The Effect of Thioridazine and Promazine on the Isolated Contracting Rat Heart

Landmark, Knud; Glomstein, Anders; Øye, Ivar

doi:10.1111/j.1600-0773.1969.tb00504.x

Cited by 24 publications

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References 6 publications

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“…Recently LANDMARK et al (1969) and LANGSLET (1969) showed that the tranquilizing phenothiazine derivatives produced similar ECG-changes in the isolated perfused rat heart. Following the addition of different phenothiazine derivatives to the perfusion medium they found a dose dependent decrease in rate and impulse conduction velocity, and in higher doses, also various degrees of AV-block.…”

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ECG‐Changes Induced by Phenothiazine Drugs in the Anaesthetized Rat

Langslet

1970

Acta Pharmacologica et Toxicologica

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Absrruct:The ECG has been recorded in barbiturate anaesthetized rats during intravenous infusion of levomepromazine, chlorpromazine, prochlorperazine and perphenazine. All the drugs decreased impulse-generation and propagation in the heart. The magnitude of the changes in heart rate, PQ-QRS-and QT-time was dose dependent, and the relative order of potency of the drugs was as follows: 1. perphenazine and prochlorperazine, 2. chlorpromazine and 3. levomepromazine. Perphenazine, prochlorperazine, chlorpromazine and levomepromazine in 2.5 X 10-5 M concentration increased the PQ-time to about 130 % , 128 % , 122 % and 117 % respectively, of the PQ-time before infusion. The magnitude of the changes in rate, QT-and QRS-intervals was in the same range. At higher concentrations, all the drugs caused AV-block of variable degree. Qualitatively these changes are similar to those induced by the drugs in the isolated perfused rat heart; quantitatively, however, these in vivo findings do not correspond to the in vitro findings recently described by the present author. Levomepromazine which in vitro was unique in changing the ECG-pattern at much lower concentrations than the other phenothiazine derivatives, is less potent than perphenazine, prochlorpromazine and chlorpromazine in vivo. Possible explanations for this discrepancy are discussed.

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confidence: 98%

ECG‐Changes Induced by Phenothiazine Drugs in the Anaesthetized Rat

Langslet

1970

Acta Pharmacologica et Toxicologica

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“…It has been shown that several phenothiazine derivatives exert a negative inotropic influence on isolated heart preparations ( MELVILLE & DRAPEA~J 1958;HAMACHER .& HILDEBRANDT 1964;LANDMARK et al 1969). It seems possible that a reduction in the strength of the contractions may be the cause of the reduced K' loss as has been discussed by PAK et al (1966).…”

Section: K N U D Landmarkmentioning

confidence: 97%

“…perfusate ( LANDMARK et al 1969;LANGSLET 1969). The cardiac effect of these drugs thus appears to be independent of intact nervous and hormonal influences.…”

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The Effect of Thioridazine and Promazine in Reducing the Potassium Loss from Isolated Perfused Rat Hearts

Landmark

1971

Acta Pharmacologica et Toxicologica

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A bstruct: Electrically stimulated isolated rat hearts were perfused with a Ringer solution containing a low concentration of K+. At the end of a control period of 20 min. the cumulative K+ loss from the hearts was approximately 30 meq./kg dry weight. This value was used in each experiment as reference (100 per cent) for the total loss found after a subsequent additional test period of 30 min. The addition of promazine and thioridazine to the perfusate at the end of the control period reduced the further K+ loss. The values found in the different groups at the end of the test period were: Control group (10 hearts): 154 f 11.6 per cent; with promazine 10-6 M added (8 hearts): 103 f 5.6 per cent; with promazine 2.5 X 10-5 M added (10 hearts): 74 f 10.5 per cent and with thioridazine 10-5 M added (8 hearts): 110 f 5.8 per cent. In another type of experiments, ouabain 1.5 X 10-0 M was added at the end of the control period. This drug caused an increased K+ loss (181 f 14.2 per cent) and ventricular fibrillation in 6 out of 8hearts. Promazine 2.5 X 10-6 M added before ouabain, prevented the development of fibrillation in another group of 7 hearts, and also markedly reduced the K+ loss, It is concluded that phenothiazines reduce the K+ permeability of the heart muscle membranes.

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Facile Syntheses of the Three Major Metabolites of Thioridazine

Morrow

Millership

Collier

2005

Helvetica Chimica Acta

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Efficient, mild syntheses of the three major metabolites 2 ± 4 of the important antipsychotic drug thioridazine (1) have been developed. The cardiotoxic metabolite 2 with a ring sulfoxide moiety was prepared in 96% yield by oxidation of 1 with NaIO 4 under acidic conditions. Four different procedures were elaborated for the selective side-chain sulfide oxidation of 1 to mesoridazine (3), giving rise to yields of up to 91%. Finally, sulforidazine (4) was synthesised via oxidation of the sulfoxide 3 in the presence of either KMnO 4 or t-BuOOH under basic conditions. Except for the oxidation with t-BuOOH, all reactions took place under mild conditions within a few minutes, were nicely reproducible, and afforded medium-to-high yields of the desired products, which could be readily purified by column chromatography.Introduction. ± Thioridazine (1) 1 ) is a chiral, tricyclic drug used in racemic form for the treatment of schizophrenia and other psychiatric disorders, and produces few extrapyrimidal side effects (a regular side effect in antipsychotic therapy) [1 ± 2]. Like all other antipsychotic agents, the ability of 1 to alleviate psychotic symptoms is attributed to antagonistic blocking of central dopamine receptors, which compensates for the overactivity of this neurotransmitter [3]. However, the individual enantiomers of 1 have been shown to produce significantly different pharmacologic effects. Several authors have reported a difference in the distribution of the enantiomers in blood plasma and in various human tissues [4 ± 6]. Furthermore, it has been shown that ()-(R)-thioridazine ((R)-1; see Scheme) has a 2.7-times higher affinity than the (À)-(S)-isomer for the important D 2 receptors, which are most strongly related to alleviation of psychotic symptoms in rat brain [3].It has been recognised that the pharmacologic effects of thioridazine therapy are not only attributed to the parent drug, but also to the major metabolites: the ring sulfoxide 2, the side-chain sulfoxide mesoridazine (3), and the side-chain sulfone sulforidazine (4). All these compound are known to significantly contribute to the overall pharmacological profile of thioridazine-based drug therapy [7 ± 20]. In fact, compounds 3 and 4 have been shown to be ca. 50% more potent than the parent drug 1 [7 ± 10], and the ring sulfoxide 2, although not considered to contribute to the observed antipsychotic activity, is reported to be the major cause of cardiotoxic side effects associated with the administration of 1 [14 ± 20].Despite the importance of the metabolites 2 ± 4, there is still minimal information regarding the pharmacologic and pharmacokinetic effects of the isomers of these compounds, and there are currently only a few useful methods for their synthesis from

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The Effect of Thioridazine and Promazine on the Isolated Contracting Rat Heart

Cited by 24 publications

References 6 publications

ECG‐Changes Induced by Phenothiazine Drugs in the Anaesthetized Rat

ECG‐Changes Induced by Phenothiazine Drugs in the Anaesthetized Rat

The Effect of Thioridazine and Promazine in Reducing the Potassium Loss from Isolated Perfused Rat Hearts

Facile Syntheses of the Three Major Metabolites of Thioridazine

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