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G Sedek

Publications and source records attributed to G Sedek.

At least 19 recordsLinked to original sources
PubMed1999

Uncontrollability, depression, and the construction of mental models.

Three studies examined mental model generation after preexposure to uncontrollability and in a depressive state. The purpose of the experiments was to test the implications of the cognitive exhaustion model, applying an explicit conceptualization of social mental models and a process-tracing method developed by U. von Hecker (1997). An experimental situation was created for observation of consecutive, rule-based construction steps as a function of input diagnosticity, and for the quality assessment of constructed mental models. The findings show that participants preexposed to uncontrollability, as well as depressed students, were able, as were controls, to identify rule-relevant information needed for model construction. However, they were less able than control participants to engage in a more cognitively demanding and generative step of processing (i.e., in integrating the pieces of input information into a coherent mental model of sentiment relations).

Adolescent↗
PubMed1998

The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation.

Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/ carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg and once with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and once with placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa was unaffected by tolcapone in all treatment groups and the maximum plasma concentration (Cmax) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60-90% and levodopa t1/2 by 20-60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD Cmax decreased by 80% and AUC by 70% with tolcapone. The tolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.

Administration, Oral↗
PubMed1997

Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly.

OBJECTIVES: The multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving concomitant carbidopa and levodopa. METHODS: Thirty-six volunteers from 55 to 75 years old participated in this double-blind, placebo-controlled, ascending multiple-dose study. Tolcapone was studied at dosages of 100, 200, 400, or 800 mg three times daily (t.i.d.) in four sequential groups. Each group consisted of nine participants who had been randomized to receive either placebo (n = 3) or tolcapone (n = 6). Tolcapone or placebo was coadministered with carbidopa and levodopa (25 and 100 mg, respectively) for 7 days. Assessments included tolerability, pharmacokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes. RESULTS: By inhibiting COMT, tolcapone reduced levodopa metabolism to 3-O-methyldopa, resulting in a twofold increase in levodopa exposure (area under the curve) and elimination half-life, without changing levodopa peak plasma concentration. These effects were similar on days 1 and 7 of treatment. Development of tolerance to COMT inhibition was not observed. Onset of effect was rapid (day 1 of treatment), and the maximum effect on levodopa pharmacokinetics was already observed with 100 or 200 mg tolcapone t.i.d. At these dosages, tolcapone pharmacokinetics were linear and stable; accumulation occurred with 800 mg t.i.d. The combination of tolcapone and carbidopa-levodopa was generally well tolerated, although more nausea and vomiting were observed at higher dosages (400 to 800 mg t.i.d.), particularly in women. CONCLUSION: Tolcapone shows promise as an effective adjunct to levodopa in the treatment of Parkinson's disease. Clinical pharmacology data indicate that the therapeutic regimen should be 100 or 200 mg t.i.d.

Administration, Oral↗
PubMed1996

Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects.

OBJECTIVE: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. METHODS: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio 1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone; its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long halflife of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. CONCLUSION: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson's disease.

Aged↗
PubMed1995

Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa.

1. Single oral doses of the catechol-O-methyltransferase (COMT) inhibitor tolcapone (10-800 mg) or placebo were administered simultaneously with a dose of levodopa/benserazide 100/25 mg to seven sequential groups of six healthy male subjects in a two-way crossover study. 2. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa (3-OMD) were determined in conjunction with COMT activity in erythrocytes. 3. The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase in dopaminergic stimulation. 4. Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-dependent decrease in the formation of 3-OMD. Tolcapone increased the area under the concentration-time curve and elimination half-life of levodopa. The maximum effects were obtained at a dose of about 200 mg when both parameters increased approximately twofold. The drug had no influence on the maximum concentration of levodopa. 5. Tolcapone was rapidly absorbed and eliminated with, on average, a tmax of 1.5 h and a t1/2 of 2.3 h. The drug showed dose-proportional pharmacokinetics, in contrast to 3-O-methyltolcapone whose formation was relatively decreased at higher doses. 6. Plasma concentrations of tolcapone correlated with inhibition of COMT activity in erythrocytes and suppression of 3-OMD levels, but not with changes in levodopa pharmacokinetics.

Adult↗
PubMed1993

Effects of uncontrollability on subsequent decision making: testing the cognitive exhaustion hypothesis.

The cognitive exhaustion model of helplessness--predicting withdrawal from constructive effortful processing after uncontrollability--was applied to decision making. After unsolvable problems (or no preexposure), Ss requested information from a matrix with 5 alternatives (films) x 10 attributes and then chose the best film. Films in a set were either similar (difficult decision) or dissimilar (easy decision) in attractiveness. As predicted, Ss with an uncontrollable preexposure spent less time on predecisional information search, disregarded their own importance criteria when asking for information, and had attention highly focused on a selected option for the easy decision condition but diffused across options for the difficult decision condition. The implications of these findings for understanding cognitive mechanisms of learned helplessness and depression are discussed.

Adolescent↗
PubMed1990

When cognitive exertion does not yield cognitive gain: toward an informational explanation of learned helplessness.

This study tested a new information-processing explanation of learned helplessness that proposes that an uncontrollable situation produces helplessness symptoms because it is a source of inconsistent, self-contradictory task information during problem-solving attempts. The flow of such information makes hypothesis-testing activity futile. Prolonged and inefficient activity of this kind leads in turn to the emergence of a state of cognitive exhaustion, with accompanying performance deficits. In 3 experiments, Ss underwent informational helplessness training (IHT): They were sequentially exposed to inconsistent task information during discrimination problems. As predicted, IHT was associated with subjective symptoms of irreducible uncertainty and resulted in (a) performance deterioration on subsequent avoidance learning, (b) heightened negative mood, and (c) subjective symptoms of cognitive exhaustion.

Achievement↗
PubMed1989

Repeated failure: a source of helplessness or a factor irrelevant to its emergence?

We tested the validity of the egotism model of human helplessness. In contrast to the original theoretical approach of Seligman and his associates, which points to response-outcome noncontingency as the main source of helplessness, the egotism alternative proposes that repeated failure itself is the critical determinant of helplessness symptoms. Repeated failure threatens the self-esteem of the subject, who supposedly engages in a least-effort strategy during the test phase of a typical learned helplessness study, which results in performance impairment. To examine the egotism explanation, we gave subjects noncontingent-feedback training with or without repeated failure on five consecutive discrimination problems. In two experiments, noncontingent-feedback preexposure produced helplessness deficits in performance on avoidance learning, whereas repeated failure appeared irrelevant to helplessness. This and our other findings from research are inconsistent with the egotism explanation and support instead Seligman's original proposal, in which helplessness is attributed to prolonged experience with noncontingency.

Achievement↗
PubMed1980

Directly measured tension-time index as a correlate of myocardial oxygen consumption.

Left ventricular systolic pressure (LVSP) and stress in the outer layers of the left ventricular wall were directly recorded in 10 anaesthetised, open-chested dogs. Left ventricular oxygen consumption (VO2) was calculated from the difference in oxygen content in the arterial and in the coronary sinus blood and from the left ventricular coronary flow (LVCF). LVCF was measured in the shunt between the carotid artery and left coronary artery (2 experiments) or in the shunt between the coronary sinus and jugular vein. Tension-time index was calculated either as the product of the mean LVSP and time (TTI(P)), or as the product of mean systolic stress and time (TTI(sigma)). Both TTIs were changed within the broad range by means of exsanguination and blood infusion. Contractility was changed by means of Inderal or noradrenaline infusion. In all experimental conditions VO2/100 g/stroke correlated linearly (P less than 0.01) with TTI(sigma), with correlation coefficient r greater than 0.8. When TTI(P) was used, correlation coefficient r was less than 0.6 and no correlation was found in one series of experiments with noradrenaline infusion. It is concluded that TTI calculated from the directly measured wall stress is a very good correlate of the VO2, which is not the case when the 'classical' TTI is used.

Animals↗
PubMedDate not supplied

Evidence against systolic intramural forces as the primary cause of subendocardial preponderance of ischemia.

Verification of the current view that subendocardial preponderance of ischemia is due to greater forces generated in the deep myocardial layer during systole was undertaken. In anesthetized mongrel dogs transient ischemia was produced in two different situations of altered systolic forces. First, in order to remove that part of the systolic force which is related to intracavitary pressure, left ventricular bypass was created and the left ventricle vented. Second, in order to even out the transmural distribution of the remaining part of the forces, which is due directly to distortion and displacement of contracting fibers, ventricular fibrillation was induced in addition to venting under conditions of total cardiopulmonary bypass. In both series of experiments the ischemic area was then reperfused, normal circulation re-established and the animal allowed to survive for 3-5 days. After sacrifice, ischemic necrosis was found almost exclusively in the subendocardium. The persistence of subendocardial preponderance of ischemia under conditions of left ventricular venting and absence of coordinated contraction shows that uneven distribution of intramural forces generated during systole is not the primary cause of this preponderance.

Animals↗