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PubMed1994

Effect of zimeldine and its metabolites on [3H]thymidine incorporation in lymphocyte cultures from psychiatric patients with or without a hypersensitivity reaction during zimeldine therapy.

Lymphocyte transformation test (LTT) was applied to 28 patients who had developed a hypersensitivity syndrome (HSS) during treatment with the antidepressant drug zimeldine. Twenty-seven patients treated with zimeldine without any symptom of an HSS were matched controls. Zimeldine and its metabolites norzimeldine and CPP 200 all induced statistically significant increased [3H]thymidine incorporation in cultured lymphocytes from the HSS patients compared with the controls, norzimeldine being the most potent inducer. The results indicate an immunoreactive process in the development of the HSS induced by zimeldine.

Adult↗

PubMed1983

A double-blind, controlled evaluation of zimeldine, imipramine and placebo in patients with primary affective disorders.

Zimeldine, imipramine and placebo were studied in a randomized, double-blind, parallel group comparison of 119 patients with primary affective disorders. These out-patients were between 18 and 65 years of age and all received placebo single-blind during an initial 3-7-day washout period. During the subsequent 6-week double-blind period, patients were titrated from 50 mg b.d. to 150 mg b.d. with zimeldine, a potent and selective inhibitor of 5-HT reuptake, with imipramine, an inhibitor of noradrenaline and 5-HT reuptake, or with a corresponding number of placebo capsules. The zimeldine treatment group had significantly lower mean HAM-D scale total scores than the placebo and imipramine groups at week 4 and last available assessment. There was a significantly greater proportion of patients showing an improvement of 50% or more in HAM-D score, among the zimeldine group than in the placebo group at week 4, and among the imipramine group at weeks 4, 6 and last available assessment. The Clinical Global Impression (CGI) scales and the 56-item Hopkins Symptom Check-list (HSCL-56) self-rating inventory both showed significantly more improvement in the zimeldine patients than in the placebo or the imipramine patients. Fewer zimeldine patients reported adverse experiences than imipramine patients. Dry mouth was the most frequently reported adverse experience, occurring significantly more often in the imipramine group than the zimeldine or the placebo groups; significantly more zimeldine than placebo patients reported dry mouth. Headache was the only other adverse experience which occurred more often in the zimeldine than in the placebo group. The imipramine group had consistently higher mean pulse rates than the other two groups, and postural hypotension was also more common in the imipramine group.

Adolescent↗

PubMed1990

Effects of zimeldine, a selective 5-HT reuptake inhibitor, combined with ritanserin, a selective 5-HT2 antagonist, on waking and sleep stages in rats.

Sleep and waking in rats were studied 8 h following administration of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (zimeldine), a selective 5-HT2 antagonist (ritanserin) and a combination of ritanserin and zimeldine. Consistent with earlier findings, zimeldine gave a biphasic effect on sleep and waking. Waking was increased the first 3 h, followed by an increase in deep slow wave sleep (SWS-2), maximal in hours 4 and 5. Ritanserin gave an increase in SWS-2 that was spread out over the recording period. Ritanserin + zimeldine also gave a biphasic effect as zimeldine did, and the initial increase in waking and the following increase in SWS-2 tended to be stronger. Thus, ritanserin did not block the initial waking effect seen after zimeldine administration, indicating that this waking effect was not due to 5-HT2 stimulation. The increase in SWS-2 seemed to reflect an addition of the increases following the zimeldine and ritanserin alone conditions. This suggests that the increase in SWS-2 seen after 5-HT reuptake inhibition and 5-HT2 blockade are independent phenomena. Zimeldine alone, ritanserin alone and the combination all gave a clear reduction of rapid eye movement sleep.

Animals↗

PubMed1987

Neonatal desipramine or zimeldine treatment causes long-lasting changes in brain monoaminergic systems and alcohol related behavior in rats.

To study the relationship between neonatal antidepressant administration, active (REM) sleep and adult alcohol-related behavior, rat pups were treated daily with 5 mg/kg desipramine (DMI) or 25 mg/kg zimeldine SC from the 6th to the 19th postnatal days. Movement sensitive mattress ("SCSB") measurements showed that zimeldine treatment suppressed active sleep throughout the whole treatment period, but DMI was more effective during the first 8 days than during the last treatment days. At the age of 70 days, the zimeldine-treated rats expressed a selective increase of some components of activity in the open field test, and the DMI rats had a higher defecation score compared to the controls. Furthermore, the zimeldine-rats responded with a decrease in ambulation in the open field to an alcohol dose which generally stimulates locomotion in rats. At the age of 3 months the DMI and zimeldine rats showed increased voluntary intake of 10% (v/v) alcohol. Measurement of brain monoamines revealed that the neonatal treatment with DMI or zimeldine interfered with the normal development and function of the monoamine neuronal systems: the concentrations of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), and their metabolites were altered in several brain regions. The results thus suggest that neonatal treatment with DMI or zimeldine suppresses active sleep and has an influence on later alcohol-related behavior, possibly due to a long-lasting defect in brain monoaminergic transmission.

Alcohol Drinking↗

PubMed1984

The effect of acute zimeldine and alaproclate administration on the acquisition of two-way active avoidance: comparison with other antidepressant agents, test of selectivity and sub-chronic studies.

The dose-dependent effect of acute zimeldine and alaproclate treatment upon the acquisition of two-way and one-way active avoidance in the rat was studied in a single-session and in a repeated-sessions design. Zimeldine (5-20 mg/kg, IP), but not alaproclate, caused disruptions of two-way avoidance acquisition. Acquisition deficits were also caused by citalopram and fluoxetine but not the other antidepressant drugs tested. Zimeldine, but not alaproclate or desipramine, caused a slight but non-significant impairment of one-way active avoidance; neither zimeldine nor alaproclate produced any effects upon fear conditioning and retention testing. The long-term action of p-chloroamphetamine (2 X 10 mg/kg) antagonised the acute zimeldine effect totally, and chronic treatment with zimeldine (15 days, 1 X 50 mumol/kg) and chlorimipramine (15 days, 2 X 10 mumol/kg) also caused some partial blockade of the two-way avoidance deficit. These data seem to suggest some involvement of serotonin (5-HT) in the observed disruptions of two-way active avoidance caused by acute zimeldine treatment.

Alanine↗

PubMed1989

Popliteal lymph node reactions in mice induced by the drug zimeldine.

The antidepressant drug zimeldine was screened for immune modulating properties using the popliteal lymph node (PLN) assay as a test system in mice. In immunocompetent as well as congenitally athymic nude mice, footpad injection of 1.0 mg zimeldine triggered a bimodal footswelling. A transient oedematous swelling, histologically characterized by mast cell degranulation, was followed by infiltration of polymorphnuclear cells. A dose-dependent PLN enlargement to the agent was observed, which appeared to be more pronounced in immunocompetent mice as compared with athymic nude mice, and in H-2b mice as compared with H-2d mice. After injection of 1.0 mg zimeldine into the footpad of C57BL/10 mice, significant enlargement was already observed by 3 days after injection, was optimal around day 9 and persisted for at least 30 days. Histologically, PLN reactions were characterized by blast transformation of lymphocytes and expansion of paracortical areas prior to germinal center reactions in enlarged follicles. Size of both areas gradually decreased as the medulla filled with plasma cells, 7-30 days after injection. The observed reactions could not be transferred with syngeneic lymph node cells after prior exposition to zimeldine in vivo or in vitro. We conclude that zimeldine induces strong and persistent PLN enlargement, blastogenesis and prominent germinal center reactions. Immunocompetent T-cells are apparently conducive, but not prerequisite to these reactions, which suggests involvement of multiple mechanisms including those mediated by inflammatory reactions in the foot. It is unlikely that the observed enlargement of PLN can be attributed to a direct chemical modification of leukocyte membranes by zimeldine. The protracted nature of the reaction may indicate that zimeldine somehow interferes with inhibitory feedback mechanisms.

Animals↗

PubMed1994

Adverse experiences during treatment with zimeldine on special licence in Sweden.

Adverse experiences during licensed treatment with the antidepressant serotonin (5-HT) reuptake inhibitor zimeldine in Sweden are presented. Data were obtained from a written inquiry of 694 patients and 67 reports to the Medical Products Agency. The spectrum of adverse symptoms was in agreement with those reported in previous studies on zimeldine. The most frequent adverse experiences were headache, nausea, myalgia, signs of liver function disturbance, arthralgia, neurological symptoms, fever and insomnia. No new case of the Guillain-Barré syndrome was found. The estimated frequency of the zimeldine-induced hypersensitivity syndrome (HSS), comprising fever, myalgia and/or arthralgia and signs of liver function disturbance, ranged from 1.4% to 13% in the inquiry and from 0.63% to 3.4% in the report part of the study. Adverse experiences usually had a considerably higher incidence during the first 6 weeks of zimeldine treatment than thereafter. This is in agreement with the clinical experience that most of the adverse reactions occur early during zimeldine treatment. However, a number of adverse experiences did occur with a later onset. This may justify a prolongation of the compulsory 4 weeks' testing of liver function that is required during licensed treatment. There were significantly fewer patients who developed fever among the patients who had experienced previous zimeldine treatment than among those who had not. Otherwise there was no statistically significant difference in frequency of adverse symptoms between these two groups. Consequently zimeldine treatment per se does not seem to predispose to development of an HSS or other types of adverse reactions during subsequent therapy.

Adolescent↗

PubMed1983

Zimeldine in depressive illness--efficacy and safety data.

Two studies of zimeldine in depressive illness are reported, one a double-blind, placebo-controlled trial, the other an open evaluation. In both studies, zimeldine was shown to have antidepressant properties. No simple relationship between plasma zimeldine or norzimeldine and clinical effect was demonstrated in eight patients treated for 6 weeks. Minor changes in electrocardiographic parameters were noted in some zimeldine patients. Side-effects attributable to zimeldine treatment were generally of mild to moderate severity and the drug was well tolerated. During the studies, one patient overdosed on zimeldine (5.2 g) and, although plasma concentrations were excessive, minimum side-effects were recorded. Two cases of suspected adverse drug reactions with zimeldine are described.

Adolescent↗

PubMed1983

A multicentre double-blind comparative trial of zimeldine and imipramine in primary major depressive disorders.

Zimeldine, a new antidepressant with a selective inhibition of 5-HT reuptake, was compared with imipramine in a double-blind comparative study. The trial was conducted on 95 patients with primary major depressive disorder, of endogenous character. During the 4-week study period clinical efficacy was evaluated by using the Hamilton Depression (HAM-D) scale, Beck's Inventory and global ratings. Zimeldine (100 mg b.d.) was shown to have as good an antidepressive effect as imipramine (50 mg t.d.s.) when evaluated on the HAM-D scale. Assessment of the symptom improvement on this rating scale suggested that zimeldine was more effective in improving the patient's insight of the disease. There was no significant difference between zimeldine and imipramine as assessed by a final global improvement rating scale as well as by the patient's own impression. Exploratory data analysis revealed that zimeldine was significantly more effective than imipramine in the following groups; patients over 40 years of age; patients whose initial onset of illness occurred at over 40 years; patients with a history of at least three episodes of depressive illness; patients with mild to moderate depression; and patients who had previously failed to show an appreciable response to other antidepressant treatment. Analysis of global safety ratings revealed that zimeldine is significantly safer than imipramine, with a lower incidence of adverse symptoms involving the autonomic nervous system, especially anticholinergic reactions. No significant difference was observed between the two groups with respect to abnormal laboratory reports. One zimeldine patient developed symptoms suggesting a hypersensitivity reaction (fever, skin eruption and elevation of plasma levels of transaminases), which led to the patient's withdrawal from drug treatment.

Adolescent↗

PubMed1992

The 5-HT1A antagonist (-)-alprenolol fails to modify sleep or zimeldine-induced sleep-waking effects in rats.

Sleep and waking in rats were studied for 8 h following administration of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (zimeldine), a putative 5-HT1A antagonist (L(-)-alprenolol hydrogene tartrate monohydrate [(-)-alprenolol]) and a combination of (-)-alprenolol and zimeldine. Consistent with earlier findings, zimeldine gave a biphasic effect on sleep and waking. Waking was increased during the first 3 h, followed by a small decrease. Deep slow-wave sleep (SWS-2) showed the opposite trend. An initial decrease in SWS-2 was followed by an increase after around 3 h. Rapid eye movement sleep was markedly suppressed and latencies to sleep increased after zimeldine. (-)-Alprenolol had no effects on the different sleep and waking stages or latencies to sleep. The 5-HT1A antagonist also failed to modify the effects of zimeldine administration. The behavioral syndrome induced by a selective 5-HT1A agonist [8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT)] was clearly antagonized by administration of (-)-alprenolol, indicating that (-)-alprenolol was an efficient 5-HT1A blocker. The data indicate that the sleep-waking effects of zimeldine cannot easily be explained by stimulation of 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Effects of zimeldine and its metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis in Lewis rats.

The influence of the selective serotonin (5-HT) reuptake inhibiting antidepressant zimeldine and its metabolite norzimeldine was tested on experimental allergic neuritis (EAN) in Lewis rats, which is an animal model of the Guillain-Barré syndrome (GBS) in man. Zimeldine and norzimeldine both suppressed clinical signs of actively induced EAN when given at a dose of 20 mg/kg/day intraperitoneally via osmotic pumps. The effects of zimeldine, its metabolites norzimeldine and CPP 200 as well as of the antidepressants clomipramine, imipramine and maprotiline on in vitro immune response were tested. Thereby we used an immunospot assay for interferon-gamma (IFN-gamma) produced by lymph node mononuclear cells (MNC), which reflects number of memory T lymphocytes activated by antigen or lectin, in this experiment bovine peripheral nerve myelin (BPM) and phytohemagglutinin (PHA), respectively. In the IFN-gamma secretion assay zimeldine, CPP 200, clomipramine and maprotiline all in a concentration-dependent mode reduced the number of IFN-gamma secreting cells while norzimeldine and imipramine did not affect the IFN-gamma secretion. In assays for proliferation in response to antigen or lectin, the concentration 10(-4) M was judged toxic for all substances tested, and at concentrations below that all but zimeldine showed a dose-dependent slight reduction of MNC proliferation. The action of several drugs on induced T cell secretion of IFN-gamma suggests that the mechanisms for the suppressive effect of zimeldine and norzimeldine on EAN symptoms can be due to an action on myelin T cell autoreactivity. All the monoamine reuptake inhibiting antidepressants tested in this study showed immunomodulatory effects by either a reduction of the number of IFN-gamma-secreting cells or the MNC proliferation. These observations call for further studies of immunological mechanisms in the pathogenesis of mental disorders as well as on the potential role of drugs acting on the monoamine systems in the treatment of recognized autoimmune diseases.

Animals↗

PubMed1984

Zimeldine to geriatric patients in once daily dosage. A pharmacokinetic and clinical study.

The therapeutic efficacy, tolerability and pharmacokinetics of zimeldine in elderly depressed patients were evaluated after administration of different doses of the drug in once daily evening doses. The doses of zimeldine were 100 mg during the first 2 weeks, 150 mg during the next 2 weeks and 200 mg during the last 2 weeks. Nine of the 11 patients (mean age 78 years) included in the study completed the 6-week treatment period, and all nine improved according to the Hamilton depression rating scale. The drug was well tolerated and the side effects were few and mild. No influence of clinical importance was noted in haematology, liver and kidney functions, EEG, blood pressure or pulse rate. Steady-state plasma concentrations of zimeldine, and its active metabolite norzimeldine, were achieved in most cases after 1 week of treatment in each dose regimen. The plasma concentrations increased linearly with the increase in dose. The maximal interindividual variations in plasma concentrations were 8-fold for zimeldine and 3-fold for norzimeldine . The plasma levels of both zimeldine and norzimeldine were higher in the elderly than reported earlier in younger patients. The ratio of norzimeldine/zimeldine concentrations was reduced in the elderly, indicating a reduction of the metabolic capacity. The results suggest that zimeldine can be administered in a once daily dosage regimen to elderly patients, but they should be given a lower dose than younger patients.

Aged↗

PubMed1985

Alaproclate a novel antidepressant? A biochemical and clinical comparison with zimeldine.

Clinical and biochemical effects of two selective 5-HT uptake inhibitors, zimeldine and alaproclate, were studied in 24 hospitalized patients with endogenous depression. According to a randomized parallel group design 14 patients were treated with zimeldine and 10 with alaproclate. The dosage of both zimeldine and alaproclate was 200 mg daily. For the evaluation of the clinical effect, Montgomery & Asberg Depression Rating Scale (MADRS) was used. Seven of 14 patients treated with zimeldine and seven of 10 treated with alaproclate improved. 5-HT uptake inhibition in patients' platelets and concentration of amine metabolites (5-HIAA, HVA, HMPG) in CSF were studied before and during treatment. After 3 weeks of treatment with zimeldine 5-HIAA and HMPG in CSF decreased significantly while HVA in CSF increased significantly. Zimeldine produced a significant 5-HT uptake inhibition in platelets. During treatment with alaproclate no significant change in amine metabolites concentration in CSF was found and there were no mean changes on 5-HT uptake inhibition in platelets.

Adult↗

PubMed1986

Pharmacokinetics of zimeldine in male alcoholics.

The pharmacokinetics of zimeldine, a 5-HT reuptake blocker with antidepressive effects, was studied after a single oral dose and after multiple oral administration in 19 alcoholic males, 10 with and 9 without chronic liver damage. The average plasma concentration of zimeldine as assessed by the AUC values (area under the plasma concentration-time curve) was significantly higher in the chronically liver damaged patients than in the patients without chronic liver damage. The plasma half-life of zimeldine was also significantly longer in the chronically liver damaged patients. There were no differences in the obtained pharmacokinetic parameters between the patients having nonchronic liver damage and healthy control subjects. The pharmacokinetics of the active metabolite norzimeldine (resulting from N-demethylation of zimeldine) showed no differences between the two groups of alcoholics and the healthy controls. The IgA values were significantly correlated to both the AUC and plasma half-life of zimeldine. No other correlation between clinical chemistry parameters and pharmacokinetic parameters of zimeldine and norzimeldine were found.

Adult↗

PubMed1985

Evaluation of zimeldine in Alzheimer's disease. Cognitive and biochemical measures.

Neuropsychological and neurochemical effects of zimeldine, a relatively specific serotonin reuptake blocker, were examined in four patients with clinically diagnosed Alzheimer's disease, in a double-blind, placebo-controlled, crossover study. Individualized doses of zimeldine were administered to achieve target plasma zimeldine concentrations of approximately 50 (low) to 100 (high) ng/mL. Overall, there was no significant effect of zimeldine on memory or reaction time measures as compared with placebo. The drug significantly reduced (by up to 38%) 5-hydroxyindoleacetic acid concentrations in the cereobrospinal fluid and almost abolished (90% reduction) platelet serotonin uptake. Cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol, a major metabolite of norepinephrine, and homovanillic acid, the major metabolite of dopamine, were not altered. Our findings indicate that alterations in central and peripheral serotoninergic function by a serotonin reuptake blocker (zimeldine) are unaccompanied by measurable changes in memory and/or reaction time in patients presumed to have Alzheimer's disease.

Aged↗

PubMed1984

Effects of zimeldine, mianserin and amitriptyline on psychomotor skills and their interaction with ethanol a placebo controlled cross-over study.

13 healthy volunteers participated in a double-blind, four-period, cross-over study. In each period, the trial drugs (placebo, zimeldine, amitriptyline and mianserin) were given in fixed dosages for 8 days; amitriptyline 10-50 mg twice daily, mianserin 10-30 mg twice daily and zimeldine 200 mg once daily. Ethanol 1 g/kg bodyweight was drunk 2 hours after drug intake on Days 1 and 8 of each period, the latter being separated by a 2 week wash-out period. Ratings of subjective feelings and side effects, and performance tests were done on Days 1 and 8 of each period before, 1.5, 3 and 4.5 h after drug intake, i.e. 2 of the tests were performed under the influence of ethanol. Mianserin decreased critical flicker frequency, slowed reactions under discriminative stimulation and tended to cause nystagmus, but only on Day 1 (after the first 10 mg dose). Amitriptyline impaired coordination on Days 1 (after the initial 10 mg dose) and 8, and lowered the flicker threshold on Day 8 at "steady state" (after the 50 mg morning dose). Both these antidepressants were felt to be sedative, especially in the initial phase of the treatment, and they interacted additively with ethanol. No impairment of psychomotor skills was associated with zimeldine, only a subjective sedative effect of the 200 mg dose was seen on Day 1. Zimeldine did not enhance the effects of ethanol; it even showed some antagonism of ethanol-induced body sway in the standing steadiness test. In contrast to amitriptyline and mianserin, zimeldine was regarded as not harming psychomotor skills, and as not having any observable interaction with ethanol.

Adult↗

PubMed1987

Similar effect on REM sleep but differential effect on slow wave sleep of the two 5-HT uptake inhibitors zimeldine and alaproclate in cats and rats.

Sleep and waking in cats and rats were studied 6-10 hours following acute administration of zimeldine, alaproclate or saline. The effects on slow wave sleep of the two compounds markedly differed in the cats. Following zimeldine, sleep with a high amount of synchronized slow waves (SWS-2) was increased, and total sleep was unchanged. Following alaproclate, SWS-2 did not increase, and total sleep was reduced. In the rats, zimeldine increased SWS-2 during the first 4 hours after administration, while there was no change in SWS following alaproclate. Both zimeldine and alaproclate increased REM latency and reduced REM sleep in both species with somewhat more pronounced effects in cats than in rats. The results on SWS-2 following zimeldine are consistent with earlier results following serotonin depletion in both species. The differential effects on SWS-2 are discussed in terms of regional differences in uptake inhibition and other differences between the two uptake inhibitors. The results on REM sleep confirm earlier results involving serotonin uptake inhibitors and serotonin precursor loading and indicate that increased synaptic serotonin concentrations suppress REM sleep.

Alanine↗

PubMed1995

Lesion of descending 5-HT pathways increases zimeldine-induced waking in rats.

Sleep, waking, and EEG power spectra were investigated in rats with spinal 5,6-dihydroxytryptamine (5,6-DHT) lesions, following 20 mg/kg zimeldine or vehicle IP injections. 5,6-DHT selectively lesioned the descending serotonergic pathways. Lesion alone did not change sleep and waking stages compared to baseline, except for a reduction in REM sleep. Consistent with earlier findings, zimeldine in nonlesioned rats increased waking the first 2 h of recording. Zimeldine treatment in lesioned rats gave a significant additional 50% increase in waking the first 2 h and a corresponding decrease in total slow wave sleep, suggesting a potentiation of these effects. Zimeldine gave no significant changes in waking EEG power spectral density. Lesion gave a tendency to reduction between 4.0 and 15.5 Hz compared with baseline, and between 10.0 and 16.5 compared to the independent control group. In both comparisons, the combined treatment strengthened this effect, again suggesting a potentiating effect of lesion. In sleep, zimeldine reduced power over the whole spectrum (0.5-20.0 Hz), less in the lower frequencies than in the higher frequencies.

Afferent Pathways↗