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Biomedical subjects

A Darragh

Publications and source records attributed to A Darragh.

At least 37 records · Page 2Linked to original sources
PubMed1985

Single-dose and steady-state pharmacokinetics of piroxicam in elderly vs young adults.

Age-dependent changes in pharmacokinetics are considered a possible factor contributing to a higher risk of side-effects from drug treatment in the elderly. However, very little is known about the kinetics and metabolism of most NSAI agents in geriatric subjects. In a prospective age-comparison study, the single dose and steady-state pharmacokinetics of piroxicam 20 mg once daily were determined in 44 subjects ranging in age from 30 to 80 years. Plasma concentrations, elimination half-life, AUC, and volume of distribution were not influenced by age or sex and were in agreement with previously reported results in young adults. Pharmacokinetic parameters in 18 patients with evidence of mild or moderate renal impairment at study entry were not different from those in patients without impairment. Based on this and other studies, elderly patients receiving the recommended dose of piroxicam are not exposed to undue risk related to pharmacokinetic considerations.

Acetylglucosaminidase↗
PubMed1985

Central effects in man of the novel schistosomicidal benzodiazepine meclonazepam.

The novel benzodiazepine derivative, meclonazepam (3-methylclonazepam) has been found to be orally effective at high doses against all stages of schistosomiasis. Animals studies have shown it to have a high therapeutic index and a profile of behavioural activity typical of the benzodiazepines. The effects of single oral doses of meclonazepam, 1, 2 and 4 mg on central arousal, psychomotor performance and subjective mood were studied in two double-blind placebo controlled studies in healthy volunteers. In doses exceeding 1 mg, meclonazepam caused marked dose-related impairment in cognitive and psychomotor functions as well as shifts in mood reflecting sedation and ataxia. These effects were most prominent in the first 3 h after administration, with moderate sedation still present 6 h after the 4 mg dose. The implications of these findings for the use of benzodiazepine agents in the treatment of schistosomiasis are discussed.

Adult↗
PubMed1985

Metabolism and pharmacokinetics of the dihydropyridine calcium antagonist, ryosidine, in man.

The metabolic fate of [14C]ryosidine (ryodipine) has been investigated after oral administration to human subjects (by capsule), and to rats and dogs (in solution). The excretion patterns of 14C were similar for all three species: about 50% dose was excreted in urine, mainly in 24 h, but a proportion was excreted slowly, particularly by humans. Absorption in man appeared to be less than in the animal species, probably as a result of the capsule dosage form used. Mean concentrations of total 14C in human plasma reached a peak value of 0.41 microgram equiv./ml at four hours and declined biphasically thereafter (mean terminal t1/2 = 28 h). Unchanged ryosidine was only detected in plasma from two to six hours (mean t1/2 = 80 min), and never accounted for more than 5% of the plasma 14C. The extent of binding of ryosidine to the plasma proteins (in vitro) was similar (greater than 90%) to that of total 14C (in vivo; mainly metabolites). Less than 0.5% of the dose to human subjects was excreted via the kidneys as unchanged ryosidine, whereas the bulk of the extractable faecal 14C was in the form of unchanged drug and presumably represented unabsorbed material. The principal routes of biotransformation of ryosidine in all three species involved oxidative aromatization of the 1,4-dihydropyridine ring, followed by ester hydrolysis, O-dealkylation, hydroxylation of an alpha-methyl group (and lactonization) and some glucuronidation, although quantitative interspecies differences were apparent.

Administration, Oral↗
PubMed1984

Isosorbide dinitrate plasma concentrations and bioavailability in human subjects after administration of standard oral and sublingual formulations.

The bioavailability of isosorbide dinitrate from formulations containing 5, 10, and 20 mg in tablets and 10 mg in solution for oral use and 5 mg in tablets for sublingual use, has been compared. When adjusted for dose, the peak mean plasma drug concentrations after oral administration were similar (e.g., 9.2 ng/mL after a 10-mg tablet) and about one-half that obtained after sublingual administration. Drug concentrations declined monoexponentially with mean half-lives ranging from 25-36 min. The relative bioavailability of isosorbide dinitrate from the oral formulations was not significantly different (p greater than 0.05) over the dose range studied, whereas the relative bioavailability after sublingual administration was about twice as great (p less than 0.01) as that after oral administration. The plasma drug concentration-time profile after administering the 5-mg sublingual tablet was similar to that obtained after administering orally a solution containing 10 mg, indicating that the latter should be as clinically effective as the former.

Administration, Oral↗
PubMed1984

Isosorbide 5-mononitrate kinetics.

The kinetics of isosorbide 5-mononitrate (5-ISMN) were studied in 12 healthy subjects after intravenous infusion and oral doses of 20 mg. Kinetic parameters calculated by model-independent methods or by assumption of a one-compartment open model were in good agreement. Mean (+/- SD) systemic clearance of 5-ISMN was 127 +/- 21 ml/min, volume of distribution was 48.5 +/- 6.1 l, t 1/2 was 4.4 +/- 0.5 hr, and mean residence time was 6.2 +/- 0.7 hr. At the end of intravenous infusion of 5-ISMN at a rate of 8 mg/hr for 2.5 hr, mean plasma drug concentrations reached 356 +/- 39 ng/ml. Oral doses of 5-ISMN were essentially completely absorbed (93% +/- 13% systemic availability), and mean peak plasma drug concentrations of 388 +/- 70 ng/ml occurred at 0.83 +/- 0.46 hr. Mean absorption t 1/2 was 19 +/- 12 min. Unlike other vasodilator organic nitrates in clinical use, 5-ISMN is notable for its relatively long t 1/2, essentially complete oral absorption, lack of active metabolites, and low intersubject variability in kinetics.

Absorption↗
PubMed1984

Metabolic fact of 14C-isosorbide 5-mononitrate in humans.

Single oral doses of 20 mg of the carbon-14 labelled form of the antianginal drug isosorbide 5-mononitrate (5-ISMN, Elantan) were essentially completely absorbed and excreted fairly rapidly in the urine. Means of 24, 52, 78, 93 and 96% dose were excreted during 6, 12, 24, 48 and 120 h, respectively. Concentrations of 14C reached peak levels at about 1-2 h when about 86% of the 14C was associated with the parent drug, 5-ISMN (peak mean level 430 ng/ml), and the remainder mainly with the pharmacologically-inactive denitrated product isosorbide. Because the plasma (and urinary) half-life of isosorbide was longer (about 8-9 h) than that of 5-ISMN (about 4.5 h), the proportions of the former in plasma increased relative to the latter. Concentrations of 14C in whole-blood and plasma were similar, implying that 5-ISMN diffused into blood cells. Concentrations of 5-ISMN in saliva and plasma were almost identical, presumably because of the almost negligible plasma protein binding of the drug (less than 5%). At least five metabolites of 5-ISMN were detected in urine - these were isosorbide (about 37% dose), conjugated material (about 25% dose) presumably mainly 5-ISMN-glucuronide, sorbitol (about 7% dose), the parent drug 5-ISMN (about 2% dose) and two unidentified metabolites (about 7 and 4% dose, respectively). The conjugated material was excreted in the urine relatively more rapidly than the denitrated product, isosorbide.

Adult↗
PubMed1984

[Bioavailability of isosorbide-5-mononitrate from delayed-action formulations].

The relative bioavailability of isosorbide-5-mononitrate (IS-5-MN) has been determined after a 3-day period of dosing with 20 mg in standard-release reference tablets and sustained-release capsules at 12-h intervals, 40 mg in sustained-release capsules (Olicard 40 retard) at 24-h intervals and after single oral dose of 60 mg sustained-release capsules (Olicard 60 retard), in a cross-over study with 12 human subjects. Accumulation factors of 1.1-fold or 1.2-fold occurred during administration of 20 mg in standard- or sustained-release tablets and capsules respectively at 12-h intervals, and negligible accumulation of drug occurred after administration of 40 mg in sustained-release capsules at 24-h intervals or was calculated by the superposition principle to occur after doses of 60 mg in sustained-release capsules at 24-h intervals. The mean extent of bioavailability of IS-5-MN from the 20 mg, 40 mg and 60 mg sustained-release capsules was 79%, 67% and 70% respectively, of that from the standard-release reference tablets. The posterior probability that the bioavailability of IS-5-MN was included within the limits 60%-90% of the reference tablets was 97%, 86% and 95% for the 20 mg, 40 mg and 60 mg sustained-release capsules respectively. Means of peak plasma levels of IS-5-MN after administration of the sustained-released capsules were linearly related to the doses administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1983

Determination of heptaminol in human plasma and urine by high-performance liquid chromatography.

Heptaminol was measured in plasma and urine following pre-column derivatisation with o-phthalaldehyde and reversed-phase high-performance liquid chromatography employing fluorescence detection. The limits of detection were sufficient for pharmacokinetic studies of the drug after clinically-used doses. Plasma concentrations of heptaminol reached peak levels (2.19 micrograms/ml) at 0.75 h after single oral doses (0.47 g of heptaminol) and declined with a half-life of 2.1 h (+/- 0.5 S.D.). Heptaminol was well absorbed and excreted rapidly, mainly unchanged in urine, 82% dose (+/- 10 S.D.).

Amino Alcohols↗
PubMed1983

Platelet uptake of serotonin following repeated administration of 3-cyano-imipramine to healthy volunteers.

In a double blind, placebo-controlled study the effects of daily oral administration of 3-cyano-imipramine on the 3H-serotonin uptake capacity of platelets were investigated in healthy volunteers. The initial dose was 1 mg, rising to 3 mg daily for 7 days. A rapid and profound inhibition of 3H-serotonin uptake was observed in platelets isolated from the treated subjects. During repeated administration, uptake was reduced to less than 10% of pre-drug values. Five days after the final dose uptake had only partially recovered, to 53% of pre-drug values. A similar inhibition profile was observed when serum from the treated subjects was incubated with normal platelets and 3H-serotonin. The results establish 3-cyano-imipramine as a potent inhibitor of platelet serotonin uptake in humans.

Adolescent↗
PubMed1983

Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788.

The benzodiazepines are typified by a profile of side effects which includes drowsiness, ataxia and incoordination. Ro 15-1788, an imidazodiazepine derivative, exhibits marked antagonism of the behavioural and biochemical effects of the benzodiazepines in animals and man. It is devoid of any behavioural activity in animals, except at very high doses. In the present study the effects of single rising oral doses of Ro 15-1788 on cognitive, psychomotor and subjective function in man have been assessed using a battery of psychometric tests designed to identify the sedative action of the benzodiazepines. At all doses up to 600 mg, Ro 15-1788 demonstrated none of the classical behavioural effects of the benzodiazepines.

Adult↗
PubMed1983

Effects of a single oral dose of 3-cyano-imipramine on serotonin uptake and content of platelets in healthy volunteers.

Changes in platelet serotonin uptake and content were investigated following administration of a single oral dose of 3-cyano-imipramine to healthy volunteers. The uptake of 3H-serotonin by platelets harvested from these subjects was almost completely inhibited 4 h after dose administration. This inhibition continued for at least 24 h. Plasma taken from the subjects inhibited the uptake of 3H-serotonin by platelets isolated from non-treated subjects. A small but significant reduction in platelet serotonin content was observed 3.75 h after dosing and was still evident after 24 h.

Administration, Oral↗
PubMed1983

The effect of PK5078, a new serotonin uptake inhibitor, on serotonin levels and uptake in human platelets, following administration to healthy volunteers.

PK 5078 is a recently developed compound which inhibits specifically the neuronal reuptake of serotonin and enhance its release. PK 5078 was administered to healthy male volunteers in single and multiple oral doses and the effects on platelet serotonin uptake and content were examined. A significant dose-related inhibition of 3H-serotonin uptake by platelets was observed following single oral doses of PK 5078 (25-150 mg), with maximal inhibition at 75 mg. This was evident 2 h after dosing and was still marked after 10 h. Plasma collected from the subjects after dosing also had a considerable dose-related effect on the uptake of 3H-serotonin by untreated platelets. No significant alteration in platelet serotonin content was observed after single doses of PK 5078. When PK 5078 (50 mg) was administered twice daily for 9 days there was a rapid and sustained reduction in 3H-serotonin uptake by platelets, which returned to pretreatment levels 2 days after discontinuation of the drug. A similar response was observed when plasma from these subjects was incubated with untreated platelets. The rate of depletion of endogenous platelet serotonin was much slower with minimum levels being attained on the morning after the final dose. The recovery following withdrawal was also slow with serotonin levels approaching pre-dose values 14 days after the final dose of PK 5078.

Adolescent↗
PubMed1983

The percutaneous absorption and excretion of promestriene (3-propoxy-17 beta-methoxy-1,3,5(10)-estratriene) in rats and humans.

The percutaneous absorption of 3H-promestriene (an antiseborrhoeic agent; 3-propoxy-17 beta-methoxy-1,3,5(10)-estratriene) was studied in rats and human subjects. Extensive and continual absorption of the tritium label (about 50% dose in 3 days) occurred in rats when the treated area of skin (ca. 30 micrograms/cm2) was occluded; when unabsorbed material was washed off after 6 h, a substantial proportion of the applied 3H (about 25% dose) had been absorbed to be excreted later. In contrast, less than 1% of the 3H applied to the skin of human volunteers (0.1-0.5 mg/cm2) was absorbed within 6 h and subsequently excreted. In rats, tissue concentrations of 3H were greatest in the liver, adrenals and ovaries.

Absorption↗
PubMed1983

The metabolic fate of the anti-androgenic agent, oxendolone, in man.

After intramuscular administration of 16 beta-ethyl-17 beta-hydroxy-4-4-[4-14C]estren-3-one (14C-oxendolone; 300 mg) to 3 human subjects, excretion of 14C was very slow and incomplete despite a 20-day sample collection period. During this time, means of 37% and 21% of the administered 14C were recovered in urine and faeces, respectively, and if excretion continued at the same rate, approximately 90% of the administered 14C would have been excreted during 5-12 weeks. Peak plasma 14C concentrations were reached at 3-6 days after dosing, when they represented 0.2-1.1 micrograms equiv./ml, and declined very slowly thereafter with a half-life of 5.0-6.6 days. Concentrations of unconjugated drug-related steroids circulating in plasma never exceeded about 0.1 microgram/ml. Mass spectroscopic analysis of isolated urinary and faecal metabolites indicated that the principal routes of biotransformation of oxendolone in man are similar to those of the endogenous androgens-namely, reduction of the 4,5-double bond, further reduction of the saturated 3-ketone to the 3 alpha-hydroxysteroid, and oxidation of the 17 beta-alcohol to the corresponding ketone, followed by conjugation, mainly with glucuronic acid, and excretion in the urine and bile.

Adult↗
PubMed1983

Ro 15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability.

In a double-blind, placebo-controlled three-way cross over study, the efficacy of Ro 15-1788 200 mg, a new benzodiazepine antagonist, in blocking the amnesic, cognitive, psychomotor and subjective effects of diazepam 20 mg, was investigated in a group of six healthy male volunteers. The amnesic effects of diazepam were markedly attenuated by the combined administration of Ro 15-1788. The psychomotor and subjective effects of diazepam by mouth were most pronounced 2.5 h after administration. Concurrent oral administration of Ro 15-1788 completely prevented these effects at 2.5 h. Plasma diazepam concentrations observed after administration of the combination of diazepam and the antagonist did not differ from those observed following diazepam alone.

Adolescent↗
PubMed1983

The metabolism of the anti-inflammatory drug eterylate in rat, dog and man.

Oral doses of 14C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal 14C was probably derived in part, from biliary-excreted material. Peak plasma 14C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicyclate concn. reached a peak (10.9 and 19.8 micrograms/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 micrograms/ml, respectively) and declined with a half-life of about one hour. Tissue concn. of 14C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concn. were lower than those in the corresponding plasma. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major 14C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the 14C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.

Acetanilides↗
PubMed1983

Vasoactive intestinal polypeptide in obesity.

Twenty-six patients who were more than 35 per cent above their ideal weight were examined before the introduction of a weight reduction programme. At the end of a three-month period, seven patients had lost more than 10 per cent of their body weight. These patients had significantly lower triglyceride levels, fasting gastric inhibitory polypeptide levels (GIP) and prolactin levels. Fasting vasoactive intestinal polypeptide levels (VIP) before commencing diet were raised in six of the 19 patients who subsequently did not lose weight whereas the seven patients who lost weight had normal VIP levels (X2 = 3.07, P less than 0.05). Patients with high VIP levels had higher triglyceride levels, higher mean C-terminal glucagon-like immunoreactivity (C-GLI) and higher post glucose infusion secretin levels. There was a significant correlation between triglycerides and VIP. The significance of abnormally high VIP levels in obesity and the inability of these patients to lose weight is discussed.

Adult↗