Analgesic and tolerance-inducing effects of the highly selective delta opioid agonist [D-Pen2,D-Pen5]enkephalin in mice.

The novel and highly selective, conformationally restricted enkephalin analogue for delta-opioid receptors, [D-Pen2,D-Pen5]enkephalin (DPDPE; Pen = penicillamine), was studied in various in vivo tests for analgesia, tolerance and physical dependence. Intracerebroventricular (i.c.v.) administration of DPDPE caused a dose-dependent, naloxone-reversible antinociception, measured with the heat-irradiant (tail-flick) method. Acute tolerance developed to the antinociceptive effect of DPDPE. DPDPE also caused mild signs of physical dependence (withdrawal hypothermia and body weight loss) after repeated peptide treatment. Severe signs of morphine withdrawal (e.g. withdrawal jumping) on the other hand, could not be reversed by the administration of DPDPE. It is concluded that the activation of central delta-opioid receptors may play a role in controlling pain mechanisms, and that this activation is followed by the rapid development of a tolerance to this action.

Central effects of the potent and highly selective mu opioid antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) in mice.

The ability of the selective cyclic mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), to inhibit the acute and chronic effects of morphine in vivo was studied in mice. Intracerebroventricular (i.c.v.) administration of CTOP antagonized the analgesic effect of morphine in a dose-dependent manner, as measured by the heat-irradiant (tail-flick) method. CTOP was more effective than naloxone in inhibiting analgesia on a molar basis. CTOP also antagonized the acute morphine-induced hypermotility. CTOP caused withdrawal hypothermia and a loss of body weight in morphine-dependent animals. After the development of morphine-induced chronic dependence, CTOP administered i.c.v. caused a dose-dependent loss of body weight and hypothermia, and was about 10-400 times more potent than naloxone. CTOP administered alone to drugnaive mice did not cause antinociception, changes in body weight or body temperature.

Prognostic value of simple exercise test parameters in patients with dilated cardiomyopathy.

The prognostic value of maximal exercise capacity as well as that of the simple exercise systolic blood pressure and heart rate variables were evaluated in 50 patients with dilated cardiomyopathy. Patients were treated beside digitalis and/or diuretics with vasodilators aggressively. Exercise was performed on an upright bicycle ergometer. Continuous, multistage, symptom limited, maximal tests were carried out. Patients were followed up for 23.5 +/- 15.2 months. Both one-way and multivariate analyses of data showed, that not only the maximal exercise capacity related significantly to the survival, but the several simple systolic blood pressure and heart rate variables (their values at peak exercise and their increase during the test) did so as well. Considering parameters separately, maximal exercise capacity was found the strongest predictor of survival, though the power of the calculated rate-pressure product at peak exercise, that of the systolic blood pressure at peak exercise as well as that of the increase in heart rate during the test proved nearly as strong as the maximal exercise capacity did. Anyway, the multivariate analysis showed that the former parameters were dependent on maximal exercise capacity. Some parameters with individual prognostic value proved independent from each other. Combined consideration of the systolic blood pressure at peak exercise and the increase of heart rate during exercise resulted in the highest predictive power which exceeded even the power of maximal exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prognostic value of exercise parameters and simple non-invasive variables of left ventricular function in dilated cardiomyopathy]. / Terheléses vizsgálati paraméterek és egyszerü, noninvazív bal kamra funkciós változók prognosztikus értéke dilatatív cardiomyopathiában.

Authors assessed the prognostic value of some simple, routinely used non-invasive parameters in dilated cardiomyopathy. Fifty patients, 43 male and 7 female, mean NYHA class 2.3, treated with digitalis, diuretics and vasodilators, were tested. Mean follow up time was 24 months. The evaluated parameters were as follows: maximal exercise capacity, heart rate, systolic blood pressure, as well as rate-pressure product at peak exercise, their increase during the test, fractional shortening measured by M-mode echocardiography, mean pulmonary capillary wedge pressure estimated by apexcardiography and clinical grade of heart failure (NYHA class). Exercise test was multistage, symptom limited, maximal upright bicycle ergometer test. Both one-way and multivariate analysis showed that except of fractional shortening all of the evaluated parameters related significantly to the survival. According to the one-way analysis maximal exercise capacity, rate-pressure product and systolic blood pressure at peak exercise as well as the estimated value of mean pulmonary capillary wedge pressure proved to be the strongest prognosticators. Multivariate analysis showed that the prognostic value of the rate-pressure product at peak exercise and that of the estimated mean pulmonary capillary wedge pressure proved to be additive, their combined consideration resulted in the highest accuracy of prediction.

Tracking the migration of cardially delivered therapeutic stem cells in vivo: state of the art.

Cell-based therapy is a promising, novel therapeutic strategy for cardiovascular disease. The rapid transition of this approach from the benchside to clinical trials has left a gap in the understanding of the mechanisms of cell therapy. Monitoring of cell homing and the fate of cardially delivered stem cells is fundamental for clarification of the myocardial regenerative process. Noninvasive imaging techniques allow an in vivo evaluation of the survival, migration and differentiation of implanted stem cells over time, and by this means, can help to answer unresolved questions. The most promising in vivo tracking methods involve the direct, nonspecific labeling of cells including MRI, radionuclide imaging and the use of reporter-gene imaging. This review summarizes the most important results of animal and human studies in which the fate and biodistribution of cardially delivered stem cells are assessed through different in vivo tracking methods.

Prediction of the effect of bisoprolol in dilated cardiomyopathy.

Survival improvement by beta-blocker treatment in patients with chronic heart failure appears to be related to the intermediate-term changes in left ventricular function. The therapeutic potential of beta blockade might be increased by early identification of patients in whom left ventricular function would deteriorate. We aimed at predicting the intermediate-term effect of bisoprolol on left ventricular systolic and diastolic function in patients with dilated cardiomyopathy. Twenty-five patients with symptomatic chronic heart failure treated with bisoprolol were investigated. As a background, tailored therapy with digitalis, diuretics and vasodilators was given. Prediction of the 6-month (intermediate-term) effect of bisoprolol was investigated, using baseline values and short-term (1-month) changes of simple, noninvasive parameters obtained at rest and during maximal exercise. Multivariate analysis resulted in reliable predictions, there was close correlation between the observed and predicted changes of left atrial filling pressure (R = 0.87) and left ventricular ejection fraction (R = 0.74). The baseline value of left ventricular ejection fraction, short-term changes of the pulse amplitude and the double product proved independent predictors of intermediate-term changes of left ventricular ejection fraction. The baseline value of mean pulmonary capillary wedge pressure, heart rate, and increase in heart rate during maximal exercise were predictors of the intermediate-term changes in mean pulmonary capillary wedge pressure. In dilated cardiomyopathy, the intermediate-term effects of bisoprolol on left ventricular ejection fraction and mean pulmonary capillary wedge pressure can be predicted reliably by simple noninvasive variables in the early treatment phase.