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Biomedical subjects

W A Colburn

Publications and source records attributed to W A Colburn.

At least 19 recordsLinked to original sources
PubMed1995

Surrogate biochemical markers: precise measurement for strategic drug and biologics development.

More efficient drug and biologics development is necessary for future success of pharmaceutical and biotechnology companies. One way to achieve this objective is to use rationally selected surrogate markers to improve the early decision-making process. Using typical clinical chemistry methods to measure biochemical markers may not ensure adequate precision and reproducibility. In contrast, using analytical methods that meet good laboratory practices along with rational selection and validation of biochemical markers can give those who use them a competitive advantage over those who do not by providing meaningful data for earlier decision making.

Biological Products↗
PubMed1995

Pharmacologic profile of diaspirin cross-linked hemoglobin in hemodialysis patients.

Various hemoglobin compounds have been evaluated as potential oxygen-carrying, blood volume expanders, but toxicity has prevented clinical application. Diaspirin cross-linked hemoglobin (DCLHb) represents a modified hemoglobin compound that is derived from human red blood cells and maintained in a tetrameric configuration by cross-linkages between the two alpha chains of the hemoglobin molecule. In a randomized, placebo-controlled, single-blind, cross-over trial, DCLHb's safety and pharmacologic parameters were evaluated in 18 subjects receiving chronic hemodialytic therapy. A 30-minute infusion of 25, 50, or 100 mg/kg DCLHb or placebo was given at the start of routine hemodialysis. One week later, the alternate treatment (placebo or DCLHb) was administered. Maximum plasma hemoglobin concentrations and terminal half-life values were calculated for each dosage group. Dialysate was collected and assayed for hemoglobin. Changes in systolic and diastolic blood pressure from baseline and the volume of hypertonic saline administered for treatment of hypotension during hemodialysis were measured. The maximum plasma hemoglobin concentrations increased with DCLHb dose and occurred at the end of DCLHb infusion. The mean (+/- SD) terminal half-life ranged from 2.1 +/- 1.0 hours in the 25 mg/kg DCLHb group to 4.3 +/- 1.4 hours in the 100 mg/kg group, but did not differ significantly between groups. Mean baseline plasma hemoglobin corrected areas under the plasma concentration-time curves increased from 89 to 1,136 mg/hr/dL across the fourfold dose range. Diaspirin cross-linked hemoglobin was not dialyzable as none was detected in dialysate. The maximum increase in systolic blood pressure from baseline increased significantly with DCLHb dose compared with placebo (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Drugs and endogenous ligands compete for receptor occupancy.

Dietary and endogenous ligands compete with drugs for receptor occupancy and therefore should be considered during therapeutic interventions and during pharmacokinetic/pharmacodynamic modeling. When disease is the result of an overabundance of these natural ligands, antibodies and/or their Fab fragments may be useful as therapeutic agents to reverse the effects of the natural ligands.

Antibodies↗
PubMed1992

Clinical pharmacokinetics of procaterol: dose proportionality after administration of single oral doses.

Procaterol is a potent, orally active beta 2-agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effective when administered as single or multiple (Q8H) 50 and 75 micrograms doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 micrograms doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for tmax, the apparent elimination rate constant, Cl/F, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose-normalized AUC, Cmax, and amount excreted unchanged in urine (Ae) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied.

Administration, Oral↗
PubMed1990

Multiple-dose propranolol administration does not influence the single dose pharmacokinetics of quinapril and its active metabolite (quinaprilat).

To evaluate the influence of multiple dose propranolol administration on the single dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, a drug-drug interaction study was performed in ten healthy volunteers. Each subject received a single 20 mg quinapril oral dose on Days 1 and 16 of the study. Oral propranolol doses of 40 mg BID were initiated on Day 3, titrated gradually to 80 mg TID by Day 10, and continued at 80 mg TID through Day 17. Comparable mean quinapril pharmacokinetic parameter values as well as comparable mean quinaprilat pharmacokinetic parameter values determined following quinapril administered alone and following quinapril administered with propranolol, indicate that propranolol does not alter the single dose pharmacokinetics of quinapril or quinaprilat.

Adult↗
PubMed1990

Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain.

To determine the relationship between changes in plasma methadone concentration and pharmacodynamic effects, plasma methadone profiles and pharmacodynamics (analgesia and sedation) were measured during and after the continuous infusion of methadone for 180 to 270 minutes in 15 patients with pain caused by cancer. An increase in plasma methadone concentration resulted in a rapid increase in pain relief or sedation. The estimates of values of 50% of maximum effect (Css50) for pain relief and sedation obtained with a pharmacokinetic-pharmacodynamic model varied tenfold to twentyfold among patients; the mean Css50 value for pain relief (0.359 +/- 0.158 [SD] micrograms/ml) was virtually the same as the mean Css50 value for sedation (0.336 +/- 0.205 [SD] micrograms/ml). Similarly, the mean gamma (slope function) for pain relief (4.4 +/- 3.8 [SD]) and sedation (5.8 +/- 5.4 [SD]) did not differ. Examination of hysteresis plots of data obtained during the infusion and for 4 to 5 hours after cessation of the infusion revealed a very rapid equilibration between plasma methadone values and the sites mediating pain relief. There was no indication of the development of tolerance to the pharmacodynamic effects of methadone during the study. This report describes a method for quantitating the pharmacokinetic-pharmacodynamic relationships of the desirable and undesirable effects of opioid analgesics.

Adult↗
PubMed1990

Theophylline dosage adjustment during enoxacin coadministration.

Based on the results of a previous study which demonstrated a 50% reduction in theophylline clearance during coadministration of 400 mg of enoxacin twice a day (b.i.d.), a sequential-design study was completed with seven nonsmoking, healthy adult female human volunteers. The subjects were given 200 mg of theophylline (Theo-Dur) orally every 12 h for 4 days. On day 5, the subjects began receiving 400 mg of enoxacin with each theophylline dose, and the dosage of theophylline was reduced to 100 mg b.i.d. This regimen was continued through day 8, after which enoxacin was discontinued. The theophylline dosage was increased to 200 mg b.i.d. on day 9, and theophylline monotherapy continued through day 12. The mean apparent theophylline clearance decreased by approximately 50% during enoxacin coadministration. No significant differences in mean theophylline maximum concentration in serum, time to maximum concentration in serum, lowest concentration observed, or area under the concentration-time curve during the steady-state dosing were observed before, during, or after enoxacin coadministration when the theophylline dosage was reduced to 100 mg b.i.d. Reduction of the theophylline dose by 50% at the onset of enoxacin dosing maintained constant theophylline concentrations in plasma. A return to the original theophylline dose immediately upon cessation of enoxacin therapy resulted in a transient 35% increase in theophylline concentrations in plasma which lasted 24 to 48 h before returning to preenoxacin values. Although a 50% reduction in the theophylline dose maintained constant mean theophylline concentrations when enoxacin was administered concomitantly, it appears that larger dose reductions (up to 75%) could be required in patients with high theophylline clearances. In addition, larger transient increases in the theophylline concentration in plasma may be observed in these patients upon cessation of enoxacin therapy if the theophylline dose is immediately returned to normal. Thus, it is recommended that theophylline concentrations in plasma be monitored when concurrent enoxacin therapy is required.

Adult↗
PubMed1989

Differences in oral verapamil absorption as a function of time of day.

As part of a multiple dose bioavailability study, 80-mg verapamil hydrochloride tablets were administered to healthy subjects every 8 hours for 15 doses. Statistically significant successive decreases in verapamil maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC) values were observed corresponding to dosing at 8 AM, 4 PM, and 12 AM. Mean Cmax and AUC values from the 12 AM dose were decreased 36% and 30%, respectively, relative to those from the 8 AM dose. Similar effects on norverapamil pharmacokinetics were observed. Decreased Cmax and AUC values show that verapamil absorption is influenced by the time of day when doses are administered. Pharmacokinetic simulation results suggest that the rate of absorption is reduced approximately by one half and two thirds during the 4 PM and 12 AM dosing intervals, respectively, relative to the 8 AM dosing interval. The reductions in verapamil absorption as a function of time of administration observed in this study may in part explain previous reports of reduced antihypertensive effect during evening and night hours as compared to daytime hours.

Administration, Oral↗
PubMed1989

The clinical pharmacokinetics of quinapril.

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose proportional following single oral 2.5- to 80-mg Q doses. Q absorption and hydrolysis to QT is rapid with peak Q and QT concentrations occurring one and two hours postdose, respectively. Peak plasma QT concentrations were approximately fourfold higher than those of Q (923 vs 207 ng/mL following 40-mg Q). Dose-proportional QT area under the curve and dose-independent percent of dose excreted in urine as QT demonstrate that the extent of Q conversion to QT is constant over the dose range studied. Q and QT were eliminated from plasma with apparent half-lives of 0.8 and 1.9 hours and apparent plasma clearances of 1,850 and 220 mL/min, respectively, over the 2.5- to 80-mg dose range. Following oral 14C-Q, 61% and 37% of radiolabel was recovered in urine and feces, respectively. Q plus QT accounted for 46% of radioactivity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketopiperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an administered dose excreted in urine as each of these metabolites. Peak plasma concentrations of these metabolites are similar to that of Q, and each is eliminated rapidly with a half-life of approximately one hour. Urinary excretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clearance of both Q and QT is independent of dose, and metabolism to compounds other than QT is not extensive.

Absorption↗
PubMed1988

Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses.

A randomized, four-way cross-over study was conducted in eight healthy male volunteers to determine the relative and absolute bioavailability of prednisone (PN) and prednisolone (PL). PN and PL were administered as single, oral 10-mg tablet doses and as 10-mg zero-order 0.5-hour intravenous infusions. Comparable mean PN and PL maximum plasma concentrations (Cmax), times for Cmax, areas under the plasma concentration-time curves (AUC), and apparent elimination rate constants between tablet treatments demonstrated that PN and PL tablets were bioequivalent. Absolute bioavailability (F) determinations based on plasma PL concentrations were independent of which IV treatment was used as reference and indicated complete systemic availability of PL from both PN and PL tablets. However, F based on plasma PN data was contradictory. Using IV PN as reference, approximately 70% systemic availability was observed from both tablets, whereas using IV PL as reference, systemic availability was greater than unity. PN and PL are model compounds that exemplify the difficulties involved in accurately determining the relative and absolute bioavailability of substances that undergo reversible metabolism.

Administration, Oral↗
PubMed1988

Physiologic pharmacokinetic modeling.

Although physiologic modeling has not gained the widespread acceptance that was originally projected, it may serve as the basis for future PK/PD modeling approaches. In addition, with more effort applied to developing in vitro and animal-to-human predictions, physiologic modeling may assume a higher position in the pharmacokinetic modeling hierarchy.

Animals↗
PubMed1988

Combined pharmacokinetic/pharmacodynamic (PK/PD) modeling.

Several compartmental and noncompartmental approaches have been successfully applied to PK/PD modeling. Although great opportunities exist to expand on these techniques, application of these methods to relate concentrations of all drugs to their effects is possible.

Humans↗