钙调素对微管组装的调节作用

利用我们建成的钙调素表达可调细胞模型－ＲＣ３细胞，对ＣａＭ高表达时微管组装行为进行了研究，当用生理剂量的地塞米松处理ＲＣ３细胞，细胞内ＣａＭ水平提高，而管蛋白浓度没有变化，造成钙调素／管蛋白比值上升，ＭＴ解聚，但同时加入ＣａＭ拮抗剂三氟拉嗪处理时，则可抑制ＭＴ的解聚，Ｃ３Ｈ１０Ｔ１／２转化细胞ＣａＭ含量的增加是引起ＭＴ解聚的主要因素，ＴＦＰ处理可恢复ＭＴ组装。ＲＣ３细胞ＣａＭ高表达导致ＭＴ解聚的实     

Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer

 Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine, could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m² per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-gp. P-gp expression was detected both in the patient who responded to vinblastine plus trifloperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in this heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop. Received: 12 January 1995/Accepted: 11 August 1995     

Trifluoperazine: A comparison between regular and high doses

A comparison between regular and high doses of Trifluoperazine (TR-60 mg and TR-600 mg) was made on 26 newly admitted schizophrenics with acute psychotic symptoms. Eleven received the regular dose of the drug (TR-60 mg) and 15 received the high dose (TR-600 mg). Treatment's duration was 6 weeks. Psychiatric evaluations were done by means of Patient Personal Data Inventory, Brief Psychiatric Rating Scale, Impatient Multidimensional Psychiatric Scale, Digit Symbol Test, Continuous Scanning, Side Effects, and Extrapyramidal Status. Almost all patients from both groups generally improved from the beginning to the end of the study with TR-, but the results provide no support for the contention that very high doses of TR-are more effective than regular doses.On sabbatical year, from the National Institute of Mental Health, Rockville, Maryland.     

三氟拉嗪诱导白血病细胞系K562分化的实验研究

目的 观察三氟拉嗪对白血病细胞系K562的诱导分化作用.方法 采用液体培养、MTT和集落培养实验观察三氟拉嗪对K562细胞增殖的影响,同时采用联苯胺染色观察细胞内血红蛋白含量变化,并采用流式细胞术检测CD71分化抗原,以评价三氟拉嗪对K562细胞的诱导分化作用.结果 三氟拉嗪可上调K562细胞膜CD71分化抗原的表达量,升高细胞内血红蛋白含量,并抑制K562细胞增殖.结论 三氟拉嗪具有诱导K562细胞分化的作用.     

Trifluoperazine: a rynodine receptor agonist

Trifluoperazine (TFP), a phenothiazine, is a commonly used antipsychotic drug whose therapeutic effects are attributed to its central anti-adrenergic and anti-dopaminergic actions. However, TFP is also a calmodulin (CaM) antagonist and alters the Ca²⁺ binding properties of calsequestrin (CSQ). The CaM and CSQ proteins are known modulators of sarcoplasmic reticulum (SR) Ca²⁺ release in ventricular myocytes. We explored TFP actions on cardiac SR Ca²⁺ release in cells and single type-2 ryanodine receptor (RyR2) channel activity in bilayers. In intact and permeabilized ventricular myocytes, TFP produced an initial activation of RyR2-mediated SR Ca²⁺ release and over time depleted SR Ca²⁺ content. At the single channel level, TFP or nortryptiline (NRT; a tricyclic antidepressant also known to modify CSQ Ca²⁺ binding) increased the open probability (Po) of CSQ-free channels with an EC₅₀ of 5.2 μM or 8.9 μM (respectively). This Po increase was due to elevated open event frequency at low drug concentrations while longer mean open events sustained Po at higher drug concentrations. Activation of RyR2 by TFP occurred in the presence or absence of CaM. TFP may also inhibit SR Ca uptake as well as increase RyR2 opening. Our results suggest TFP and NRT can alter RyR2 function by interacting with the channel protein directly, independent of its actions on CSQ or CaM. This direct action may contribute to the clinical adverse cardiac side effects associated with these drugs.     

Changes in opiate activity of rat pituitary following acute administration of neuroleptics

An increase was found in the opiate activity of pituitary extracts obtained from rats injected with the neuroleptic drugs trifluoperazine and sulpiride. The increase of opiate activity, measured by bioassay, was particularly evident 2 h after the administration of sulpiride. Dexamethasone completely prevented the neuroleptic-induced effect. Trifluoperazine and sulpiride may have affected dopaminergic mechanisms regulating endorphin storage in the pituitary.     

三氟拉嗪对癫痫大鼠NO、NOS、SOD、MDA的影响

目的探讨钙调蛋白抑制剂三氟拉嗪(TFP)对癫痫大鼠NO、NOS、SOD、MDA含量的影响。方法将SD大鼠随机分为对照组、模型组、TFP低剂量组、TFP高剂量组,模型组腹腔注射生理盐水4mL/kg、TFP低剂量组腹腔注射TFP1mg/kg、TFP高剂量组腹腔注射TFP2mg/kg,以上三组30min后腹腔注射戊四氮37.5mg/kg;对照组只予以腹腔注射生理盐水。测定大鼠海马组织NO、NOS、SOD、MDA含量。结果模型组NO、NOS、MDA含量明显升高,SOD含量明显减少,与对照组比较,差异有统计学意义(P0.01);给药后TFP低、高剂量组NO、NOS、MDA含量减少,SOD含量升高,与模型组比较,差异有统计学意义(P0.05或P0.01)。结论 TFP能增加癫痫大鼠海马组织SOD含量,减少NO、NOS、MDA含量,能减轻癫痫大鼠海马组织神经元的损伤。     

Evaluating the CANSAS self-report (CANSAS-P) as a screening instrument for care needs in people with psychotic and affective disorders

The metabolic profiles of Chinese patients treated with second-generation antipsychotic (SGA) medication and first-generation antipsychotic (FGA) medication were compared. The sample comprised 99 patients treated with SGA (risperidone, olanzapine and ziprasidone) and 99 with FGA (chlorpromazine, haloperidol and trifluoperazine) from the outpatient clinic of a teaching hospital in Hong Kong. The most frequent psychiatric diagnosis was schizophrenia, followed by affective disorder and other psychiatric diagnoses. Subjects were measured for body weight, body height, fasting lipid and glucose levels. SGA was associated with higher LDL-cholesterol level than FGA. Individual comparison of different antipsychotics showed that patients on olanzapine had the greatest increases in cholesterol and triglycerides among all antipsychotics. The finding suggested SGA, particularly olanzapine, were associated with more metabolic risk factors than first-generation antipsychotics.     

Protective effect of trifluoperazine on hydrogen peroxide-induced apoptosis in PC12 cells

This study investigated effects of trifluoperazine (TFP) against the cytotoxicity induced by H₂O₂ in PC12 cells and the mechanisms thereof. Different concentrations of H₂O₂ (100-500 μM) induced a significant decrease in cell viability accompanied by increased oxidative stress and cell apoptosis. Pretreatment with TFP inhibited H₂O₂-induced cell viability loss. The flow cytometric assay showed that TFP can inhibit intracellular reactive oxygen species (ROS) generation and reduce the cell apoptosis. The electrophysiological recordings indicated that when treated with H₂O₂, the calcium current was significantly increased. Pretreatment with TFP increased mitochondrial membrane potential (MMP) in cells of oxidative injury. These results suggested that TFP can reduce apoptosis by inhibiting ROS generation and preventing loss of MMP in cells. Meanwhile, the protective effect of TFP on the cell apoptosis may be related to the calcium overload. TFP may inhibit the calcium overload process to achieve the protection against apoptosis.