A comparative study of a new once-a-day theophylline preparation with Theo-Dur given twice daily.
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Adolescent↗
Biomedical subjects
L I Harrison
Publications and source records attributed to L I Harrison.
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↗
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↗
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↗
The pharmacodynamic and pharmacokinetic interaction of flecainide acetate with propranolol: effects on cardiac function and drug clearance.
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Adult↗
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↗
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↗
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↗
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↗
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↗
Salicylic acid plasma levels following multiple doses of Norgesic Forte and aspirin.
Plasma salicyclic acid levels from the recommended multiple dose regimen of Norgesic Forte (orphenadrine citrate, aspirin, and caffeine) were compared to those from an equivalent multiple dose regimen of aspirin alone in 24 volunteers. The drugs were administered double-blind so that side effects could also be compared. No statistically significant differences were found between Norgesic Forte and aspirin in peak or trough levels, time to peak level, area under the curve, or mean steady-state level of salicylic acid. Mean steady-state levels averaged 154 +/- 46 (+/- SD) and 152 +/- 49 micrograms/ml on days 5 and 10 following Norgesic Forte versus 161 +/- 49 and 154 +/- 47 micrograms/ml following aspirin. Thus, the aspirin in Norgesic Forte provides an anti-inflammatory amount of salicylic acid equivalent to that of plain aspirin. There was no evidence that the combination of orphenadrine citrate, caffeine, and aspirin in Norgesic Forte caused increased or unusual side effects compared with aspirin alone.
Adult↗
Comparative absorption of theophylline following multiple doses of a sustained-release formulation and an elixir in humans.
This multiple-dose, crossover study in 18 healthy adult men compared the oral absorption of theophylline from Theolair-SR sustained-release tablets (TSR) given two times a day with that from a reference elixir given four times a day. No difference in the extent of absorption of theophylline from either formulation was seen. At steady state (day 5), the ratio of the AUC for TSR over a 12-hour dosing interval to the AUC for the elixir over a six-hour dosing interval, was 0.944 +/- 0.191 (mean +/- SD). Thus the extent of theophylline absorption from TSR is equivalent to that from the reference elixir (P greater than 0.25). TSR has the advantage of allowing less frequent dosing intervals than are necessary for the elixir.
Adult↗
Absorption, biotransformation, and pharmacokinetics of salicylsalicylic acid in humans.
The absorption, biotransformation, and pharmacokinetics of the antiinflammatory drug salicylsalicylic acid (SSA) were studied. Healthy adult males received 1000 mg SSA and 1300 mg aspirin according to a crossover design either as a single oral dose (12 subjects) or three times a day for five days (4 subjects). A newly developed, high-pressure liquid chromatographic assay permitted selective, direct measurement of SSA in the presence of high concentrations of salicylic acid, one of its metabolites. Following a single dose, SSA was promptly absorbed (mean time to peak level 1.5 hour) and was eliminated from plasma with a mean half-life of 1.1 hour. Less than 1 per cent was excreted in the urine as unchanged SSA. SSA did not accumulate in the plasma during multiple dosing. Plasma levels of salicylic acid following single and multiple doses of SSA indicate that SSA is extensively hydrolyzed to salicylic acid in the body. The slightly lower levels of salicylic acid after SSA than after aspirin may reflect direct biotransformation of some of the SSA to an SSA conjugate, without hydrolysis to salicylic acid.
Absorption↗
Comparative absorption of theophylline from theophylline-guaifenesin tablets and liquid and from a reference theophylline liquid.
This single-dose, three-way crossover study in 18 healthy adults compared the oral absorption of theophylline from a theophylline-guaifenesin tablet and from a theophylline-guaifenesin liquid with absorption from a theophylline liquid. Each dose form contained 500 mg theophylline and, when indicated, 400 mg guaifenesin. The extents of theophylline absorption from the formulations were within 10% of each other. The absolute differences in the areas under the curve among the formulations were small and, although significantly higher statistically for the theophylline-guaifenesin tablet, are without therapeutic consequence. The theophylline plasma level curves from each of the three formulations were similar. Comparable theophylline absorption and elimination characteristics were seen.
Adult↗
High-pressure liquid chromatographic determination of salicylsalicylic acid, aspirin, and salicylic acid in human plasma and urine.
A high-pressure liquid chromatographic method was developed for the separation and quantitation of salicylsalicylic acid (I), aspirin (II), and salicylic acid (III) in human plasma and urine. The method for plasma involves the selective extraction of I--III and an internal standard, alpha-phenylcinnamic acid, into methylene chloride from acidified plasma, followed by evaporation of the organic phase and dissolution of the residue in methanol. A 25-microliter aliquot is analyzed on a reversed-phase column with UV detection. Urine is treated similarly with hexane as the extracting solvent. If 300 nm is used as the monitoring wavelength, the assays of I and III are linear over the concentration range of 1--150 microgram/ml in both plasma and urine. If 280 nm is used as the monitoring wavelength, II can be quantitated along with I and III; however, detector sensitivities of I and III are two to three times greater at 300 nm. The accuracy and precision of the methods for I--III are adequate for clinical pharmacokinetic studies. Following therapeutic doses of I in humans, the method was applied successfully to the determination of I and III in plasma and urine.
Anti-Inflammatory Agents↗
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↗
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↗
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↗