Chlorpromazine, an Inverse Agonist of D1R-Like, Differentially Targets Voltage-Gated Calcium Channel (CaV) Subtypes in mPFC Neurons.

The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal CaV conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces CaV2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits CaV1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect CaV2.1, CaV2.3, or CaV3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain.

Constitutive activity of the dopamine (D5 ) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV 3.2 and CaV 3.3 currents.

BACKGROUND AND PURPOSE: CaV 3.1-3 currents differentially contribute to neuronal firing patterns. CaV 3 are regulated by G protein-coupled receptors (GPCRs) activity, but information about CaV 3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV 3 functionality. D5 recpetor and CaV 3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. EXPERIMENTAL APPROACH: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV 3.1-3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1 /D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV 3 currents and excitability parameters using the patch-clamp technique. We completed our study with computational modelling and imaging technique. KEY RESULTS: We found a higher sensitivity to TTA-P2 (CaV 3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine-treated animals compared with vehicle-treated animals. We found that CaV 3.2 and CaV 3.3-but not CaV 3.1-are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine-treated animals in comparison with vehicle-treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV 3 currents levels. CONCLUSIONS AND IMPLICATIONS: Native hippocampal CaV 3 and recombinant CaV 3.2-3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.

Bilateral ocular deposit of chlorpromazine / Depósito ocular bilateral de clorpromazina

ABSTRACT Chlorpromazine is a medication widely used in psychiatry for the treatment of psychoses, especially schizophrenia. Since 1964, published articles have been correlating this medication with the appearance of ocular alterations. In this paper, we report the case of a 65-year-old patient with ocular effects due to long-term therapy with chlorpromazine. Biomicroscopy of both eyes presented diffuse granular brown deposits, most prominent at the deep stroma and corneal endothelium level. Also showed anterior subcapsular brown deposits with a stellate pattern in the lens. The total amount exceeds 2.000g (significant for the ocular alterations described) considering the patient's daily dosage of chlorpromazine of 300mg for ten years. After performing complete ophthalmic evaluation and discarding other causes for the ocular deposits, we diagnosed a secondary corneal deposit and cataract due to the use of chlorpromazine. This case reinforces the importance of periodic follow-up with an ophthalmologist for chlorpromazine users to trace ocular changes, heeding the exposure time and its dosage.

RESUMO A clorpromazina é uma medicação muito empregada na psiquiatria para tratamento de psicoses, especialmente em casos de esquizofrenia. Desde 1964 existem artigos publicados que correlacionam o uso dessa medicação com o aparecimento de alterações oculares. Neste trabalho, relatamos o caso de um paciente de 65 anos com efeitos oculares devido à terapia de longo prazo com clorpromazina. A biomicroscopia de ambos os olhos apresentou depósitos granulares difusos e de cor marrom, mais proeminente ao nível do estroma profundo e do endotélio da córnea, além de depósitos castanhos subcapsulares anteriores centrais em um padrão estrelado no cristalino. Considerando a dose diária de clorpromazina de 300mg por 10 anos usada pelo paciente, a quantidade total ultrapassa 2.000g (dose considerada significativa para as alterações oculares descritas). Após avaliação oftalmológica completa e descartado outras causas desses depósitos oculares, foram diagnosticados depósito corneano e catarata secundários ao uso de clorpromazina. O caso apresentado reforça a importância do acompanhamento oftalmolÓgico periÓdico de usuários de clorpromazina para o rastreio de alteraçÕes oculares, atentando-se ao tempo de exposição à droga e à posologia da mesma.

Sobre la llamada revolución psicofarmacológica: el descubrimiento de la clorpromazina y la gestión de la locura / On the so-called psychopharmacological revolution: the discovery of chlorpromazine and the management of madness

Resumen El artículo analiza la fragilidad y los problemas existentes en la tesis que afirma la existencia de una verdadera revolución en el campo de la psiquiatría biológica, que se habría operado entre 1952 y 1954, con el descubrimiento de la clorpromazina. Para eso se analizan los discursos y las estrategias que posibilitaron el descubrimiento de esta droga que servirá de modelo para la producción de nuevos psicofármacos. Se intenta entender, también, qué es lo que se considera como "eficacia terapéutica" de la droga.

Abstract This article analyzes the shortcomings and problems of the thesis that a true revolution took place in the field of biological psychiatry between 1952 and 1954 thanks to the discovery of chlorpromazine. To do so, it analyzes the discourses and strategies that led to the discovery of this drug, which became a model for the production of new psychopharmaceuticals. It seeks to understand, also, what is meant by "therapeutic efficacy" with regard to this drug.

Light and electron microscopy of chlorpromazine-induced hyperpigmentation.

Chlorpromazine may induce abnormal skin hyperpigmentation in exposed areas, described as slate-gray, purple, or blue-grayish discoloration. A 58-year-old man with schizophrenia, had been taking chlorpromazine for 5 years, and his sun-exposed skin areas exhibited a blue-grayish color. Large deposits of brown pigment and granular basophilic material were seen in the dermis with light microscopy. HMB-45 and anti-Melan-A antibody immunostaining labeled some pigment in the dermis. Transmission electron microscopy identified deposits among dermal collagen bundles collagen in both transverse and longitudinal sections. In the latter, an arboriform aspect of deposits was quite clear, and some melanophages were also seen. The three-dimensional examination of the dermis with scanning electron microscopy also identified deposits, which at higher magnification demonstrated an appearance in the shape of leaves, grass-like, interspersed with normal collagen. These results suggest a complex pathogenic mechanism, including deposition of dermal melanin together with drug itself and potentially additional unknown metabolites.

Chlorpromazine-impregnated catheters as a potential strategy to control biofilm-associated urinary tract infections.

Aim: This study proposes the impregnation of Foley catheters with chlorpromazine (CPZ) to control biofilm formation by Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae. Materials & methods: The minimum inhibitory concentrations (MICs) for CPZ and the effect of CPZ on biofilm formation were assessed. Afterward, biofilm formation and the effect of ciprofloxacin and meropenem (at MIC) on mature biofilms grown on CPZ-impregnated catheters were evaluated. Results: CPZ MIC range was 39.06-625 mg/l. CPZ significantly reduced (p < 0.05) biofilm formation in vitro and on impregnated catheters. In addition, CPZ-impregnation potentiated the antibiofilm activity of ciprofloxacin and meropenem. Conclusion: These findings bring perspectives for the use of CPZ as an adjuvant for preventing and treating catheter-associated urinary tract infections.

Corrigendum: Biochemical Pathways Triggered by Antipsychotics in Human Oligodendrocytes: Potential of Discovering New Treatment Targets.

[This corrects the article DOI: 10.3389/fphar.2019.00186.].

Biochemical Pathways Triggered by Antipsychotics in Human [corrected] Oligodendrocytes: Potential of Discovering New Treatment Targets.

Schizophrenia is a psychiatric disorder that affects more than 21 million people worldwide. It is an incurable disorder and the primary means of managing symptoms is through administration of pharmacological treatments, which consist heavily of antipsychotics. First-generation antipsychotics have the properties of D2 receptor antagonists. Second-generation antipsychotics are antagonists of both D2 and 5HT2 receptors. Recently, there has been increasing interest in the effects of antipsychotics beyond their neuronal targets and oligodendrocytes are one of the main candidates. Thus, our aim was to evaluate the molecular effects of typical and atypical drugs across the proteome of the human oligodendrocyte cell line, MO3.13. For this, we performed a mass spectrometry-based, bottom-up shotgun proteomic analysis to identify differences triggered by typical (chlorpromazine and haloperidol) and atypical (quetiapine and risperidone) antipsychotics. Proteins which showed changes in their expression levels were analyzed in silico using Ingenuity® Pathway Analysis, which implicated dysregulation of canonical pathways for each treatment. Our results shed light on the biochemical pathways involved in the mechanisms of action of these drugs, which may guide the identification of novel biomarkers and the development of new and improved treatments.

Mechanisms of interaction of biodegradable polyester nanocapsules with non-phagocytic cells.

The interaction of polymer nanocapsules (NC) prepared from four biodegradable polyesters with variable polymer hydrophobicity (PCL, PLA, PLGA and PLA-PEG) was investigated in the non-phagocytic Vero, Caco-2 and HepG2 cell lines. The NC, labeled with the highly lipophilic fluorescent indocarbocyanine dye DIL, had very similar sizes (approx. 140 nm) and negative zeta-potentials. Asymmetric flow field-flow fractionation evidenced NC colloidal stability and negligible transfer of the dye to serum proteins in the incubation medium. The cytotoxicity of the NC was evaluated via MTT assay over a large polymer concentration range (1-1000 µg/mL) and time of exposure (2, 24 and 48 h). The NC were safe in vitro up to a concentration of approx. 100 µg/mL or higher, depending on the cell line and nature of the polymer. Vero cells were more sensitive to the NC, in particular NC of the more hydrophobic polymer. The cells were exposed to endocytosis inhibitors, incubated with NC, and the cell-associated fluorescence was quantified by spectrofluorometry. HepG2 cells presented a 1.5-2-fold higher endocytic capacity than Caco-2 and Vero cells. The main mechanism of NC uptake was caveolin-mediated endocytosis in HepG2 and Vero cells, and macropinocytosis in Caco-2 cells. Polymer hydrophobicity had an effect on the level of NC associated to HepG2 cells and to a lesser extent on the endocytosis mechanisms in Vero and Caco-2 cells. The NC uptake levels and endocytosis mechanisms differed significantly between cell lines tested.

Iron overload prevents oxidative damage to rat brain after chlorpromazine administration.

The hypothesis tested is that Fe administration leads to a response in rat brain modulating the effects of later oxidative challenges such as chlorpromazine (CPZ) administration. Either a single dose (acute Fe overload) or 6 doses every second day (sub-chronic Fe overload) of 500 or 50 mg Fe-dextran/kg, respectively, were injected intraperitoneally (ip) to rats. A single dose of 10 mg CPZ/kg was injected ip 8 h after Fe treatment. DNA integrity was evaluated by quantitative PCR, lipid radical (LR·) generation rate by electron paramagnetic resonance (EPR), and catalase (CAT) activity by UV spectrophotometry in isolated brains. The maximum increase in total Fe brain was detected after 6 or 2 h in the acute and sub-chronic Fe overload model, respectively. Mitochondrial and nuclear DNA integrity decreased after acute Fe overload at the time of maximal Fe content; the decrease in DNA integrity was lower after sub-chronic than after acute Fe overload. CPZ administration increased LR· generation rate in control rat brain after 1 and 2 h; however, CPZ administration after acute or sub-chronic Fe overload did not affect LR· generation rate. CPZ treatment did not affect CAT activity after 1-4 h neither in control rats nor in acute Fe-overloaded rats. However, CPZ administration to rats treated sub-chronically with Fe showed increased brain CAT activity after 2 or 4 h, as compared to control values. Fe supplementation prevented brain damage in both acute and sub-chronic models of Fe overload by selectively activating antioxidant pathways.

Chlorpromazine and dimethyl sulfoxide modulate the catalytic activity of the plasma membrane Ca2+-ATPase from human erythrocyte.

The plasma membrane Ca2+-ATPase (PMCA) removes Ca2+ from the cytosol into the extracellular space. Its catalytic activity can be stimulated by calmodulin (CaM) or by limited proteolysis. We evaluated the effect of chlorpromazine (CPZ) and dimethyl sulfoxide (DMSO) over the hydrolytic activity of PMCA. Activity was monitored in three different forms: native, CaM-activated and proteolyzed by trypsin. CPZ appears to inhibit PMCA without directly interfering with the C-terminal site, since it is affected by CaM and proteolysis. Although the treatment of PMCA with trypsin and CaM produces an activation, it also produces an enzymatic form that is more sensitive to inhibition by CPZ. The same case was observed in the DMSO inhibition experiments. In the absence of CPZ, DMSO produces a progressive loss of activity, but in the presence of CPZ the profile of activity against DMSO changes and produces a recovery of activity, indicating a possible partition of CPZ by the solvent. Increasing Ca2+ concentrations indicated that CPZ interacts with PMCA rather than with CaM. This observation is supported by docking analysis that suggests that the CPZ-PMCA interaction is non-competitive. We propose that CPZ interacts with the state of lower affinity for Ca2 +.

Advantages of the Alpha-lipoic Acid Association with Chlorpromazine in a Model of Schizophrenia Induced by Ketamine in Rats: Behavioral and Oxidative Stress evidences.

Schizophrenia is a chronic mental disorder reported to compromise about 1% of the world's population. Although its pathophysiological process is not completely elucidated, evidence showing the presence of an oxidative imbalance has been increasingly highlighted in the literature. Thus, the use of antioxidant substances may be of importance for schizophrenia treatment. The objective of this study was to evaluate the behavioral and oxidative alterations by the combination of chlorpromazine (CP) and alpha-lipoic acid (ALA), a potent antioxidant, in the ketamine (KET) model of schizophrenia in rats. Male Wistar rats (200-300 g) were treated for 10 days with saline, CP or ALA alone or in combination with CP previous to KET and the behavioral (open field, Y-maze and PPI tests) and oxidative tests were performed on the last day of treatment. The results showed that KET induced hyperlocomotion, impaired working memory and decreased PPI. CP alone or in combination with ALA prevented KET-induced behavioral effects. In addition, the administration of KET decreased GSH and increased nitrite, lipid peroxidation and myeloperoxidase activity. CP alone or combined with ALA prevented the oxidative alterations induced by KET. In conclusion, the treatment with KET in rats induced behavioral impairments accompanied by hippocampal oxidative alterations, possibly related to NMDA receptors hypofunction. Besides that, CP alone or combined with ALA prevented these effects, showing a beneficial activity as antipsychotic agents.

Electroencephalographic study of chlorpromazine alone or combined with alpha-lipoic acid in a model of schizophrenia induced by ketamine in rats.

Schizophrenia is characterized by behavioral symptoms, brain function impairments and electroencephalographic (EEG) changes. Dysregulation of immune responses and oxidative imbalance underpins this mental disorder. The present study aimed to investigate the effects of the typical antipsychotic chlorpromazine (CP) alone or combined with the natural antioxidant alpha-lipoic acid (ALA) on changes in the hippocampal average spectral power induced by ketamine (KET). Three days after stereotactic implantation of electrodes, male Wistar rats were divided into groups treated for 10 days with saline (control) or KET (10 mg/kg, IP). CP (1 or 5 mg/kg, IP) alone or combined with ALA (100 mg/kg, P.O.) was administered 30 min before KET or saline. Hippocampal EEG recordings were taken on the 1st, 5th and 10th days of treatment immediately after the last drug administration. KET significantly increased average spectral power of delta and gamma-high bands on the 5th and 10th days of treatment when compared to control. Gamma low-band significantly increased on the 1st, 5th and 10th days when compared to control group. This effect of KET was prevented by CP alone or combined with ALA. Indeed, the combination of ALA 100 + CP1 potentiated the inhibitory effects of CP1 on gamma low-band oscillations. In conclusion, our results showed that KET presents excitatory and time-dependent effects on hippocampal EEG bands activity. KET excitatory effects on EEG were prevented by CP alone and in some situations potentiated by its combination with ALA.

Development of new hCaM-Alexa Fluor® biosensors for a wide range of ligands.

Eight new fluorescent biosensors of human calmodulin (hCaM) using Alexa Fluor® 350, 488, 532, and 555 dyes were constructed. These biosensors are thermodynamically stable, functional, and highly sensitive to ligands of the CaM. They resolve the problem of CaM ligands with similar spectroscopic properties to the intrinsic and extrinsic fluorophores of other biosensors previously reported. Additionally, they can be used in studies of protein-protein interaction through Förster resonance energy transfer (FRET). The variation in Tm (range 78.07-81.47 °C; 79.05 to WT) is no larger than two degrees in all cases in regards to CaM WT. The Kds calculated with all biosensors for CPZ and BIMI (a new inhibitor of CaM) are in the range of 0.45-1.86 and 0.69-1.54 µm respectively. All biosensors retain their ability to activate Calcineurin about 70%. Structural models built "in silico" show their possible conformation taking the fluorophores in protein thus we can predict system stability. Finally, these new biosensors represent a biotechnological development applied to an analytical problem, which aims to determine accurately the affinity of inhibitors of CaM without possible interference, to be put forward as possible drugs related to CaM.

Influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury

PURPOSE:To analyze the influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury.METHODS:Sixteen Wistar rats - split in two groups - have been used: control group, receiving 3 mg/kg isotonic saline solution through caudal vein, and, the chlorpromazine group, receiving 3 mg/kg-IV of such medication. The nephrectomy of the left kidney lower third was carried out; immediately, the test-drug was administrated. After 15 minutes of test-drug administration, the renal pedicle was clamped; in 60 minutes of ischemia it was released. After 24 hours of the renal reperfusion, the rats were, once more, anesthetized and submitted to total left nephrectomy, and, afterwards, to euthanasia. Histological findings regarding ischemia have been evaluated and compared between the groups.RESULTS:There was no statistical difference related to inferior renal pole histological analysis. Regarding 60-minute renal ischemia, chlorpromazine has statistically reduced the accrual of leucocytes within the vasa recta renis (p=0.036) and the congestion of peritubular capillaries (p=0.041). When conducting joint analysis of histological patterns, the control group showed a median score of 11 and chlorpromazine group of 5.5 (p=0.036).CONCLUSION:Chlorpromazine significantly reduced the occurrence of secondary damage to ischemia and reperfusion process in the overall histological analysis.(AU)

Influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury

ABSTRACT PURPOSE: To analyze the influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury. METHODS: Sixteen Wistar rats - split in two groups - have been used: control group, receiving 3 mg/kg isotonic saline solution through caudal vein, and, the chlorpromazine group, receiving 3 mg/kg-IV of such medication. The nephrectomy of the left kidney lower third was carried out; immediately, the test-drug was administrated. After 15 minutes of test-drug administration, the renal pedicle was clamped; in 60 minutes of ischemia it was released. After 24 hours of the renal reperfusion, the rats were, once more, anesthetized and submitted to total left nephrectomy, and, afterwards, to euthanasia. Histological findings regarding ischemia have been evaluated and compared between the groups. RESULTS: There was no statistical difference related to inferior renal pole histological analysis. Regarding 60-minute renal ischemia, chlorpromazine has statistically reduced the accrual of leucocytes within the vasa recta renis (p=0.036) and the congestion of peritubular capillaries (p=0.041). When conducting joint analysis of histological patterns, the control group showed a median score of 11 and chlorpromazine group of 5.5 (p=0.036). CONCLUSION: Chlorpromazine significantly reduced the occurrence of secondary damage to ischemia and reperfusion process in the overall histological analysis.

Triancinolona intra-vítrea e clorpromazina retrobulbar como alternativas ao manejo do olho cego doloroso / Intravietrea trianciclone and retotubulbar chlorpromazine as alternative to blind paintful eye manegement

RESUMO Objetivo: O objetivo desde estudo foi avaliar a efetividade da triancinolona intra-vítrea e da clorpromazina retrobulbar como alternativas no manejo da dor ocular em olhos cegos. Métodos: Este foi um estudo prospectivo intervencionista não-randomizado de pacientes com olho cego doloroso não responsivo ao tratamento tópico e sem indicação de evisceração atendidos no Serviço de Oftalmologia do Hospital Governador Celso Ramos no ano de 2010. Após exame oftalmológico e ultrassonografia ocular modo B, os pacientes foram divididos em dois grupos. Pacientes do Grupo 1 possuíam glaucoma intratável e receberam injeção retrobulbar de clorpromazina 2,5ml, e pacientes do Grupo 2 possuíam olhos phthisicos com componente inflamatório e receberam injeção intra-vítrea de triancinolona 0,3ml. Foram realizadas avaliações com 1, 3 e 6 meses após o procedimento e a dor quantificada de forma subjetiva em uma escala de 0 a 10 (sem dor e com o máximo de dor, respectivamente). Resultados: Foram incluídos 38 olhos, sendo 15 no Grupo 1 e 21 no Grupo 2. Houve predomínio do sexo masculino e idade média de 54 anos. A causa mais prevalente de olho cego doloroso foi o glaucoma neovascular. Tanto a injeção de clorpromazina retrobulbar quanto a de triancinolona intra-vítrea mostraram-se eficazes no controle da dor ocular em olhos cegos no período do estudo (p<0,001). Ocorreu uma redução de 77,1% no uso de colírios (p<0,01) após a aplicação das medicações. Conclusão: Tanto a injeção de clorpromazina retrobulbar quanto a de triancinolona intra-vítrea mostraram resultados significativos no controle da dor ocular em olhos cegos, além de uma redução no uso de colírios. A clorpromazina é um medicamento de baixo custo, com melhor perfil de efeitos adversos e mostrou resultados discretamente melhores relação à triancinolona. Possíveis viéses identificados no estudo são o de tempo e seleção.

ABSTRACT Objective: The objective of this study was to evaluate the efficacy of intravitreal triamcinolone and retrobulbar chlorpromazine as alternatives in the management of ocular pain in blind eyes. Methods: This was a non-randomized interventional prospective study of patients with painful blind eye unresponsive to topical treatment and without indication of evisceration treated at the Hospital Governador Celso Ramos Ophthalmology Service in 2010. After ocular examination and ocular B mode ultrasound, patients were divided into two groups. Group 1 patients had intractable glaucoma and received retrobulbar injection of chlorpromazine 2.5ml, and Group 2 patients had phthisics eyes with inflammatory component and received intravitreal triamcinolone injection 0.3ml. Evaluations were performed at 1, 3 and 6 months after the procedure and quantified pain subjectively on a scale from 0 to 10 (no pain and maximum pain, respectively). Results: 38 eyes were included, 15 in Group 1 and 21 in Group 2. There was a predominance of males with a mean age of 54 years. The most prevalent cause of painful blind eye was the neovascular glaucoma. Any retrobulbar injection of chlorpromazine as the intravitreal triamcinolone shown to be effective in the control of ocular pain in the eye blind study period (p <0.001). There was a 77.1% reduction in eye drops (p <0.01) after application of medication. Conclusion: Both the retrobulbar injection chlorpromazine as the intravitreal triamcinolone showed significant results in the control of ocular pain in blind eyes, and a reduction in the use of eye drops. Chlorpromazine is a low cost product, with a better adverse effect profile and showed slightly better results compared to triamcinolone. Potential bias identified in the study are the time and selection.

Acute and chronic ecotoxicological effects of four pharmaceuticals drugs on cladoceran Daphnia magna.

The occurrence of pharmaceuticals in the aquatic environment has received increasing attention in recent years, as concerns have risen about their environmental persistence, biological activity and different effects toward nontarget organisms. Considering the magnitude of concentrations (ng L(-1) to mg L(-1)) and their often-specific modes of action, the assessment of physiological responses of exposed aquatic biota may provide significant information regarding the potential ecological consequences of exposure to these contaminants. The present study intended to assess the acute and chronic effects of four pharmaceuticals: acetaminophen, chlorpromazine, diclofenac sodium and propranolol in the cladoceran species Daphnia magna. Parameters such as immobility, total of offspring and rate of population increase were analyzed. Results of acute exposures showed a considerable variability of toxicity among pharmaceuticals, with the following ranking of toxicity: diclofenac (EC50 = 123.3 mg L(-1)) < propranolol (EC50 = 5.531 mg L(-1)) < acetaminophen (EC50 = 2.831 mg L(-1)) < chlorpromazine (EC50 = 1.805 mg L(-1)). The chronic toxicity data showed the exertion of reproductive adverse effects. The compounds chlorpromazine and propranolol caused a significant decrease in fecundity, and the rate of population increase parameter suffered a significant decrease from 0.33 mg L(-1) to 0.128 mg L(-1) onwards, respectively. The levels of exposure to which our test organism was acutely and chronically exposed were above those already reported in the wild. Nevertheless, the extensive production, prescription and release of pharmaceuticals drugs will continue to grow in the future, and consequently their loadings to the environment can result in potential long-term ecological risks to aquatic biota.

Enhancement of the antibiotic activity of aminoglycosides by extracts from Anadenanthera colubrine (Vell.) Brenan var. cebil against multi-drug resistant bacteria.

The aim of this work was to evaluate the antimicrobial activity of ethanol (EEAC) and hexane (HFAC) extracts from the stem bark of Anadenanthera colubrina (Vell.) Brenan var. cebil alone or in combination with aminoglycosides against multi-drug resistant (MDR) bacteria. Minimal inhibitory concentrations (MICs) of the extracts were determined by using microdilution assay. For the evaluation of extracts as modulators of antibiotic resistance, MICs of neomycin and amikacin were determined in presence or absence of each compound at sub-inhibitory concentrations. Both EEAC and HFAC did not show antimicrobial activity against MDR strains tested. However, the addition of EEAC and HFAC enhanced the activity of neomycin and amikacin against Staphylococcus aureus SA10 strain. When the natural products were replaced by chlorpromazine, the same effect was observed. Anadenanthera colubrine var. cebil may be a source of phytochemicals able to potentiate the aminoglycoside activity against MDR S. aureus by the inhibition of efflux pump.

Efeito antipsicótico da associação da clorpromazina e ácido lipóico em modelo de esquizofrenia induzido pela cetamina em ratos

A esquizofrenia, síndrome neuropsiquiátrica caracterizada por comprometimento das funções cerebrais, apresenta, além de sintomas comportamentais, alterações eletroencefalográficas, está associada a uma desregulação das respostas imunológicas e componente oxidativo. No entanto, o papel do dano oxidativo nas alterações eletroencefalográficas presentes na esquizofrenia não está completamente esclarecido. Desta maneira, este estudo teve como objetivo avaliar os efeitos antipsicóticos da associação de clorpromazina (CP) e ácido lipóico (ALA), em modelo de esquizofrenia induzido por cetamina (KET), em ratos. Foram utilizados ratos Wistar machos (200-300 g), tratados durante 10 dias e divididos em dois protocolos experimentais. No primeiro, os animais foram divididos em quatro grupos (n = 10) e tratados com solução salina (controle) ou cetamina (10, 50 ou 100 mg/kg). No segundo, os animais foram divididos em nove grupos (n = 10), tratados com solução salina (controle), ácido lipóico (100 mg/kg), cetamina (10 mg/kg), clorpromazina (1 ou 5 mg/kg) sozinha ou associada a cetamina (CP1 ou CP5+KET) ou associada ao ácido lipóico (ALA+CP1 ou CP5+KET)...

Schizophrenia, a neuropsychiatric syndrome characterized by brain functions impairment, presents besides the behavioral symptoms, electroencephalographic changes and it is associated with a dysregulation of immune responses and oxidative component. However, the role of the inflammatory and oxidative damage on the electroencephalographic alterations present in schizophrenia was not completely clarified. Thus, this study aimed to investigate the electroencephalographic, behavioural and neurochemical effects in the hippocampus of rats treated with chlorpromazine alone or associated with lipoic acid in the model of schizophrenia induced by ketamine. However, the role of oxidative damage in electroencephalographic changes present in schizophrenia is not fully understood. As a result, this study aimed to evaluate the effects of the antipsicotics association of chlorpromazine (CP) and lipoic acid (ALA) in the schizophrenia model induced by ketamine (KET) in rats. Wistar male rats (200-300 g) were tested. They were treated for 10 days and divided into two experimental protocols: At first the animals were divided into 4 groups (n = 10) and treated with saline (control) or ketamine (10, 50, or 100 mg/kg). In the second, the animals were divided into 9 groups (n = 10) treated with saline (control), lipoic acid (100mg/kg), ketamine (10mg/kg) and chlorpromazine (1 or 5 mg/kg) alone or and ketamine (CP1 and CP5+KET) or associated with lipoic acid (ALA+CP1 and CP5+KET)...