Trimipramine--an atypical neuroleptic?

Trimipramine and clozapine show some similarities in their receptor binding profiles. Since both have the same affinity for the D2 receptor and since the affinity for this receptor correlates closely with the antipsychotic potency of a drug, an antipsychotic efficacy of trimipramine in acute schizophrenia could be expected. Therefore 28 schizophrenic patients in an acute phase were treated with trimipramine up to 400 mg/d in an open clinical trial. For the whole group of patients the BPRS total score changed from 58 +/- 5 before treatment to 46 +/- 18 at the last rating (p less than 0.05). According to our clinical judgement the patients were divided into three subgroups. Thirteen patients showed a good remission under trimipramine so that they could be discharged on a trimipramine maintenance treatment. They improved on the BPRS from 58 +/- 6 before treatment to 32 +/- 8 at endpoint. Six patients deteriorated during the first week of treatment and had to be withdrawn from the study. Nine patients showed insufficient improvement or became worse after an initial improvement. The observed side-effects (dry mouth, sedation, sweating, increased appetite, constipation, tremor, vertigo) are well known under trimipramine and were therefore expected. Beyond these, one patient developed a cardiac insufficiency. No clinical relevant extrapyramidal side-effects occurred. Since the improvement of florid psychotic symptoms seems to be markedly higher under trimipramine than the one reported under placebo, our results indicate that trimipramine may have an antipsychotic potency.

The metabolic fate of 2H-labelled propafenone in man.

The metabolism of propafenone was studied in three humans by using 300 mg of the deuterated compound given orally. The excretion of propafenone and its metabolites was assessed by measuring the deuterium content in the excretion products by means of a microwave plasma detector. At selected times the metabolic pattern in plasma, urine, bile and feces was determined. The metabolites were isolated and the structure of the main compounds was characterized. Propafenone is absorbed completely and quantitatively metabolized. Unchanged propafenone is excreted neither in the urine nor in the feces in amounts of more than 1% the dose. The percentage of free unconjugated propafenone of the total deuterium content in the plasma was about 10% 3 and 6 hours after application. Conjugates of hydroxylated derivatives of propafenone are present predominantly in the plasma. The excretion of the metabolites takes place mainly by way of the feces, 53% of the dose is excreted by this route within 48 hours. Urinary elimination accounted for 18.5 and 38% of the dose within 48 hours in two humans. It was possible to elucidate the structure of 11 metabolites, accounting for more than 90% of the dose administered. The major metabolites are conjugates of 5-hydroxypropafenone and hydroxy-methoxy-propafenone with glucuronic and sulphuric acid and propafenone glucuronide. Furthermore, metabolic products of oxydative deamination pathway were identified, i.e. a glycol and a lactic acid derivative. C-C splitting yields a relatively large amount of 3-phenyl-propionic acid, while cleavage of the ether group leads to a phenolic product and is only of minor importance.

The effect of the composition of food on the absorption of sulfameter.

The present investigation is concerned with the influence of the composition of food on the absorption of sulfameter. Six physically healthy patients each were given 2 g of sulfameter simultaneously with a high lipid, high protein and high carbohydrate test meal. This experiment was designed as a threefold crossover study, and there was a randomized assignment of patients to the different conditions. The results show that sulfameter is significantly better absorbed when administered with a high lipid meal than when given with a high protein or high carbohydrate meal, demonstrated by the areas under the serum concentration curves (AUC), by the peak serum concentration and by the cumulative renal excretion.

The pharmacokinetic aspects of therapy with psychotropic agents.

This contribution is concerned with a critical appraisal of the concept that plasma levels of psychotropic agents govern their pharmacodynamic action. In this regard, there are at least three problems: 1. identification of the chemical course of reaction between the introduced pharmacon and its resultant metabolites in reference to the totality of the organism and its biochemical reaction pattern; 2. the course of this reaction relative to intra- and interindividual differences; and 3. the influence of the kinetics as a result of concentration diversities, conditioned by different distributing patterns within the organism. Decisive factors here are: mode of application, blood distribution volume, reaction and/or elimination rate, and, finally, interaction of combined drugs.

[Pseudo-hallucinations after long-term lithium treatment]. / Pseudohalluzinationen nach langjähriger Lithiumbehandlung.

A 58-year old women with a history of recurrent depressive episodes had been on successful prophylaxis with lithium carbonate in controlled therapeutic dosage for 11 years. At this time she experienced with increasing frequency mostly visual, sometimes auditory pseudohallucinations which disappeared after stopping the lithium medication. Because a subsequent depressive episode did not respond to tricyclic antidepressants or to a MAO-inhibitor the patient was again prescribed lithium. At therapeutic lithium blood levels the previous perceptual disorders then returned.

[On the pharmacokinetics of gentamycin. / Clinico-pharmacological study on the course of gentamycin concentrations in serum during large-volume infusions (author's transl)]. / Zur Pharmakokinetik von Gentamycin. Klinisch-pharmakologische Untersuchungen zum Konzentrationsverlauf von Gentamycin im Serum während hochvolumiger Infusionen.

Infusions of large volumes have a remarkable influence on the blood levels of gentamycin insofar that with normal dosages no effective concentrations can be found in the serum of the patient. The present investigation was planned as a pharmacokinetic model with the aim of finding out the possible reasons for this phenomenon. The results show that the infusions enhance the total clearance tremendously. Furthermore the elimination half-life of gentamycin is much shorter under infusion conditions. This explains the subtherapeutic blood levels.

Pharmacokinetics of potassium ampicillin.

Potassium ampicillin was studied in normal volunteers. It was administered orally to a group of five male subjects in a single dose of 500 mg. Peak plasma concentrations (2.00-6.75 microgram/ml) were reached within 1.30 to 2.23 h. The pharmacokinetic parameters were computed according to the two-compartment open model. The mean value of elimination half-life was 0.96 h, and the urinary recovery was about 66% of the administered dose within 6 h. The apparent distribution volume had an average of 0.8 l/kg. This indicates that there exists a more or less uniform potassium ampicillin distribution throughout the various body compartments.

[Medicamentous therapy of alcoholic polyneuropathy. Randomized double-blind study comparing 2 vitamin B preparations and a nucleotide preparation]. / Die medikamentöse Therapie der alkoholischen Polyneuropathie. Randomisierte Doppelblindstudie zum Vergleich zweier Vitamin-B-Präparate und eines Nukleotid-Präparates.

In a randomized double-blind study involving 303 patients with alcoholic polyneuropathy the efficacy and tolerability of the combinations thiamine/pyridoxine, benfotiamine/pyridoxine, and the nucleotides of cytidine and uridine administered orally for 21 days were compared. Pain and paraesthesia, measured on a visual 10-cm-long analogue scale, as also pallaesthesia and the strength of the dorsiflexion and plantar flexors of the foot, clearly improved in all treatment groups. Clinically relevant differences in efficacy were not observed. All the drugs tested were well tolerated.

[Activation of the complement system with clinical dextran (Macrodex 6%) in 10 patients in a cross-over design against 0,9%-NaCl]. / Untersuchung zur Aktivierung des Komplementsystems durch klinisches Dextran (Macrodex 6%) an 10 Probanden im Cross-over-Design gegen 0,9%-NaCl.

The possibility of activation of the complement system with clinical Dextran 60 (500 ml Macrodex 6% infusion) as compaired with 500 ml 0.9% NaCl was investigated within a one week interval in 10 volunteers of both sexes in a cross-over design. Anaphylactoid symptoms, which would indicate a release of biological activities, were not induced by Dextran 60 or 0.9% NaCl. Neither could a change in blood pressure, heart rate, in the whole hemolytic complement activity nor in the leucocyte and thrombocyte count be determined. Therefore, a clinical relevant activation of the complement system in normal persons by Macrodex 6% can not be assumed.

Absolute bioavailability of amezinium. A cross-over study after i.v. and p.o. application.

The absolute bioavailability and pharmacokinetics of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (amesiniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, were examined following i.v. injection (10 mg) and single p.o. doses administered to eight healthy male volunteers. After i.v. injection plasma levels of amezinium were described by a tri-exponential function and the mean half-lives of the three phases were 0.08, 1.5 and 14 h, respectively. The volume of distribution at steady state ranged between 201 and 476 1. After p.o. doses of tablets, absorption of the drug obviously commenced immediately after dosing. After 0.5 h the absorption took place more rapidly and peak plasma levels between 31 and 61 ng/ml were reached after 1.2 to 2.4 h. The mean terminal half-life in plasma was 13 h after p.o. doses. 77% of the i.v. dose was excreted unchanged in the urine over 48 h; the mean excretion after the p.o. dose was 32%. Within the first 7 h the renal clearance of amezinium was considerably higher than afterwards. The mean absolute bioavailability determined by means of the area under the plasma concentration-time curve (AUC) was 53% and ranged between 40% and 74%.

Pharmacokinetics of low molecular (monovalent) dextran (Dx 1) in volunteers.

Dextran-induced side effects were attributed to preformed antibodies that cross-react with dextran. These antibodies can be blocked by monovalent haptens (dextrans 1) in animals. Dextran 1 is also well tolerated in humans. Plasma levels and renal excretion of monovalent dextran (dextran 1, molecular weight around 1,000) were measured in five volunteers after intravenous administration of 20 ml 15% dextran 1 (3 g), and in one volunteer after intravenous administration of 50 ml (7.5 g). Measurements could be satisfactorily described by a two-compartment open model with elimination from the central compartment only: mean half-life for the beta phase of 1.9 h, a mean cumulative asymptotic elimination of dextran in the urine of 75%, and a mean renal clearance of 137 ml/min with a mean total clearance of 187 ml/min were estimated. The terminal half-life of dextran 60 (Macrodex) was 24 h (median). In volunteers with dextran antibodies no anaphylactoid symptoms were observed after Dx 1. In conclusion, the intravenous preinjection of dextran 1, owing to its pharmacokinetic behavior, should prevent antibody-mediated side effects after infusions with clinical dextrans (e.g., Macrodex, Rheomacrodex).

[Correlation of "latent hyperthyroidism" with psychological and somatic changes]. / Korrelation einer "Latenten Hyperthyreose" mit psychischen und somatischen Veränderungen.

The study reported here was undertaken to establish the degree to which a person in a preclinical state of hyperthyroidism, with (by definition) euthyroid T3 and T4 levels but suppressed TRH on testing, already exhibits psychological changes and clinical symptoms. Two groups of 20 patients each, with clear clinical and preclinical hyperthyroidism (as defined by laboratory parameters), were studied, as well as a group of 20 controls. The subjects' psychological state of mind was investigated using self-rating scales, including the state-trait-anxiety inventory (STAI), "Befindlichkeits"-Skala (Bf-S'), depression scale (D-S'), and a list of adjectives (EWL-K) with 14 different aspects of affective moods. Cognitive achievements were evaluated using the d2 test. Subjects were examined for somatic symptoms in accordance with Crooks' index of hyperthyroidism. The results clearly showed that typical psychological and somatic changes are already present in preclinical hyperthyroidism, these changes being partly identical with those of definite hyperthyroidism. In both patient groups, a significant increase in anxiety, a sense of not feeling well, and emotional irritability were found, as well as a tendency towards depressiveness, and an increased lack of vitality and activity. Attentiveness and concentration in both patient groups were lower than in the control group. Both patient groups showed the same prevalence of symptoms, such as palpitations, preference of cold over heat, excessive sweating, nervousness, fine digital tremor, and increased heart rate. With regard to the results, the diagnosis "preclinical hyperthyroidism" thus gains importance. Further prospective studies are required to answer the question whether antithyroidal treatment will influence the described psychological and somatic state of patients with preclinical hyperthyroidism.

[Homosexual pedophilia and functional networks - An fMRI case report and literature review]. / Homosexuelle Pädophilie und funktionelle Netzwerke - fMRI-Fallstudie.

Pedophilia is a complex bio-psycho-social disorder often associated with serious offending. Knowledge about neurobiological correlates that could serve as diagnostic and maybe even as prognostic markers is limited. FMRI examination, which shows neuronal activation in vivo and therefore represents a neurobiological correlate, was not done in pedophilia so far. We report on results of an fMRI examination in a homosexual pedophilic sex offender who differed significantly in neuronal activation during exposure to arousing visual material (young boys in underwear) from normal controls. In self assessment on a visual analogous scale the pedophilic offender scored the pictures of the boys as not being interesting and sexually not stimulating. Nevertheless presentation of the pictures of the boys resulted in the pedophilic offender in a significant activation of the attention network and the right orbitofrontal cortex. In contrast to the controls there was no activation of left hemispheric areas relevant for speech. The study design will be continued in a larger sample to examine whether there is a possible neurobiological correlate of pedophilia which can be changed by therapeutic interventions.

Investigations on the pharmacokinetics of propafenone in man.

The pharmacokinetics of propafenone (Rytmonorm) was studied in 19 healthy volunteers. Propafenone was given intravenously (commercial ampoules of 70 mg) and orally in different doses (150, 300, 450 mg) and forms (solution, commercial film tablets). The results show a dose dependence of bioavailability and maximum plasma concentrations after oral application with over-proportionate increase at higher dose levels yielding bioavailabilities up to 40-50% with single applications of 450 mg. This is interpreted as saturability of a presystemic mechanism during invasion (most probably of the metabolizing enzyme systems of the liver). The mean rate constant of elimination after intravenous application is beta = 0.28 h-1 (95% confidence limits: 0.24-0.33 h-1) corresponding to a half-life of 2.5 h. There are no significant differences in these values after oral application and different dosages. The total plasma clearance of 1.0 1/min (95% confidence limits: 0.9-1.1 1/min) is almost exclusively metabolic. After 12 days of oral dosing (2 tablets of 150 mg propafenone daily) no statistically significant changes of kinetic parameters could be demonstrated although with some volunteers the total clearance decreased. It is considered that in some persons with relatively low clearance the plasma concentrations may reach levels at which a saturation of enzymatic reactions of metabolism may become relevant even after application of such low single doses as 150 mg.

Sequential psychological testing during the course of autoimmune hyperthyroidism.

Although the psychological disturbances accompanying Graves' disease are well known, the time required for normalisation of these disturbances during antithyroid drug treatment is not known. Therefore sequential psychological testing during the course of Graves' disease was done. There are also contradictory results concerning the possible correlation of neurophysiological and psychological test results during the course of Graves' disease with thyroid hormone values. Finally, psychological disturbances have been proposed as possible etiologic factors in Graves' disease. In our study, a significant decrease in anxiety and irritability could be observed at the time euthyroidism was achieved. Self-evaluations of depressivity, activity, exhaustion, well-being, extraversion, introversion, and the ability to concentrate changed 1 or 2 months after euthyroidism was induced. Similar test results could be observed after induction of euthyroidism by antithyroid drugs and subtotal thyroid resection. Therefore the mode of therapy does not seem to influence the course of normalisation of psychological parameters. In contrast to other investigations there was hardly any correlation between thyroid hormone values and psychological test results or the ability to concentrate. Nontheless, patients with Graves' disease showing high scores for depression and anxiety exhibit abnormal peripheral helper/suppressor T-lymphocyte relations. Furthermore, patients suffering from Graves' disease tend to be more anxious than controls. It remains to be determined whether an increased susceptibility to psychological disturbances has led to these alterations of lymphocyte subsets in Graves' disease patients with severe depression and anxiety.

[The role of TSH psychological and somatic changes in thyroid dysfunctions]. / Die Rolle des TSH für psychische Veränderungen und Befindlichkeitsveränderungen bei Schilddrüsenfunktionsstörungen.

The characteristic psychic and somatic features found in patients with overt hyper- or hypothyroidism are usually attributed to elevated or diminished levels, respectively, of thyroid hormones. This concept does not sufficiently explain our previous investigations in which the same symptoms, albeit attenuated, were also seen in patients suffering from so-called latent disturbances of thyroid function. This state of disorder, however, exhibits normal concentrations of peripheral thyroid hormones. Only the response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH) stimulation is in accordance with the behaviour of the overt thyroid dysfunction and enables its differentiation from the euthyroid state. In this context, we investigated the question as to whether pathologic signs in thyroid disorders are correlated to alterations of peripheral thyroid hormones or to changes in the hypothalamus pituitary axis. Therefore, we investigated two groups of ten patients each who suffered from latent hyper- or hypothyroidism, respectively, and ten euthyroid controls. All were matched from sex and age. Endocrine function was estimated by TRH testing, TT3, TT4 and thyroxine binding globulin (TBG). Psychologic testing was performed by questionnaires concerning subjective somatic symptoms, emotional disturbances, psychomotoric performance, cognitive impairment and personality. Patients with latent hyperthyroidism were more subject to somatic symptoms and affective complaints than were those who had latent hypothyroidism. As compared with controls, there were significant differences in exhaustion and pain in the limbs and heart. In terms of affective complaints, patients were more depressive, anxious, touchy and irritable; their personalities showed a higher degree of emotional lability, excitement and irritability.(ABSTRACT TRUNCATED AT 250 WORDS)

Subclinical hyperthyroidism: physical and mental state of patients.

We investigated whether subclinical hyperthyroidism [subnormal basal thyroid-stimulating hormone (TSH) level, attenuated TSH response to thyrotropin-releasing hormone (TRH) stimulation, peripheral thyroid hormones within normal range] is accompanied by physical and mental changes. Thirty-five subclinically hyperthyroid patients (27 female, 8 male) were compared with 60 overtly hyperthyroid patients (51 female, 9 male) and with 28 euthyroid control patients (18 female, 10 male) with respect to physical symptoms, affective state, short-term memory, ability to concentrate and psychomotor performance. Patients with subclinical hyperthyroidism ranged between the other two groups. The major difference between controls and subclinically hyperthyroid patients was an increase in frequency of nervous symptoms and symptoms due to an increase of metabolic rate and thermal regulation changes. The major differences between subclinically hyperthyroid and overtly hyperthyroid patients were psychomotor impairment and symptoms of increased metabolic rate. Self-ratings of affective state tended to be similar in patients with subclinical and overt hyperthyroidism. The ability to concentrate and short-term memory were not impaired in any group. Symptoms in patients with subclinical hyperthyroidism probably result from central changes which lead to attenuated TSH responses to TRH, or from elevated but still normal thyroxine levels, which possibly enhance the effect of catecholamines.

[Comparison of the effects of the anthracene derivative danitracen (WA335-BS) and amitriptyline in depressive patients (author's transl)]. / Wirkung des Anthracenderivats Danitracen (WA 335-BS) im Vergleich zu Amitriptylin bei depressiven Patienten

9,10-Dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol (danitracen, WA 335) is a substance with a stronger peripheral and partly central antiserotonin and antihistamine effect than cyproheptadine. In 5 different hospitals, WA 335 (3 X 1 mg/die) was investigated versus amitriptyline (3 X 50 mg/die) in a double-blind study in 116 depressive patients of different nosology. In the end of the investigation period (20 days), under WA 335 treatment 67.7% and under ami-riptyline treatment 66.7% of the patients showed an improvement of 50% = decrease in the Hamilton depression score. However, a decrease of 50% in the selfrating scale (von Zerssen) was only shown by 57% of the patients under WA 335 administration and 51% under amitriptyline administration. There were no significant differences seen as regards course and side effects of the two drugs. Like amitriptyline, WA 335 shows sedative properties at the beginning of therapy.