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Biomedical subjects

D M Pierce

Publications and source records attributed to D M Pierce.

At least 19 recordsLinked to original sources
PubMed1995

Granisetron as antiemetic therapy in children with cancer.

The safety and efficacy of the new 5HT-3 antagonist granisetron as an antiemetic in children with cancer was evaluated in 40 children at a single dose of 40 micrograms/kg. No adverse affects attributable to the granisetron were noted. The overall major and complete response rate was 82.5% and this was highest in the younger children. Only 2 patients showed no response. Pharmacokinetic studies showed associations between some pharmacokinetic parameters and age which were no longer apparent after normalisation for body weight. Granisetron is an effective and very well-tolerated antiemetic and appears to be an important addition to the supportive care available for children with cancer.

Adolescent↗
PubMed1994

Pharmacokinetics and tolerability of ascending intravenous doses of granisetron, a novel 5-HT3 antagonist, in healthy human subjects.

The pharmacokinetics and tolerance of granisetron, a novel 5HT3-receptor antagonist which is under development as an anti-emetic agent have been studied after administration of single 30 min intravenous infusions to three groups of 8 healthy male subjects, in a series of placebo-controlled ascending dose studies (50, 80, 100 and 130 micrograms.kg-1 to group 1; 150, 180, 200 and 230 micrograms.kg-1 to group 2 and 270 and 300 micrograms.kg-1 to group 3). Plasma and urine samples were analysed for granisetron by HPLC with fluorimetric detection. Administration of granisetron was well tolerated by the volunteers and there were no serious adverse effects reported. Pharmacokinetic parameters and dose-normalised plasma levels appeared to be independent of dose in the range 50 to 300 micrograms.kg-1, although there was extensive inter-subject variability. Granisetron was extensively distributed, with mean volumes of distribution ranging from 186-264 l at the various doses. Total plasma clearance was, in general, rapid (mean values of 37.0 to 49.9 l.h-1) and predominantly non-renal, with most subjects excreting less than 20% of the dose unchanged in urine. Mean t1/2 values ranged from 4.1 to 6.3 h and MRT from 5.2 to 8.1 h.

Adult↗
PubMed1992

The tolerance to and pharmacokinetics of penciclovir (BRL 39,123A), a novel antiherpes agent, administered by intravenous infusion to healthy subjects.

The tolerance to and pharmacokinetics of intravenously administered penciclovir (BRL 39,123A), a novel anti-herpes agent, were investigated in 15 healthy male subjects. The volunteers were divided into three groups, receiving either 10, 15 or 20 mg/kg penciclovir by a 60 min constant-rate infusion. Blood samples were taken sequentially up to 48 h after the start of the infusion and urine collections made at appropriate intervals up to 72 h. After a simple solid phase extraction, concentrations of penciclovir in plasma and urine were determined using HPLC with U.V. detection. Mean values of Cmax, corresponding usually with the end of infusion, and of AUC appeared to increase proportionately with dose. Furthermore, there was no evidence that dose significantly affected any individual pharmacokinetic parameter. Penciclovir was distributed into tissues with an overall mean volume of distribution of approximately 1.5 l.kg-1, i.e. approximately double that of body water. It was rapidly eliminated, with a mean total plasma clearance of 39.3 l.h-1, and a mean terminal-phase half-life of 2.0 h. The majority of the dose, approximately 70%, was excreted unchanged in the urine. Mean renal clearance of BRL 39,123 was 28.1 l.h-1, which exceeds normal glomerular filtration rate and approaches renal plasma flow. At all dose-levels, the infusions of penciclovir were well tolerated, with no evidence of drug-related adverse events.

Acyclovir↗
PubMed1990

The pharmacokinetics of oral indoramin during pregnancy.

1. The pharmacokinetics of indoramin (Baratol; Wyeth) and its active metabolite 6-hydroxyindoramin administered to 13 women as a single 37.5 mg dose of indoramin were compared under pregnant and post-partum conditions. 2. No significant differences were observed between values determined under pregnant and post-partum conditions, for any pharmacokinetic parameter. Cmax and AUC values in individual subjects differed, in most cases, by no more than two-fold, i.e. the same order of magnitude as intra-subject variation seen in volunteers dosed repeatedly with indoramin. 3. Median values of Cmax, AUC(0.24) and t 1/2,z were of a similar order to values seen previously in normal volunteers after a single 37.5 mg dose. 4. It is concluded that in treating hypertension associated with pregnancy, this study does not provide evidence to depart from the usual clinical practice of titrating indoramin dosage with control of blood pressure as the end-point, keeping in mind the restriction of the dose-limiting side-effect of sedation.

Adult↗
PubMed1990

A review of the clinical pharmacokinetics and metabolism of the alpha 1-adrenoceptor antagonist indoramin.

1. The alpha 1-adrenoceptor antagonist indoramin is rapidly and extensively absorbed after oral administration, but with only low to moderate bioavailability (8-24% median) from the tablet (Baratol). Although plasma protein binding is high (72-86%), the drug is widely distributed into tissues (with median Vz 6.3-7.7 l/kg after i.v. dosage). 2. Elimination of indoramin is rapid in most healthy volunteers, with median plasma clearances of 18-26 ml/min per kg, after i.v. dosage. Elimination occurs principally by metabolism, the major route being indole 6-hydroxylation, followed by sulphate conjugation of 6-hydroxyindoramin. The faecal route of excretion predominates (45-50% of dose), with a further 35-40% in the urine. 3. Extensive variation in single-dose oral pharmacokinetics of indoramin is due largely to the existence of a poor metabolizer phenotype which co-segregates with that of debrisoquine. 4. On repeated administration (37.5 mg twice daily) to healthy volunteers, plasma concentrations of indoramin accumulate 3-4-fold above those anticipated from single-dose kinetics. However, steady state is achieved within the first week of dosing. 5. The pharmacokinetics of indoramin are substantially altered in the elderly. The oral AUC for a 50 mg dose is increased approx. 5-fold and the t1/2 2.5-fold. 6. Cirrhotic liver disease enhances bioavailability and decreases clearance, approx. 2-fold in each case for single oral and i.v. doses of 50 mg and 0.15 mg/kg respectively. 7. After oral indoramin Cmax and AUC are both raised (58% and 25%, respectively, for a 50 mg dose) by co-ingested ethanol (0.5 g/kg). After i.v. indoramin, kinetics are unaffected by alcohol, but indoramin (0.175 mg/kg) slightly increases (26%) blood ethanol concentrations during the first hour after dosing. 8. The pharmacodynamics of indoramin appear to be related to the combined pharmacokinetics of the drug and its 6-hydroxylated metabolite, which contributes to the antihypertensive effect.

Adrenergic alpha-Antagonists↗
PubMed1990

The clinical pharmacology of granisetron (BRL 43694), a novel specific 5-HT3 antagonist.

Granisetron is a novel specific 5-HT3 receptor antagonist whose effects have been evaluated in an extensive programme of volunteer studies. Single intravenous doses of 2.5-300 micrograms/kg of granisetron over 30 min, and of 40-160 micrograms/kg, administered over 3 min, were very well tolerated. There were no serious adverse events. There were no consistent or clinically important effects on cardiovascular parameters (pulse rate, blood pressure, ECG). Single doses of 40-200 micrograms/kg (30 min infusion) or 160 micrograms/kg (3 min infusion) did not influence subjective state, psychomotor performance or EEG. The only adverse event reported consistently more frequently with granisetron than placebo was constipation; this generally subsided spontaneously after 24-72 h. In volunteers, granisetron was widely distributed and also rapidly eliminated, largely through non-renal mechanisms. Granisetron exhibited essentially linear kinetics over the dose range studied (30-300 micrograms/kg). There was considerable inter-subject variability in terminal phase half-life and total plasma clearance. Biological activity of granisetron, as evidenced by significant inhibition of cutaneous 5-HT-induced, axon-reflex flare, was still apparent 24 h after a single dose of 40 micrograms/kg. Repeated intravenous doses of granisetron (up to 160 micrograms/kg b.d. for 7 days) were also well tolerated. As in the single dose studies, constipation was the only adverse event reported consistently more with active treatment than with placebo, but in no case did this necessitate withdrawal from the study or administration of a laxative.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1989

High-performance liquid chromatographic method for the determination of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL-39123) in human plasma and urine.

A rapid, sensitive and reliable reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection has been developed for the assay of a novel anti-herpes agent, 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL-39123), in human plasma and urine. The drug and the internal standard, the structural analogue BRL-42377, were extracted from the biological matrix by adsorption on a cation-exchange column and were subsequently eluted under alkaline conditions prior to HPLC. The method is reproducible, with coefficients of variation of ca. 5%, and linear from 0.1 to at least 30 micrograms ml-1 in plasma and from 50 to at least 2000 micrograms ml-1 in urine. The method has been used extensively to measure BRL-39123 in plasma and urine samples generated during clinical studies and is adequate for defining pharmacokinetics at projected therapeutic doses.

Acyclovir↗
PubMed1989

Pharmacokinetic interaction between indoramin and ethanol.

1. The effect of ethanol consumption (0.5 g/kg) on the pharmacokinetics of the alpha adrenoceptor antagonist indoramin, administered orally (50 mg) or intravenously (0.175 mg/kg) has been investigated in young volunteers. Sedation was also assessed using a visual analogue scale. 2. After oral indoramin administration, ethanol caused increases of 58% (P less than 0.01) in Cpmax, and 25% (P less than 0.05) in AUC. There was no effect of alcohol on elimination half-life. The combination of ethanol and indoramin was more sedative than indoramin alone. 3. Ethanol did not alter the pharmacokinetics of an intravenous dose of indoramin. However indoramin caused a small but statistically significant increase (26%) in blood ethanol concentrations during the first 1.25 h after dosing. Both indoramin and ethanol caused sedation. 4. The increased bioavailability of oral indoramin in the presence of ethanol may reflect some enhanced absorption, but it is also consistent with inhibition of first-pass metabolism of a flow-limited drug. The clinical implications are discussed.

Administration, Oral↗
PubMed1988

Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite.

Intra- and inter-subject variation in the kinetics of indoramin and its active metabolite 6-hydroxyindoramin have been studied in 5 young, healthy, male volunteers administered a single oral dose of the drug on 5 separate occasions. Inter-subject variation represented the main source of variability in indoramin plasma concentrations with, for example, the between-subjects sum of squares (a measure of the contribution to the total variability) representing around 97% of the total sum of squares for Cmax and AUC (0-24). Intra-subject and inter-subject coefficients of variation (C.V.s) were circa 20% and 100% respectively for both these parameters. Variability in 6-hydroxyindoramin concentrations was much lower and was approximately equally derived from intra- and inter-subject variation, with the C.V.s being approximately 44% for both Cmax and AUC (0-24). The results imply that the kinetic behaviour of indoramin within an individual will prove relatively consistent, despite widespread inter-subject variation, once an appropriate dosage regime has been established.

Administration, Oral↗
PubMed1987

The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine.

Five poor metabolisers (PM) and seven extensive metabolisers (EM), of debrisoquine, all healthy volunteers, received 50 mg indoramin orally following an overnight fast. Plasma concentrations of indoramin and 6-hydroxyindoramin were determined by HPLC with fluorimetric detection. In PM subjects, mean values of Cmax (158 ng/ml) and AUC(0-24) (2556 ng X h X m-1) for indoramin were substantially elevated and t 1/2 beta (18.5 h) prolonged by comparison with values in the EM subjects (21.6 ng/ml, 151 ng X h X ml-1 and 5.2 h respectively). For 6-hydroxyindoramin, on the other hand, Cmax (12.4 ng/ml) and AUC (0-8) (47.5 ng X h X ml-1) in PM subjects were significantly lower than in the EM subjects (28.2 ng/ml and 94.7 ng X h X ml-1). There was a tendency to a higher incidence of side-effects in the PM group. Although the difference did not achieve statistical significance (0.1 greater than p greater than 0.05), all the PM subjects experienced sedation compared to only two in the EM group. Differences in blood pressure and pulse rate between the two groups were small. It is concluded that the oxidative metabolism of indoramin is subject to genetic polymorphism, which is probably under the control of the same gene locus as that influencing debrisoquine oxidation. The clinical consequences are discussed.

Adult↗
PubMed1987

Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects.

We have studied the pharmacokinetics and absolute systemic availability of indoramin (50 mg) given orally in solution or as a tablet with reference to intravenously administered drug (0.15 mg/kg) in 9 healthy volunteers. After intravenous administration the median apparent volume of distribution was 6.3 l X kg-1, plasma clearance was 20.0 ml X min-1 X kg-1, and terminal half-time was 4.1 h. When given by tablet indoramin was absorbed with moderate rapidity, with a median tmax of 1.5 h. The median systemic availability was 24%. After oral administration in solution the drug was more rapidly absorbed, with a median tmax of 1.0 h (p less than 0.01). The median systemic availability was 43% (15-85%). Plasma concentrations of an active metabolite, 6-hydroxyindoramin, after single oral doses in either dosage form, were of a similar order to those of unchanged drug and fell with similar rapidity. After intravenous administration, however, concentrations of the metabolite were negligible.

Absorption↗
PubMed1986

Pharmacokinetics of indoramin and its metabolite 6-hydroxyindoramin after single and multiple doses to cirrhotic liver patients.

Pharmacokinetic data obtained after intravenous and single and repeat chronic oral dosing of indoramin in nine patients with liver cirrhosis are described. Median plasma clearance is 11.2 ml/min/kg. Terminal disposition half-life is prolonged after intravenous as well as acute and chronic oral dosing (9.1 versus 10.7 versus 12.2 h). Median volume of distribution is 11.2 L/kg. Bioavailability is increased with a wide range of distribution from 12.2 to 75.4%. There is a slight tendency of accumulation during twice daily oral dosing that cannot be explained by the degree of prolongation of half-life. The kinetics of the main metabolite, 6-hydroxyindoramin, are substantially comparable to the kinetics of indoramin with a ratio of 6-hydroxyindoramin/indoramin calculated from the area under plasma concentration-time curve of 0.3, which is within the range of normal. All data suggest that the changed pharmacokinetics are due to altered liver perfusion as would be expected from a substance with a plasma clearance in the magnitude of liver perfusion in normal volunteers. It seems likely that, in patients with liver cirrhosis, similar alpha 1 blocking effects may be achieved with lower doses than in patients with normal liver function.

Administration, Oral↗
PubMed1984

Pharmacodynamic correlates of modified absorption: studies with lormetazepam.

The bioavailability, pharmacokinetics, and effects on performance of lormetazepam (1 mg) have been compared using soft gelatin capsule and tablet formulations. Lormetazepam was more rapidly absorbed from the soft gelatin capsule (tmax = 1.0 +/- 0.2 h) than from the tablet (tmax = 2.4 +/- 0.4 h), and the plasma concentration-time curve for the capsule was shifted to the left. Bioavailability and elimination kinetics did not differ between the formulations. The number of substitutions in the digit symbol test was reduced between 0.5 and 1.5 h for both formulations (P less than 0.001), but the degree of impairment at 0.5 h was greater after the capsule than after the tablet (P less than 0.01). Visuo-motor co-ordination was impaired from 0.5 to 1.5 h after the tablet and the capsule (P less than 0.01), and extended to 5.5 h after the tablet (P less than 0.05). These observations reflect the differences in the plasma concentration-time curves.

Absorption↗
PubMed1984

The pharmacokinetics of fentiazac and its metabolite, p-hydroxyfentiazac, after twice-daily oral administration to male volunteers.

The pharmacokinetics of the anti-inflammatory agent fentiazac and its principal plasma metabolite, p-hydroxyfentiazac, have been investigated after repeated oral administration of fentiazac to male volunteers. Each volunteer received 200 mg of fentiazac twice daily for 15 d. Absorption was quite rapid, though some inter-subject variation in rates of absorption and bioavailability was observed. tmax values after the first dose ranged from 0.75-3 h while Cpmax values were 1050-4880 ng/ml. Elimination of fentiazac from plasma occurred rapidly in curvilinear fashion, so that concentrations were only 1% of their maximum value by 12 h after dosing. Maximum concentrations of p-hydroxyfentiazac after a single dose of fentiazac were 25.6-79.4% of those of fentiazac and were achieved at similar times. The metabolite was more slowly eliminated; the mean concentration of p-hydroxyfentiazac 12 h after a single dose was still 8% of its maximal value. On repeated administration, AUC0-12 h values for fentiazac and hydroxyfentiazac increased, as indicated by accumulation factors of 1.17 +/- 0.11 and 1.30 +/- 0.11 on days 8 and 15, respectively, for fentiazac and 1.72 +/- 0.15 and 1.77 +/- 0.10 for hydroxyfentiazac. There was no significant difference between days 8 and 15 in the extent of accumulation of either compound. Trough concentrations of fentiazac and hydroxyfentiazac on days 12 and 15 were similar to those on day 8. The clinical significance of these observations is discussed.

Acetates↗
PubMed1982

The disposition of a novel tetrahydroquinoline, tiquinamide, in rats and patas monkeys.

The absorption of tiquinamide occurred rapidly and extensively in both rats and patas monkeys. The major site of localization of radioactivity was in the stomach in both species. Tiquinamide was 50-60% bound to rat plasma and 50-75% to monkey plasma. The elimination of unchanged drug from plasma took place rapidly, with half lives of 1.6 h in rats and 0.7 h in monkeys. Elimination of total radioactivity in the rat was very slow and monoexponential, with a half-life of 90 h. However, in the monkey it took place in a biphasic manner and most radioactivity was eliminated in the first phase with a half-life of 0.75 h. Possible reasons for the species difference in elimination are discussed. The principle route of excretion in both species was via the urine. Excretion was slower in the rat than in the monkey. In the former species, only 50% of the administered dose was excreted in the first 24 h after dosing, and a further 12% was recovered from the carcasses after 7 days. In the monkey, however, excretion was virtually complete in the first 6 h.

Animals↗