Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethyl-phenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man.

OBJECTIVE: The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers. MATERIALS AND METHODS: 25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days. RESULTS: All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-infinity values of 15.5 +/- 4.3 ng/ml and 119 +/- 41 ng x h/ml for bimodal release d-MPH, 17.9 +/- 5.3 ng/ml and 115 +/- 40 ng A h/ml for immediate release d-MPH, and 16.4 +/- 4.4 ng/ml and 122 +/- 36 ng x h/ml for d,l-MPH bimodal release, respectively. CONCLUSIONS: In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).

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.

Pharmacokinetics of N-acetylprocainamide in patients profiled with a stable isotope method.

N-Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA-13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 +/- 2.6 L (mean +/- SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady-state distribution volume of 1.45 +/- 0.09 L/kg were similar to normal subject values. The least-squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age-associated decrease. The oral NAPA dose was 78.0% +/- 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r = 0.89, p = 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.

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.

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.

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.

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.

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).

Effect of tolcapone on plasma levodopa concentrations after coadministration with levodopa/carbidopa to healthy volunteers.

Tolcapone (Ro 40-7592) is a novel inhibitor of catechol-O-methyltransferase that is being developed for clinical use in the treatment of Parkinson's disease as add-on therapy to a combination of levodopa and a peripheral amino acid decarboxylase inhibitor (benserazide or carbidopa). The current single-blind, randomized study was designed to evaluate the effect of tolcapone compared with placebo on plasma levodopa concentrations in healthy volunteers concomitantly receiving 25 mg of carbidopa and 100 mg of levodopa (Sinemet 25-100) and to assess the tolerability and safety of this combination. Placebo or tolcapone at doses of 5, 10, 25, 50, 100, 200, 400, and 800 mg was coadministered orally with Sinemet 25-100. Each dose was tested in a crossover fashion in a new group of six participants who each received active drug on one occasion and placebo on the other. Tolcapone increased the area under the plasma concentration-time curve and half-life of levodopa approximately twofold, without appreciably increasing the peak concentration. The maximum effect on levodopa half-life was observed with the 200-mg dose. Adverse effects were minor at all doses.

Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients.

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Evaluation of extravascular resistance in the unloaded fibrillating left ventricle of the dog.

In open-chest anaesthetized dogs the relative magnitude of extravascular resistance in the superficial and deep left ventricular myocardium was estimated from the flow through the isolated vascular segments inserted at different depths of the myocardium. It was confirmed that in the normally working heart extravascular resistance was significantly greater in the deep than in the superficial layer. In the unloaded fibrillating left ventricle no difference in extravascular resistance between these layers could be detected. Since it had been found previously that subendocardial preponderance of ischaemia persists in the unloaded fibrillating left ventricle (Sedek and Michalowski, submitted for publication), the present observation is a further challenge for the current view that the subendocardium is more vulnerable to ischaemia because extravascular resistance is greater in this layer.

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.

Inotropic and electrophysiological effects of AB--2, a new antiarrhythmic agent, on isolated cardiac preparations.

Effects of AB--2, a compound structurally related to quinidine, on the force of contraction and intracellular potentials were studied in isolated cardiac preparations obtained from guinea pigs, rabbits, cats and dogs. AB--2 in concentrations of 3 and 6 microM increased the force of contraction of both ventricular and atrial muscle. This effect was absent in reserpinized preparations. In concentrations of 24-96 microM, AB--2 induced a concentration-dependent depression of contraction (ED50 approximately equal to 55 microM). Electrophysiological effects consisted of: 1) concentration-dependent reduction of maximum rate of depolarization (Km for guinea pig ventricular and atrial muscles was 72 and 111 microM, resp.) with no change in the resting membrane potential; 2) shortening of action potential duration in ventricular and Purkinje fibers while prolongation in atrial muscle; 3) reduction of pacemaker activity in Purkinje fibers. It is concluded that electrophysiological effects of AB--2 are similar to those of Class I antiarrhythmic agents.

A new approach to the direct measurement of tension within the outer layers of the left ventricular wall of the dog heart.

Tension was measured within the outer layers of the left ventricular wall of the dog heart with the strain-gauge force transducer coupled to the wall at diastole without the distortion of its geometry. The transducer still attached to the wall or its segments was calibrated with the passive forces and with the known active force on the isolated, beating heart. The differences between the readings of the transducer and the calibrating force did not exceed 20% and in most experiments they were much smaller. The transducer was practically insensitive to the force perpendicular to the measured one. The proposed method seems to be more reliable than the formerly used by these and other authors.