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Biomedical subjects

R Amrein

Publications and source records attributed to R Amrein.

At least 19 recordsLinked to original sources
PubMed1996

Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomised, placebo-controlled multicentre trial.

The efficacy of the benzodiazepine antagonist flumazenil has been assessed clinically in a double blind, randomised, placebo-controlled multicentre study in patients with grade I-III portosystemic encephalopathy. In an ancillary study reported here the effect of flumazenil on the electroencephalogram (EEG) was analysed in 32 patients who had EEG grading according to protocol. Following the baseline observation period, patients were randomised to receive (at 1 min interval) 3 sequential bolus injections of flumazenil (0.4, 0.8 and 1 mg) or placebo followed by infusions of flumazenil (1 mg/h) or placebo for 3 h. Patients were monitored for 5 h after infusion. A positive response was defined as 1 point improvement in EEG grade. After independent analysis of the EEG gradings 5 out of 17 (29%) flumazenil treated patients showed an improvement in EEG grading (3 after bolus, 2 during follow-up) compared to 2 out of 15 (13%) placebo treated patients (1 after bolus, 1 during follow-up) (95% confidence interval of difference: -12% to + 50%). Of the 5 EEG responders after flumazenil, 3 also had an improvement in clinical PSE grading (none after bolus, 2 during infusion, 1 during follow-up), compared to neither of the 2 EEG responders after placebo. EEg responders did not differ from non-responders with respect to Child-Pugh score, basal EEG, PSE grade and positivity for benzodiazepines. In conclusion, treatment perspectives for flumazenil in portosystemic encephalopathy appear to be present for only a minority of patients; however, this study yields no support for a major role of benzodiazepine antagonists in the treatment of hepatic encephalopathy.

Adult↗
PubMed1996

Postvitrectomy positioning complicated by ulnar nerve palsy.

PURPOSE: Ulnar nerve palsy is an unusual complication of postvitrectomy positioning. METHOD: We report two such cases. RESULTS: Both patients developed ulnar nerve palsy after maintaining a face-down position for 2 to 4 weeks after vitrectomy with intraocular perfluoro-octane. The neuropathy resolved in one patient after he was instructed to avoid prolonged pressure on his flexed elbows, whereas the other patient ultimately required surgical decompression of the nerve at the elbow. CONCLUSION: Ulnar nerve palsy can result from postvitrectomy positioning associated with prolonged direct pressure on the ulnar nerve or compression of the ulnar nerve via flexion of the elbow.

Adult↗
PubMed1996

Moclobemide: a paradigm of research in clinical psychopharmacology.

The pre-clinical development of moclobemide is an example of broad research combined with serendipity. Moclobemide was first hypothesized as being an antilipaemic or antibiotic, but the screenings were negative. The search for its antidepressant qualities, based on anticholinergic tests, also proved negative and moclobemide was then suspected of being an antipsychotic before its specific and reversible monoamine oxidase (MAO)-A inhibition qualities were detected. After the establishment of its lack of relevant interference with tyramine pressure response, clinical trials were launched in 1977. In the first stage, multiple, small open and double-blind studies were carried out. Two decisive, large, multicentre, double-blind studies were later performed in Latin America and Austria. Further trials have confirmed the broad antidepressant activity of reversible monoamine oxidase inhibitors (RIMA), which is not confined to any one subtype of depression and which show good tolerability and low toxicity. Since moclobemide has been available on the market, extensive meta-analyses of a large data set provided a series of methodological results: factor structure of the Hamilton Depression Scale (HAMD), optimal criteria of efficacy, predictors of response, onset of action for antidepressants and placebo.

Antidepressive Agents↗
PubMed1996

Antidepressants and drug-metabolizing enzymes--expert group report.

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.

Antidepressive Agents↗
PubMed1996

Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.

BACKGROUND: Portal systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be effective in ameliorating PSE. AIMS: To determine the efficacy of flumazenil in patients with non-comatous mild to moderate PSE (stages I to III) due to severe chronic liver disease. PATIENTS: 49 male and female adults without symptoms of severe bleeding and sepsis and who screened negative for benzodiazepine in both blood and urine, were included in the study. METHODS: Patients were randomised to receive either three sequential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either flumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading and vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures were improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement). RESULTS: The mean average improvement in the PSE score in the subjects treated with flumazenil was not statistically significantly different from placebo. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significant (seven of 28 v none of 21; p = 0.015). Flumazenil was well tolerated. CONCLUSIONS: A subgroup of patients with PSE resulting from chronic liver disease may benefit from the administration of flumazenil.

Chronic Disease↗
PubMed1996

Moclobemide in elderly patients with cognitive decline and depression: an international double-blind, placebo-controlled trial.

BACKGROUND: The new reversible MAOl moclobemide was compared with placebo in the treatment of elderly patients with DSM-III diagnosis of dementia and/or of major depression. METHOD: Six hundred and ninety-four elderly patients with symptoms of depression and cognitive decline entered an international, multi-centre, double blind trial in which they were randomly allocated to treatment with either moclobemide 400 mg daily or placebo for 42 days. Five hundred and eleven patients met DSM-III criteria for dementia and were also depressed (DEM+D); 183 did not meet DSM-III criteria for dementia but met the criteria for DSM-III major depressive episode and also suffered from cognitive decline (MDE+CD). RESULTS: Analysis of the 17 and 24-item Hamilton Depression Scale scores showed that moclobemide, compared with placebo, produced significantly greater improvement in both the demented and depressed groups (P = 0.001 both diagnostic groups). There was an improvement in cognitive function as measured by the SCAG Factor 1 in moclobemide treated patients (P = 0.005 DEM+D; P = 0.02 MDE+CD). There was no evidence of decline in cognitive function as the result of treatment. Clinical global assessment of tolerance was 'excellent' and 'good' in 88% of the moclobemide and in 92% of the placebo treated patients. The proportion of patients discontinuing treatment prematurely was similar in both treatment groups. There were no significant differences in side-effects between treatment groups. There were no significant changes in vital signs, ECG or laboratory findings in either treatment group. There were no dietary restrictions and no report of any tyramine reaction. CONCLUSIONS: Moclobemide was shown to be a safe, well tolerated and effective antidepressant, which did not cause impairment of cognitive function in elderly patients with a DSM-III diagnosis of dementia and/or DSM-III major depression.

Aged↗
PubMed1995

Moclobemide and tricyclic antidepressants in severe depression: meta-analysis and prospective studies.

There is no generally accepted definition of severe depression, but hospitalization, high scores on rating scales, and the presence of psychotic symptoms are widely considered to be indicators of severe cases. For the purpose of this analysis of the antidepressant efficacy of the reversible inhibitor of monoamine oxidase A moclobemide, all hospitalized cases were selected from the current database of comparative studies and compared with the standard tricyclics imipramine and clomipramine. The cases from comparisons of moclobemide and imipramine were analyzed together, because in accordance with the recommended range of doses, the dose ratio over all studies was approximately 3:1 (moclobemide: N = 238, mean dose, 453 mg/day; imipramine: N = 248, mean dose, 159 mg/day). The cases from comparisons of moclobemide and clomipramine could only be analyzed over all studies if dose was taken into account, because the dose ratio of approximately 3:1 was only given in one study (moclobemide: N = 62, mean dose, 466 mg/day; clomipramine: N = 66, mean dose, 154 mg/day), whereas the dose ratio over the other, earlier studies was approximately 2:1 (moclobemide: N = 58, mean dose, 258 mg/day; clomipramine, N = 59, mean dose, 124 mg/day). The efficacy as judged on the Hamilton Rating Scale for Depression (HAM-D) and Global Assessment of Efficacy was analyzed for subgroups of inpatients, according to different severity bands (17-item HAM-D baseline total score, cut-off, 28 points) and according to the presence or absence of mood-congruent psychotic features. The results of our analysis failed to reveal any difference in efficacy between moclobemide and imipramine in any subgroup of hospitalized depressives, including patients in the highest HAM-D severity band and psychotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressive Agents↗
PubMed1995

Pharmacology of flumazenil.

Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist available for clinical use. It is a specific competitive antagonist at benzodiazepine receptors, which are associated with receptors for gamma-aminobutyric acid, the most important inhibitory neurotransmitter in the central nervous system. Administered orally, it has a low bioavailability and the preferred route is intravenous. Its usual clinical role is to reverse the effects of benzodiazepine sedation; however, administered before, or with, other benzodiazepines, it modifies their effects, the extent of such modification depending on the dose, duration of effect and relative receptor affinity of the agonist. Flumazenil also reverses adverse physiological effects of benzodiazepines. Its indications include reversal of benzodiazepine-induced sedation, termination of benzodiazepine-induced anaesthesia, return of spontaneous respiration and consciousness in intensive care patients and the treatment of paradoxical reactions to benzodiazepines. Other potential indications include its use in hepatic encephalopathy, alcohol intoxication and coma; however, these claims still require substantiation. Following sedation reversed with flumazenil, minimal residual effects of the agonist can sometimes be detected using psychomotor tests and are due to the relatively short half-life of flumazenil, but are of no clinical consequence. There is concern that flumazenil could precipitate an acute withdrawal syndrome following long-term benzodiazepine administration; however, the available evidence suggests otherwise and that it could be useful in the treatment of benzodiazepine tolerance. The existence of flumazenil is important, with implications for future research and the development of minimally invasive therapy and day-case surgery. With increasing pressures on non-anaesthetically trained practitioners to perform sedation, flumazenil has important implications for safety.

Administration, Oral↗
PubMed1995

Relevance of reversible inhibitors of monoamine oxidase type A and of reuptake inhibition for noradrenaline turnover.

Noradrenaline (NA) and serotonin, monoamines that increase neurotransmission at the monoaminergic synapses, remain primary targets for antidepressant drugs. To help elucidate NA's role in the action of antidepressants, a model was set up allowing for a simulation of NA turnover under various conditions examining 3 compartments: newly synthesized vesicular NA, released synaptic NA, and vesicular NA reuptake across neuronal membranes. We compared the influence of the reversible MAO inhibitor, moclobemide, and the NA reuptake inhibitor, desipramine, both useful in regaining baseline synaptic NA concentrations. Moclobemide appears less sensitive to fluctuations either in drug concentrations and/or physiological determinants of NA turnover; we conclude that it may influence brain function in a more regulatory way than reuptake inhibitors.

Animals↗
PubMed1995

Co-induction of anaesthesia: the rationale.

Combination therapy with two or more different drugs, with the intention of reaching the same therapeutic goal, was heavily criticized for a long time. However, it is accepted today, especially when advantages over monotherapy can be shown. For the induction of anaesthesia or for long-term sedation in the intensive care unit, combination therapy may offer an improved effect profile, a more balanced ratio of desired versus adverse effects, an improved time-course of effect, simpler treatment requirements or lower costs. Midazolam and propofol have been investigated as potential partners for those two indications. The mechanism of action, pharmacokinetic properties, pharmacological effect, the way in which they interact at the receptor site, the differences in pharmaceutical formulations, the side-effect profiles and economic considerations were compared. Animal experiments and clinical pharmacology studies have shown that midazolam and propofol have synergy with other centrally active drugs. It could be expected that the relationship between desired effects and adverse effects could be improved by skilful use of the synergism between midazolam and propofol. Co-induction of anaesthesia and co-administration in long-term sedation can offer improvements in therapeutic situations compared with monotherapy. These improvements are in terms of a more suitable effect profile, a more favourable ratio of desirable effects to side-effects, optimization of the time-course of effects and reduced costs.

Anesthesia↗
PubMed1994

Monoamine oxidase inhibitors, cognitive functions and neurodegenerative diseases.

Recent data obtained in animals and in humans suggest that both MAO-A and MAO-B inhibitors present cognitive enhancing properties of possible interest in the treatment of cognitive disorders. In addition, the rational for using selegiline as a neuroprotector in Parkinson's disease may also be applicable in Alzheimer's disease in which a dramatic increase in the MAO-B activity has been reported. It seems then worthwhile to investigate the neuroprotective effect of MAOIs in humans and to assess, furthermore, the real therapeutical benefit of their cognitive enhancing properties.

Alzheimer Disease↗
PubMed1994

Safety and efficacy during long-term treatment with moclobemide.

Safety aspects [adverse events, blood pressure and heart rate, weight, and laboratory tests (liver parameters, hemoglobin, leukocytes)] of long-term treatment in 1,120 patients are discussed. Adverse events during this long-term treatment were also compared with those of a subgroup of these patients who, before long-term treatment, were treated on a short-term basis (n = 706). Efficacy [Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression of Efficacy (CGI), and occurrence of relapses and recurrences] in a homogeneous sample of 485 patients is also discussed. The adverse events most frequently observed during long-term treatment were insomnia, headache, and dizziness. Insomnia and headache were also most often occurring in the compared sample of patients with short-term treatment, whereas dizziness during this treatment period ranked at the fifth position. Supine and standing mean blood pressure did not consistently change during long-term treatment, the most prominent increases in comparison with baseline were seen in the period > 1 year of treatment (6.3 mm Hg supine/7.2 mm Hg standing). Comparison of blood pressure values in the hypertensive range at baseline and during long-term treatment revealed no statistical difference (McNemar test p = 0.07829). Mean heart rate slightly decreased during long-term treatment (by a maximum of 6.3 beats/min supine, 8.2 beats/min standing). Mean weight did not change between baseline and treatment end point. There were 23 patients with a weight loss of 10 kg or more and 16 patients with a weight gain of 10 kg or more. For none of the laboratory parameters tested was there a statistical significance regarding shifts from normal to pathological values. HAM-D mean total scores in the above-mentioned subgroup of patients decreased from 25.05 points at baseline (n = 485) to 7.88 points after 1 year of treatment (n = 139). Seventy-five patients who had favorably responded to treatment (total responders n = 300) relapsed during the first 6 months of treatment. During the second half-year of treatment the recurrence rate was 14.8%, and during the third 6 months the recurrence rate was 12.2%. CGI in the same subsample of patients in whom HAMD was evaluated (n = 485) compared with those patients who did not drop out during the short-term period up to 44 days and entered long-term treatment (n = 401) showed that the percentage of the ratings "no change/worse" was higher in the sample that also included patients who withdrew from treatment during the short-term period.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

RIMA--a new concept in the treatment of depression with moclobemide.

Moclobemide, a specific reversible inhibitor of monoamine oxidase that shows a preference for the A isoenzyme, has been developed as a new antidepressive agent. Unlike earlier generation monoamine oxidase inhibitors, moclobemide is devoid of any clinically significant tyramine interaction, thus making dietary restrictions during therapy unnecessary. In comparative trials, moclobemide has been found to be superior to placebo and similar to imipramine, clomipramine, and amitriptyline in clinical efficacy. Long-term trials involving moclobemide therapy for up to one year have indicated that antidepressant efficacy can be maintained for this period. Tolerance is good and is significantly better than for tricyclic antidepressants. In addition, unlike the tricyclic antidepressants, overdoses of moclobemide do not appear to be life-threatening.

Benzamides↗
PubMed1992

Interactions of moclobemide with concomitantly administered medication: evidence from pharmacological and clinical studies.

Interactions may occur on pharmacological or pharmacokinetic grounds. Both types of interactions are discussed in relationship with the pharmacological and pharmacokinetic data of moclobemide, a reversible MAO-inhibitor. A variety of interaction studies either designed more specifically as kinetic or as dynamic studies have been performed with moclobemide. The results of these studies are presented. In view of these results as well as in view of data stemming from clinical trials it can be concluded that apart from interactions with cimetidine and pethidine, moclobemide has been shown to be devoid of relevant interactions.

Animals↗
PubMed1992

Long-term treatment with moclobemide. An open-label, non-comparative, multiple-distributed study in patients with a major depressive episode as defined by DSM-III.

Evaluation of 247 patients receiving long-term moclobemide treatment showed that it was effective as an antidepressant, as measured both by decrease in HAMD mean total score and the doctor's evaluation of therapeutic effect. In patients who had been treated for 6 months or less, results were less favourable (ratings of 'very good' or 'good' in 31.5%, compared with 81.3% in patients treated for more than 6 months). This was due to a higher number of drop-outs, as a result of insufficient efficacy in the first 6 months. In those patients who responded favourably, 9.2% relapsed within 6 months of commencing treatment; of the remaining responders, 16% relapsed during months 7-12. In terms of the doctor's evaluation of side-effects, tolerability was 'very good' or 'good' in 88.2%.

Antidepressive Agents↗
PubMed1992

Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine.

In a double-blind, parallel group trial, 78 subjects with social phobia received moclobemide (a new reversible inhibitor of monoamine oxidase A) phenelzine, or placebo. After eight weeks, both active drugs-phenelzine somewhat more than moclobemide--were clinically and statistically significantly more effective than placebo, as assessed by rating scales. There was some further improvement between weeks 8 and 16, particularly in the moclobemide group; at week 16, 82% of the moclobemide and 91% of the phenelzine-treated patients were almost asymptomatic. Moclobemide was, however, much better tolerated than phenelzine. Patients withdrawn from active drugs had relapsed by week 24, providing additional support for the efficacy of the active drugs.

Adult↗
PubMed1992

RIMA: a safe concept in the treatment of depression with moclobemide.

Moclobemide--a new, safer antidepressant drug--is described and clinical studies are reviewed. Moclobemide represents a new class of drug, the so-called RIMA compounds--reversible inhibitors of MAO-A. Unlike classical monoamine oxidase (MAO) inhibitors, moclobemide is devoid of hepatotoxicity and has only a slight potentiating effect on the hypertensive action of tyramine; treatment does not require a tyramine-restricted diet. Studies comparing moclobemide with tricyclic antidepressants (TCAs) indicate that moclobemide is significantly better tolerated than TCAs and slightly less well tolerated than placebo.

Antidepressive Agents, Tricyclic↗