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Biomedical subjects

L G Miller

Publications and source records attributed to L G Miller.

At least 163 records · Page 9Linked to original sources
PubMed1987

Trazodone kinetics: effect of age, gender, and obesity.

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

Adult↗
PubMed1987

Benzodiazepine receptor binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose alprazolam.

Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of alprazolam (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of alprazolam (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprazolam↗
PubMed1987

Clonazepam pharmacokinetics, brain uptake, and receptor interactions.

The 7-nitrobenzodiazepine derivative clonazepam is initially biotransformed by nitroreduction, followed by acetylation. Neither the amino- nor the acetamido- metabolites appear to have important pharmacologic activity. Clonazepam elimination half-life falls in the range of 20 to 80 hours, but means within the population and variance are not well defined. Absorption of orally administered clonazepam is 80% or more. In experimental studies, clonazepam appears to diffuse passively from plasma into brain, with a constant brain-plasma concentration ratio. The drug disappears in a parallel fashion from both brain and plasma, with no evidence of sequestration in brain tissue. Clonazepam has a relatively high molar affinity for the benzodiazepine receptor in vitro, and the fractional extent of benzodiazepine receptor occupation by clonazepam in vivo is directly and predictably related to the drug's concentration in brain tissue. Acute behavioral effects are in turn directly related to the extent of receptor occupancy. Compared to other benzodiazepines, the reportedly unique clinical properties of clonazepam are neither associated with unusual/unexpected pharmacokinetic properties or with a qualitatively different in vivo interaction with the presumed benzodiazepine binding site.

Acetylation↗
PubMed1987

Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions.

A tracer radioligand technique employing [3H]Ro 15-1788 was used to measure in vivo benzodiazepine receptor occupancy in mice. Animals were administered clonazepam (CNZ) or lorazepam (LRZ) i.p. or i.v., followed by [3H]Ro 15-1788. Plasma and cerebral cortical concentrations of the drug and cortical benzodiazepine receptor occupancy were determined at varying doses and times after administration. For both drugs, plasma and brain concentrations decreased in parallel with decreasing doses and with time, and the brain/plasma ratios remained constant. Receptor occupancy was maximal for CNZ and LRZ at doses above 1 and 4 mg/kg, respectively, and decreased with decreasing doses. Comparison of receptor occupancy with brain concentration yielded IC50 values of 21 ng/g for CNZ and 133 ng/g for LRZ. The apparent dissociation constant (Kd) for CNZ was 56 pmol/g and, for LRZ, 372 pmol/g. Hill plots yielded slopes of 1.30 for CNZ and 1.71 for LRZ. Alterations in the nonspecific uptake or elimination of Ro 15-1788 did not explain occupancy changes, inasmuch as brain concentrations of unlabeled Ro 15-1788 (6 mg/kg) were not changed by LRZ administration. The correlation between receptor occupancy and the pharmacodynamic actions of these drugs in blocking pentylenetetrazol seizures and inducing rotarod ataxia indicated that ED50 for these effects occurred at receptor occupancy of 30 to 60% for both drugs.

Animals↗
PubMed1987

The triphasics: insights for effective clinical use.

Three triphasic oral contraceptive preparations are currently being widely used in the United States. These are Ortho-Novum 7/7/7 (Ortho Pharmaceutical), Tri-Norinyl (Syntex) and Triphasil (Wyeth). The hormone manipulation in these formulations more closely mimics the normal menstrual cycle and decreases the total amount of hormone delivered. These drugs were formulated to decrease menstrual irregularities and nuisance side effects and increase menstrual control, while maintaining efficacy and safety. This article describes these products, their mechanisms of action, efficacy and selected areas of concern for clinical practice in relation to side effects, safety and menstrual control. Findings and suggestions related to the therapeutic administration, patient use, counseling and management of these newer oral contraceptives will assist the nurse practitioner in providing optimum care to the consumer.

Contraceptives, Oral, Combined↗
PubMed1986

Measurement of nitrous oxide reductase activity in aquatic sediments.

Denitrification in aquatic sediments was measured by an N(2)O reductase assay. Sediments consumed small added quantities of N(2)O over short periods (a few hours). In experiments with sediment slurries, N(2)O reductase activity was inhibited by O(2), C(2)H(2), heat treatment, and by high levels of nitrate (1 mM) or sulfide (10 mM). However, ambient levels of nitrate (<100 muM) did not influence activity, and moderate levels (about 150 muM) induced only a short lag before reductase activity began. Moderate levels of sulfide (<1 mM) had no effect on N(2)O reductase activity. Nitrous oxide reductase displayed Michaelis-Menten kinetics in sediments from freshwater (K(m) = 2.17 muM), estuarine (K(m) = 14.5 muM), and alkaline-saline (K(m) = 501 muM) environments. An in situ assay was devised in which a solution of N(2)O was injected into sealed glass cores containing intact sediment. Two estimates of net rates of denitrification in San Francisco Bay under approximated in situ conditions were 0.009 and 0.041 mmol of N(2)O per m per h. Addition of chlorate to inhibit denitrification in these intact-core experiments (to estimate gross rates of N(2)O consumption) resulted in approximately a 14% upward revision of estimates of net rates. These results were comparable to an in situ estimate of 0.022 mmol of N(2)O per m per h made with the acetylene block assay.

Journal Article↗
PubMed1986

Metabolism of reduced methylated sulfur compounds in anaerobic sediments and by a pure culture of an estuarine methanogen.

Addition of dimethylsulfide (DMS), dimethyldisulfide (DMDS), or methane thiol (MSH) to a diversity of anoxic aquatic sediments (e.g., fresh water, estuarine, alkaline/hypersaline) stimulated methane production. The yield of methane recovered from DMS was often 52 to 63%, although high concentrations of DMS (as well as MSH and DMDS) inhibited methanogenesis in some types of sediments. Production of methane from these reduced methylated sulfur compounds was blocked by 2-bromoethanesulfonic acid. Sulfate did not influence the metabolism of millimolar levels of DMS, DMDS, or MSH added to sediments. However, when DMS was added at approximately 2-muM levels as [C]DMS, metabolism by sediments resulted in a CH(4)/CO(2) ratio of only 0.06. Addition of molybdate increased the ratio to 1.8, while 2-bromoethanesulfonic acid decreased it to 0, but did not block CO(2) production. These results indicate the methanogens and sulfate reducers compete for DMS when it is present at low concentrations; however, at high concentrations, DMS is a "noncompetitive" substrate for methanogens. Metabolism of DMS by sediments resulted in the appearance of MSH as a transient intermediate. A pure culture of an obligately methylotrophic estuarine methanogen was isolated which was capable of growth on DMS. Metabolism of DMS by the culture also resulted in the transient appearance of MSH, but the organism could grow on neither MSH nor DMDS. The culture metabolized [C]-DMS to yield a CH(4)/CO(2) ratio of approximately 2.8. Reduced methylated sulfur compounds represent a new class of substrates for methanogens and may be potential precursors of methane in a variety of aquatic habitats.

Journal Article↗
PubMed1985

Advice of manufacturers about effects of temperature on biologicals.

Information was obtained from manufacturers on the stability of biologicals when exposed to higher-than-recommended temperatures, and procedures were developed for determining whether the quality of these products is compromised after such exposure. Questionnaires were sent to 24 manufacturers asking for product information regarding stability of frozen biologicals exposed to refrigeration or room temperature, stability of refrigerated biologicals exposed to room temperature, shelf life under optimal conditions, and recommended transport temperature. Information was provided by 20 of the manufacturers. Some manufacturers declined to make general recommendations; instead, they stated that the manufacturer should be contacted regarding the individual situation. The responses indicated that most products do not require freezing for storage and transport. Most must be stored refrigerated but can be transported at room temperature. Use of manufacturers' stability recommendations can help the pharmacist determine whether biologicals are of an acceptable quality for patient use.

Allergens↗
PubMed1984

[Role of the locus coeruleus in the development of cerebrovascular disorders in acute myocardial ischemia].

Experiments on rats were made to examine the total cerebral blood flow during locus coeruleus (LC) stimulation, acute myocardial ischemia and in the presence of acute myocardial ischemia after LC precoagulation . LC electric stimulation caused a decrease in the cerebral blood flow. The most profound cerebrovascular disorders were observed in animals with acute myocardial ischemia without LC precoagulation and were followed by cardiac arrhythmias. Cerebrovascular hemodynamic disorders occurring in acute myocardial ischemia were prevented by LC coagulation. It is suggested that the cerebrovascular disorders are consequent on the formation in the LC of the hyperactive determinant structure and play a role of a secondary pathogenetic factor in heart regulation disorders.

Acute Disease↗
PubMed1983

Asbestos exposure correlates with alterations in circulating T cell subsets.

Peripheral blood lymphocytes were analysed from 40 subjects with occupational asbestos exposure and 40 controls matched for age and smoking habits. Patients were classified by duration of exposure as short or long, and by chest radiograph as normal, pleural plaques or interstitial changes. As a group, subjects with asbestos exposure had decreased percentages of OKT3+ and OKT8+ cells and increased OKT4+/OKT8+ ratio compared to controls. Correcting for age and smoking, those with short exposure were similar to controls, while those with long exposure had decreased percentages OKT3+ and OKT8+ cells and an increased OKT4+/OKT8+ ratio. Among radiographic subgroups, those with normal radiographs were similar to controls, but those with plaques had increased circulating OKT4+ cells, and those with interstitial changes had decreased percentages OKT3+ and OKT8+ cells and OKT8+ cells/mm3, with an increased OKT4+/OKT8+ ratio. There were no differences between subjects and controls in OKT10+ cells and OKIa+ cells. There appears to be a progressive decrease in percentage OKT8+ cells and increase in OKT4+/OKT8+ ratio with increasing exposure to asbestos, as determined by length of exposure and by radiographic abnormalities.

Antibodies, Monoclonal↗
PubMed1983

[Experimental and clinical study of the efficacy of intracarotid administration of curantil in the treatment of cerebral ischemia].

Curantil intracarotid injection resulted in brain blood supply and in brain oxygen consumption increase as well as in redox processes normalization in 75 cats with main brain arteries occlusion and heart insufficiency induced by chemical necrosis of the myocardium. A single intravenous injection of a higher curantil dose resulted in a significantly less effect. Long-term (3-72 hours) curantil infusion led to the improvement of the functions disturbed (limb movements, speech, vision) in 32 of 42 patients with brain ischemic insult. The greatest therapeutic efficacy was observed in patients with nonobturated brain infarction induced by brain vascular spasm or cardiocerebral vascular insufficiency.

Adult↗
PubMed1982

T-lymphocyte subsets in smoking and lung cancer: Analysis of monoclonal antibodies and flow cytometry.

In order to determine whether abnormalities of immunoregulatory T-cells occur in patients with lung cancer, we characterized peripheral T-lymphocytes in 26 patients with untreated lung cancer. The results in patients with primary squamous cancer (SC) (n = 10), primary adenocarcinoma (AC) (n = 7), and secondary lung metastases (M) (n = 9) were compared with each other and to subjects without cancer (n = 48), including nonsmokers (n = 29) and smokers (n = 19). We found that OKT3+ (mature, peripheral (T-lymphocytes, including both OkT4+ (inducer/helper) and OKT8+ (cytotoxic/suppressor) lymphocytes, were increased in light-to-moderate smokers, but that OKT4+ cells were decreased n heavy smokers (p less than 0.05). The ratio of OKT4+ to OKT8+ (4/8) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in light-to-moderate smokers, but was decreased in heavy smokers (p less than 0.05). The profile of circulating T-cells in patients with SC was similar to the smokers. In contrast, in patients with AC, we found a decreased percentage of OKT8+ cells (p less than 0.05). The 4/8 ratio was elevated in patients with AC (p less than 0.05). In patients with M, there was a decreased percentage of OKT3+ cells reflected in both OKT4+ and OKT8+ subsets. The 4/8 ratio in patients with M was low. Thus, a number of abnormalities in circulating T-cells was found both in smokers and in patients with lung cancer. These results suggest that immunoregulatory abnormalities contribute to the pathogenesis of lung cancer.

Adenocarcinoma↗