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Biomedical subjects

A S Rosen

Publications and source records attributed to A S Rosen.

14 recordsLinked to original sources
PubMed1999

Zaleplon pharmacokinetics and absolute bioavailability.

The pharmacokinetics and absolute oral bioavailability of zaleplon were assessed to evaluate the extent of presystemic metabolism of this new nonbenzodiazepine hypnotic agent. A partially randomized, single-dose, four-period crossover study was conducted in 23 healthy subjects. Subjects received 1 and 2.5 mg intravenous (i.v.) infusions of zaleplon during the first and second periods, respectively, and then were randomly assigned to receive a 5 mg oral dose or 5 mg i.v. infusion of zaleplon in a crossover design during the final two periods. Zaleplon pharmacokinetics were determined in 20 subjects (ten men and ten women) after the two 5 mg treatments. The oral and i.v. doses of zaleplon administered in this study were safe and well-tolerated. Following i.v. administration, zaleplon had a moderate to high systemic clearance (mean +/- S.D., 0.94 +/- 0.20 L/h/kg), rapid elimination (half-life, t1/2 = 1.05 +/- 0.13 h), and a steady-state volume of distribution of 1.27 +/- 0.25 L/kg, indicating substantial distribution into extravascular tissues. Zaleplon was rapidly absorbed after oral administration, and the mean apparent elimination t1/2 was similar to that obtained after i.v. infusion. The absolute bioavailability was 30.6 +/- 10.2%.

Acetamides↗
PubMed1995

Correlation of anoxic neuronal responses and calbindin-D28k localization in stratum pyramidale of rat hippocampus.

Immunohistochemical staining for the calcium-binding protein calbindin-D28k (CaBP) was combined with Lucifer Yellow (LY) identification and intracellular recording of changes in membrane parameters of pyramidal neurons in CA2, CA1, and the subiculum of rat hippocampal slices during brief exposure (4.0 +/- 0.19 min) to N2. Anoxia evoked either a depolarization or hyperpolarization of membrane potential (VM) (+21.5 +/- 2.79 mV above VM = -70.5 +/- 1.50 mV, n = 30 and -7.2 +/- 0.72 mV below VM = -68.2 +/- 1.34 mV, n = 24, respectively) and a fall in membrane resistance of approximately 20%. Differences in the response could be correlated with the presence or absence of CaBP and the localization of neurons in different layers of stratum pyramidale and sectors of the hippocampus. For neurons immunopositive for calbindin (CaBP(+)), depolarization was observed more frequently (83%) than hyperpolarization (17%); in contrast, 44% of responses of calbindin-negative (CaBP(-)) neurons were depolarizing and 56% were hyperpolarizing. Depolarizations of CaBP(+) neurons were more gradual in slope, and more rapidly reached a plateau in comparison with those recorded in CaBP(-) neurons. Responses of neurons in the superficial layer of stratum pyramidale (in which 79% of CaBP(+) pyramidal neurons were situated) were mainly depolarizing (91%), while for those in the deep layer (which contained 89% of the CaBP(-) cells) such responses were observed less often (45%). Depolarization was also more common than hyperpolarization for cells located in CA2/CA1c/CA1b (63%) than in the CA1a/subicular region (37%). The depolarizing response of the majority of pyramidal neurons which are CaBP(+), superficial, and closer to CA3 may reflect an efficient buffering of intracellular Ca2+, which maintains a low [Ca2+]i, steep gradient for Ca2+ influx and may facilitate the movement of Ca2+ away from points of entry. The neurons which are CaBP(-), deep, and closer to subiculum and in which N2 evokes hyperpolarization, on the other hand, may have a sustained elevation/accumulation of cytosolic Ca2+ which could activate K+ conductance, inhibit Ca2+ influx, and stabilize the membrane potential. These experiments provide a functional correlate for CaBP and suggest that it may have a significant role in Ca2+ homeostasis and the determination of selective neuronal vulnerability.

Animals↗
PubMed1995

Sulfonylurea therapy improves glucose disposal without changing skeletal muscle GLUT4 levels in noninsulin-dependent diabetes mellitus subjects: a longitudinal study.

A major pathological feature of noninsulin-dependent diabetes (NIDDM) is defective insulin-stimulated glucose transport in skeletal muscle. When NIDDM subjects are assessed as a group, GLUT4 gene expression in skeletal muscle varies widely and is not different from that in controls. Thus, longitudinal studies are needed to assess whether changes in GLUT4 expression in muscle of NIDDM subjects could be responsible for changes in glucose disposal. The question is timely because recent studies in transgenic mice show that increasing GLUT4 expression can increase insulin-stimulated glucose uptake in vivo and in vitro. Here we use a longitudinal design to investigate the effects of 8 weeks of therapy with the sulfonylurea gliclazide on glycemic control, glucose tolerance, insulin-stimulated glucose disposal, and GLUT4 expression in muscle of 10 obese NIDDM subjects. Subjects were on a weight-maintaining diet. Gliclazide treatment results in increased serum C-peptide, decreased hemoglobin-A1c, decreased glucose excursion on glucose tolerance test, and 35% increased insulin-stimulated glucose disposal. Gliclazide therapy is not associated with any change in DNA or protein content per g muscle or any alteration in GLUT4 levels expressed either per microgram membrane protein or per DNA. In summary, the improvement in glycemic control and glucose disposal in NIDDM subjects receiving gliclazide therapy cannot be explained by increased expression of GLUT4 in muscle. Thus, therapeutic effects on insulin-stimulated glucose disposal can be achieved in NIDDM subjects without altering GLUT4 expression in muscle.

Adult↗
PubMed1994

Influence of temperature on anoxic responses of neocortical pyramidal neurons.

Intracellular recordings were made in pyramidal neurons of layers II-III of rat fronto-parietal neocortical slices. The membrane and synaptic properties and effects of brief (4-6 min) anoxia-anoxic depolarization and synaptic depression--were recorded at temperatures between 26 and 37.5 degrees C. In normoxic conditions, both warming (> or = 35 degrees C) and cooling (< or = 32 degrees C) induced a reduction in the amplitude of early and late excitatory postsynaptic potentials and abolished inhibitory postsynaptic potentials. Excitatory postsynaptic potential latency decreased with warming and increased with cooling. Warming also induced spontaneous brief depolarizations, had a general slow depolarizing effect on resting membrane potential, and decreased input resistance. During oxygen deprivation, the steepness of the rising phase of the anoxic depolarization and the duration of the repolarization phase were augmented by warming above 36.5 degrees C (3.7 +/- 0.1 vs 1.9 +/- 0.1 mV/min and 8.75 +/- 0.98 vs 4.16 +/- 0.28 min, respectively). The peak amplitude of the anoxic depolarization increased in only one-third of trials (6.6 +/- 0.6 vs 4.3 +/- 0.4 mV). Warming potentiated the depressant effect of anoxia: at 36.5 degrees C early excitatory postsynaptic potential amplitude decreased to 32.3 +/- 5.2% of control compared with 58.3 +/- 1.2% at 33.5 degrees C, the late excitatory postsynaptic potential was abolished in < 2 min, and the recovery of the compound excitatory postsynaptic potential was prolonged (12.8 +/- 0.8 vs 7.8 +/- 0.3 min). Cooling reduced the amplitude of the anoxic depolarization and increased the input resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Anoxic depression of excitatory and inhibitory postsynaptic potentials in rat neocortical slices.

1. The effects of brief anoxia (4-6 min replacement of O2 by N2) on synaptic potentials evoked from layer IV and/or the white matter were studied in pyramidal neurons of layers II-III from rat neocortical slices. 2. The early and late components of excitatory postsynaptic potentials (EPSPs) showed differential sensitivity to anoxia: within 2 min the late EPSP (lEPSP) disappeared, whereas the amplitude of the early EPSP (eEPSP) decreased by 70% at 5 min of anoxia. Recovery was complete within 4-11 min. 3. Both fast and slow inhibitory postsynaptic potentials (IPSPs) were extremely sensitive to lack of O2 and were abolished earlier than the lEPSP evoked by the same stimulus. As well, recovery of the IPSPs was always more delayed than that of the EPSPs. 4. A transient increase in excitability during early anoxia and/or midrecovery, manifested as enhanced probability of spiking in 25% of neurons, is attributed to the higher sensitivity of IPSPs compared with EPSPs. 5. The anoxic-induced depression of the lEPSP and IPSPs, which are generated close to the soma, is not due to depolarization-induced occlusion; however, occlusion may cause an attenuation of the eEPSP at dendritic sites. 6. The depression of the EPSPs is not a result of a decreased transmembrane Na+ gradient after inactivation of Na-K-adenosine triphosphatase (Na-K-ATPase). Although ouabain induced a depolarization similar to that of anoxia, it did not affect EPSP amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Expression of GLUT1 and GLUT4 glucose transporters in skeletal muscle of humans with insulin-dependent diabetes mellitus: regulatory effects of metabolic factors.

Insulin-dependent diabetes mellitus (IDDM) is associated with insulin deficiency and insulin-resistant glucose uptake in skeletal muscle. To investigate the molecular mechanisms for this insulin resistance, we examined the expression of GLUT1 and GLUT4, glucose transporter genes in vastus lateralis muscle from 20 IDDM subjects and 10 nondiabetic controls. Both groups had a mean age of 34 yr and were nonobese. Fasting free plasma insulin levels were similar in control and IDDM subjects but hemoglobin A1c (HbA1c), fasting plasma glucose and free fatty acid levels were significantly higher in IDDM subjects. Euglycemic clamp studies over a range of insulin concentrations in these IDDM subjects previously showed both decreased insulin sensitivity and decreased maximally insulin stimulated glucose utilization. In this study, Northern blotting of muscle ribonucleic acid (RNA) revealed a single 3.0-3.5 kb transcript for both GLUT1 and GLUT4 with no change in messenger RNA (mRNA) size or abundance with IDDM. In IDDM subjects, GLUT1 mRNA levels correlated positively with HbA1c whereas GLUT4 mRNA levels correlated negatively with fasting plasma glucose but not with HbA1c. Neither mRNA correlated with fasting plasma insulin or free fatty acid levels or with daily insulin dose. Immunoblotting of total muscle membranes for GLUT4 showed a single band of mol mass of approximately 45 kilodaltons with no change in size or abundance with IDDM. There was no significant correlation between GLUT4 polypeptide levels and HbA1c, fasting plasma glucose, insulin, or free fatty acids, daily insulin dose, duration of diabetes, or subject age but in IDDM subjects GLUT4 protein levels correlated negatively with body mass index. Thus, impaired expression of glucose transporters in muscle is not essential for the pathogenesis of insulin-resistant glucose uptake in IDDM. No direct regulatory role of chronic glycemic control or plasma insulin levels on GLUT4 expression is evident. In contrast, recent ambient glucose levels may affect levels of GLUT4 mRNA but not GLUT4 protein, suggesting important posttranscriptional regulation of this protein. Since glucose transport has been shown to be rate limiting for glucose utilization in muscle in IDDM, these results suggest impaired translocation or activation of glucose transporters in IDDM.

Actins↗
PubMed1991

Glucose concentration inversely alters neocortical slice excitability through an osmotic effect.

Neurological problems can develop when blood glucose levels rapidly rise or fall yet there has been little experimentation at a cellular level to assess how neurophysiological change may be induced. Using intracellular recording in the rat neocortical slice preparation, we examined pyramidal neurons of layers II-III as saline D-glucose concentration was altered. Single cell properties, synaptic transmission and epileptiform discharges were studied in control saline and compared with corresponding data when osmolality was raised with D-glucose by 20-80 mOsm. Although single cell properties were not significantly altered, the amplitude of evoked early and late EPSPs were proportionally reduced within 5 min. A similar but more pronounced effect was observed with mannitol, whereas freely permeable dimethylsulfoxide (DMSO) was without effect. Hyposmolality increased the amplitude of evoked early and late EPSPs. Therefore the dampening of synaptic transmission by D-glucose appears osmotic in origin. D-glucose was osmotically effective only above 30 mM probably because it is cell-permeable at lower concentrations. In slices made epileptogenic by Mg(2+)-free saline, increasing D-glucose decreased the frequency and increased the duration of interictal bursts. Again mannitol mimicked the glucose effects and hyposmotic change gave opposing responses. The inverse relation between glucose concentration and neocortical excitability correlates well with clinical observations that an acute reduction in blood glucose from hyperglycemic levels (as follows insulin over-administration) can evoke generalized seizure.

Animals↗
PubMed1991

Depolarizing effects of anoxia on pyramidal cells of rat neocortex.

The response of rat neocortical pyramidal neurons (layers II III) in vitro to brief periods of anoxia is a reversible depolarization of 3.8 +/- 1.01 mV (mean +/- S.E.M.; n = 114), which is accompanied by a moderate decrease in input resistance and significant depression of evoked synaptic activity. This effect is mimicked by ouabain, and is partially attenuated by the excitatory amino acid (EAA) antagonist, kynurenic acid. The estimated reversal potential (Vrev) for the anoxic depolarization (AD) is between -35 and -40 mV; in the presence of TTX a Vrev of -65 mV is obtained. Although a partial failure of Na(+)-K(+) pump activity and release of EAAs may contribute the generation of the AD, other processes are likely to be involved.

Animals↗
PubMed1990

Osmotic effects upon excitability in rat neocortical slices.

Acute osmotic disturbances can lead to profound neurological problems, yet there has been little experimentation at a cellular level to assess if neurophysiological changes are induced by altered osmolality. Using extra- and intracellular recording in the rat neocortical slice preparation, we examined pyramidal neurons of layers II-III under changing osmotic conditions. Single cell properties, field potentials, synaptic transmission and epileptiform discharges were studied in control saline (295 mOsm) and compared with corresponding data collected during exposure to osmolalities between 245 and 375 mOsm. Single cell properties (resting membrane potential, cell input resistance, action potential threshold and duration) did not change significantly, but neuronal interactions were considerably influenced by osmotic change within minutes. Hyposmolality increased the amplitude of evoked field potentials and of excitatory postsynaptic potentials recorded intracellularly. Hyperosmolality, induced with mannitol, decreased these parameters. Electrotonic coupling, as gauged by the degree of dye coupling and by cell input resistance, was not influenced by shifts in osmolality. The clinical finding that overhydration promotes seizure onset was examined in slices made epileptogenic in Mg2(+)-free saline. Hyposmolality increased the frequency and decreased the duration of interictal bursts, whereas raising osmolality with mannitol had opposite effects. None of the aforementioned effects occurred when osmolality was increased with a freely permeable substance such as dimethylsulfoxide, nor could they be ascribed to changes in saline Na+ or Ca2+ concentrations. The results are consistent with hyposmotic solutions reducing extracellular space by causing cells to swell. Theoretically, during population discharge, this should both concentrate K+ released extracellularly and possibly increase field (ephaptic) interactions. How lowered osmolality strengthens spontaneous and evoked excitatory synaptic transmission in neocortex is not yet clear. However, it may be an important mechanism underlying the increased seizure susceptibility of patients and experimental animals with lowered plasma osmolality. Conversely, suppression of excitatory postsynaptic potentials by osmotically active substances may be involved in the lowered seizure susceptibility observed clinically.

Action Potentials↗
PubMed1989

Seizure susceptibility and the osmotic state.

In some unknown manner, water uptake by brain cells (hyposmolality) promotes generalized seizure in humans and experimental animals, whereas cell dehydration (hyperosmolality) protects against it. We have replicated both scenarios in slices of hippocampus undergoing electrographic seizures. Surprisingly, a shift in osmolality does not change the excitability of individual neurons but rather, it alters the degree to which neurons interact. Hyposmolality enhances both excitatory synaptic transmission in neocortex and field (ephaptic) effects, the latter arising when cortical cells fire as a population. We propose that these increased excitatory interactions promote the synchrony that characterizes epileptiform activity.

Action Potentials↗