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PubMed1975

[Placental transfer of psychotherapeutics of the thioxanthene type (author's transl)].

The hitherto existing investigations on the placental transfer of psycholeptic drugs mostly do not answer the question whether the active compounds themselves or their metabolites or both get into the fetus. As published informations on this problem partly are contradictory the placental transfer of psycholeptic drugs was investigated with the thioxanthenes flupentixol and chlorprothixen for examples. After oral application to rats on the 15th and 20th days of gestation the intact thioxenthenes themselves as well as their sulfoxides and desalkylated metabolites were detectable in placenta, uterus and fetus. The last mentioned substances and the intact thioxanthenes were determined quantitatively. The concentration (mug/g tissue) in the fetus is lower than in uterus and placenta. The results are discussed.

Animals↗
PubMed1976

[Tricyclic psychotropic drugs: complications and therapy of Choloprothixen-intoxication (author's transl)].

The broad use of tricyclic psychotropic drugs demands from the physician to take in account the side effects of these drugs. These side effects relate primarily to the cardiovascular system. We describe a suicidal Chlorprothixen(Taractan-)intoxication of a 27 year old female patient. The progress of this intoxication was characterized by severe arrhythmias, mainly ventricular tachycardias. The pathogeneisis of the cardiotoxic reaction is discussed. Since there is no specific antidot against these drugs, therapy of side effects is limited to symptomatic treatment including administration of cholinergic drugs. Severe cardiovascular reaction also can be found, when the drugs are used in therapeutic doses. The cardiodepressive effect of tricyclic psychotropic drugs may lead to considerable complications, especially in older patients.

Adult↗
PubMed2003

[Psychotropic drugs used in a psychiatric hospital (pharmaco-epidemiologic aspects)].

The aim of the study was to optimize psychopharmacotherapy in a big psychiatric hospital. It was conducted in Moscow Alekseev psychiatric hospital No 1, using a method of comparison of standard psychotropic treatment and medication strategy suggested by the expert group. An analysis of the treatment of 966 patients with different mental disorders revealed that 78.3% were in need of neuroleptic assignment that was in line with routine practice. The expert's conclusions were postulated as follows: a need in phenothyazines is significantly lower than that observed in practice. Xantens and tyoxantens (chlorprothixene, flupentixol, zuclopenthixol, zuclopenthixol decanoate, zuclopenthixol acetate), benzamides (sulpiride) and such atypical antipsychotics as risperidone, olanzapine and quentiapine are underused in the treatment. Comparing to usual practice, more patients (35.8%) need antidepressants treatment. Thymoleptics should be assigned in greater daily doses. Selective inhibitors of serotonin reuptake (paroxetine, fluoxetine, citalopram, sertraline), reversible MAO A inhibitors (pyrazidolum), "double-action" drugs (mirtazapine, milnacipran) are recommended for wider usage. Less patients (33.4%) are in need of tranquilizers, though a number of medications used is consistent with a recommended one. Normothymics may be assigned to essentially less part of the patients and 18% of them need nootropics that is consistent with routine practice.

Antidepressive Agents↗
PubMed1991

[The effect of various non-ulcer pharmaceuticals on nocturnal gastric pH in healthy subjects].

The effects of 4 non-ulcer drugs and the M1-antagonist pirenzepine on the nocturnal intragastric pH were investigated in 12 healthy volunteers. We tested single doses of pirenzepine (100 mg), Chlorprothixene (30 mg), clonidine (75 micrograms), ketotifen (3 mg) and nifedipine (30 mg) in an randomized, single-blind, cross-over study. The nocturnal intraluminal pH is significantly elevated not only by pirenzepine but also by the other substances. As expected pirenzepine (mean nocturnal pH = 2.49 +/- 0.22) shows the most distinct effect, nifedipine (mean nocturnal pH = 1.72 +/- 0.20) the most sparsely effect. The other drugs are nearly half as effective as pirenzepine. The acid suppressive side effect of the non-ulcer remedies is considered to be important for the treatment of ulcer patients with concomitant diseases.

Adult↗
PubMed1977

[Therapy of childhood schizophrenia].

Due to the multifacet genesis and variability of clinical phenomenology, the therapy of childhood schizophrenia must be multidimensional. Formerly applied techniques like electroshock- and insulin-therapy are now replaced by pharmaco-therapy, primarily with phenothiazines, butyrophenones and chlorprothixens. The dosage depends on age, body weight or body surface. Because of extrapyramidal motor side effects, combinations with anticholinergic drugs may be necessary. Psychopharmaco-therapy alone, however, is insufficient. High emphasis must be placed on psychotherapy and educational guidance and counselling of the psychotic child. Participation in play groups, sports, muscial activities, arts and crafts, and acting helps make it possible to improve communication behaviour and to transform aggressive anxiety defense into stabilized control of emotions and impulses. In addition to successive integration of the psychotic child into small groups, play therapy with the single child is meaningful. In this case, a constant and confidential relation between therapist and child is extremely important and only possible if the therapist attempts to place himself into the magic-animistic phantasies of the psychotic child. He has first to learn the psychotic language of his patient in order to support more reality-oriented behaviour processes of the child's thinking, preceiving and performing later on. In this manner, the magic-omnipotent phantasies can be dissolved and an increasing orientation of the child toward reality can be encouraged. This involves strengthening and support of non-pathological ego-functions and initiation of a new level of ego-functioning. Such an integrated developmental concept can best be realized through play therapy.

Antipsychotic Agents↗
PubMed1987

Topographic brain mapping of EEG in neuropsychopharmacology--Part II. Clinical applications (pharmaco EEG imaging).

Multi-lead analysis of drug-induced changes in human brain function as monitored by the scalp-recorded electroencephalogram (EEG) and subsequent imaging of topographic pharmaco-EEG maps has become possible and practical with the advent of modern mini- and micro-computers. The present paper gives a survey about topographic analyses of pharmaco-EEG data obtained in systematic double-blind, placebo-controlled studies in normal healthy volunteers involving representative drugs of 5 different psychopharmacological classes, such as neuroleptics (chlorprothixene), antidepressants (imipramine), tranquilizers (diazepam), psychostimulants (caffeine), and antihypoxidotics/nootropics (pyritinol). The determination of cerebral bioavailability utilizing time- and dose-efficacy relations, as well as the evaluation of bioequipotency of different formulations of compounds is shown. Topographic pharmaco-EEG seems not only to confirm our previous knowledge that quantitative analysis of the human EEG in combination with certain statistical procedures ("quantitative pharmaco-EEG") is a valuable method to determine if, how, when and at which dosage a drug will be centrally effective, but also to have the potential to show effects of psychotropic drugs on the target organ--the human brain--which could not be previously picked up by single lead recordings. Topographic pharmaco-EEG imaging can be viewed as an enlargement of our armamentarium to better understand the mode of action of psychotropic drugs in human neuropsychopharmacology, as well as to monitor and (eventually) predict therapeutic efficacy in patients.

Adult↗
PubMedDate not supplied

The influence of chronic treatment with antidepressant neuroleptics on the central serotonin system.

Chronic administration of antidepressant neuroleptics chlorprothixene (CPX) and levomepromazine (LMZ) increases the sensitivity of one kind of serotonergic receptors in CNS-5-HT2 receptors (which are involved in such behavioral responses as head-twitches and hyperthermia in heat adapted rats), but do not change 5-HT1 receptor population (responsible for the rate of serotonin synthesis). These results confirm once more the hypothesis about the existence of at least two types of serotonin receptors in the CNS. They also indicate that antidepressant neuroleptics, which are potent serotonin 5-HT2 and alpha 1-adrenergic blocking agents, after chronic administration affect the serotonin system in a manner similar to that produced by chronic treatment with classical antidepressant drugs.

Amitriptyline↗
PubMed1979

The pharmacological profile of a potential hypnotic compound RU 31158.

RU 31158, 6-(orthochlorophenyl)-1, 2-dihydro-2 (N-methylpiperazine-1-yl) methylene-8-nitro-IH, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one methanesulphonate, demonstrated potent hypnotic activity compared to diazepam when examined in the mouse and rat. RU 31158 potentiated minimal hypnosis in mice induced by both hexobarbital and chlorprothixene with ED50 values of 2.15 (1.53-3.01) and 0.69 (0.46-1.02) mg/kg p.o. respectively; these compared to values for diazepam of 17.00 (11.25-25.67) and 3.60 (2.25-5.76) mg/kg p.o. RU 31158 also potentiated hexobarbital in the rat with an ED50 value of 1.2 (0.7-2.0) mg/kg p.o. as compared to 32.0 (27.5-38.5) mg/kg p.o. for diazepam. Sleep studies in the rat confirmed the hypnotic properties of RU 31158, and also showed that the duration of action at 8.0 and 16.0 mg/kg p.o. was not longer than 9 hours. RU 31158 also showed potent minor tranquilizer, anxiolytic, and anti-convulsant properties in a series of pharmacological tests.

Animals↗
PubMed1982

[In-patient withdrawal treatment of heroin addicts with neuroleptics (author's transl)].

The results are reported of 144 abrupt withdrawal treatment in heroin addicts (102 in males, 42 in females). Neuroleptics were given intravenously (partly via subclavia catheter) or orally and the results compared with one another. Parenteral treatment needed much more specialist supervision and control and had a much higher complication rate. It should be used only on the individual special case. The initial withdrawal lasts about 4 days with an oral dosage of 270 mg levopromazine in males and 240 mg in females or 540 mg chlorprothixene in males and 520 mg in females per 24 hours. The only side effects encountered were tachycardia and the occasional occurrence of extrapyramidal signs. The liver function tests did not show any significant changes during the treatment.

Adolescent↗
PubMed1982

The sedative-hypnotic properties of quazepam, a new hypnotic agent.

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1, 4-benzodiazepine-2-thione (Sch 16134, quazepam) is a new hypnotic drug with demonstrated clinical efficacy. Quazepam has been shown in our laboratories to have potent hypnotic activity and fewer side effects at effective doses than flurazepam, which was studied concurrently. Hypnotic potency was estimated in mice via antagonism of electroshock-induced convulsions (ECS), potentiation of hexobarbital-induced sleeping time, and chlorprothixene potentiation. The respective oral ED50's (95% fiducial limits) in the 3 tests were 0.9 (0.4-2.0), 0.5 (0.3-0.8) and 0.05 (0.02-0.08) mg/kg for quazepam and 1.6 (1.1-2.3), 0.6 (0.4-1.0) and 0.11 (0.07-0.42) mg/kg for flurazepam. The duration of action of quazepam as measured by antagonism of ECS in mice was similar to that of flurazepam at equi-effective doses but quazepam had a faster onset. When potential tolerance to hypnotic efficacy was studied, quazepam did not show tolerance after dosing 20 mg/kg p.o. twice daily (b.i.d.) for 5 days, whereas tolerance was seen with flurazepam at equi-effective doses b.i.d. for 5 days. In conscious, unrestrained squirrel monkeys and cats, quazepam produced sedation with less ataxia and less evidence of CNS stimulant action than flurazepam. On the basis of the aforementioned studies, quazepam should be an effective hypnotic with less potential for ataxia, paradoxical excitation, and tolerance than flurazepam.

Animals↗
PubMed1984

Kinetic studies with competitive inhibitors indicate a sequential mechanism for dopamine beta-hydroxylase.

Competitive inhibitors have been used to study the kinetic mechanism of action of the multireactant enzyme dopamine beta-hydroxylase (dopamine beta-monooxygenase EC 1.14.17.1). The copper chelator penicillamine, which was found to be a competitive inhibitor of ascorbate, gave noncompetitive inhibition with respect to tyramine. The antidopaminergic drug cis-chlorprothixene, a competitive inhibitor for tyramine, produced uncompetitive inhibition with respect to ascorbate. These findings are consistent with an ordered sequential mechanism, with ascorbate as the initial substrate to add to the enzyme. The pharmacological relevance of dopamine beta-hydroxylase inhibition by penicillamine is also discussed.

Animals↗
PubMed1994

Crystal and molecular structures of tricyclic neuroleptics.

The X-ray crystal structures of three tricyclic neuroleptics have been completed and are reported herein. These include amitriptyline hydrochloride (I), chlorprothixene hydrochloride (II), and ethopropazine hydrochloride (III). The structures were compared with the structures of similar molecules with similar pharmacological activity. It was found that there is a great deal of flexibility in the structures of these molecules, which makes it difficult to determine the pharmacologically active conformations. Crystallographic data: (I) C20H24NCl, monoclinic space group P2(1)/a, a = 13.812(4) A, b = 9.140(2) A, c = 14.345(4) A, beta = 96.82(2) degrees, Z = 4, final R = 0.059 for 1630 observed (l > 3 sigma(l)) reflections. (II) C18H20NSCl2.CHCl3, monoclinic space group C2/c, a = 29.416(4) A, b = 6.986(1) A, c = 23.374(3) A, beta = 109.78(1) degrees, Z = 8, final R = 0.046 for 1436 observed reflections. (III) C19H25N2SCl, monoclinic space group P2(1)/c, a = 8.849(1) A, b = 14.475(2) A, c = 14.832(1) A, beta = 98.72(1) degrees, Z = 4, final R = 0.039 for 2583 observed reflections.

Antidepressive Agents, Tricyclic↗
PubMed1992

Pharmacokinetic interaction between carbamazepine and neuroleptics after combined prolonged treatment in rats.

This study investigates how neuroleptics of phenothiazine or thioxanthene structure influence the pharmacokinetics of carbamazepine. Experiments were carried out on male Wistar rats. Carbamazepine and the neuroleptics were administered i.p., separately or together, for 2 weeks in the following daily doses (mg/kg): carbamazepine 15 during the 1st week of treatment and 20 during the 2nd week of treatment, promazine 10, chlorpromazine 2, perazine 10, chlorprothixene 2, flupenthixol 0.5. One hour after the last injection of carbamazepine and/or the neuroleptic, samples of blood plasma and brain were taken to determine the concentrations of carbamazepine and two of its metabolites: 10,11-epoxide and trans-10,11-diol. The neuroleptics increased the concentration of carbamazepine in plasma and in brain, but tended to decrease (with the exception of chlorpromazine) the concentration of the epoxide and increased the concentration of trans-10,11-diol. Metabolic in vitro studies did not show any significant differences between rats treated with carbamazepine alone and those treated with carbamazepine plus neuroleptic in the rates of the carbamazepine epoxidation, of 10,11-epoxide hydrolysis or of 1-naphthol glucuronidation.

Animals↗
PubMed1981

The functional role of the noradrenergic neurons in the thermoregulatory circuits in mice.

Intracerebroventricular (i.c.v.) treatment of mice with 6-hydroxydopamine (6-OHDA; 20--50 micrograms per mouse), which depletes brain noradrenaline (NA) and DA, completely prevents or significantly diminishes the hypothermic effect of various classes of drugs: dopaminomimetics--apomorphine (0.5--10 mg/kg), piribedil (40--100 mg/kg), bromocriptine (3 to 10 mg/kg), CM 29-712 (2--10 mg/kg), d, l-amphetamine (1--2 mg/kg), and L-DOPA (10--100 mg/kg) in combination with Ro 4-4602 (5--40 mg/kg); cholinomimetics--oxotremorine (0.04--0.05 mg/kg), arecoline (5--10 mg/kg) and pilocarpine (2--3 mg/kg); neuroleptics--chlorpromazine, promazine, perphenazine, chlorprothixene, haloperidol, fluanisone (5--10 mg/kg); central alpha-adrenoblocker aceperone (20--40 mg/kg); inhibitor of tyrosine-hydroxylase alpha-methyltyrosine (200--300 mg/kg); inhibitor of dopamine-beta-hydroxylase--disulfiram (150--250 mg/kg) and FLA-63 (15--25 mg/kg). This antihypothermic effect was demonstrated up to 3 months after administration of 6-OHDA for DA-mimetics and neuroleptics and up to 3 weeks for cholinomimetics. The hypothermic effect of presumable GABA-mimetics Phenybut (100--150 mg/kg) and Lioresal (10--25 mg/kg) was enhanced by a prior 6-OHDA treatment. Pretreatment of mice with desipramine (25 to 30 mg/kg i.p.), protriptyline (20 mg/kg) or AW 15(1)1129 (15--20 mg/kg) 20--45 min before 6-OHDA administration protects the central NA-ergic neurons from a destructive effect of 6-OHDA and partially or completely counteracts the antihypothermic as well as prohypothermic (in the case of GABA-mimetics) effect of 6-OHDA. In rats desipramine counteracted antihypothermic effect of 6-OHDA in the case of piribedil, but not of apomorphine. Intracerebroventricular treatment of mice with a low (15 microgram) dose of 5, 6-dihydroxytryptamine (5, 6-DHT) enhanced the hypothermic effects of DA-mimetics; higher doses of 5, 6-DHT (26 and 30 micrograms) and 5, 7-DHT (40 and 46 micrograms) diminished the hypothermic effects; the antihypothermic effect of 6-OHDA was stronger than that of equimolar doses of 5, 6- or 5,7-DHT; desipramine pretreatment counteracted antihypothermic effects of 5, 6-DHT and 5, 7-DHT as well as depletion of brain NA they produce. The data presented reveal the key position for NA-ergic neurons in a temperature regulation and, particularly, in effects of various drugs on body temperature in mice. The tentative fragment of the neuronal thermoregulatory circuit is proposed in attempt to account for the presented an other known data concerning drug action (and interactions) on core temperature in mice.

Animals↗
PubMed1986

The effect of neuroleptics on imipramine demethylation in rat liver microsomes and imipramine and desipramine level in the rat brain.

A study of the cytochrome P-450 level and imipramine (IMI) demethylase activity in liver microsomes of rats treated concurrently with IMI and chlorpromazine (CPZ) or IMI and chlorprothixene (CPX) for two weeks were carried out. Concomitant administration of IMI and CPZ or IMI and CPX elevated the cytochrome P-450 level and accelerated IMI demethylation in in vitro study. Kinetic study of IMI demethylation carried out in the absence or in the presence of CPZ or CPX revealed that those neuroleptics inhibited IMI demethylation via competitive mechanism. Simultaneously with the enzymatic study the brain level of IMI and its demethylated metabolite desipramine (DMI) was assessed. It was found that 1 hr after withdrawal of IMI and CPZ or IMI and CPX the brain level of IMI was elevated in comparison with that of IMI treated animals, and the ratio between DMI/IMI brain concentration was decreased. When the assessment of IMI and DMI brain level was performed 24 hr after withdrawal of IMI and CPZ or IMI and CPX, there was no difference between the concentration of IMI and DMI in both, experimental and control animals.

Animals↗
PubMed1990

Tricyclic drugs reduce proton motive force in Leishmania donovani promastigotes.

Tricyclic compounds have been suggested as potential anti-leishmanial drugs. We have studied the effect of tricyclic drugs on several cellular functions in L. donovani promastigotes. Imipramine inhibits proline transport and reduces delta pH and cellular ATP at relatively high concentrations (IC50 = 50-80 microM). High concentrations of imipramine are also required to kill L. donovani promastigotes (LD50 greater than 50 microM). The presence of a chlorine atom in the side ring of either imipramine or promazine results in a three-fold increase in both IC50 and LD50 values. Tricyclic compounds in which the nitrogen in the middle ring was substituted with a carbon atom (amitryptyline and chlorprothixene) are most effective in causing cell death and in decreasing proline transport and delta pH (IC50 congruent to 5 microM), whereas depletion of cellular ATP requires a higher drug concentration (IC50 = 12 microM). Transchlorprothixene has IC50 values for proline transport, delta pH and cellular ATP that are similar to those of amitriptyline, whereas the cis isomer is less active. Imipramine, chlomipramine and chlorpromazine decrease the membrane potential in promastigotes. There is a direct correlation between inhibition of membrane transport of proline and the size of the membrane potential at various concentrations of the drugs. Taken together, the multiple effects of the tricyclic drugs on cellular functions in Leishmania suggest that the drugs cause cellular death by non-specific mechanisms, probably involving a general increase in membrane permeability.

Adenosine Triphosphate↗
PubMed1983

Neuroleptic inhibition of 6,7-ADTN-induced hyperactivity after injection into the nucleus accumbens. Specificity and comparison with other models.

The dopamine agonist 6,7-ADTN induced locomotor stimulation after injection into the nucleus accumbens of rats. This hyperactivity was stereospecifically antagonized by peripheral injection of typical and atypical neuroleptics, except sulpiride, regardless of structural class. The potency of 14 neuroleptics correlated significantly to that in other neuroleptic in vivo models in rats, i.e. cataleptogenic and amphetamine-antagonistic (stereotypy, circling) activity. Sulpiride was inactive after peripheral injection, whereas intraacumbens sulpiride antagonized 6,7-ADTN-induced hyperactivity with a higher potency than that found for locally injected cis-(Z)-flupentixol, haloperidol and clebopride. Blockade of alpha 1-adrenergic receptors by systemic prazosin or locally injected phentolamine also antagonized 6,7-ADTN, whereas antagonists of alpha 2-adrenergic, beta-adrenergic, muscarinic and serotoninergic receptors were without effect. Furthermore, the cis-(Z)-flupentixol and haloperidol-induced 6,7-ADTN blockade was only slightly or not reversed by additional antimuscarinic (scopolamine) or antiserotonergic (methysergide) treatment. It is concluded that antagonism of 6,7-ADTN-induced hyperactivity is a relevant model for detecting neuroleptic activity with minimal influence of anticholinergic and antiserotonergic activity, but that the dopamine receptor within the nucleus accumbens responsible for the locomotor stimulation is similar to that involved in other behavioural effects of neuroleptics. It is suggested that an apparent preferential limbic action of some neuroleptics (e.g. clozapine and chlorprothixene) is more likely to be explainable by their simultaneous blocking effect on dopaminergic, alpha-adrenergic and muscarinic receptors.

Amphetamine↗