A sensitive, selective, accurate, precise and reproducible triple-quadrupole liquid chromatographic-mass spectrometric assay was developed and validated for BMS-181885 (I), a 5HT1 agonist, in human plasma using BMS-181101 as the internal standard (IS). The method involved solid phase extraction of plasma containing I and the IS using Isoelute CN cartridges. The supernatant was then evaporated to dryness at 40 degrees C. The residue was dissolved in 100 microL of the injecting solvent. The HPLC column was ODS-3, 2 x 100 mm. The mobile phase comprised 10 mM ammonium formate (pH = 4) and acetonitrile, 55:45 v/v, used in an isocratic condition. The mass spectrometer was programmed to admit the protonated molecules at m/z 461 (I) and m/z 370 (IS) via the first quadrupole filter and to select reaction monitoring of ions at m/z 152 for I and IS for the quantification. Standard curves were fitted to a weighted quadratic function over the concentration range 0.2-200 ng/mL. The lowest standard concentration (0.2 ng/mL) was experimentally established as the lower limit of quantitation of the assay. The mean predicted quality control concentrations deviated within +/- 11% of the corresponding nominal values; the intra-assay and inter-assay precisions were within 7.0% relative standard deviation. I was stable in the injection solvent at 4 degrees C for at least 24 h and for at least three freeze-thaw cycles. Freezer stability of I in plasma was demonstrated for at least 3 months. The extraction recovery of I was established as 97%. The validated assay was applied to a pharmacokinetic study of I in humans.
1998-09-01·Journal of Pharmaceutical Sciences3区 · 医学
Absolute Bioavailability and Dose Proportionality of BMS-181885, an Antimigraine Agent, Following the Administration of Single Intranasal Doses to Cynomolgus Monkeys
3区 · 医学
作者: Srinivas, Nuggehally R. ; Shyu, Wen Chyi ; Soong, Chi Wen ; Greene, Douglas
The pharmacokinetics of BMS-181885 were linear over the intranasal dose range of 2-10 mg in monkeys. The nasal absorption of BMS-181885 was rapid with the Cmax attainment approx. 30 min after dosing. Thus, intranasal administration of BMS-181885 may represent a potential alternative to the i.v. route of administration.
1998-06-26·European Journal of Pharmacology3区 · 医学
BMS-181885, a 5-HT1B/1D receptor ligand, in experimental models predictive of antimigraine activity and coronary side-effect potential
3区 · 医学
作者: Saxena, Pramod R. ; De Vries, Peter ; Heiligers, Jan P. C. ; Bax, Willem A. ; Maassen Van Den Brink, Antoinette ; Yocca, Frank D.
Many acutely acting antimigraine drugs have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have investigated the effects of BMS-181885 (3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-me thyl-3-cyclobuten-3-yl)amino-1H-indole), a 5-HT1B/1D receptor ligand. In anaesthetised pigs, BMS-181885 (10, 30, 100 and 300 microg kg(-1)) decreased the total carotid blood flow and conduction, exclusively at the expense of the arteriovenous anastomotic fraction as the capillary fraction did in fact increase. The highest dose (300 microg kg(-1)) produced a reduction of 52+/-6% from the baseline arteriovenous anastomotic flow. When carotid haemodynamic changes after a single 100 microg kg(-1)dose of BMS-181885 or sumatriptan were studied at different time-points, BMS-188185 had a longer duration of action. Both BMS-181885 (pD2:7.9+/-0.1; Emax:9+/-3% of the contraction to 100 mM K+) and sumatriptan (pD2:6.3+/-0.1; Emax:28+/-8% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that (i) the longer-lasting vasoconstrictor action of BMS-181885 on porcine carotid arteriovenous anastomoses may be related to its reported slow dissociation from 5-HT1B/1D receptor, and (ii) BMS-181885 should be able to abort migraine headaches in patients. It will be interesting to find out whether these properties are clinically important so that the drug exhibits less headache recurrence and coronary side-effects than sumatriptan.