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Biomedical subjects

J W Findlay

Publications and source records attributed to J W Findlay.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1984

Triprolidine radioimmunoassay: disposition in animals and humans.

A hapten derivative of triprolidine, bearing an acrylic acid side chain ortho to the pyridine ring nitrogen atom, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with the resulting drug-protein conjugate resulted in the production of antisera capable of binding a radioiodinated tyramine conjugate of the triprolidine hapten derivative at high antiserum dilutions (1:70,000-1:150,000). These antisera were used to develop a radioimmunoassay (RIA) for triprolidine in human plasma with a sensitivity limit of 0.1 ng/mL (0.01 ng of actual mass). The known hydroxymethyl and carboxyl metabolites of triprolidine cross-reacted weakly (less than 2 and less than 0.05%, respectively) with this antiserum. The RIA could be used for the direct analysis of triprolidine in human and rabbit plasma, but not for rat or dog plasma, presumably due to the presence of other interfering substances (possibly metabolites). The validity of the RIA procedure in human plasma was demonstrated by comparative analysis of a number of samples by quantitative TLC (r = 0.985, slope = 1.076). The assay was employed to describe the pharmacokinetics of triprolidine in the rabbit (t 1/2, beta = 1.7 h). The assay had adequate sensitivity to detect low circulating drug concentrations in humans after therapeutic oral doses and also substantiated previous disposition experiments with triprolidine in humans (t 1/2, beta = 2.27 h). TLC analysis demonstrated that the absolute oral bioavailability of triprolidine (1-mg/kg dose) in the dog was low (4%). A comparison of triprolidine pharmacokinetic parameters in dogs, rabbits, rats, and humans revealed considerable similarity in elimination characteristics in these species.

Animals↗
PubMed1984

Pseudoephedrine and triprolidine in plasma and breast milk of nursing mothers.

Plasma and milk concentrations of pseudoephedrine and triprolidine were determined (by radioimmunoassay) in three lactating mothers over 12-48 h after ingestion of a combination medication containing 60 mg of pseudoephedrine hydrochloride and 2.5 mg of triprolidine hydrochloride monohydrate. Pseudoephedrine concentrations in milk were consistently higher than those in plasma. The total amount of drug in milk, as judged by areas under the respective curves (AUC), was two to three times greater than in plasma. Triprolidine concentrations in milk and plasma were more variable between subjects than those of pseudoephedrine. AUC values for milk and plasma were similar for one subject, while the plasma value exceeded that for milk in another woman. The fraction of the dose excreted in milk was estimated to be 0.4-0.7% for pseudoephedrine and 0.06-0.2% for triprolidine.

Adult↗
PubMed1983

Radioimmunoassay for bupropion in human plasma: comparison of tritiated and iodinated radioligands.

We evaluated the potential usefulness of 125I-labeled p-hydroxybupropion in a direct radioimmunoassay for bupropion in human plasma as compared with a currently used [3H]bupropion dextran-coated charcoal method. In both radioimmunoassay methods succinoylpropylbupropion antiserum was used that was highly specific for unchanged drug, cross reactivities with known bupropion metabolites being less than 0.3%. However, the use of 125I-labeled p-hydroxybupropion afforded greater sensitivity (0.3 microgram/L vs 0.6 microgram/L with [3H]bupropion) and was readily adaptable to the more convenient polyethylene glycol separation method. Between-assay CVs were 3.8 to 12.2% (mean 7.6%) with the 125I-based radioimmunoassay and 5.1 to 11.5% (mean 7.5%) with the 3H-based assay. Agreement between the two radioimmunoassay determinations of buproprion in human plasma samples collected over a 60-h period after oral drug administration was excellent (slope = 1.086, r = 0.989). We find the 125I-based assay a convenient and suitable alternative to the [3H]bupropion assay in pharmacokinetic studies in humans.

Adult↗
PubMed1982

Plasma levels of a novel antidysrhythmic agent, meobentine sulfate, in humans as determined by radioimmunoassay.

A radioimmunoassay for the quantitation of meobentine sulfate, a novel antidysrhythmic and antifibrillatory agent in biological fluids, is described. Antisera were raised in rabbits in response to immunization with a conjugate of bovine serum albumin and a meobentine analog with a propionic acid sidechain ortho to the methoxyl group. These antisera have low affinities for N- and O-desmethylmeobentine metabolites, which show less than 5% cross-reaction in radioimmunoassay procedures employing either tritiated or radioiodinated radioligands. The radioimmunoassay using[125I]meobentine was capable of detecting less than 0.4 ng/ml (40-pg mass) of meobentine. This assay was used to demonstrate the absorption of meobentine in humans after oral administration and also permitted studies of meobentine sulfate disposition in human plasma following two (2.5 and 5 mg/kg) oral doses. Mean peak meobentine concentrations in plasma occurred 3 hr postdose in both cases and were 230 and 451 ng/ml following the 2.5- and 5-mg/kg doses, respectively. The approximate mean terminal half-life after all treatments was 12 hr.

Animals↗
PubMed1982

Codeine disposition in smokers and nonsmokers.

The bioavailability of codeine and extent of its transformation to morphine were stated in 12 smoking and 11 nonsmoking subjects after single doses 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12-hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half-life (t1/2), or areas under plasma concentration-time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 +/- 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 +/- 2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 +/- 4.9%) and in nonsmokers (50.2 +/- 2.1%) did not offer. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first-pass O-demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O-demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

Administration, Oral↗
PubMed1982

An evaluation of the effects of smoking on codeine pharmacokinetics and bioavailability in normal human volunteers.

Cigarette smoking has been shown to increase the clearance of several drugs, including pentazocine, theophylline, and phenacetin. This effect presumably is mediated through enzyme induction, resulting from inhaled polycyclic aromatic hydrocarbons. Because the O-demethylation pathway for codeine is similar to that of other drugs known to be influenced by cigarette smoking, a study was conducted to compare the pharmacokinetics and metabolism of codeine in smokers and nonsmokers. Twelve volunteers with no history of cigarette smoking and ten volunteers who smoke cigarettes were studied; an open, two-treatment, simultaneous parallel and crossover study design was used. Each volunteer received a single dose of codeine sulfate 60 mg po and codeine phosphate 60 mg im, in random treatment order, at one-week intervals. Serial blood samples were collected up to 12 hours after dosing, and plasma codeine and morphine concentrations were measured by radioimmunoassay. There was no significant difference between smokers and nonsmokers in either codeine or morphine areas under the plasma concentration-time curves (AUCs), with either route of administration. The relative codeine bioavailability in these groups was 54.8 +/- 4.9 percent and 50.2 +/- 2.1 percent (mean +/- SE), respectively. Smoking was associated with greater variability in plasma concentrations. Interestingly, greater morphine:codeine AUC ratios were observed in both groups after oral than after intramuscular administration. Cigarette smoking should have no clinically important influence on codeine absorption or disposition.

Adult↗
PubMed1981

Morphine in cow and human milk: could dietary morphine constitute a ligand for specific morphine (mu) receptors?

Morphine has been found in cow and human milk at concentrations of 200 to 500 nanograms per liter. Multistep purification yields a material that has immunological, biological, pharmacological, and chemical properties identical to those of morphine. Similar morphine-like material, which has been tentatively identified in some common plant sources, may be a ubiquitous dietary constituent and a possible source for the material in milk. Since morphine (mu) receptors have a low affinity for enkephalins, and since morphine-like materials have been described in brain and intestine, it is possible that morphine in food may be the source of this material and a normal ligand specific for mu receptors.

Animals↗
PubMed1981

Stereospecific radioimmunoassays for d-pseudoephedrine in human plasma and their application to bioequivalency studies.

Antiserum to d-pseudoephedrine was raised in New Zealand White rabbits in response to immunization with a conjugate of bovine serum albumin and d-pseudoephedrine-N-3-propionic acid. The hapten was prepared by reaction of methyl acrylate with d-pseudoephedrine, followed by ester hydrolysis. Sodium boro[3H]hydride reduction of dl-ephedrine gave [alpha-3H]-dl-ephedrine, and a Welsh rearrangement with acetic anhydride followed by deacetylation gave [alpha-3H]-dl-pseudoephedrine, which was used as a radioligand in radioimmunoassay procedures for direct plasma analyses. Three sensitive radioimmunoassay procedures were developed, two using [3H]pseudoephedrine as the radioligand and either adsorption on coated charcoal or polyethylene glycol precipitation for separation of antibody-bound from free radioligand. The third method used an [125I]tyrosine methyl ester analog of pseudoephedrine and charcoal separation, preceded by extraction and derivatization of pseudoephedrine with methyl acrylate. All three assays could detect less than or equal to 2.5 ng of pseudoephedrine/ml. The antiserum was stereospecific, showing low cross-reactivities with l-pseudoephedrine and d- and l-ephedrines. d-Norpseudoephedrine and some other related compounds also had low cross-reactivity in these radioimmunoassay procedures. Excellent agreement was found between pseudoephedrine concentrations in human plasma determined by radioimmunoassay and by a standard GLC method. The utility of radioimmunoassay was illustrated by application of one of these procedures to an assessment of the bioequivalence of immediate- and sustained-release pseudoephedrine formulations in normal volunteers. A sustained-release preparation containing 120 mg of pseudoephedrine hydrochloride given every 12 hr was shown by AUC comparisons to be bioequivalent to an immediate-release tablet (containing 60 mg of pseudoephedrine hydrochloride) given every 6 hr.

Adult↗
PubMed1981

Pharmacokinetics of bupropion, a novel antidepressant agent, following oral administration to healthy subjects.

The pharmacokinetics of bupropion hydrochloride, a structurally novel antidepressant agent, have been studied in healthy male and female subjects following administration of single oral doses of 50, 100 and 200 mg. Plasma drug concentrations were determined directly by a specific radioimmunoassay (r.i.a.), while urinary measurements required a prior solvent extraction to remove substances interfering in the assay. Bupropion appeared rapidly in the plasma, suggesting good absorption. Drug plasma concentration-time data were fitted well to a two-compartment open model of drug disposition by use of the computer program NONLIN. By comparison of AUC, Cmax and tmax values, the pharmacokinetics of bupropion were found to be linear across the 50-200 mg dose range in both sexes. When the data were normalized for subjects' body weights, no differences between pharmacokinetic parameters for male and female subjects were found. Mean disposition half-lives across treatments were 1.2-1.4 h for t1/2 alpha and 10.7-13.8 h for the t1/2 beta. Bupropion was extensively bound (85%) to human plasma proteins over a wide drug concentration range. Less than 1% of a 200 mg oral dose of bupropion hydrochloride appeared in the urine of 16 subjects as unchanged drug, indicating extensive metabolism of the parent compound.

Administration, Oral↗
PubMed1981

Analgesic drugs in breast milk and plasma.

The disposition of salicylic acid, phenacetin, caffeine, and codeine, and two metabolites, acetaminophen and morphine, was studied in breast milk and plasma of two lactating mothers after single oral doses of a compound analgesic. Salicylic acid penetrated poorly into milk, with peak levels of only 1.12 to 1.60 micrograms/ml, whereas peak plasma levels were 33 to 43.4 micrograms/ml. The drug was also eliminated more slowly from milk than plasma. In contrast, caffeine and phenacetin kinetics in breast milk and plasma were similar, but milk levels were somewhat lower than plasma levels in both subjects. Metabolically produced acetaminophen levels in both fluids were much higher than those of the parent drug, phenacetin, in one subject, but early plasma and milk phenacetin levels exceeded those of acetaminophen in the other subject, thereafter dropping sharply to assume the pattern of the first subject. Elimination of the metabolite, acetaminophen, from milk was slower than from plasma (subject 1, half-life (t1/2) of drug in milk, 4.7 hr; t1/2 in plasma, 2.9 hr). In both subjects codeine concentrations in milk were 1.5 to 2.4 times as high as in plasma at the same times after drug. Metabolically produced morphine levels in milk from both mothers were low but exceeded those in plasma after 1 hr. Calculations based on average milk concentrations over the 12 hr after drug in subject 1 revealed milk excretion of 0.7% or less of the ingested dose of each drug. Similar calculations based on predicted steady-state milk drug concentrations in subject 2 indicated maximum milk excretion of 2.7% of the dose. In each case caffeine was excreted in the milk in the greatest amount.

Acetaminophen↗