Fundamental & clinical pharmacology
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Fundam Clin Pharmacol · Jan 1999
Effects of competitive NMDA receptor antagonists on excitatory amino acid-evoked currents in mouse spinal cord neurones.
The effects of CGP 37849 [DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoate] and its ethylester CGP 39551 on whole-cell currents evoked by the endogenous excitatory amino acids, L-glutamate and L-aspartate, were studied in cultured mouse spinal cord neurones. Although CGP 37849 was the more potent compound, both antagonists inhibited 20 microM L-aspartate or 2 microM L-glutamate currents concentration-dependently and reversibly. We calculated IC50 values of 370 +/- 180 nM for CGP 37849 and 2200 +/- 140 nM for CGP 39551 (inhibition of L-aspartate current), and 210 +/- 25 nM for CGP 37849 and 6000 +/- 4700 nM for CGP 39551 (inhibition of L-glutamate current). ⋯ Upon application of 1 microM CGP 37849 and 10 microM CGP 39551, the L-aspartate concentration--current curve shifted to higher concentrations, and resulted in a 5- and 13-fold increase in the EC50 of L-aspartate, respectively, whereas Imax was not changed by application of the antagonists. Thus, the potent NMDA antagonists CGP 37849 and CGP 39551 were shown to inhibit excitatory amino acid responses specifically by competitive binding to the neurotransmitter recognition site of the NMDA receptor. Selective, competitive antagonism of L-glutamate- and L-aspartate-evoked NMDA receptor responses probably underlies the effects of CGP 37849 and CGP 39551 such as their anticonvulsant, neuroprotectant and antidepressant actions.
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Fundam Clin Pharmacol · Jan 1999
Effects of interleukin-10 and modulators of cyclic AMP formation on endotoxin-induced inflammation in rat lung.
The aim of this study was to investigate the effects of IL-10, a cell permeable analogue of cyclic AMP, dibutyryl-cAMP (db-cAMP), modulators of intracellular cyclic AMP such as phosphodiesterase (PDE) inhibitors and a beta 2-adrenoceptor agonist, salmeterol, on pulmonary inflammation following acute lung injury induced by endotoxin exposure in rats. Pulmonary inflammation was induced in adult Wistar rats by a 60-min exposure to endotoxin (lipopolysaccharide, LPS, 100 micrograms/mL). 4 h later bronchoalveolar lavage (BAL) was performed. ⋯ The present data show that the selective PDE4 inhibitor, rolipram, and the non-selective PDE inhibitor, theophylline, markedly reduced the pulmonary inflammation associated with acute lung injury in the rat. These effects may be mediated in part by IL-10 rather than by cyclic AMP, as demonstrated by the potent inhibitory activity of exogenous IL-10 on the increase in TNF-alpha release in BAL fluid of rats exposed to LPS.
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Fundam Clin Pharmacol · Jan 1995
Population pharmacokinetics of amikacin in intensive care unit patients studied by NPEM algorithm.
The population pharmacokinetics of amikacin was studied in 40 intensive care unit patients (212 plasma concentrations) by NPEM algorithm using a one-compartment model. The population was best characterized by the following pharmacokinetic parameters: renal clearance relative to creatinine clearance (Cs = 0.96 +/- 0.33), and either the total volume of distribution (Vd = 23.9 +/- 7.0 l) or the volume of distribution relative to body weight (Vs = 0.36 +/- 0.10 l.kg-1. The volume of distribution was increased with respect to the usual value of 0.25 l.kg-1. ⋯ The medians and standard deviations of Cs and Vs were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 29 patients by the bayesian method, with two blood samples per patient. For each patient, the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 h with no significant bias and good precision (2.9 mg.l-1 for peaks and 0.5 mg.l-1 for troughs). This study confirms the ability of the NPEM algorithm to provide reference population values for use in bayesian monitoring of aminoglycoside therapy.