Biomedical subjects
Publications and source records attributed to Y D Lapierre.
A case of altered kinetics of amitriptyline in a patient with porto-caval anastomosis and liver cirrhosis who showed an unusually strong sedative response to the drug, is presented. Therapy with tricyclic antidepressants should be initiated with lower doses and adjusted by plasma level monitoring in patients with liver by-pass.
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A single injection of diazepam (10 mg/kg, s.c.), haloperidol (2 mg/kg, i.p.) or chlorpromazine (10 mg/kg, i.p.) decreased the ambulatory as well as sniffing behaviour of rats. These behavioural responses were further decreased when diazepam was administered concurrently with the neuroleptic. Acute haloperidol or chlorpromazine treatment increased striatal dopamine as well as cerebro-cortical norepinephrine turnover. In contrast, diazepam diminished the release of both of these catecholamines. When diazepam was administered together with haloperidol or chlorpromazine, a further decrease particularly in dopamine release was seen in striatum. This effect of diazepam on norepinephrine and dopamine turnover persisted even after 21 days of daily treatment, Similarly, the sedative effect of diazepam elicited in the form of depressed locomotor activity was also apparent after long-term administration of this benzodiazepine. However, chronic administration of neuroleptics enhanced the spontaneous locomotor activity and sniffing behaviour by about 25%. Furthermore, repeated neuroleptic treatment decreased the synthesis and turnover of dopamine and norepinephrine. This was reflected in decreased tyrosine hydroxylase and homovanillic acid level in striatum as well as by low concentration of 3-methoxy-4-hydroxyphenylethylene glycol in the cerebral cortex. When diazepam was administered together with haloperidol or chlorpromazine for 21 days, behavioural activity remained elevated and was comparable to groups of rats receiving neuroleptics alone. The cocomitant injection of diazepam and neuroleptics for 21 days elicited a synergistic effect on decreased synthesis and release of dopamine as well as norepinephrine. These data provide neurochemical evidence for potentiation of the neuroleptic effects by a benzodiazepine.
Clinical observations are not always consistent with laboratory findings where half-life or pharmacokinetics do not always correlate with pharmacodynamics, ie. clinically effective duration of action. The parent compound, chlordiazepoxide, was observed to have anticonvulsant, anxiolytic, muscle relaxant properties to varying degrees. Subsequently, diazepam seemed to exert a greater potency in these three areas. The final metabolite, oxazepam, has been observed to have a different therapeutic profile. The advent of the triazolo compounds brought a new dimension to benzodiazepine treatment both in primary and side effects. The relationship between blood levels and clinical efficacy is considered in the light of clinical observations as well as in the perspective of clinical management. Problems of tolerance and escalation of dosage must be addressed in the administration of these drugs where the confluence of pharmacokinetic and pharmacodynamic findings may serve as a guide in the management of anxious patients.
Two hundred and thirty eight patients (144 males, 94 females) on long-acting neuroleptics; mainly fluphenazine decanoate, were surveyed and evaluated for abnormal involuntary movements and associated risk factors. A highly significant correlation was found between the three scales used in the evaluation. The prevalence rate for the transient, acute extrapyramidal syndrome was 37.38%, while that of tardive dyskinesia was 57%. Half of the tardive dyskinesia cases were of minimal severity. Most of these were located in orofacial region. Tardive dyskinesia was more frequent in younger patients but more severe in older age groups. Other associated risk factors were tremors and rigidity, and use of antiparkinsonien drugs. Tardive dyskinesia is a common abnormal involuntary movement in patients on long-acting neuroleptic. Early recognition of TD in this population could help in planning for its prevention by the use of minimum effective dose of medication.
This was a single-blind, open study undertaken to assess the antidepressant efficacy of mianserin, a new tetracyclic antidepressant in in-patients with major depression (DSM III). The relationship between steady state plasma levels and clinical response, and the predictability of steady-state mianserin plasma levels from a single point determination after an initial dose of the drug were also studied. There was remarkable clinical improvement as measured by the significant (P 0.001) reduction in mean HDRS scores after first week of active treatment which continued till day 28 when mean HDRS scores were reduced to about 50% of initial mean scores. There was a modest correlation (r = 0.623, n.s.) between the steady state levels of mianserin and the plasma concentration 12 hours after initial dose. No significant cardiovascular effect was noted throughout the course of treatment. Mianserin is a safe, efficacious antidepressant with minimal cardiovascular effects. Further clinical investigations of this new useful drug are recommended.
Suriclone, a new psychotherapeutic agent chemically unrelated to benzodiazepines or phenothiazines was assessed in a single-blind dose-ranging study to determine its efficacy and safety in out-patients with generalized anxiety disorder. Suriclone was an effective anxiolytic drug at a dose range between 1.2 mg. and 3.6 mg. per day. The drug, when effective, has a duration of action between 6 and 8 hours. There was no evidence of a rebound phenomenon. There was, however, a rapid return to pre-treatment level of anxiety. Side effects were few, mild and transient. This new molecule may herald an advance in the treatment of these disorders and should be investigated more fully.
Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.
We studied mianserin kinetics after a single (60 mg) dose in eight inpatients suffering from depression. There was a considerable interpatient variability in plasma levels. Mean peak plasma levels (+/- SEM) were 114 +/- 26 ng/ml and were reached between 1 and 3 hr. The decline of mianserin levels in plasma was biphasic. The mean elimination t 1/2 was 21.6 +/- 3.1 hr and ranged from 10.7 to 40.8 hr. The estimated first-pass loss ranged from 26% to 48% (mean, 37%) and was lower than that reported for tertiary amine tricyclic antidepressants. The mean apparent volume of distribution (15.7 +/- 2.2 l/kg; 9.7 to 28.8 l/kg) was in the range of that for imipramine but somewhat lower than for maprotiline. Apparent total body clearance ranged from 0.33 to 0.81 l/hr/kg (mean +/- SEM, 0.52 +/- 0.05 l/hr/kg) and was of the order of that after maprotiline. Our results indicate that mianserin kinetics are in most respects similar to those of tertiary amine tricyclic antidepressants (e.g., imipramine) and the tetracyclic maprotiline.
The present investigation assessed 45 anxious neurotic adult patients treated double-blindly in three randomized drug groups; bromazepam, diazepam and placebo. Non-signal, simple and complex signal stimuli were presented to monitor electrodermal activity changes at baseline, 4 h, 1 week and 14 days of treatment. The results indicate that patients with generalized anxiety disorder treated with bromazepam developed decreased skin conductance during the presentation of visual, auditory, and tactile stimuli presentations. Such skin conductance changes were not significant for patients on diazepam and placebo. Future clinical and research implications of these perceptual and psychophysiological results are discussed in conjunction with the usage of a functional-realistic-instrumental paradigm rather than studying anxiety on an attentional-arousal continuum.
Daily haloperidol injection at the dose of 5 mg/kg for 34 days did not change the levels of dopamine in the corpus striatum, frontal cortex, and midbrain of rats. However, the gamma-aminobutyric acid (GABA) level was increased by 27% in the corpus striatum. Haloperidol withdrawal for 4 days after 30-day treatment increased GABA levels of the corpus striatum and the frontal cortex to 140 and 125%, respectively, of control values. GABA, by its inhibitory actions, depleted dopamine level in the corpus striatum and frontal cortex by 17 and 29%, respectively. Administration of SL76002, a new GABA agonist, for 4 days at the dose of 400 mg/kg i.p. to haloperidol-withdrawn rats increased GABA levels in striatum by 23% of control values. The dopamine levels were also decreased significantly in the frontal cortex and corpus striatum. Our data demonstrate that SL76002, by altering the GABA levels, probably influences DA functioning in the corpus striatum, a region responsible for involuntary movements.
This study was carried out to compare the efficacy of chlormethiazole and chlordiazepoxide in the treatment of acute alcohol withdrawal syndrome in 40 patients. Repeated biochemical, clinical, and psychophysiological measurements were obtained in a randomized, double-blind design in which one group of patients received chlormethiazole and a second group received chlordiazepoxide over a period of 7 days. Analysis indicated both drugs to be of equivalent potency and were equally well tolerated by patients. The more severe aspects of withdrawal were brought under control within the first 4 days of treatment. However, even at 7 days, there still persisted some symptoms attributable to the withdrawal from alcohol.
The effects of a relatively new antidepressant drug, fluvoxamine, were compared with those produced by chlorimipramine on the 5-hydroxytryptamine system in rat brain. Daily treatment with fluvoxamine (25 mg/kg, i.p.) and an equivalent dose of chlorimipramine (28 mg/kg, i.p.) for 7 days reduced (3H)5-hydroxytryptamine uptake by crude synaptosomes (P2 pellet) of brain to 56 and 45%, respectively, but produced no change in midbrain monoamine oxidase activity. Repeated administration of these drugs significantly decreased tryptophan hydroxylase activity as well as tryptophan level in the midbrain region. The concentration of 5-hydroxyindoleacetic acid also was lowered in several discrete areas of the brain, but no change was seen in the endogenous levels of 5-hydroxytryptamine. Our data suggest that fluvoxamine, like chlorimipramine, is a potent inhibitor of 5-hydroxytryptamine uptake. Unlike tricyclic antidepressants, fluvoxamine does not seem to produce any sedation in animals, which was evidenced by no significant change in spontaneous locomotor activity.
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Antidepressants recently marketed, under development, or in clinical trials are reviewed in terms of the neurotransmitter systems they preferentially affect, dosage ranges, side effect profiles, and comparative efficacy. The development of these agents contributes not only to treatment efforts but to our understanding of the mechanisms underlying depression.