with renal or hepatic insufficiency have not been evaluated and no dosage regimen can be recommended in these patients. Method of administration Aldurazyme is to be administered as an intravenous infusion. The initial infusion rate of 2 U/kg/h may be incrementally increased every fifteen minutes, if tolerated, to a maximum of 43 U/kg/h. The total volume of the administration should be delivered in approximately 3-4 hours. For information on pre-treatment, see section 4.4. For instruction on dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Severe hypersensitivity (e.g. anaphylactic reaction) to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8). 4.4 Special warnings and precautions for use Infusion-associated reactions Patients treated with Aldurazyme may develop infusion-associated reactions (IARs), defined as any related adverse event occurring during the infusion or until the end of the infusion day (see section 4.8). Some of these IARs may be severe (see below). Patients treated with Aldurazyme should be closely monitored and all cases of infusion-associated reactions, delayed reactions and possible immunological reactions reported. Antibody status should be regularly monitored and reported. Severe IARs have been reported in patients with pre-existent severe underlying upper airway involvement and therefore specifically these patients should continue to be closely monitored and only be infused with Aldurazyme in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available. Patients with an acute underlying illness at the time of Aldurazyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient's clinical status prior to administration of Aldurazyme. Based on the Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation of treatment. Patients who have developed antibodies or symptoms of IARs should be treated with caution when administering Aldurazyme (see sections 4.3 and 4.8). In clinical studies IARs were usually manageable by slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol or ibuprofen), thus enabling the patient to continue treatment. As there is little experience on resumption of treatment following prolonged interruption, use caution due to the theoretical increased risk of hypersensitivity reaction after treatment interruption. With initial administration of Aldurazyme or upon re-administration following interruption of treatment, it is recommended that patients be administered pre-treatment medicines (antihistamines and/or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise the potential occurrence of IARs. If clinically indicated, administration of pre-treatment medications with subsequent infusions of Aldurazyme should be considered. In case of a mild or moderate IAR, treatment with antihistamines and paracetamol/ibuprofen should be considered and/or a reduction in the infusion rate to half the infusion rate at which the reaction occurred. In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and treatment with antihistamines and paracetamol/ibuprofen should be considered. The infusion can be restarted with a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion at which the reaction occurred. In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should be considered (antihistamines and paracetamol/ibuprofen and/or corticosteroids) and a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion at which the previous reaction occurred. As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible. If these reactions occur, immediate discontinuation of Aldurazyme is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed. Excipients This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous solution (see section 6.6). To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Based on its metabolism, laronidase is an unlikely candidate for Cytochrome P450 mediated interactions. Aldurazyme should not be administered simultaneously with chloroquine or procaine due to a potential risk of interference with the intracellular uptake of laronidase. 4.6 Fertility, pregnancy and lactation Pregnancy There are inadequate data on the use of Aldurazyme in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown. Therefore Aldurazyme should not be used during pregnancy unless clearly necessary. Breast-feeding Laronidase may be excreted in milk. Because there are no data available in neonates exposed to laronidase via breast milk, it is recommended to stop breast-feeding during Aldurazyme treatment. Fertility There are no clinical data on the effects of laronidase on fertility. Preclinical data did not reveal any significant adverse finding (see section 5.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects Summary of the safety profile The majority of the related adverse events in the clinical trials were classified as infusion-associated reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years) and 35% of the patients in the under 5 study (up to 1 year of treatment). Some of the IARs were severe. Over time the number of these reactions decreased. The most frequent adverse drug reactions (ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity, flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased, tachycardia and chills. Post-marketing experience of infusion-associated reactions revealed reporting of cyanosis, hypoxia, tachypnoea, pyrexia, vomiting, chills and erythema, in which some of these reactions were severe. Tabulated list of adverse reactions ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5 years and older and treated up to 4 years are listed below using the following categories of frequency: 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) and not known (cannot be estimated from the available data). Due to the small patient population, an ADR reported in a single patient is classified as common. MedDRA System Organ Class Very common Common Not known Immune system disorders Anaphylactic reaction Psychiatric disorders Restlessness Nervous system disorders Headache Paraesthesia, dizziness Cardiac disorders Tachycardia Vascular disorders Flushing Hypotension, pallor, peripheral coldness Respiratory, thoracic and mediastinal disorders Respiratory distress, dyspnoea, cough Cyanosis, hypoxia, tachypnoea, bronchospasm, respiratory arrest Gastrointestinal disorders Nausea, abdominal pain Vomiting, diarrhoea Skin and subcutaneous tissue disorders Rash Angioneurotic edema, swelling face, urticaria, pruritus, cold sweat, alopecia, hyperhidrosis Erythema, facial edema, laryngeal edema, edema peripheral Musculoskeletal and connective tissue disorders Arthropathy, arthralgia, back pain, pain in extremity Musculoskeletal pain General disorders and administration site conditions Pyrexia, infusion site reaction Chills, feeling hot, feeling cold, fatigue, influenza like illness Extravasation Investigations Body temperature increased, oxygen saturation decreased A single patient with pre-existing airway compromise developed a severe reaction three hours from the start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction, requiring tracheostomy. This patient tested positive for IgE. Additionally, a few patients who had a prior history of severe MPS I- related upper airway and pulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, and facial oedema (see section 4.4). Paediatric population ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age and mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild to moderate in severity. MedDRA System Organ Class MedDRA Preferred term Frequency Cardiac disorders tachycardia Very common General disorders and administration site conditions pyrexia Very common chills Very common Investigations blood pressure increased Very common oxygen saturation decreased Very common In a phase 4 study 33 MPS I patients received 1 of 4 dose regimens: 100 U/kg IV every week (recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks or 300 U/kg IV every 2 weeks. The recommended dose group had the fewest number of patients who experienced ADRs and IARs. The type of IARs was similar to those seen in other clinical studies. Description of selected adverse reactions Immunogenicity Almost all patients developed IgG antibodies to laronidase. Most patients seroconverted within 3 months of initiation of treatment; although seroconversion in patients under 5 years old with a more severe phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 years and older). By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients had no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never seroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAG level, whereas patients with high antibody titers showed variable reduction in urinary GAG. The clinical significance of this finding is unknown since there were no consistent relationships between IgG antibody level and clinical efficacy endpoints. In addition 60 patients in the Phase 2 and 3 studies were tested for in-vitro neutralising effects. Four patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/or urinary GAG reduction. The presence of antibodies did not appear to be related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies. The occurrence of IgE antibodies was not fully explored. 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system below. United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal 4.9 Overdose No case of overdose has been reported. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Enzymes. ATC code: A16AB05. MPS I disease Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous and multisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatan sulfate and heparan sulfate in many cell types and tissues. Mechanism of action The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion, laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors. Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kDa. Laronidase is comprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modifications sites. Clinical efficacy and safety Three clinical trials were performed with Aldurazyme to assess its efficacy and safety. One clinical study focussed mainly on assessing the effect of Aldurazyme on the systemic manifestations of MPS I such as poor endurance, restrictive lung disease, upper airway obstruction, reduced joint range of motion, hepatomegaly and visual impairment. One study mainly assessed the safety and pharmacokinetics of Aldurazyme in patients less than 5 years old, but some efficacy measurements were included as well. The third study was conducted to evaluate the pharmacodynamics and safety of different dose regimens of Aldurazyme. To date there are no clinical data that demonstrate any benefit on the neurological manifestations of the disorder. The safety and efficacy of Aldurazyme was assessed in a randomised, double-blind, placebo controlled, Phase 3 Study of 45 patients, ranging in age from 6 to 43 years. Although patients representing the full range of the disease spectrum were enrolled, the majority of the patients were of the intermediate phenotype, with only one patient exhibiting the severe phenotype. Patients were enrolled with a Forced Vital Capacity (FVC) less than 80% of the predicted value and had to be able to stand for 6 minutes and to walk 5 meters. Patients received either 100 U/kg of Aldurazyme or placebo every week for a total of 26 weeks. The primary efficacy endpoints were changes in percent of predicted normal FVC and absolute distance travelled in the six-minute walk test (6MWT). All patients subsequently enrolled in an open label extension study where they all received 100 U/kg of Aldurazyme every week for an additional 3.5 years (182 weeks). Following 26 weeks of therapy, Aldurazyme-treated patients showed improved respiratory function and walking ability as compared to placebo as indicated below. Phase 3, 26 weeks of treatment compared to placebo p value Confidence interval (95%) Percent Predicted FVC (percentage point) mean 5.6 - median 3.0 0.009 0.9 - 8.6 6MWT (meters) mean 38.1 - median 38.5 0.066 -2.0 - 79.0 The open label extension study showed improvement and/or maintenance of these effects up to 208 weeks in the Aldurazyme/Aldurazyme group and 182 weeks in the Placebo/Aldurazyme group as indicated in the table below Aldurazyme/Aldurazyme Placebo/Aldurazyme At 208 weeks At 182 weeks Mean change from pre-treatment baseline Percent predicted FVC (%)1 - 1.2 - 3.3 6MWT (meters) + 39.2 + 19.4 Apnea/Hypopnea Index (AHI) - 4.0 - 4.8 Shoulder flexion Range Of Motion (degrees) + 13.1 + 18.3 CHAQ/HAQ Disability Index 2 - 0.43 - 0.26 1 The decrease in percent predicted FVC is not clinically significant over this timeframe, and absolute lung volumes continued to increase commensurate with changes in height in growing paediatric patients. 2 Both groups exceeded the minimal clinically important difference (-0.24) Of the 26 patients with abnormal liver volumes at pre-treatment baseline, 22 (85%) achieved a normal liver size by the end of the study. There was a rapid reduction in the excretion of urinary GAG (µg/mg creatinine) within the first 4 weeks, which was maintained through the remainder of the study. Urinary GAG levels decreased by 77% and 66% in the Placebo/Aldurazyme and Aldurazyme/Aldurazyme groups, respectively; at the end of the study one-third of the patients (15 of 45) had reached normal urinary GAG levels. To address the heterogeneity in disease manifestation across patients, using a composite endpoint that summed up clinically significant changes across five efficacy variables (percent predicted normal FVC, 6MWT distance, shoulder flexion range of motion, AHI, and visual acuity) the global response was an improvement in 26 patients (58%), no change in 10 patients (22%), and a deterioration in 9 patients (20%). A Phase 2 open-label, 1-year study was conducted that mainly assessed the safety and pharmacokinetics of Aldurazyme in 20 patients less than 5 years of age at the time of enrolment (16 patients with the severe phenotype and 4 with the intermediate phenotype). The patients were scheduled to receive Aldurazyme 100 U/kg weekly infusions for a total duration of 52 weeks. Four patients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary GAG levels at Week 22. Eighteen patients completed the study. Aldurazyme was well tolerated at both dosages. The mean urinary GAG level declined by 50% at Week 13 and was reduced by 61% at the end of the study. Upon study completion, all patients showed reductions in liver size and 50% (9/18) had normal liver size. The proportion of patients with mild left ventricular hypertrophy decreased from 53% (10/19) to 17% (3/18), and mean left ventricular mass normalized for body surface area decreased by 0.9 Z-Score (n=17). Several patients showed an increase in height (n=7) and weight (n=3) for age Z-score. The younger patients with the severe phenotype (< 2.5 years) and all 4 patients with the intermediate phenotype exhibited a normal rate of mental development, whereas the older patients with a severe phenotype made limited or no gains in cognition. A phase 4 study was conducted to evaluate the pharmacodynamic effects on urinary GAGs, liver volume, and 6MWT, of different Aldurazyme dose regimens. In this 26-week open label study, 33 MPS I patients received 1 of 4 dose regimens of Aldurazyme: 100 U/kg IV every week (recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks; or 300 U/kg IV every 2 weeks. No definite benefit was shown with the higher doses over the recommended dose. The 200 U/kg IV every 2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly infusions; however, there is no evidence that the long term clinical efficacy of these two dose regimens is equivalent. 5.2 Pharmacokinetic properties After intravenous administration of laronidase with an infusion time of 240 minutes and at a dose of 100 U/kg body weight pharmacokinetic properties were measured at Weeks 1, 12 and 26. Parameter Infusion 1 Mean ± SD Infusion 12 Mean ± SD Infusion 26 Mean± SD Cmax (U/ml) 0.197 ± 0.052 0.210 ± 0.079 0.302 ± 0.089 AUC ∞ (h•U/ml) 0.930 ± 0.214 0.913 ± 0.445 1.191 ± 0.451 CL (ml/min/kg) 1.96 ± 0.495 2.31 ± 1.13 1.68 ± 0.763 Vz (l/kg) 0.604 ± 0.172 0.307 ± 0.143 0.239 ± 0.128 Vss (l/kg) 0.440 ± 0.125 0.252 ± 0.079 0.217 ± 0.081 t1/2 (h) 3.61 ± 0.894 2.02 ± 1.26 1.94 ± 1.09 Cmax showed an increase over time. The volume of distribution decreased with continued treatment, possibly related to antibody formation and/or decreased liver volume. The pharmacokinetic profile in patients less than 5 years old was similar to that of older and less severely affected patients. Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of laronidase in a clinically significant way. Renal elimination of laronidase is considered to be a minor pathway for clearance (see section 4.2). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity and toxicity to reproduction. Genotoxic and carcinogenic potential are not expected. 6. Pharmaceutical particulars 6.1 List of excipients Sodium chloride Sodium phosphate monobasic, monohydrate Sodium phosphate dibasic, heptahydrate Polysorbate 80 Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vials: 3 years Diluted solutions: From a microbiological safety point of view, the product should be used immediately. If not used immediately, in-use storage should not be longer than 24 hours at 2°C - 8°C provided that dilution has taken place under controlled and validated aseptic conditions. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 5 ml concentrate for solution in a vial (type I glass) with a stopper (siliconised chlorobutyl rubber) and a seal (aluminium) with a flip-off cap (polypropylene). Pack sizes: 1, 10 and 25 vials. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Each vial of Aldurazyme is intended for single use only. The concentrate for solution for infusion has to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is recommended that the diluted Aldurazyme solution be administered to patients using an infusion set equipped with a 0.2 µm in-line filter. Preparation of the Aldurazyme Infusion (Use Aseptic Technique) • Determine the number of vials to be diluted based on the individual patient's weight. Remove the required vials from the refrigerator approximately 20 minutes in advance in order to allow them to reach room temperature (below 30°C). • Before dilution, visually inspect each vial for particulate matter and discoloration. The clear to slightly opalescent and colourless to pale yellow solution should be free of visible particles. Do not use vials exhibiting particles or discoloration. • Determine the total volume of infusion based on the individual patient's weight, either 100 ml (if body weight is less or equal than 20 kg) or 250 ml (if body weight is more than 20 kg) of sodium chloride 9 mg/ml (0.9%) solution for infusion. • Withdraw and discard a volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion from the infusion bag equal to the total volume of Aldurazyme to be added. • Withdraw the required volume from the Aldurazyme vials and combine the withdrawn volumes. • Add the combined volumes of Aldurazyme to the sodium chloride 9 mg/ml (0.9%) solution for infusion. • Mix the solution for infusion gently. • Prior to use visually inspect the solution for particulate matter. Only clear and colourless solutions without visible particles should be used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands. 8. Marketing authorisation number(s) EU/1/03/253/001-003 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 10 June 2003 Date of latest renewal: 10 June 2008 10. Date of revision of the text 12/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. --------------------------------------------------- 产地国家：荷兰 原产地英文商品名: Aldurazyme solution for infusion 100U/ml/vials 10vials/box 原产地英文药品名: laronidase 中文参考商品译名: Aldurazyme注射浓缩液 100U/毫升 10瓶/盒 中文参考药品译名: 拉罗尼酶 生产厂家英文名: Genzyme Therapeutics --------------------------------------------------- 产地国家：荷兰 原产地英文商品名: Aldurazyme solution for infusion 100U/ml/vials 25vials/box 原产地英文药品名: laronidase 中文参考商品译名: Aldurazyme注射浓缩液 100U/毫升 25瓶/盒 中文参考药品译名: 拉罗尼酶 生产厂家英文名: Genzyme Therapeutics --------------------------------------------------- 产地国家：瑞士 原产地英文商品名: ALDURAZYME Inf Konz 500IE/5ml/vials 原产地英文药品名: laronidase 中文参考商品译名: Aldurazyme注射浓缩液 500U/5毫升/瓶 中文参考药品译名: 拉罗尼酶 生产厂家英文名: Sanofi-Aventis (Suisse) SA ----------------------------------------------------- 附：小儿糖原贮积病Ⅰ型诊断与治疗 病因 糖原是由葡萄糖构成的高分子多糖，主要贮存在肝脏和肌肉中作为备用能量，正常肝和肌组织中分别含有约4%和2%糖原。摄入体内的葡萄糖在葡萄糖激酶、葡糖磷酸变位酶和尿苷二磷酸葡糖焦磷酸化酶的催化下形成尿苷二磷酸葡萄糖（UD-PG）。然后在糖原合成酶和分支酶的作用下，形成树状结构的糖原大分子。糖原的分解主要由磷酸化酶和脱支酶的反复作用下形成葡萄糖，或在葡萄糖苷酶的催化下分解为麦芽糖等低聚糖。上述糖原合成和分解过程中任一酶的缺陷即导致不同临床表现的各型糖原贮积病。 GSD-Ⅰ是由于肝、肾等组织中葡萄糖-6-磷酸酶系统活力缺陷，造成过多的糖原贮积于其中，不仅导致其体积增大，而且功能也遭受损害。 临床表现 本型患儿临床表现轻重不一，重症在新生儿期即可出现严重低血糖、酸中毒、呼吸困难和肝脏增大等症状；轻症病例则常在婴幼儿期因生长迟缓、腹部膨胀等而就诊。由于慢性乳酸酸中毒和长期胰岛素/胰高糖素比例失常，患儿身材明显矮小，骨龄落后，骨质疏松。腹部因肝脏持续增大而显著膨隆；肌肉松弛，四肢伸侧皮下常有黄色瘤可见；但身体各部比例和智能等都正常。患儿时有低血糖发作和腹泻发生。少数婴幼儿在重症低血糖时尚可伴发惊厥，但亦有血糖降至0.56mmol/L（10mg/dl）以下而无明显症状者，随着年龄的增长，低血糖发作次数可以减少。由于血小板功能不良，患儿常有鼻出血等出血倾向。 检查 1.空腹血生化检测 生化异常包括低血糖、酮症酸中毒、乳酸血症及高脂血症。重症低血糖常伴有低磷血症。三酰甘油、胆固醇脂肪酸和尿酸均显著增高 2.糖耐量试验 呈现典型的糖尿病特征。患儿空腹血糖低而果糖耐量试验和半乳糖耐量试验特异性增高。由于患儿不能使半乳糖或果糖转化为葡萄糖，因此在半乳糖或果糖耐量试验中血葡萄糖水平不见升高。 3.肾上腺素试验 皮下注射1∶1000肾上腺素0.02ml/kg，注射前和注射后10，20，30，40，50，60分钟，分别测血糖，正常者血糖上升40%～60%；糖原贮积病患儿血糖无明显上升。 4.胰高血糖素试验 胰高糖素或肾上腺素试验亦不能使患儿血糖明显上升。糖肌注胰高血糖素30µg/kg（最大量1mg），于注射后0，15，30，45，60，90，120分钟分别取血测血糖。正常时15～45分钟内血糖升高1.5～2.8mmol/L，原贮积病葡萄糖-6-磷酸酶缺乏时在空腹或餐后均无血糖升高。 5.黏多糖检查 （1）血黏多糖检查  黏多糖末梢血白细胞，淋巴细胞和骨髓血细胞中可见到异染的大小不等、形状不同的深染颗粒，有时呈空泡状，颗粒称Reilly氏颗粒，经证实为黏多糖。 （2）尿黏多糖酸检查  患儿尿中排出大量酸性黏多糖，可超过100mg/24小时（正常为3～25mg/24小时），尿中排出硫酸皮肤素和类肝素。 6.活组织检查 （1）肝脏活组织检查  可见肝细胞增大糖原增加；葡萄糖-6-磷酸活性酶降低或消失。 （2）肌肉活组织检查  糖原含量稍增加糖原结构正常血小板中葡萄糖-6-磷酸活性酶亦可降低或消失。 7.酶检查 可测定尿中各种酶的活性，各型黏多糖增多症均有相应的酶活性降低。患儿白细胞成纤维细胞或肝细胞，尿中缺乏α-艾杜糖醛酸酶。 8.基因检测 可通过外周血白细胞DNA分析进行基因检测。 9.血小板膜检查 血小板膜释放ADP能力减低，因此其黏附率和聚集功能低下。多数患儿肝功能正常。 10.影像学检查 X线检查可见骨质疏松和肾脏肿大。背柱、头颅X线示仅有轻微改变。 B超和CT扫描可发现肝、肾肿大，少数病程较长患儿肝脏并发有单个或多个腺瘤。 诊断 根据病史、体征和血生化检测可供做出初步临床诊断，糖代谢功能试验可能有助于诊断。以肝组织的糖原定量和葡萄糖-6-磷酸酶活性测定作为确诊依据。 治疗 在空腹低血糖时，由于胰高糖素的代偿机制促进了肝糖原分解，导致患儿体内6-磷酸葡萄糖累积和由此生成过量的乳酸、三酸甘油酯和胆固醇等一系列病理生化过程。因此，从理论上讲，任何可以保持正常血糖水平的方法即可阻断这种异常的生化过程并减轻临床症状。 1.药物治疗 维生素类药物，如B族维生素、维生素C等。有感染给抗生素治疗。 2.手术治疗 做门-腔静脉吻合术改善本病的生化异常。 3. 特异性的酶替代治疗及基因治疗 最有希望治疗黏多糖增多症的方法是特异性的酶替代治疗药物ALDURAZYME(LARONIDASE)及基因治疗，二者可改善患儿的临床表现以及生存情况。 特异性酶替代治疗可有两种不同的形式。一种是直接给体内输入经过微包裹的酶，此为直接法。另一种则为间接法，即利用反转录病毒进行转基因处理，使患儿自体的周围血淋巴细胞或骨髓造血祖细胞逆向转化为含有正常酶基因的细胞，或通过骨髓移植给患儿体内植入含有正常酶基因的骨髓细胞，从而使患儿体内可以自身合成所缺乏的黏多糖代谢酶。