Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder
| Autor: | Johannes Tauscher, Smriti Iyengar, Gerard J. Marek, William Kielbasa, David Mozley, François Vandenhende, Xiaomei Peng, Donald R. Gehlert |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male medicine.medical_specialty Pyridines Liebowitz social anxiety scale Substance P Placebo Gastroenterology law.invention Radioligand Assay Neurokinin-1 Receptor Antagonists Pharmacokinetics Randomized controlled trial law Internal medicine medicine Animals Humans Pharmacology (medical) Radionuclide Imaging Biological Psychiatry Pharmacology Dose-Response Relationship Drug Social anxiety Antagonist Brain Receptors Neurokinin-1 Triazoles Anxiety Disorders Paroxetine Peptide Fragments Psychiatry and Mental health Treatment Outcome Anti-Anxiety Agents Neurology Anxiety Neurology (clinical) Stereotyped Behavior medicine.symptom Gerbillinae Psychology medicine.drug Clinical psychology |
| Zdroj: | European Neuropsychopharmacology. 20:80-87 |
| ISSN: | 0924-977X |
| DOI: | 10.1016/j.euroneuro.2009.10.005 |
| Popis: | The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [ 11 C]GR205171 was used healthy volunteers receiving 1–100 mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1 mg to 93% with 100 mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of > 30 mg LY686017 led to sustained trough RO of over 80%. 189 outpatients 1 suffering from SAD were randomly assigned to 12-weeks treatment with 50 mg/d LY686017 ( N = 77), placebo ( N = 74), or 20 mg/d paroxetine ( N = 38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect