title: Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study.
abstract: Lesopitron, a 5-hydroxytryptamine 1A agonist, is a new potential anxiolytic of the azapirone class. It has greater potency in animal models of anxiety than buspirone, gepirone, or ipsapirone, and it lacks the antidopaminergic effects associated with buspirone. Lesopitron has been tolerated at single doses up to 50 mg and repeated dosages of 45 mg/day in healthy volunteers. Forty-two patients with generalized anxiety disorder (GAD) were enrolled in this double-blind bridging study to determine the safety and tolerability of fixed doses of lesopitron (20, 25, 30, 40, 45, 50, and 60 mg two times a day) over a 6 1/2-day inpatient administration period. Each of the seven panels included six patients (four drug/two placebo). One patient in the 25-mg, two-times-a-day panel voluntarily withdrew because of increased anxiety symptoms. One patient experienced severe orthostatic hypotension at 60 mg two times a day, and moderate to severe adverse events (dizziness, lightheadedness, nausea, headache) occurred in two other patients at this dosage. The most commonly reported adverse events in all the panels were headache, dizziness, and nausea. Lesopitron is rapidly absorbed in patients, having a time to maximum concentration (Tmax) ranging from 0.5 to 1 hour, and its elimination half-life ranged from 1.1 to 5.6 hours. Peak plasma concentrations showed high interindividual variability for lesopitron, but increased linearly with dose for the main metabolite, 5-hydroxylesopitron. We defined the maximum tolerated dose in GAD patients as 50 mg two times a day, twice as high as the highest dose tested in healthy volunteers.
authors.affiliation: California Clinical Trials, Beverly Hills, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Sramek
authors.forename: A
authors.initials: A
authors.lastname: Fresquet
authors.forename: G
authors.initials: G
authors.lastname: Marion-Landais
authors.forename: J
authors.initials: J
authors.lastname: Hourani
authors.forename: S S
authors.initials: SS
authors.lastname: Jhee
authors.forename: L
authors.initials: L
authors.lastname: Martinez
authors.forename: C M
authors.initials: CM
authors.lastname: Jensen
authors.forename: K
authors.initials: K
authors.lastname: Bolles
authors.forename: A T
authors.initials: AT
authors.lastname: Carrington
authors.forename: N R
authors.initials: NR
authors.lastname: Cutler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D014151:Anti-Anxiety Agents; D010879:Piperazines; D011743:Pyrimidines; C075568:lesopitron