Hans Jörg Gaertner

Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking

Plasma norharman and harman levels were measured by solvent extraction and HPLC with fluorescence detection in alcohol-dependent patients undergoing in-patient abstinence treatment and in control subjects. In both groups, randomly collected samples from smokers contained higher mean norharman levels than those from non-smokers. In three volunteers norharman concentrations rose sharply after smoking of one or two cigarettes and declined to near-basal levels within one hour after one cigarette. When 12 patients kept a smoking-free interval of at least 6 h, they had similarly low plasma norharman concentrations (20 +/- 8 pg/ml) as 18 non-smoking control subjects (17 +/- 8 pg/ml) or as 13 smoking controls who had abstained from smoking (20 +/- 6 pg/ml). Ten of the patients smoked one cigarette and within 5-10 min attained norharman levels of 177 +/- 147 pg/ml plasma. The high prevalence of smokers among chronic alcoholics probably explains the previous finding of elevated norharman plasma levels in these patients.

Side effects of clozapine.

In addition to the low risk of agranulocytosis, several more frequent side effects are associated with clozapine therapy. We tried to estimate the incidence of these side effects. We analysed 391 treatments in 315 inptients, who received clozapine alone or combined with other neuroleptic and antidepressant drugs. Two thirds were combined treatments, one third were treatments with clozapine alone (i.e., no other neuroleptic, antidepressant or anticonvulsive drugs were allowed). The numbers in brackets show the incidence based on the analysis of the treatments with clozapine alone. In 49% (61%) of the treatments a rise in the liver enzyme values was observed. However, counting only the cases in which a two-fold increase over the normal values was observed, the incidence was reduced to 20% (31%). Increase in temperature was observed in 4% (6%) and leukopenia (leukocyte count under 3500/μl) was recorded in 2% (2%). Hypotensive dysregulation (systolic blood pressure under 90 mm Hg) was observed in 25% of all treatments and pharmacogenic delirium in 8%. No cases of agranulocytosis were observed. Mean treatment duration was 56 days, mean daily dosage 257 mg. The mean age of the patients was 34 years. In the overall evaluation 71% of the treatments were classified as successful; clozapine therapy was continued after discharge in 68% of the treatments. Adverse reactions (delirium, rise in temperature, hypotension, fatigue, rise in liver enzymes) necessitated a change of medication in 17% of the treatments. Change-over to another neuroleptic drug due to ineffectiveness of clozapine was necessary in 7% of the treatments. The quality of the data is somewhat adversely influenced by the fact that the study was conducted retrospectively on the basis of medical records.

Antidepressive effect and pharmacokinetics of amitriptyline with consideration of unbound drug and 10-hydroxynortriptyline plasma levels

In 27 inpatients with primary affective disorder the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured prior to a 4-week treatment with 150 mg amitriptyline (AT)/day. Ratings according to the Hamilton depression scale were performed before therapy and repeated after 2 and 4 weeks. Plasma levels of AT, nortriptyline (NT), and E-10-hydroxynortriptyline (OHNT) were assayed weekly, and binding of AT to plasma proteins was determined in one sample. Better therapeutic results were obtained at intermediate, as compared to low and high concentrations of AT or AT plus NT. Independent evaluation of AT and metabolite levels revealed that patients with AT of 50–125 mg/ml responded particularly well when NT did not exceed 95 ng/ml or when NT plus OHNT was below 150 ng/ml. Outside this ‘therapeutic window’ the outcome was markedly poorer. Interindividual variation of AT binding was much smaller than variation of total concentrations. Evaluation of free, instead of total levels did not help to clarify the relationship between clinical and pharmacokinetic variables. Plasma levels within the optimal ranges were found in more patients with high than with low MHPG excretion. The frec fraction of OHNT in plasma of healthy subjects was about 35%.

Relevance of liver enzyme elevations with four different neuroleptics: a retrospective review of 7,263 treatment courses.

Data on liver enzyme elevations were collected in a retrospective study of 7,263 treatment courses with haloperidol, clozapine, perphenazine, and perazine. Charts of 233 patients hospitalized between 1980 and 1992 at Tübingen University Psychiatric Clinic were selected because clinically relevant increases of liver enzymes had been detected during monotherapy with one of the four examined neuroleptics. At least one hepatic enzyme (mostly alanine aminotransferase [ALAT]) exceeded the established reference range of 3-fold elevations of ALAT, aspartate aminotransferase, γ-glutamyl transpeptidase, and glutamate dehydrogenase and 2-fold elevations of alkaline phosphatase (AP) during monotherapy with clozapine in 15%, perazine in 7.6%, perphenazine in 4%, and haloperidol in 2.4% of the cases. If all liver enzyme abnormalities with any elevation greater than the conventional upper limits are considered, incidences were as follows: clozapine, 78%; perphenazine, 62%; perazine, 59%; and haloperidol, 50%. Testing for overall differences within the four neuroleptics resulted in significantly different incidences of liver enzyme elevations (χ2 test, p < 0.0001). Threefold increases of AP (>540 U/L) were seen in three patients receiving haloperidol (0.3%) only. Twofold increases of AP (>360 U/L) were distributed as follows: clozapine, 1%; haloperidol, 0.8%; perazine, 0.3%; and perphenazine, 0.1%. Only in the group with 1-fold elevations of AP (>180 U/L) were the differences within the drug regimens significant (clozapine, 40.3%; haloperidol, 33.2%; perphenazine, 23.4%; and perazine, 23.1%; χ2 test, p < 0.0001). In the period under study, no instance of icterus occurred.

Formation of identical metabolites from piperazine- and dimethylamino-substituted phenothiazine drugs in man, rat and dog

Abstract Degradation of the piperazine ring in the phenothiazine drugs perazine, trifluoperazine, fluphenazine, prochlorperazine and perphenazine in vivo leads to the formation of γ-(phenothiazinyl-10)-propylamine (PPA) and of its ring-substituted analogues CF 3 -PPA and Cl-PPA. The sulfoxides of these metabolites have been identified as urinary biotransformation products in patients ingesting perazine or fluphenazine, in rats treated chronically with perazine, trifluoperazine, prochlorperazine or perphenazine, and in a dog given fluphenazine. The structures of the compounds have been confirmed by mass spectrometry. The primary amines are also known metabolites of dimethylamino-substituted phenothiazines, since PPA results from didemethylation of promazine, and CF 3 -PPA and Cl-PPA (= nor 2 -chlorpromazine) are formed from triflupromazine and chlorpromazine, respectively.

Metabolism of trifluoperazine, fluphenazine, prochlorperazine and perphenazine in rats: In vitro and urinary metabolites

Abstract In vitro and in vivo metabolites of trifluoperazine, fluphenazine, prochlorperazine and perphenazine were isolated by solvent extraction and thin layer chromatography and quantified by u.v. spectroscopy. In liver microsomes from male rats all four drugs underwent N -dealkylation. N -oxidation, sulfoxidation and aromatic hydroxylation. The relative rates of these reactions depended on the substrate concentration, N -oxidation being favoured at higher concentrations. N -Demethylation of trifluoperazine proceeded faster than removal of the hydroxyethyl group from fluphenazine which led to the same metabolite N [γ-(2-trifluoromethyl-phenothiazinyl-10)-propyl] piperazine. The same applied to the dealkylation of prochlorperazine and perphenazine. Following oral administration of 10 mg/kg of the drugs, male rats excreted 1.8−4 per cent of the dose within the first 12 hr in urine in the form of the sulfoxide and the N -dealkylated sulfoxide. In vivo , too, the N -hydroxyethyl group was removed to a smaller extent than the N -methyl group. N -Oxides were not detected in urine at this dose level, but when 25 or 50 mg/kg prochlorperazine were administered, rats excreted small amounts of the N -oxide.

Plasma levels, psychophysiological variables, and clinical response to amitriptyline

Hamilton depression scale ratings and physiological measurements were made for 37 patients with primary depression before treatment with amitriptyline (150 mg/day) and again after 2 and 4 weeks of treatment; plasma drug levels were determined weekly. Improvement was maximal at mean amitriptyline + nortriptyline concentrations of 125-200 ng/ml (14 patients), while at lower levels the outcome was significantly poorer (12 patients). Highly variable results were seen in 11 patients with levels between 200 and 301 ng/ml, with lesser improvement occurring in those patients who exhibited poor habituation of the skin resistance response before treatment. Other psychophysiological variables showed significant changes during treatment, but no correlation with clinical results or drug levels.

Validation of a therapeutic plasma level range in amitriptyline treatment of depression.

In the course of a double-blind study, 29 depressed patients received amitriptyline 150 mg/day for 4 weeks. Scores on the Hamilton Depression Rating Scale were assessed before treatment and after 2 and 4 weeks, and plasma levels of amitriptyline, nortriptyline, and (E)-10-hydroxynortriptyline were monitored weekly. Response reflected by percent reduction of Hamilton Depression Rating Scale score and by final score was better at steady-state amitriptyline + nortriptyline concentrations of 125-210 ng/ml than at lower and higher plasma levels. This applied to the total group and to the subgroup of 22 female patients. The data confirm the results of a previous study performed in the same hospital. An influence of the (E)-10-hydroxynortriptyline concentration in plasma on therapeutic outcome was not discernible. The results suggest that plasma level monitoring may be helpful when patients do not respond to conventional amitriptyline doses.

Do urinary MHPG and plasma drug levels correlate with response to amitriptyline therapy

Twenty-nine inpatients with primary affective disorder were treated with 150 mg amitriptyline (AT) daily for 28 days. Pretreatment urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in two or three 24-h urine samples. Plasma levels of AT and nortriptyline (NT) were determined after 14, 21, and 28 days of treatment. MHPG excretion was significantly correlated with clinical response to treatment. Responders defined by two different methods showed higher pretreatment MHPG excretion than nonresponders. Correspondingly, high MHPG excretors (median split) showed significantly more improvement than low excretors. These relationships were even more apparent when possibly incomplete urine samples (creatinine excretion below 1000 mg/24 h) were excluded. The high and low MHPG subgroups did not significantly differ from each other in their plasma levels of AT, NT, or AT plus NT. A significant rank correlation between clinical response and plasma levels of AT and/or NT did not exist, but there was a trend towards lower levels in responders.

Single-dose kinetics of the neuroleptic drug perazine in psychotic patients

Eight male and two female unmedicated psychotic patients received 100 mg perazine orally and seven blood samples were taken within 25 h. Plasma levels of perazine and its demethylated metabolite were analyzed by HPLC with electrochemical detection. They exhibited large interindividual variations, with maximal concentrations as well as AUC values of perazine differing more than 10-fold. From the decay of plasma levels during the last 12–18 h half-lives were estimated to be between 7.5 and 16 h; they did not correlate with AUC. There was a significant positive correlation between AUC and age. Desmethylperazine was consistently present at lower concentrations than the parent drug during the first 12 h.