喹硫平早期辅助治疗对首诊强迫症患者脱落率的影响

目的:研究早期联合喹硫平( quetiapine,QUE)治疗对首诊强迫症(obsessive-compulsive disorder,OCD)药物治疗脱落率的影响.方法:对146例门诊首诊并且接受5-羟色胺再摄取抑制剂 (selective serotonin reuptake inhibitors ,SSRIs)治疗的OCD患者进行回顾性研究,调查一般资料、治疗前症状自评量表(SCL-90)评分、首诊药物方案、脱落情况,按照首诊药物方案分为SSRIs组(108例)和SSRIs+QUE组(38例).脱落定义为在12周之前终止治疗.通过二元Logistic回归分析了解脱落的影响因素.结果:首诊SSRIs+QUE组的脱落率为34.2％(13/38),SSRIs组脱落率为70.4％(76/108),差异具有统计学意义(x2=15.44,P＜0.01).回归分析结果显示,脱落的发生和首诊药物方案、治疗前强迫症状严重程度相关,首诊联合喹硫平治疗可降低脱落率(Wals=10.041,P＜0.01),治疗前强迫症状轻的患者更容易发生脱落(Wals=8.196,P＜0.01).结论:首诊联合喹硫平可降低OCD患者的脱落率,使得更多的患者从随后的治疗中获益.     

Fluvoxamine: a selective serotonin re-uptake inhibitor for the treatment of obsessive-compulsive disorder

Fluvoxamine is the selective serotonin re-uptake inhibitor with the largest database in the treatment of obsessive-compulsive disorder, a severe, and often chronic, anxiety disorder associated with substantial impairment in functioning. The selective serotonin re-uptake inhibitors represent a first-line treatment in patients with obsessive-compulsive disorder. These agents work primarily by blocking the re-uptake of serotonin into the presynaptic nerve terminal, which is believed to be mediated by their effects on the serotonin transport system. In the last two decades, the anti-obsessional effect of fluvoxamine has been tested in several double-blind, placebo-controlled and active-comparison studies, demonstrating its superior efficacy over obsessions and compulsions compared with non-serotonergic antidepressants (i.e., desipramine) and equal efficacy to clomipramine (a tricyclic antidepressant with potent serotonin re-uptake inhibition) and other selective serotonin re-uptake inhibitors (paroxetine and citalopram). However, compared with clomipramine, the selective serotonin re-uptake inhibitor fluvoxamine showed fewer side effects and better tolerability. This reflects the poor affinity of this compound for adrenergic, muscarinic, cholinergic or histaminergic receptors.     

帕罗西汀联合针刺治疗难治性强迫症的对照研究

目的 探讨针刺治疗难治性强迫症患者的临床效果和安全性.方法 将60例难治性强迫症患者随机分为研究组(帕罗西汀+针刺,n=30)和对照组(帕罗西汀,n=30)进行治疗,疗程为8周.采用耶鲁-布朗强迫症状评定量表(Y-BOCS)、汉密尔顿抑郁量表(HAMD)评价两组疗效;采用副作用量表(TESS)评价两组安全性.结果 研究组和对照组有效率分别为80.0％和66.7％,差异有统计学意义(P＜0.05);治疗后,研究组Y-BOCS、HAMD评分下降更明显(P＜0.01);两组在治疗过程中出现的副作用比较,差异无统计学意义(P＞0.05).结论 针刺合并帕罗西汀治疗难治性强迫症可提高疗效,且安全性好,值得进一步推广应用.     

舍曲林与氯米帕明治疗难治性强迫症对照研究

目的探讨舍曲林与氯米帕明治疗难治性强迫症的疗效和不良反应。方法对难治性强迫症60例,随机分为两组,分别用舍曲林与氯米帕明治疗8周。采用强迫症量表（Y-BOCS）和副反应量表（TESS）评价疗效及不良反应。结果两药的总体疗效相仿。舍曲林不良反应小,尤其是心血管系统及抗胆碱能不良反应少。结论舍曲林尤适用于难治性强迫症。     

Delayed obsessive-compulsive disorder symptom exacerbation after a single dose of a serotonin antagonist in fluoxetine-treated but not untreated patients

Enhanced serotonergic transmission may underlie therapeutic effects of serotonin reuptake inhibitors in obsessive-compulsive disorder. However, such treatment may decrease serotonin receptor responsivity. We investigated whether the serotonin antagonist metergoline would exacerbate or further improve systems in fluoxetine-responsive patients. Pilot results suggested open metergoline produced delayed symptom worsening in fluoxetine-treated patients. Fourteen patients continuing fluoxetine received metergoline and placebo (double-blind, randomized). Symptom ratings continued for 1 week afterwards. Ten unmedicated patients underwent the same procedures. Symptoms improved 4 h after both metergoline and placebo. The day after metergoline but not placebo, fluoxetine-treated patients had significantly increased anxiety, obsessions and compulsions, abating over several days. Depression was unchanged. Metergoline had no similar delayed effects in unmedicated patients. Metergoline levels were higher in fluoxetine-treated patients. These results, consistent with less conclusive earlier findings, suggest that prolonged changes in brain serotonin function underlie symptom re-emergence following administration of metergoline to fluoxetine-treated patients with obsessive-compulsive disorder. Received: 24 November 1997/Final version: 21 April 1998     

N-acetylcysteine attenuates dimethylnitrosamine induced oxidative stress in rats

Oxidative stress has been implicated in the pathogenesis and progression of various hepatic disorders and hence screening for a good hepatoprotective and antioxidant agent is the need of the hour. The present study was aimed to investigate the hepatoprotective and antioxidant property of N-acetylcysteine (NAC) against dimethylnitrosamine (DMN) induced oxidative stress and hepatocellular damage in male Wistar albino rats. Administration of single dose of DMN (5 mg/kg b.w.; i.p.) resulted in significant elevation in the levels of serum aspartate transaminase and alanine transaminase, indicating hepatocellular damage. Oxidative stress induced by DMN treatment was confirmed by an elevation in the status of lipid peroxidation (LPO) and reduction in the activities of enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and in the levels of non-enzymic antioxidants, reduced glutathione, vitamin-C and vitamin-E in the liver tissue. DMN induced oxidative stress and hepatocellular membrane instability was further substantiated by a decline in the status of the membrane bound ATPases in the liver tissue. Post-treatment with NAC (50 mg/kg b.w.; p.o.) for 7 days effectively protected against the DMN induced insult to liver by preventing the elevation in the status of the serum marker enzymes and LPO, and restoring the activities of both the enzymic and non-enzymic antioxidants and membrane bound ATPases towards normalcy. These results demonstrate that NAC acts as a good hepatoprotective and antioxidant agent in attenuating DMN induced oxidative stress and hepatocellular damage.     

The selective serotonin reuptake inhibitor paroxetine is effective in more generalized and in less generalized social anxiety disorder

RATIONALE: The DSM-IV includes the specifier "generalized" to refer to social anxiety disorder (social phobia) patients if the fears include "most social situations". The focus on interventions such as the selective serotonin reuptake inhibitors (SSRIs) for generalized social anxiety disorder arguably runs the risk that inadequate treatment will be provided to patients with the non-generalized or discrete subtypes. There are, however, few data to address whether more generalized and less generalized subgroups of social anxiety disorder differ in response to medication. OBJECTIVE: To compare response of more generalized and less generalized social anxiety disorder to pharmacotherapy. METHODS: Data from three randomized placebo-controlled double-blind multicenter trials of the SSRI paroxetine in social anxiety disorder were pooled. Response on the Clinical Global Impression Global Improvement item was analyzed using logistic regression, and change in total Liebowitz Social Anxiety Score was analyzed using analysis of variance, with both models incorporating treatment (paroxetine vs placebo), subgroup (more generalized vs less generalized), demographic, and clinical variables. RESULTS: The prevalence of more generalized social anxiety disorder was higher in females than in males. However, there was no significant difference in terms of age or clinical characteristics (duration of condition, baseline pulse, mean arterial blood pressure). At treatment endpoint there were significant treatment effects (for paroxetine vs placebo), but no significant subgroup effects (for more generalized vs less generalized). CONCLUSIONS: Although the current database is limited insofar as few patients with discrete social anxiety disorder would have been included, it is helpful in addressing the value of medication for patients lying on the spectrum from generalized to non-generalized and discrete social anxiety disorder. Paroxetine was effective in both more generalized and in less generalized social anxiety disorder.     

Paracetamol-induced hepatotoxicity: Lack of enhancement of the hepatoprotective effect of N-acetylcysteine by sodium sulphate

The potential role of sodium sulphate in possible enhancement of the hepatoprotective action of N-acetylcysteine (NAC) in paracetamol (PCM) overdose was examined. The effects of sodium sulphate (200 mg/kg) in combination with NAC (400 mg/kg) administered intraperitoneally 2 h post-PCM dose, on mortality rate and plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were investigated in mice 24 h after receiving a single oral dose of 400 mg/kg PCM. In addition, the effect on the mortality rate of PCM-treated animals of co-administering 400 mg/kg sodium sulphate with NAC (200 or 400 mg/kg) was also studied. NAC alone caused a marked reduction in the mortality rate of PCM-treated mice and a sharp drop in their plasma AST and ALT activities to near normal values. However, no additional reduction in plasma levels of AST and ALT was observed when sodium sulphate was co-administered with NAC. Similarly, sodium sulphate (200 mg/kg) administered alone to PCM-treated mice had no effect on the high mortality rate or the elevation in plasma AST and ALT activities observed in these animals. Furthermore, increasing the dose of sodium sulphate to 400 mg/kg did not influence the mortality rate. It is therefore concluded that sodium sulphate neither protects against paracetamol-induced hepatotoxicity nor enhances the hepatoprotective action of N-acetylcysteine.     

N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression

The circulatory inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is increased in pathological conditions, such as diabetes, which initiate or exacerbate vascular endothelial injury. Both nitric oxide (NO) and reactive oxygen species may play a dual role (i.e., inhibiting or promoting) in TNF-alpha-induced endothelial cell apoptosis. We investigated the effects of the antioxidant N-acetylcysteine on TNF-alpha-induced apoptosis in human vascular endothelial cell (cell line ECV304) apoptosis, NO production and lipid peroxidation. Cultured vascular endothelial cell (ECV304) were either not treated (control), or treated with TNF-alpha (40 ng/ml) alone or TNF-alpha in the presence of N-acetylcysteine at 30 mmol/l or 1 mmol/l, respectively, for 24 h. Cell viability was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was assessed by flow cytometry. TNF-alpha-induced endothelial cell apoptosis was associated with increased inducible NO synthase but reduced endothelial NO synthase (eNOS) protein expression. NO production and the levels of the lipid peroxidation product malondialdehyde were concomitantly increased. Treatment with NAC at 30 mmol/l restored eNOS expression and further increased NO production as compared to TNF-alpha alone, resulting in improved cell viability and reduced apoptosis. This was accompanied by increased superoxide dismutase activity, increased glutathione peroxidase production and reduced malondialdehyde levels. N-acetylcysteine at 1 mmol/l, however, did not have significant effects on TNF-alpha-induced endothelial cell apoptosis and cell viability despite it slightly enhanced glutathione peroxidase production. N-acetylcysteine attenuation of TNF-alpha-induced human vascular endothelial cell apoptosis is associated with the restoration of eNOS expression.     

乙酰半胱氨酸对四氯化碳诱导的原代培养大鼠肝细胞损伤的保护作用

目的观察乙酰半胱氨酸（NAC）对四氯化碳（CCl4）诱导的原代培养大鼠肝细胞损伤的作用。方法在24孔细胞培养板上,用CCl4诱导原代培养肝细胞损伤,分别加入不同浓度的NAC,培养20 h后,测定上清液谷草转移酶（AST）活性,并MTT法检测细胞活力。结果 NAC在100μmol.L-1内,对正常培养的大鼠肝细胞没有影响;在4～100μmol.L-1内,NAC能剂量依赖性地抑制CCl4诱导的肝细胞活性的降低,EC50约为20μmol.L-1;当浓度为100μmol.L-1时,可以逆转CCl4诱导的肝损伤,使肝细胞释放AST降到接近正常水平,并明显改善肝细胞形态学变化。结论 NAC对CCl4诱导的肝损伤具有保护作用。     

阿立哌唑合并5-羟色胺再摄取抑制剂与氯米帕明治疗5-羟色胺再摄取抑制剂无效强迫障碍的临床对照研究

目的探索5-羟色胺再摄取抑制剂(SSRIs)治疗无效的强迫障碍的治疗方案。方法将73例强迫障碍患者随机分为3组:(1)增效剂组26例,在原用SSRIs药物剂量不变的基础上加用阿立哌唑治疗,起始量为5 mg·d~(-1),最大剂量不超过20 mg·d~(-1);(2)换药组24例,停用SSRIs药,换为氯米帕明单药治疗,初始剂量50～75 mg·d~(-1),逐渐增加至150～225 mg·d~(-1);(3)对照组23例,继续使用原SSRIs药单药治疗。疗程均为12 wk。用Yale-Brown强迫量表(Y-BOCS)、大体评定量表(GAS)评定疗效,并观察不良反应。结果治疗wk 8、wk 12末增效剂组和换药组Y-BOCS、Y-BOCS强迫思维、Y-BOCS强迫行为和GAS评分均无显著差异(P>0.05)。治疗wk 12末,增效剂组4项评分均与对照组有非常显著差异(P<0.01),换药组除Y-BOCS强迫思维外其余3项评分与对照组比较均有显著差异(P<0.01)。增效剂组、换药组和对照组显效率分别为50%、38%、13%:换药组和增效剂组显效率无显著差异(x~2=0.79,P>0.05),增效剂组和对照组有非常显著差异(x~2=7.58,P<0.01),换药组和对照组相比无显著差异(x~2=3.70,P=0.055)。换药组不良反应发生率和增效剂组相比无显著差异(P>0.05);2组和对照组相比,均有显著差异(P<0.05)。结论对于SSRIs治疗效果不理想的强迫障碍,可使用阿立哌唑增效或换为氯米帕明作为候选的治疗方案,二者疗效和安全性相近。     

Toxicity and oxidative stress of acrylonitrile in rat primary glial cells: preventive effects of N-acetylcysteine

Brain is a target organ for acrylonitrile (ACN) toxicity. The objective of the current work was to investigate ACN cytotoxicity in rat primary glial cells, using N-acetyl-l-cysteine (NAC) as a potential protective agent. Cells were exposed in vitro to different concentrations of ACN for different time intervals. Cell membrane integrity was assessed by trypan blue exclusion and lactate dehydrogenase (LDH) leakage. Approximately 50% membrane damage was observed in the incubations containing 1.0mM ACN for 3h. Therefore, these experimental conditions were used in subsequent studies. ACN enhanced lipid peroxidation, as indicated by malondialdehyde (MDA) accumulation, and depleted reduced glutathione (GSH) level with no change in total glutathione. Also, ACN was activated to cyanide (CN(-)) with dramatic decrease in ATP level. Cell treatment with NAC prior to exposure to ACN afforded some protection; as indicated by reducing MDA level and elevating level of both reduced and total glutathione. Further, pretreatment with NAC inhibited CN(-) formation and caused an increase in ATP level. Our results indicate that ACN is toxic to rat primary glial cells as evidenced by induction of oxidative stress and generation of CN(-) with subsequent energy depletion. NAC can play an important role against ACN-induced oxidative damage.     

Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder

Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT_1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT_1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT_1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT_1A receptor-effector system complex possibly involving subsensitivity of the 5-HT_1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT_1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.Part of this work was presented at the 17th Congress of the CINP, Kyoto, Japan, September 10–14, 1990     

The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine

In the past decade, clinical evidence has increasingly shown that the liver is a target organ for 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") toxicity. The aims of the present in vitro study were: (1) to evaluate and compare the hepatotoxic effects of MDMA and one of its main metabolites, N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and (2) to investigate the ability of antioxidants, namely ascorbic acid and N-acetyl-L-cysteine (NAC), to prevent N-Me-alpha-MeDA-induced toxic injury, using freshly isolated rat hepatocytes. Cell suspensions were incubated with MDMA or N-Me-alpha-MeDA in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 3 h. To evaluate the potential protective effects of antioxidants, cells were preincubated with ascorbic acid in the final concentrations of 0.1 and 0.5 mM, or NAC in the final concentrations of 0.1 and 1 mM for 15 min before treatment with 1.6 mM N-Me-alpha-MeDA for 3 h (throughout this incubation period the cells were exposed to both compounds). The toxic effects were evaluated by measuring the cell viability, glutathione (GSH) and glutathione disulfide (GSSG), ATP, and the cellular activities of GSH peroxidase (GPX), GSSG reductase (GR), and GSH S-transferase (GST). MDMA induced a concentration- and time-dependent GSH depletion, but had a negligible effect on cell viability, ATP levels, or on the activities of GR, GPX, and GST. In contrast, N-Me-alpha-MeDA was shown to induce not only a concentration- and time-dependent depletion of GSH, but also a depletion of ATP levels accompanied by a loss in cell viability, and decreases in the antioxidant enzyme activities. For both compounds, GSH depletion was not accompanied by increases in GSSG levels, which seems to indicate GSH depletion by adduct formation. Importantly, the presence of ascorbic acid (0.5 mM) or NAC (1 mM) prevented cell death and GSH depletion induced by N-Me-alpha-MeDA. The results provide evidence that MDMA and its metabolite N-Me-alpha-MeDA induce toxicity to freshly isolated rat hepatocytes. Oxidative stress may play a major role in N-Me-alpha-MeDA-induced hepatic toxicity since antioxidant defense systems are impaired and administration of antioxidants prevented N-Me-alpha-MeDA toxicity.     

Serum and lung levels of thiamphenicol after administration of its glycinate N-acetylcysteinate ester in experimentally infected guinea pigs

Thiamphenicol is an analogue of chloramphenicol and is characterised by a broad spectrum of action. In this study, serum and lung levels of thiamphenicol (TAP) were studied in infected guinea pigs after the administration of thiamphenicol glycinate N-acetylcysteinate (TGA). Animals received a single dose of TGA (15 mg/kg, subcutaneously) immediately after intra-tracheal infection with Haemophilus influenzae (about 10⁷ CFU/animal). Serum and lung concentrations of TAP were determined at 0, 1, 3, 6, 12 and 24 h after drug administration by means of HPLC. TAP serum levels were elevated at 1 h and remained detectable for 24 h after drug administration. Tissue lung levels were comparable to peak serum concentrations but remained higher and decreased more slowly than serum concentrations.     

Ondansetron augmentation in patients with obsessive-compulsive disorder who are inadequate responders to serotonin reuptake inhibitors: Improvement with treatment and worsening following discontinuation

Object: The aim of this study was to evaluate low-dose ondansetron as an augmentation strategy in patients with obsessive-compulsive disorder (OCD) who do not adequately respond to serotonin reuptake inhibits (SRIs). Methods: Twenty-one OCD patients who had not responded adequately to an SRI received 12 weeks of single-blind ondansetron augmentation initiated at 0.25 mg BID for 2 weeks, and titrated to 0.5 mg BID for an additional 10 weeks. Patients were rated every two weeks using the Yale–Brown Obsessive Compulsive Scale (YBOCS) and Clinical Global Impressions Scale (CGI). Treatment response was defined as an additional 25% reduction in YBOCS score from the score at the initiation of ondansetron augmentation, an end of treatment YBOCS score of ≤24 and a CGI-Improvement (CGI-I) score of ≤2. Upon completion of treatment course patients were followed for 4 weeks. Results: At week 12, twelve of the 21 (57%) patients were responders. The average reduction in the YBOCS score for the overall group was 27.2%. Responders had an average 44% YBOCS score reduction and 76.9% CGI-I reduction. After discontinuation of ondansetron the YBOCS worsened an average of 15.5% in the entire sample and 38.3% in the responder subsample. No clinically meaningful side effects were reported. Conclusion: OCD patients who do not adequately respond to an SRI may benefit from augmentation with a low-dose of ondansetron. This may provide an alternative approach to augmentation with atypical antipsychotic agents, with a more favorable safety profile.     

Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells

An animal study in rats and a cell culture study in normal human lung epithelial cells were conducted to evaluate the efficacy of N-acetyl-l-cysteine (NAC) in paraquat intoxication and associated inflammatory and oxidative stress. The effectiveness of post treatment was measured by the change of mortality rates and markers of oxidative stress, including glutathione, malondialdehyde and superoxide anion production. In addition, the levels of nitric oxide were also examined in both animal and cell culture system. NAC treatment does significantly increase the probability of survival in paraquat-intoxicated rats. It can suppress the serum malondialdehyde levels and production of superoxide anions, and conversely, augment total glutathione concentrations in all studying tissues significantly. Moreover, NAC treatment post in paraquat intoxication could reduce destruction of lung tissue, showing less inflammatory cell infiltration in interstitial stroma and mild vascular congestion. The levels of nitrite in serum and BALF were lower than those of the PQ-treated rats. Similarly, levels of iNOS expression and nitrite formation were significantly lower in normal human lung epithelial cells treated with PQ and NAC than PQ-treated alone cells.