Hormonal and temperature responses to the 5-HT 1A receptor agonist flesinoxan in normal volunteers

Pitchot, William; Wauthy, Jacques; Hansenne, Michel; Pinto, Emmanuel; Fuchs, Sonia; Reggers, Jean; Legros, Jean-Jacques; Ansseau, Marc

doi:10.1007/s00213-002-1177-0

Cited by 21 publications

(15 citation statements)

References 36 publications

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“…In the studies reported by Young et al (19) and McAllister-Williams and Massay, (20), however, a decrease in core body temperature was observed for the placebo response which explains this poor prediction. Conversely, no such placebo response was observed in the studies conducted by Seletti et al (12) and Pitchot et al (13). For the cortisol response the rate of the increase was respectively under and over predicted for the high and the low dose of the studies reported by Seletti et al, and Pitchot et al Close inspection of Fig.…”

Section: Resultsmentioning

confidence: 81%

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Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

et al. 2007

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Purpose. The aim of the present study was to assess whether two widely used biomarkers for 5-HT 1A -receptor mediated responses in the rat (hypothermia and corticosterone increase) could be scaled to man using allometric principles. Materials and Methods. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models were developed and characterized in rats for the standard 5-HT 1A -receptor agonists, buspirone and flesinoxan. Allometric scaling was investigated on the basis of simulation taking into account the inter-individual variability and clinical study design. The model-predicted effects of both flesinoxan and buspirone were compared to those published in the literature. Results. The main finding of this analysis was that for both hypothermia and cortisol increase, the model could predict the extent of the pharmacological response in man adequately. For the hypothermic response, the time course of the response was also predicted with a high degree of accuracy. In contrast, in the case of the cortisol response, the observed time lag was, despite the fact that it fell within the model uncertainty, not predicted. Conclusions. Based on these analyses, it is concluded that allometrically scaled mechanism based PK-PD models are promising as a means of predicting the pharmacodynamic responses in man. This approach provides for a novel way of interpreting and scaling pre-clinical pharmacological responses and ultimately facilitates the understanding and prediction of pharmacological responses in man.

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Section: Resultsmentioning

confidence: 81%

“…Since few papers reported the actual body weight of the subjects, often healthy volunteers, a body weight of 70 kg was assumed. This is considered a reasonable assumption since the average body weight of the subjects in the studies reported by Seletti et al (12) and Pitchot et al, (13) were 73.2 and 73.8 kg, respectively.…”

Section: Methodsmentioning

confidence: 89%

Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

et al. 2007

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“…This relatively poor penetration appears to arise because flesinoxan is a substrate for P-glycoprotein, a multidrug transporter, which actively effluxes it from the brain at the blood-brain barrier (van der Sandt et al, 2001). In man, the evidence that flesinoxan crosses the bloodbrain barrier is indirect: it causes elevation of ACTH, cortisol, and growth hormone while reducing temperature by mechanisms that are believed to be centrally mediated (de Koning and de Vries, 1995;Pitchot et al, 2002;Seletti et al, 1995). Furthermore, a single 0.5 mg dose produces similar EEG activity to 20 mg buspirone (Solvay Pharmaceuticals, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…In rats, flesinoxan suppresses firing activity in dorsal raphe serotonergic neurons and dorsal hippocampus pyramidal neurons, and crosses the blood-brain barrier, albeit relatively slowly (Hadrava et al, 1995). In man, 1 mg intravenous flesinoxan produces a 5-HT 1A agonist profile: it significantly elevates adrenocorticotropic hormone, cortisol, growth hormone, and prolactin while reducing temperature (Pitchot et al, 2002;Seletti et al, 1995). A 1 mg oral dose behaves similarly but does not elevate prolactin (de Koning and de Vries, 1995).…”

Section: Introductionmentioning

confidence: 98%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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“…Finally, flesinoxan is a phenylpiperazine derivative initially developed as an antihypertensive [69]. This drug has total antagonism to 5-HT 1A -R with high affinity [70]. Various studies have demonstrated its antidepressant properties, particularly in treatment-resistant DDM patients [71].…”

Section: Serotonin -A Chemical Messenger Between All Types Of Living mentioning

confidence: 99%

Association of 5-HT1A Receptors with Affective Disorders

Soria-Fregozo¹,

Vega²,

FranciscoRodríguez-Landa³

et al. 2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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Serotonin or 5-hydroxytryptamine (5-HT) is synthesized in both the brain and peripheral system, which exert their actions at a wide family of receptors classified as 5-HT 1 to 5-HT 7 . Pharmacological, behavioral, and clinical studies involve particularly to the 5-HT 1A receptors (5-HT 1A -R) -auto-receptors (presynaptic) and heteroreceptors (postsynaptic) -in the control of motivated behavior, and consequently in the physiopathology of affective disorders and in the action mechanism of antidepressant drugs. In this way, some research support that 5-HT 1A -R participates in the delayed effect of different types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), and tricyclic drugs, principally. The therapeutic effect of serotonergic drugs as the SSRIs, starting with the binding to auto-receptors, which produces increases of 5-HT in the synaptic cleft as consequence of blockade of serotonin reuptake. While these molecular events occur initially, in the long-term are produced plastic changes at neuronal level, as well as down-regulation of the 5-HT 1A -R, which is associated with the therapeutic effects of antidepressant drugs. The purpose of this chapter is to analyze and discuss the current information about of 5-HT 1A -R-mediated signaling cascades, the intracellular signaling of 5-HT 1A -R, in addition to their expression and pharmacology that are important to treatment of affective disorders symptoms.

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Hormonal and temperature responses to the 5-HT 1A receptor agonist flesinoxan in normal volunteers

Cited by 21 publications

References 36 publications

Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Association of 5-HT1A Receptors with Affective Disorders

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