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PubMed1991

Debrisoquine oxidation phenotype during neuroleptic monotherapy.

The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers. The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.5%). Treatment with phenothiazine antipsychotics (chlorpromazine, levomepromazine and thioridazine) was associated with a higher debrisoquine metabolic ratio than treatment with haloperidol. On the other hand, treatment with clothiapine appeared not to interfere with debrisoquine oxidation. Oral administration of 50 mg thioridazine daily to 8 healthy subjects resulted in a marked increase in the debrisoquine metabolic ratio and 4 of them were transformed into phenotypically poor metabolizers. The results confirm the fact that phenothiazines, and to a lesser extent haloperidol, inhibit the oxidative metabolism of debrisoquine. They show also that clothiapine administration does not disturb the debrisoquine metabolic ratio.

Adult↗
PubMed1981

Chronic treatment with antidepressants: protentiation of clonidine-induced aggression in mice via noradrenergic mechanism.

The chronic (10 mg/kg i.p. twice daily, 10 days)-and not the acute-administration of amitriptyline, maprotiline or zimelidine enhances aggressiveness induced by clonidine in mice. An analogous potentiation of clonidine-induced aggressiveness was obtained with chronic administration (the schedule as above) of levomepromazine (2 mg/kg) or thioridazine (5 mg/kg) but not of spiperone (0.2 mg/kg). Fluoxetine (10 mg/kg), atropine (5 mg/kg), propranolol (10 mg/kg) or metergoline (0.5 mg/kg) given chronically (the schedule as above) also had no effect. The enhancement of clonidine aggressiveness induced by prolonged treatment with imipramine (10 mg/kg) was prevented by cycloheximide, an inhibitor of protein synthesis. The results supply further evidence for the previously proposed hypothesis that chronic administration of antidepressants enhances the responsiveness of central postsynaptic noradrenaline receptors.

Aggression↗
PubMed1995

Effects of Antidepressants and antipsychotics on the 5HT2 receptor-mediated signal transducing system in human platelets.

The IC50 values of the antidepressants amoxapine, mianserin, desipramine, clomipramine and imipramine, and the antipsychotics spiroperidol, chlorpromazine, levomepromazine and haloperidol for 3H-ketanserin binding, 5HT-induced intracellular Ca2+ increase, 5HT-induced shape change and 3H-paroxetine binding in human platelets were measured and the correlations of each parameter were examined. Results were as follows. Both the antidepressants and the antipsychotics had inhibitory effects on 3H-ketanserin binding, 5HT-induced intracellular Ca2+ increase and 5HT-induced shape change and there were significant positive correlations between the IC50 values of these three parameters. On the other hand, there were no significant correlations between the IC50 values in 3H-paroxetine binding and those in the other three parameters. These results suggest that 3H-ketanserin binding, 5HT-induced intracellular Ca2+ increase and 5HT-induced shape change are useful and reliable tools for the assessment of the effects of the antidepressants and the antipsychotics on the 5HT2 receptor-mediated signal transducing system in human platelets.

Adult↗
PubMed1994

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors.

It was the aim of the present study to determine the affinities of four neuroleptics and five antidepressants for histamine H3 receptors. In rat brain cortex membranes, the specifically bound [3H]-N alpha-methylhistamine was monophasically displaced by clozapine (pKi 6.15). The other drugs did not completely displace the radioligand even at 100 microM; the pKi values were: haloperidol (4.91); sulpiride (4.73); amitriptyline (4.56); desipramine (4.15); levomepromazine (4.14); fluovoxamine (4.13); maprotiline (4.09); moclobemide (< 4.0). The effect of clozapine was further examined in a functional H3 receptor model, i.e., in superfused mouse brain cortex slices preincubated with [3H]-noradrenaline. The electrically evoked tritium overflow was not affected by clozapine 0.5-32 microM. However, clozapine shifted the concentration-response curve of histamine for its inhibitory effect on the evoked overflow to the right, but did not affect the maximum effect of histamine. The Schild plot yielded a pA2 value of 6.33. In conclusion, clozapine shows an intermediate affinity and potency (as a competitive antagonist) at H3 receptors. The Ki value of clozapine at H3 receptors resembles its Ki value at D2 receptors (the target of the classical neuroleptics), but is higher than its Ki values at D4, 5-HT2 or muscarinic acetylcholine receptors, which according to current hypotheses, might be involved in the atypical profile of clozapine.

Animals↗
PubMed1990

Drug utilization in breast-feeding women. A survey in Oslo.

In a retrospective questionnaire survey of 885 women who had given birth 3-5 months before, fewer of those who were still breast-feeding at 4 months (n = 645) were using drugs than those who had stopped breast-feeding before 4 months (n = 240), during the 2 week period preceding registration. The average number of doses (Defined Daily Doses/1000 women/day) was 166 and 307, respectively, in that period. The number of doses taken was significantly associated with the use of oral contraceptive agents (p less than 0.005) and young maternal age (p less than 0.05). Most of the variation in drug use between breast-feeding and not breast-feeding mothers was probably due to the greater use of contraception by the latter. The number of drugs used per mother in the 4 month period seemed to be best predicted by her and her infant's disorders. Long-term medication in breast-feeding women included many drugs for which there is incomplete or no data about milk transfer, e.g. salbutamol, clemastine, dexchlorpheniramine, phenylpropanolamine, cromoglycate and levomepromazine. The disorders most extensively treated with drugs in this period were dyspepsia, haemorrhoids and inflammation of the breast. The finding that smoking was associated with early weaning and consumption of alcohol with prolonged breast-feeding calls for further investigation. More information on these drug and health issues to the breast-feeding mother is highly desirable.

Adult↗
PubMedDate not supplied

In vitro forecasting of drugs that may interfere with codeine bioactivation.

The O-demethylation of codeine (methylmorphine) into morphine is mediated by the polymorphic cytochrome P450 DB1 (P450 IID6). By means of in vitro screening in human liver microsomes we have studied the effect on codeine bioactivation of several drugs used as analgesics or as adjuvants for pain control. In microsomes from an extensive metabolizer subject, paracetamol (acetaminophen) and NSAIDs (acetylsalicylic acid, diclofenac, indomethacin, piroxicam, and pirprofen), benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flunitrazepam, and midazolam), and anticonvulsants (carbamazepine and phenytoin) did not alter the reaction. There was marked inhibition of in vitro morphine production by neuroleptics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline). Enzyme kinetics showed competitive inhibition by neuroleptics (chlorpromazine Ki = 0.5 microM) and antidepressants (clomipramine Ki = 6.8 microM), which are substrates of the polymorphic monooxygenase. Due to the low affinity of codeine for P450 DB1 (Km = 100-200 microM), its bioactivation in extensive metabolizers, and thus its analgesic efficacy, is liable to vary greatly when it is combined with any drug that has a high affinity for the polymorphic isozyme.

Acetaminophen↗
PubMedDate not supplied

Interspecies variability and drug interactions of loxapine metabolism in liver microsomes.

Loxapine is a dibenzoxazepine neuroleptic that is metabolized by the liver in humans. In the present study, we investigated first in vitro loxapine metabolism in liver microsomes from various species including rats, mice, guinea pigs, dogs, rabbits, monkeys and humans. This enables us to choose between species to further validate drug-drug interaction studies. We observed the formation of desmethyl- and hydroxy- metabolites of loxapine after incubation of the different species liver microsomes. Hydroxylation pathway was major in all species. Wide interspecies variability of loxapine metabolism was observed. Loxapine metabolism was similar in human, guinea pig and dog microsomes. We screened in vitro effects of 67 molecules, representative of 8 therapeutic classes, on loxapine metabolism. Loxapine (100 microM) was incubated with guinea pig liver microsomes (1 mg/ml) 30 min at 37 degrees C with and without the presence of interacting drug. We found that most of psychotropics (alimemazine, cyamemazine and levomepromazine), antifungal (ketoconazole), anticancer drugs (daunorubicin, pirarubicin) and analgesic (nefopam) inhibited more than 50% of hydroxyloxapine formation in vitro. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.

Animals↗
PubMed2000

Influence of drugs on myocardial iodine-123 metaiodobenzylguanidine uptake in rabbit myocardium.

About 15 years ago, iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging was introduced for the evaluation of myocardial sympathetic nerve function. Two uptake mechanisms for MIBG have so far been identified: uptake type I, a saturable, energy-dependent mechanism, and uptake type II, a non-saturable, energy-independent mechanism. We incubated isolated rabbit myocardial tissue samples with 123I-MIBG in order to assess the uptake characteristics and the influence of varying incubation conditions. Furthermore, we examined the effects of several drugs and uptake inhibitors on the myocardial uptake of MIBG. The in vitro myocardial uptake of MIBG reached a steady plateau at 23.87%+/-3.63% after 1 h, i.e. a concentration gradient of 10, in a thermo-independent manner within a concentration range from 1.5 to 1500 microM. This indicates an unsaturable uptake process in the tested concentrations. Preincubation with the following drugs caused a significant inhibitory effect on myocardial MIBG uptake: haloperidol, levomepromazine, metoprolol, labetalol and clomipramine. According to our findings, the uptake mechanism seems to be an unspecific process, but the concentration gradient of 10 makes passive diffusion unlikely. Further studies with uptake-II-blocking substances as well as with isolated myocardial cells will be needed to clarify the nature of the myocardial MIBG uptake mechanism.

3-Iodobenzylguanidine↗
PubMed2003

Phenothiazines suppress proliferation and induce apoptosis in cultured leukemic cells without any influence on the viability of normal lymphocytes. Phenothiazines and leukemia.

PURPOSE: The purpose of the present study was to investigate the effects of phenothiazines (at clinically relevant doses) on the viability and proliferation of leukemic cell lines and normal lymphocytes, and to investigate the possibility of specific induction of apoptosis in leukemic cells. METHODS: Phenothiazines with different chemical structure and hydrophobicity were used: chlorpromazine (CPZ); levomepromazine (LVPZ); prometazine (PMZ); trifluoperazine (TFPZ); thioridazine (TRDZ). The leukemic cell lines used were: Daudi and Raji (derived from Burkitt's lymphoma), K-562 (derived from myelogenous leukemia), and BALL-1, MOLT-4, HPB-ALL and CCRF-HSB-2 (derived from acute lymphoblastic leukemia). The cytotoxicity of the phenothiazines was determined by a CellTiter-Glo luminescent cell viability assay, using ATP bioluminescence as a marker of cell viability as well as a marker of mitochondrial activity. The proliferation of leukemic cells was determined using a CellTiter-AQ cell proliferation assay which is based on the reduction of a methyl-tetrazolium compound to the formazan product. Apoptosis induction was estimated using phosphatidylserine (PSer) translocation to the cell surface and DNA fragmentation as characteristics of the process. RESULTS: Phenothiazines (at concentrations in the range 0.1-10 micro M) did not affect the viability of normal lymphocytes during a 24-h incubation. Moreover, about 15-20% increase in ATP bioluminescence was observed in normal cells during treatment with 40 micro M phenothiazines. In contrast, the phenothiazines manifested strong cytotoxicity and antiproliferative activity against leukemic cells. The most powerful drugs were TFPZ and TRDZ, followed by CPZ. They showed a significant cytotoxic effect against leukemic cells even at 5-10 micro M. The most sensitive cell lines were MOLT-4 and Raji, and the most resistant were HPB-ALL and CCRF-HSB-2. All phenothiazines induced PSer exposure on the surface of leukemic cells, but not of normal lymphocytes. TFPZ, TRDZ and CPZ also induced DNA fragmentation in almost all leukemic cell lines during a 48-h incubation. The strongest apoptotic agent was TRDZ. The apoptosis induction was not accompanied by a significant release of cytochrome c from the mitochondria into the cytoplasm of native cells. Moreover, the drugs markedly suppressed Ca(2+)-induced cytochrome c release in isolated mitochondria of leukemic cells. CONCLUSIONS: The results suggest that in clinically relevant doses (up to 20 micro M) some phenothiazines (TFPZ, TRDZ, CPZ) expressed a selective cytotoxicity and antiproliferative activity, and induced apoptosis in leukemic cells without any influence on the viability of normal lymphocytes. It is considered that the mechanism of apoptosis induction in phenothiazine-treated leukemic cells is associated with inhibition of mitochondrial DNA polymerase and decreased ATP production, which are crucial events for the viability of cancer cells.

Adenosine Triphosphate↗
PubMed1978

Benzamides and classical neuroleptics: comparison of their actions using 6 apomorphine-induced effects.

The effects of 6 benzamides and 8 classical neuroleptics were studied on 6 different apomorphine-induced effects. These drugs did not antagonize all the effects in the same way. The differences are discussed according to the two types of dopaminergic receptor hypothesis. Some apomorphine-induced effects (stereotyped behavior, circling behavior, climbing behavior, and increased motor activity) could be related to stimulation of one type of dopaminergic receptor, other effects (hypothermia and decreased activity) to the other type. Pimozide, sulpiride, thioproperazine, GRI 1665 and TER 1546, could block selectively one type of dopaminergic receptor, at least in a given range of doses. Clozapine, chlorpromazine, levomepromazine, and thioridazine, could block selectively the other type of dopaminergic receptor. Haloperidol, metoclopramide, prochlorperazine, sultopride, and tiapride, could block both types of dopaminergic receptors with equal intensity whatever the dose.

Animals↗
PubMedDate not supplied

Decreased concentration of high density lipoprotein cholesterol in schizophrenic patients treated with phenothiazines.

In chronic schizophrenic patients treated with phenothiazines (Chlorpromazine, Levomepromazine, Perphenazine) for long periods (average = 8 years), high density lipoprotein cholesterol (HDL-C) levels were significantly lower (P less than 0.001) compared with normal controls. The HDL subfractions showed that HDL3-C was significantly low (P less than 0.005) whereas HDL2-C was not. Both serum apo A-I and apo A-II levels were also low (P less than 0.005 and P less than 0.001, respectively) in schizophrenics treated with phenothiazines. The serum triglycerides (TG) level was significantly higher (P less than 0.05) in patients treated with phenothiazines than in controls. No significant differences in total cholesterol (TC), TG and HDL-C were found between users and nonusers of benzodiazepine in schizophrenic patients receiving phenothiazines. In addition to chronic schizophrenic patients, 8 new patients with schizophrenia and related diseases were studied. The serum HDL-C level decreased by 24% within 1 week following administration of phenothiazines. No significant differences were found in TC and TG levels for 10 weeks after initiation of phenothiazine administration.

Adult↗
PubMed1989

Isolation-induced social behavioral deficit test: effect of tranquilizing drugs.

Mice were reared in isolation for one week. Then, one isolated and one group-reared mouse were observed together under an inverted beaker for two minutes. The number of escape attempts of the isolated mouse were half of those of the grouped mouse. This is considered as a social behavioral deficit. The present study was undertaken to assess the effect of neuroleptics and various anxiolytic agents on this behavioral deficit. Neither acute administration of chlorpromazine, levomepromazine, sulpiride, flupentixol, pipotiazine, pimozide and haloperidol nor the subchronic (5 days) administration of flupentixol, pipotiazine and pimozide impaired the behavioral deficit. Diazepam and triazolam increased, chlordiazepoxide, hydroxyzine and buspirone did not modify the behavioral deficit. It is concluded that neuroleptics and anxiolytic agents did not impair the isolation-induced social behavioral deficit either because of inadequate doses or duration of administration or because this behavioral state is unresponsive to neuroleptics and anxiolytic agents.

Animals↗
PubMed1989

Doubleblind evaluation of the antimanic properties of carbamazepine as a comedication to haloperidol.

1. Today carbamazepine is the most important alternative to neuroleptic drugs for the treatment of manic psychoses. Often carbamazepine is administered as a comedication to a neuroleptic. 2. A doubleblind study with 20 patients suffering from manic or schizomanic psychoses was performed to determine whether carbamazepine and haloperidol in comedication are more effective than haloperidol alone. 3. Under the tested conditions (24 mg haloperidol p.d.) only the smaller amount of additional medication with levomepromazine in the experimental group gave evidence for the antimanic effect of carbamazepine in combination with haloperidol. 4. Especially the patients with pure manic psychoses seem to benefit from carbamazepine as an adjunct to haloperidol.

Adult↗
PubMed1986

Variation in the ability of neuroleptics to block the inhibitory influence of dopaminergic neurons on the activity of cells in the rat prefrontal cortex.

The stimulation of the ventro-medial mesencephalic tegmentum (VMT) induces an inhibition of the spontaneous activity of prefrontal cortical cells and blocks the excitatory responses evoked by the stimulation of the medio-dorsal nucleus of the thalamus (MD). This effect is mediated by the activation of the mesocortical dopaminergic (DA) system. In the present study, the influence of the systemic administration of several neuroleptics on the inhibition of prefrontal cortical cells induced by VMT stimulation has been analyzed in ketamine anaesthetised rats. The acute IP administration of fluphenazine (2 mg/kg), spiroperidol (2 mg/kg) or (+/-)sulpiride (100 mg/kg) reversed the inhibitory responses. Moreover, the number of cortical cells inhibited by VMT stimulation was considerably decreased after these treatments. Surprisingly, neither haloperidol at any dose used (0.1 to 0.5 mg/kg IV or 0.5 to 5 mg/kg IP) nor levomepromazine (25 mg/kg IP) nor the long acting neuroleptic, pipotiazine palmitic ester (32 mg/kg SC) blocked the inhibitory effect of VMT stimulation and in fact they lengthened the duration of the inhibition. Finally, the inhibition of MD evoked spikes in prefrontal cortical cells produced by VMT stimulation was no longer observed after sulpiride but persisted after haloperidol administration. Our findings confirm that the mesocortico-prefrontal DA neurons exert an inhibitory influence on target cells but they reveal differences in the efficacy of neuroleptics in blocking this effect.

Animals↗
PubMed1992

Sensitive determination of phenothiazines in body fluids by gas chromatography with surface ionization detection.

Fourteen phenothiazine derivatives were tested for their detection by gas chromatography (GC) with surface ionization detection (SID). The sensitivity of GC-SID was highest with trimeprazine and levomepromazine, which contain aliphatic tertiary amino side chains, and lowest with thiethylperazine and thioproperazine, which contain sulphur residues. Chlorpromazine, trimeprazine and promazine showed excellent linearity between the SID response and the drug amount in the range 0.25-3.0 pmol on-column. Their detection limits were as low as ca. 5-10 pg (15-30 fmol) on-column (250-500 pg per ml of body fluid). A detailed procedure for isolation of phenothiazines from human whole blood and urine using Sep-Pak C18 cartridges, before the GC with SID, is also presented. The recoveries of the drugs (100 pmol), which were added to 1 ml of whole blood or urine, were more than 79%. The baselines remained steady as the column temperature was increased.

Chromatography, Gas↗
PubMed1993

Determination of chlorpromazine in human breast milk and serum by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) assay was developed for the determination of chlorpromazine in serum and human breast milk. Chlorpromazine in serum and human breast milk was extracted by a rapid and simple procedure based on C18 bonded-phase extraction, and a reversed-phase HPLC separation technique was developed. Chlorpromazine and levomepromazine as the internal standard were detected by ultraviolet absorbance at 254 nm. Determination was possible for chlorpromazine in the concentration range 10-300 ng/ml. The recoveries of chlorpromazine added to serum and human breast milk were 80.1-87.6 and 80.3-84.4%, respectively, with coefficients of variation of less than 10.2 and 7.8%. The method is applicable to drug level monitoring in the serum and human breast milk of patients treated with chlorpromazine.

Chlorpromazine↗