Reducao do tempo de latencia para o efeito antidepressivo pela administracao de pindolol / Pindolol as a means to decrease the latency period to obtain antidepressant effect

Diferentes farmacos antidepressivos aumentam os niveis extracelulares de serotonina (5-HT) nos nucleos da rafe e do mesencefalo. Como resultado desse aumento, ocorre ativacao dos autoreceptores somatodendriticos 5-HT que, por mecanismo de feedback negativo, determina uma subsequente reducao na liberacao de 5-HT. Esse mecanismo tem sido implicado como uma das causas do retardo no inicio de acao dos inibidores da recaptacao de serotonina (ISRSs) apos sua administracao...

Treatment of antidepressant nonresponders: augmentation or switch?

Selective serotonin reuptake inhibitors (SSRIs) are now commonly used in the treatment of major depression. In all patients starting treatment, the intent-to-treat response rate is about 50%. The other 50% will require some change in treatment, either augmentation or switch to a different agent. In this report, augmentation strategies are reviewed, with special attention to those strategies that have been used with the SSRIs. The data for switching antidepressants also are reviewed. Although there are no direct comparison studies of augmentation strategies versus switching that address the question of relative efficacy, the tactical issues that pertain to augmentation or switching are discussed.

Alterations in iron metabolism and the erythron in major depression: further evidence for a chronic inflammatory process.

There is now some evidence that major depression is accompanied by biochemical and immune changes pointing to the presence of a chronic inflammatory response. The latter condition is reportedly characterized by changes in iron (Fe) metabolism and the erythron, such as decreased serum Fe and transferrin (Tf) and increased serum ferritin, lower number of red blood cells (RBC), lower hematocrit (Htc) and hemoglobin (Hb). The aim of the present study was to examine Fe metabolism and the erythron in 38 major depressed subjects versus 15 normal volunteers, as well as the effects of antidepressant treatments on these variables. Major depressed subjects had significantly lower serum Fe and Tf, a lower number of RBC, lower Htc and Hb, and a significantly increased number of reticulocytes than normal controls. Serum ferritin was significantly higher in major depressed patients with melancholia than in those with simple major depression and normal controls. Mean corpuscular volume (MCV), MC Hb (MCH), MC Hb concentration (MCHC) and RBC distribution width (RDW) were not significantly different between major depressed subjects and normal controls. Treatment with antidepressants during 5 weeks had no significant effect on the alterations in number of RBC and reticulocytes, Htc, Hb, Fe and Tf. There were significant relationships between the above Fe and erythron variables and established immune-inflammatory markers of major depression, e.g., lowered serum albumin and zinc and the increased electrophoretically-separated alpha 1-globulin fraction. The results suggest that the disorders in Fe metabolism and the erythron during major depression may be induced by the immune-inflammatory response in that illness.

The 5-HT1B receptor mediates the effect of d-fenfluramine on eating caused by intra-hypothalamic injection of neuropeptide Y.

d-Fenfluramine (0.63 mg/kg i.p.), a serotonin (5-hydroxytryptamine, 5-HT) releaser and re-uptake inhibitor, reduced the eating caused by neuropeptide Y (235 pmol) injected into the paraventricular nucleus of the hypothalamus. The 5-HT1 and 5-HT2 receptor antagonist metergoline (1.0 and 2.0 mg/kg i.p.) and the 5-HT1A and 5-HT1B receptor antagonist (+/-)-cyanopindolol (3.0 and 8.0 mg/kg s.c.) significantly antagonized the effect of d-fenfluramine. The 5-HT2A and 5-HT2C receptor antagonist mesulergine (0.1 and 0.3 mg/kg s.c.) and the 5-HT2A receptor antagonist ketanserin (2.5 and 5.0 mg/kg i.p.) did not significantly modify the effect, nor did the 5-HT1A and 5-HT1B receptor antagonist (-)-propranolol (20-40 nmol), injected bilaterally into the paraventricular nucleus of the hypothalamus. The results suggest that d-fenfluramine reduces neuropeptide Y's hyperphagia by indirectly stimulating 5-HT1B receptors outside the paraventricular nucleus of the hypothalamus.

Effects of pindolol on the cardiovascular response to tracheal intubation.

Laryngoscopy and tracheal intubation often cause hypertension, tachycardia and arrhythmias, which may be exaggerated during rapid-sequence induction of anaesthesia. We have studied the efficacy of pindolol in attenuating the cardiovascular responses to laryngoscopy and intubation in patients receiving pindolol 2 micrograms kg-1 or 4 micrograms kg-1 3 min before induction of anaesthesia in a double-blind design. The data were compared with those in a control group receiving saline. Each group consisted of 10 patients undergoing elective surgery. Anaesthesia was induced with thiopentone 5 mg kg-1 i.v. and tracheal intubation was facilitated with vecuronium 0.2 mg kg-1. Patients receiving saline showed a significant increase in mean arterial pressure and heart rate associated with tracheal intubation. These increases after tracheal intubation were reduced in pindolol 4 micrograms kg-1 treated patients compared with those in the control group (P less than 0.05). Pindolol 2 micrograms kg-1 attenuated tachycardia in response to intubation but did not affect hypertension. These data suggest that a bolus injection of pindolol 4 micrograms kg-1 is a simple, practical and effective method for attenuating cardiovascular responses to laryngoscopy and tracheal intubation.

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.

Pharmacokinetics after a single oral dose of bopindolol in patients with cirrhosis.

The plasma concentration-time curve of the hydrolysis product of bopindolol has been investigated in 14 patients with cirrhosis and in 15 healthy volunteers given a single oral dose of 2 mg bopindolol. Cirrhosis was confirmed by history and clinical examination or liver biopsy. The time to maximum concentration, maximum concentration and AUC of hydrolyzed bopindolol were similar in the patients and controls. However, the elimination half-life was 6.0 h in controls and 9.5 h in cirrhotics. Antipyrine clearance was markedly decreased in patients with cirrhosis, but no correlation was found with the pharmacokinetic parameters of hydrolysed bopindolol. Although the AUC was not significantly altered in patients with cirrhosis, the longer half-life of hydrolysed bopindolol suggests impairment of its disposition in liver disease, which could lead to significant accumulation of drug during chronic dosing.

[Antihypertensive effect of bopindolol on stroke-prone spontaneously hypertensive rats (SHRSP)].

The antihypertensive effect of bopindolol, a long-acting beta-adrenoceptor blocking agent, was investigated in stroke-prone spontaneously hypertensive rats (SHRSP). One group received tap water during the period of 8 to 32 weeks of age. The average dose of bopindolol administered was calculated from water intake to be approximately 1.4 mg/kg/day. The lowering effect in blood pressure of bopindolol was apparent at the age of 14 weeks, and this continued up to the end of the experiment. Bopindolol significantly reduced the heart rate. Plasma levels of urea nitrogen (BUN), triglyceride, and phospholipid of SHRSP treated with bopindolol were lower than those of the control SHRSP. One of the 8 control SHRSP died, and no rats treated with bopindolol died during the experiment. The histopathological study revealed that three of the control SHRSP had cerebral apoplexy, whereas there was no evidence of cerebral apoplexy in the treated SHRSP. Chronic treatment of bopindolol clearly alleviated myocardial fibrosis and hypertrophic changes in the left ventricular wall of the heart. Decreases in the incidence of proliferative arteritis and malignant nephrosclerosis in the kidney and necrotizing arteritis of the mesenteric arteries were observed in SHRSP treated with bopindolol. The data presented indicate that bopindolol is a powerful antihypertensive agent.

[Perioperative therapy in juvenile pheochromocytoma]. / Die perioperative Therapie beim kindlichen Phäochromozytom.

The article reports on the paediatric-anaesthesiological treatment of 6 phaeochromocytomas in 5 children who were 8 to 16 years of age. Therapeutic recommendations for the perioperative medication of infantile phaeochromocytoma patients are involved. The therapeutic aim of this study was the management of the effects of phaeochromocytoma before and after extirpation of the tumour, the effect of the phaeochromocytoma being of an alpha-adrenergic and beta-adrenergic cardiovascular nature and transmitted by catecholamines. Preoperative stabilization of blood pressure by means of the alpha-blocker phenoxybenzamine and a subsequent intraoperative, controlled reduction of blood pressure by means of sodium nitroprusside were found to be an effective, safe and easily appreciated therapeutic concept for the perioperative care of paediatric phaeochromocytoma patients. Considerable individual differences in dose an duration of the necessary preoperative phenoxybenzamine administration rendered ward control of therapy recommendable. The risk of complete alpha-sympathicolysis by additive drug effects during premedication and induction of anaesthesia, had to be taken into consideration for conducting phenoxybenzamine therapy. Additional administration of the beta-blocker pindolol successfully controlled the intraoperatively manifested tachycardial heart rhythm phases without provoking any complicating arrhythmias. During the entire perioperative treatment of the patients it is mandatory to ensure sufficient substitution of intravascular volume to prevent hypotensive complications. Our patients did not need any cardiac and sympathicomimetic drugs as postoperative administration. None of the patients had any perioperative complications worth mentioning.

Análise fonomecanocardiográfica em pacientes hipertensos tratados com pindolol / Phonomechanocardiographic analysis in hypertensive patients treated with pindolol

Com o objetivo de avaliar as alteraçöes da funçäo ventricular esquerda em pacientes tratados com pindolol, mensuraram-se os intervalos sistólicos (IS) através da fonomecanocardiografia (FMC) em 19 pacientes. Selecionaram-se hipertensos com diastólica acima de 95 mmHg submetidos a FMC controle e posteriormente a medicaçäo com pindolol na dose de 10 - 15mg/dia, reajustada no 15§ dia. No 30§ dia de tratamento, reavaliou-se, observando reduçäo > ou = 10% dos níveis tensionais em 14 pacientes (74%), sem alteraçöes significativas em ISS. Dos sete (36,8%) pacientes que após tratamento näo reduziram a TA diastólica abaixo de 95mmHg, cinco (71,4%) apresentaram QS igual ou maior de 0,41. Todos com TA distólica controlada apresentaram QS abaixo de 0,38. Conclui-se que, nas doses empregadas, a droga reduz significativametne os níveis tensionais dos pacientes hipertensos estudados, principalmente os com QS abaixo de 0,41, sem alterar a funçäo ventricular esquerda avaliada por parâmetros fonomecanocardigráficos

[Therapy of postoperative arrhythmias (author's transl)]. / Therapie postoperativer Herzrhythmusstörungen.

Severe supraventricular and ventricular tachyarrhythmias occurred after surgery in 9 patients. Oxprenolol or pindolol were used as primary drugs in 8 cases. The effect of therapy was documented quantitatively by an arrhythmia computer with trendscription and alarm recording. Beta-receptor blockade was successful in 6 cases. On supraventricular tachycardia with Wolff-Parkinson-White syndrome was abolished by quinidine. Severe ventricular instability with fibrillation following myocardial infarction was temporarily suppressed by lidocaine. One fatal outcome was caused by severe illness. Although all patients were suffering from coronary artery and/or hypertensive heart disease with diminished cardiac reserve, no serious side effects were directly related to beta-receptor blockade. Therefore beta-receptor blocking drugs are recommended as drugs of first choice in the treatment of postoperative arrhythmias induced by sympathetic overstimulation. Dysrhythmias based on cellular pathology should be treated with conventional antiarrhythmic drugs alone or combined with beta-blockers.

Effect of dihydroergotoxine on cyclic-AMP-generating systems in rat cerebral cortex slices.

In slices of rat cerebral cortex, cyclic-AMP formation is stimulated in response to added noradrenaline (NA), isoproterenol (ISP) or adenosine. The effect of ISP could be antagonized only by the selective beta-adrenoceptor-blocking agent pindolol, whereas the stimulating effect of NA could be antagonized by both alpha- and beta-adrenoceptor-blocking agents. Dihydroergotoxine (DHET) at low concentrations (10(-8)M) antagonized the stimulating effect of NA but not of ISP or adenosine, suggesting that this substance has a high affinity for central alpha-adrenoceptors. We could also show that DHET is accumulated in rat cerebral cortex after repeated oral application. In slices of cortex obtained from rats after treatment with DHET for 3 and 6 weeks, but not after 1 week, NA had a significant lower effect on cyclic-AMP formation than in slices from corresponding controls.

Hormonal control of liver regeneration.

Two peaks in cyclic AMP production in rat livers 4 and 12h after partial hepatectomy (MacManus et al., 1972) were confirmed and a third peak established at 22h, which is the peak of DNA synthesis. The increases in cyclic AMP were prevented by beta-adrenergic blocking agents, propranolol and pindolol, without affecting ornithine decarboxylase induction or DNA synthesis. The alpha-blocking agents, phenoxybenzamine and phentolamine, given at the time of partial hepatectomy, delayed the rise in ornithine decarboxylase normally found 4h after operation, but did not affect DNA synthesis. If the alpha-blocking agents were given at 9-12h or 18h, the onset of DNA synthesis was delayed. Phenoxybenzamine did not affect the induction of ornithine decarboxylase in intact rat livers by glucagon or growth hormone, but did inhibit induction by dexamethasone. The induction of ornithine decarboxylase produced by dexamethasone was inhibited by 17alpha-hydroxy-progesterone; this compound also blocked the induction of ornithine decarboxylase in livers of partially hepatectomized rats.