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Biomedical subjects

L G Miller

Publications and source records attributed to L G Miller.

At least 73 records · Page 4Linked to original sources
PubMed1992

Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone.

Several classes of nonbenzodiazepine compounds, including imidazopyridines such as alpidem and zolpidem and cyclopyrrolones, e.g., zopiclone, have effects similar to benzodiazepines and may act at the benzodiazepine receptor in brain. We characterized the binding of these compounds to the benzodiazepine site in three brain regions using specific uptake of the high-affinity ligand [3H]Ro15-1788 (flumazenil). For alpidem, benzodiazepine binding was decreased in cortex and hippocampus with increasing drug dose. For zolpidem, receptor binding was reduced in cortex without a dose-response effect and no effect was observed on cerebellar binding. Zopiclone did not alter binding except for a decrease in binding at the lowest dose evaluated and an increase in binding above control at the highest dose. These data corroborate prior studies indicating that the imidazopyridines appear to act at the benzodiazepine receptor, but do not support receptor subtype selectivity of zolpidem. The limited effect of zopiclone except for increased binding at high doses is also consistent with prior studies suggesting that zopiclone acts at a site distinct from the benzodiazepine receptor.

Animals↗
PubMed1992

Chronic benzodiazepine administration. X. Concurrent administration of the peripheral-type benzodiazepine ligand PK11195 attenuates chronic effects of lorazepam.

Chronic administration of benzodiazepine active at the tau-aminobutyric acidA receptor ("central" benzodiazepine sites) is associated with behavioral tolerance and receptor downregulation. Recent reports indicate possible interactions between central sites and benzodiazepines active at "peripheral-type" sites located primarily on non-neuronal cells. To evaluate these interactions during chronic administration, we treated mice with lorazepam for 1 to 14 days alone or in combination with the peripheral-type site ligand PK11195 [N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3-carboxamid e]. Lorazepam was associated with tolerance at 7 days, but tolerance was not observed during concurrent administration of PK11195. Lorazepam was also associated with benzodiazepine receptor down-regulation in cortex and hippocampus at 7 days. With concurrent administration of PK11195, this effect remained in cortex but was absent in hippocampus. tau-Aminobutyric acid-dependent chloride uptake was reduced in both cortex and hippocampus with lorazepam, but not with concurrent lorazepam and PK11195. PK11195 administration alone did not affect behavior or neurochemical parameters, or did it alter brain lorazepam concentrations. These data indicate that concurrent PK11195 administration attenuates behavioral and neurochemical effects of chronic lorazepam administration.

Animals↗
PubMed1992

Chronic low-dose alprazolam augments gamma-aminobutyric acid(A) receptor function.

After acute administration of low doses, alprazolam displays unusual behavioral and neurochemical characteristics. To determine whether chronic low-dose alprazolam has unique effects, we treated mice for 1-14 days with alprazolam 0.2 mg/kg per day and evaluated open-field activity, benzodiazepine receptor binding, t-butylbicyclophosphorothionate binding, and muscimol-stimulated chloride uptake. Open-field activity in treated mice was similar to that of control mice at each timepoint during alprazolam administration. Similarly, benzodiazepine receptor binding in vivo was unchanged in five brain regions. Benzodiazepine receptor binding in vivo was unchanged in five brain regions. Benzodiazepine binding in vitro in the cortex was unaffected by alprazolam treatment, as was t-butylbicyclophosphorothionate binding in the cortex. However, muscimol-stimulated chloride uptake was increased after 2 and 4 days of alprazolam compared with results after 1, 7, and 14 days. These results are consistent with prior reports of unusual effects of low-dose alprazolam and extend these findings to chronic administration.

Alprazolam↗
PubMed1992

Kinetics, brain uptake, and receptor binding of tandospirone and its metabolite 1-(2-pyrimidinyl)-piperazine.

Tandospirone is an azaspirodecanedione derivative under investigation as an antidepressant. Metabolism of tandospirone in humans and rodents leads to 1-(2-pyrimidinyl)-piperazine (1-PP), presumed to have pharmacologic activity. To determine the relative contributions of tandospirone and 1-PP after tandospirone administration, we evaluated open-field activity, pharmacokinetics, and receptor binding of tandospirone and 1-PP in a mouse model. Tandospirone significantly reduced open-field activity during 30 minutes at doses of 1-20 mg/kg. 1-PP had no significant effect on activity except for a trend toward reduction at 20 mg/kg. At 30 minutes after administration, plasma and cortex concentrations of tandospirone and 1-PP increased in proportion to dose. Plasma protein binding (free fraction) for tandospirone was 30.4%, and for 1-PP, 87.5%. Receptor binding studies indicated that tandospirone bound with high affinity to serotonin1A sites, and with low affinity to serotonin2, alpha 1, alpha 2, and benzodiazepine sites. 1-PP bound with high affinity to alpha 2 sites and with low affinity to the other sites evaluated. A "receptor occupancy index" of tandospirone cortex concentrations divided by receptor affinity suggests that after acute administration of tandospirone, effects are likely to be due to the parent compound rather than to the metabolite. Similar conclusions are likely to be correct for other azaspirodecanediones, including buspirone.

Animals↗
PubMed1992

Improving prescription documentation in the ambulatory setting.

Use of a standard prescription pad, although it adequately meets the needs of drug delivery, requires the physician to document prescribed medications separately in the medical record. Failure to do so may lead to under-recognition of problems of potential drug interactions and adverse drug reactions, delays in prescription refills, and other areas of quality of care, especially in a setting where multiple physicians may be involved in the care of a patient. Of 83 prescriptions written in a primary care clinic, only 11 (13%) were noted on the chart medication form when physicians used prescription pads. Implementation of a "one-write" noncarbon prescription form that generated an instant copy increased prescription documentation to 83% (49 of 59 prescriptions) (x2 = 68.86; p < 0.005) over a one-week period. In a follow-up study conducted approximately 3.5 years after the initial intervention, use of the "one-write" form had maintained at 82% prescription documentation (32 of 39) prescriptions) (x2 = 52.05; p < 0.005). A "one-write" copy system could improve clinical care by improving medication documentation in the medical record.

Ambulatory Care↗
PubMed1992

Oxaprozin: a once-daily nonsteroidal anti-inflammatory drug.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of oxaprozin are reviewed. Oxaprozin, a nonsteroidal anti-inflammatory drug (NSAID) under consideration for approval by the Food and Drug Administration, is characterized as a propionic acid. By inhibiting cyclo-oxygenase, oxaprozin decreases the formation of prostaglandin (PG) precursors from arachidonic acid, resulting in decreased PG biosynthesis and reduced pain and inflammatory responses. Oxaprozin is well absorbed after oral administration, and peak plasma concentration is reached in three to six hours. Oxaprozin is primarily eliminated by urinary excretion of the unchanged drug. It has a long elimination half-life and persists in synovial fluid. In clinical studies, oxaprozin was equally or more effective than aspirin and as effective as naproxen in the treatment of rheumatoid arthritis. For treatment of osteoarthritis, oxaprozin was as effective as naproxen and more effective than aspirin or piroxicam. Studies have also shown oxaprozin to be effective therapy for juvenile rheumatoid arthritis and ankylosing spondylitis. Oxaprozin, like other NSAIDs, can cause gastrointestinal adverse effects. Other possible adverse effects include allergic reactions, analgesic nephropathy, hepatotoxicity, and increased bleeding times. For adults, the anticipated daily dosage is 600-1200 mg given as a single dose for rheumatoid arthritis, osteoarthritis, and analgesia. In children, oxaprozin 10-20 mg/kg/day has been used to treat juvenile rheumatoid arthritis. Oxaprozin is as effective as other NSAIDs and offers once-daily dosing; however, it does not offer any therapeutic advantage over other currently available NSAIDs.

Animals↗
PubMed1991

Chronic benzodiazepine administration. IX. Attenuation of alprazolam discontinuation effects by carbamazepine.

Clinical studies suggest that carbamazepine may attenuate effects of alprazolam discontinuation. Since discontinuation of chronic alprazolam in a mouse model is associated with behavioral alterations and upregulation at the gamma-aminobutyric acidA (GABAA) receptor, we studied the effects of carbamazepine administration after alprazolam (2 mg/kg/day) discontinuation. Open-field activity was increased in mice 4 days after alprazolam discontinuation, but this effect was reduced significantly by continuous infusion of carbamazepine, 25 or 100 mg/kg/day. Benzodiazepine receptor binding in vivo was increased in cortex at 2 and 4 days after alprazolam discontinuation, and in hypothalamus at 4 days; with carbamazepine, 100 mg/kg/day, binding in both regions at these time points was similar to control values. Similar results were observed in cortex with benzodiazepine receptor binding in vitro. GABA-dependent chloride uptake was also increased at 4 days alprazolam administration. Treatment with carbamazepine attenuated (P less than 0.10) this increase. Carbamazepine alone after vehicle did not alter benzodiazepine binding or GABA-dependent chloride uptake. These results indicate that carbamazepine administration after alprazolam discontinuation attenuates behavioral and neurochemical alterations associated with discontinuation.

Alprazolam↗
PubMed1991

Chronic benzodiazepine administration. VIII. Receptor upregulation produced by chronic exposure to the inverse agonist FG-7142.

Treatment with benzodiazepine agonists is associated with the development of behavioral tolerance and receptor downregulation, whereas antagonist administration has been reported to lead to increased activity and receptor upregulation. To determine the effects of chronic inverse agonist administration, mice were treated with FG-7142 (20 mg/kg/day) by implanted s.c. osmotic pumps for 1 to 14 days. No seizures were observed in FG-7142-exposed animals. Open-field activity was unchanged as compared to controls at days 1 and 2, but was elevated significantly at days 4 and 7. Activity was reduced below control values at day 14. Benzodiazepine receptor binding determined in vivo was unchanged for days 1, 4 and 7 within the hippocampus but was elevated at day 14. Binding remained unchanged in the cortex, cerebellum, hypothalamus and pons-medulla for the duration of drug exposure. Cortical benzodiazepine binding assessed in vitro was unchanged at days 1 and 2 but increased at days 4, 7 and 14 vs. vehicle treated controls. Binding at the gamma-aminobutyric acid site was increased at day 7 whereas binding of t-[35S]butylbicyclophosphoro-thionate was increased at days 7 and 14 of FG-7142 exposure. Maximal muscimol-slimulated [36Cl-] uptake was elevated at days 4, 7 and 14 compared to day 1 of exposure. These results demonstrate that chronic continuous exposure to FG-7142 is associated with an absence of kindled seizures and with behavioral and neurochemical changes indicative of gamma-aminobutyric acidA receptor upregulation.

Animals↗
PubMed1991

Chronic exposure to a benzodiazepine partial agonist does not alter GABAA receptor function in cultured neurons.

The benzodiazepine partial agonist Ro16-6028 does not lead to GABAA receptor downregulation in vivo. To assess effects of this compound in vitro, cultured neurons were exposed to Ro16-6028, 1 and 10 microM. GABA-dependent chloride uptake was unaffected at either dose of Ro16-6028 from 2 to 10 days, in contrast to decreased function observed with clonazepam, 1 microM, at 10 days, Ro16-6028 exposure did not alter GABA-independent chloride uptake, total neuronal protein, or cellular protein synthesis.

Animals↗
PubMed1991

Effect of exogenous carnitine on carnitine homeostasis in the rat.

The interaction of exogenous carnitine with whole body carnitine homeostasis was characterized in the rat. Carnitine was administered in pharmacologic doses (0-33.3 mumols/100 g body weight) by bolus, intravenous injection, and plasma, urine, liver, skeletal muscle and heart content of carnitine and acylcarnitines quantitated over a 48 h period. Pre-injection urinary carnitine excretion was circadian as excretion rates were increased 2-fold during the lights-off cycle as compared with the lights-on cycle. Following carnitine administration, there was an increase in urinary total carnitine excretion which accounted for approx. 60% of the administered carnitine at doses above 8.3 mumols/100 g body weight. Urinary acylcarnitine excretion was increased following carnitine administration in a dose-dependent fashion. During the 24 h following administration of 16.7 mumols [14C]carnitine/100 g body weight, urinary carnitine specific activity averaged only 72 +/- 4% of the injection solution specific activity. This dilution of the [14C]carnitine specific activity suggests that endogenous carnitine contributed to the increased net urinary carnitine excretion following carnitine administration. 5 min after administration of 16.7 mumol carnitine/100 g body weight approx. 80% of the injected carnitine was in the extracellular fluid compartment and 5% in the liver. Plasma, liver and soleus total carnitine contents were increased 6 h after administration of 16.7 mumols carnitine/100 g body weight. 6 h post-administration, 37% of the dose was recovered in the urine, 12% remained in the extracellular compartment, 9% was in the liver and 22% was distributed in the skeletal muscle. In liver and plasma, short chain acylcarnitine content was increased 5 min and 6 h post injection as compared with controls. Plasma, liver, skeletal muscle and heart carnitine contents were not different from control levels 48 h after carnitine administration. The results demonstrate that single, bolus administration of carnitine is effective in increasing urinary acylcarnitine elimination. While liver carnitine content is doubled for at least 6 h following carnitine administration, skeletal muscle and heart carnitine pools are only modestly perturbed following a single intravenous carnitine dose. The dilution of [14C]carnitine specific activity in the urine of treated animals suggests that tissue-blood carnitine or acylcarnitine exchange systems contribute to overall carnitine homeostasis following carnitine administration.

Acylation↗
PubMed1991

Chronic benzodiazepine administration: from the patient to the gene.

Chronic benzodiazepine administration is associated with the development of tolerance and dependence. To evaluate the cellular mechanisms for these phenomena the authors developed a mouse model of chronic benzodiazepine exposure. The benzodiazepine agonists lorazepam, alprazolam, and clonazepam produced tolerance in this system, which was associated in each case with benzodiazepine and GABAA receptor downregulation. After discontinuation, a syndrome that included increased motor activity and receptor upregulation occurred with each of these compounds. A benzodiazepine antagonist, flumazenil, and an inverse agonist, FG 7142, were associated with receptor upregulation and increased activity during chronic administration. In contrast, a partial agonist (Ro16-6028) did not produce tolerance or receptor changes. Similar results were obtained in a culture system for clonazepam, flumazenil, and FG 7142. The increase in receptor binding after lorazepam discontinuation may be due to enhanced receptor synthesis. Changes in gene expression for GABAA receptor subunits also occur with chronic lorazepam administration, and they follow alterations in binding.

Alprazolam↗
PubMed1991

Chronic benzodiazepine administration. VII. Behavioral tolerance and withdrawal and receptor alterations associated with clonazepam administration.

Clonazepam administration may lead to tolerance and "withdrawal" syndromes in clinical use. To assess the effects of this drug in a mouse model, we administered clonazepam (1.5 mg/kg/day) for 1-14 days and evaluated open-field activity, cortical clonazepam concentrations, and binding and function at the GABAA receptor. We also evaluated the same parameters at 1, 2, 4 and 7 days after discontinuation of 7 days of clonazepam administration. During chronic treatment, tolerance developed to the effects of clonazepam on motor activity at 7 days and persisted to 14 days. Cortical clonazepam concentrations did not change significantly during this period. Benzodiazepine receptor binding in vivo was decreased in cortex at days 7 and 14 of clonazepam, but was unchanged in other regions. Binding determined in vitro was also decreased at these points. TBPS (t-butylbicyclophosphorothionate) binding in cortex was slightly, but not significantly, decreased. Muscimol-stimulated chloride uptake was also decreased at days 7 and 14. After clonazepam discontinuation, open-field activity returned to control values at 1 day but was increased above baseline at 4 days. Benzodiazepine binding in vivo and in vitro, as well as TBPS binding, were increased at 4 days. Muscimol-stimulated chloride uptake was also increased at this point. These results indicate that chronic clonazepam administration is associated with tolerance to motoric effects, with discontinuation effects, and with receptor alterations in a mouse model. Clonazepam is similar to other benzodiazepines in this regard.

Animals↗
PubMed1991

Prenatal exposure to benzodiazepine--I. Prenatal exposure to lorazepam in mice alters open-field activity and GABAA receptor function.

Prenatal exposure to benzodiazepines may lead to developmental abnormalities in humans and animals. To assess the behavioral and neurochemical effects of such exposure, pregnant mice were treated with lorazepam, 2 mg/kg/day, from days 13-20 of gestation, and open-field activity was assessed in offspring at 3 and 6 weeks of age and the function of GABAA receptors at 6 weeks of age. Activity was increased in mice exposed to lorazepam, compared to untreated or vehicle-treated controls at 3 weeks, but was unchanged at 6 weeks. Muscimol-stimulated uptake of chloride was decreased in lorazepam-treated mice, compared to controls, with a decrease in maximum uptake but no change in the EC50 for muscimol. Concentrations of lorazepam in maternal plasma and brain showed a similar brain:plasma ratio as previously reported and concentrations in fetal brain were about 50% of maternal levels. Lorazepam persisted for 48 hours after birth in dams but not in the offspring. These results indicate persistent behavioral and neurochemical alterations after prenatal exposure to lorazepam. This model may be useful in assessing other effects of prenatal exposure to benzodiazepine.

Animals↗
PubMed1991

Prenatal benzodiazepine administration. II. Lorazepam exposure is associated with decreases in [35S]TBPS binding but not benzodiazepine binding.

Prenatal benzodiazepine exposure has been associated with neurobehavioral alterations in humans and animals. To determine effects of prenatal benzodiazepine exposure on binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites on the GABAA receptor in mature offspring, we treated mice with lorazepam, 2 mg/kg/day, during days 13-20 of gestation. Binding was assessed at 6 weeks of age. There were no differences among controls, vehicle- or lorazepam-exposed mice in benzodiazepine receptor binding determined in vivo or in vitro. However, receptor density for [35S]TBPS binding sites was decreased in lorazepam-exposed offspring compared to the other groups. These data are consistent with prior neurochemical results indicating decreased TBPS binding and GABAA receptor function in several systems.

Animals↗
PubMed1991

Persistent elevation in GABAA receptor subunit mRNAs following social stress.

Stress is associated with alterations in GABA/benzodiazepine binding and function. We evaluated effects of social stress on GABAA receptor subunit (alpha 1 and gamma 2) mRNAs by Northern hybridization. In cortex, no change was observed in either subunit mRNA immediately after stress, but a 4 hours mRNAs for both subunits were increased. These changes persisted for 72 hours after stress, and returned to baseline levels at 7 days. No changes in mRNAs were observed in sham-treated mice. No changes in either subunit mRNA were observed in stressed or sham-treated mice in cerebellum or hippocampus. In undefeated resident mice, mRNAs for both subunits in cortex were unaffected at 24 hours after the stress episode. Social stress is associated with increases in GABAA receptor alpha 1 and gamma 2 subunit mRNAs in cortex.

Animals↗
PubMed1991

Accelerated benzodiazepine receptor recovery after lorazepam discontinuation.

Benzodiazepine discontinuation can lead to a behavioral syndrome in animals and humans. In a mouse model, this syndrome is associated with benzodiazepine receptor up-regulation. The protein-modifying reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), has been used to irreversibly inactivate a number of neurotransmitter receptors including benzodiazepine receptors, and thus allows estimation of receptor recovery in vivo. To assess benzodiazepine receptor recovery after benzodiazepine discontinuation, we treated mice with lorazepam (LRZ), 2 mg.kg-1.day-1 for 1 wk. After 24 h, EEDQ (12.5 mg/kg) was administered, and benzodiazepine binding in the cortex and cerebellum was determined after 4-144 h. EEDQ treatment decreased receptor density in the cortex in both LRZ- and vehicle-treated groups by approximately 50%, with no change in apparent affinity as previously reported. Binding in both groups returned to control values after 96 h. Kinetic analysis indicated a more rapid increase in binding in LRZ-compared with vehicle-treated animals, with t1/2 for LRZ 19.1 h, and for vehicle, 30.8 h (P less than 0.05). Receptor density was decreased in the cerebellum after EEDQ by approximately 40% in both treatment groups, with no change in apparent affinity. Receptor density returned to control values at 96 h, with no difference in kinetics in LRZ- compared with vehicle-treated mice. The decrease in receptor t1/2 associated with lorazepam discontinuation is consistent with the observed increase in benzodiazepine receptors in this setting.

Animals↗