Albendazole as a promising molecule for tumor control.

This work evaluated the antitumor effects of albendazole (ABZ) and its relationship with modulation of oxidative stress and induction of DNA damage. The present results showed that ABZ causes oxidative cleavage on calf-thymus DNA suggesting that this compound can break DNA. ABZ treatment decreased MCF-7 cell viability (EC50=44.9 for 24h) and inhibited MCF-7 colony formation (~67.5% at 5µM). Intracellular ROS levels increased with ABZ treatment (~123%). The antioxidant NAC is able to revert the cytotoxic effects, ROS generation and loss of mitochondrial membrane potential of MCF-7 cells treated with ABZ. Ehrlich carcinoma growth was inhibited (~32%) and survival time was elongated (~50%) in animals treated with ABZ. Oxidative biomarkers (TBARS and protein carbonyl levels) and activity of antioxidant enzymes (CAT, SOD and GR) increased, and reduced glutathione (GSH) was depleted in animals treated with ABZ, indicating an oxidative stress condition, leading to a DNA damage causing phosphorylation of histone H2A variant, H2AX, and triggering apoptosis signaling, which was confirmed by increasing Bax/Bcl-xL rate, p53 and Bax expression. We propose that ABZ induces oxidative stress promoting DNA fragmentation and triggering apoptosis and inducing cell death, making this drug a promising leader molecule for development of new antitumor drugs.

Homocysteine increase after acute myocardial infarction--can it explain the differences between case-control and cohort studies?

Several case-control studies agree that elevated homocysteinemia (HC) is a risk factor for cardiovascular disease, particularly for acute myocardial infarction (AMI). However, this agreement does not extend to prospective studies--some of which confirm and others (MRFIT and Karelia) reject this relation. After an AMI there are significant changes in biochemical and laboratory parameters, including a decrease in cholesterolemia, which takes several months to return to baseline levels. The evolution of HC after AMI is still unknown. In this work we set out to evaluate the evolution of homocysteinemia values after acute myocardial infarction. We evaluated fasting homocysteinemia in 34 sequential patients after admission to the Intensive Care Unit and after confirmation of acute myocardial infarction (26 male; mean age 63.8 +/- 13.9 years) in the first 36 hours, between the 3rd and 6th day, and one month after AMI. Simultaneously, we studied traditional risk factors and performed routine laboratory tests. The mean values found for HC were 13.85 +/- 5.46 mol/l in the first 36 hours after AMI, 16.16 +/- 6.63 mol/l between the 3rd and the 6th day, and 16.27 +/- 7.27 mol/l one month after myocardial infarction. The difference between the first and the second, and between the first and the third measurements, was significant (p < 0.05). The HC values found 3-6 days and one month after myocardial infarction were similar (p = 0.88). A highly significant correlation was found between HC values assessed in the first and second (correlation coefficient [CC] = 0.62) and in the second and third measurements (CC = 0.57), both with p = 0.001. We can conclude that HC levels increase significantly 36 hours after an acute myocardial infarction, an increase of around 20%, which is maintained until at least one month after the infarction. In these circumstances the difference in the vascular risk of HC found between case-control and prospective studies may be explained, at least partially, by the HC increase after AMI.

The natural history of closed mitral commissurotomy--a 20 year follow-up.

AIM: To study the natural history of mitral stenosis in a Portuguese population submitted to closed commissurotomy. METHODS-POPULATION: All the patients submitted to closed mitral commissurotomy in Pulido Valente Hospital. The commisurotomies were performed from 1956 to 1978 and included a total of 1,134 patients (220 males). Based on the clinical records, we studied the baseline characteristics of all the patients (n = 1134) at the time of surgery. An average of 20 years after surgery, we sent a questionnaire to all these patients. The patients who filled out the questionnaire (n = 352) represented the total Population in terms of the principal clinical characteristics. Based on these answers, we studied the long-term results of closed commissurotomy. RESULTS: Closed commissurotomy was performed before the age of 20 in about 10% of the patients and after the age of 49 in only 1.6%. The initial symptoms occurred at 22.0 years and commissurotomy was performed at 30.4 years (averages). The procedure was successful: 99% of patients improved significantly after commissurotomy and two thirds had major or total improvement. CONCLUSIONS: In the natural history of these commissurotomized patients the events were early, with symptoms in their twenties and surgery in their thirties. The events occurred earlier in males than in females. Closed commissurotomy presented, in this study and with these patients, very good results with improvement in 99% of the patients. The positive results the commissurotomies were important and long lasting: there was a low rate of re-intervention (16%) and hospitalization (35%) twenty years after surgery and 53% of the patients are still alive. These good results can be, at least in part, explained by the low age of this population at the time of surgery.

Analysis of the role of nitric oxide in the relaxant effect of the crude extract and fractions from Eugenia uniflora in the rat thoracic aorta.

This study has evaluated the possible role played by the L-arginine-nitric oxide pathway in the vasorelaxant action of the hydroalcoholic extract from Eugenia uniflora, and fractions from the extract, in rings of rat thoracic aorta. The addition of an increasing cumulative concentration of hydroalcoholic extract from E. uniflora (1-300 micrograms mL-1) caused a concentration-dependent relaxation response in intact endothelium-thoracic aorta rings pre-contracted with noradrenaline (30-100 nM). The IC50 value, with its respective confidence limit, and the maximum relaxation (Rmax) were 7.02 (4.77-10.00) micrograms mL-1 and 83.94 +/- 3.04%, respectively. The removal of the endothelium completely abolished these responses. The nitric oxide synthase inhibitors N omega-nitro-L-arginine (L-NOARG, 30 microM) and N omega-nitro-L-arginine methyl ester (L-NAME, 30 microM), inhibited the relaxation (Rmax) to -10.43 +/- 7.81% and -3.69 +/- 2.62%, respectively. In addition, L-arginine (1 mM), but not D-arginine (1 mM), completely reversed inhibition by L-NOARG. Methylene blue (30 microM), a soluble guanylate cyclase inhibitor, reduced the relaxation induced by the extract to 14.60 +/- 7.40%. These data indicate that in the rat thoracic aorta the hydroalcoholic extract, and its fractions, from the leaves of E. uniflora have graded and endothelium-dependent vasorelaxant effects.

[Amiodarone and the lung]. / Amiodarona e pulmão.

The pulmonary toxicity induced by amiodarone is one of the major complications that can limit the use of this potent antidysrhythmic agent. The authors perform a bibliographical revision concerning the toxic effects of amiodarone in the lung, pathogenesis, clinical, radiologic and pathologic features, diagnostic problems, risk factors and prognostic data.

[Pharmacological stimulation with dipyridamole in thallium-201 myocardial perfusion scintigraphy: a study of the secondary effects]. / Estimulação farmacológica com dipiridamol na cintigrafia miocárdica de perfusão com tálio-201: estudo dos efeitos secundários.

To evaluate the safety of intravenous dipyridamole thallium-201 imaging as an alternative to exercise thallium imaging in the evaluation of coronary artery disease, clinical data from 140 patients were retrospectively analyzed. Adverse effects were experienced by 39 patients (27.9%) with a total number of 52 effects: chest pain (23), dizziness (13), headache (7), nausea (7), dyspnea (2). All patients presented complete relief of symptoms. In 15 patients administration of aminophylline was necessary. Major effects (fatal and non fatal myocardial infarction and acute bronchospasm) were not registered. Vital sign data change observed after infusion of dipyridamole was: decreased blood pressure and increased pulse rate. Patient's age and incidence of coronary artery disease did not differ significantly in the subgroup of patients with adverse effects versus the group of patients without it.

[Acute and chronic sequential atrioventricular pacing in patients with obstructive-type hypertrophic myocardiopathy resistant to medical therapy]. / Electroestimulação aurículo-ventricular sequencial aguda e crónica em doentes portadores de miocardiopatia hipertrófica de tipo obstrutivo resistente à terapêutica médica.

An evaluation was undertaken regarding two female patients suffering from obstructive hypertrophic cardiomyopathy, with high and strongly symptomatic gradients, as well as evidencing a resistance to medication with beta-blockers, verapamil and disopyramide when administered in maximal doses. These patients were provided with the implant of a definitive type DDD pacemaker, with an auricular electrocatheter placed on the right auricular appendix, and with a bipolar ventricular catheter placed on the apex of the right ventricle. The generator was programmed with a short AV so as to ensure that the ventricular stimulation would at any given time be the result of the ventricular contraction would be initiated at the apex portion of the right ventricle. With these therapeutics, we observed not only a reduction or even the gradient, but also the complete elimination of the existing symptoms--angor, dyspnea, dizziness, palpitations and fainting--with the resulting normalcy of the quality of life of the patients. All taken into account we are of the opinion that these therapeutics are, in the case of patients suffering from obstructive hypertrophic cardiomyopathy, a valid alternative for surgical treatment by means of myectomy or myotomy, but without the morbidity and mortality rates presented by such methods.

Aqueous outflow system in familial amyloidotic polyneuropathy, Portuguese type.

Familial amyloidotic polyneuropathy (FAP) is a hereditary disease which may present a wide range of ocular manifestations. Glaucoma is amongst the most serious complications of FAP. We report the results of ultrastructural study of the trabecular meshwork in a glaucomatous patient with the Portuguese form of FAP. This study showed that there was marked anatomical disruption of the uveoscleral, cornoscleral meshworks and juxtacanalicular tissue characterized by (a) accumulation of amyloid fibrils in the intertrabecular spaces; (b) degeneration of the endothelial cells; (c) homogeneous and/or multilayered plaques of basement membrane-like material loading the intertrabecular spaces or protruding to the lumen of the Schlemm's canal; and (d) degeneration of unmyelinated nerve fibres. These morphological changes and an analysis of the literature suggest that mechanical and neuropathic events can be co-existing factors which enhance the resistance to aqueous humour outflow, leading to increased intraocular pressure and glaucoma in the Portuguese form of FAP.

[Treatment of heart insufficiency in the elderly with converting enzyme inhibitors]. / Terapêutica da insuficiência cardíaca do idoso com os inibidores da enzima de conversão.

The main objectives of the treatment of Congestive Heart Failure are the improvement of quality of life and the reduction of mortality. Both are accomplished by the ACE inhibitors. The most important trials on the effect of ACE inhibitors on the improvement of the quality of life are reviewed. Trials about the reduction of mortality with ACE inhibitors are analysed. The sudden death problem was considered and so the relationship of this with ventricular arrhythmias. The recent evidence of a beneficial effect of captopril was reported. At last we analyse secondary effects of these drugs on the treatment of Heart Failure in old patients.

[What is the value of myocardial perfusion studies with isotopes in patients with complete left bundle branch block?]. / Qual o valor dos estudos de perfusão miocárdica com isótopos em doentes com bloqueio completo de ramo esquerdo?

The prognosis of left bundle branch block is determined by associated cardiovascular disease. Exercise electrocardiography is not helpful in detecting ischemia in these patients. Exercise thallium-201 scintigraphy has been widely accepted for that purpose. The authors made an overview of several studies suggesting that exercise thallium-201 scintigraphy has low specificity regarding left anterior descending coronary artery disease. They also review the mechanisms of perfusion defects in patients with left bundle branch block without coronary artery disease. One important question to be clarified is weather small defects are unrelated to coronary artery disease. Finally the authors analyse a few methods to increase diagnostic accuracy of perfusion scintigraphy in left bundle branch block. First the employment of a new criterium that requires the apex to be abnormal to indicate left anterior descendent artery disease. Second Pharmacological Stress with Dipyridamole or Adenosine. Third imaging with Tc-99m-MIBI.

[The use of diuretics in heart insufficiency in the elderly]. / A utilização dos diuréticos na insuficiência cardíaca do idoso.

The kidney function alterations with age and on congestive heart failure, are reviewed as the pharmacocynetic and pharmacodynamic of the diuretics on old patients with this syndrome. The therapeutic importance of hiposodic diet was considered. The reasons for the susceptibility of old people to diuretics and the criteria for the choice of the diuretic on this age, are reviewed. So are the most important adverse effect of diuretics on old people and the contra-indication for the use of these drugs on elderly. The importance of hypocalaemia on old people and how to prevent or correct it are considered. The haemodynamic risks of an excessive diureses are reviewed. Finally, we propose some recommendations about the use of diuretics on the elderly.

Antihypertensive treatment and regression of atherosclerosis.

Reduction of high blood pressure has an effect on coronary mortality and morbidity lower than expected. One of the possible explanations is the different anti-atherogenic capacity of anti-hypertensive drugs. Reduction of high blood pressure has, by itself, an anti-atherogenic effect, but, for some anti-hypertensive drugs, there is experimental and clinical evidence of anti-atherogenic properties. For calcium antagonists experimental data have been published reporting reduction of aortic lipidic deposition and decrease of arterial proliferation. The INTACT trial has shown that the development of new atherosclerotic lesions was delayed by nifedipine. For beta-blockers, in spite of the negative effect on atherogenic fractions, the experimental evidence, so far collected, suggests a possible anti-atherogenic effect. ACE inhibitors have been experimentally studied and its anti-atherogenic effect reported on studies with the WHHR rabbit and cynomolgus monkey. The different possible mechanisms for these anti-atherogenic properties are analysed. Ketanserine is a serotonin antagonist witch anti-atherogenic capacity is under investigation on the PACK trial. The results that were published so far seem to confirm that capacity.

[Heart failure in the elderly (from diagnosis to therapy)]. / A insuficiência cardíaca no idoso (do diagnóstico à terapêutica).

After some considerations about the importance of heart failure on the elderly, the medical literature about epidemiologic and necropsy data on etiologic forms of heart failure, is reviewed. The importance of the associated pathologies to heart failure on the elderly is evaluated in what the diagnosis and treatment of this syndrome is concerned. We characterize the physiopathologic types of heart failure on the elderly. We refer how important is to recognize the treatable forms of heart failure, mainly the aortic valve stenosis.

[Effect of converting enzyme inhibitors in cardiac insufficiency mortality in the elderly]. / Efeito dos inibidores do enzima de conversão na mortalidade dos idosos em insuficiência cardíaca.

In a retrospective study we analyse two populations of aged patients in congestive heart failure, one treated with ACE inhibitors other not and the other with conventional therapy. Both populations received the same medication (diuretics and digitalis) and are equivalent in age, sex distribution, NYHA functional class and echocardiographic left ventricular parameters. Comparing the mortality of the two populations at the first, second and third year of follow-up, a statistically significant reduction in mortality was found on the ACE inhibitors treated population, at the first year. However, this reduction did not reach statistical significance at second and third years. The results are similar to trials in which the effects of ACE inhibitors are studied on general populations in heart failure.

[Specifying for the general physician. Digitalis therapy in elderly patients]. / Especificando para o generalista. A terapêutica digitálica no doente idoso.

The experimental and clinical evidence on the decreased efficacy of digitalis on old age are reviewed. The trials on the efficacy of digitalis on elderly in heart failure and sinus rythm, are analysed and we try to characterize the sub-group of responders. So we try to explain the criteria to choose the therapeutic dose, to avoid intoxication and to interpret the seric concentrations. We describe the pharmacocynetics of digitalis on old people on heart failure which can explain the susceptibility to intoxication. We reviewed the incidence of digitalis intoxication on old age and the difficulties on its recognition.

[Morpho-functional characteristics of the heart in the elderly]. / Aspectos morfo-funcionais do coração do idoso.

Alterations in cardiovascular structure and function with advancing age are reviewed. The difficulty to distinguish between aged related alterations and those due to coronary disease are analysed. The results of the studies in which coronary disease are excluded are compared with those in which that situation was present. Cardiac output, systolic volume and peripheral vascular resistence are the differences. The physiological adaptations of the heart to effort are analysed. The adaptation of the heart to effort is quite different according to Coronary Disease have been excluded or not on the population.