Pharmacodynamics of nomifensine: a review of studies in healthy subjects.

A review of pharmacodynamic studies of nomifensine in healthy subjects indicates that nomifensine caused neither negative nor positive (euphoric) mood alterations and led to no impairments in various tests of performance and to some improvement in vigilance, attention, and psychomotor performance. Nomifensine was shown to alter the waking EEG in a manner similar to desimipramine. In marked contrast to nomifensine's pharmcokinetics, its CNS effects were shown to reach a maximum after 6 hours and to last for more than 8 hours. The sleep EEG was not altered significantly. Biochemical models confirmed nomifensine's noradrenergic and dopaminergic mode of action.

The pharmacokinetics of nomifensine. Comparison of pharmacokinetics and pharmacodynamics using computer pharmaco-EEG.

Pharmacokinetics and pharmacodynamics of nomifensine infusions as compared with oral preparations were investigated in a double-blind place-controlled crossover study in 10 healthy normal volunteers. They received randomized in weekly intervals 75 mg nomifensine and placebo intravenously as well as placebo, 75 and 150 mg nomifensine orally. Blood samples, quantitative EEG evaluations, psychometric tests, blood pressure, pulse rate and side effects were obtained and monitored at the hours 0, 1, 2, 4, 6 and 8. Nomifensine serum levels were determined by a radioimmunoassay; peak levels occurred within the first 2 h, the elimination half-life was around 2 h, both results indicating fast absorption and elimination. While the evaluation of the total nomifensine demonstrated almost identical bioavailability of the oral and intravenous form, free nomifensine levels after 75 mg i.v. were more similar to those after 150 mg than 75 mg p.o. Digital computer period analysis of the EEG confirmed nomifensine as a drug with a significant effect on the CNS as compared with placebo, showing in fact an antidepressant 'pharmaco-EEG profile' similar to desipramine. Evaluation of dose-effect curves demonstrated that 75 mg i.v. was the most effective drug, being closer to 150 than 75 mg p.o. The latter oral dosage could be discriminated from placebo only in certain variables at certain times. Concerning time-effect, nomifensine was most effective around the 6th hour post-drug, which was similar to the psychometric findings, thus showing a considerable delay compared to the peak serum concentration. Relating pharmacodynamic findings to pharmacokinetic results it became evident that free nomifensine may be of far greater importance for the drugs encephalotropic and psychotropic properties than the total unconjugated and conjugated nomifensine--thus justifying the development of a parenteral preparation. Finally, the relationship of blood levels and CNS effects was found to have a characteristic 'hysteresis loop' shape suggesting a delay of pharmacodynamic effects as opposed to the serum concentrations. This delay may be due to a slowly formed active metabolite, the drug acting on deep compartment receptors or both.

Standardized mental stress in healthy volunteers induced by delayed auditory feedback (DAF).

Using delayed auditory feedback (delay 0.175 s) a standardized form of mental stress was investigated in 8 healthy male volunteers. After a resting period and a period of undelayed reading, the volunteers were exposed for 5 min to the DAF stress. During the DAF period heart rate increased by 10% and systolic and diastolic blood pressure increased by 9% and 18%, respectively. As a measure of acute sympathetic activation, plasma concentrations of norepinephrine and epinephrine rose by 68% and 49%, respectively. The activity od dopamine-beta-hydroxylase in plasma was increased by 25%. From these results it can be concluded that the DAF procedure provides a suitable method for inducing a standardized mental stress in normal subjects, which can be measured as changes in biochemical and cardiovascular variables.

Pharmacokinetics of single and multiple doses of clobazam in humans.

1. The pharmacokinetics of clobazam and its biotransformation product N-desmethylclobazam were investigated after single and multiple doses in normal subjects. 2. The relevant physicochemical properties of clobazam were measured and are presented. Different assay methods (radiochemical, fluorimetric and gas chromatographic) were applied and the results correlated. 3. After single doses the pharmacokinetic profile of clobazam includes time to peak levels 1--4 h after dosing, peak levels increasing linearly with the logarithm of dose, and terminal half-lives of about 18 hours. At least 87% of an oral dose is absorbed, as indicated by urinary recovery of labelled material. 4. In multiple-dose studies unchanged clobazam levelled off at minimum steady-state concentrations within one week of dosing. During 28 d of medication N-desmethylclobazam accumulated to near steady-state levels about eight times higher than those of the unchanged compound. 5. No pharmacokinetic interactions were discovered between clobazam and the antidepressant nomifensine.

Pharmacodynamic comparison of the acute effects of nomifensine, amphetamine and placebo in healthy volunteers.

In a double blind cross over trial the effects of single doses of 100 mg nomifensine, 15 mg racemic amphetamine and placebo were compared in 9 healthy volunteers. Assessments of choice reaction behavior, simple reaction time, critical flicker fusion and attention on continuous calculations were performed together with a series of self rating scales, a side-effect list and vital signs before and 90 min., 180 min. and 360 min. after each administration. While the only significant nomifensine effect was an increase of correct solutions in the continuous calculation task, amphetamine differed from nomifensine and placebor in a number of subjective variables which describe emotional changes typical for drug stimulation. Subjects also expressed the will to have amphetamine prescribed for fatigue and loss of drive, whereas preferences for nomifensine were virtually the same as for placebo. Under amphetamine heart rate and blood pressure were increased and side-effects were frequent. It is concluded that nomifensine showed none of those subjectively pleasant amphetamine effects which are responsible for the reinforcement function leading to amphetamine dependence.

[Psychic drugs: predicting therapeutic effects and doses by test models with normal subjects (author's transl)]. / Psychopharmaka: Modellversuche an gesunden Versuchspersonen zur Vorhersage therapeutischer Effekte und Dosen

Pharmacopsychology is concerned with the effects of drugs on "psychic" processes. It is attempted to demonstrate approaches which meet the criteria of scientific methodology. These approaches are based upon observation of somatic and/or behavioral changes. The steps from "naive" observation to the generation of objective data consist mainly of strict control of the observational situation and of technical refinement of the observation methods. Two kinds of pharmacopsychological models in healthy volunteers are described: models of normal and models of abnormal behaviour. Their relevance for the prediction of therapeutic drug effects and dosage is discussed. Possible new approaches are demonstrated: a) utilization of feedback form clinical investigation to control the relevance of pharmacopsychological models and, b) the concept of symptomatic volunteers, who are shown to be more suitable models than non-selected subjects.

Pharmacokinetics of nomifensine in impaired renal function.

1. In uremia, an increased frequency of adverse drug reactions is observed at elevated plasma levels of active drug. This is a consequence of decreased renal elimination of unchanged drug or pharmacologically active metabolites. 2. To study the pharmacokinetics of nomifensine in uremia, a single dose of nomifensine maleate 50 mg was given to 10 patients with a glomerular filtration rate between 0 and 61 ml/min. In three additional patients on maintenance haemodialysis, the influence of dialysis on the elimination of nomifensine after single oral doses of 50 mg was studied. 3. Blood samples were obtained before and at regular half-hourly or hourly intervals after administration. Plasma levels of nomifensine were examined using a radioimmunological determination method and pharmacokinetic parameters were calculated by computer program. 4. Whereas in healthy subjects the half-life of nomifensine was found to be 1.8 h, this parameter was found to be prolonged in renal patients. In a patient with a creatinine clearance of 0 ml/min the elimination half-life was 46 hours. Nomifensine is not eliminated by haemodialysis. 5. Our findings suggest that nomifensine should not be administered to renal patients with a glomerular filtration rate below 25 ml/minute.

Kinetic interaction of nomifensine with a 1, 5-benzodiazepine (clobazam).

1. Among the numerous possibilities of drug interactions, pharmacokinetic interactions may cause mutual changes in absorption, distribution, metabolism and elimination of either drug. In the present study this approach was used to investigate pertinent effects of nomifensine and clobazam. 2. Ten normal subjects participated in an intra-individual comparison of nomifensin 75 mg alone and in combination with clobazam 15 and 30 mg. The study design was carried out according to a Latin square in double-blind conditions. One-week wash-out periods were used between the trial days. Serum levels of nomifensine were measured by radioimmunoassay (RIA) and of original clobazam by gas chromatography (GC). Classical criteria for bioavailability (peak serum levels, time of peak, area under the serum level time curve) and the half-life of elimination from the serum were used for retrieval of pharmacokinetic information. 3. Results showed no relevant differences in the criteria mentioned above, after administration of each drug alone or in combination. Therefore, extrapolations were made to multiple dose kinetics based on assumptions derived from practical therapy. They showed comprehensive agreement with therapeutic results in depressed patients. 4. The use of the classical criteria for bioavailability, in addition to the calculation of the half-time of elimination from serum, provides sufficient information for the decision whether pharmacokinetic drug interaction is present or absent. There was no such interaction after single doses of nomifensine or clobazam.

Dynamic interaction of nomifensine with alcohol.

1. Nine healthy volunteers participated in a comparative study of the effects of nomifensine, nomifensine plus alcohol, and placebo plus alcohol, on aspects of psychomotor performance. 2. The study was carried out according to a Latin square design and each treatment was separated from the preceding treatment by 7 days. 3. Placebo plus alcohol impaired performance, increased pulse rate and blood pressure, and increased feelings of activity and euphoria. 4. Nomifensine plus alcohol produced the same subjective and objective changes as placebo plus alcohol, but in no instance were changes any greater. 5. Nomifensine alone produced none of these changes. 6. It was concluded that single doses of nomifensine did not potentiate the effect of alcohol.

Comparison of nomifensine and placebo.

1. Methodological reasons are discussed which make placebo-controlled trials on antidepressant drugs necessary. 2. The ethical problem of treating a sick patient with an inactive compound are shown to have an impact on the methodology of such trials. 3. Three double-blind placebo-controlled trials with nomifensine are reviewed; one in neurotic depression, one in psychotic depression and one in geriatric patients showing depressive symptoms. 4. In all three trials the effect of nomifensine has been shown to be superior to that of placebo.

Recent immigration and studies of ethnic assimilation.

Studies of ethnic assimilation are frequently based upon status comparisons between the foreign born and their "children," the second generation. The assumption that recent immigration has been negligible and that the foreign born represent a closed population is implicit in that procedure. However, analysis of official statistics indicates that immigrants who arrived since World War II now comprise a substantial share of the foreign-born population, while the foreign born who arrived before quota restrictions are rapidly being depleted by mortality. Recent immigrants, as intended by quota legislation, are of much higher socioeconomic status than immigrants who arrived before World War 1. Hence, characteristics of both recent immigrants and earlier arrivals are confounded in data for the foreign-born population. Existing data do not permit rigorous assessment of this confusion or adequate control for it. This paper suggests that tabulations of the foreign born by "year of arrival" would improve the sociological utility of data for ethnic groups.

Cohort migration.

Most migration analyses focus on net migration and are concerned with areal redistributions of population. Migration may also be studied as an event in the life-cycle of an individual, and migration rates may be defined as properties of cohorts. A number of efforts to examine migration as a cohort process has been hampered by the character of available data [or the United States. Rather than await the development of a registration system-either directly or via social security and tax records-the collection of residence histories is suggested as the most feasible approach to obtaining suitable data. A schematic representation of residence histories clarifies their relation to other types of migration data and illustrates the need to design such surveys with specific research purposes in mind. Exploratory work with the 1958 Residence History Supplement to the Current Population Survey (by Beale, Shryock, myself, and various colleagues) demonstrates the utility of this approach.Local studies have made fruitful use of residence histories but typically are unable to delineate birth cohorts or other appropriate base populations exposed to risk. Development of cohort migration techniques analogous to the life table approach to mortality or cohort Jertility analysis requires national data. But migration, unlike Jertility and mortality, involves events that are reversible and repeatable. Hence the demographer's stock of analytic tools requires expansion. To the sociologist-demographer, experimentation with cohort migration models seems to be getting at one of the crucial methodological problems of sociology, the analysis of social mobility. A mutually profitable interchange with students of social mobility is envisaged.