Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Moclobemide is an effective and well-tolerated antidepressant for the treatment of elderly depressed patients.

In this double-blind study forty-seven patients with hay fever were treated for 8 days with either terfenadine 60 mg twice a day, astemizole 10 mg once a day or placebo. On the second day of treatment terfenadine was statistically significantly superior to astemizole and placebo according to the ratings of symptomatology, efficacy and individual symptoms. The median onset of symptom alleviation was 3 hours for terfenadine and 2 days for astemizole. On the eighth day both astemizole and terfenadine were statistically significantly more efficacious than placebo, but no significant differences were found between the two drugs. Both drugs were well tolerated.

The effects of terfenadine and pseudoephedrine, alone and in combination, have been assessed in a nasal provocation test and in perennial rhinitis. In a double-blind, placebo-controlled cross-over nasal provocation test, twelve men allergic to grass pollen were treated with two daily doses of placebo, terfenadine 60 mg, pseudoephedrine 120 mg, or the combination of the two, for 2 days preceding each test. The allergic reaction threshold, based on rhinorrhoea, sneezing and nasal inspiratory peak flow rate, was raised significantly both by terfenadine and pseudoephedrine, and their effects appeared additive (repeated measures analysis of variance). In a double-blind, randomized clinical study of perennial rhinitis two parallel groups, the efficacy and tolerability of terfenadine and terfenadine-pseudoephedrine were compared in 50 patients. Symptoms and signs in both groups were improved after 14 days of treatment. Differences between groups showed a trend in favour of terfenadine-pseudoephedrine, for swelling of the nasal mucosa (rhinoscopy) they were statistically significant. Both medications were well tolerated overall, although adverse events and reactions were more frequent in the terfenadine-pseudoephedrine group. In conclusion, terfenadine-pseudoephedrine and its constituents taken alone were effective. The combination performed better, but adverse events were somewhat more frequent with the combination than with terfenadine alone.

Eight healthy men received an oral dose of 0.25 mg/kg diazepam followed 40 min later by an intravenous infusion of 100 ml physiological sodium chloride solution, with or without 4.4 mg/kg theophylline. Psychomotor function was assessed after each blood sampling up to 5 h post-infusion. Thirty min after diazepam psychomotor performance measured by Card Sorting test and Digit Symbol Substitution test was impaired and subjects felt sleepy and could think less clearly (two factors of the Clyde Mood Scale). Theophylline antagonized the diazepam-induced impairment statistically significantly for up to 5 h and subjects felt less tense and less apprehensive (State Anxiety Inventory). Since pharmacokinetic parameters of diazepam seemed not to be different after theophylline, interaction at receptor level can be assumed.

The interaction between cimetidine and two tricyclic antidepressants was examined in healthy subjects. One tricyclic, imipramine, is primarily metabolized to a demethylated active metabolite, desipramine. The other, nortriptyline, is largely metabolized to a 10-hydroxylated metabolite. It was assumed that pretreatment with cimetidine, because of its inhibition of metabolic pathways of both demethylation and hydroxylation as well as its ability to reduce hepatic extraction of these drugs, would increase bioavailability and decrease clearance of both drugs. Such was the case with imipramine, but the bioavailability of nortriptyline was not increased. Further, the bioavailability of the 10-hydroxy metabolite of nortriptyline was increased rather than decreased. The degree of change in these kinetic variables varied widely between individuals. Thus it is not possible to predict which subjects might develop evidence of toxicity to tricyclics when cimetidine is added to the treatment program. The monitoring of tricyclic plasma concentrations is probably desirable in such circumstances.

We have assessed the effects of terfenadine on rhinitis symptoms associated with the common cold in 91 patients in a double-blind placebo-controlled study. The patients received three doses of either terfenadine 60 mg (n = 44) or placebo (n = 47) at about 12-h intervals, starting in most patients within 48 h from the onset of symptoms. Because of deviations from the protocol, 28 cases were classified as not eligible for efficacy evaluation, but were nevertheless analysed. Excellent/good or moderate efficacy was reported by 63% of eligible and 59% of all patients who received terfenadine (placebo 40% and 51% respectively, p = 0.049 and 0.113 respectively). 68% of eligible and 52% of all patients indicated that they would take terfenadine again (placebo 23%, for both p = 0.002). Two h after tablet intake mean nasal airflow was increased by 11 l.min-1, SD 8 (placebo -1 l.min-1, SD 6, p = 0.005). Symptoms were improved and rhinoscopy showed reduced swelling and redness of the mucosa and reduced nasal secretion and obstruction (basically unchanged in the placebo group). Therefore, terfenadine seems to act favourably on the acute rhinitis symptoms associated with the common cold. Since terfenadine is devoid of anticholinergic activity, nose symptoms during the initial stage of the common cold may be mediated to an important degree by histamine.

This double-blind, randomized multi-centre study was designed to compare efficacy and tolerability of 120 mg terfenadine taken once daily (in the morning) with the established regimen of 60 mg terfenadine taken twice daily in the treatment of seasonal rhinitis. Two comparable groups, a total of 191 hay fever patients, were treated for 1 week. Symptom severity was assessed by the investigators before and at the end of the treatment (visual analogue scale), and daily by the patient (four-point rating scale). All symptoms improved to a similar degree in both groups. Differences between the two groups were not statistically significant, except for nasal symptoms in three cases as assessed by the visual analogue scale in one centre (better relief in the group given 120 mg terfenadine once daily). Tolerability was good and similar in both groups. The data presented show that in the treatment of hay fever 120 mg terfenadine given once daily is an effective, convenient and well tolerated alternative to the regimen of 60 mg terfenadine given twice daily.