[The Ethics Committee meeting in Belgium May 7, 2004, on human experimentation]. / Les comités d'éthique face a la loi belge du 7 mai 2004 sur l'expérimentation humaine.

The European directive 2001/20/EC concerning the performance or clinical trials has been transposed in the Belgian law of May 7, 2004, entitled "Loi relative aux expérimentations sur la personne humaine" (Moniteur belge, May 18, 2004)". The range of the law is larger than those of the directive. Several new elements must be underlined: 1. Any experimentation on a human being may only begin if the promoter received a positive advice from an ethical committee according to the provision of the law. 2. For multicentric assays, a single opinion, identical for all the participating centres must be obtained. This implies a close dialogue between the ethical committees. A central committee is proposed by the industrial promoter. Each clinical trial of a drug must have a unique identification number obtained at the European agency for the evaluation of medicinal products (EMEA). 3. Taking into account the fear of the pharmaceutical industry that some clinical studies could be "delocalized", the authorities accepted to reduce to twenty- eight days (instead of 60) the delay granted to the ethical committee in order to produce their single opinion. 4. The law of May 7, 2004, clearly defines the dispositions related to the protection of the participants. Particular dispositions are foreseen for the protection of minors, incapable adults and patients in emergency. 5. The promoter endorses, even without fault, the responsibility of the damage caused to the participant or his descendants. An insurance covering this risk must be contracted.

A new approach to the qualitative evaluation of functional disability in dementia.

BACKGROUND: Dementia patients suffer from the progressive deterioration of cognitive and functional abilities. Instrumental disabilities usually appear in the earlier stages of the disease while basic disabilities appear in the more advanced stages. In order to differentiate between mild, moderate and severe patients both instrumental and basic functional disabilities should be taken into account simultaneously. OBJECTIVES: The objective of this study was to find a new method for classifying dementia patients based on their disabilities by using a basic and an instrumental Activities of Daily Living (ADL) scale. METHODS: Functional disability was assessed in a Belgian cohort of dementia patients using the Katz and Lawton Instrumental Activities of Daily Living (IADL) scales. A k-means derived clustering method allocated patients to disability clusters according to their Katz and Lawton scores. In order to validate the classification, we compared socio-demographic, clinical and costs parameters between the groups. RESULTS: The clustering method allocated patients between three clusters: dependent, non-dependent with instrumental functional disability (ND-IFD) and non-dependent. Dependence, as defined by these clusters, significantly correlates with age, residential setting, MMSE, patient's quality of life and costs. CONCLUSION: This new classification of patients suffering from dementia will provide better understanding of functional disabilities and will complement the evaluation of disease severity based on cognitive function.

[The measurement of sense of competence in caregivers of patients with dementia]. / La mesure du sentiment de compétence chez les aidants de patients déments.

BACKGROUND: In the context of a cohort study on the socio-economic consequences of dementia in Belgium, we evaluated the validity, reliability and feasibility of the French version of the Dutch Sense of Competence questionnaire (SCQ), and of its short version (the SSCQ), in caregivers of demented patients The questionnaire was based on Zarit's burden interview and on a theoretical family-crisis model. METHODS: Construct validity was evaluated by factor analysis and by comparison of the results with those of the original SCQ study. Reliability was evaluated by Cronbach's alpha and by item-total correlations. Feasibility was assessed by a standardized index of missing values. RESULTS: The three domains found in the original SCQ were identified by factor analysis: consequences of involvement in care for the personal life of the caregiver, satisfaction with one's own performance as a caregiver and satisfaction with the elderly person as a recipient of care. The mean scores were similar to those in the original study, except for the consequences for personal life. Cronbach's alpha for both the SCQ and the SSCQ exceeded the 0.70 criterion. Two of the 27 items did not meet the item-total correlation criterion; the SSCQ items all met the criterion. The standardised index of missing values was deemed acceptable. CONCLUSIONS: The French versions of the SCQ and the SSCQ are valid and reliable. Like the Dutch version, the French version of the SCQ can be a useful outcome measure for the evaluation of intervention studies and the SSCQ is suitable for the daily practice.

Cognitive impairment, dementia and quality of life in patients and caregivers.

OBJECTIVE: To study the impact of cognitive impairment and severity of dementia on the quality of life (QoL) of patients and their caregivers. DESIGN: Descriptive cross-sectional study within the NAtional Dementia Economic Study. SETTING: 231 general practices and 15 specialist clinics in Belgium. SUBJECTS: 605 patients aged > or = 65 years: 106 referent subjects without cognitive impairment (R), 113 subjects with cognitive impairment and no dementia (CIND), 386 subjects with mild (83), mild/moderate (108), moderate (62) or severe (133) dementia (D1 to D4). OUTCOME MEASURES: QoL of patients: COOP/WONCA charts, Katz's Activities of Daily Living (ADL) scale, Lawton's Instrumental Activities of Daily Living (IADL) scale. QoL of caregivers: COOP/WONCA charts, SF-36 questionnaire, short-form Beck Depression Inventory, Sense of Competence questionnaire (SCQ). MAIN RESULTS: QoL of patients: For R, CIND and D1 to D4 patients, dependence for ADL reached 5%, 6%, 16%, 20%, 48% and 79%, respectively, and mean IADL scores were 5.6, 5.0, 3.4, 2.0, 0.6 and 0.1, respectively. QoL of caregivers: The main impact of caregiving was on mental health, with SF-36 MCS scores of 51.3, 47.7 and 45.4 for R, CIND and all D patients and respectively 32.6%, 31.3% and 42.5% depression prevalence. Sense of competence decreased with severity of patient's cognitive impairment. Caregivers of CIND patients always rated intermediate between R and D1 patients. Caregivers of D3 patients were the most affected ones. CONCLUSION: The data suggest that improving the cognitive status of patients and providing assistance to caregivers would be complementary ways of action to support caregiving of patients living at home.

The economic impact of dementia in Belgium: results of the National Dementia Economic Study (NADES).

OBJECTIVES: To estimate costs associated with dementia and its severity and to identify main cost determinants. DESIGN: One-year prospective cohort study. SETTING: 231 general practitioners (GPs) and 15 specialist clinics throughout Belgium. SUBJECTS: 605 patients aged > or = 65 years (219 referent patients, 218 demented patients at home and 168 demented patients in institution). OUTCOME MEASURES: Medical costs (visits to GPs/specialists, physiotherapy, hospitalisation, nursing, incontinence, medication) and non-medical costs (special equipment, services, professional help and caregiving). RESULTS: Total monthly costs amounted to 368.50 Euro dollar for referent patients, 445.56 Euro dollar for demented patients at home and 2301.7 Euro dollar for demented patients in institutions. Highest costs were measured in patients with severe dementia (556.88 Euro dollar at home, 2465.28 Euro dollar in institutions). In demented patients at home, 60% of costs were accounted for by the health system, with hospitalisation and medication being the main cost components (36% and 20%). In demented patients in institution, 46% of the costs were accounted for by the health system, with residential costs and nursing being the main cost components (42% and 32%). In multivariate covariance analysis, the main determinants of costs for demented patients at home were physical dependence and co-morbidity (neoplasm, cardiovascular disease). The adjusted difference between demented and referent patients was 25 Euro dollar per month. CONCLUSIONS: A large fraction of the costs observed in dementia is explained by the association of dementia with physical dependence, co-morbidity and need for caregiving. From an economic point of view, the results support the caring for patients at home.

Effect of intermittent and continuous exposure to electromagnetic fields on cultured hippocampal cells.

This study was designed to assess the effect of 50 Hz electromagnetic fields (EMFs) on hippocampal cell cultures in the presence or absence of either sodium nitroprusside (SNP, a NO donor) or Fe2+ induced oxidative stress. One week old cultured rat hippocampal cells were exposed to either intermittent EMFs (IEMFs, 50 Hz, 0-5 mT, 1 min ON/OFF cycles, repeated 10 times every 2 h, 6 times/day during 48 h) or continuous EMFs (CEMFs, 50 Hz, 0-5 mT for 48 h). In a second set of experiments, the effect on such EMFs applied in combination with oxidative stress induced by 0.5 microM Fe2+ or SNP was estimated. At the end of both sets of experiments, cell mortality was assessed by lactate dehydrogenase measurements (LDH). Neither type of exposure to EMFs was observed to modify the basal rate of cell mortality. The exposure to CEMFs in presence of either NO or Fe2+ did not induce any significant increase in cell death. However, when cells were exposed to EMFs in the presence of NO, we observed a significant increase in cell death of 11 and 23% (P<0.001) at 2.5 and 5 mT, respectively. This effect had some specificity because IEMFs did not modify the effect of Fe2+ on cell mortality. Although the effects of IEMFs reported in this study were only observed at very high intensities, our model may prove valuable in trying to identify one cellular target of EMFs.

Evidence for a modulatory role of Ih on the firing of a subgroup of midbrain dopamine neurons.

A previous investigation has suggested that the hyperpolarization-activated cation current Ih does not contribute to the spontaneous firing of midbrain dopaminergic neurons. This conclusion was reached using Cs(-1). We have re-examined this question with extracellular recordings in slices using the more specific blocker ZD7288. In two-thirds of the cells, low concentrations of ZD7288 induced a decrease of the spontaneous firing. The maximal inhibition was about 40% and the mean IC50 was 1.6 microM. This effect was probably direct because it persisted in the presence of antagonists of various receptors. These concentrations of ZD7288 had no effect in the remaining one third of the examined cells. However, the highest concentration of ZD7288 (300 microM) abolished the firing of all dopaminergic neurons, probably by a mechanism unrelated to the blockade of Ih. We conclude that Ih controls to a certain extent the firing of a majority of midbrain dopaminergic neurons.

[Dementia in Belgium: prevalence in aged patients consulting in general practice]. / La démence en Belgique: taux de prévalence chez les sujets âgés consultant en médecine générale.

Early detection of dementia is an important element for the efficacy of therapies currently proposed to slow down disease progression. This detection mainly relies on general practitioners. In order to estimate the impact of dementia on health services, we have estimated from the data of the NAtional Dementia Economic Study (NADES) the prevalence rate of dementia in patients aged > or = 65 years living at home and consulting in general practice. The study population was based on the sampling of consecutive patients consulting a general practitioner, irrespective of the reason and location of the consultation. The diagnosis of dementia was based on the CAMDEX performed at home in patients presenting > or = 3 warning signs of dementia. The prevalence rate of dementia among 2.234 registered patients living at home was 14.3% (CI95: 12.6-16.0). In age groups 65-74, 75-84 and > or = 85 years, it was 7.0%, 17.5% and 18.5%, respectively, in men, and 6.1%, 15.8% and 25.2%, respectively, in women. The percentage of demented with mild, mild to moderate, moderate and severe dementia was 35.0%, 38.8%, 13.1% and 13.1%, respectively. After adjusting for the age and sex distribution of the Belgian population, the prevalence rate in patients aged > or = 65 years was estimated at 11.3%. A diagnosis of dementia had already been made by a specialist in 41.5% of patients with dementia, with figures of 19.3%, 34.3%, 41.9% and 60.9% according to the severity of disease (mild, mild to moderate, moderate, severe). The onset of first symptoms had preceded the diagnosis by an average of 1 year. Our results show a high prevalence rate of dementia in the elderly living at home consulting in general practice, and less than half of the patients had previously been diagnosed. It is possible that a systematic detection will not be performed as long as specific treatments are not made widely available.

The inclusion of fluoxetine into gamma-cyclodextrin increases its bioavailability: behavioral, electrophysiological and pharmacokinetic studies.

The inclusion of a drug into cyclodextrin generally results in the modification of its physical and chemical properties and sometimes can increase its oral bioavailability. The aim of this study was to compare the effects of the fluoxetine HCl/gamma-cyclodextrin complex to that of traditional fluoxetine HCl. In the forced swimming test in mice, fluoxetine HCl/gamma-cyclodextrin was more effective than fluoxetine HCl, the ED30s being, respectively, 9.5 and 16.9 mg/kg PO. Both compounds (10 mg/kg PO) were able to reduce the firing rate of dorsal raphe neurons in the rat. However, between-groups comparisons showed no significant differences between fluoxetine HCl treated animals and the vehicle group, while fluoxetine HCl/gamma-cyclodextrin appeared significantly more effective than vehicle from minute 25 of the measurement period. In healthy volunteers, the relative oral bioavailability, calculated as the ratio AUC 0-infinity fluoxetine HCl/gamma-cyclodextrin on AUC 0-infinity fluoxetine HCl (20 mg PO), was equal to 249.9%. The three experiments taken together suggest that the complexation of fluoxetine HCl into gamma-cyclodextrin increases its pharmacological efficacy in animals, this effect being related to an enhancement of its oral bioavailability as demonstrated in human healthy subjects.

Propofol protects cultured brain cells from iron ion-induced death: comparison with trolox.

The anesthetic propofol (PPF) has been shown to be an antioxidant in acellular experiments. This study was designed to assess the ability of PPF to protect primary-cultured brain cells against iron-mediated toxicity. A comparison with trolox (TX), a hydrosoluble vitamin E analogue, was performed. Rat cortical cells were exposed to 10 microM FeSO(4), PPF and/or TX. After a 4-h incubation, PPF and TX improved cell survival (lactate dehydrogenase measurements) in a concentration-dependent manner. The respective EC(50s) of each substance were 4 and 4.6 microM. The maximal effect was obtained at a 25-microM concentration which is similar to concentrations of PPF used clinically. The combination of both drugs at certain concentrations showed a complete protection of the cells, a significant decrease in intracellular peroxide production (dichloro-fluorescein diacetate (DCF-DA) fluorescence, 4-h incubation), in lipoperoxidation (thiobarbituric acid reactive substances fluorescence, PPF 6.25 microM+TX 12.5 microM) and an additive protective effect. This was true after 4- and 16-h incubation. These data suggest that PPF is neuroprotective. Moreover, the combination with a vitamin E analogue confers long duration protection against oxidative stress.

Calcium release from internal stores is required for the generation of spontaneous hyperpolarizations in dopaminergic neurons of neonatal rats.

We recently have demonstrated the existence of spontaneous hyperpolarizations in midbrain dopaminergic neurons of neonatal but not adult rats. These events are mediated by the opening of apamin-sensitive K(+) channels after a rise in the intracellular concentration of Ca(2+). They are resistant to tetrodotoxin in most cases and are probably endogenous (i.e., not synaptically activated). Here their mechanism was investigated. Cyclopiazonic acid (10 microM), a specific inhibitor of endoplasmic reticulum Ca(2+) ATPases, reversibly abolished the events. Caffeine, which promotes Ca(2+) release from intracellular stores, had concentration-dependent effects. At 1 mM, it markedly and steadily increased the frequency and the amplitude of the hyperpolarizations. At 10 mM, it induced a transient increase in their frequency followed by their cessation. All these effects were quickly reversible. Ryanodine (10 microM), which decreases the conductance of Ca(2+) release channels, irreversibly blocked the spontaneous hyperpolarizations. Dantrolene (100 microM), a blocker of Ca(2+) release from sarcoplasmic reticulum of striated muscle, did not affect the events. On the other hand, Cd(2+) (100-300 microM), a broad antagonist of membrane voltage-gated Ca(2+) channels, significantly reduced the amplitude and the frequency of the hyperpolarizations. However, when the frequency of the events was increased by 1 mM caffeine, Cd(2+) affected them to a smaller extent, whereas cyclopiazonic acid still abolished them. We conclude that internal stores are the major source of Ca(2+) ions that induce the K(+) channel openings underlying the spontaneous hyperpolarizations of these neurons.

Activity-dependent neurotrophic factor peptide (ADNF9) protects neurons against oxidative stress-induced death.

Activity-dependent neurotrophic factor (ADNF) and a 14-amino acid fragment of this peptide (sequence VLGGGSALLRSIPA) protect neurons from death associated with an array of toxic conditions, including amyloid beta-peptide, N-methyl-D-aspartate, tetrodotoxin, and the neurotoxic HIV envelope coat protein gp120. We report that an even smaller, nine-amino acid fragment (ADNF9) with the sequence SALLRSIPA potently protects cultured embryonic day 18 rat hippocampal neurons from oxidative injury and neuronal apoptosis induced by FeSO4 and trophic factor withdrawal. Among the characteristics of this protection are maintenance of mitochondrial function and a reduction in accumulation of intracellular reactive oxygen species.

Methodological issues in a cost-of-dementia study in Belgium: the NAtional Dementia Economic Study (NADES).

The NAtional Dementia Economic Study (NADES) is an on-going prospective, one-year cohort study developed in Belgium to assess the socio-economic consequences of dementia in a group of patients and their caregivers (n = 400). Comparison is made with a group of subjects with cognitive impairment and no dementia (n = 100) and a group of subjects without any cognitive impairment (n = 100). Recruitment of subjects is based on screening of warning signs of dementia by general practitioners, followed by a Cambridge Mental Disorders of the Elderly Examination (CAMDEX) performed at home. This paper presents an overview of the study protocol and the rationale for basic design options, such as the choice of study population, screening strategy, and methods used for the case validation. It also presents preliminary results on the prevalence of dementia in general practice, the sensitivity and specificity of the warning signs as a screening test of dementia, and the validity of a computerised case ascertainment algorithm based on DSM-III-R criteria.

Effects of JL 3, a putative antidepressant, on rat noradrenergic and serotonergic systems.

Using in vitro electrophysiological procedures, we confirm the inhibitory effect of 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1, 4]benzothiazepine (JL 3), on dorsal raphe serotonergic (IC(50)=14 microM) and noradrenergic neurons (IC(50)=4.5 microM). The effect on dorsal raphe neurons was reduced by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- cyclohexanecarboxamide (WAY-100635), suggesting the importance of 5-HT(1A) receptor stimulation. Yohimbine, and ritanserin, to a lesser extent, blocked the inhibitory effect of JL 3 on locus coeruleus neurons indicating that alpha(2)-adrenoceptors and 5-HT(2A) receptors may be implicated in the effects. Because of its negligible alpha(2)-adrenoceptor affinity, the effect of JL 3 on locus coeruleus neurons, would have to be indirect. JL 3 may interfere with the norepinephrine transporter site (IC(50)=0.34 microM). JL 3 tended to reinforce the hypertensive effect of norepinephrine, while it strongly inhibited the hypertensive effect of tyramine, further indicating an interaction at the norepinephrine transporter site level.

Spontaneous apamin-sensitive hyperpolarizations in dopaminergic neurons of neonatal rats.

Spontaneous apamin-sensitive hyperpolarizations in dopaminergic neurons of neonatal rats. J. Neurophysiol. 80: 3361-3364, 1998. Intracellular recordings from substantia nigra slices revealed the existence of spontaneous hyperpolarizations (amplitude 2-8 mV, duration 100-400 ms) at -60 mV in most dopaminergic neurons of neonatal (9-15 days) but not adult rats. These events were blocked by apamin (300 nM) and bicuculline methochloride (100-300 microM), which blocks apamin-sensitive currents. They were unaffected by the selective gamma-aminobutyric acid-A (GABAA) antagonists SR95531 (100 microM) and picrotoxin (30-50 microM), the GABAB antagonist CGP35348 (300 microM), the D2 antagonist haloperidol (1 microM), and the metabotropic antagonist MCPG (1 mM). The hyperpolarizations were strongly attenuated or abolished when recording electrodes contained 200 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. They were resistant to tetrodotoxin in the majority of the cells. They had some voltage dependency and were in some cases transiently potentiated when cells were briefly depolarized by current injection. We conclude that dopaminergic neurons have developmentally regulated physiological properties. These spontaneous hyperpolarizations might affect the firing rate of these cells, which was found to be lower in neonates than in adults.

Regional action of brofaromine on rat brain MAO-A and MAO-B.

1. Brofaromine (CGP 11,305 A) belongs to a new generation of monoamine oxidase (MAO) inhibitors. These compounds induce short, reversible and selective inhibition of brain MAO of type A. 2. The aim of this work is to study monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) activities of several rat brain regions after increasing doses of brofaromine. 3. Brofaromine inhibits MAO-A activities in a dose dependent manner in all brain regions examined. 4. The largest reduction was found in hippocampal formation, striatum and prefrontal cortex respectively. ID50 is 2 times lower in hippocampus than in remaining brain. 5. Brofaromine does not inhibit MAO-B activities in the different regions examined. 6. Brofaromine is a very selective inhibitor of rat brain MAO-A with a preferential action on telencephalic monoaminergic nerve terminals.

[Introduction to the theory of pharmaco-economics]. / Introduction théorique à la pharmaco-économie.

This article presents an overview of the principles of pharmaco-economic evaluation. A pharmaco-economic evaluation is a comparison of the costs and effects of at least two therapeutic strategies, including at least one drug. It is mostly useful if a new treatment is more effective and more costly than a reference one. The way the effects of treatments are expressed defines several types of analyses: cost minimisation, cost-effectiveness, cost-utility and cost-benefit. The costs measured can be direct (medical and non-medical) and indirect (tangible and intangible). The principle of decision analysis is illustrated.

[An acetylsalicylic acid-dypiridamole combination (Asasantine) in the prevention of the recurrence of cerebrovascular accidents (a cost-effectiveness analysis)]. / Association AAS-dypiridamole (Asasantine) dans la prévention des récidives d'AVC (analyse coût-efficacité).

On the basis of the results of the European stroke Prevention Study (ESPS 2) obtained on 6,602 patients, we used a Markov model to perform a cost-effectiveness analysis of a combination of a low-dose of acetylsalicylic acid (ASA) (25 mg b.i.d.) and sustained-release dipyridamole (DP) (200 mg b.i.d.) versus a low-dose of acetylsalicylic acid alone in the prevention of recurrent stroke in Belgium. The perspective was that of the Social Security. Total costs per patient over 5 years amounted to 1,317,718 FB for placebo, 1,312,015 FB for ASA and 1,326,526 FB for ASA-DP, with respectively 3.16, 3.25 and 3.33 stroke-free life years (SFLY). For 1,000 patients followed over 5 years, the number of SFLYs gained by ASA-DP is 170 when compared to placebo and 100 when compared to ASA. As compared to placebo, ASA is a dominant strategy and the combination AAS-DP has a cost-effectiveness ratio of 50,569 FB per SFLY gained. The cost-effectiveness ratio of ASA-DP vs. ASA was 176,963 FB per SFLY gained and was not substantially modified in sensitivity analyses. The favourable cost-effectiveness ratio for ASA-DP is mainly explained by the reduction of costs associated with the acute treatment of stroke.

A quantitative pharmacological study of the cholinergic depolarization of hippocampal pyramidal cells in rat brain slices.

Intracellular recordings were performed in rat brain slices and the pharmacology of the depolarizing effect of cholinomimetic drugs on hippocampus CA1 pyramidal cells was quantitatively investigated. Acetylcholine (ACh) and muscarine induced a concentration-dependent depolarization of these cells. The EC50 values were respectively 159 +/- 54 microM and 0.7 +/- 0.15 microM. Physostigmine (1 microM) or tacrine (1 microM) induced a marked shift in the concentration-response curve for ACh. Both drugs were equipotent in this respect. The EC50 values for ACh became, respectively, 2.4 +/- 1.5 microM and 3 +/- 0.9 microM. The depolarizing effect of ACh was completely blocked by atropine, confirming the involvement of a receptor of the muscarinic type. In order to determine the subtype of muscarinic receptor involved, the EC50 values of muscarine were determined in the presence of atropine (100 nM), pirenzepine (1 microM) or AFDX116 (10 microM). The deduced pKB for the antagonists were, respectively, 8.9, 7.4 and 6.5. Comparison with binding data suggests that M1 receptors play a prominent role in the depolarizing effect of cholinomimetic drugs on CA1 pyramidal cells.

Comparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data.