Regulatory volume decrease in Leishmania mexicana: effect of anti-microtubule drugs

The trypanosomatid cytoskeleton is responsible for the parasite's shape and it is modulated throughout the different stages of the parasite's life cycle. When parasites are exposed to media with reduced osmolarity, they initially swell, but subsequently undergo compensatory shrinking referred to as regulatory volume decrease (RVD). We studied the effects of anti-microtubule (Mt) drugs on the proliferation of Leishmania mexicana promastigotes and their capacity to undergo RVD. All of the drugs tested exerted antiproliferative effects of varying magnitudes [ansamitocin P3 (AP3)> trifluoperazine > taxol > rhizoxin > chlorpromazine]. No direct relationship was found between antiproliferative drug treatment and RVD. Similarly, Mt stability was not affected by drug treatment. Ansamitocin P3, which is effective at nanomolar concentrations, blocked amastigote-promastigote differentiation and was the only drug that impeded RVD, as measured by light dispersion. AP3 induced 2 kinetoplasts (Kt) 1 nucleus cells that had numerous flagella-associated Kts throughout the cell. These results suggest that the dramatic morphological changes induced by AP3 alter the spatial organisation and directionality of the Mts that are necessary for the parasite's hypotonic stress-induced shape change, as well as its recovery.

Comparison of the effect of non-antifungal and antifungal agents on Candida isolates from the gastrointestinal tract

Non-antifungal drugs appear promising in treatment of opportunistic infections of Candida spp. that are often resistant to current antifungals. The broth macrodilution method [NCCLS M27-P document] was used to compare the antifungal activity of trifluoperazine, pro-pranolol, and lansoprazole with that of ketoconazole and amphotericin B, using 50 yeast isolates from the Gl tract. The minimum fungicidal concentrations [MFCs], resistance rates and the time required for fungicidal activity of the drugs [2 - 48 hours] were determined. The most effective antifungal activity was exhibited by trifluoperazine. Its MFC was 32 microg/mL for Candida albicans [3.3% resistance] and Candida spp. [0% resistance] yeasts, and 64 ug/mL for Candida tropicalis with 10% resistance. The MFC for C. albicans and Candida spp. was comparable to that of ketoconazole. However, the time required for the inhibitory effect [6 hr] was shorter than that of ketoconazole [48 hr] or amphotericin B [24 hr]. The time required for the inhibitory activity on C. tropicalis was 24 hr, which was shorter than that of ketoconazole and amphotericin B [48 hr]. A considerable number [40%] of Candida spp. showed resistance to ketoconazole, and 20% of C. tropicalis showed resistance to amphotericin B. Trifluoperazine, an antipsychotic drug, exhibited effective antifungal activity with the MFC, comparable to ketoconazole [32 microg/mL]. Among the three yeast groups, C. tropicalis showed resistance to trifluoperazine and amphotericin B, and Candida spp. was considerably resistant to ketoconazole. Trifluoperazine could be considered as an alternative antifungal when encountering Candida spp. resistant to current antifungals

Adicción a biperideno y síndrome anticolinérgico: a propósito de un caso / Biperiden addiction and anticholinergic syndrome: a case report

Se reporta el caso de un paciente de 46 años de edad, con diagnóstico de esquizofrenia, en tratamiento desde los 26 años, con trifluoperazina y decanoato de flufenazina y uso concomitante de biperideno por los efectos adversos, que desarrolló dependencia al biperideno llegando a tomar, en la última semana antes de su hospitalización 14 mg diarios. El día de su ingreso tomó 20 mg, desarrollando un cuadro compatible con síndrome anticolinérgico, que se complicó con hiponatremia severa, acidosis metabólica con alcalosis respiratoria, leucocitosis, fiebre y elevación de la creatinfosfoquinasa, por lo que la impresión diagnóstica inicial fue de síndrome neuroléptico maligno. Su evolución fue favorable, saliendo de alta a la semana.

We report the case of a 46-year-old man diagnosed with schizophrenia, treated with trifluoperazine and fluphenazine decanoate since he was 26 years old, with concomitant use of biperiden for adverse effects. He developed dependence to biperiden, taking in the last week, prior to his hospitalization, 14 mg daily. The day of his admission he took 20 mg, developing an anticholinergic syndrome, complicated with severe hyponatremia, metabolic acidosis with respiratory alkalosis, leukocytosis, fever and creatine phosphokinase elevation, due to this he was initially focused as a neuroleptic malignant syndrome. He had a favorable outcome; being discharged one week later.

Antipsychotic treatment and weight gain: does risperidone behave differently in Pakistani psychiatric patients?

Studies from the Western world have shown that antipsychotic medications in psychiatric patients result in weight gain and other metabolic diseases. This study was undertaken to investigate whether any one of the five most commonly prescribed antipsychotics, [risperidone, olanzepine, trifluoperazine, quetiapine and haloperidol] could behave differently in terms of causing weight gain among patients attending the psychiatric outpatient clinics in a tertiary care hospital in Karachi, Pakistan. For this retrospective cohort study, data were collected from outpatient records of the Aga Khan University Hospital, from 2003 to 2007. Demographic and clinical data were analysed. Repeated measures ANOVA, using a linear mixed model approach was used to assess weight gain over time due to the use of antipsychotic medications. A total of 124 subject records [68 males and 56 females] were evaluated. One-way ANOVA revealed that the groups being prescribed with antipsychotics were comparable with respect to age, duration of treatment and weight measurements. Frequencies were calculated which showed that weight increases significantly over time with respect to the prescribed antipsychotic medications, except for risperidone. Repeated measures ANOVA using the linear mixed model approach showed that the serial weight measurements were significantly different across the follow up times [p<0.05]. Four of the commonly prescribed antipsychotic drugs do result in an increase in weight; however risperidone has no such effect, making it an option in treating psychiatric disorders without worrying for any gain in weight. In view of the increased prevalence of obesity and other metabolic diseases, measures should be taken towards careful prescription of antipsychotic medications

Delusión parasitaria como una expresión de trastorno psicológico asociado con la diálisis / Delusional parasitosis as an expression of the psychological disorder associated with dialysis

Se presenta una paciente de 66 años de edad, del sexo femenino con antecedentes de infarto agudo del miocardio, de salud mental e insuficiencia renal crónica terminal. Se mantuvo en tratamiento de diálisis peritoneal intermitente y se interconsultó con Psiquiatría por sentir y ver ¿bichos¿ que le caminaban por todo el cuerpo y salían por todos los orificios naturales y el del catéter de diálisis peritoneal. Las muestras de los supuestos parásitos fueron analizadas microscópicamente y en ninguna se constató su presencia, se trató de tejidos provenientes de la ropa de cama o de las prendas de vestir. Se le realizaron estudios parasitológicos seriados y en ninguno se obtuvo evidencia de una forma de vida parasitaria. El examen físico minucioso de la piel y de los orificios naturales y el examen físico neurológico no demostraron alteraciones. Después de varias valoraciones se estableció el diagnóstico de delusión parasitaria. Se le puso tratamiento con trifluoperazina y gotas florales, se actuó con terapia de grupo e individual y se obtuvo mejoría del cuadro clínico, pero sin solucionarlo completamente. En conclusión, el trastorno psicológico que presentó la paciente es secundario al proceso orgánico con afectación general que supone la insuficiencia renal crónica terminal y el tratamiento de diálisis. La insuficiencia renal crónica terminal es una enfermedad que genera múltiples factores estresantes ya sea por sus síntomas generales, la acumulación de toxinas, el tratamiento farmacológico y los efectos estresantes de la diálisis.

We presented the case of a female patient aged 66, with history of acute myocardial infarction, mental health and a end-stage chronic renal failure. She was maintained under treatment with intermittent peritoneal dialysis and an inter-consultation with the Psychiatry Service was arranged because she felt and saw bugs walking over all her body that came out from all the natural orifices and from the orifice of the catheter of the peritoneal dialysis. Samples of the supposed parasites were analysed under the microscope and they were really fabrics from bed linen or from clothes. Serial parasitological studies were conducted and there was no evidence of parasite life. In the meticulous physical examination of the skin and of the natural orifices, as well as in the neurological physical examination no alterations were found. After some assessments, she was diagnosed delusional parasitosis. The treatment included Trifluoperazine and floral drops, group and individual therapy. The clinical picture improved, but without a definitive solution. In conclusion, the psychological disorder in this patient is secondary to an organic process with general affectation caused supposedly by end-stage chronic renal failure, and the dialysis treatment. The end-stage chronic renal failure is a disease generating multiple stressing factors due to its general symptoms, the accumulation of toxins, the pharmacological treatment, and the stressing effects of dialysis.

Measurement of antioxidant activity with trifluoperazine dihydrochloride radical cation

A novel, rapid and cost-effective trifluoperazine dihydrochloride (TFPH) decolorization assay is described for the screening of antioxidant activity. A chromogenic reaction between TFPH and potassium persulfate at low pH produces an orange-red radical cation with maximum absorption at 502 nm in its first-order derivative spectrum. TFPH was dissolved in distilled water to give a 100 mM solution. The TFPH radical cation solution was made by reacting 0.5 mL of the solution with K2S2O8 (final concentration: 0.1 mM) and diluting to 100 mL with 4 M H2SO4 solution. A linear inhibition of color production was observed with linearly increasing amounts of antioxidants, with correlation coefficients (R²) ranging from 0.999 to 0.983. The antioxidant capacity of standard solutions of an antioxidant was evaluated by comparing with the inhibition curve using Trolox as the standard. Comparison of antioxidant capacity determined with this newly developed TFPH assay and with the well-known 2,2'-azinobis-[3-ethylbenzthiazoline-6-sulfonic acid] (ABTS)-persulfate decolorization assay indicated the efficacy and sensitivity of the procedure. The proposed assay is less expensive (costs about US$4 per 100 assays) and requires only 20 min for preparation of radical cation solution in comparison with ABTS assay, in which almost 12-16 h are required for preparation of a stable ABTS radical cation solution. The present assay has the advantage over ABTS assay that it can be used to measure the antioxidant activity of the samples, which are naturally found at a pH as low as 1, because the radical cation itself has been stabilized at low pH.

Effect of chemosensitizers on minimum inhibitory concentrations of fluconazole in candida albicans

To evaluate the effect of chemosensitizers on the in vitro activity of fluconazole against Candida albicans strains. Using Clinical Laboratory Standard Institute method, antifungal activity of fluconazole was determined alone and in combination with 16 chemosensitizers that included verapamil, reserpine, quinine, quinidine, gemfibrozil, lansoprazole, tamoxifen, diltiazem, desipramine, nicardipine, cyclosporine, chlorpromazine, prochlorperazine, promethazine, thioridazine, and trifluoperazine. Further studies were done using double combinations of selected chemosensitizers with fluconazole [28 combinations]. For testing combinations, half of the minimum inhibitory concentration [MIC] of each agent was selected in order to avoid the effect of the drug alone. One reference strain [ATCC90028] and one clinical isolate of C. albicans were used for testing the in vitro activity. Broth dilution method was used to determine the MICs of fluconazole and chemosensitizers. Of the 16 chemosensitizers tested, 3 exhibited in vitro activity by increasing fluconazole susceptibility to 7-fold. The MICs of the reference strain and clinical isolate for fluconazole were 5.5 and 0.55 MU g/ml, respectively, and these were reduced to 0.76 MU g/ml by gemfibrozil, 0.83 MU g/ml by quinine, and 0.76 MU g/ml by chlorpromazine in the reference strain, with MIC reduction to 0.08 MU g/ml by all three chemosensitizers in the clinical isolate. Some double combinations reduced the MIC of fluconazole to 10- to 100-fold, even when the chemosensitizers were not effective alone. The most effective double combinations were those of chlorpromazine with either reserpine or nicardipine

Effects of psychotropic drugs on the thrombin-induced liberation of arachidonate in human platelets

To compare the effects of chlorpromazine [CPZ], prochlorperazine [PCP], trifluoperazine [TFP], clozapine [CLO], haloperidol [HPD], quetiapine [QTP], pimozide [PMZ], and olanzapine [OLP] as well as the tricyclic antidepressants amitriptyline AMI, imipramine IMI, and nortriptyline NTP on thrombin-induced liberation of arachidonic acid AA in platelets. This work was carried out at the Department of Biomedicine, University of Bergen, Norway in 2006-2007. Human platelets pre labelled with [3H] arachidonate were incubated with thrombin in the absence and presence of the drugs, and the amount of free [3H] arachidonate liberated was determined. Myosin light chain [MLC] phosphorylation was determined in [32P] phosphate-labelled platelets after sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of the drugs on the molecular area and surface pressure of phospholipid monolayers were determined in the Langmuir apparatus. All drugs reduced arachidonate liberation with the ranking order of increasing potency: OLP. The mechanisms for reduction of arachidonate liberation is thought to interfere with activation of cytosolic phospholipase A2 [cPLA2] by alteration of the PLA2 phospholipid substrate structure in platelet membranes

Promoting Effect of Hydrogen Peroxide on 1-Methyl-4-phenylpyridinium-induced Mitochondrial Dysfunction and Cell Death in PC12 Cells

The promoting effect of hydrogen peroxide (H2O2) against the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+) in differentiated PC12 cells was assessed by measuring the effect on the mitochondrial membrane permeability. Treatment of PC12 cells with MPP+ resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species (ROS) and depletion of GSH. Addition of H2O2 enhanced the MPP+-induced nuclear damage and cell death. Catalase, Carboxy-PTIO, Mn-TBAP, N-acetylcysteine, cyclosporin A and trifluoperazine inhibited the cytotoxic effect of MPP+ in the presence of H2O2. Addition of H2O2 promoted the change in the mitochondrial membrane permeability, ROS formation and decrease in GSH contents due to MPP+ in PC12 cells. The results show that the H2O2 treatment promotes the cytotoxicity of MPP+ against PC12 cells. H2O2 may enhance the MPP+-induced viability loss in PC12 cells by promoting the mitochondrial membrane permeability change, release of cytochrome c and subsequent activation of caspase-3, which is associated with the increased formation of ROS and depletion of GSH. The findings suggest that H2O2 as a promoting agent for the formation of mitochondrial permeability transition may enhance the neuronal cell injury caused by neurotoxins.

Olanzapine-induced obesity and diabetes in Indian patients: a prospective trial comparing olanzapine with typical antipsychotics.

The association of hyperglycaemia and weight gain with the use of atypical antipsychotics has been documented. However, there is still not enough data from India. The fact that Indian patients usually have a lower body weight compared to European and American counterparts makes it difficult to extrapolate available data to the Indian context. The purpose of this study is: (a) To compare the prevalence of hyperglycaemia in schizophrenic patients taking olanzapine with those taking typical antipsychotics, and (b) to follow-up non-diabetic, non-obese schizophrenics on a stable regimen of antipsychotic monotherapy and determine the proportion of patients who develop weight gain, diabetes or impaired glucose tolerance; comparing the effects of olanzapine versus typical antipsychotics. Fifty-five schizophrenic patients attending psychiatry outpatients' department and on stable antipsychotic monotherapy for at least 6 weeks were included in the study. Those with a family or personal history of diabetes were excluded. There were 28 cases on olanzapine and 27 on either haloperidol or trifluoperazine. Fasting blood glucose estimation and body-mass Index (BMI) were recorded at baseline, at 6 weeks, and at 12 weeks. The two groups were comparable with respect to age, genderwise composition, and duration of illness. There was no significant difference in baseline glycaemic status or BMI. At the end of 12 weeks, olanzapine was not associated with any significant change in body weight, BMI or plasma fasting glucose. Duration of use of antipsychotic emerged as the only statistically significant risk factor for developing hyperglycaemia across both groups.

Differential Inhibition of MPP+- or 6-Hydroxydopamine-induced Cell Viability Loss in PC12 Cells by Trifluoperazine and W-7

The present study assessed the effect of calmodulin antagonists trifluoperazine and W-7 against the cytotoxicity of MPP+ and 6-hydroxydopamine (6-OHDA) in relation to the mitochondrial dysfunction and cell death in PC12 cells. Trifluoperazine (an inhibitor of the mitochondrial permeability transition and calmodulin antagonist) and W-7 (a specific calmodulin antagonist) significantly attenuated the MPP+- induced cell viability loss in PC12 cells with a maximum inhibition at 0.5~1microM; beyond these concentrations the inhibitory effect declined. Both compounds at this concentration range did not cause cell death significantly. In contrast to MPP+, the trifluoperazine and W-7 did not depress the cytotoxic effect of 6-OHDA. Addition of trifluoperazine and W-7 inhibited the cytosolic accumulation of cytochrome c and caspase-3 activation in PC12 cells treated with MPP+ and attenuated the formation of reactive oxygen species and the depletion of GSH, whereas both compounds did not reduce the effect of 6-OHDA. The results show that trifluoperazine and W-7 may attenuate the cytotoxicity of MPP+ by inhibition of the mitochondrial permeability transition and calmodulin. Meanwhile, the cytotoxic effect of 6-OHDA seems to be mediated by the actions, which are different from MPP+.

Photo-oxidative damage to isolated rat liver mitochondria induced by phenothiazines

Photosensitization is a well-known side-effect of phenothiazines that could involve photochemically promoted oxidative damage to mitochondria, leading to the impairment of metabolic functions and apoptosis. In this work, for the first time, we investigated the effects of photoexcited thioridazine (TR), trifluoperazine (TFP) and fluphenazine (FP) on isolated rat liver mitochondria. Under UV irradiation, the presence of these phenothiazines led to a dose-dependent lack of the respiratory control ratio. These effects were not accompanied by significant swelling and oxidation of protein thiol groups but were accompanied by lipid peroxidation. Lycopene and sorbate, well-known quenchers of singlet oxygen and triplet species, respectively, were ineffective at protecting mitochondrial lipids against the damage promoted by the excited phenothiazines, suggesting that photochemically-produced cation radicals were the pro-oxidant species. Corroborating this proposal, butylated hydroxytoluene (BHT) completely inhibited the lipid peroxidation induced by UV irradiation in the presence of phenothiazines. These novel results make a significant contribution to the understanding of the photochemical properties of phenothiazines in biological systems

Implication of Egr-1 in trifluoperazine-induced growth inhibition in human U87MG glioma cells

The early growth response gene-1 (Egr-1) is a tumor suppressor which plays an important role in cell growth, differentiation and apoptosis. Egr-1 has been shown to be down-regulated in many types of tumor tissues. Trifluoperazine (TFP), a phenothiazine class of antipsychotics, restored serum-induced Egr-1 expression in several cancer cell lines. We investigated the effect of Egr-1 expression on the TFP-induced inhibition of cell growth. Ectopic expression of Egr-1 enhanced the TFP-induced antiproliferative activity and downregulated cyclin D1 level in U87MG glioma cells. Our results suggest that antipsychotics TFP exhibits antiproliferative activity through up-regulation of Egr-1.

Mania e gravidez: implicações para o tratamento farmacológico e proposta de manejo / Mania and pregnancy: issues related to pharmacologic treatment and management proposal

O tratamento de doenças psiquiátricas na gravidez é complexo, implicando decisões clínicas difíceis, sem contar-se com dados da literatura que embasem aplamente estas decisões. O transtorno afetivo bipolar é comum em mulheres em idade fértil, e há alto risco de ocorrência de manifestações clínicas na gravidez e no período pós-parto. Os autores revisam o conhecimento atual sobre o uso de psicotrópicos para episódio maníaco na gravidez e o efeito no desenvolvimento fetal e da criança. Enfatizam que, hoje, o uso de psicotrópicos na gravidez é apropriado em muitas situações clínicas, mas nenhuma decisão é completamente isenta de risco. Também apresentam uma proposta de manejo da doença em relação ao uso de psicotrópicos na gravidez, para pacientes com transtorno bipolar, e para aquelas que desejam engravidar.

Premenstrual manic disorder: review of literature, case report and the efficacy of trifluoperazine

A selective review of literature revealed only a few case reports of premenstrual mania, hereto referred as premenstrual manic disorder [PMMD]. The anamnesis of a woman who developed manic episodes, one week before each menstrual cycle that used to remit after the onset of menstruation, is described. The continuing use of trifluoperazine satisfactorily improved her premenstrual manic symptoms and also prevented the subsequent premenstrual manic relapses. In addition to proposing tentative research criteria of PMMD, its underlying etiological mechanisms together with treatment perspectives are discussed comprehensively

Construction and expression of anti-CD3/ anti-Pgp Diabody / 生物工程学报

The use of tumor antigen specific antibodies for the delivery of therapeutic agents offers the possibility of targeting therapy with reduced toxicity to normal tissues compared to conventional treatments. However, several factors restrict the use of anti-PGP monoclonal antibodies(Mabs). First, Pgp is expressed in normal tissues, particularly in epithelial and endothelial cells of the gastrointestinal tract, liver, kidney, blood brain barrier, choroids plexus and other organs. It plays a significant role to transport drugs and toxins in these organs. Therefore, anti-PGP antibodies in combination with cytotoxic compounds or radiolabelled antibodies should neither inhibit the activity of PGP, nor harm the cells which expressed PGP normally. BiMab exploit the specificity of Mab and ensures activation of cellular cytotoxic mechanisms which kill tumor cells only, but not harm normal cells. It will provide a strategy for resistant cancer therapy using anti-PGP antibodies. Second, Repeated administration of murine antibodies generates a strong human anti-mouse immune (HAMA) response in up to 50% of patients after the first dose, and appro ximately 90% following a second treatment. In an effort to reduce the toxicity and antigenicity, we focus to produce anti-PGP antibodies which have the binding activity only, but not inhibit the function of the "pump", and to construct a small and partially humanized recombinant molecule with dual specificity for both PGP and CD3 complex to activate the host immune response toward the tumour. PCR and overlap PCR were used to construct anti-CD3/ anti-Pgp Diabody. DNA sequence was analyzed by the Terminus of Dideoxy Nucleotide. The product was purified by affinity chromatography and analyzed by both the detection of western blot and size exclusion chromatography; its antigen-binding activity was examined by FACS, cellular RIA. Plasmid pAYZDCP which expressed the anti-CD3/anti-Pgp Diabody was constructed correctly. The diabody was recovered in high yield( up to 2mg/ L) after E-taq purification and predominantly(90%) as a dimer. The diabody can bind to Jurkat cells (CD3+) and K562/A02 cells(Pgp+). The affinities of the diabody were similar with the anti-CD3 ScFv or anti-Pgp ScFv, respectively. The anti-CD3/ anti-Pgp BsF(ab')2 was first recast into the diabody format and succeeded to obtain high level expression. The results of some biological activity experiments indicated that the diabody could bind to Jurkat cells and K562/A02 cells. Multidrug resistance can be reversed experimentally by a variety of drugs, among which the best known are verapamil and trifluoperazine, which unfortunately are of limited use in practice due to severe collateral cardiac toxicity. Anti-PGP x anti-CD3 diabody will provide another therapeutic strategy against multidrug resistance cancer.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: II - fenotiazinas piperazínicas / Fifty yearts of antipsychotic drugs in psychiatry: II - piperazine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica, com a redescoberta da clozapina e a introduçäo de novos antipsicóticos atípicos, é feito um balanço sistemático das substância desenvolvidas nos últimos 50 anos. As substâncias introduzidas até o presente säo reunidas nos grupos-tioxantênicos com estrutura aparentada às fenotiazinas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzamidas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - dibenzodiazepinas, benzisoxazólicos, tienobenzodiazepinas, dibenzotiazepinas, benzisotiazólicos, didroindolonas, imidazolidinonas -, além de compostos ainda em desenvolvimento. Neste artigo, o segundo da série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperazínica, carfenazina, clorimpifenina, dixirazina, flufenazina, metofenazina, oxaflumazina, perazina, perfenazina, proclorperazina, tietilperazina, tiopropazato, tioproperazina e trifluperazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento cientíco acumulado através da experimentaçäo e da utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes fantasia e códigos de cada composto, além de dados sobre sua eventual comercializaçäo no país

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: I. fenotiazinas alifáticas / Fifty years of antipsychotic drugs in psychiatry: I. aliphatic phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo de novos antipsicótivos atípicos, é feito um balanço sistemático das substâncias desenvolvidas nos últimos 50 anos, após breve histórico dos antecedentes e dos primórdios dos antipsicóticos tradicionais da era que se encerra. As substâncias introduzidas até o presente säo reunidas nos grupos químicos tradicionais - fenotiazinas (alifáticas, piperazínicas, piperidínicas e outros compostos näo-tioxantênicos com estrutura aparentada às fenotiazinas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzamidas, indóis, dibenzoxazepinas - e em grupos químicos mais recentes - dibenzodiazepinas, benzisoxazólicos, tienobenzodiazepinas, dibenzotiazepinas, benzisotiazólicos, didroindolonas, imidazolidinonas -, além de compostos ainda em desenvolvimento. Neste primeiro artigo de uma série com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral alifática, com utilidade na prática clínica ou de importância histórica: acepromazina, alimemazina, ciamemazina, clorpromazina, levomepromazina, metopromazina, promazina, prometazina e triflupromazina. Com base em bibliografia específica, säo discutidos aspectos técnicos e é revisado o conhecimento obtido através da experimentaçäo e da utilizaçäo clínica destes derivados, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre sua fórmula estrutural, fórmula molecular, nomes químicos, nomes fantasia e códigos para cada composto, além de dados sobre eventual comercializaçäo no país

Effect of serum and hydrogen peroxide on the Ca2+/calmodulin-dependent phosphorylation of eukaryotic elongation factor 2(eEF-2) in Chinese hamster ovary cells

Eukaryotic elongation factor eEF-2 mediates regulatory steps important for the overall regulation of mRNA translation in mammalian cells and is activated by variety of cellular conditions and factors. In this study, eEF-2 specific, Ca2+/CaM-dependent protein kinase III (CaM PK III), also called eEF-2 kinase, was examined under oxidative stress and cell proliferation state using CHO cells. The eEF-2 kinase activity was determined in the kinase buffer containing Ca2+ and CaM in the presence of eEF-2 and [gamma-32P] ATP. The eEF-2 kinase activity in cell lysates was completely dependent upon Ca2+ and CaM. Phosphorylation of eEF-2 was clearly identified in proliferating cells, but not detectable in CHO cells arrested in their growth by serum deprivation. The content of the eEF-2 protein, however, was equivalent in both cells. Using a phosphorylation state-specific antibody, we show that oxidant such as H2O2, which triggers a large influx of Ca2+, dramatically enhances the phosphorylation of eEF-2. In addition, H2O2-induced eEF-2 phosphorylation is dependent on Ca2+ and CaM, but independent of protein kinase C. In addition, okadaic acid inhibits phosphoprotein phosphatase 2A(PP2A)-mediated eEF-2 dephosphorylation. These results may provide a possible link between the elevation of intracellular Ca2+ and cell division and suggest that phosphorylation of eEF-2 is sensitive cellular reflex on stimuli that induces intracellular Ca2+ flux.