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OBJECTIVE: To evaluate the effectiveness of eletriptan for acute migraine treatment and patient satisfaction with the drug in usual clinical practice settings. METHODS: Male and female patients of practicing neurologists, aged 18 to 65 years, were eligible for inclusion in the study if they met International Headache Society criteria for migraine. RESULTS: Of 637 patients enrolled, 611 completed the study. At 1 hour post-dose headache response was 59.5% (average from three attacks), pain-free 13%, absence of vomiting 86.3%, and improvement in functioning 55%. Headache recurrence occurred in 12%, second dose was used by 12.6% patients, and rescue medication by 6.4%. Patient preference for eletriptan versus any other triptan used in the past was 97%. CONCLUSION: In this real-life setting, eletriptan displayed high efficacy, consistency of response over three attacks and was preferred by 97% patients (Tab. 2, Fig. 5, Ref. 16). Full Text (Free, PDF) www.bmj.sk.

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Adenosine is an endogenous nucleoside that has been shown to be beneficial for the myocardium in different settings by a large number of experimental studies. In this article, we 1) outline adenosine's metabolic pathways, 2) address cardioprotective properties of adenosine, and 3) discuss possible implications of the two recently published clinical studies disclosing a positive effect of adenosine monophosphate deaminase 1 (AMPD1) gene mutation on cardiovascular survival in heart failure and ischemic heart disease. (Fig. 2, Ref. 84.)

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Besides the reduction of angiotensin II formation, locally increased kinins may play a role in the cardiovascular action of angiotensin converting enzyme (ACE) inhibitors. To characterize the contribution of bradykinin to the effects of ACE inhibition by captopril on the development of pressure overload hypertrophy, sham-operated rats and rats with ascending aortic constriction were treated with captopril (80 mg/kg/day) or captopril and B2 kinin receptor antagonist HOE 140 (0.5 mg/kg/day) for 7 weeks. Left ventricular mass and geometry, hydroxyproline concentration and myosin isozymes (marker of a fetal phenotype) were assessed. Rats with aortic constriction exhibited a marked increase in left ventricular weight and diastolic pressure-volume relationship was shifted to smaller volumes. Signs of congestive heart failure were not apparent. The hydroxyproline concentration remained unaltered. However, the proportion of isomyosin V3 was increased (p < 0.05). Administration of captopril reduced (p < 0.05) systolic blood pressure, body and cardiac weight in all treated rats. The reduction of left ventricular weight was disproportionally higher in pressure overloaded rats, thus the relative left ventricular weight decreased by 15% (p < 0.05). Captopril augmented the isomyosin V1 expression (p < 0.05) in sham operated as well as pressure overloaded rats. The isomyosin V1 percentage was inversely related to the relative left ventricular weight. Two different (p < 0.05) correlation lines were detected for untreated and captopril treated rats. None of captopril associated effects were removed by simultaneously administered B, kinin receptor antagonist HOE 140. Thus, stimulation of bradykinin B2 receptor appears not to mediate the effects of captopril on cardiac growth and contractile proteins during the development of pressure overload hypertrophy.

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It remains unknown whether angiotensin-converting enzyme (ACE) inhibition can prevent heart failure in rats with a fixed high pressure load of the left ventricle and if this effect could be attributed to normalization of contractile protein phenotype and cardiac collagen content. Rats with constriction of the ascending aorta were treated with the ACE inhibitor quinapril (6 mg kg(-1) day(-1)) (n=95) or placebo (n=96) (starting 6 weeks post surgery. Quinapril treatment improved survival markedly (P<0.0000001) during the 24 weeks observation period. There were 69 deaths with placebo and only 25 deaths with quinapril. At the end of the observation period signs of left ventricular backward failure were, however, detected in 75 rats with placebo and in 67 rats treated with quinapril (P=0.229). Cox proportional hazard model with time-dependent covariates was used to document that the effect of quinapril treatment had been dependent on time. Quinapril had no significant effect on the development of morphological signs of left ventricular dysfunction after the first 54 days of treatment. The increased isomysin V(3) proportion of hypertrophied non-failing hearts was also not affected by quinapril treatment. Irrespective of treatment, failing hypertrophied hearts were characterized by an increase in left ventricular volume (P<0.05), percentage of the 'foetal' isomyosin V(3) (P<0.05), and hydroxyproline concentration (P<0.05). While the cause of the improved survival remains unknown, quinapril did apparently not interfere with the restitution of 'foetal' gene expression of pressure overloaded cardiomyocytes leading to depressed myocardial performance, ventricular dysfunction and the consecutive myocardial fibrosis.

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1. Etomoxir (2[6(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), an irreversible carnitine palmitoyl-transferase 1 inhibitor, reduces the expression of the myocardial foetal gene programme and the functional deterioration during heart adaption to a pressure-overload. Etomoxir may, however, also improve the depressed myocardial function of hypertrophied ventricles after a prolonged pressure overload. 2. To test this hypothesis, we administered racemic etomoxir (15 mg kg(-1) day(-1) for 6 weeks) to rats with ascending aortic constriction beginning 6 weeks after imposing the pressure overload. 3. The right ventricular/body weight ratio increased (P<0.05) by 20% in etomoxir treated rats (n = 10) versus untreated rats with ascending aortic constriction (n = 10). Left ventricular weight was increased (P<0.05) by 8%. Etomoxir blunted the increase in left ventricular chamber volume. Etomoxir raised the proportion of V1 isomyosin (35+/-4% versus 24+/-2%; P<0.05) and decreased the percentage of V3 isomyosin (36+/-4% versus 48+/-3%; P<0.05). 4. Maximum isovolumically developed pressure was higher in etomoxir treated rats than in untreated pressure overloaded rats (371+/-22 versus 315+/-23 mmHg; P<0.05). Maximum rates of ventricular pressure development (14,800+/-1310 versus 12,340+/-1030mmHg s(-1); P<0.05) and decline (6440+/-750 versus 5040+/-710 mmHg s(-1); P<0.05) were increased as well. Transformation of pressure values to ventricular wall stress data revealed an improved myocardial function which could partially account for the enhanced function of the whole left ventricle. 5. The co-ordinated action of etomoxir on ventricular mass, geometry and myocardial phenotype enhanced thus the pressure generating capacity of hypertrophied pressure-overloaded left ventricles and delayed the deleterious dilative remodelling.

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Left ventricular hypertrophy with adequate wall thickness, preserved adult phenotype and extracellular matrix may be useful in the prevention of heart failure. Because activation of subtype 1 of angiotensin II (AT1) receptors is thought to be involved in the hypertrophic response of cardiomyocytes, we tested the potential of systemic AT1 blockade to modify the development of left ventricular hypertrophy due to pressure overload. Sham-operated rats and rats with ascending aorta constriction were treated with losartan (30 mg/kg/day) for 8 weeks. Left ventricular geometry, dynamics of isovolumic contractions, hydroxyproline concentration as well as myosin isozymes (marker of fetal phenotype) were assessed. Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure-volume relationship was shifted to smaller volumes. An enlarged ventricular pressure-volume area and increased (p < 0.05) peak values of +dP/dtmax and- dP/dtmax demonstrated an enhanced overall ventricular performance. Signs of congestive heart failure were not apparent. In contrast, parameters of myocardial function (normalized length-stress area, +d delta /dtmax and -d delta /dtmax) were depressed (p < 0.05), indicating an impaired myocardial contractility. The hydroxyproline concentration remained unaltered. However, the proportion of beta-myosin heavy chains (MHC) was increased (p < 0.05). Administration of losartan decreased (p < 0.05) blood pressure and body weight in sham operated and pressure overloaded rats. By contrast, neither the concentric left ventricular hypertrophy or depressed myocardial function nor the increased beta-MHC expression were significantly altered. Thus, activation of AT1 receptors appears not to be involved in the initial expression of the fetal phenotype of pressure overloaded heart which may be responsible for the progressive functional deterioration of the hypertrophied ventricle.

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To test the ability of the heart to express characteristic geometric features of concentric and eccentric hypertrophy concurrently, constriction of the ascending aorta was performed in 4-week-old rats. Simultaneously, these rats were treated with an arteriolar dilator minoxidil. An examination 6 weeks after induction of the hemodynamic overload revealed no signs of congestion in systemic or pulmonary circulation in rats with aortic constriction or minoxidil-treated sham-operated rats. The magnitude of hemodynamic overload caused by aortic constriction or minoxidil treatment could be considered as equivalent, because the same enlargement of left ventricular pressure-volume area was necessary to compensate for either pressure or volume overload. Myocardial contractility decreased in rats with aortic constriction, and the compensation was achieved wholly by the marked concentric hypertrophy. Volume overload in minoxidil-treated rats was compensated partially by the eccentric hypertrophy and partially by the increased myocardial contractility. In contrast, increased lung weight and pleural effusion were found in all minoxidil-treated rats with aortic constriction. Unfavorable changes in left ventricular mass and geometry, relatively high chamber stiffness, and depressed ventricular and myocardial function were responsible for the massive pulmonary congestion.

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BACKGROUND: Numerous studies have demonstrated diverse abnormalities in subcellular structures of pressure-overloaded hypertrophied and failing heart. Long-term administration of etomoxir, a carnitine palmitoyltransferase-1 inhibitor, partially normalized the proportion of myosin isozyme V1 and number of active Ca2+ pumps in hypertrophied rat myocardium. METHODS AND RESULTS: To test the hypothesis that long-term etomoxir treatment improves the performance of hypertrophied ventricle, sham-operated rats and rats with ascending aorta constriction were treated with racemic etomoxir (15 mg/kg per day) for 12 weeks. Left ventricular geometry, dynamics of isovolumic contractions, as well as myosin isozymes as marker of etomoxir-induced phenotype changes were assessed. Etomoxir stimulated (P<.05) slight hypertrophic growth in right and left ventricles of sham-operated rats as well as in right ventricles but not in overloaded left ventricles of rats with aortic constriction. In all treated rats, etomoxir increased (P<.05) maximal developed pressure, left ventricular pressure-volume area, and +/- dP/dt(max). Enhanced values (P<.05) of derived indexes of myocardial performance (normalized stress-length area, maximal rate of wall stress rise, and decline) indicated that myocardial changes were responsible for the improved performance. The etomoxir treatment increased selectively (P<.05) the proportion of myosin V1 in pressure-overloaded left ventricles. CONCLUSIONS: The long-term treatment with etomoxir improved functional capacity of pressure-overloaded left ventricle, which can be attributed to an enhanced myocardial performance. Chronic carnitine palmitoyltransferase-1 inhibition may thus represent a candidate approach for developing novel agents that are useful in the prevention of undesirable consequences of pressure overload-induced cardiac hypertrophy.

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We investigated the effect of captopril on the growth of the left ventricle in an experimental model of aortic insufficiency. Four groups of rabbits were studied 28 days after experimental intervention: 1. control, 2. control with captopril (10 mg/kg/day), 3. aortic insufficiency, 4. aortic insufficiency with captopril (10 mg/kg/day). Aortic insufficiency induced hypertrophic growth of the left ventricle demonstrated by increased weight and ribonucleic acid (RNA) concentration. Administration of captopril only slightly attenuated the weight increase of the left ventricle and the increase in concentration of left ventricular RNA. However, captopril reduced the concentration of left ventricular deoxyribonucleic acid (DNA) both in the control and even more in the group with aortic insufficiency. The chronic haemodynamic overload enhanced mitochondrial respiration in the left ventricle which was not influenced by captopril. We conclude that captopril in the dose 10 mg/kg/day did not prevent hypertrophy of the left ventricle but reduced left ventricular DNA concentration.

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To define vascular effects of an enhanced dietary alpha-linolenic acid intake, 28 spontaneously hypertensive rats were fed a 3% sunflowerseed oil (44% linoleic acid) diet; in 3 groups (7 rats each), the diet was supplemented with 1, 2.5 or 5% linseed oil containing 62% alpha-linolenic acid. alpha-Linolenic acid was incorporated up to 12% in the aorta of the 5% linseed oil group. The eicosapentaenoic acid content was not significantly increased. The content of arachidonic acid and docosatetraenoic acid was moderately reduced in rats fed 5% linseed oil. The generation of 6-keto-PGF1 alpha (degradation product of prostacyclin) assessed by HPLC/electrochemical detection was, however, markedly increased (p < 0.05) in rats fed 2.5 and 5% linseed oil. The minor prostanoids TXB2, PGE2 and PGF2 alpha were not significantly altered. The high systolic and diastolic blood pressure of SHR monitored by radio telemetry was more effectively reduced (p < 0.05) in the light, i.e. sleep, cycle. An increased prostacyclin formation and lowered vascular arachidonic acid content associated with enhanced dietary alpha-linolenic acid intake would thus be expected to prove beneficial in the prevention of vascular disorders.

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Adaptation of the rabbit heart to volume load of the left ventricle is characterized by hypertrophic growth. This process involves an increase in the mass and changes in the composition of the myocardium. In the fifth week after perforation of the aortic valve an increase in phospholipid content and in mitochondria and a decrease in protein content was observed in the myocardium. These changes precondition a transient hyperfunction of the cardiomyocytes, but they presumably lead also to the eventual loss of contractile capacity. When the hypertrophic process occurs under conditions of nonspecific beta-adrenergic blockade, the required increase in left ventricular mass is achieved yet the content of phospholipids, proteins and mitochondria remains unchanged. Long-term blockade of beta-adrenergic receptors may be one of the modes of affecting the expression of cardiac genes in such a way that the hypertrophic myocardium does not develop conditions resulting in heart failure.

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In the course of adaptation of the rabbit heart to volume load passive diastolic properties of the hypertrophic ventricle and myocardium were changing significantly. On day 30 following perforation of the aortic valve stiffness of the ventricle was reduced, yet normalized ventricular stiffness and myocardial stiffness were increased. These changes were prevented by beta adrenergic blockade during development of adaptation of the heart to volume load. Although ventricular stiffness was reduced, normalized ventricular stiffness and myocardial stiffness remained at the level of control values. The demonstrated effect of beta adrenergic blockade on passive diastolic properties of the ventricle and myocardium may be of value in preventing heart failure due to chronic hemodynamic load. (Tab.3,Ref.15.).

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Selection of the optimal model for a specific experiment considerably determines the results and their correct interpretation. The model of the isolated cardiomyocyte is increasingly being used in experimental cardiology as it provides several advantages in comparison to models in which the heart tissue remains relatively complete. Similarly as in other models, the factors limiting its use have to be known also in the case of the isolated cardiomyocyte. To minimalize misinterpretation of results the given problem is to be handled at all available levels.

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The authors investigated the effect of a newly synthetized haemorheological drug VULM 957 for basic haemorheological parameters in vitro and on the cerebral flow in vivo. It was revealed that substance VULM 957 inhibits in a dose-dependent and time-dependent way the platelet aggregation, reduces the viscosity of blood, increases the deformability of red blood cells and increases the cerebral blood flow. Analysis of possible mechanisms of action of VULM 957 indicates that the observed positive haemorheological effects are due to the influence on the fluidity of the platelet and red cell membrane. The increased cerebral blood flow after administration of VULM 957 depends obviously on the reduced viscosity of the blood and the inhibited formation of platelet microaggregates. The presented results justify the assumption that VULM is a perspective substance in the therapy of cerebrovascular diseases.

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Induced insufficiency of the aortal valve in rabbits is followed by gradual adaptation of the heart to volume load. In the period of developing hypertrophy, we studied the changes in the passive diastolic properties of the ventricle. By analyzing the passive relationship between the volume of the ventricular cavity and the intraventricular pressure, the stiffness of the ventricle, normalized ventricular stiffness, and myocardial stiffness were determined. On day 30 after inducing the volume verload, the stiffness constant of the ventricle was statistically significantly reduced, whereas the constant of normalized ventricular stiffness and the constant of myocardial stiffness were statistically significantly increased. The increased stiffness of the myocardium, which characterizes the volume verloaded, left ventricle in the period of developing hypertrophy, may represent one of the changes causing reversal of the adaptive response of the heart to hemodynamic verload after a certain period of time, gradually resulting in the development of the syndrome of heart failure.

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