Chronopharmacology: Tailoring Therapy to Endogenous Rhythms.

Chronopharmacology aims at the use of biological rhythms in the clinical treatment so as to enhance both effectiveness and tolerance and minimize the side effects of a drug by determining the best biological time for its administration. Chronopharmacology is useful to solve problems of drug optimization. In the human organs, the metabolic fate of a pharmacologic agent as well is not constant as a function of time. Thus, the chronobiological approach of drug administration involves a lesser risk of errors than the conventional homeostatic approach. Chronopharmacology is now used as a routine to treat various disorders like hypertension, angina, cancer and various psychotic disorders. The newer drug delivery systems that are designed with the chronopharmacological approach hold great scope for delivering better patient care in terms of efficacy, tolerance and safety parameters of the drug. This review aims at introducing chronopharmacology, the role of the regulatory system of biological clock in pharmacotherapy and the benefits it has conferred in various clinical conditions.

High gender -specific susceptibility to curare- a neuromuscular blocking agent

Curare, a selective skeletal muscle relaxant, has been used clinically to reduce shivering and as an anesthetic auxiliary in abdominal surgery. It is also widely used in animal experiments to block neuromuscular junction activity. Effective doses of curare diminish muscle contraction without affecting brain function, but at higher doses it is known to be lethal. However, the exact dose of curare initiating muscle relaxation vs. lethal effect has not been fully characterized in mice. In this study we carefully examined the dose-response for achieving muscle inactivity over lethality in both male and female mice (C57BL6/J). The most striking finding of this study is that female mice were highly susceptible to curare; both the EDm and LDm were at least 3-fold lower than male littermates. This study shows that gender-specific differences can be an important factor when administering skeletal muscle relaxants, particularly curare or other analogous agents targeted to the neuromuscular junction.

Protective effect of maternal prenatal melatonin administration on rat pups born to mothers submitted to constant light during gestation

We studied the effects of adverse conditions such as constant light (LL) on the circadian rhythm of malate (MDH, EC 1.1.1.37) and lactate (LDH, EC 1.1.1.27) dehydrogenase activities of the testes of male Wistar rats on postnatal day 28 (PN28), anxiety-like behavior (elevated plus-maze test) at PN60 and sexual behavior at PN120. The rats were assigned to mother groups on day 10 of pregnancy: control (12-h light/dark), LL (light from day 10 to 21 of pregnancy), and LL+Mel (LL and sc injection to the mothers of a daily dose of melatonin, 1 mg/kg body weight at circadian time 12, from day 17 to 21 of pregnancy). LL offspring did not show circadian rhythms of MDH (N = 62) and LDH (N = 63) activities (cosinor and ANOVA-LSD Fisher). They presented a 44.7 percent decrease in open-arm entries and a 67.9 percent decrease in time (plus-maze test, N = 15, P < 0.001, Mann-Whitney U-test and Kruskal-Wallis test), an increase in mounting (94.4 percent), intromission (94.5 percent) and ejaculation (56.6 percent) latencies (N = 12, P < 0.01, Mann-Whitney U-test and Kruskal-Wallis test) and lower numbers of these events (61, 59 and 73 percent, respectively; P < 0.01, N = 12) compared to controls. The offspring of the LL+Mel group presented MDH and LDH circadian rhythms (P < 0.05, N = 50, cosinor and ANOVA-LSD Fisher), anxiety-like and sexual behaviors similar to control. These findings supported the importance of the melatonin signal and provide evidence for the protective effects of hormones on maternal programming during gestation. This protective action of melatonin is probably related to its entrainment capacity, favoring internal coupling of the fetal multioscillatory system.

Effect of chewing khat in changing circadian rhythm for acute myocardial infarction patients in Sana'a city and it's role as a risk factor for acute myocardiac infarction in Yemen

Although the risk factors for acute MI were studied thoroughly in different countries worldwide, few studies in our country had been done, and cover only limited aspects of acute myocardial infarction [MI], for this reason we start this study to determine the general characters and risk factors of Yemeni patients presented with acute [MI]; and to highlight on the possible role of Khat chewing as potential risk factor for [MI] in our country in addition to its possible effect in changing its circadian rhythm. The study was prospective; hospital based descriptive study including all patients admitted with the diagnosis of acute MI to the 3 main general hospitals in Sana 'a city in the period from 1 October 2005 to 30 September 2006. Name, age, gender, residence, habits, time of onset of chest pain and previous history or family history of ischemic heart disease [IHD] was taken. Body mass index [BMI] and blood pressure were recorded, fasting lipid profile and blood sugar were measured. The data was collected and then analyzed using SPSS system. During the study period, 264 patients were admitted with a mean age of 50 years, all of them were married with predominant male gender 84%. Risk factors observed in our study were Khat chewing in 90.15%, smoking in 72%, hypertension in 21%, obesity in 15.96%, hyperlipidemia in 27%, diabetes mellitus [DM] in 24% and past history of ischemic heart disease was found in 13%. We notice that the onset of chest pain in most of our patients was in the afternoon 34% and early night hours 24%, which is opposite to the usual circadian rhythm of acute Ml in other parts of the world which is predominant in the early morning. Yemeni patients sustained acute MI are younger than western people or even other Arab countries. Common risk factors as hypertension, DM and hyperlipidemia were noticed only in minority of our patients. Smoking is a common risk factor after Khat chewing habit which was proposed as new risk factor. Circadian rhythm of acute MI in Yemen is differing from other part of the world

Circadian variation in lipid peroxidation induced by benzene in rats.

Time-dependent effect of benzene, a potent carcinogenic industrial solvent, on lipid peroxidaiton and associated mechanisms has been studied in liver and kidney of rats. Significant differences were observed in the values of urinary phenol, microsomal malondialdehyde, reduced glutathione (GSH) and cytochrome P4502E1 in rats treated with benzene in morning and evening hours. Higher were the values for urinary phenol and hepatic microsomal malondialdehyde in rats administered benzene in evening hours. Contrarily, higher were the values for GSH and cytochrome P4502E1 in rats treated with benzene in morning hours. Increased microsomal lipid peroxidation has been attributed to low GSH status, whereas increased phenol concentration could be related to low activity of cytochrome P4502E1 in the liver of rats in evening hours. It is concluded that circadian rhythmicity in hepatic drug metabolizing enzyme system and GSH contributes in toxicity of benzene. The results are important from occupational health point of view.

Implicaciones clínicas y pronósticas del estudio circadiano de la modulación simpático-vagal de la variabilidad de la frecuencia cardiaca en pacientes con hipertensión arterial pulmonar grave / Clinical implications and prognostic significance of the study on the circadian variation of heart rate variability in patients with severe pulmonary hypertension

Introducción: La reducción en la variabilidad de la frecuencia cardiaca ha sido identificada como factor de riesgo en enfermedad cardiovascular, pero su descripción en hipertensión arterial pulmonar severa se desconoce. Material y métodos: Se estudiaron pacientes con hipertensión arterial pulmonar grave, 32 con hipertensión pulmonar primaria, 34 con hipertensión pulmonar secundaria a cardiopatía congénita (Eisenmenger) y 44 sujetos control sin evidencia de enfermedad. La evaluación del registro ambulatorio de la frecuencia cardiaca se realizó por métodos convencionales. El análisis espectral y la relación a baja y alta frecuencia se realizó utilizando el método de Fourier. Comparaciones entre día y noche se realizó entre los grupos. Después de conocer el perfil circadiano, 15 pacientes con hipertensión pulmonar fueron seleccionados para recibir tratamiento al azar con Treprostinil (Prostaglandina) o placebo por vía subcutánea. Posteriormente (3 meses) se analizaron nuevamente los parámetros de variabilidad de frecuencia cardiaca y de hemodinámica para conocer el impacto de dicha terapéutica. Resultados: Se detectó un estado franco de hipertonía simpática en el grupo de hipertensión pulmonar, sobre todo en los pacientes con hipertensión pulmonar primaria. El efecto de Treprostinil fue claramente asociado con disminución del tono simpático y un aumento de la capacidad física. Conclusiones: Los pacientes con hipertensión arterial pulmonar, cursan con equilibrio simpático-vagal alterado sobre todo durante el día. Hay pérdida del ritmo circadiano. Dichos trastornos pueden ser reversibles con la aplicación de treprostinil. El equilibrio simpáticovagal de la frecuencia cardiaca es un instrumento no invasivo que permite estratificar mejor al paciente con hipertensión arterial pulmonar grave.

BACKGROUND: A reduction of heart rate variability (HRV) is currently considered an independent risk factor for morbidity, mortality and severity of severalcardiac disease, however, the dynamic sympathovagal modulation on HRV during 24 hr in primary pulmonary hypertension (PPH) had not been described. METHODS: 24 hr Holter monitoring (HA) were recorded in 32 patients (mean age 34, +/-12, 90% female) with severe primary pulmonary hypertension (mean pulmonary pressure, 90:t:12 mm Hg), and in 34 patients (mean age 36 +/-14, 60% female) with Eisenmenger syndrome (ES) secondary to septal ventricular defect or atent ductus arteriosus. A control group (n=44) paired for age, gender and arterial pulmonary pressure was included. HRV time and spectral parameters (mean, SDNN, SDANN, rMSSD, PNN50, LF, HF and LF/HF ratio) were analyzed during three periods: 24 hr; day (8-22:00), night (23-07:00) and also every hour of recording at 5 min-intervals). After detection of sympatho-vagal balance 15 patients were randomized, Treprostinil (prostaglandin) was administered to 6 patients and subcutaneous placebo to 9. RESULTS: HRV frequency parameters during 24 hr HM were significantly different among groups. LF/HF (day) 5.9:1:12.5:1:1P.001 and LF/HF night) 2.8:tlvs.1.5:l:.8.034. Sympathovagal modulation on 24 hr HRV showed that heart rate circadian rhythm is clearly altered in both PPH and ES, but the sympathetic tone in PPH is higher at l 24 hr. (p < .05), after administering treprostinil a recovery of sympathovagal balance was observed CONCLUSIONS: Autonomic cardiac disturbance is clearly present in PPH and ES. The circadian rhythm of HRV is first lost due to an increase of sympathetic tone. These changes may be markers of autonomic disbalance that favor the development of arrhythmias and sudden death. The sympathovagal balance in PPH could be considered an important risk marker.

N-Phthaloyl gamma-aminobutyric acid affects biochemical circadian rhythms in Wistar rats.

N-Phthaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar rats and 24 hr rhythms of glucose, cholesterol, total protein and lactic acid levels in blood were studied under semi-natural light dark conditions. P-GABA administration caused desynchronisation of the rhythms; while glucose and lactic acid rhythms were advanced, cholesterol and total protein rhythms were delayed. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA may reduce the photic information received by the clock. The results could be explained by slightly less than 1 hr daily delays (or) advances respectively which would bring the peak times to the points 21 days after the start of administration.

Cronoterapia cardiovascular: uma nova perspectiva no tratamento das cardiopatias / Cardiovascular chronotherapy: a new approach to the cardiopathies treatment

De acordo com o conceito de homeostase da fisiologia humana, o corpo näo deveria sofrer variaçöes durante o tempo. No entanto, recentemente, foram demonstradas variaçöes ao longo de um período de 24 horas (variaçäo circadiana) em vários sistemas do corpo humano, dentre os quais o cardiovascular. Em decorrência de tais modificaçöes provocadas no corpo, predispondo o indivíduo a doenças cardiovasculares em um determinado período do dia, surgiu o conceito de cronoterapia. O objetivo da cronoterapia nas doenças cardiovasculares é o de liberar concentraçöes variadas da droga em tempos diferentes durante o período de 24 horas de acordo com a necessidade biológica, a fim de, teoricamente, aumentar a eficácia da droga e reduzir os seus efeitos adversos. Além disso, evidências atuais de algumas enfermidades, cujos sintomas mostram um ritmo circadiano de ocorrência, respondem melhor ao tratamento quando os medicamentos säo administrados de maneira coordenada com esse ritmo.

Variaçäo circadiana do efeito do etomidato associado ao fentanil na anestesia para curetagem uterina / Ciradian variation of etomidate associated to fentanyl in uterine curettage anesthesia

Justificativa e objetivos - a maioria dasw funçöes orgânicas apresenta variaçöes farmacodinâmicas e farmacocinéticas controladas por sincronizadores externos e osciladores internos. O objetivo deste estudo foi verificar a variaçäo circadiana nos efeitos da associaçäo do etomidato com o fentanil em quatro períodos do dia, em pacients submetidas a anestesia para curetagem uterina. Métdo - participaram do estudo 24 pacientes, com idade entre 15 e 35 anos, estado físico ASA I, submetidas a anestesia venosa com etomidato (0,3 mg.kg elevado a menos um), para curetagem uterina de curta duraçäo, após a administraçäo prévia de fentanil - 2 µg.kg elevado a menos um (1º min.) e lidocaína - 0,5 mg.kg elevado a menos um (4º min.). Após a injeçäo de etomidato foram verificados o período de induçäo, o tempo de sono e o aparecimento de efeitos colaterais em cada hora do dia, sendo as pacientes agrupadas em quatro períodos para efeito comparativo dos resultados (manhä, tarde, noite, madrugada). Resultados - no período da madrugada observou-se induçäo mais rápida (43,3 ñ 6 s) com tempo de sono (12,2 ñ 2 min.) e inconsciência (13,2 ñ 2 min.) mais prolongados, mas sendo mais freqüente a apnéia. A tarde, ao lado de intensas mioclonias (83,3 por cento), näo se observou dor à injeçäo ou apnéia. De manhä, 23 das pacientes necessitaram de dose hipnótica complementar. Conclusöes - o etomidato associado ao fentanil induz hipnose noturna mais intensa e com grande estabilidade hemodinâmica, mas com freqüência variável de efeitos colaterais: à tarde, predominam as mioclonias e à noite, a apnéia. Há variaçäo circadiana no efeito hipnótico do etomidato para curetagem uterina.

Temporal oscillations of phosphatases in N-phthaloyl gamma-aminobutyric acid treated rats.

N-pathaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar and 24 hr rhythms of acid and alkaline phosphatases were studied under light-dark conditions. P-GABA administration advanced the peak times of phosphatases. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA might reduce the photic information received by the clock. The results could be explained by slight daily advances which would bring the peak times to the points 21 days after the start of administration.

Ritmo circadiano de las crisis hipertensivas: Implicaciones terapéuticas / Circadian variation of the hypertensive crisis

Antecedentes. Los eventos cardiovasculares agudos tienden a presentarse con un ritmo circadiano, que en algunos padecimientos -como el infarto agudo del miocardio- tienen repercusiones terapéuticas. Objetivo. Evaluar si las crisis hipertensivas poseen un ritmo circadiano, y si éste modifica la respuesta de las mismas al tratamiento. Material y métodos. Se evaluaron 50 pacientes que acudieron a nuestro hospital con diagnóstico de crisis hipertensiva (tensión arterial media > 130 mmHg y evidencia de daño al órgano blanco), registrandose hora de inicio de los síntomas, características del daño al órgano blanco, hora de consulta y respuesta al tratamiento. Esta se evaluó mediante ANDEVA de una dirección y t de Student. Resultados. 70 por ciento de los pacientes acudió a consulta después de las 12:00 h. Se detectaron dos picos de presentación de crisis hipertensivas, el más importante entre las 17 y las 19 h (45 por ciento de los casos), y un segundo pico entre las 9 y las 11 h (25 por ciento de los casos). Entre las 18 y 19 h, el número de casos fue significativamente mayor que el resto del día (p>0.001). Al evaluar la respuesta al tratamiento no hubo diferencias significativas en el control de las crisis hipertensivas respecto a la hora de presentación de las mismas. Conclusiones. Las crisis hipertensivas tienen un ritmo circadiano para su presentación; sin embargo, éste no repercute en la respuesta de las mismas al tratamiento con dinitrato de isosorbide en aerosol

Circadian time-dependent effects of fencamfamine on inhibition of dopamine uptake and release in rat striatal slices

Fencamfamine (FCF) is a central stimulant that facilitates central dopaminergic transmission through inhibition of dopamine uptake and enhanced release of the transmitter. We evaluated the changes in the inhibition of uptake and the release of striatal [3H]-dopamine at 9:00 and 21:00 h, times corresponding to maximal and minimal behavioral responses to FCF, respectively. Adult male Wistar rats (200-250 g) maintained on a 12-h light/12-h dark cycle (lights on at 7:00 h) were used. In the behavioral experiments the rats (N = 8 for each group) received FCF (3.5 mg/kg, ip) or saline at 9:00 or 21:00 h. Fifteen minutes after treatment the duration of activity (sniffing, rearing and locomotion) was recorded for 120 min. The basal motor activity was higher (28.6 + 4.2 vs 8.4 + 3.5 s) after saline administration at 21:00 h than at 9:00 h. FCF at a sigle dose significantly enhanced the basal motor activity (38.3 + 4.5 vs 8.4 + 3.5 s) and increased the duration of exploratory activity (38.3 + 4.5 vs 32.1 + 4.6 s) during the light, but not the dark phase. Two other groups of rats (N = 6 for each group) were decapitated at 9:00 and 21:00 h and striata were dissected for dopamine uptake and release assays. The inhibition of uptake and release of [3H]-dopamine were higher at 9:00 than at 21:00 h, suggesting that uptake inhibition and the release properties of FCF undergo daily variation. These data suggest that the circadian time-dependent effects of FCF might be related to a higher susceptibility of dopamine presynaptic terminals to the action of FCF during the light phase which corresponds to the rats' resting period.

La melatonina en el sistema inmunoneuroendocrino / Melatonin in the immuno-neuro-endocrine system

El conocimiento actual de las relaciones neuroendocrinas e inmunológicas confiere un rol importante a la melatonina (MT) en la regulación de los ritmos circadianos de los mamíferos. La función de la glándulapinela en todas las especies es traducir información del ciclo luz/oscuridad a los ritmos fisiológicos del organismo. La MT es producida casi exclusivamente en la oscuridad. En los humanos la secreción ocurre en correspondencia a la edad, disminuyendo en la vejez; guarda relación inversa con la temperatura del cuerpo; evidencia un efecto anti-estrés, posiblemente a través del sistema opioide; favorece la respuesta inmunológica y protege frente al daño tisular que provocan los radicales libres, por su fuerte acción antioxidante. La MT ha sido usada con éxito en la inducción del sueño en personas que ven perturbado su ritmo habitual de sueño por trabajos nocturnos, el síndrome de jet-lag u otras causas. No se ha logrado beneficio en el tratamiento de trastornos mayores del sueño, ni en la depresión ni en otros trastornos psiquiátricos. La presencia de receptores para la MT en múltiples órganos y sistemas estimula actualmente la investigación clínica sobre estas funciones posibles de la melatonina

Influence of melatonin on blood morphology in male albino mice.

Influence of melatonin on diurnal changes in hematological profiles was examined in male albino mice, at six hourly interval. Melatonin treatment either once daily (25 micrograms at 1700 hrs) or twice daily (25 micrograms at 0900 and 1700 hrs) for two weeks resulted in an alternation in the RBC rhythm. Generally the effect was suppressive though at some times the counts were marginally increased. Total WBC counts were increased and there was apparently a change in their rhythm too. Interestingly the differential WBC counts exhibited different patterns in, once and twice daily melatonin-treated mice. Melatonin given once daily predominantly stimulated the absolute lymphocyte count whereas the twice daily regimen predominantly stimulated the neutrophil count. This perhaps is related to the varied exposures of the animals to melatonin in the two experimental setups. Erythrocyte indices like mean cell volume, mean cell hemolglobin and mean cell hemoglobin concentration in both the experiments correlated with hemoglobin and hematocrit values. It may be concluded that melatonin has a modulatory role in hemopoiesis and its rhythms. The stimulatory effect of melatonin on WBC supports its purported immunopotentiating action.

Aplicaciones terapéuticas de la melatonina en la medicina del sueño y en la psiquiatría / Therapeutic uses of melatonin in sleep and in psichiatric disorders

La glándula pineal es la principal interfaz entre el medio ambiente luminoso, el SNC y el sistema endocrino. Su función primaria es la secreción de melatonina, con máximos durante el período de oscuridad. Diversos estudios han demostrado que la melatonina provee una señal interna de sincronización para numerosos ritmos circadianos. Una de las aplicaciones terapéuticas mejor definidas de la melatonina es su utilidad en trastornos circadianos del sueño, como el síndrome de fase retardada del sueño, jet-lag, trastornos del trabajo en turnos, insomnio en edad avanzada y alteraciones periódicas del sueño en la ceguera. La melatonina tiene muy baja toxicidad y no ha presentado efectos indeseados agudos demostrables en seres humanos. Sin embargo, se carece de información sobre sus efectos a largo plazo, por lo que es necesaria su farmacovigilancia.

Efecto antihipertensivo de la amlodipina 48 a 72 horas después del tratamiento: un estudio con presurometría ambulatoria / Antihypertensive effect of amlodipine 48 a 72 hours after treatment: a study with ambulatory blood pressure monitoring

Se llevó a cabo este estudio abierto, simple ciego, no comparativo y controlado con placebo en 30 pacientes sin evidencia de hipertensión secundaria, para evaluar la eficacia de la amlodipina administrada en una sola dosis al día. Después de un período de placebo de dos semanas, siguió un período de 10 semanas de tratamiento activo; la dosis inicial de amlodipina fue de 5 mg una vez al día, la cual se aumentó a 10 mg a las cuatro semanas, en los pacientes en los que no se controló la hipertensión. La determinación de la presión arterial de manera convencional se efectuó en la semana 0, al final de la primera y segunda semanas y cada dos semanas en la fase de titulación y al fin del estudio; las cifras obtenidas al final de la segunda semana del período de placebo se tomaron como basales. El monitoreo ambulatorio de la presión arterial se llevó a cabo el último día del período placebo, el primer día de tratamiento activo, durante el último día del período de mantenimiento y durante las 48 a 72 horas que siguieron a la última dosis. Los resultados demuestran que la amlodipina es efectiva en el control de la presión arterial a lo largo de las 24 horas del día y que su actividad antihipertensiva perdura aún en el lapso entre las 48 y 72 horas posteriores a la suspensión del tratamiento

Avaliaçäo do potencial gerado na interface eletrodo de referência-pele na medida do pH esofagiano / Evaluation of generated potential in the electrode-skin interface in esophageal pH measure

Para medição do pH esofagiano usa-se normalmente um eletrodo de vidro não combinado, o qual necessita de uma referência externa. Esta referência externa é obtida por meio de um eletrodo descartável de prata-cloreto de prata, que deve ser fixado na pele do paciente. Na interface eletrodo de referência-pele, é gerado um potencial cuja variação pode ser confundida com uma alteração na medida do pH esofagiano. Quantifica-se neste trabalho esta variação de potencial, com a finalidade de verificar a sua influência na monitoração 24 horas do pH.

ln order to measure the esophageal pH we normally use a combined glass electrode. which needs an externai reference. This externai reference is got through a silver-silver chloride electrode, which must be fixed to thc patient skin. ln the electrode-skin interface a potential is developed and its variation can be confused with an alteration of the esophageal pH measure. ln this work. this potential variation is quantified in order to verity its intluence in the 24 hours esophageal pH monitoring

Anestesia subaracnóidea com bupivacaína 0,5 por cento e lidocaína 2 por cento isentas de glicose e em dose fixa: da eficácia/toxicidade matutina e vespertina / Spinal anesthesia with 0,5 per cent bupivacaine and 2 per cent lidocaine without glucose in a fixed dose: efficacy/toxicity in the morning and in the afternoon

Justificativa e objetivos - Estudos sobre a raquianestesia isobarica (RAI) tem demonstrado sua utilidade para cirurgias perineais e ortopedicas de membros inferiores. Destacam-se a analgesia prolongada e o excelente bloqueio motor ao lado de discreta repercussao hemodinamica. O objetivo deste estudo foi avaliar eventual variacao circadiana na analgesia e dispersao cefalica das solucoes de lidocaina e bupivacaina sem glicose, no periodos matutino e vespertino, em pacientes de diferentes idades. Metodo - Participaram do estudo cinquenta e um pacientes, ASA I ou II, alocados aleatoriamente em dois grupos: Grupo Matutino (7-12h) e Grupo Vespertino (12-19h). A escolha do anestesico local (bupivacaina 0,5 ou lidocaina 2 em solucao isenta de glicose tambem foi aleatoria. A puncao subaracnoidea foi realizada no espaco L3 - L4 com agulha 7 (Quincke), por via mediana ou paramediana, sendo injetado o volume de 3 ml em 60 segundos. Foram pesquisados: a) latencia do bloqueio sensitivo; b) dispersao cefalica da analgesia; c) duracao da analgesia; d) as intercorrencias e as necessidades de correcao farmacologica hemodinamica. Resultados - A latencia do bloqueio sensitivo foi maior no periodo matutino. Os pacientes do grupo matutino apresentaram bloqueio sensitivo mais baixo (T8 - T10) e os do grupo vespertino necessitaram correcao farmacologica. Nao houve necessidade de complementacao analgesica per-operatoria. Nao se observou cefaleia nas primeiras 48h do pos-operatorio. conclusao - De acordo com este estudo a anestesia subaracnoidea, com solucao isenta de glicose, apresenta inicio de analgesia mais rapido e maior dispersao cefalica a tarde,ao lado de menor toxicidade matutina.

Eficácia do sotalol nas arritmias ventriculares idiopáticas com origem em trato de saída de ventrículo direito / Efficacy of Sotalol in Patients With Idiophatic Right Ventricular Arrhythmias

PURPOSE--To evaluate the effects of sotalol in patients (pts) with idiophatic ventricular arrhythmias (VT) from right ventricular outflow tract. METHODS--Eighteen pts with VT were enrolled (five with monomorphic repetitive ventricular tachycardia - MRVT). Pts were submitted to a double-blind crossover randomized study (placebo vs. 320 mg/po/d/sotalol; four weeks each), after a wash-out control period. Holter recording were recorded in control and placebo and drug periods. Eligible pts have > 50/h isolated ventricular premature beats (VPB) in control, with or without paired VPB or nonsustained VT (NSVT- > 3 beats, > 100bpm). Drug efficacy criteria was: > 75//reduction in isolated VPB and > 90//of paired VPB or NSVT. The effects of the drug on uncorrected QT interval was evaluated and also on circadian rhythm of VT through the hourly pNN50/VPB ratios. Values are given as mean +/- SD. Three recordings were compared by using paired Student's ®t® test. Statistical significance was assumed for p < 0.05. RESULTS--Differences between control and placebo were NS. Drug was effective in 61//of pts, reducing the 3 types of ET (VPB: placebo = 23.508 +/- 34.537; drug: 975 +/- 1357; paired placebo = 443 +/- 587; drug = 9 +/- 20). The drug was evaluated in 4 pts with MRVT, reducing all ectopic events, with efficacy of 60//over VPB and paired and 80//over NSVT (VPB: placebo = 52.639 +/- 42.207; drug: 1631 +/- 2062; paired: placebo = 796 +/- 754; drug: 20 +/- 30; NSVT: placebo = 4287 +/- 6343; drug: 9 +/- 11). Mean QT interval was 0.40 +/- 0.01s in control and 0.50 +/- 0.04s in the drug period, with no correlation between duration and efficacy. Sotalol modified the circardian rhythm of VPB in the non-responders group, mainly during the morning. CONCLUSION--Sotalol was effective in control of VT, mainly the MRVT. Its effect on VPB circadian rhythm may independently contribute to the overall efficacy profile and myocardial protective effect of this drug

Daily variation in plasma concentration of fencamfamine and striatal dopamine receptors in rats

Fencamfamine (FCF) is a psychostimulant drug classified as an indirect dopamine agonist. In the present study we evaluated the daily variation in plasma FCF concentration and in striatal dopamine receptors. Adult male Wistar rats (250-300 g) maintained on a 12-h light/12-h dark cycle (lights on at 07:00 h) were used. Rats received FCF (10.0 mg/kg, ip) at 09:00, 15:00, 21:00 or 03:00 h and blood samples were collected 30 (N = 6) or 60 (N = 6) min after the injections. Plasma FCF was measured by gas chromatography using an electron capture detector. Two-way ANOVA showed significant differences in FCF concentration when blood samples were collected 30 min after the injection, and the highest value was obtained following injection at 21:00 h. Moreover, at 15:00, 21:00 and 03:00 h, plasma FCF levels were significantly lower 60 min after injection when compared to the 30-min interval. Two other groups of rats (N = 6) were decapitated at 09:00 or 21:00 h and the striata were dissected for the binding assays. The Bmax for [3H]-spiroperidol binding to striatal membranes was higher at 21:00 h, without changes in affinity constant (Kd). In conclusion, plasma FCF levels and dopamine receptors undergo daily variation, a phenomenon that should be considered to explain the circadian time-dependent effects of FCF