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Biomedical subjects

M S Roberts

Publications and source records attributed to M S Roberts.

At least 199 records · Page 11Linked to original sources
PubMed1988

Management of asymptomatic gallstones in the diabetic patient. A decision analysis.

The management of asymptomatic cholelithiasis in patients with diabetes is controversial. We used decision analysis to compare expectant management to prophylactic cholecystectomy in asymptomatic diabetic patients. Relevant probabilities were derived from the literature or expert opinion. Hypothetical cohorts of patients were followed for their lifetimes under each strategy. Expectant management was almost always the superior course. For example, a 30-year-old diabetic man gains an average of 6.1 months of life by choosing expectant management over prophylactic surgery. The superiority of expectant management was invariant to changes in age, sex, and the extent to which major surgical complications affect the future quality of life. Prophylactic cholecystectomy was superior only with extremely high estimates of the likelihood of developing symptomatic disease, the probability of requiring emergency surgery after symptoms develop, and emergency surgical mortality rates. However, no single factor had sufficient impact to alter the optimal decision by itself; the probabilities of several untoward events had to be increased simultaneously to favor prophylactic cholecystectomy. Prophylactic surgery for silent gallstones in diabetic patients does not increase life expectancy or quality of life and may in fact reduce it. This result holds over a wide range of basic assumptions.

Acute Disease↗
PubMed1988

The effects of posture on the pharmacokinetics of intramuscular benzylpenicillin.

Previous reports have produced conflicting results as to whether changes in posture affected the pharmacokinetics of the penicillins. We have studied the pharmacokinetics of intramuscularly administered benzylpenicillin in normal subjects during bedrest and ambulation and compared it with data obtained following intravenous administration of the same dose to the same subjects under the same conditions. The values of area under the curve, total clearance, mean residence time and renal clearance found during ambulation were 1175 (min.min.l-1), 488 (ml.min-1), 101 (min), and 264 (ml.min-1) (means). The corresponding values for bedrest were 1032 (min.mg.l-1), 544 (ml.min-1), 96.7 (min), and 315 (ml.min-1). There was a significant difference between the areas under the curve with change of posture but not between any of the other pharmacokinetic variables. The differences observed in this study are unlikely to be of clinical relevance. We suggest that the differences between the results of this study and those of previous studies may be related to the level of exercise undertaken by the subjects in the various studies.

Adult↗
PubMed1988

Models of hepatic elimination: comparison of stochastic models to describe residence time distributions and to predict the influence of drug distribution, enzyme heterogeneity, and systemic recycling on hepatic elimination.

The residence time distribution of noneliminated solutes in the liver can be represented by a variety of stochastic models. The dispersion model (closed and mixed boundary conditions), gamma distribution, log normal distribution and normal distribution models were used to describe output concentration-time profiles after bolus injections into the liver of labeled erythrocytes and albumin. The dispersion model and log normal distribution model provide the best representation of the data and give similar estimates of relative dispersion and availability for varying hepatocellular enzyme activity. The availability of solutes eliminated from the liver by first-order kinetics is determined by the residence time distribution of the solute in the liver and not on events occurring in the liver when a uniform enzyme distribution is assumed. Both enzyme heterogeneity (axial or transverse) and hepatocyte permeability may affect solute availability. A more complex model accounting for enzyme distribution and the micromixing of solute within the liver is required for solutes undergoing saturable kinetics.

Biological Transport↗
PubMed1988

Clinical applicability of current pharmacokinetic models: splanchnic elimination of 5-fluorouracil in cancer patients.

What can be inferred from limited clinical data by using current models of hepatic elimination? We examined this question by analyzing previously published data on the steady-state uptake of the anticancer agent 5-fluorouracil (5-FU) in seven cancer patients in terms of the venous equilibration model, the undistributed and distributed forms of the sinusoidal perfusion model, and the convection-dispersion model. Because of appreciable extrasplanchnic removal of 5-FU, the value of the steady infusion rate was not used in our analysis. When the data from all patients were pooled by plotting the measured hepatic venous concentration against the measured hepatic arterial concentration, the high concentration data fell on a limiting straight line of slope 1, indicating that at high dose rates elimination of 5-FU in both the liver and gastrointestinal tract was close to saturation. The intercept of this line gave a model-independent estimate of Vmax/Q = 48.0 +/- 11.6 (SD) microM for the pooled data set, where Vmax is the maximum splanchnic elimination rate of 5-FU, and Q is the hepatic blood flow. The low concentration data points fell on a limiting straight line through the origin, from which model-dependent values of the Michaelis constant were determined. The venous equilibration model gave Km = 9.4 microM, while the undistributed sinusoidal perfusion model gave Km* = 26.5 microM. With these values of Km, both models fit the pooled data equally well. These methods were applied to analyses of the five individual data sets which contained sufficiently high concentration data points. The resulting mean values were Vmax/Q = 41.0 +/- 5.1 (sem) microM, Km = 8.4 +/- 1.3 microM and Km* = 23.2 +/- 3.2 microM. However, the splanchnic region is a highly heterogeneous organ system, for which an undistributed analysis provides no more than an upper bound on the Michaelis constant Km+ (Km+ less than or equal to Km*). A perfusion model distributed to represent total splanchnic elimination is developed in the Appendix. Using previous estimates of the degree of functional heterogeneity in the liver alone, this model yields Km+ values for individual patients which have a mean of 20.3 +/- 2.8 microM.

Fluorouracil↗
PubMed1988

Direct correlation between a negative autoregulatory response element at the cap site of the herpes simplex virus type 1 IE175 (alpha 4) promoter and a specific binding site for the IE175 (ICP4) protein.

In transient-expression assays, the IE175 (alpha 4) promoter region of herpes simple virus is down-regulated after cotransfection with DNA encoding its own protein product (IE175 or ICP4). The inhibition by IE175 proved to be highly specific for its own promoter region and did not act on either the herpes simplex virus type 1 IE110 (alpha 0) or human cytomegalovirus major immediate-early promoters. Furthermore, the inhibition was still exhibited by IE175 effector plasmids driven by strong heterologous promoters and therefore must be a direct autoregulatory response that cannot be explained by promoter competition effects. In gel mobility retardation assays with infected-cell nuclear extracts, a prominent and specific DNA-protein complex was formed with DNA fragments containing sequences from -108 to +30 in the IE175 promoter region. This activity was not present in mock-infected samples. Even stronger binding occurred with a fragment containing sequences from -128 to +120 in the IE110 promoter, but this second locus was not associated with any detectable response phenotype in cotransfection assays. Supershift experiments with an anti-IE175 monoclonal antibody confirmed the presence of the IE175 protein in both DNA-protein complexes. In the IE175 promoter, specific binding correlated closely with the presence of an intact autoregulatory signal near the cap site as judged by the loss of both activities in a 3'-deleted promoter fragment lacking sequences from -7 to +30. Insertion of a cloned 30-mer synthetic oligonucleotide sequence from positions -8 to +18 in IE175 restored both IE175 binding activity and the down-regulation phenotype. Direct shift-up assays with a similar 30-base-pair (bp) oligonucleotide containing 21 bp from positions -75 to -55 of IE110 (which encompasses a consensus ATCGTC motif) also produced a specific DNA-protein complex containing the IE175 protein. This ATCGTC motif proved to be a necessary component of both the IE110 and IE175 binding sites, but was insufficient on its own for complex formation. Finally, deletion of 2 bp from positions -3 and -4 within the ATCGTC sequence in the IE175 cap site region abolished both binding activity and the IE175-dependent autoregulation phenotype.

Animals↗
PubMed1987

On the relation between extended forms of the sinusoidal perfusion and of the convection-dispersion models of hepatic elimination.

Two models of hepatic elimination, the distributed sinusoidal perfusion model, and the convection-dispersion model, are extended and then compared for first order kinetics in the steady-state. The sinusoidal perfusion model is extended by the inclusion of intrahepatic sites of mixing between sinusoids. The degree of such mixing is estimated for taurocholate elimination by isolated perfused rat livers by a comparison of anatomical and kinetic estimates of uptake heterogeneity, using previously published data. The dispersion model is generalized by the inclusion of distributions of enzyme activity along the flow. Direct comparison of the two models in the limit in which the degree of dispersion is small, allows the flow-dependence of the dispersion coefficient to be determined, thereby greatly extending the explanatory power of the convection-dispersion model. Finally, the effect of intrahepatic mixing sites on uptake by Michaelis-Menten kinetics is quantified in terms of the distributed sinusoidal perfusion model, with results which may be applicable to capillary beds in general.

Animals↗
PubMed1987

Rapid high-performance liquid chromatographic assay for the simultaneous analysis of non-steroidal anti-inflammatory drugs in plasma.

A high-performance liquid chromatographic assay has been developed for the determination of a number of non-steroidal anti-inflammatory drugs in plasma. The samples were prepared by adding acetonitrile and perchloric acid to 200 microliter of plasma. Diclofenac, fenoprofen, ketoprofen, naproxen, phenylbutazone, piroxicam and sulindac were quantified in the supernatant produced using a mobile phase of phosphoric acid 0.03% (pH 2.5)-acetonitrile and a detecting wavelength of 254 nm. The reproducibility, linearity, precision and specificity of the assay were determined and found to be satisfactory. Alteration of the detection wavelength to 229 nm also permitted accurate determination of ibuprofen concentration in plasma. While reduction of the organic solvent content of the mobile phase and alteration of wavelength to 313 nm produced a system capable of quantifying salicylate and its metabolites in plasma and by further reducing the detecting wavelength to 237 nm, aspirin also was quantifiable. These methods have been applied in a cross-sectional study of medication compliance among rheumatoid arthritis patients treated with non-steroidal anti-inflammatory drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1986

Kinetics of sorption of ionizable solutes by plastic infusion bags.

Aqueous solutions of several ionizable substances were stored in plastic infusion bags and the sorption of the substances monitored with time. The substances used were p-nitrophenol, p-toluidine, warfarin sodium [3-(alpha-acetonylbenzyl)-4-hydroxycoumarin sodium salt] and trifluoperazine hydrochloride (10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride). The rate and extent of sorption for each substance varied with pH and was consistent with a preferential uptake of the un-ionized species. The uptake of p-nitrophenol and p-toluidine was adequately described by a diffusion model derived assuming that sorption is rate-controlled by the diffusivity of the solute in the plastic matrix, and that only the un-ionized species was sorbed by the plastic matrix. However, the uptake of warfarin sodium and trifluoperazine hydrochloride was described more accurately by a diffusion model in which the diffusional resistance of the plastic matrix and of an interfacial resistance barrier both contributed to the diffusional resistance encountered in the sorption process. It appeared that the rate of uptake of the un-ionized form of these solutes was diminished due to the influence of interfacial or aqueous diffusional barriers. Solute lipophilicity and degree of ionization appeared to be important factors determining the relative contribution of the respective barriers to the overall diffusional resistance.

Absorption↗
PubMed1986

Extrahepatic metabolism and distribution of aspirin in vascular beds of sheep.

The dispositions of aspirin, its metabolite, salicylic acid, and its subsequent metabolite, salicyluric acid, were studied in eight anesthetized sheep infused with aspirin (61 and 485 microgram X min-1 X kg-1) for 75 min. Plasma samples were withdrawn from the portal vein, hepatic vein, pulmonary artery, left ventricle, left femoral vein, and left femoral artery. Significant extraction of aspirin occurred across the liver and hind leg, with mean availabilities of 0.75, 0.98, and 0.82 observed across the liver, lung, and hind leg, respectively. The extraction of aspirin was not affected by coadministration of sodium salicylate (30-1200 mg equiv salicylic acid). This extraction reflected hydrolysis of aspirin to salicylic acid; the metabolism of aspirin in the hind leg, lung, and liver being confirmed with tissue homogenate studies. The metabolism of aspirin in the extrahepatic tissues is significant in relation to the proposed selective presystemic acetylation of platelet cyclooxygenase by aspirin and the use of low-dose aspirin for thrombotic indications.

Animals↗