The conditional stimulation of rat organic cation transporter 2, but not its human ortholog, by mesoridazine: the possibility of the involvement of the high-affinity binding site of the transporter in the stimulation.

OBJECTIVES: To study the functional consequences of the human and rat forms of OCT2 in the presence of phenothiazines. METHODS: MDCK cells expressing human or rat OCT2 were established, and MPP+ transport was determined by uptake assays. Concentration dependency was studied for the stimulatory/inhibitory effects of phenothiazines on MPP+ transport. KEY FINDINGS: Among the 11 phenothiazines examined, the majority were found to have comparable effects on transporter function between the orthologous forms, while three phenothiazines, particularly mesoridazine, had complex impacts on transporter function. For rOCT2, mesoridazine stimulated transport at 0.1 and 1 µmMPP+ with the mesoridazine concentration-uptake curve becoming bell-shaped. This conditional effect became less pronounced at 30 µmMPP+, resulting in an inhibition curve with a typical profile. For hOCT2, mesoridazine behaved as a typical inhibitor of transporter function at all MPP+ concentrations, although the kinetics of inhibition were still affected by the substrate concentration. CONCLUSIONS: The conditional stimulation by mesoridazine in rOCT2, and the lack thereof in hOCT2, may be a manifestation of the interaction of phenothiazine with substrate binding at the high-affinity site of the OCT2. As OCT2 was previously indicated in some drug-drug interactions, the conditional stimulation of OCT2 and its potential species-differences may be of practical relevance.

Altering extracellular potassium concentration does not modulate drug block of human ether-a-go-go-related gene (hERG) channels.

1. Drug-induced block of the rapidly activating delayed rectifier K+ current (I(Kr)), encoded by human ether-a-go-go-related gene (hERG), has been linked to acquired long QT syndrome (aLQTS). Hypokalaemia is a recognized risk factor in aLQTS. To further understand why hypokalaemia is a risk factor in aLQTS, we examined the effect of [K+]o on drug block of the hERG potassium channel stably expressed in human embryonic kidney (HEK-293) cells using whole-cell voltage-clamp techniques. 2. The effects of selected [K+]o (1-20 mmol/L) on hERG block with four structurally diverse compounds (dofetilide, mesoridazine, quinidine and terfenadine) from different therapeutic classes were evaluated. Reducing [K+]o from 20 to 1 mmol/L had little effect on IC50 values for hERG current block for all four compounds. For example, evaluating quinidine in external potassium concentrations of 20, 10, 5 and 1 mmol/L resulted in IC50 values of 1.82 +/- 0.33, 2.04 +/- 0.28, 1.57 +/- 0.52 and 1.14 +/- 0.21 mmol/L, respectively. No statistically significant difference (P > 0.35, anova) was observed between drug block of hERG in different external potassium concentrations. These data are in contrast with previously reported results examining hERG channel modulation expressed in AT-1 cells under similar experimental conditions. 3. These results demonstrate that [K+]o does not directly modulate drug block of hERG channels expressed in an HEK-293 cell line. The enhanced risk of Torsades de Pointes associated with hypokalaemia in aLQTS may be due to reduction of other (non-hERG) potassium currents, further reducing the repolarization reserve, and not due to direct modulation of hERG block by [K+]o.

Mesoridazine: an open-channel blocker of human ether-a-go-go-related gene K+ channel.

Mesoridazine, a phenothiazine antipsychotic agent, prolongs the QT interval of the cardiac electrocardiogram and is associated with Torsade de pointes-type arrhythmias. In this study, we examined the effects of mesoridazine on human ether-a-go-go-related gene (HERG) K+ currents. HERG channels were stably expressed in human embryonic kidney 293 cells and studied using standard whole-cell patch-clamp technique (37 degrees C). Mesoridazine blocked HERG currents in a concentration-dependent manner (IC50 550 nM at 0 mV); block increased significantly over the voltage range where HERG activates and saturated at voltages eliciting maximal HERG channel activation. Tonic block of HERG current by mesoridazine (1.8 microM) was minimal (< 2-4%). The rate of the onset of HERG channel block was rapid and dose dependent (tau = 54 +/- 7 ms at 0 mV and 1.8 microM mesoridazine), but not significantly affected by test potentials ranging from -30 to +30 mV. The V1/2 for steady-state activation was shifted from -31.2 +/- 1.0 to -39.2 +/- 0.5 mV (P < 0.01). The apparent rate of HERG channel deactivation was significantly reduced (fast tau = 153 +/- 8 vs. 102 +/- 6 ms at -50 mV, P < 0.01; slow tau = 1113 +/- 63 vs. 508 +/- 27 ms, P < 0.01). The inactivation kinetics and voltage dependence of steady-state inactivation of the HERG channel were not significantly altered by mesoridazine. These findings demonstrate that mesoridazine is a potent and rapid open-channel blocker of HERG channels. This block would explain the QT prolongation seen clinically at therapeutic concentrations (0.3-3.6 microM).

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país

Neuroleptics and learning: effects of haloperidol, molindone, mesoridazine and thioridazine on the behavior of pigeons under a repeated acquisition procedure.

The purpose of the present study was to examine the effects of haloperidol (0.3-10 mg/kg), molindone (0.3-5.6 mg/kg), mesoridazine (0.3-10) and thioridazine (0.3-25 mg/kg) on the behavior of pigeons exposed to a repeated acquisition procedure. At sufficiently high doses, each of these neuroleptics increased error rates (interfered with learning) and reduced rate of responding. When the drugs were compared on the basis of absolute doses administered, haloperidol disrupted behavior at doses considerably lower than the other drugs. If, however, chlorpromazine equivalent doses were examined, haloperidol was the least disruptive of the four drugs. Comparing the degree of behavioral disruption produced by the four drugs with their relative neuroreceptor affinities for dopamine D-2, cholinergic muscarinic, histamine H1, alpha-1 adrenergic and alpha-2 adrenergic receptors suggests that behavioral disruption cannot be attributed in any simple way to dopamine or acetylcholine receptor blockade. The relationship between the behavioral effects of neuroleptics and their simple neuropharmacological actions must be considered as highly tentative.

Comparative antidopaminergic properties of thioridazine, mesoridazine and sulforidazine on the corpus striatum.

The functional antidopaminergic potencies of the atypical antipsychotic drug thioridazine (THD), as well as its active metabolites mesoridazine (MES) and sulforidazine (SUL), were assessed by testing their blockade of the inhibitory effects of endogenous dopamine (DA) or apomorphine on the electrically evoked release of radiolabeled DA and acetylcholine (ACh) from perfused rabbit striatal slices. These functional comparisons (reflecting presynaptic and postsynaptic DA receptors, respectively) were correlated with potency estimations of these drugs in competing for D2 DA receptors (i.e., [3H]spiperone binding sites) in rabbit striatal homogenates. Similar orders of potency (SUL greater than MES much greater than THD) were found for blockade of pre- and postsynaptic DA receptors modulating DA and ACh release, respectively, as well as in competing for [3H]spiperone binding sites in the striatum. MES, SUL and haloperidol were 2 to 3 times more potent at DA release modulatory receptors than postsynaptic DA receptors. In contrast, THD was 8 times more potent at antagonizing the apomorphine-induced inhibition of DA release than against apomorphine's effect on ACh release. THD was virtually inactive in antagonizing the inhibition of ACh release induced when nomifensine was used to increase endogenous synaptic DA, despite significantly antagonizing these effects on DA release in the same slices. Together, these data indicate that: 1) MES and SUL are responsible for a significant part of the antidopaminergic effects attributed to THD; 2) THD should produce less cholinergic activation than other neuroleptics; and 3) that nonreceptor-mediated effects at high THD concentrations may mask effects due to receptor blockade.

Comparative anticholinergic properties of thioridazine, mesoridazine and sulforidazine.

The anticholinergic properties of thioridazine (THD) and its metabolites mesoridazine (MES) and sulforidazine (SUL) were compared to the antimuscarinics atropine and quinuclidinylbenzilate (QNB). THD, MES and SUL were virtually inactive in antagonizing the carbachol-induced inhibition of evoked ACh release from perfused rabbit striatal slices. This lack of effect was seen even when dopamine influences were abolished by treatment with reserpine and alpha-methyl-p-tyrosine. The lack of functional anticholinergic potency contrasted with the affinity of THD for muscarinic receptors measured as competition for [3H]QNB binding sites in striatal homogenates (Ki values: atropine, 2.7 nM; THD 14 nM; SUL, 66 nM; and MES, 90 nM). Both atropine and QNB blocked carbachol-induced inhibition of ACh release in a dose-dependent manner (IC50 values vs. 3 microM carbachol: 0.5 nM for QNB; 1.25 nM for atropine). THD, only 5 times less potent than atropine in competing for [3H]QNB binding sites, was inactive in antagonizing carbachol-induced ACh release. At very high concentrations (3-30 microM), THD, MES and SUL did enhance dopamine efflux and inhibit ACh release. In summary, the lack of effect of THD on release modulatory muscarinic receptors suggest that THD is selective for the M1 subtype. Because the M2 subtype is a small fraction of the total population in the striatum, it is not surprising that they would escape recognition in the QNB binding assays. These data suggest that inhibition of ACh release may contribute to the actions of THD only at very high doses, or when drug accumulation is abnormal.

Greater potency of mesoridazine and sulforidazine compared with the parent compound, thioridazine, on striatal dopamine autoreceptors.

The electrically evoked overflow of dopamine (DA) from perfused rabbit striatal slices was used to assess the relative functional potencies of thioridazine, a phenothiazine antipsychotic agent, and two of its major metabolites, mesoridazine (thioridazine-2-sulfoxide) and sulforidazine (thioridazine-2-sulfone). Thioridazine (1000 nM) enhanced the electrically evoked overflow of DA by 18.3 +/- 4.6% (n = 4) at 0.3 Hz. Mesoridazine and sulforidazine likewise produced only small increases (5-20%) in evoked overflow of DA from slices stimulated at 0.3 Hz. At this frequency of stimulation, apomorphine (30 nM) inhibited the overflow of DA by 71.4 +/- 8.43% (n = 40). All three drugs antagonized, in a concentration-dependent fashion, the inhibitory effect of apomorphine (30 nM) on electrically evoked DA release at 0.3 Hz. The IC50 for thioridazine for antagonizing the effect of apomorphine was 130 nM, whereas that for mesoridazine was 14.4 nM and for sulforidazine was 6.1 nM. These results indicate that thioridazine and its two clinically active metabolites can block striatal DA autoreceptors involved in modulating DA release. The observation that mesoridazine and sulforidazine were significantly more potent than the parent drug is consistent with the hypothesis that a major part of the pharmacologic responses to thioridazine may be a consequence of its metabolism to active compounds.

The effects of nortriptyline and mesoridazine on neurons and glia in vitro.

The ultrastructural changes produced by Mesoridazine and Nortriptyline in neurons and glia in vitro are reported. Concentrically laminated bodies (CLB) and increased numbers of dense bodies were produced by exposure to these drugs. The number and complexity of the CLB increased with increased dose and longer time in vitro and their formation appeared to be reversible.

Mesoridazine (Serentil) in personality disorders--a controlled trial in adolescent patients.

A double-blind study vs. placebo was carried out over a 6-week period in thirty adolescent patients to determine the efficacy and safety of mesoridazine, in the form of 10 mg tablets, in the treatment of symptoms associated with various personality disorders. The average daily dose for the 15 patients in the mesoridazine group was 27.3 mg in the first and 44.7 mg in the sixth week. Mesoridazine relieved anxiety to a highly significant degree when compared with placebo and proved significantly more effective than placebo also in terms of mean improvement scores for depression and hostility. Significant reductions were likewise achieved in the overall severity of the disorders and in the severity of nearly all the other symptoms. The incidence of adverse reactions did not differ significantly from that following placebo administration. No extrapyramidal symptoms were noted.

Mesoridazine and human sleep.

1 Mesoridazine, a phenothiazine of short half-life, and potentially useful as an hypnotic, has here been investigated using volunteers of late middle age. 2 The electrophsiological recording of all-night sleep was studied in seven subjects for a 7-week period during which ther received mesoridazine (10 mg nightly) for 3 weeks. The drug reduced the frequency of transitions into wakefulness and stage 1 (drowsiness) and reduced the time spent in stage 1; there was a withdrawal rebound. Mesoridazine increased REM sleep above baseline levels and a rebound fall below baseline occurred on withdrawal. The drug did not alter the amount of stage 3 + 4 slow wave sleep. 3 Subjective self-ratings were assessed in a 6-week study of sixteen subjects. Sleep quality improved on mesoridazine (10 mg nightly) but there was diminution of zest and freshness 20 min after rising. Daytime concentration and anxiety were rated as not affected either by administration or withdrawal.

Polygraphic sleep studies in rats and humans: their use in psychopharmacological research.

The effects of selected centrally acting drugs on sleep after single administration to rats and humans were studied using polygraphic sleep recording techniques. D-Amphetamine, a stimulant, had similar effects in both species: reduction of total sleep time, of N(non-)REM- and particularly REM (rapid eye movement)-sleep, increased restlessness during sleep. The psychodepressants mesoridazine and, in particular, nitrazepam had relatively little effects on sleep stages. In doses which did not cause side effects they reduced restlessness during sleep. The most typical effect of the antidepressant imipramine was a dose dependent reduction of REM-sleep duration in both species, without impairment of NREM-sleep. The central dopamine agonist, bromocriptin, had little effect on sleep and did not reduce total sleep and REM-sleep. These examples suggest that polygraphic sleep studies are a sensitive and stable method for the study of centrally acting drugs. The specificity of the model is illustrated by its ability to differentiate chemically and pharmacologically different drug classes. The validity of the model, i.e., its ability to allow predictions from the laboratory conditions to the therapeutic situation, varies in different drug classes. Investigations in normal subjects and animals appear to be relevant for the study of CNS-stimulants, whereas for CNS-depressants studies in sleep-disturbed subjects or animals are more likely to provide dependable results.

Effect of mesoridazine administration and withdrawal on performance in an older age group.

Seven subjects, aged 48-62 years, took a placebo capsule nightly for 3 weeks, mesoridazine 10 mg for 3 weeks, and then placebo for 3 weeks. Mesoridazine is a short half-life phenothiazine useful as a hypnotic. Performance was assessed during three experimental sessions on each test day. In spite of subjective sleepiness 20 min after rising, psychomotor performance 1-3 h later was not imparied, except possibly manual dexterity after the first dose. Neither auditory vigilance, nor digit symbol substitution were affected noticeably by the drug at any time of day. Card sorting of varying degrees of complexity was unimpaired, though there was a suggestion that the drug might be associated with better performance on the most complex task.