Stereoselective high-performance liquid chromatographic assay with fluorometric detection for the isomers of mivacurium in human plasma.
A high-performance liquid chromatographic assay with fluorometric detection was developed for the analysis of the stereoisomers of mivacurium, a new short-acting neuromuscular blocker, in plasma. The isomers were isolated from plasma by solid-phase extraction with C18 and anion-exchange cartridges. The extracts were chromatographed on a LiChrosphere 60 RP Select B column (125 mm x 4.6 mm I.D.) using a mobile phase of acetonitrile-water (4:6, v/v) containing 0.005 M octanesulfonic acid. The fluorescence excitation and emission wavelengths were 202 and 320 nm, respectively. The accuracy and precision of the assay, expressed as the percentage deviation of measured values from true values and the percentage coefficient of variation, respectively, were less than or equal to 10% at all concentrations except for the percentage coefficient of variation at the lower limit of quantitation (5 ng/ml). The assay has been successfully used for the analysis of plasma samples from a pharmacokinetic study in human volunteers.
Effect of Edrophonium and Neostigmine on the Pharmacokinetics and Neuromuscular Effects of Mivacurium
Background: Previous studies demonstrated that both edrophonium and neostigmine affect mivacurium’s pharmacokinetics, thereby potentially affecting its recovery profile. However, those studies were not clinically relevant because mivacurium was still infused after the antagonists were given. In the present study, the authors gave antagonists (or placebo) after discontinuing a mivacurium infusion, thereby obtaining data that are more clinically relevant. Methods: In 18 patients, mivacurium was infused at 10 &mgr;g · kg−1 · min−1 for 40 min, the infusion was discontinued for 15 min and then restarted at the same rate for another 40 min. Patients were randomized to receive 500 &mgr;g/kg edrophonium, 50 &mgr;g/kg neostigmine, or saline at discontinuation of the second infusion; all subjects received 1 mg atropine. Plasma was sampled during the final 10 min of each infusion to determine steady state mivacurium concentrations and for 15 min after each infusion. Twitch tension was recorded. Mivacurium concentrations after each of the two infusions were compared. Results: After discontinuation of the second infusion, mivacurium concentrations were larger than those after the first infusion at 2 min with edrophonium and at 2, 4, and 7 min with neostigmine. With both neostigmine and edrophonium, twitch tension recovered after infusion #2 more rapidly than after infusion #1; however, the magnitude of this effect was small. Conclusion: Edrophonium transiently slows the rate at which mivacurium concentrations decrease; this is consistent with our previous findings. Neostigmine has a similar, although longer, effect. Despite altering mivacurium’s elimination characteristics, both drugs facilitate neuromuscular recovery, although their benefit is small.
The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats
We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. Basal mean BP and HR were 115±2 and 165±3 mmHg and 345±10 and 410±14 beats min−1 in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys‐desArg9‐BK significantly increased the BP of WKY and SHR by 7±1 and 19±2 mmHg, respectively. One nmol Sar[D‐Phe8]‐desArg9‐BK, a kininase‐resistant B1 agonist, increased the BP of WKY and SHR by 19±2 and 17±2 mmHg, respectively and reduced HR in both strains. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8‐desArg9‐BK or AcLys[D‐βNal7,Ile8]‐desArg9‐BK (R715), significantly decreased mean BP in SHR (by 9±2 mmHg the former and 14±3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein‐conjugated ODNs was detected in brain areas surrounding cerebral ventricles. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.