Classic monoamine oxidase (MAO) inhibitors, such as tranylcypromine and phenelzine, are effective anti-depressant drugs. They earned, however, a notorious reputation because of their propensity to induce drug-drug and drug-food interactions (1). Many of these interactions can be attributed to the potentiation of the effects of indirectly acting sympathomimetic compounds. Tyramine, which is a constituent of several nutrients, and pressor amines such as phenylpropanolamine, ephedrine, and pseudoephedrine, which are often found in over-the-counter cough and cold medicines, in combination with irreversible, non-selective MAO inhibitors may lead to severe hypertension, hyperpyrexia, arrhythmias, and even death (2,3).
The advent of reversible MAO inhibitors that are selective for a particular isoenzyme has led to a resurgence in the use of these drugs in neuropsychiatric disorders (4). Moclobemide is a reversible and selective MAO-A inhibitor whose antidepressant properties and good tolerability have been extensively documented (5,6). Because of its selectivity and reversibility, moclobemide is not prone to induce drug-drug interactions at the pharmacokinetic and pharmacodynamic level (7). Several studies were performed to investigate the interaction between moclobemide and tyramine. Moclobemide potentiates the tyramine pressor response approximately twofold to fivefold, depending on the route of tyramine administration (i.v. or oral) and the interval between application of the two compounds (8,9). This interaction is unlikely to be of clinical relevance, as large amounts of tyramine would have to be ingested to induce clinically relevant increases in blood pressure (10). Classic MAO inhibitors, by comparison, increase the sensitivity to tyramine >20-fold (11).
Possible interactions between moclobemide and other indirectly acting sympathomimetic amines have been only sparsely investigated. Moclobemide increased the sensitivity to the blood-pressure response to i.v. phenylephrine by twofold (12).
The objectives of this study were to assess the effects of oral ephedrine added to steady-state moclobemide treatment in healthy volunteers. Ephedrine was selected as a model compound for the study of interactions between sympathomimetic amines and moclobemide because it elicits more pronounced cardiovascular effects than pseudoephedrine and phenylpropanolamine (13-15).
Thirteen healthy white subjects (age range, 19-36 years) participated in this study. Initially, six subjects of each gender were recruited, but one male subject was withdrawn from the study because he was involved in a traffic accident during the ambulatory phase of the study (day 3). This subject was replaced by another male participant. Ethics committee approval was obtained from the Roche Welwyn Clinical Pharmacology Unit Independent Ethics Committee. All subjects gave written informed consent before any screening procedures were performed. The study was conducted in full conformity with the principles of the Declaration of Helsinki and its amendments. Subjects were considered to be healthy, as assessed by medical history, physical examination, ECG, and clinical laboratory determinations. Tests for drugs of abuse in blood and urine also were performed. No concomitant medication was allowed during the study, with the exception of oral contraceptives, which were taken by five of the six female subjects.
This was a partly open (days 3-9) and partly double-blind (days 1-2 and 10-11), randomized, placebo-controlled crossover study. On days 3-9, the subjects were ambulant but came to the clinic for drug administration in the morning. Each subject received a diary for recording adverse events and times of evening drug intake during the ambulatory period. On day 1, subjects received two doses of either placebo (matching ephedrine capsules) or of ephedrine HCl, 50 mg, given 4 h apart. In most cough and cold preparations, the dose of ephedrine is 10-20 mg, and therefore it was anticipated that optimal conditions were established to detect a significant interaction, should one exist. On day 2, subjects received the opposite assignment from day 1. On days 3-10, all subjects received moclobemide, 300 mg b.i.d. (tablets of 150 mg), which constitutes the upper part of the recommended therapeutic dose range. Before dosing at 09.00 h and 20.00 h, the subjects had breakfast and dinner, respectively. A last dose of 300 mg was given at 09.00 h on day 11. On days 10 and 11 (i.e., when the subjects were receiving steady-state moclobemide treatment (16), the procedures of days 1-2 were repeated. Moclobemide and ephedrine/placebo were taken simultaneously. The randomizations for days 1-2 and 10-11 were independent of each other.
Adverse events were assessed by spontaneous reports, observations, and questioning at regular intervals. The intensity of the adverse events was rated on a 3-point scale (mild, moderate, and severe), and the potential relation to drug was assessed by the investigator before breaking the code. Sitting blood pressure, heart rate, ECG, and body temperature were measured at frequent intervals on study days 1, 2, 10, and 11. Blood pressure was recorded by using automated Spacelab recording devices. At discharge from the clinic, a physical examination and routine clinical laboratory tests were performed. Blood samples of 10 ml for pharmacokinetics were collected in polypropylene tubes containing EDTA as anticoagulant just before drug intake on day 1 and just before and 2 h after drug intake on days 10 and 11.
Plasma concentrations of moclobemide and two of its metabolites, Ro 12-5637 and Ro 12-8095 (17), were determined according to previously described methods (16,18). The quantification limit for this assay was determined to be ≈10 μg/l for all three substances. Assay of quality control samples at four different concentrations indicated an interassay reproducibility with a coefficient of variation of <9% and an inaccuracy <8% for all three analytes.
Adverse events and clinical laboratory data were evaluated descriptively. Clinical laboratory values were compared with the normal ranges supplied by the analyzing laboratory.
For each pharmacodynamic variable (systolic blood pressure, diastolic blood pressure, and heart rate), the individual area under the effect-time curve (AUE), maximal effect (Emax), and time of maximal effect (tEmax) were determined on study days 1, 2, 10, and 11. From the measurements obtained just before morning drug intake on these days, the median value was taken as reference point (baseline) for all calculations and was considered to be the value at drug intake (time 0). By taking the median value of the four measurements, the influence of intraindividual variability (e.g., because of anxiety at the beginning of the study) was reduced. AUE was calculated as the area between the extrapolated baseline and the measured values between times 0 and 8 h by using linear trapezoidal rule. Only areas above the extrapolated baseline were considered for the calculation because only the sympathomimetic effects of ephedrine were of clinical relevance in the context of this study. Emax was calculated as the difference between the reference point and the highest value obtained.
The potentiation factor (PF) for AUE of combined moclobemide and ephedrine treatment versus ephedrine treatment alone was calculated as eqn. (1)
The potentiation factor for Emax was calculated analogously. Treatment groups and study days were statistically compared for AUE and Emax values. For comparison between the treatments, the paired t test was used in an exploratory way. Results were considered statistically significant at the p < 0.05 level.
The influence of ephedrine, given at a 2 × 50 mg dose, on moclobemide steady-state concentrations was explored statistically. Three-way analysis of variance with the factors subject, period, and treatment (α = 0.05) were applied to the observed moclobemide levels on days 10 and 11.
The original population of 12 subjects was supplemented by a thirteenth, as replacement for one subject who did not complete the study (see Methods). Another subject was excluded from the pharmacodynamic analyses because of erroneous dosing of study medication on day 1. Table 1 lists the total and most frequently reported adverse events. In the first 2-day crossover period, nine of 12 subjects experienced a total of 13 adverse events while receiving ephedrine, whereas only four of 12 subjects reported a total of four adverse events when taking placebo. The commonest adverse events during ephedrine treatment were palpitations and headache. During multiple dosing with moclobemide, the commonest adverse events were insomnia and impaired concentration. When subjects progressed to the second crossover phase, when ephedrine or placebo was added to moclobemide at steady state, 11 of 12 subjects reported a total of 31 adverse events on the combination of ephedrine-moclobemide, but only three of 12 subjects reported three adverse events when taking combined placebo-moclobemide. The commonest adverse events during the active drug combination were palpitations, headache, and lightheadedness. The only adverse events during placebo-moclobemide treatment were three cases of headache. Two adverse events were reported to be of severe intensity: nausea in a female subject during treatment with ephedrine alone and menstrual pain in another female subject during treatment with moclobemide alone. There were very few changes noticed in clinical laboratory parameters, and these were not suggestive of any trends. Some abnormalities were seen in ECG recordings. One subject showed inverted T-waves on study day 11, 2 h after administration of 300 mg moclobemide and 50 mg ephedrine. A repeated ECG 4 h later, after a further dose of ephedrine 50 mg, was normal. Another subject also showed an abnormal ECG on study day 11, 2 h after administration of 300 mg moclobemide and 50 mg ephedrine, with a junctional rhythm and retrograde inverted P waves. A repeated ECG, after an additional dose of 50 mg ephedrine, showed the same findings. The trace slowly reverted to normal and was completely normal by the following day.
Fig. 1 presents the average time course of systolic (SBP), diastolic blood pressure (DBP), and heart rate (HR) for the ephedrine and placebo treatments, alone and in combination with moclobemide. Ephedrine induced a clear increase in SBP and a less marked increase in DBP. The influence on HR was not substantial. Steady-state moclobemide treatment did not have a detectable influence on any vital sign. When combined with ephedrine, however, moclobemide potentiated markedly the effects of ephedrine on SBP and DBP, whereas there was a slight attenuating effect on HR. The time courses of the vital signs after the first and second dose of ephedrine were similar.
The pharmacodynamic parameters derived from SBP, DBP, and HR values for the different treatments are listed in Table 2. Ephedrine alone compared with placebo treatment caused a significant increase in all pharmacodynamic parameters, with the exception of Emax for DBP. The combination of moclobemide and ephedrine resulted in significantly enhanced AUE and Emax values of SBP and DBP compared with treatment with ephedrine alone or with moclobemide-placebo. Compared with ephedrine monotreatment, the combination moclobemide-ephedrine showed decreased AUE and Emax values for HR. No systematic pattern of changes in tEmax was observed. Table 3 gives the derived potentiation factors for the different vital signs.
No drug or metabolite was measurable in samples collected before the start of moclobemide administration. Table 4 lists the plasma concentrations of moclobemide and its metabolites at 2 h after administration of the morning dose in combination with either placebo or ephedrine (day 10 or 11). Moclobemide and metabolite levels in one subject were undetectable or very low for unknown reasons. Another subject omitted the evening moclobemide dose on day 10. These subjects were excluded from the pharmacokinetic analyses.
Analysis of variance showed no statistically significant differences between the 2-h levels determined when moclobemide was administered with ephedrine or with placebo.
The conditions of this study were optimized to detect a significant interaction between moclobemide and ephedrine if this should exist. For this purpose, high therapeutic doses of both drugs were administered.
The commonest adverse events associated with ephedrine treatment, either alone or in combination with moclobemide, were palpitations and headache. Moclobemide when given alone was generally well tolerated. Moclobemide had no effect on blood pressure and heart rate, which confirms previous studies in healthy volunteers and in patients, demonstrating negligible effects of moclobemide on these cardiovascular parameters (19-21). This also justifies the calculation of the median of the four predose vital-sign measurements as a reference value. There were several cases of insomnia, previously been reported to be an adverse event associated with the use of reversible MAO-A inhibitors (20,22). In combination with ephedrine, however, moclobemide increased the incidence of adverse events. Light-headedness was reported by recipients of ephedrine and moclobemide but not by recipients of ephedrine alone.
The results of our study are in agreement with the scanty data on ephedrine's effects on blood pressure (23). Ephedrine stimulates both α- and β-adrenergic receptors in addition to acting as an indirect sympathomimetic by releasing norepinephrine from its storage sites (i.e., it acts as a mixed direct/indirect agonist) (24). It causes moderate increases in SBP and HR caused by vasoconstriction and cardiac stimulation (25,26). The two doses of ephedrine (50 mg) added to steady-state treatment with 300 mg moclobemide b.i.d. caused a potentiation of the effects of ephedrine on BP. It has been demonstrated that inhibitors of MAO increase the amount of norepinephrine in noradrenergic tissues (27). The inhibition of neuronal MAO (i.e., MAO-A) in the mitochondria at nerve endings by moclobemide produces an increase in both the monoamine content of tissues and the cytoplasmic concentration of MAO substrates (3,28). Ephedrine treatment had no influence on plasma concentrations of moclobemide and its metabolites. Because ephedrine is not a substrate of MAO, an influence of moclobemide on the pharmacokinetics of ephedrine is also very unlikely. Therefore the potentiation by moclobemide of the cardiovascular effects of ephedrine must be attributed to a pharmacody namic interaction.
Calculation of potentiation factors is a widely used method of quantifying the interaction between sympathomimetic amines and MAO inhibitors. A considerable variability in potentiation factors, particularly with respect to AUE, was found. For DBP, only one subject showed an AUE potentiation factor >7 (i.e., a value of 65.8). In this subject, only a very weak response to ephedrine alone but a sustained response to the combination was observed. A potentiation factor of ≈4 can be derived from our study with respect to the BP-increasing effect of combined moclobemide and ephedrine. This potentiation is in accordance with the increase in several symptomatic adverse events obtained after administration of the drug combination. Similar potentiation factors also have been reported for the combination of phenylephrine-phenelzine (29), phenylephrine-moclobemide (12), and ephedrine-phenelzine (27). It is also in close agreement with the results of tyramine-interaction studies (9). Brofaromine, another reversible and selective MAO-A inhibitor, caused a 3.3-fold increase in pressor sensitivity to phenylpropanolamine (30). The similarity between the results of the latter and of our study is striking, considering the different methods used. Whereas ephedrine treatment alone caused a significant increase in HR, combined treatment with moclobemide and ephedrine resulted in effects not different from those of the moclobemide-placebo combination. This may be explained by compensatory vagal activity occurring as a reflex to increased arterial BP.
From a clinical point of view, it is relevant to examine also the extreme vital-sign values obtained in this study because they could be critical in patient populations at risk. The largest increases in SBP and DBP after ephedrine monotreatment were 35 and 22 mm Hg, respectively. Similarly, for the combination of moclobemide and ephedrine, maximal increases were observed of 76 and 40 mm Hg for SBP and DBP, respectively. These maximal changes in BP must be considered clinically significant because they are beyond the limits obtained, for example, during strenuous physical exercise (31). However, the ephedrine dosage used in this study is at the upper limit clinically used as single dose. Ephedrine is still administered orally to some patients with mild bronchial asthma and bronchospasms associated with chronic bronchitis or emphysema. The dose in these patients is 25-50 mg, given 3-4 times per day, and therefore the combined use of ephedrine and moclobemide in these patients would seem to be inappropriate. The effect of the combination of moclobemide with lower doses of ephedrine as in cough and cold preparations (usually 10-20 mg) cannot be directly derived from the results of this study but is unlikely to cause changes in BP larger than those during physical exercise.
Acknowledgment: The clinical part of this study was conducted at the Roche Clinical Pharmacology Unit, Welwyn, U.K., with Dr. G. R. McClelland acting as the principal investigator. The assistance of Demetrio Pisano in preparing this manuscript is gratefully acknowledged.
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