Pharmacokinetically Governed Design of Animal Toxicity Studies of a New Antidepressant Drug

Hümpel, M.; Kühne, G.; Lehmann, M.; Poggel, A.

doi:10.1007/978-3-642-71248-7_37

Cited by 11 publications

(4 citation statements)

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“…The cAMP-specific PDE4 has attracted considerable attention for the treatment of airway inflammatory diseases, since its inhibition results in attenuated inflammatory responses (1,3,4). However, the therapeutic potential of PDE4 inhibitors has been limited by the side effects of nausea and emesis, observed both in humans and in various animal species following the administration of structurally diverse compounds (5)(6)(7)(8)(9). A major challenge in the development of new generations of PDE4 inhibitors is the improvement of the therapeutic index of this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Robichaud¹,

Stamatiou²,

Jin³

et al. 2002

J. Clin. Invest.

261

138

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A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Robichaud¹,

Stamatiou²,

Jin³

et al. 2002

J. Clin. Invest.

261

138

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“…Emesis is a major side effect associated with inhibitors of type 4 cyclic nucleotide phosphodiesterase (PDE4). It has been reported in man and in various animal species endowed with a vomiting reflex (Horowski & Sastre‐Y‐hernandez, 1985; Humpel et al ., 1986; Heaslip & Evans, 1995; Silvestre et al ., 1998; Murdoch et al ., 1998; Robichaud et al ., 1999). Recently, our group postulated that PDE4 inhibitors were able to trigger the emetic reflex through a sympathetic pathway, by mimicking the pharmacological actions of a pre‐synaptic alpha 2 ‐adrenoceptor inhibition (Robichaud et al ., 2001).…”

Section: Introductionmentioning

confidence: 99%

Assessing the emetic potential of PDE4 inhibitors in rats

Robichaud

Savoie

Stamatiou

et al. 2002

British J Pharmacology

111

112

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1 Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha 2 -adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter eect since it appears to re¯ect the emetic potential of PDE4 inhibitors. 2 Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg ]-substance P (NK 1 receptor agonist, 6 mg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5 In summary, this model is functionally coupled to PDE4, speci®c to alpha 2 -adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.

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“…Aus Versuchen an Ratten mit wiederholter oraler TBTO-Gabe wurde berechnet, dass das Fließgleichgewicht nach etwa vier Wochen erreicht ist (Hümpel et al 1987).…”

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“…27% und daraus eine ungefähre dermale Penetrationsrate von 0,9 mg TBTO cm 2 und Stunde bzw. 0,36 mg Zinn/cm 2 und Stunde(Hümpel et al 1987). Eine reizende Wirkung auf die Haut…”

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n‐Butylzinnverbindungen [MAK Value Documentation in German language, 2012]

2012

The MAK‐Collection for Occupational Health and Safety

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Pharmacokinetically Governed Design of Animal Toxicity Studies of a New Antidepressant Drug

Cited by 11 publications

References 0 publications

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Assessing the emetic potential of PDE4 inhibitors in rats

n‐Butylzinnverbindungen [MAK Value Documentation in German language, 2012]

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