英文药名: Solian (Amisulpride Tablets)

中文药名: 阿米舒必利片, 氨磺必利

此药品需要处方

生产品牌药厂家: Sanofi Aventis

药品说明

阿米舒必利Amisulpride（氨磺必利）

【药代动力学】
苯甲酰胺的衍生物，分子量为369.5，为单斜晶体。作用快速，口服吸收迅速，一次用50mg的Tmax约0.5h，口服200mg约4h后出现第二高峰。生物利用度为43％，血浆蛋白结合率为17％，能迅速通过血脑屏障。服用50mg后T1/2为17.3h，服200mg后T1/2为14.5h。

【药理作用】
D2受体阻滞剂。体外放射性配体结合试验发现，阿米舒必利对人类DA受体亚型D2/D3有高度的亲和力，对Dl、D4、D5亚型却无任何识别能力，对其他神经递质受体和药物作用位点也缺乏明显的亲和力。阿米舒必利在大鼠边缘系统取代【3H】racolopride结合半数有效量(ED50)为17.3±1.86mg／kg，在纹状体ED50为43.6±6.2mg/kg，有明显差异。而氟哌啶醇、remoxipride在这两个区域的ED50非常接近。用非苯甲酰胺类DA拮抗剂3H-螺哌隆作配体也证明阿米舒必利对边缘系统的选择性作用。
动物试验发现，低剂量阿米舒必利(≤10mg／kg)选择性影响突触前DA受体，并控制DA的合成和释放。高剂量(40～80mg/kg)占据突触后D2受体并出现拮抗作用，同时降低纹状体ACh水平，引起DA周转加快及阻断阿朴吗啡(APO)诱导的咬齿行为。
临床作用有明显两极性，小剂量有振奋、激活作用，用于分裂症阴性症状，大剂量有镇静作用，可治疗急性精神障碍病人。对抑郁也有效。短期（6周）、中期（6个月）临床试验（随机、双盲、空白对照）均证明阿米舒必利能改善SANS量表评分。
Reinfri提出其对分裂症原发阴性症状或缺损症状的最佳剂量为100mg／d。Speller等发现阿米舒必利治疗1年对慢性、以阴性症状为主的分裂症病人的疗效有限，与氟哌啶醇相比无明显差别(P>0.05)，但阿米舒必利组在意志缺乏、情感淡漠方面有较大改善。
对急性分裂症病人，阿米舒必利与氟哌啶醇、氟哌噻吨疗效相似，控制阳性症状的剂量以400～800mg／d最佳。对抑郁症状阿米舒必利(50mg／d)与丙咪嗪疗效相当，但耐受性、安全性较好。对老年抑郁症的疗效与舍曲林相似。对婴幼儿孤独症等也有效。

【用法用量】300～1200mg/d。

【制剂】法国商品名为Solian，意大利为Deniban和Sulamid，澳大利亚为Deniban。有片剂、针剂，规格有50mg, 100mg, 200mg, 400mg。

【不良反应】
主要有睡眠障碍、体重增加、闭经、泌乳、神经过敏及轻度EPS。与氟哌啶醇、利莫必利、利培酮不同的是，高剂量阿米舒必利(100mg/kg)不会引起动物的僵住反应，提示阿米舒必利发生EPS的倾向很小。阿米舒必利与酒精无协同作用，低剂量几乎不影响常人的认知功能。有报道服用3g未致死（血浓度为9.6mg/L）。

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英文商品名：Solian

中文商品名：首利安

醫師為何開此藥?
精神異常引起之相關症狀。

如何使用此藥?
請遵照醫師指示服藥，即使覺得病情好轉，亦不可隨意停藥。

使用此藥時該注意什麼?
1.下列患者禁止使用本藥—對本藥成分過敏者、嗜鉻細胞瘤患者、會激發泌乳激素之腫瘤的患者、15歲以下兒童。
2.癲癇、巴金森氏症患者應謹慎使用。
3.因有低血壓及鎮靜之可能性，老年人應謹慎使用。
4.若您有服用其他藥品，請告知您的醫師，特別是會造成低血壓及鎮靜之藥物。
5.腎功能不全患者醫師會主動為您調整劑量。
6.請將本劑連同藥袋放置於室溫之陰涼乾燥處避光儲存，請勿冷藏或冷凍。請勿放在孩童可以取得的場所。
7.服用此藥期間如需服用其它藥品時，請主動告訴您的醫師或藥師。

此藥品可能引起的副作用及處理方式：
若症狀持續數日或嚴重時，請停藥並立即就醫或與醫師連絡。
可能發生鎮靜、嗜眠、視力模糊、性慾降低、體重增加、顫動、肌肉僵硬、流涎、運動減退、靜坐不能、不自主運動等症狀。

忘記服藥時該怎麼辦：
若忘記服藥,則於想起時儘快服用；如果一天服藥超過兩次以上，若距離下次服藥時間少於4小時，則不需要補服，按原時間服用即可，切勿一次服用兩倍劑量。

懷孕或哺乳時該怎麼辦：
如果您準備懷孕或已懷孕，應告知並與您的醫師討論；不建議於授乳期間使用本品，最好能改用其它的乳製品以取代母乳。

包装规格:100毫克/片 30片/盒 、50毫克/片 60片/盒 、200毫克/片 60片/盒、400毫克/片 30片/盒

生产厂家:赛诺菲安万特

生产厂家英文名:Sanofi Aventis

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【原产地英文商品名】SOLIAN 400mg/tab 30tabs/box
【原产地英文药品名】AMISULPRIDE
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·首利安 100毫克/片 30片/盒
·首利安 200毫克/片 60片/盒
·首利安 400毫克/片 30片/盒
·首利安 50毫克/片 60片/盒
【中文参考药品译名】阿米舒必利
【生产厂家中文参考译名】赛诺菲安万特
【生产厂家英文名】Sanofi Aventis

Introduction
Amisulpride is manufactured by Lorex-Synthelabo under the trade name Solian. Tablets are available in  50 mg or 200 mg formats. The recommended doses are between 400 mg/day and 800 mg/day. Amisulpride appears to be effective against negative symptoms at low doses e.g. 100 mg daily.

Summary
Amisulpride is a second generation antipsychotic, a substituted benzamide. Amisulpride appears to be an effective agent in treating schizophrenia for what are characterised as positive and negative symptoms. The recommended doses are between 400 mg/day and 800 mg/day. Amisulpride demonstrates a good global safety profile, particularly when compared with first generation antipsychotics, such as haloperidol. There are interesting studies that point towards amisulpride's antidepressant effect in dysthymia and one could speculate on possible roles in affective psychoses and chronic fatigue syndrome.

Indications
Primarily recommended by the manufacturer for the positive and negative symptoms of acute and chronic schizophrenia in adults.

As ever though there are prescriptions of the drug outside licensed indications and there are reports of the drug's unofficial use for other conditions, even such apparently unrelated conditions as dysthymia, (Boyer et al, 1999 and Smeraldi, 1998).

Prescription for children and adolescents has been reported in the literature, (Toren et al, 1998)

Pharmacology
Amisulpride has 'dual dopamine blockade' and a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses (Schoemaker et al, 1997)  - at low doses (< or = 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. It binds selectively with a high affinity for human dopaminergic D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM)  receptors and is devoid of affinity for D1, D4 and D5 receptor subtypes. It has no affinity for serotonergic alpha-adrenergic, H1 histaminergic or cholinergic receptors. Amisulpride acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses (Boyer et al, 1999)

There are two absorption peaks - one hour post-dose and a second 3-4 hours after taking the tablet. The elimination half-life is 12 hours.

Absolute bioavailability is 48%.

Amisulpride is weakly metabolised by the liver. There are two inactive metabolites. The drug is mainly eliminated unchanged by the kidney. 50% of an iv dose is eliminated by the kidney  - of which 90% is eliminated in the first 24 hours.

Structure
Amisulpride is a substituted benzamide.

Efficacy
A four week double blind randomised study  of 319 schizophrenia sufferers compared amisulpride with 16 mg haloperidol daily and found the efficacy was best at 400mg to 800 mg daily (measured according to the Brief Psychiatric Rating Scale (BPRS) and the PANSS) (Peuch et al).

Positive symptoms in schizophrenia
Wetzel et al (1998)  compared amisulpride with flupenthixol  a conventional antipsychotic (a thioxanthene). The study ran for  6 weeks and involved  132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (amisulpride: 1000 mg/day; flupenthixol: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: amisulpride: 956 mg; flupenthixol: 22.6 mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. ANCOVA analysis showed that reductions of BPRS scores  were more pronounced under amisulpride. Due to adverse events, significantly fewer amisulpride patients (6%) were withdrawn from the study (flupenthixol: 18%). Extrapyramidal tolerability was better in the amisulpride group.

Negative Symptoms in schizophrenia
Amisulpride's efficacy against negative symptoms was investigated by Boyer et al (Boyer et al, 1995). In this parallel group, double blind, placebo controlled trial patients had to have high negative symptoms scores on the Scale for the Assessment of Negative Symptom (SANS) to be included. The authors said these were 'pure negative forms of schizophrenia'. 104 inpatients received amisulpride 100 mg daily, 300 mg daily or placebo. Amisulpride doses were significantly more effective on negative symptoms than placebo (p<0.02). Interestingly enough the differences between the 100 mg daily and 300mg daily groups were 'minimal' according to the authors. Withdrawal symptoms from previous antipsychotics were controlled by a 6 or 12 week washout period.

Loo et al (1997) performed a multi-centre, randomised parallel group, double blind study looking again at fairly low doses (100 mg daily) compared with placebo. 141 patients received either amisulpride or placebo (69 receiving the drug). The study used SANS and Scale for the Assessment of Positive Symptoms (SAPS)  on DSM-III criteria patients.  All efficacy assessments were in favour of amisulpride.

Danion et al (1999) performed a  placebo-controlled study of amisulpride on  primary negative symptoms. After completion of a 4-week washout period, schizophrenic patients with primary negative symptoms participated in a 12-week, multicentre double-blind trial of placebo (N = 83), amisulpride, 50 mg/day (N = 84), or amisulpride, 100 mg/day (N = 75). They were evaluated with the SANS, the SAPS, the BPRS, and the Montgomery-Asberg Depression Rating Scale (MADRS). Both amisulpride treatment groups showed significantly greater improvement in negative symptoms than the placebo group. The improvement in negative symptoms was independent of any improvement in positive symptoms.

Dysthymia
Smeraldi (1998) reported a multicentre, double blind, parallel group study in which 281 patients with DSM III-R diagnosis of dysthymia or a single episode of major depression in partial remission were randomised and given either 3 months of treatment with amisulpride 50 mg/day or fluoxetine 20 mg/day. The baseline MADRS total score was reduced by at least 50% in 74.1% of patients (103/139) with amisulpride and 67.4% (87/129) with fluoxetine (P =0.230). No significant differences between treatment groups were found in the reductions in mean total score with the MADRS, Widlöcher psychomotor retardation scale, Sheehan disability scale, and CGI. Anxiety measured by HAM-A total mean score decreased significantly more with amisulpride (63%) than with fluoxetine (54%; P = 0.021). There were 13 dropouts due to adverse events with amisulpride and ten with fluoxetine. The number of patients reporting at least one adverse event was similar in the two groups (amisulpride 47.5%; fluoxetine 40.9%). As expected, in the amisulpride group endocrine-like adverse events in female patients were the most common, while nausea, dyspepsia, anorexia and insomnia occurred more frequently with fluoxetine.

Lecrubier et al (1997)  compared  amisulpride (50 mg/daily)  to imipramine (100 mg/daily) in the treatment of patients with DSM-III-R criteria for primary dysthymia, dysthymia with major depression or major depression in partial remission. A total of 219 patients were included. Both analyses (intention-to-treat and "per protocol' analysis) detected significant differences between groups (active treatment vs. placebo) on all main rating scales (CGI, MADRS, ERD, and SANS). The number of patients reporting at least one adverse event was higher in the imipramine group than in the two other, mainly due to anticholinergic effects. 

Further work from this French group compared amisulpride and amineptine with placebo, (Boyer et al, 1999). During this 3-month study of 323 patients, amisulpride (50 mg/day) was compared to amineptine (200 mg/day) in the treatment of primary dysthymia. Both amisulpride and amineptine were found to be statistically superior to placebo on the Clinical Global Impression (item 2), Montgomery-Asberg Depression Rating Scale and the Scale for the Assessment of Negative Symptoms.

This observed antidepressant activity was enthusiastically followed up by work such as that of Papp and Wieronska (2000) who used two animal behavioural models: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). The dosing appeared to be critical in that lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. Amisulpride's onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed.

These results provided further support for clinical observations that amisulpride may possess potent and rapid antidepressant activity.

Cautions and contra-indications
In the elderly amisulpride can cause hypotension and sedation. There are no systematic published data on efficacy in children less than 15.

Renal impairment significantly reduces the clearance and prolongs the elimination half-life of amisulpride and risperidone (Caccia, 2000). If there is renal insufficiency there should be a reduction in the dose of amisulpride. The dose should be halved if the creatinine clearance is between 30-60 ml/min and reduced to a third for clearances between 10-30 ml/min.

Prescription should be avoided if there is proven hypersensitivity to the drug,  a prolactin dependent tumour, phaeochromocytoma, pregnancy or lactation.

Side Effects
Insomnia, anxiety, agitation are common side effects (occurring in 5-10%). Somnolence, constipation, nausea, vomiting and dry mouth may occur in up to 2% of patients. Other side effects include weight gain, acute dystonia, extrapyramidal side effects, tardive dyskinesia, hypotension, bradycardia and QT prolongation.

Amisulpride can cause  hyperprolactinaemia and thus may lead to galactorrhoea, gynaecomastia, breast pain and amenorroea. Amisulpride's endocrine effects are remarked on throughout the relevant literature. Grunder et al (1999)  compared the endocrine actions of amisulpride and flupenthixol, (a mixed D1/D2-like antagonist also blocking serotonin, H1, and D1 receptors) -on anterior pituitary hormone secretion in schizophrenic patients. Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing hormone (TRH) was injected i.v. to investigate drug effects on TRH-stimulated secretion of prolactin, TSH, and GH. Prolactin plasma levels were markedly elevated in both treatment groups. This elevation was significantly more pronounced in females(but not males) with amisulpride than with flupenthixol. The prolactin response to TRH was significantly blunted by amisulpride only in male subjects. Interestingly enough, low basal prolactin levels predicted improvement of negative symptoms in patients treated with amisulpride. 

Amisulpride may reduce reaction time in those using machinery. Seizure threshold reduction. May exacerbate Parkinson's disease. Neuroleptic malignant syndrome is a rare though possible side effect.

The drug has been given to healthy volunteers and compared to haloperidol (Raemarkers, 1999). Amisulpride 400 mg daily had  some mild adverse effects on psychomotor and cognitive performance, but no significant extrapyramidal disturbances in the group as a whole.   On clinical rating scales or during a structured psychiatric interview it produced no signs of mental disturbances. Haloperidol ubiquitously impaired psychomotor and cognitive performance in a similar fashion after the first and the final doses and produced extrapyramidal disturbances in nearly every subject, the most common being akathisia and the most severe, in the case of one individual, being acute dystonia. Haloperidol produced a number of mental disturbances, the most noteworthy being negative symptoms.

Looking at the results from 11 studies Coulouvrat and Donddey-Novel (1999) concluded that in these studies of a total of 1933 patients amisulpride demonstrated a satisfactory global safety profile. There was an absence of cardiovascular events. Extrapyramidal side effects were fewer than with haloperidol, endocrine events were similar to risperidone. Haematological and liver function problems were absent on laboratory tests. Their conclusion was that from a safety perspective amisulpride was superior to reference compounds.

Long term safety data (Colonna et al, 2000) looked at 370 patients receiving amisulpride over 12 months compared to 118 patients on haloperidol. The overall incidence of endocrine events was comparable between groups (4% for amisulpride, 3% for haloperidol), but extrapyramidal events were predictably fewer in the amisulpride group. Maintenance of efficacy was comparable in both treatment groups

Interactions
Co-administered ethanol increased the AUC by over 10%. There are no apparent interactions with benzodiazepines.

Comparison with other antipsychotics
Peuskens et al (1999) compared amisulpride with risperidone and found a marginal superiority for amisulpride. Their study was double-blind and involved 228 patients allocated, after a short wash-out period, to amisulpride 800 mg (n = 115) or risperidone 8 mg (n = 113) for 8 weeks. Decreases in mean BPRS total score were 17.7 +/- 14.9 for amisulpride and 15.2 +/- 13.9 for risperidone. All the individual factors on the BPRS showed a numerically greater improvement in the amisulpride group There was a trend towards greater improvement in negative symptoms patients receiving amisulpride. Patients receiving risperidone experienced an increase in body weight, which was significantly greater than for amisulpride (P = 0.026).
Compared to the previous gold standard antipsychotic haloperidol amisulpride has a superiority in treating schizophrenia in terms of positive and negative symptoms and a more acceptable side effect profile, (Collona et al, 2000). Carriere et al (2000) found that compared to haloperidol amisulpride had a beneficial effect on the quality of life measured by the Quality of Life Scale (QLS) and the Functional Status Questionnaire (FSQ).

Conclusions
Amisulpride appears to be an effective agent in treating schizophrenia for what are characterised as positive and negative symptoms (negative symptoms particularly at low doses e.g. 100 mg daily). Quality of life and function appears to be better on amisulpride than haloperidol. Further more it appears to initially have a good global safety profile. There are interesting studies that point towards its antidepressant effect in dysthymia and one might speculate on possible roles in affective psychoses and chronic fatigue syndrome.