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Biomedical subjects

L I Harrison

Publications and source records attributed to L I Harrison.

At least 19 recordsLinked to original sources
PubMed1992

Effect of food on salsalate absorption.

To assess the effect of food on salsalate absorption, single 1500-mg oral doses of salsalate were administered to 17 men under fasted and fed conditions according to a randomized open-label crossover design. A 7-day washout separated treatment periods. Blood samples were drawn throughout the 48-h period following dose administration and the resulting plasma samples assayed by high-performance liquid chromatography (HPLC) for unchanged drug, salsalate, and the major metabolite, salicylic acid. When results for the fasted and fed treatments were compared, no significant differences were observed in the pharmacokinetic parameters for the major metabolite salicylic acid or in the extent of absorption of unchanged drug; however, the rate of salsalate absorption was affected. Although the time-to-peak for salsalate was significantly delayed by approximately 1 h in the presence of food, the peak level was not significantly affected. The lack of difference between the two treatments for the therapeutic moiety, salicylic acid, indicates a lack of a significant food effect on single doses of salsalate.

Absorption↗
PubMed1989

Pharmacokinetic properties of sustained-release theophylline (Theolair-SR) in relation to timing of doses after low-fat meals.

Pharmacodynamic and pharmacokinetic properties of sustained-release anyhdrous theophylline (Theolair-SR) were similar when doses were given either immediately after or two hours after low-fat meals in children with moderate asthma requiring daily theophylline maintenance. Asthma and pulmonary function values were maintained and approached values for healthy subjects during both treatment regimens.

Adolescent↗
PubMed1988

Steady-state evaluation of two controlled-release theophylline preparations in children.

The absorption profiles of Theolair-SR and Theo-Dur were studied in 23 asthmatic children (mean age 11 years). A 250-mg dose of each product was administered twice a day until steady state was attained (mean, 8 days). Both products maintained adequate theophylline levels over 12 hours, although Theolair-SR gave significantly higher serum levels and a 19% greater extent of theophylline absorption. The mean Cmax-Cmin was also significantly greater for Theolair-SR. Both products should be considered comparable for practical use.

Absorption↗
PubMed1986

Salsalate kinetics in patients with chronic renal failure undergoing hemodialysis.

A 1500 mg dose of salsalate (SSA) was given to five patients undergoing chronic hemodialysis on an interdialytic day and again before dialysis. Compared with control subjects, patients undergoing dialysis had a lower peak plasma SSA level (17 +/- 3 vs. 45 +/- 2 micrograms/ml; P less than 0.01) that occurred slightly later. In contrast, plasma salicylic acid (SA), the active SSA metabolite, had a similar but later peak level that remained substantially higher. Therefore, the AUC for SA was increased by 50% and the SA t1/2 was prolonged in the patients receiving dialysis (8.1 +/- 0.7 vs 3.8 +/- 0.2 hours; P less than 0.01). During a single treatment, dialysis clearance reduced plasma SA levels, removed 18% of total body SA, and returned the SA t1/2 to nearly normal. Because the elimination of SA is impaired in patients undergoing dialysis, the interdialytic SSA dosage should be reduced. Hemodialysis improves SA kinetics and may be followed by a normal SSA replacement dose. However, periodic monitoring of plasma SA levels is recommended when SSA dosing is begun in patients receiving dialysis.

Administration, Oral↗
PubMed1986

Comparative absorption of inhaled and intramuscularly administered atropine.

The inhalation of atropine sulfate was investigated in a randomized, 4-period, rising-dose study. Atropine sulfate 2, 4, and 6 mg by inhalation, and atropine free base 1.67 mg (equivalent to 2.0 mg atropine sulfate) by intramuscular (IM) injection were given to 8 healthy, nonsmoking subjects. Serum atropine sulfate concentrations were monitored during an 8-h period by radioimmunoassay. Mean serum concentrations and area under the serum concentration-versus-time curves (AUC) increased as the inhaled dose increased. Peak concentrations (mean +/- SD) were 11.5 +/- 3.4, 16.4 +/- 6.2, and 18.0 +/- 3.1 ng/ml for the 2, 4, and 6 mg doses, and 11.7 +/- 2.5 ng/ml for the IM dose. The time to peak concentration for each dose was similar (mean, 0.8 to 1.9 h). The AUC ratio of the 2-mg inhaled and IM doses was 1.11 +/- 0.41. The observed bronchodilating, anticholinergic, and other pharmacologic effects were seen after all dose concentrations and were typical of atropine. This study showed that inhalation is an efficient way to administer atropine sulfate for systemic use.

Absorption↗
PubMed1985

Plasma and urine levels of flumequine and 7-hydroxyflumequine following single and multiple oral dosing.

Plasma and urine concentrations of flumequine and its microbiologically active metabolite, 7-hydroxyflumequine, were determined in healthy subjects following single oral doses of 400, 800, and 1200 mg of flumequine, and following multiple oral doses of 800 mg given four-times daily. After administration of the single oral doses, antimicrobial levels in plasma and urine were rapidly attained, were proportional to the dose given, and were maintained for 12 to 24 h. The multiple dosage regimen yielded antimicrobial levels in both plasma and urine that were several-fold higher than the levels required to inhibit the growth of susceptible bacteria. Following both the single and multiple dose regimens, the plasma elimination half-life of flumequine was about 7h. The excretion of 7-hydroxyflumequine in the urine contributed significantly to the antimicrobial activity.

Administration, Oral↗
PubMed1985

Effects of salsalate (nonacetylated salicylate) and aspirin on serum prostaglandins in humans.

Prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and salicylic acid were measured in blood samples from 10 healthy men after administration of antiinflammatory doses of aspirin (3.9 g/day) or salsalate (3.0 g/day). Each medication was given for 3 days, followed by an observation period of 13 days. Plasma salicylate concentrations were slightly, but generally insignificantly, higher during aspirin dosing, although both drugs produced salicylic acid levels in the antiinflammatory range. Serum levels of PGE2 and TXB2, which reflected synthesis of cyclo-oxygenase products by platelets, were minimally affected by salsalate but profoundly suppressed by aspirin. When medication was discontinued, the effects of salsalate on serum PGE2 and TXB2 were readily reversible within 36 h, whereas the recovery from aspirin was still incomplete after 13 days of observation. These results indicate that the two orally administered salicylates have differential effects on prostaglandin synthesis in platelets and may also differ in their therapeutic and adverse effects.

Adult↗
PubMed1984

Determination of flumequine and a hydroxy metabolite in biological fluids by high-pressure liquid chromatographic, fluorometric, and microbiological methods.

A sensitive and specific high-pressure liquid chromatographic method is described for the determination of the antibacterial drug flumequine and a major metabolite, 7-hydroxyflumequine, in human plasma and urine. The assay was linear over a concentration range of 1 to 120 micrograms/ml for both compounds. This method is compared with fluorometric and microbiological assays for flumequine. These latter methods did not differentiate between flumequine and any fluorescent or antimicrobiologically active metabolites. However, because essentially all drug in the plasma was found to be flumequine in radiolabeled studies, levels of unchanged drug in the plasma could be quantitated by either high-pressure liquid chromatography or fluorometry. Although only high-pressure liquid chromatography was able to specifically measure flumequine in the urine, the antimicrobial activity of the urine, which is more therapeutically relevant due to antimicrobially active metabolites, could be quantitated by either the fluorometric or the microbiological assay.

Biological Assay↗
PubMed1977

Physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat.

A plasma flow rate-limited pharmacokinetic model was developed to describe the distribution of digoxin to the heart, liver, kidneys, skeletal muscle, and GI tract in the rat. The model also provides for renal, hepatic (metabolic and biliary), and GI clearance as well as for biliary and GI secretion and GI reabsorption of digoxin. Predicted concentrations of digoxin in the heart, liver, skeletal muscle, and plasma were consistent with experimental observations in conscious rats after an intravenous dose. The model was extended to describe digoxin concentrations in the plasma of bile duct-ligated rats and ureter-ligated rats, simply by modifying appropriate clearance parameters. Excellent agreement was obtained between predicted and observed urinary excretion rates of digoxin for 12 hr after in intravenous dose to normal and bile duct-ligated rats.

Animals↗
PubMed1977

Physiologically based pharmacokinetic model for digoxin disposition in dogs and its preliminary application to humans.

A physiologically based pharmacokinetic model for digoxin disposition developed in the rat was modified to account for the interspecies differences in tissue-to-plasma digoxin concentration ratios and applied to the dog. The model provided a quantitative assessment of the time course of digoxin concentrations in dog plasma, various tissues, and urine. It also predicted the effect of renal failure on digoxin pharmacokinetics in the dog. An attempt to scale the dog model to humans by simply considering differences in organ volumes, organ flow rates, and digoxin clearances was partially successful. Good predictions of plasma digoxin concentration and urinary digoxin excretion after a single dose and of steady-state plasma, heart, and skeletal muscle digoxin concentrations were obtained. However, the model predicted considerably higher kidney digoxin concentrations than are actually found. Although the model adequately characterized the time course of digoxin concentrations in patients with moderate renal impairment, it provided a relatively poor fit to that observed in anuric patients.

Animals↗
PubMed1976

Influence of cholestasis on drug elimination: pharmacokinetics.

A two-compartment model representing the body and the GI tract, with elimination occurring in each compartment, was used to study, in theory, the influence of impaired biliary excretion on drug disposition. The results suggest that cholestasis can either increase or decrease a drug's half-life, depending upon the relative values of the two elimination rate constants, In all cases, however, impaired biliary excretion reduced the initial elimination of drug from the body and increased the half-life of the alpha-phase of drug disposition.

Biopharmaceutics↗
PubMed1975

Transport of L-4-azaleucine in Escherichia coli.

The uptake of L-4-azaleucine was examined in Escherichia coli K-12 strains to determine the systems that serve for its accumulation. L-4=Azaleucine in radio-labeled form was synthesized and resolved by the action of hog kidney N-acylamino-acid amidohydrolase (EC 3.5.1.B) on the racemic alpha-N-acetyl derivative of DL-[dimethyl-14C]4-azaleucine. L-4-Azaleucine is taken up in E. coli by energy-dependent processes that are sensitive to changes in the pH and to inhibition by leucine and the aromatic amino acids. Although a single set of kinetic parameters was obtained by kinetic experiments, other evidence indicates that transport systems for both the aromatic and the branched-chain amino acids serve for azaleucine. Azaleucine uptake in strain EO317, with a mutation leading to derepression and constitutive expression of branched-chain amino acid (LIV) transport and binding proteins, was not repressed by growth with leucine as it was in parental strain EO300. Lesions in the aromatic amino acid transport system, aroP, also led to changes in the regulation of azaleucine uptake activity when cells were grown on phenylalanine. Experiments on the specificity of azaleucine uptake and exchange experiments with leucine and phenylalanine support the hypothesis that both LIV and aroP systems transport azaleucine. The ability of external azaleucine to exchange rapidly with intracellular leucine may be an important contributor to azaleucine toxicity. We conclude from these and other studies that at least four other process may affect azaleucine sensitivity: the level of branched-chain amino acid biosynthetic enzymes; the level of leucine, isoleucine, and valine transport systems; the level of the aromatic amino acid, aroP, uptake system; and, possibly, the ability of the cell to racemize D and L amino acids. The relative importance of these processes in azaleucine sensitivity under various conditions is not known precisely.

Biological Transport, Active↗
PubMedDate not supplied

Transdermal nitroglycerin systems: methods for comparison.

A number of transdermal nitroglycerin delivery systems are able to maintain a constant plasma level of nitroglycerin for up to 24 hours, even though the drug's elimination half-life is only a few minutes. Unfortunately, wide variations in plasma drug levels reported in studies of transdermal delivery systems can make plasma level comparisons between products inappropriate and misleading. Other measures of clinical performance include adhesive properties and patient preference. In one adhesion study, Minitran demonstrated superior adhesive properties when compared with Transderm-Nitro, Nitro-Dur II, and a medical reference tape. In patient preference studies involving several hundred patients with angina pectoris, patients consistently selected Minitran over Transderm-Nitro or Nitro-Dur II, citing patch size, shape, ease of application, comfort, better patch adhesion, and reduced instances of skin irritation.

Administration, Cutaneous↗
PubMedDate not supplied

Performance of a new transdermal nitroglycerin adhesive patch formulation.

This two-period crossover study in 24 healthy men compared the transdermal absorption of nitroglycerin from a new 20-cm2 nitroglycerin adhesive transdermal patch applied for a single 24-hour period (q24hr) with that from one inch of 2% nitroglycerin ointment applied over a 50-cm2 area every eight hours (q8hr) during a single 24-hour period. The observed differences in pharmacokinetic parameters were expected, based on product design (q24hr vs q8hr) and surface area (20 cm2 vs 50 cm2); however, when corrected for surface area, the mean plasma AUC ratios indicated that the patch delivered about 1.5 times more drug than the ointment. The patch delivery of nitroglycerin was confirmed by patch residual results, which indicated nitroglycerin was released at a rate of 0.75 mg/cm2/24 hrs. The patch exhibited good skin adhesion throughout the 24-hour application period.

Administration, Cutaneous↗