Use of neuroendocrine effects in discrimination between CNS-active drugs in the rat

Different psychotropic drugs were investigated in order to determine their effect on the release of prolactin and corticosterone and their influence on the tuberoinfundibular dopamine (TIDA) neuron activity. The results were used in a principal component analysis, which grouped the psychotropic drugs into different clusters. In the plot showing these clusters the anxiolytic drugs were found to be grouped together and differ from the antidepressant drugs by their potent ability to increase plasma corticosterone. The antipsychotic drugs formed a separate group being clustered together. Typical neuroleptic and atypical antipsychotic drugs could be separated within the cluster by their different effects on plasma prolactin and corticosterone and on TIDA neuron activity. The results indicate that the neuroendocrine profiles of antidepressant and anxiolytic drugs are different from those of antipsychotic drugs and that the neuroendocrine measurements could be a useful tool in the early classification of psychotropic drugs. © 1993 Wiley-Liss, Inc.     

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs

Cytochrome P450 CYP2D6 is the most extensively characterized polymorphic drug-metabolizing enzyme. A deficiency of the CYP2D6 enzyme is inherited as an autosomal recessive trait; these subjects (7% of Caucasians, about 1% of Orientals) are classified as poor metabolizers. Among the rest (extensive metabolizers), enzyme activity is highly variable, from extremely high in ultrarapid metabolizers, to markedly reduced in intermediate metabolizers. The CYP2D6 gene is highly polymorphic, with more than 70 allelic variants described so far. Of these, more than 15 encode an inactive or no enzyme at all. Others encode enzyme with reduced, "normal" or increased enzyme activity. The CYP2D6 gene shows marked interethnic variability, with interpopulation differences in allele frequency and existence of "population-specific" allelic variants, for instance among Orientals and Black Africans. The CYP2D6 enzyme catalyses the metabolism of a large number of clinically important drugs including antidepressants, neuroleptics, some antiarrhythmics, lipophilic beta-adrenoceptor blockers and opioids. The present-day knowledge on the influence of the genetic variability in CYP2D6 on the clinical pharmacokinetics and therapeutic effects/adverse effects of psychotropic drugs is reviewed.     

Psychiatry,psychopharmacology and P-450s

The cytochrome P-450 enzyme family is one of the major drug metabolizing systems in man. Over the last decade, advances in molecular biology, in vitro and clinical pharmacology techniques have increased our understanding of their role in the metabolism of psychotropic drugs, the effects of psychotropics on enzyme inhibition and induction, and how the pharmacokinetics of psychotropics are affected by changes in enzyme activity. There is also greater awareness of the influence of factors such as age, gender, race and environment on enzyme activity. This information can be of considerable assistance to psychiatrists, to help with rational prescribing, or to prevent or minimize the potential for drug interactions.     

A quantitative assessment of CNS sympatho-inhibition produced by psychotropic drugs

As one index of sympathetic reactivity, electrodermal responses (EDR) were evoked from central (hypothalamic) and peripheral (ulnar nerve) sites in pentobarbital-anesthetized cats. When compared with intravenous chlorpromazine (ED₅₀ ～ 1.0 mg/kg), only thioridazine, trifluoperazine and pimozide were less potent than chlorpromazine in reducing the amplitude of these centrally-evoked sympathetic-cholinergic responses. Perphenazine and methotrimeprazine (a non-neuroleptic phenothiazine) were about twice as potent as chlorpromazine. Haloperidol and triflupromazine were about 5 times as potent and chlorprothixine was more than 10 times as potent. None of these agents reduced the peripherally-evoked electrodermal response, indicating a CNS mode of action. Diazepam was without effect at either site. In addition, pretreatment with yohimbine (0.5 mg/kg, i.v.) did not significantly alter the ED₅₀ for any of the above drugs. These results demonstrate that all of the phenothiazines and non-phenothiazine neuroleptics tested produced a dose-dependent central sympatho-inhibition and that diazepam does not. The results also suggest that there is no significant correlation between central symphatho-inhibition and the antipsychotic potency of these compounds and that their depression of central sympathetic outflow is independent of α-adrenergic mechanisms in the CNS.     

Pharmacological profile of the antidepressant adinazolam, a triazolobenzodiazepine

Adinazolam, which is a 1-dimethylaminomethyl triazolobenzodiazepine, is an effective anxiolytic agent as defined by suppression of stress-induced increases in plasma corticosteroids. Adinazolam is also an effective antagonist of pentylenetetrazole. The 1-dimethylaminoethyl triazolo analog, U-43,465F, was inactive in the stressed rat test and only weakly active against pentylenetetrazole. Adinazolam and U-43,465F have been previously shown to have antidepressant activity in classical screening tests. They have also been found to potentiate the effect of norepinephrine and this is consistent with the activity of the known antidepressants; U-43,465F was found to be equieffective to imipramine in this test. Adinazolam was also effective; however, the magnitude of the potentiation was not as great. The uptake of norepinephrine was only weakly affected by either compound. Potentiation or uptake of serotonin were not significantly-altered pharmacological factors. Receptor binding studies were negative except at the benzodiazepine receptor. Chronic treatment with adinazolam did not decrease the number of beta-adrenergic receptors in the cerebral cortex of the rat, in contrast to the positive effect of imipramine. The discovery of triazolobenzodiazepines with antidepressant activity is of special interest. These agents will hopefully have lower toxicity than the tricyclic antidepressants and thus possess a more favourable therapeutic index. This would be advantageous in the treatment of depression.     

The pharmacological interactions between direct-acting antivirals for the treatment of chronic hepatitis c and psychotropic drugs

ABSTRACT

Introduction: Most direct-acting antivirals (DAAs) and psychotropic drugs are metabolized by or induct/inhibit CYP enzymes and drug transporters. Although they are frequently coadministered, the drug–drug interactions (DDIs) have been little studied. Therefore, the aim of this review is to describe the interactions between the approved DAA or combination regimens and the main psychoactive substances, including legal and illegal drugs of abuse.

Areas covered: We performed a literature search on PubMed database on drug interactions with the currently available antivirals for hepatitis C and a review of the information on pharmacokinetics, metabolism, and drug interactions from www.hep-druginteractions.org and from all the Summary of Product Characteristics (SmPC). This review covers the DDI between the DAA regimens approved, such as simeprevir and sofosbuvir, paritaprevir, glecaprevir, voxilaprevir, ombitasvir, ledipasvir, daclatasvir and sofosbuvir, elbasvir and grazoprevir, sofosbuvir and velpatasvir, glecaprevir/pibrentasvir, sofosbuvir and velpatasvir, and main psychotropic agents.

Expert Commentary: DAA regimens based on sofosbuvir combination usually have less DDI than protease inhibitor-based regimens. Among protease inhibitors regimens, new combinations, such as glecaprevir/elbasvir and grazoprevir/elbasvir, seemed to have less DDI than the combination POrD (paritaprevir/ombitasvir/ritonavir/dasabuvir). However, the analysis of each interaction is theoretical and further interaction studies would be necessary to confirm actual effect.     

Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients

The in vivo pharmacokinetic interaction between two selective serotonin reuptake inhibitors (SSRI) (fluvoxamine, fluoxetine) and tricyclic antidepressants (TCAs) (amitriptyline, clomipramine) or neuroleptics (haloperidol, cyamemazine, levomepromazine, propericiazine) was assessed in 29 in-patients. They were phenotyped twice with dextromethorphan and mephenytoin: first in steady state conditions while under treatment with TCAs or neuroleptics; and also 10 days after an associated treatment with fluvoxamine (150 mg day⁻¹) or fluoxetine (20 mg day⁻¹).A clear and statistically significant increase in the mean urinary metabolic ratio (MR) of dextromethorphan/dextrorphan and in the mean mephenytoin S/R ratio (S/R) was seen with the fluvoxamine and fluoxetine treatment. The mean MR increased from 0.13 to 0.27 (P<0.01) with fluoxetine and from 0.34 to 0.84 with fluvoxamine (P<0.05). The (dextromethorphan) “extensive metabolizer” phenotype switched to the “poor metabolizer” phenotype in six patients by the 10-day fluoxetine treatment, and in two patients by the fluvoxamine treatment. The mean S/R increased from 0.24 to 0.34 (P<0.05) with fluoxetine, and from 0.33 to 0.58 (P<0.002) with fluvoxamine.These results are in agreement with the observed modification of TCA plasma levels after the SSRI association. During fluvoxamine treatment, amitriptyline and clomipramine plasma levels (P<0.06 both) tendentially increased, and those of demethylclomipramine decreased (P<0.06). Fluoxetine addition lead to a significant increase (P<0.02) of the desmethylclomipramine plasma levels. Fluvoxamine induced a moderate augmentation of the plasma levels of haloperidol and its reduced metabolite and no change in the plasma levels of cyamemazine and levomepromazine. But patients treated with neuroleptics are to few to draw any firm conclusion.This study suggests, that fluoxetine and fluvoxamine differ in their interaction with the metabolism of some other basic psychotropic drugs, by a mechanism which implies CYP2D6 and CYPmeph and possibly other isoformes of cytochrome P-450. Moreover, the interactions produced varied with the TCA prescribed.     

Uptake of3H-noradrenaline by adrenergic nerves of rat iris incubated in plasma from patients treated with various psychotropic drugs

Summary Rat iris, which is richly innervated by adrenergic nerves, was incubated with³H-noradrenaline (³H-NA) in plasma from patients receiving clinical treatment with chlorpromazine, thioridazine, opipramol, chlorprothixene, trifluoperazine and haloperidol. The uptake of³H-NA by the iris was compared with that found in control samples of plasma. Chlorpromazine significantly inhibited the uptake of³H-NA; no effect on NA uptake was found in plasma from patients on lithium, opipramol or the other neuroleptic drugs, i. e. only clinical doses of chlorpromazine and tricyclic antidepressant drugs inhibited neuronal NA uptake. A cross-over study of nortriptyline and amitriptyline (50 mg t.i.d.) was performed in 6 patients. Both the plasma concentrations of nortriptyline (the main metabolite of amitriptyline) and the inhibition of NA uptake in the rat iris were greater when the patients were taking nortriptyline.     

Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT_1A, 5‐HT₇, and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione ( 4b ) behaved as strong and selective antagonist of 5‐HT_1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands’ affinity and potency in the 5‐HT_1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient P_app for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.     

五参安神合剂对小鼠镇静、催眠和免疫功能的影响

目的观察五参安神合剂对小鼠镇静、催眠和免疫功能的影响。方法观察给药后药物对小鼠自主活动情况、戊巴比妥钠致小鼠睡眠时间、士的宁致小鼠惊厥作用的影响,测定小鼠脾指数、胸腺指数和白细胞数。结果五参安神合剂能明显减少小鼠自主活动,缩短戊巴比妥钠致小鼠睡眠潜伏期,延长戊巴比妥钠致小鼠睡眠时间,能对抗士的宁致小鼠惊厥的作用,升高小鼠脾脏指数、胸腺指数和白细胞数。结论五参安神合剂具有镇静、催眠和增强免疫功能的作用。     

A comparison of the psychotropic profiles of tofisopam and diazepam

Summary Twelve normal subjects were tested on a number of measures both before and 1,3 and 5 h after 10 mg diazepam, 100 and 200 mg tofisopam and a placebo. The measures included self-ratings of mood, bodily symptoms, hostility and sleep, the electroencephalogram (EEG), reaction time, tapping, digit symbol substitution, the symbol copying test, and plasma levels. Diazepam showed a clear profile of action, producing EEG changes, pronounced sedation and psychological impairment. The last two effects were maximal at 1 h and had worn off by 5 h. The EEG was recorded at 3 h only. Tofisopam in no way resembled diazepam. It produced no changes on the EEG or psychological tests and a very mild stimulant effect was apparent on the ratings. While diazepam was easily detectable in the blood, tofisopam did not bind to benzodiazepine receptors.     

神安胶囊的主要药效学研究

目的 观察神安胶囊对实验动物的镇静催眠作用。方法 采用抖笼换能器法、玻璃倾斜法及翻正反射法测定神安胶囊对正常小鼠及大鼠的镇静协调作用。结果 神安胶囊高、中、低剂量组均能明显抑制正常小鼠的活动次数，抑制苯丙胺的中枢兴奋作用，降低大鼠的协调运动，明显延长戊巴比妥钠阈剂量的小鼠睡眠时间，增加动物入睡数。结论 神安胶囊具有较明显的镇静催眠作用。     

Acute Effects of Oxazepam,Diazepam and Methylperone,alone and in Combination with Alcohol on Sedation,Coordination and Mood

Abstract Effects on critical flicker fusion frequency (CFFF), coordination and mood were studied after single oral doses of placebo, alcohol (0.5 ml ethanol/kg b. wt.), oxazepam (10, 20 and 40 mg), diazepam (5, 10, 20 and 40 mg) and methylperone (10, 25 and 50 mg), given either alone, or simultaneously with alcohol or with delayed alcohol administration. Methylperone was found to have a depressant effect similar to or greater (on a weight basis) than that of diazepam and oxazepam respectively. The correlation between sedative and antianxiety effect is discussed. The decrease in CFFF was parallelled by a decreased coordination ability. Alcohol alone had no effect on our parameters, but when given simultaneously with the drugs, it markedly increased the effect of diazepam, while the effect of oxazepam and methylperone were affected to a much lesser degree. The effect of the drugs on psychomotor skills and the interaction between alcohol and the drugs have important implications when treating out-patients. Methylperone as a potential anti-anxiety agent is discussed.     

Degree of Sedation Obtained with Various Doses of Diazepam and Nitrazepam

Abstract Using critical flicker fusion (CFF)determination and estimation of drowsiness in eight healthy volunteers the sedative-hypnotic effects of diazepam and nitrazepam were studied. Three dose levels of each drug were used, so that dose-effect curves could be produced. The most reliable results were obtained with the CFF method, and significant dose-effect relations could be demonstrated. The CFF deviation after diazepam initially related well to the concentration in blood serum, but after 4–6 hours the CFF depression vanished rapidly, while the drug concentration remained high. After nitrazepam the signs of drowsiness occurred similarly, while the drug concentration in serum showed on an average a slower rise. The effects began to disappear before the nitrazepam concentration had reached a peak. A rapid tachyphylaxis at the receptor sites seems to be responsible for this incongruity. Nitrazepam exerted significantly stronger sedative effects than diazepam, particularly when the respective serum concentrations were taken into account. This confirms that nitrazepam should be a more efficient sleeping drug, although diazepam also has considerable sedative-hypnotic action.     

Organic Anion and Cation Transport in Vitro by Dog Choroid Plexus: Effects of Neuroleptics and Tricyclic Antidepressants

Abstract Dog lateral choroid plexus accumulates the cation ¹⁴C-emepronium and the divalent anion ¹²⁵I-iodipamide in vitro. At 10 μM, high potency neuroleptics with a substituted piperazine side chain and also haloperidol depress only the uptake of the cation and even stimulate the uptake of the anion. In contrast, at 1-10 μM, the accumulation of both test substances is inhibited by neuroleptics and tricyclic antidepressants with an aliphatic side chain. Such unspecific effects on seemingly unrelated transport systems at concentrations reached clinically in the CSF might explain some side actions of low potency neuroleptics and antidepressants.