Details

Autor(en) / Beteiligte

• Saletu, B.
• Schulz, H.
• Herrmann, W. M .
• Anderer, P.
• Shrotriya, R. C.
• Vanbrabant, E.

Titel

BMS-181168 for Protection of the Human Brain against Hypoxia: Double-Blind, Placebo-Controlled EEG Mapping Studies

Ist Teil von

• Pharmacopsychiatry, 1994-09, Vol.27 (5), p.189-197

Ort / Verlag

Stuttgart: Thieme

Erscheinungsjahr

1994

Quelle

MEDLINE

Beschreibungen/Notizen

• Abstract In a double-blind, placebo-controlled, crossover trial, the antihypoxidotic properties of BMS-181168 (previously BMY 21502) - a 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2-pyrrolidinone alleviating impairment of learning and memory in the animal - were studied utilizing EEG mapping under an experimental hypoxic hypoxidosis. The later was induced by a fixed gas combination of 9.8% oxygen (O 2 ) and 90.2% nitrogen (N 2 ) (found at 6000m altitude), which was inhaled for 23 minutes under normobaric conditions by 16 healthy male volunteers (aged 25-35 years, mean 27.2 years). After an adaption session, they received in radomized order at weekly intervals oral single doses of placebo, or of 100mg, 200mg and 400mg BMS-181168. Evaluation of blood gases (PO 2 , PCO 2 , SO 2 ), adverse events, and EEG mapping was carried out prior to drug administration and 2, 4, 6 and 8 hours post-drug, on each occasion under normoxic and transient hypoxic conditions. Hypoxemia was controlled by drawing arterialized capillary blood samples from the earlobes after hypermization of the latter (after 0, 14, and 23 minutes of hypoxic gas inhalation) and by oximetry. After 23 minutes of inhalation, analysis showed a drop in PO 2 from 98 to 48 mm Hg, in PCO 2 from 41 to 31 mm Hg and in SO 2 from 97 to 80%. Descriptive statistical analyses of EEG mapping data demonstrated under hypoxia/placebo conditions an increase in delta/theta activity and a decrease in the alpha activity as well as a slowing of the delta/theta centroid and an increase in the alpha and beta centroid, which suggests a marked deterioration in physysiological vigilance. At all three doses, BMS-181168 significantly attenuated this hypoxia-induced deterioration in brain function, as delta/theta decreased, alpha activity increased, and the centroid of the of the combined delta/theta waves was accelerated. Multivariate statistics demonstrated that brain protection was dose-dependent (most pronounced after 400 mg), starting as early as the second hour and increasing up to the eight hour. The extent of brain protection was highlighted by the fact that the hypoxia-induced increase in delta activity (42% after placebo) was attenuated by BMS-181168 down to 4-11%.