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Pharmacokinetics of the active metabolites of ethyl loflazepate in elderly patients who died of asphyxia associated with benzodiazepine-related toxicity.

Kamijo Y, Hayashi I, Nishikawa T, Yoshimura K, Soma K.

Department of Emergency and Critical Care Medicine, Kitasato University, School of Medicine, 1-15-1 Kitasato, Sagamihara Kanagawa 228-8555, Japan. yk119@kitasato-u.ac.jp

We determined the pharmacokinetics of ethyl loflazepate (Lof) in elderly patients who died of benzodiazepine-related toxicity. Three elderly patients with body mass indexes of less than 17 kg/m2 died of asphyxia after having taken maintenance doses of Lof for 2 to 3 weeks. We measured serum concentrations of the active metabolites of Lof using gas chromatography-mass spectrometry and a benzodiazepine receptor assay to determine the pharmacokinetics of each. On admission, the serum concentrations of the active metabolites of Lof ([Lofl) were 256 ng/mL, 425 ng/mL, and 177 ng/mL in cases 1, 2, and 3, respectively. Serum benzodiazepine-receptor binding activities, expressed as diazepam equivalent concentrations ([Bz]), were 1800 ng/mL, 2200 ng/mL, and 1500 ng/mL. The T1/2(beta) of [Lof] were 124 and 121 h in cases 1 and 2 and the T1/2(beta) of [Bz] were 75 and 87 h. The distribution volume in the elderly was reduced due to a small lipid compartment, and total drug clearance was decreased due to the decline in liver and kidney function. These changes did not prolong T1/2(beta) but did increase plasma concentrations of active metabolites, especially in case 2, and a slight decrease in protein binding increased the amount of free active metabolites greatly.

Variation of input-output properties along the somatodendritic axis of pyramidal neurons.

Oviedo H, Reyes AD.

Center for Neural Science, New York University, New York, New York 10003, USA. oviedo@cshl.edu

The firing evoked by injection of simulated barrages of EPSCs into the proximal dendrite of layer 5 pyramidal neurons is greater than when comparable inputs are injected into the soma. This boosting is mediated by dendritic Na+ conductances. However, the presence of other active conductances in the dendrites, some of which are nonuniformly distributed, suggests that the degree of boosting may differ along the somatodendritic axis. Here, we injected EPSC barrages at the soma and at the proximal, middle, and distal segments of the apical dendrite and measured boosting of subthreshold and suprathreshold responses. We found that although boosting was maintained throughout the apical dendrite, the degree of boosting changed nonmonotonically with distance from the soma. Boosting dipped in the middle dendritic segments as a result of the deactivation of the hyperpolarization-activated cation current, Ih, but increased in the distal dendrites as a result of the activation of Ca2+ conductances. In the distal dendrites, EPSC barrages evoked repetitive bursts of action potentials, and the bursting pattern changed systematically with the magnitude of the input barrages. The quantitative changes in boosting along the somatodendritic axis suggest that inputs from different classes of presynaptic cells are weighted differently, depending on the location of the synaptic contacts. Moreover, the tight coupling between burst characteristics and stimulus parameters indicate that the distal dendrites can support a coding scheme that is different from that at sites closer to the soma, consistent with the notion of a separate dendritic integration site.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15901779&query_hl=1

Modulation of presynaptic Ca2+ entry by AMPA receptors at individual GABAergic synapses in the cerebellum.

Rusakov DA, Saitow F, Lehre KP, Konishi S.

Molecular Neurobiology Laboratory, Mitsubishi Kagaku Institute of Life Sciences, and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 194-8511, Japan. d.rusakov@ion.ucl.ac.uk

Cerebellar Purkinje cells (PCs) receive GABAergic input that undergoes powerful retrograde modulation by presynaptic cannabinoid and glutamate receptors. Here we examine a distinct modulatory mechanism at these synapses, which does not require postsynaptic depolarization and acts via presynaptic AMPA receptors. We find that this mechanism operates mainly in the somatic vicinity of PCs in which large boutons of basket cell axons form synapses on the PC soma. We use fast confocal microscopy and detailed kinetic modeling to estimate that, in these boutons, an action potential opens 100-200 Ca2+ channels, eliciting a brief 3-5 microM transient, followed by a longer-term, 15-30 nM rise of free Ca2+ (above the resting level of approximately 100 nM). Brief activation of local AMPA receptors suppresses Ca2+ entry (probably by silencing 20-40 P/Q-type channels) in a subgroup of terminals that tend to show a higher dynamic range of Ca2+ signaling. The results provide the first quantitative description of presynaptic Ca2+ kinetics and its modulation by AMPA receptor activation (most likely via a glutamate spillover-mediated mechanism) at identified GABAergic synapses.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15901774&query_hl=1

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