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At least 19 recordsLinked to original sources
PubMed1993

The metabolism of piperidine-type phenothiazine antipsychotic agents. III. Mesoridazine in dog, human and rat.

1. The metabolism of mesoridazine was studied in female rats (20 mg/kg, oral), female dogs (50 mg over 30 h, oral) and adult male volunteers (25 mg, oral). 2. Solvent extracts of urines from each species were directly analysed by h.p.l.c.-mass spectrometry with a plasmaspray interface. In the case of phenolic metabolites the urinary extracts were derivatized with a silylating reagent (with and without prior enzymic hydrolysis) prior to analysis. The structures of metabolites, with the exceptions of mesoridazine N-oxide and phenols, were confirmed by comparison of their chromatographic behaviours and mass spectra with those of authentic standards. 3. Compounds identified in the urine of all three species were mesoridazine, sulforidazine, mesoridazine ring sulphoxide, sulforidazine ring sulphoxide, N-desmethylmesoridazine ring sulphoxide, the lactam of sulforidazine ring sulphoxide and phenolic derivatives of mesoridazine and sulforidazine. Whereas the unconjugated phenolic metabolite of sulforidazine was present in urine of all three species, the conjugated form was identified only in dog and rat urines. Also, the unconjugated phenolic metabolite of mesoridazine was identified only in the urine of dog and human, but rat urine contained only the conjugated form. 4. Other metabolites found were: the lactam of mesoridazine (rat), the lactam of mesoridazine ring sulphoxide (rat and human), mesoridazine N-oxide (human) and sulforidazine N-oxide (dog and human). 5. Mesoridazine and six of its metabolites present in urines of human, rat and dog were quantified by a h.p.l.c.-u.v. method. The mean total excretion of measured analytes in human, rat and dog were 6.3, 2.6 and 29.1%, respectively. The excretion of the lactam of sulforidazine ring sulphoxide was greater in human (0.4%) and rat (0.2%) than dog (0.02%). Moreover, the urinary excretion of the lactam of mesoridazine ring sulphoxide in human and rat constituted 0.4% and 0.2%, respectively. Of the three lactams found in rat the lactam of mesoridazine was present in the least amount (0.05%). 6. Interspecies comparison of the lactam metabolites indicated that both qualitatively and quantitatively human more closely resembled rat than dog. On the other hand, N-oxide metabolites were detected in human and dog but not in rat.

Adult↗
PubMed2004

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).

Cell Line↗
PubMed1986

Mesoridazine and thioridazine: clinical effects and blood levels in refractory schizophrenics.

Seven schizophrenic (according to DSM-III criteria) inpatients completed a two-phase study; each phase had a 1-week drug-free period followed by 6 weeks of a drug trial. The first phase uniformly involved treatment with chlorpromazine, and in the second phase patients received either mesoridazine (N = 3) or thioridazine (N = 4). Clinical ratings (Brief Psychiatric Rating Scale and Clinical Global Impressions) and neuroleptic blood levels were obtained weekly throughout the study. Whereas patients failed to respond to chlorpromazine 1800 mg/day, response to mesoridazine 400 mg/day and to thioridazine 800 mg/day was established on all Brief Psychiatric Rating Scale factors except for anxiety-depression. A higher neuroleptic blood level was achieved with mesoridazine or thioridazine at less than half the reference chlorpromazine dosage. Correlations between neuroleptic blood level and clinical response were positive for mesoridazine, negative for chlorpromazine, and nonsignificant for thioridazine. These findings are consistent with earlier research. We conclude that drug-resistant schizophrenics seem to improve clinically with mesoridazine or thioridazine, unlike with chlorpromazine, and that for mesoridazine this difference may be a function of selective dopamine receptor blockade.

Adult↗
PubMed1984

Red blood cell and plasma levels of thioridazine and mesoridazine in schizophrenic patients.

Thioridazine and mesoridazine levels and levels of thioridazine plus metabolites were determined in plasma and red blood cells (RBC) by gas-liquid chromatography (GLC) and spectrofluorometry (SP), respectively, in schizophrenic patients treated with fixed doses of thioridazine. There was wide interpatient variability in RBC:plasma ratios for thioridazine and mesoridazine, a higher ratio of thioridazine to mesoridazine in RBC than plasma, and a higher ratio of GLC total (thioridazine plus mesoridazine), to SP-determined total drug constituents in RBC than in plasma. RBC showed a monotonic increase in drug levels with dose, whereas levels of drug in the plasma began to level off above the 250 mg/day dose. Drug levels 24 h after the acute dose did not predict steady-state blood levels in plasma or RBC.

Adolescent↗
PubMed1987

Development of a radioimmunoassay procedure for mesoridazine and its comparison with a high-performance liquid chromatographic method.

A radioimmunoassay (RIA) procedure for mesoridazine was developed using an antiserum raised in rabbits immunized with N-(2-carboxyethyl) desmethylmesoridazine-porcine thyroglobulin conjugate. The RIA procedure enabled the quantitation of 40 pg of mesoridazine in a 200-microliters human plasma sample with a coefficient of variation of less than 5%. Except for N-desmethylmesoridazine, the antiserum showed no marked cross-reaction with any of the other available potential cross-reactants. Furthermore, statistically indistinguishable results were obtained for the determination of mesoridazine in the presence or absence of a fivefold excess of thioridazine or sulforidazine. This RIA procedure was compared with a high-performance liquid chromatographic (HPLC) method by determining concentrations of mesoridazine in plasma samples from human volunteers over 72 h after administration of single 50-mg oral doses of thioridazine hydrochloride. Good correlation existed between the assay values (n = 55) determined by the RIA and HPLC methods (r2 = 0.940), but the slope of the regression line was significantly different from 1.0 (p less than 0.05, when RIA values were plotted on the gamma axis and HPLC values were plotted on the chi axis; p less than 0.001, when HPLC values were plotted on the gamma axis and RIA values were plotted on the chi axis). The plot of the differences between these two assay values against the average of the assay values showed, however, that the differences were independent of the concentration range studied. Moreover, statistically favorable comparisons were obtained for area under the plasma level/time curve to 48 h (AUC0(48)), Cmax, and Tmax calculated from the data obtained by the two methods.

Animals↗
PubMed1976

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.

Aged↗
PubMed1984

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.

Animals↗
PubMed1984

Partitioning of thioridazine and mesoridazine in human blood fractions.

The partitioning of 3H-thioridazine and 3H-mesoridazine in fresh human whole blood was studied. The packed red blood cells were solubilized using the New England Nuclear protocol for whole blood solubilization. The plasma fraction was further fractionated into protein bound and free drug by molecular ultrafiltration. All solutions were counted in Biofluor LSC cocktail and corrected for quenching. Greater than 99% of the labeled drug was bound to the red blood cells and plasma protein. For thioridazine, 59% is bound to RBC, 41% is bound to plasma protein and 0.7% is free; for mesoridazine, 63% is bound to RBC, 37% is bound to plasma protein and 0.9% is free. Though substantial overlap is found in the bound percentage for mesoridazine and thioridazine, more mesoridazine binds to RBC than thioridazine (p less than 0.01). There is no statistically significant relationship between the amount of drug bound to the RBC or to plasma protein and the percent free drug. Though the total drug concentration is the same (1 microgram/ml) the percent free drug is quite variable across subjects by as much as a factor of three. Since free drug is the pharmacologically active portion and therefore determinant of clinical response, the reported variation in free drug concentration at the same total blood concentration invalidates the measurements of total serum or plasma drug concentration as predictive of clinical response.

Blood Proteins↗
PubMed1981

Mesoridazine -- a pharmacodynamic and pharmacokinetic profile.

Available data on the clinical effectiveness and side effects of mesoridazine are reviewed, and an attempt is made to relate clinical efficacy to phenothiazine pharmacokinetics. Both controlled and open-label clinical studies have attested to the efficacy of mesoridazine in schizophrenia, as well as certain other psychiatric disorders. Clinical observations of the effectiveness of mesoridazine in patients refractory to treatment with thioridazine and other neuroleptics may be related to its slow rate of inactivation and to the relatively large proportion of free mesoridazine that is available for penetration to the target sites in the brain.

Biological Availability↗
PubMed1977

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.

Adolescent↗
PubMed1987

Rapid death resulting from mesoridazine overdose.

A 23-year-old mentally retarded woman was brought to the emergency department 2-2.5 hr after ingesting an unknown quantity of mesoridazine. She was lethargic and somewhat uncooperative, but did answer questions. Her ECG was normal. She was treated with gastric lavage, 50 g activated charcoal, and 10 oz magnesium citrate solution. Her condition continued to decline until, at 2 hr after arrival, she was comatose and becoming increasingly hypotensive. Her ECG showed long runs of markedly widened QRS complexes. The patient was given an iv infusion of dobutamine to maintain blood pressure. She suffered a convulsion, loss of blood pressure, and developed ventricular tachycardia which progressed to ventricular fibrillation unresponsive to electrical cardioversion, pacing, and vigorous prolonged CPR. She was pronounced dead 6-6.5 hr after the ingestion. Antemortem blood level of mesoridazine was 16 micrograms/ml and no other drugs were detected. While sudden deaths have been reported with therapeutic doses of mesoridazine and its parent thioridazine, deaths are uncommon in overdose. Rapid death seen in this case emphasizes the importance of close monitoring and aggressive treatment of phenothiazine overdoses.

Adult↗
PubMed1976

GLC analysis of thioridazine, mesoridazine, and their metabolites.

A GLC method for measuring thioridazine, mesoridazine, their metabolites, and possibly other phenothiazines was developed. By using this method, seven different phenothiazine derivatives, thioridazine, and six known thioridazine metabolites were extracted and separated. This method was tested by assaying plasma samples from 30 hospitalized psychiatric patients receiving thioridazine or mesoridazine.

Chromatography, Gas↗
PubMed1981

Cardiac conduction and rhythm disturbances following suicidal ingestion of mesoridazine.

The phenothiazine derivatives, particularly chlorpromazine and thioridazine, are known to produce significant electrocardiographic abnormalities. Until now, documented life-threatening arrhythmias have not been reported following large doses of mesoridazine, the besylate salt of a metabolite of thioridazine and a relatively recent addition to the phenothiazine group. We describe such a case in which alterations in both impulse conduction (first-degree atrioventricular block, prolonged QRS duration, and right axis deviation) and impulse formation (supraventricular and ventricular tachycardia) were noted following a suicidal ingestion of mesoridazine. The electrophysiologic mechanisms underlying phenothiazine-induced arrhythmogenesis are reviewed.

Adult↗
PubMed1988

Cardiotoxic manifestations of mesoridazine overdose.

We present a case of malignant arrhythmias associated with hypocalcemia and subsequent cardiac arrest in a 20-year-old woman due to ingestion of 3.1 g mesoridazine in a suicide attempt. There were unexplained alterations in serum electrolytes preceding the cardiac arrest. The patient subsequently recovered and was transferred to a psychiatric hospital. Despite the paucity of data on the potential cardiotoxicity associated with mesoridazine overdose, this case demonstrates that malignant arrhythmias and cardiac arrest occur; consequently, these patients probably require constant ECG monitoring.

Adult↗
PubMed1987

Synthesis and properties of haptens for the development of radioimmunoassays for thioridazine, mesoridazine, and sulforidazine.

For the separate development of radioimmunoassay procedures for thioridazine and its two major active metabolites, mesoridazine and sulforidazine, three haptens, respectively, 2-methylthio-, 2-methylsulfinyl-, and 2-methylsulfonyl-substituted 10-[2-[1-(2-carboxyethyl)-2-piperidinyl]ethyl]-10H-phenothiazine, were synthesized and characterized. Thioridazine hapten was coupled to bovine serum albumin, whereas the haptens for mesoridazine and sulforidazine were coupled to porcine thyroglobulin. The number of hapten residues per mole of carrier protein was determined in each case by an ultraviolet spectrophotometric method. Polyclonal antibodies to each hapten-protein conjugate were obtained in rabbits, and titers of the antisera were checked by evaluating their binding characteristics to the appropriate tritiated analyte. A hapten for the ring sulfoxide metabolite of thioridazine was also synthesized.

Animals↗
PubMed1975

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.

Age Factors↗
PubMed2004

Diastereotopic analysis of mesoridazine besylate (Serentil).

NMR studies were conducted with the aim of determining the diastereoisomeric ratio of a commercially supplied sample of mesoridazine (MES) and to compare the results with a freshly synthesised sample of MES. The results indicated that the commercially supplied MES consisted almost entirely of one diastereoisomeric pair, which was in agreement with previous findings reported by Eap et al. The synthesised sample of MES was analysed by NMR in two stages: 1) as the initial product isolated as the free base from the direct synthesis, and 2) as the free base isolated from the crystallised besylate salt of the synthetic product. The NMR results show that the initial synthetic product consisted of two equal pairs of diastereoisomers. The diastereoisomeric pairs were further separated by the addition of the chiral shift reagent (R)-(-)-N-(3,5 dinitrobenzoyl)-alpha-benzylamine to reveal equal quantities of all four enantiomers, clearly observed at the methyl sulfoxide proton peak of the NMR scan. The sample obtained from the crystallisation of MES besylate, however, indicated a significant difference, with a diastereoisomeric ratio of 75:25. The results suggest that MES besylate undergoes preferential crystallisation of one pair of diastereoisomers, with the other pair remaining in solution.

Crystallization↗