关于精制蝮蛇抗栓酶的问答

于1991年5月下旬在昆明召开的中国蛇毒酶临床应用研讨会后,陆续收到许多读者来信,询问精制蝮蛇抗栓酶有关问题。为了能较全面地回答读者来信,采访了有关专家并做了某些调查,对几个共同问题公开做答,不专门复信,见谅。一、精制蝮蛇抗栓酶的本质是什么?答:根据昆明会议信息。精制蝮蛇抗栓酶就是原来的“江浙蝮蛇毒抗栓酶-3号”,由中国医科大学老年病防治中心在沈阳第一制药厂生产的江浙蝮蛇抗栓酶(Svate)基础上,经过两次分离所得的产物。经过动物实验及临床验证认为:毒副反应明显低于原江浙蝮蛇抗栓酶。为了区别于原江浙蝮蛇抗栓酶,已被辽宁省卫生厅批准正式批量生产。商品名称为“精制蝮蛇抗栓酶”。为什么要取消“江浙”二字,其     

大剂量精制蝮蛇抗栓酶冲击疗法治疗急性脑梗死93例

大剂量精制蝮蛇抗栓酶冲击疗法治疗急性脑梗死９３例赵世君（辽宁省锦州市太和区医院血栓科１２１００１）我们于１９９３年开始采用大剂量精制蝮蛇抗栓酶（ＡＰＩ）,治疗急性脑梗死９３例,取得了满意效果,开辟了急性脑梗死溶栓疗法,现报告如下：１临床资料１．１一般...     

蛇岛牌精制蝮蛇抗栓酶治疗Ⅱ型水病并脑梗死

目的 观察蛇岛牌精制蝮蛇抗栓酶对Ⅱ型糖尿病并脑梗死的疗效。方法 各选择１３５例Ⅱ型糖尿病并脑梗死患者为治疗组和对照组,两组患者既往史和伴发病积分无显著差异。两组均在直病后６－７２ｈ开始治疗,治疗组：用精制蝮蛇麦首剂３．０ＩＵ,每日１次,连续使用３次,隔日改为１．０ＩＵ治疗１０次,每疗程为１４天。对照组：好ｍｌ,每日１次,共１４次。治疗中行凝血指标测定、颅ＣＴ、血汉变检查及副作用观察,然后进行统计学     

蛇岛牌精制蝮蛇抗栓酶治疗Ⅱ型糖尿病并脑梗死

目的观察蛇岛牌精制蝮蛇抗栓酶对Ⅱ型糖尿病并脑梗死的疗效。方法各选择１３５例Ⅱ型糖尿病并脑梗死患者为治疗组和对照组,两组患者既往史和伴发病积分无显著差异。两组均在起病后６～７２ｈ开始治疗。治疗组：用精制蝮蛇抗栓酶首剂３．０ＩＵ,每日１次,连续使用３次,隔日改为１．０ＩＵ治疗１０次,每疗程为１４天。对照组：低分子右旋糖酐５００ｍｌ,每日１次,共１４次。治疗中行凝血指标测定、颅ＣＴ、血流变检查及副作用观察,然后进行统计学处理。结果治疗后,神经功能评分,血流变有显著差异,治疗组疗效优于对照组,无副作用。且对糖尿病并发症有很好的治疗作用,但与无糖尿病脑梗死者相比疗效略差。结论精制蝮蛇抗栓酶治疗糖尿病并脑梗死优于低分子右旋糖酐对照组,对肾脏无损害。     

蝮蛇抗栓酶治疗冠心病

应用蝮蛇抗栓酶治疗15例冠心病患者,其中12例为慢性冠心病患者,3例为急性心肌梗塞患者.治疗结果表明:治疗后心电图示心肌缺血改善者达72.7%,心脏 B 超示室壁运动改善者达80%,心阻抗血流图示 PEP/LVET 明显下降,P<0.01,CI 明显增高.P<0.05,说明蝮蛇抗栓酶具有明显的改善心肌缺血和左心室功能的作用。     

蝮蛇抗栓酶与精制蝮蛇抗栓酶制剂的比较研究

本文作者对以东北长白山白眉蝮蛇毒为原料生产的两种酶制剂——蝮蛇抗栓酶与精制蝮蛇抗栓酶进行了比较研究。用 HPLC 柱层析粗毒得到15个蛋白峰,同时对两种酶制剂以 HPLC 层析用两根层析柱串联上样层析以提高其分辩率,得到两个图谱,蝮蛇抗栓酶有7个蛋白峰,而精制品有3～4个蛋白峰.同时以 SDS-PAGE 电泳图谱.蝮蛇抗栓酶呈现7～8条谱带,精制品有4～5条谱带,并与已知分子量的标准蛋白进行对比,结果表明两种酶制剂均非单一组分.蝮蛇抗栓酶谱带较多,精制品较纯.其分子量均在2～6万之间.蝮蛇抗栓酶几个组分有协同作用,每次剂量在0.25～0.50单位,即有明显疗效,而精制品临床用药剂量较大,每次0.75～1.0单位,多者达1.25单位(3～5支).     

蝮蛇抗栓酶治疗庆大霉素中毒

应用蝮蛇抗栓酶治疗庆大霉素中毒6例,其中1例由于合并严重神经症状及应用蝮蛇抗栓酶时间延长,需8个月治愈,余5例因应用蝮蛇抗栓酶及时,两周即治愈.总之,应用蝮蛇抗栓酶治疗6例庆大霉素中毒患者均获得理想效果。     

蝮蛇抗栓酶治疗冠心病临床观察

我院用蝮蛇抗栓酶治疗冠心病３０例,取得较好的疗效,现报告如下。１　资料与方法１１　病例选择　所选病例均为１９９７年１月至１９９８年１２月我院收治的住院病人,共３０例,全部经心电图、血脂检查,所有病例均符合１９７９年ＷＨＯ公布的冠心病诊断标准。男１９例,女１１例年龄４８～７０岁,病程５～１２年,其中稳定型心绞痛１２例,不稳定型心绞病６例,并发室上性心动过速６例,陈旧性心肌梗死２例。１２　治疗方法　患者治疗前停用其它溶栓、抗凝药物、查出血时间、凝血时间、血常规、肝功能及肾功能。用药前做蝮蛇抗栓酶…     

蝮蛇抗栓酶治疗急性软组织损伤

本文试用蝮蛇抗栓酶治疗急性软组织损伤２５例进行治疗观察,同样取得较好的疗效,说明急性软组织损伤主要是局部血循环障碍,气滞血瘀,蝮蛇抗栓酶有改善血循环消肿止痛、抗炎的作用。     

Translocation of AIF in the human and rat striatum following protracted haloperidol, but not clozapine treatment

Loss of mitochondrial membrane integrity and consequent release of apoptogenic factors may be involved in mediating striatal neurodegeneration after prolonged treatment with the typical antipsychotic drug haloperidol. Apoptosis-inducing factor (AIF), an intramitochondrial protein, may have a large influence on mediating haloperidol-induced striatal neuron destruction. Translocation of this protein from mitochondria to the nucleus promotes cell death independently of the caspase cascade. To examine how AIF may contribute to haloperidol-induced apoptosis, AIF translocation was observed in three haloperidol treatment paradigms. SH-SY5Y cells were treated with both haloperidol and clozapine and examined for AIF immunofluorescence. Immunohistochemistry was also performed on human striatal sections obtained from the Stanley Foundation Neuropathology Consortium and on rat brain sections following 28 days of antipsychotic drug treatment. In the cellular model haloperidol, but not clozapine treatment increased the nuclear AIF immunofluorescent signal and decreased cell viability. Corollary to these findings, striatal sections from patients who had taken haloperidol and rats who were administered haloperidol both had an elevated nuclear AIF signal. The results provide novel evidence implicating the involvement of AIF in haloperidol-associated apoptosis and its relevance to the development of typical antipsychotic drug-related adverse effects such as tardive dyskinesia.     

Neuroleptics Up-Regulate Adenosine A2a Receptors in Rat Striatum: Implications for the Mechanism and the Treatment of Tardive Dyskinesia

Abstract: Neuroleptics, which are potent dopamine receptor antagonists, are used to treat psychosis. In the striatum, dopamine subtype-2 (D₂) receptors interact with high-affinity adenosine subtype-2 (A_2a) receptors. To examine the effect of various neuroleptics on the major subtypes of striatal dopamine and adenosine receptors, rats received 28 daily intraperitoneal injections of these drugs. Haloperidol (1.5 mg/kg/day) increased the density of striatal D₂ receptors by 24% without changing their affinity for [³H]sulpiride. Haloperidol increased the density of striatal A_2a receptors by 33% (control, 522.4 ± 20.7 fmol/mg of protein; haloperidol, 694.6 ± 23.6 fmol/mg of protein; p < 0.001) without changing their affinity for [³H]CGS-21680 (control, 19.2 ± 2.2 nM; haloperidol, 21.4 ± 2.3 nM). In contrast, haloperidol had no such effect on striatal dopamine subtype-1 (D₁) and adenosine subtype-1 (A₁) receptors. Binding characteristics and the pharmacological displacement profile of the increased [³H]CGS-21680 binding sites confirmed them as A_2a receptors. Comparing different classes of neuroleptics showed that the typical neuroleptics haloperidol and fluphenazine (1.5 mg/kg/day) increased D₂ receptor densities, whereas the atypical neuroleptics sulpiride (100 mg/kg/day) and clozapine (20 mg/kg/day) did not (control, 290.3 ± 8.7 fmol/mg of protein; haloperidol, 358.1 ± 6.9 fmol/mg of protein; fluphenazine, 381.3 ± 13.6 fmol/mg of protein; sulpiride, 319.8 ± 18.9 fmol/mg of protein; clozapine, 309.2 ± 13.7 fmol/mg of protein). Similarly, the typical neuroleptics increased A_2a receptor densities, whereas the atypical neuroleptics did not (control, 536.9 ± 8.7 fmol/mg of protein; haloperidol, 687.9 ± 28.0 fmol/mg of protein; fluphenazine, 701.1 ± 31.6 fmol/mg of protein; sulpiride, 563.3 ± 27.2 fmol/mg of protein; clozapine, 550.9 ± 40.9 fmol/mg of protein). There were no differences in affinities for [³H]CGS-21680 or [³H]sulpiride among the various treatment groups. This study demonstrates that typical neuroleptics induce comparable up-regulation in both striatal D₂ and A_2a receptors. Thus, A_2a receptors might be a pharmacologic target for the development of novel therapeutic strategies to minimize the adverse effects of antipsychotic treatment.     

The effects of electromyographic feedback training on suppression of the oral-lingual movements associated with tardive dyskinesia

The efficacy of electromyographic feedback training in reducing the magnitude and frequency of the oral-lingual movements associated with tardive dyskinesia (TD) was investigated in a groups design. Twenty adult male inpatients diagnosed as having TD using the Abnormal Involuntary Movements Scale (AIMS) were randomly assigned to one of two treatment conditions. Following identification, all participants were initially reduced to the lowest effective dosage of neuroleptics, and then discontinued from anticholinergics. Following one month on this regimen, they were given a course of feedback training consisting of ten 14-minute sessions. Group one participants were provided with a tone contingent upon oral-lingual movements above a yoked threshold. Group two participants were given noncontingent feedback tones generated randomly. Weekly AIMS were administered as well as an initial baseline during each session to determine current level of oral-lingual activity. An analysis of session effects indicated significantly more suppression of oral-lingual activity in the contingent group versus the noncontingent feedback group. Jaw and forehead activity also measured showed reductions of similar magnitudes for both groups.This work was sponsored in part by a Research Advisory Grant from the Department of Veterans Affairs awarded to Joanne Intrator. We gratefully acknowledge the valuable contributions of K. Duvvi, S. Kemble, and L. Kolman.     

原发性纤毛运动障碍一例并文献复习

目的:报道1例原发性纤毛运动障碍(primary ciliary dyskinesia,PCD)患者的临床和病理资料,总结其临床特征和诊治要点。方法:对1例可疑原发性纤毛运动障碍患者进行病史采集、体格检查、胸部X线和CT、肺功能检查、支气管镜检查及支气管黏膜活检、电镜超微病理观察、染色体检查等相关检查,确诊为原发性纤毛运动障碍。结合该例患者诊治过程进行文献分析,明确原发性纤毛运动障碍的诊治要点及注意事项。结果:该例患者具有咳嗽、喘息等呼吸道症状,胸部X线及CT提示肺部感染及脏器全反位;肺功能提示基本正常且支气管激发试验为阴性;支气管镜检查示支气管反位及支气管炎症,取黏膜活检提示支气管黏膜慢性炎症改变;超微病理发现气道上皮细胞呈现形态扁平化、纤毛极性消失、细胞内纤毛,纤毛动力臂结构未见异常;染色体检查:46,XX,400-550条带阶段未见染色体异常;确诊为原发性纤毛运动障碍。结论:原发性纤毛运动障碍临床少见且复杂多样,容易漏诊和误诊。临床症状、胸部影像学、纤毛超微结构观察以及基因检测等相关检查联合应用有助于原发性纤毛运动障碍的临床诊断和治疗。对于呼吸道感染迁延不愈并发内脏反位者,无论有无鼻窦炎和支气管扩张,均应考虑原发性纤毛运动障碍存在可能,应当及时进行呼吸道黏膜超微病理学检查,以便尽早进行诊断和干预,减少和延缓并发症的发生。     

Gray Matter Abnormalities in Schizophrenia Patients with Tardive Dyskinesia: A Magnetic Resonance Imaging Voxel-Based Morphometry Study

Objective

The pathophysiological mechanism of TD remains unknown. All previous studies, using the region-of-interest method, focused on basal ganglion areas, were with inconsistent results. This whole-brain voxel-based morphometry (VBM) study investigate the grey matter abnormality of TD and its correlates with clinical ratings.

Method

High resolution T1-weighted brain volumetric MRI from 25 schizophrenia patients with TD (TD group), 25 age-, gender-, and handedness-matched schizophrenia patients without TD (non-TD group), and 25 matched healthy subjects (NC group) were analyzed using a VBM approach. Clinical ratings included the Positive and Negative Symptom Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Scale (SAS).

Results

The TD group had significantly smaller total gray matter volumes than the NC group (p = 0.05). Compared to the non-TD group, the TD group had significantly higher PANSS negative (p<0.001), SAS (p<0.001), and AIMS (p<0.001) scores; and smaller bilateral inferior frontal gyrus, which correlated negatively with the PANSS negative scores (r = −0.366, p<0.05); and smaller right superior frontal gyrus, which correlated negatively with AIMS scores (r = −0.399, p<0.001), and PANSS general score (r = −0.338, p<0.05).

Limitations

The cross-section design can’t separate the gray matter change to TD from the context of the illness of schizophrenia, although TD with more severe clinical psychopathology could be a phenotype.

Conclusions

The schizophrenia patients with TD had significantly reduced gray matter, mostly at the bilateral inferior frontal gyrus and the right superior frontal gyrus, which correlated with severity of clinical symptoms and involuntary movement, respectively.     

Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second‐generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first‐generation antipsychotics, FGAs). As some reports questioned this notion, we meta‐analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head‐to‐head RCTs, including 32 FGA and 86 SGA arms, were meta‐analyzed, yielding 32 FGA‐SGA pairs and 35 SGA‐SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3‐7.8%) vs. 2.6% (95% CI: 2.0‐3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39‐0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28‐0.45, p<0.0001, number‐needed‐to‐treat, NNT=20). Meta‐regression showed no FGA dose effect on FGA‐SGA comparisons (Z=?1.03, p=0.30). FGA‐SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non‐clozapine SGAs in exploratory pairwise comparisons. SGA‐SGA comparisons confirmed the olanzapine advantage vs. non‐clozapine SGAs (RaR=0.66, 95% CI: 0.49‐0.88, p=0.006, k=17, NNT=100). This meta‐analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.     

Protective Effect of L-type Calcium Channel Blockers Against Haloperidol-induced Orofacial Dyskinesia: A Behavioural, Biochemical and Neurochemical Study

Haloperidol is a classical neuroleptic drug that is still in use and can lead to abnormal motor activity such as tardive dyskinesia (TD) following repeated administration. TD has no effective therapy yet. There is involvement of calcium in triggering the oxidative damage and excitotoxicity, both of which play central role in haloperidol-induced orofacial dyskinesia and associated alterations. The present study was carried out to investigate the protective effect of calcium channel blockers [verapamil (10 and 20 mg/kg), diltiazem (10 and 20 mg/kg), nifedipine (10 and 20 mg/kg) and nimodipine (10 and 20 mg/kg)] against haloperidol induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical alterations in rats. Chronic administration of haloperidol (1 mg/kg i.p., 21 days) resulted in a significant increase in orofacial dyskinetic movements and significant decrease in % retention, coupled with the marked increase in lipid peroxidation and superoxide anion generation where as significant decrease in non protein thiols and endogenous antioxidant enzyme (SOD and catalase) levels in rat brain striatum homogenates. All these deleterious effects of haloperidol were significantly attenuated by co-administration of different calcium channel blockers. Neurochemically, chronic administration of haloperidol resulted in significant decrease in levels of catecholamines (dopamine, serotonin) and their metabolites (HVA and HIAA) but increased turnover of dopamine and serotonin. Co-administration of most effective doses of verapamil, diltiazem, nifedipine and nimodipine significantly attenuated these neurochemical changes. Results of the present study indicate that haloperidol-induced calcium ion influx is involved in the pathogenesis of tardive dyskinesia and calcium channel blockers should be tested in clinical trials with nifedipine as the most promising one.     

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting

To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin–dopamine interactions in mammals. Melatonin, the hormone produced by the pineal gland atnight, influences circadian and seasonal rhythms, most notably the sleep–wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears tobe effective in the treatment of tardive dyskinesia, a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D₂ receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.