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Biomedical subjects

D S Wilson

Publications and source records attributed to D S Wilson.

18 recordsLinked to original sources

Drug-food interaction potential of clarithromycin, a new macrolide antimicrobial.

To evaluate the effect of food on bioavailability, clarithromycin and 14-hydroxyclarithromycin (active metabolite) pharmacokinetics were assessed in 26 healthy adult volunteers after ingestion of a single oral 500-mg dose of clarithromycin in a fasting state (2 hours before breakfast after an overnight fast) and a nonfasting state (0.5 hours after the start of breakfast). Clarithromycin and 14-hydroxy metabolite plasma concentrations were measured using a high-performance liquid chromatographic technique. Food intake immediately before dosing increased the extent of absorption from the 500-mg tablet formulation by approximately 25%. The mean increase in metabolite area under the plasma concentration-time curve was approximately 9%. These results suggest that clarithromycin can be taken without regard to timing in relation to meals.

Absorption

Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.

Administration, Oral

Identification of preventable trauma deaths: confounded inquiries?

The published evaluation of methods for identifying preventable trauma deaths contains many unstudied confounding factors. To investigate the reliability of methods for identifying such preventable deaths, we compared three consensus systems using separate five-member general review panels assessing 20 non-central nervous system fatalities: panel A, independent judgments; panel B, discussion of all cases preceding individual judgments; and panel C, independent judgments followed by discussion and equivocal case reassignment. The Kappa concordance index was low for all methods (method A, 0.20; methods B and C, 0.40). Of the 11 deaths judged preventable by at least one panel, only one death was judged preventable by all three panels. Consensus agreement (four of five assessors) was 20% for panel A, 45% for panel B, and 10% for panel C (difference between panels B and C, p less than 0.03). In panel C, discussion affected the rate of equivocal case designation from 30% to 5%. Thus different consensus methods yielded different results. We conclude that individual case review can be severely flawed and therefore should not be used to measure institutional quality of patient care. We recommend that assessment of institutional performance should be based on objective evaluation methods, which require the study of patient population outcomes, rather than on subjective methods in which individual cases are reviewed.

Confounding Factors, Epidemiologic

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.

Administration, Oral

Ubiquinone protects against loss of tocopherol in rat liver microsomes and mitochondrial membranes.

Liver microsomes and submitochondrial particles (SMP) were isolated from rats fed on a vitamin E or coenzyme Q10/vitamin E enriched diet in order to clarify the antioxidant interactions between coenzyme Q10 and vitamin E. Electron spin resonance spectrometry shows that the decay of vitamin E radicals (tocopheroxy radicals) generated by the arachidonic acid/lipoxygenase oxidation system proceeded at a higher rate in vitamin E enriched microsomes and SMP than in those enriched with coenzyme Q10/vitamin E. Vitamin E levels determined by high performance liquid chromatography revealed that when subjected to enzymatic oxidation, membranes enriched with vitamin E alone were depleted of vitamin E earlier than those enriched with both coenzyme Q10 and vitamin E. These results show that coenzyme Q10 conserves vitamin E, which would help prolong membrane resistance against oxidative damage.

Animals

Mitochondrial electron transport-linked tocopheroxyl radical reduction.

alpha-Tocopherol (vitamin E) is a lipophilic chain-breaking antioxidant which inhibits lipid peroxidation in isolated mitochondrial membranes and protects membranes from oxidative damage. The primary oxidation product of vitamin E is the tocopheroxyl radical. Reduction of the tocopheroxyl radical can occur by reactions with water-soluble anti-oxidants such as ascorbate or glutathione, resulting in the recycling of vitamin E. Physiological concentrations of vitamin E are too low to allow detection of tocopheroxyl radical by ESR. After dietary supplementation with vitamin E, a 10-20-fold increase in the rat liver mitochondrial membrane content of vitamin E was achieved and this allowed for direct detection of the tocopheroxyl radical by ESR, after treatment with an oxidizing system composed of lipoxygenase and arachidonic acid. By using submitochondrial particle membranes, it was shown that NADH, succinate, and reduced cytochrome c-linked oxidation reduce the tocopheroxyl radical, preventing both accumulation of the radical and vitamin E consumption. As the electron transport chain can reduce tocopheroxyl radical it may have an important physiological role in recycling vitamin E.

Animals

Reviving the superorganism.

Individuals become functionally organized to survive and reproduce in their environments by the process of natural selection. The question of whether larger units such as groups and communities can possess similar properties of functional organization, and therefore be regarded as "superorganisms", has a long history in biological thought. Modern evolutionary biology has rejected the concept of superorganisms, explaining virtually all adaptations at the individual or gene level. We criticize the modern literature on three counts. First, individual selection in its strong form is founded on a logical contradiction, in which genes-in-individuals are treated differently than individuals-in-groups or species-in-communities. Imposing consistency clearly shows that groups and communities can be organisms in the same sense that individuals are. Furthermore, superorganisms are more than just a theoretical possibility and actually exist in nature. Second, the view that genes are the "ultimate" unit of selection is irrelevant to the question of functional organization. Third, modern evolutionary biology includes numerous conceptual frameworks for analyzing evolution in structured populations. These frameworks should be regarded as different ways of analyzing a common process which, to be correct, must converge on the same conclusions. Unfortunately, evolutionists frequently regard them as competing theories that invoke different mechanisms, such that if one is "right" the others must be "wrong". The problem of multiple frameworks is aggravated by the fact that major terms, such as "units of selection", are defined differently within each framework, yet many evolutionists who use one framework to argue against another assume shared meanings. We suggest that focusing on the concept of organism will help dispell this fog of semantic confusion, allowing all frameworks to converge on the same conclusions regarding units of functional organization.

Animals

Repletion of folate-depleted rats with an amino acid-based diet supplemented with folic acid.

Folate depletion and repletion protocols are not well standardized. Weanling rats were moderately depleted of folate in 28 d with a folate-free purified diet based on 17% amino acids as the nitrogen source. They were then folate repleted for 23 d with the amino acid diet supplemented with either 125, 250, 500, 1000 or 2000 micrograms folic acid/kg. Hematology, growth and tissue folate levels were measured in subsets of the rats when they were 24 (baseline), 52 (depleted) and 75 d old (repleted). The same measurements were made in control rats that had been fed 2 mg folic acid/kg of the amino acid diet for the same period of time. Our findings show that with repletion, growth of previously depleted rats is in direct proportion with the level of supplementation up to 1000 micrograms folic acid/kg diet. Serum folate levels of repleted rats also increased in proportion to supplementation between 500 to 2000 micrograms/kg diet, and liver folate levels increased proportionally with the level of supplement within the range of 125 to 2000 micrograms/kg diet. The 2000 micrograms/kg supplement was sufficient to restore liver folate levels equivalent to that of controls, but body weight and serum folate levels failed to catch up with that of controls in the 23-d repletion period. There was a nonlinear relationship between serum and liver folate levels: serum folate remained constant at about 6 micrograms/l as liver folate increased to about 7 micrograms/g, then serum folate diverged by increasing to 120 micrograms/l with only minor increases in liver folate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids

Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation.

Antioxidants may play a significant role in ameliorating or preventing photobiologic damage in skin that could lead to cutaneous disorders such as cancer and premature aging. The objective of this study was to assess the acute cutaneous enzymic and nonenzymic antioxidant response to a single exposure of large fluence (300 mJ/cm2) ultraviolet radiation (greater than 280 nm) in hairless mice. This treatment caused an immediate and statistically significant inhibition of glutathione reductase and catalase activity. Glutathione peroxidase and superoxide dismutase were not affected. Glutathione levels decreased and, conversely glutathione disulfide concentrations increased. A slight depletion of the total glutathione was observed, while the content of total ascorbic acid did not change. The lipophilic antioxidants alpha-tocopherol, ubiquinol 9 and ubiquinone 9 also decreased significantly, and the concentration of malondialdehyde remained constant. The free radical scavenging activity of epidermis, as assessed by reduction of the stable, cationic nitroxide radical [2,2,6,6-tetramethyl-1-piperidinoxy-4-(2',4',6'-trimethyl) methylpyridinium perchlorate] was considerably inhibited. The study indicates that immediately after exposure to a large fluence of ultraviolet radiation the enzymic and nonenzymic antioxidant capacity of skin decreases significantly.

Animals

Acute effects of near ultraviolet and visible light on the cutaneous antioxidant defense system.

Reactive oxygen species are considered to play an important role in cutaneous pathology. Enzymic and non-enzymic antioxidants can prevent oxidative damage but may be overcome by strong pro-oxidative stimuli. The acute effect of a single exposure to near ultraviolet (UVA)/visible radiation (greater than 320 nm) on various skin antioxidants was examined in hairless mice immediately after irradiation. Impairment of cutaneous catalase and glutathione reductase activity was observed. Superoxide dismutase and glutathione peroxidase were not significantly influenced. Inhibition of catalase may render skin more susceptible to the damaging effects of hydrogen peroxide and its reaction products such as the hydroxyl radical. Partially diminished glutathione reductase activity is not accompanied by a change in reduced/oxidized glutathione level immediately after irradiation. There was a tendential (not statistically significant) decrease in cutaneous tocopherol, ubiquinol + ubiquinone 9 and ascorbic acid levels, either indicating direct photodestruction or consumption by reaction products of photooxidative stress. This partial impairment of the cutaneous antioxidant defense system by near ultraviolet/visible light, showing that the most susceptible component in skin is catalase, suggests possible pharmacological interventions.

Animals

Regulated expression of the human mutant ras gene after transfection of BALB/c mouse embryo fibroblast cells.

Four continuous cell lines constructed by transfecting BALB/c mouse fibroblast cells with an expression system that has the mutant c-Ha-ras gene under control of a truncated version of the mouse metallothionein-1 (mt-1) promoter were characterized for zinc-induced phenotype switching. These cells were selected for transformation in the presence of zinc, a known inducer of the mt-1 promoter. When the transfected cells were grown in medium depleted of zinc, there was a dramatic reduction in their soft agar cloning efficiency. Adding zinc back to the medium restored the transformed phenotype in a dose-dependent manner. Analysis of the intracellular p21 levels of induced and uninduced cells showed that zinc was modulating the expression of the transfected ras gene. In vivo studies done with syngeneic mice showed that zinc-induced cells were tumorigenic and formed metastatic lesions in the lungs of the inoculated animals.

Animals

Coevolution in structured demes.

A simple model of coevolution in a subdivided population is considered. It is shown that, when there are frequency- and density-dependent interactions in each site, the sampling variation in numbers in each local site can lead to selection both through the dispersal process and through indirect effects. The model predicts that coevolved relationships between species can result from various interactions other than direct forms of competition and predation.

Animals

Pain in the neck and arm.

The clinical features of eight cases of carcinoma of the bronchus presenting as pain in the neck and arm, arising from a population of 320 000 in eight years, are described. The difficulties in establishing a diagnosis are discussed, and the implications for therapy and management are described. It would appear that carcinoma of the bronchus, whether local, as a Pancoast syndrome, or metastatic, is more common than is realized.

Adult

Evolution on the level of communities.

According to traditional models, natural selection is largely insensitive to an organism's effect on its community. Effects on the community at large cannot feed back differentially to the organisms that cause them, and, hence, cannot lead to the differential fitness of the organisms. However, if a spatial variation exists in community composition, organisms do differentially feel their own effects on the community, and this leads to a form of evolution on the community level. Without violating the principle of individual selection, the concept of an organism that exists for the "function" its performs in its community may be valid in some cases.

Animals

A theory of group selection.

In organisms possessing a dispersal phase the processes of mating, competition, feeding, and predation are often carried out within "trait-groups," defined as populations enclosed in areas smaller than the boundaries of the deme. A simple model shows that this can lead to the selection of "altruistic" traits that favor the fitness of the group over that of the individual. The extent of group selection that occurs depends mainly on the variation in the composition of genotypes between trait-groups. The traditional concepts of group and individual selection are seen as two extremes of a continuum, with systems in nature operating over the interval in between.

Animals