Disease relevance of Gepirone

• We tested the full agonists Bay R 1531 and 8-OH-DPAT and the partial agonists ipsapirone and gepirone in the model of transient global ischemia in the Mongolian gerbil [1].
• The major adverse events were light-headedness, nausea, and insomnia for gepirone and drowsiness and fatigue for diazepam [2].
• Overall, gepirone ER was well tolerated, with rates of weight gain and sexual dysfunction comparable to placebo [3].
• The hyperthermia, measured via telemetry, in the "anticipatory" phase prior to defeat and in reaction to threats, was decreased by alcohol, gepirone and diazepam; alcohol and gepirone were also effective in attenuating "anticipatory" tachycardia [4].
• The anxiolytic-like profile of hyperthermia, tachycardia, USV and defensive behavior in the "anticipatory" phase of the confrontation by alcohol, gepirone and diazepam contrasted with the lack thereof during the more intense reactive phase [4].

Psychiatry related information on Gepirone

• This preliminary study suggests the possible efficacy of gepirone in panic disorder [5].
• Ten patients suffering from generalized anxiety disorder were treated, after a single-blind placebo washout week, with the nonbenzodiazepine anxiolytic gepirone in a 6-week open label trial [6].
• Gepirone had no systematic sedative effects throughout the confrontation; infact, it dose-dependently reduced the stress-induced suppression of locomotor activity during the "anticipatory" phase [4].
• BACKGROUND: Gepirone, a 5-HT(1A) receptor agonist, has been assessed for use in the treatment of anxiety and depressive disorders [7].
• Buspirone and gepirone, however, reduced the latency period to erection [8].

High impact information on Gepirone

• Some of these drugs, including gepirone and other 5-HT1A agonists such as buspirone, have been reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials [9].
• Twice daily intraperitoneal injection of buspirone (total daily dose of 0.5 and 1 mg/kg), gepirone (0.06 and 0.125 mg/kg), 8-OH dipropylamino-tetralin (8-OH-DPAT) (0.03, 0.06, 0.125, and 0.25 mg/kg), and ipsapirone (TVXQ 7821) (0.03 and 0.06 mg/kg) eliminated escape failures [10].
• To evaluate long-term efficacy and tolerability of the serotonin 5-HT1A receptor agonist, gepirone extended release (ER), a multicenter, randomized, placebo-controlled relapse prevention study was performed in patients with recurrent major depression (DSM-IV criteria) [11].
• METHOD: This subgroup analysis was derived from an 8-week, double-blind, placebo-controlled study of gepirone ER in patients with MDD [3].
• In the hot-plate test, only certain agonists (e.g., 8-OH-DPAT) and partial agonists (e.g., gepirone) elicited antinociception and their actions were not attenuated by 5-HT1A antagonists which, themselves, were inactive in this paradigm [12].

Chemical compound and disease context of Gepirone

• Ipsapirone and gepirone, but not buspirone, facilitated lordosis in estrogen-treated rats, whereas all three drugs inhibited this behavior in rats treated with estrogen and progesterone [13].
• We have therefore examined the effects of fluoxetine, a selective 5-HT reuptake inhibitor, and gepirone, a 5-HT1A agonist, on body weight in isolated and in group-housed rats during 3 weeks of daily treatment [14].
• 5-HT2 receptor blockade by ICI 170,809 does not affect the inhibitory effect of the 5-HT1A receptor ligand gepirone on neuroleptic-induced catalepsy [15].
• These results seem to be clinically important in case other 5HT1A agonists, buspirone or gepirone (potent anxiolytics), also prevented fentanyl-induced muscle rigidity in humans [16].

Biological context of Gepirone

• In healthy volunteers, the azapirones--buspirone, ipsapirone, and gepirone--increase plasma cortisol and decrease body temperature; buspirone and gepirone also increase plasma prolactin and growth hormone [17].
• Preclinical neurochemical studies indicate that buspirone and gepirone bind selectively to presynaptic (dorsal raphe) and postsynaptic (hippocampus, cortex) 5-hydroxytryptamine1A (5-HT1A) receptor binding sites [18].
• Previously it has been shown that 5-hydroxy-tryptamine (5-HT)1A agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone increase food intake in free-feeding rats [19].
• Biotransformation of gepirone to its principal metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), was studied in human liver microsomes and in microsomes from cDNA-transfected human lymphoblastoid cells [20].
• Effect of food on the bioavailability of gepirone in humans [21].

Anatomical context of Gepirone

• In contrast, the responsiveness of postsynaptic dorsal hippocampus pyramidal neurons to 5-HT, 8-OH-DPAT, and gepirone was not altered by the 14-day gepirone treatment [22].
• Anxiolytic drugs, such as the benzodiazepines and the azapirones (ipsapirone, gepirone, buspirone), are well known to affect states of vigilance and to decrease the firing rate of serotoninergic neurones within the dorsal raphe nucleus in rats [23].
• Formation of 1-PP from gepirone in liver microsomes proceeded with a mean apparent Km ranging from 335 to 677 microM [20].
• Analysis of small intestinal longitudinal muscle of rats given the ED50 of PmP, ipsapirone, gepirone, buspirone showed that PmP concentrations in the longitudinal muscle (with attached myenteric plexus) fell within a relatively narrow range and were consistent with the appropriate transit scores [24].
• It was designed to compare the bioavailability of an oral 20-mg gepirone dose (treatment 1) with that obtained after application of the same dose by gastric intubation to the distal (treatment 2) and proximal (treatment 3) regions of the small intestine, and after 4 consecutive 5-mg gepirone doses given orally at hourly intervals (treatment 4) [25].

Associations of Gepirone with other chemical compounds

• The 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose [26].
• Ipsapirone-induced acceleration of DA turnover persisted after the selective degeneration of serotoninergic neurons by intraraphe 5,7-dihydroxytryptamine infusion, and could be reproduced by i.p. administration of other 5-HT1A agonists like buspirone and gepirone, but not 8-OH-DPAT [27].
• The same maximal drop in body temperature (approximately 2.5 degrees C) was elicited by all three agonists, 8-OH-DPAT being the most potent (EC50 = 0.05 mg/kg), followed by gepirone (1.8 mg/kg) and (+) S-20499 (8 mg/kg) [28].
• In contrast, acute doses of gepirone had little effect on rates of cocaine self-administration, while disruptions in food consumption and changes in the within-session pattern of cocaine self-administration were obtained at the highest dose of gepirone tested (1.0 mg/kg) [29].
• The results obtained suggest that the anti-immobility effect of gepirone is mediated by activation of 5-HT1A receptors, most probably located postsynaptically and that dopamine may be involved in this action [30].

Gene context of Gepirone

• 5-HT1A agonists (BAY R 1531, 8-OHDPAT, flesinoxan, gepirone, 5MeO DMT, buspirone, ipsapirone, BMY 14802) completely inhibit the aggressive behaviour irrespective of their intrinsic activities [31].
• Other 5-HT(1A) receptor agonists (buspirone, gepirone and ipsapirone) also reduced phospho-Erk1/2 levels in hippocampus [32].
• The metabolism of gepirone involves CYP3A4 and to a lesser extent CYP2D6 [33].
• Acute administration of gepirone, a 5-HT1A agonist, caused a dose dependent (1-10 mg/kg, IP) reduction in the locomotor activity (open and closed arms) of rats tested in the elevated plus-maze [34].
• Additionally, the 5-HT1A agonist, gepirone, given either systemically (10 mg/kg) or intracerebrally into the region of the dorsal raphe (14 micrograms), blocked the tryptophan hydroxylase response to CRF [35].

Analytical, diagnostic and therapeutic context of Gepirone

• New data are presented showing a lack of reinforcing effects for gepirone in rhesus monkeys when the drug was evaluated in an intravenous drug self-administration procedure [36].
• It has greater potency in animal models of anxiety than buspirone, gepirone, or ipsapirone, and it lacks the antidopaminergic effects associated with buspirone [37].
• The effects of the selective 5-HT1A receptor agonist gepirone (10 and 20 mg orally) on neuroendocrine function and temperature were assessed using a single-blind cross-over design in 12 healthy male volunteers [38].
• Mean gepirone time to reach peak concentration (tmax) after treatments 1, 2, and 3 ranged between 0.57 and 1.07 hours [25].
• RESULTS: Initial placebo-controlled clinical trials demonstrated that gepirone IR improved symptoms of depression; however, the short half-life of gepirone necessitated frequent administration, and high peak plasma concentrations at higher doses were associated with an increased incidence of adverse events [7].

References