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Biomedical subjects

J W Findlay

Publications and source records attributed to J W Findlay.

At least 19 recordsLinked to original sources
PubMed1991

Immunofluorometric assay for lamotrigine (Lamictal) in human plasma.

An immunofluorometric assay (IFA) has been developed for the potential antiepileptic agent, lamotrigine (Lamictal). The assay involves competition between lamotrigine free in solution and bound to a bovine thyroglobulin conjugate on the surface of microtiter strip wells for a limited amount of polyclonal lamotrigine antisera. The end-point of this reaction, which indicates the concentration of lamotrigine present in the solution under analysis, is detected by adding Eu(3+)-labelled anti-rabbit IgG, followed by an enhancement solution to produce a fluorescent product. Thus, the higher the concentration of lamotrigine in the sample, the less intense the fluorescence produced. The assay displays minor cross-reactivity (0.05%) by the major glucuronide metabolite (in humans) and moderate cross-reactivity (2.7%) by a minor N-oxide metabolite (in rats) of the parent drug. No interference from these sources in the analysis of plasma samples from clinical trials was demonstrated by comparative sample analysis by IFA and high-performance liquid chromatography. Intraassay accuracy and precision were excellent, greater than 90% and less than 5% coefficient of variation (CV), while interassay accuracy was greater than 95% and interassay precision (CV) was 8.8-17.0%. This assay is suitable for analysis of lamotrigine in plasma samples collected during clinical trials.

Animals↗
PubMed1991

Clinical and pharmacokinetic profiles of digoxin immune Fab in four patients with renal impairment.

Minimal pharmacokinetic data on digoxin immune Fab are currently available, especially in patients with impaired renal function. The serum concentration-time profiles of total digoxin, free digoxin, and digoxin immune Fab in four patients with moderate to severe renal impairment who received digoxin immune Fab are presented. The calculated elimination half-life of digoxin immune Fab was 25-73 hours. The calculated elimination half-life of total digoxin was 24-72 hours. Free digoxin concentrations rebounded to a peak of 1-2.9 ng/mL 44-97 hours after the administration of digoxin immune Fab. The areas under the curve for digoxin immune Fab were 213-1026 micrograms.h/mL, and total body clearances were 2.3-7.1 mL/min. The total digoxin concentrations peaked at 14-33 times the pre-Fab digoxin concentrations 5-30 hours after digoxin immune Fab administration. In comparing these data with data available from patients with normal renal function, the half-life of digoxin immune Fab and total digoxin was longer, the peak total digoxin concentration occurred later, the ratio of the peak total digoxin concentration to pre-Fab digoxin concentration was larger, and the rebound in free digoxin occurred later in patients with renal impairment. The Fab dose should not be reduced in patients with renal impairment; however, post-Fab monitoring should be extended to compensate for the prolonged half-life of Fab and later rebound of free digoxin.

Adult↗
PubMed1990

Pharmacokinetics of oral and transdermal triprolidine.

In this open, nonrandomized, three-way crossover study, six healthy male volunteers received single doses of triprolidine (TPL) hydrochloride syrup orally (2.5 mg) and wore transdermal TPL patches (5 mg and 10 mg doses) to compare the pharmacokinetic profiles and dose tolerance of the two formulations. A washout period of at least 1 week was scheduled between the three dosing periods. Blood samples were collected at defined times, and plasma concentrations were determined using a radioimmunoassay. Maximum plasma drug concentration (Cmax) decreased from 5.6 +/- 2.9 ng/mL (mean +/- SD) with oral dosing to 2.0 +/- 1.0 ng/mL and 4.2 +/- 2.0 ng/mL following 5 mg and 10 mg transdermal doses, respectively. Time to reach peak concentration (tmax) increased from 2.0 +/- 1.2 hours with oral dosing to 12.0 +/- 5.9 and 14.3 +/- 9.9 hours following 5 mg and 10 mg transdermal doses, respectively. The differences between AUC0-alpha values with the oral syrup and the 5 mg and 10 mg transdermal doses were not significant when normalized to 2.09 mg (TPL base). The bioavailabilities of the 5 mg and 10 mg transdermal doses relative to the oral 2.09 mg doses were 0.89 +/- 0.32 and 1.04 +/- 0.33, respectively. Mild erythema and pruritus were the most common adverse effects secondary to TPL transdermal application. Drowsiness observed following oral TPL, was not evident following either transdermal dose. The results of this study, therefore, indicate that TPL can be absorbed transdermally, providing consistent plasma concentrations.

Administration, Cutaneous↗
PubMed1990

Treatment of digoxin intoxication in a renal failure patient with digoxin-specific antibody fragments and plasmapheresis.

A patient with renal failure due to myeloma kidney and coincident digitalis intoxication due to prescribed daily digoxin administration was treated with digoxin-specific antibody fragments and plasmapheresis. Rapid response to therapy was noted, removal of digoxin-antidigoxin antibody complexes was confirmed, and prevention of delayed rebound toxicity was documented. We suggest that this is the therapy of choice in similar individuals.

Acute Kidney Injury↗
PubMed1989

Pharmacokinetics of acrivastine after oral and colonic administration.

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.

Administration, Oral↗
PubMed1988

Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease.

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half-life and mean residence time were increased significantly in the hemodialysis group (18.69 +/- 9.03 hours and 12.77 +/- 7.09 hours, mean +/- SD, respectively) compared with the healthy volunteer group (4.04 +/- 0.60 hours and 3.90 +/- 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple-dose codeine therapy.

Adult↗
PubMed1988

Pholcodine.

Pholcodine has antitussive activity similar to, or somewhat greater than, that of codeine in animal test systems. The drug, which has been formulated in many combination medications (45)--some rational and some quite irrational pharmacologically--also appears to be active in man, although the clear-cut demonstrations, unfortunately, are in artificially-induced cough models. Additional efficacy studies are needed. Preclinical toxicity studies demonstrate a generally safer profile for pholcodine than codeine, although pholcodine appears to have greater depressant effects on the respiratory and cardiovascular systems in animals. These effects have not been observed in man after administration of therapeutic doses. Pholcodine appears to be devoid of addiction liability in man. In contrast to codeine, pholcodine is not metabolised to morphine in man, a fact which may contribute to its more favourable toxicity profile, and it is metabolised and eliminated much more slowly than codeine.

Antitussive Agents↗
PubMed1987

Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers.

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single- (60 mg) and multiple-dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single- and last multiple-oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple-dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 +/- 33 ng/mL/hr after single dose versus 212 +/- 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple-dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.

Adult↗
PubMed1986

Comparative disposition of codeine and pholcodine in man after single oral doses.

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration.

Administration, Oral↗
PubMed1986

Pharmacokinetics of intravenous, intrathecal and epidural morphine and fentanyl in the goat.

Intrathecal and epidural catheters and an intravenous cannula were inserted in 10 goats. After administration of either morphine 4 mg, intravenously, 1 mg intrathecally or 4 and 8 mg epidurally, or fentanyl 0.1 mg intravenously, 0.05 mg intrathecally or 0.1 and 0.2 mg epidurally, venous blood and CSF were sampled at 2, 5, 10, 15, 30 min and 1, 2, 4, 6, 8 and 24 h. The concentrations of the drugs were measured by radioimmunoassay. After administration of intravenous morphine the plasma concentration-time curve fitted a 3-compartment model (body clearance = 84 +/- 23 ml/min/kg, mean +/- s.d., N = 5), while after fentanyl the plasma concentration-time curve was best described by a 2-compartment model (body clearance = 3.9-5.8 ml/min/kg, N = 3]. After intrathecal injection the elimination rates of the opioids from CSF were 0.3 to 2.0 and 0.6 to 2.4 ml/h/kg for morphine and fentanyl, respectively (N = 3). The time to reach maximum CSF concentration after epidural administration was 0.22 +/- 0.14 h for morphine (N = 6) and 0.22 +/- 0.13 h for fentanyl (N = 8). In the same goat the CSF availability was 2.3 and 11.3% for morphine and 0.8 and 3.3% for fentanyl following epidural administration of the low and high doses, respectively. After epidural administration, morphine and fentanyl are absorbed into CSF at the same rate but the relative amount of drug absorbed may be higher for morphine than fentanyl. Bulk flow is supposed to be the principal mechanism of opioid elimination from CSF.

Animals↗
PubMed1985

Pharmacodynamic and pharmacokinetics of BW 825C: a new antihistamine.

The new H1-receptor antagonist BW 825C and triprolidine (2.5 and 5 mg) were administered to 12 healthy male volunteers in a double blind placebo controlled, balanced, crossover design. Histamine antagonism was measured by assessment of flare and weal areas after intradermal injection of histamine. The 2 compounds were approximately equipotent in blocking the flare and weal response to intradermal histamine and had a similar duration of action. Triprolidine impaired performance of vigilance and reaction time (p less than 0.05) compared with placebo while BW 825C did not. Drowsiness measured using visual analogue scales followed both triprolidine treatments, but not BW 825C. BW 825C had a plasma half-life (t1/2) of 1.7 +/- 0.2 h and triprolidine of 4.6 +/- 4.3 h. The peak plasma level of BW 825C was approximately 6 times that of triprolidine. It was concluded that BW 825C might be a clinically active H1-antagonist with reduced sedative side-effects.

Adult↗
PubMed1978

Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and beta-phase elimination half-lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 ng/ml (aspirin-codeine phosphate administration) and 7.4 ng/ml (acetaminophen-codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration-time curves for morphine and codeine was 0.095 for the aspirin-codeine phosphate study and 0.12 for the acetaminophen-codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Acetaminophen↗
PubMed1977

Codeine kinetics as determined by radioimmunoassay.

Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 ng/ml) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 ng/ml) appeared within 0.75 to 1 hr. The mean plasma t1/2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5.1 L/kg, respectively. Oral, relative to intramuscular, bioavailability of codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).

Administration, Oral↗
PubMed1977

Specific radioimmunoassays for codeine and morphine. Metabolism of codeine to morphine in the rat.

Specific antisera to morphine have been raised in response to immunization with a conjugate of N-carboxypropylnormorphine with bovine serum albumin (BSA). These antisera effectively distinguish changes in substituents at the 3 and 6 positions of the alkaloid, thus reducing cross-reactivity with codeine and morphine-3-glucuronide to negligible levels. The utility of these antisera has been illustrated by their application in radioimmunoassay procedures, along with similarly specific anti-codeine sera (Findlay et al., 1976) to a study of the biotransformation of codeine to morphine in the rat. After oral administration of codeine, serum levels of morphine were low, but significantly higher than codeine levels after 15 min., indicating rapid metabolism of codeine to morphine in this species.

Animals↗