多巴胺受体激动剂治疗神经-精神疾病的研究进展

多巴胺受体激动剂(DAs)主要用于帕金森病的治疗,对其运动及非运动症状有一定的缓解作用。随着对药物特性和结构的不断研究,DAs在帕金森病和其他神经-精神类疾病的应用得到重视。本文综述近年非麦角类DAs治疗帕金森病的研究进展及新型DAs的临床前和临床试验结果,并展望多种神经-精神疾病临床治疗的发展前景。     

多巴胺受体激动剂治疗帕金森病最新进展

本文综述了多巴胺受体激动剂在帕金森病(PD)治疗中的最新进展,介绍了培高利特(pergolide)、吡贝地尔(piribedil)、普拉克索(pramipexole)和罗匹尼罗(ropinirole)等药物对帕金森病运动症状的改善及其对多巴胺能神经元保护的作用。     

新多巴胺受体激动剂甲磺酸培高利特

目的：简述甲磺酸培高利特的药理活性和临床疗效。方法：临床前药理研究主要与溴隐亭进行比较。Ｉ期临床：对７例健康自愿受试者耐受性和血催乳素作用进行研究。临床试验：２６２例帕金森患者合并美多巴用药６周；１３５例高催乳素患者用药３周与溴隐亭比较。结果：药理评价显示甲磺酸培高利特是一典型Ｄ受体激动剂。帕金森病治疗，随机双盲临床试验显示合用美多巴比安慰剂合用美多巴更为有效（Ｐ〈０．０１）；治疗高催乳素血症显示     

多巴胺受体激动剂治疗对帕金森病患者非运动症状的影响

帕金森病患者常伴发非运动症状,会对患者的生活质量造成不良影响。临床研究显示,多巴胺受体激动剂治疗能在一定程度上改善或缓解帕金森病患者的部分非运动症状,如抑郁、焦虑、快感缺失、失眠、不明原因的痛感和膀胱功能失常等,但也会带来一些非运动症状性不良反应,如精神异常、组织纤维化、日间过度嗜睡和冲动强迫行为等。因此,临床医生应善用多巴胺受体激动剂,避免严重不良反应的发生。     

多巴丝肼联合多巴胺受体激动剂治疗帕金森病的临床研究

目的探讨多巴丝肼联合多巴胺受体激动剂治疗帕金森病的临床疗效。方法选择本院2011年3月～2012年5月收治的帕金森病患者38例,分为对照组和治疗组,对照组采用多巴丝肼进行治疗,治疗组在对照组的基础上采用多巴胺受体激动剂进行治疗,治疗4个月后,观察两组患者的临床效果。结果两组治疗4个月后,治疗组的Webster评分为（8.11±1.78）分,明显低于对照组的（11.33±3.98）分,两组相比差异有统计学意义（P〈0.05）;治疗组的UPDRS评分为（10.58±6.22）分,亦明显低于对照组的（23.67±7.78）分,两组比较差异有统计学意义（P〈0.05）。结论多巴丝肼联合多巴胺受体激动剂可以有效地改善帕金森患者的自主活动能力,值得在临床上推广。     

美多巴单用及联合多巴胺受体激动剂治疗帕金森病的疗效比较

目的观察美多巴(L-dopa)单用及美多巴与多巴胺受体激动剂(溴麦角隐亭碱BM)合用治疗帕金森病的疗效与安全性。方法选取我院收治的帕金森病患者88例,随机分为两组,L-dopa组44例,单用美多巴治疗,L-dopa+BM组44例,采用L-dopa联合BM治疗,比较两组治疗后临床疗效及不良反应发生情况。结果 Webster量表和帕金森病运动功能量表(MDRSPD)的临床总有效率显示,L-dopa组分别为75.0%与77.2%,L-dopa+BM组为72.7%与75.0%。不良反应发生率两组分别为31.8%、34.1%。结论单用美多巴及美多巴联合多巴胺受体激动剂对治疗帕金森病均有较好疗效,对于早期轻度患者,可单用美多巴,对于中晚期患者,可选择美多巴联合多巴胺受体激动剂治疗。     

非麦角碱类多巴胺受体激动剂缓释制剂的研究进展

帕金森病是常见的神经系统变性疾病,药物治疗仍是目前临床上控制和缓解其症状的主要方法。多巴胺受体激动剂作为治疗帕金森病的新型手段,不仅能在早期改善患者临床症状,而且在晚期显著延缓和减轻运动并发症,因此受到药物研发人员越来越多的关注。持续、稳定的多巴胺受体刺激是控制帕金森病的有效手段,基于此理论,多巴胺受体激动剂缓释制剂发展迅速,主要对其缓释剂型及研究进展进行综述。     

多巴胺部分激动剂Aplindore

Neurogen公司最近报告了新开发的多巴胺部分激动剂aplindore用于治疗帕金森病和不宁腿综合征（RLS）的若干项Ⅱa期临床试验阳性结果。帕金森病的运动症状与多巴胺分泌细胞退化所致多巴胺缺乏有关。自20世纪60年代以来,左旋多巴-卡比多巴联用的多巴胺替代疗法一直是帕金森病的标准疗法,但这些药物往往会引发一系列副作用,包括恶心、嗜睡、幻觉和运动障碍,     

多巴胺受体激动剂的药理研究进展

目的对多巴胺受体激动剂的药理作用进行综述。方法在查阅近十几年的文献资料基础上,从多巴胺受体激动剂的分类、分布、功能、作用机制、临床应用及其副作用进行论述。结论多巴胺受体激动剂在许多的疾病治疗中已得到了广泛的临床应用,并获得相应的临床治疗效果。     

多巴胺受体激动剂治疗帕金森综合征的临床应用

帕金森综合征(PD)是一种继发性震颤麻痹,即因某种脑炎、中毒(如一氧化碳、锰、氰化物、利血平、吩噻嗪类和丁酰酞苯类药物以及三环类抗抑郁等药物中毒等)、脑血管病、颅脑损伤、脑肿瘤等引起,又称为震颤麻痹综合征[1].主要治疗药物有2类,拟多巴胺类药物包括左旋多巴、卡比多巴、司来吉兰、金刚烷胺;胆碱能受体阻断药有苯海索、丙环定.近年来多巴胺受体激动剂引起人们高度重视.该类药物有2种类型,麦角类包括溴隐亭、培高利特、卡麦角林和麦角乙脲;非麦角类包括普拉克索、罗匹尼罗、吡贝地尔、罗替戈汀和阿朴吗啡等.根据病理生理机制的研究进展,有学者推测长效多巴胺受体(DR)激动剂可持续而非波动性刺激多巴胺受体,能起到预防或延迟运动并发症发生和神经保护的作用.     

The safety of dopamine agonists in the treatment of Parkinson's disease

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease. These drugs have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients < 65 – 70 years old, because they are about as effective as levodopa, but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists could have peripheral and central side effects, which are often the reason for the discontinuation of the treatment. This review focuses on the potential negative effects related to the use of dopamine agonists in the treatment of Parkinson's disease.     

普拉克索和罗匹尼罗对体外培养的多巴胺神经元的神经营养作用

目的 :探讨新型选择性多巴胺D3受体激动剂普拉克索和罗匹尼罗对多巴胺神经元的神经营养作用及其机制。方法 :在大鼠的腹侧中脑细胞和不同部位星形胶质细胞培养基中加入普拉克索和罗匹尼罗刺激 ,观察药物对多巴胺神经元存活的影响。结果 :药物直接作用或从黑质区星形胶质细胞培养基中提取的条件培养液均可使酪氨酸羟化酶 (TH )阳性神经元数量增加 ,同时培养液中脑源性神经营养因子 (BDNF)和胶质细胞源性神经营养因子(GDNF)含量增加。而其他脑区的星形胶质细胞不能产生类似作用。结论 :普拉克索和罗匹尼罗对多巴胺神经元具有神经营养作用 ,这可能是由于其使特定区域星形胶质细胞产生并分泌了神经营养因子。     

Effects of selective dopamine receptor subtype agonists on cardiac contractility and regional haemodynamics in rats

1. Activation of dopamine (DA) receptors produces cardiovascular responses such as vasodilation and hypotension. However, knowledge of the role of specific dopamine receptor subtypes (especially D3 and D4) in the cardiovascular system is limited. The objective of the present study was to characterize the haemodynamic and cardiac responses to agonists with selectivity for D1, D2, D3 and D4 receptor subtypes. 2. Inactin-anaesthetized rats were instrumented to measure regional haemodynamic and cardiac contractility responses with slow intravenous infusion of agonists. 3. Fenoldopam (a D1 receptor agonist) decreased (P < 0.05) renal vascular resistance beginning at a dose of 3 micromol/kg. Infusion of PNU-95666E (a D2 receptor agonist) produced dose-dependent decreases (P < 0.05) in mean arterial pressure (MAP), heart rate (HR) and hindquarter vascular resistance (HQVR). Administration of BP897 (a partial D3 receptor agonist) decreased (P < 0.05) MAP and HQVR at 3 micromol/kg. PD168077 (a D4 receptor agonist) caused significant increases in HQVR at 1 micromol/kg. None of the compounds tested elicited significant changes in cardiac contractility. 4. Using selective agonists of dopamine receptor subtypes, the present studies characterize distinct cardiovascular effects in anaesthetized rats. Consistent with its well-defined effects as a D1 receptor agonist, fenoldopam administration resulted in renal vasodilation. Similar to earlier studies using the non-selective D2-like receptor agonist quinpirole, selective agonism at the D2 receptor using PNU-95666E resulted in bradycardia, hindquarter vasodilation and decreases in arterial pressure. Partial agonism at the D3 receptor with BP897 had no effect on heart rate, but did produce depressor responses driven by decreases in HQVR. Conversely, agonism of the D4 receptor using PD168077 resulted in modest hindquarter vasoconstriction that was not dose dependent. Hence, by comparison, agonism of the D4 receptor has little effect in the cardiovascular system of the rat relative to the other dopamine receptor subtype agonists tested.     

丙泊酚脑保护作用研究进展

研究显示,丙泊酚具有一定的脑保护作用。丙泊酚的脑保护作用可能与其抗氧化特性、抑制细胞内钙超载、调节γ-氨基丁酸受体、抑制细胞凋亡等机制有关。本文就近年丙泊酚脑保护作用及其机制的研究进展作一综述。     

Behavioural profile of partial D2 dopamine receptor agonists

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kgd-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blockedd-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208–911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced byd-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208–911. The profiles of SDZ 208–912 and terguride were intermediary to those of SDZ 208–911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kgd-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dosed-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208–911, preclamol and terguride was accompanied only by the low dosed-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208–912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased byd-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced byd-amphetamine.     

Recent advances towards the discovery of dopamine receptor ligands

Dopamine is a key regulator in the CNS, contributing importantly to functions of arousal and attention, initiation of movement, perception, motivation and emotion. Its imbalance has been implicated in the pathophysiology, and more clearly in the pharmacology, of a number of neurobehavioural disorders, including Parkinson’s disease, schizophrenia, mania and depression, alcohol and drug abuse, as well as attention and eating disorders. Five major dopamine receptor subtypes (D1 – D5) have been identified, with distinct differences in their genes and peptide composition, molecular functions and neuropharmacology. These receptors represent the rational targets for the treatment of a large number of neurological and psychiatric disorders. In recent years, substantial efforts have addressed the most recently described dopamine receptor types, particularly types D3, D4 and D5, although most research involves the longer-known D1 and D2 dopamine receptors. Current pharmacological efforts in medicinal chemistry and neuropharmacology include the development of D1 full agonists and D2 partial agonists, as well as agents with dopaminergic activity combined with effects at CNS serotonergic, muscarinic, adrenergic and histaminic receptors. This review provides an overview of the recent patent literature during 2003 – 2005 on the development of therapeutic agents, mainly targeting the five dopamine receptors.     

Dopamine receptor agonists for treating prolactinomas

Prolactinomas are the most common hormone-secreting pituitary tumours and cause infertility and gonadal and sexual dysfunction in both sexes. The approach to prolactinomas has changed in the last 25 years thanks to the availability of dopaminergic drugs characterised by a potent prolactin-inhibitory effect, a tumour shrinking effect associated with a satisfactory tolerability. In more recent years, cabergoline (1-[(6-allelylergolin-8β-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethyl-urea), an ergoline derivative with potent, selective and long-lasting inhibitory activity on prolactin release, has been used to suppress prolactin secretion in women with hyperprolactinaemia. Cabergoline was shown to be significantly more effective than bromocriptine in inducing a complete biochemical response and clinical efficacy and was better tolerated than bromocriptine in the majority of patients. Notable tumour shrinkage until tumour disappearance was observed during cabergoline treatment in most patients with macroprolactinoma and it was also proven effective in patients resistant to or with a poor response to bromocriptine. In view of the limited data on cabergoline-associated pregnancies and the long half-life of the drug, it is currently recommended that women hoping to become pregnant, once ovulatory cycles have been established, should discontinue cabergoline therapy 1 month before they intend to conceive. However, no data concerning negative effects on pregnancy or offspring have been reported. The great efficacy of this compound together with its excellent tolerability makes this drug the current treatment of choice for the majority of patients with hyperprolactinaemic disorders.     

Recent developments in the pharmacological treatment of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.     

Pharmacological profiles of the putative dopamine autoreceptor agonists 3-PPP and TL-99

The putative dopamine (DA) autoreceptor agonists, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and 6,7-dihydroxy-2-dimethylaminotetralin (TL-99) were compared with apomorphine in a series of tests indicative of DA receptor activation. All three agents displaced [³H]apomorphine and [³H]spiroperidol from DA recognition sites in rat brain and caused contralateral turning in the 6-hydroxydopamine lesioned rat. Apomorphine and TL-99 were generally more potent than 3-PPP. All three agents were also active at the DA autoreceptor that controls the synthesis of dopamine as indicated in vivo using the γ-butyrolactone (GBL) procedure and in vitro using a synaptosomal preparation. In addition, all agents produced emesis in beagles. Clear differences in the drugs' actions were observed in other test procedures. In the rat, apomorphine was the only compound which caused stereotypy or rotation following a reversible KCl-induced lesion of the striatum. Conversely, TL-99 and 3-PPP lacked activity in these procedures. Presumably, activity in these two tests indicates postsynaptic DA receptor activation. Each of the putative autoreceptor agonists produced a monotonic dose-related decrease in the mouse locomotor activity as opposed to the biphasic effect exerted by apomorphine. This action on the mouse locomotor activity, coupled with the results for the GBL test, provides an index of autoreceptor activation. In contrast to 3-PPP, both apomorphine and TL-99 increased locomotor activity in animals pretreated with reserpine and α-methyl-p-tyrosine and caused rotation in unilaterally caudectomized mice. In these test procedures thought to reflect activity at the postsynaptic DA receptor, TL-99 differed in its action from 3-PPP in a manner which suggests 3-PPP may be a more selective DA autoreceptor agonist.     

A review of pramipexole and its clinical utility in Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex^®, Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.