Antitumor Effect of Traditional Drugs for Neurological Disorders: Preliminary Studies in Neural Tumor Cell Lines.

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood-brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood-brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood-brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it.

Parametric evaluation of methotrimeprazine-midazolam-ketamine and methotrimeprazine-midazolam-ketamine-xylazine combination in dogs / Avaliação paramétrica das associações levomepromazinamidazolam-cetamina e levomepromazinamidazolamcetamina-xilazina em cães

PURPOSE: To evaluate the parameters of dogs anesthetized by different dissociative drugs protocols through continuous intravenous infusion. METHODS: Thirty healthy dogs of both sexes were assigned randomly to three groups (G1, G2, and G3). G1 was administered with methotrimeprazine as a pre-anesthetic medication, intravenously midazolam-ketamine as bolus for induction and midazolam-ketamine by continuous intravenous infusion for a 60 minute-period of maintenance. G2: the same as for G1. plus an increase in the midazolam dose during maintenance. G3: the same treatment as for G2, plus the addition of xylazine during maintenance. Immediately after induction the anesthetic maintenance started, and measures were taken 15 minutes after pre-medication, at 10 minutes intervals, during maintenance (M0 to M7). RESULTS: Bradycardia, atrioventricular blockage, bradypnea and hypoxemia were shown in G3. G1 and G2 showed a slight hypotension only. CONCLUSION: There were some advantages by using the continuous intravenous via: no parameters oscillation and reduction in the anesthetic recovery period. The increase in midazolam dose brought about little parametric variations which were greater when xylazine was used, with a consequent hypoxemia, bradyarrhytmia, and decrease in respiratory frequency and minute volume.

OBJETIVO: Avaliar os parâmetros de cães anestesiados com diferentes protocolos de fármacos dissociativos por infusão intravenosa contínua. MÉTODOS: Foram utilizados 30 cães, machos e fêmeas, clinicamente sadios, distribuídos aleatoriamente em três grupos (G1,G2 e G3) (*)). Em G1 utilizou-se levomepromazina como medicação pré-anestésica (MPA), midazolam-cetamina pela via intravenosa em bolus para indução e midazolam-cetamina em infusão intravenosa contínua por 60 minutos para manutenção. Em G2 procedeu-se da mesma forma que em G1 elevando-se, porém, a dose de midazolam durante a manutenção. Em G3 repetiu-se o tratamento empregado em G2, acrescentando-se a xilazina à manutenção. Após a indução, iniciou-se imediatamente a manutenção anestésica, realizando-se aferições, 15 minutos depois da MPA, em intervalos de 10 minutos, durante a manutenção (M0 a M7). RESULTADOS: Em G3 ocorreu bradicardia, bloqueio átrio-ventricular, bradipnéia e hipoxemia e em G1 e G2, discreta hipotensão. CONCLUSÃO: A via intravenosa contínua apresentou vantagens quanto a: não oscilação dos parâmetros e redução no período de recuperação anestésica. A elevação da dose de midazolam resultou em discretas variações paramétricas, estas, acentuadas pelo uso da xilazina, que causou hipoxemia, bradiarritmia, diminuição da freqüência respiratória e volume minuto.

Effects of butaclamol, clopenthixol, mepromazine and cannabinol stereoisomers on apoptosis induction.

The efflux pump of multidrug resistant mdr cells have different sensitivities to some stereoisomeric forms of CNS-active compounds. The ABC transporters of mdr cells were more sensitive to (-)butaclamol than to its stereoisomeric counterpart (8), which may function to alter the membrane structure. We suppose that the drug-accessible membrane structure possesses an important role in the induction (or prevention) of apoptosis. Therefore the apoptosis-inducing effect of three stereoisomeric pairs was studied on mouse lymphoma cells. In these experiments levo- and dextromepromazine had similiar effects. The cis- and trans-clopenthixol were less effective in apoptosis induction than the 12H-benzo(a)-phenothiazine used as a positive control. The effect of stereoisomeric pairs on induced apoptosis was studied when the cells were exposed to the stereoisomers for 60 minutes before subjection apoptosis induction by benzo(a)phenothiazine, a well-known apoptosis inducer. Then the pretreated cells were exposed to 12H-benzo(a)-phenothiazine for 60 minutes. The samples were washed and incubated for 24 hours. The cells were stained with annexin-V-FITC and propidium iodine and investigated by flow cytometry. The mdr cells with increased membrane integrity may result in the preferential killing of multidrug resistant cancer cells in the presence of some stereoisomers.

Atividade antiarritmogênica da levomepromazina em cäes submetidos à anestesia pela quetamina / The use of levomepromazine to blockade the arrhythmia induced by the epinephrine in dogs anesthetized with ketamine

Este experimento teve por objetivo avaliar a viabilidade do emprego da levomepromazina no bloqueio da atividade arritmogênica da adrenalina, em cäes anestesiados pela quetamina. Para tal, foram utilizados 30 cäes adultos, machos e fêmeas, considerados sadios, com pesos compreendidos entre 7 e 14kg. Estes foram divididos em 3 grupos de 10 animais (G1, G2 e G3). Aos cäes de G1 foi administrada, por via intravenosa, adrenalina em doses de 3, 6, 9, 12 e 15µg/kg, em intervalos de 10 minutos. Deste grupo, foram colhidos o tempo de duraçäo do efeito da catecolamina (TA), estabelecido pela contagem da freqüência cardíaca e o número total de batimentos cardíacos de origem ectópica, produzidos pela adrenalina (ESV). Aos animais do G2, foi administrada soluçäo salina a 0,9 porcento, na dose de 0,2ml/kg, por via intravenosa, seguida, 10 minutos após, da injeçäo, pela mesma via, de quetamina, na dose de 2mg/kg. Decorridos 5 minutos, iniciou-se a infusäo contínua de quetamina, por via intravenosa, na dose de 0,2mg/kg/min. Aguardou-se 5 minutos e iniciou-se a adminstraçäo de adrenalina e colheita das variáveis, conforme protocolado para o G1. Aos animais do G3, aplicou-se a mesma metodologia, substituindo-se o placebo pela levomepromazina, administrada por via intravenosa, na dose de 1mg/kg. A análise dos resultados mostrou que a levomepromazina reduz a duraçäo do efeito da catecolamina e minimiza o aparecimento de batimentos cardíacos de origem ectópica. Os achados permitiram concluir que a levomepromazina é útil no bloqueio da arritmia produzida pela adrenalina em cäes anestesiados pela quetamina.

The role of stereoselectivity of chemosensitizers in the reversal of multidrug resistance of mouse lymphoma cells.

The effect of three different stereoisomer pairs of CNS (central nervous system) active compounds was studied on the activity of human mdr1 p-glycoprotein. The methotrimeprazine, clopenthixol and butaclamol isomers had an antiproliferative effect (ID50) on the mdr1 expressing cells at 0.250 microgram/ml, while the parental cells were less sensitive having ID50 at 0.37-0.69 microgram/ml. Enantiomers of methotrimeprazine and clopenthixol had similar effectivity on the drug efflux of mdr cells. However, (-)butaclamol was found to inhibit mdr efflux-pump activity much more than the CNS active (+) isomer. Based on these results, tricyclic compounds does not seem to have stereoselectivity in methotrimeprazine and clopenthixol on the mdr reversal effect. In general, both active and inactive members of stereoisomers had a similar effect on the drug accumulation of the mdr cells. Therefore, hypothetically the CNS inactive member of stereoisomer pairs can be used as a resistance modifier without any risk in patients suffering from drug resistant cancer.

Levomepromazina e atropina como medicaçöes pré-anestésicas na anestesia pela associaçäo tiletamina/zolazepam, em cäes / Comparison between levomepromazine and atropine as premedication agents before anesthesia using tiletamine/zolazepam in dogs

O objetivo desta pesquisa foi avaliar o emprego da atropina e da levomepromazina como medicaçöes pré-anestésicas para a anestesia pela associaçäo tiletamina/zolazepam. Foram empregados 30 cäes, distribuídos em três grupos iguais. O grupo 1 (controle) foi tratado com 0,2ml/kl de soluçäo fisiológica (placebo) por via intravenosa; o grupo 2 com 0,044mg/kg de sulfato de atropina por via subcutânea e o grupo 3 com 1mg/kg de cloridrato de levomepromazina por via intravenosa. Quinze minutos após, todos os grupos receberam a associaçäo tiletamina/zolazepam na dose de 10mg/kg por via intramuscular. Antes da medicaçäo pré-anestésica, 15 minutos após a mesma e aos 15, 30, 60 e 105 minutos após a administraçäo da associaçäo tiletamina/zolazepam foram registrados: ECG, temperatura, freqüência respiratória, volume corrente, volume minuto, freqüência cardíaca, pressäo arterial, valores hemogasométricos arteriais, graus de analgesia e miorrelaxamento e reflexos protetores. Outros dados como: secreçäo salivar, período de latência, período anestésico hábil e período de recuperaçäo foram igualmente mensurados para efeito comparativo. De acordo com os resultados obtidos concluiu-se que o sulfato de atropina näo deve ser administrado como medicaçäo pré-anestésica, por potencializar a taquicardia induzida pela associaçäo tiletamina/zolazepam. A levomepromazina, além de inibir a sialorréia, mantém a estabilidade cardiorrespiratória e apresenta açäo potencializadora dos efeitos anestésicos da associaçäo.

[Glucocorticoid receptor mechanism of regulation of the activity of angiotensin-converting enzyme and new prospects in the treatment of cardiovascular diseases]. / Gliukokortikoid-retseptornyi mekhanizm reguliatsii aktivnosti angiotenzinprevrashchaiushchego fermenta i novye perspektivy lecheniia serdechno-sosudistykh zabolevanii.

Based on the concept of glucocorticoid-receptor induction of angiotensin-converting enzyme (ACE), approaches to inhibiting enzyme induction with drugs that suppress the function of type II cytoplasmic glucocorticoid receptors, (genuine glucocorticoid receptors), are suggested. Three types of inhibiting the function of type II glucocorticoid receptors by drugs were distinguished. Type I is characterized by competition of the drugs with natural and synthetic glucocorticoids for interaction with glucocorticoid receptors (cortexolone, progesterone); type II is determined by irreversible inactivation of type II glucocorticoid receptors (aminazine, tisercin); type III is related to an increase of interaction of transcorticoid receptors with natural glucocorticoids which is accompanied by a reduction of the interaction of natural glucocorticoids with genuine glucocorticoid receptors (analgin, amidopyrine). It has been established that the drugs that provoke irreversible inactivation of the function of type II glucocorticoid receptors decrease ACE activity in blood plasma and in the lungs, that may serve the main reason for their high hypotensive effect in arterial hypertension. A concept is advanced, providing evidence for the use of the classical ACE inhibitors and of type II glucocorticoid receptor inhibitors.

Teste da estimulacao sonica em gestantes hipertensas sob tratamento com beta-bloqueador (Pindolol) / Sound stimulation test during treatment of maternal hypertension with beta-adrenoceptor blockers (Pindolol)

Estudo do Teste da Estimulacao Sonica (TES) efetuado em 46 gestantes tratadas com Pindolol e Levomepromazina (9 mg/dia) divididas em tres grupos, I, II e III, respectivamente com 10, 20 e 30 mg/dia de Pindolol. Todas foram submetidas a operacao cesariana antes do inicio das contracoes do trabalho de parto. Para a analise da resposta cardiaca fetal foram consideradas a amplitude e a duracao da cardioaceleracao. Houve diminuicao da resposta cardiaca verificada por estas duas variaveis com o incremento do beta-bloqueador, sem contudo, haver significado estatistico. Todavia, a resposta cardiaca nos tres grupos foi significamente menor quando comparada com a resposta verificada por Zugaib e "col. POT. 19" em 30 gestantes hipertensas tratadas apenas com 9 mg/dia de Levomepromazina.

Antidepressants and endogenous opioid peptide systems.

The influence of antidepressants on the brain and pituitary content of immunoreactive beta-endorphin (ir-beta E) and dynorphin (ir-DYN) was studied in rats. Chronic administration of the first and second generation antidepressants imipramine, citalopram and rolipram, and of the antidepressant neuroleptics levomepromazine and chlorprothixene elevated the level of ir-beta E in the hypothalamus. Imipramine and levomepromazine also increased the level of ir-DYN in this tissue. Imipramine administered chronically potentiated stress-induced as well as morphine analgesia. The results obtained suggest that chronic antidepressants enhance the brain opioid system activity and increase the sensitivity of opiate receptors.

Inhibition of bacterial plasmid replication by stereoselective binding by tricyclic psychopharmacons.

Several dibenzazepines, thioxanthene, and phenothiazine stereoisomers were studied for their abilities to inhibit plasmid replication, intracellular transfer of R-plasmid, bacterial ATP-ase, and mouse serum cholinesterase isoenzyme. Partially saturated derivative of desipramine inhibited plasmid replication and transfer, but the fully saturated derivative was inactive. The inhibition of plasmid curing and transfer patterns did not correlate with the inhibition of ATP-ase and cholinesterase. Trans-clopenthixol was more effective in plasmid elimination than the cis-isomer. On the other hand, the cis-isomer inhibited ATP-ase and cholinesterase more than the trans-isomer. The levo- and dextro-methoxytrimeprazine also inhibited plasmid replication and enzyme activity. We believe that the tricyclic configuration of the drugs tested for stereospecific binding to bacterial receptors is more important than its side chain orientation. We believe that there is a similarity between bacterial receptor sites and neural receptor sites. Therefore, this model may be useful in the study of neuropharmacological agents as potential antibacterial agents.

[Comparative effect of psychotropic agents on orienting-motor responses and cerebral Na,K-ATPase activity in vivo]. / Sravnitel'noe deistvie psikhotropnykh sredstv na orientirovochno-dvigatel'nye reaktsii i aktivnost' Na, K-ATF-azy mozga in vivo.

Levomepromazine, chlorpromazine (10 and 30 mg/kg), etaperaxine, haloperidol (3 and 10 mg/kg) inhibited the exploratory-motor reactions of rats and the brain Na, K-ATPase activity an hour after their administration. The effects of tranquilizers as well as of antidepressants on the exploratory reactions and on the enzyme activity were not found to stand in a clearcut relation to each other. The stimulating effect of amphethamine (3 mg/kg) was accompanied by activation and suppressive action (10 mg/kg)--by inhibition of the enzyme. It is suggested that the inhibition of the brain Na, K-ATPase activity by psychotropic drugs may play a role in the mechanism of their sedative action.

[Comparative study of the effect of some psychotropic substancces on the activity of brain Na+, K+-ATPase in vitro]. / Sravnitel'noe izuchenie vliianiia nekotorykh psikhotropnykh veshchestv na aktivnost' Na+, K+-ATF-azy mozga in vitro

The activity of Na+, K+-ATPase from bovine brain in vitro was studied as affected by some neuroleptics (levomepromazine, chlorpromazine, perphenazine and haloperidol), antidepressants (imipramine and iproniazid) and psychostimulants (amphetamine) as well as by benactyzine and procaine. The degree of the enzyme inhibition by these drugs estimated by means of I 50 and apparent inhibitor constants (Ki) or rate constants (k) was different. Sensitivity of the brain Na+, K+-ATPase to the drugs decreased in the following order: levomepromazine, chlorpromazine, perphenazine, haloperidol, imipramine, iproniazid, benactyzine, procaine and amphetamine. Competition for the enzyme was revealed between sodium and some of the drugs investigated (levomepromazine, chlorpromazine, perphenazine and impramine) as well as between potassium and other drugs (haloperidol, genactyzine and amphetamine). It is suggested that the inhibition of the brain Na+, K+-ATPase by psychotropic drugs may be a part in the biochemical mechanism of their sedative-tranquilizing activity.

[Anesthetic technics for surgery in otoneurology]. / Techniques anesthésiques pour les interventions en oto-neurologie

A description is given of a technique named "Protected Sleep", which produces a deep and residual analgesia and neurolepsia, without interfering with spontaneous respiration. A deep, stable and reliable neuroanesthesia is achieved by means of a partial pharmacodynamic blockage of the neuro-humoral reaction system. It is recognisable by the following features: 1 degree a smooth transition through pre-, per- and post-operative stages, avoiding in particular immediate awakening; 2 degrees a relative arterial hypotension, low venous pressure good peripheral circulation and tissular perfusion; 3 degrees light hypothermia; 4 degrees completely spontaneous respiration. This last factor is, to our way of thinking, of great importance: The venous return remains physiologically unchanged during inspiration in the peroperative as well as in the pre- and postoperative phases, enabling the maintenance of a constant, low venous pressure. Furthermore, should danger exist, the preservation of spontaneous respiration facilitates the immediate control of the respiratory centre. In this way we can obtain: 1. An almost perfect bloodless surgical field with good conditions for dissecting. 2. A low cerebro-spinal fluid pressure. 3. Decreased brain volume. 4. Absence of postoperative haemorrage. 5. Little of no postoperative oedema. 6. Little or no postoperative hyperthermia. "Protected sleep" is a pharmacodynamic technique realised mainly through administration of a combined and sufficient dose of pethidine, N-allyl-normorphine and levome promazine. For induction, a given dose of diazepam is combined with a single dose of succinyl-choline, to facilitate intubation, followed by a large dose of the narco-neuro-leptanalgesic mixture. For maintenance, nitrous oxide, oxygen, methoxyflurane and additional doses of the mentioned mixture are administered. Undirectional gas flow, without rebreathing, is provided, using the Ruben valve. In this paper on neuroanaesthesia, the technique of "Protected Sleep" and the pre-, per- and postoperative management and positioning of the neurosurgical patient are described in detail.