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Biomedical subjects

R Lambe

Publications and source records attributed to R Lambe.

At least 19 recordsLinked to original sources
PubMed1990

Pharmacokinetics of falipamil after intravenous administration to humans.

Falipamil (2-[3-[3-(3,4-dimethoxyphenetylmethylamino]propyl]-5,6- dimethoxyphthalamidine; 1) is a new specific bradycardic agent for the treatment of sinus tachycardia. Pharmacokinetics of falipamil in humans (n = 6) was determined in plasma and urine after iv administration of 100 mg (1.85 MBq) per person of 14C-labeled drug by liquid scintillation counting and by a specific, sensitive reversed-phase totally automated HPLC system with fluorimetric detection. Recovery of total radioactivity was 91.8 +/- 3.7%, with 68.2 +/- 4.3% in urine and 23.6 +/- 2.5% in the feces. The majority of radioactivity was excreted within 24 to 48 h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is approximately 100 times less active than 1, contributed 14.1 +/- 1.6 and 4.5 +/- 0.7%, respectively, of the dose to urinary excretion. Plasma protein binding of 1 and 2 was 87.9 +/- 1.2 (concentration range: 2000-8000 ng/mL) and 89.7 +/- 0.5% (concentration range: 62.5-1000 ng/mL), respectively. Plasma concentrations of 1 peaked at 2 min at 724 +/- 173 ng/mL, declined biphasically, and were fitted to a two-compartment open model. Plasma concentrations of 2 were very low, in all cases ranging from 0 to 35 ng/mL. The dominant terminal half-life (beta-phase) of 1 from plasma was 1.8 +/- 0.6 h (range 1.4-2.9 h), mean residence time was 2.4 +/- 0.4 h, total body clearance was 1108.5 +/- 119 mL/min, and renal clearance was 117 +/- 20 mL/min. All parameters demonstrated very low intersubject variability.

Adult↗
PubMed1989

Tanakan inhibits platelet-activating-factor-induced platelet aggregation in healthy male volunteers.

An open study to investigate the PAF-acether antagonist activity of Tanakan in healthy male volunteers examined the effect of a single 15-ml oral dose on ex vivo platelet aggregation induced by adrenaline, adenosine diphosphate (ADP), collagen or PAF-acether. Aggregometry was performed on platelet-rich plasma samples from blood taken 1 h before dosing with Tanakan and 2, 4 and 8 h after intake of Tanakan. Following dosing with Tanakan there was a reduction in platelet aggregation at all doses of PAF, with 1 microM ADP and adrenaline, the most significant decreases occurred with 75 nM PAF-acether 4 h after intake (p less than 0.05) and 300 nM PAF-acether 4 h (p less than 0.01) and 8 after intake (p less than 0.05). There were no concomitant changes in coagulation, skin bleeding time, haematological and biochemical laboratory tests, blood pressure or pulse. The results provide a possible explanation for the clinical efficacy of Tanakan in the treatment of peripheral vascular disease; they also confirm that a single oral dose of 15 ml Tanakan is well tolerated.

Adult↗
PubMed1986

Study of the tolerance and diuretic properties of torasemide following oral or intravenous administration to healthy volunteers.

The tolerance and diuretic properties of torasemide after oral or intravenous administration to healthy volunteers were studied. Six groups, each of 6 subjects, were given single rising oral doses ranging from 10 to 100 mg; 8 subjects received ascending i.v. doses on alternate days, ranging from 2.5 to 80 mg. At the highest oral doses investigated (80 mg and 100 mg) a number of volunteers complained of cramps in the knees, calves and feet. These symptoms were generally of short duration. Similar effects were not encountered during the intravenous study. There were no significant changes in ECG. Some significant drug-related changes were encountered in the within-study biochemistry and haematology assessments. Torasemide proved to be a potent diuretic following oral administration at all the doses investigated and following intravenous administration at all doses except 2.5 mg. A linear relationship existed between the urine output and the logarithm of the dose, and both sodium and chloride excretion were linearly correlated with urine volume. The rate of potassium excretion was markedly lower than that of sodium and chloride and was linearly correlated with the logarithm of the urine volume. Torasemide was well tolerated from all perspectives studied. It showed a potent diuretic property, and was equally effective by the oral and intravenous routes.

Administration, Oral↗
PubMed1986

Interaction of antimicrobial agents with human peripheral blood leucocytes: uptake and intracellular localization of certain sulphonamides and trimethoprims.

The uptake of sulphamethoxazole, sulphadiazine, sulphamerazine, sulphanilamide, trimethoprim and brodimoprim by human peripheral blood leucocytes, has been investigated. High performance liquid chromatography (HPLC) was used to assay drug concentrations before and after incubation with leucocyte suspensions. Using radiolabelled material the intracellular localization of two of these compounds was also determined. The results indicated that all the investigated drugs were taken up by leucocytes. Differential studies demonstrated that mononuclear cells accumulated higher drug concentrations (0.13-0.55 microgram/10(7) cells), than resting neutrophils (0.02-0.26 microgram/10(7) cells) with the exception of sulphanilamide, which was taken up to a greater extent by neutrophils (0.75 microgram/10(7) cells). During neutrophil phagocytosis intracellular levels of all the drugs except brodimoprim increased from 3 to 130-fold as compared to resting neutrophils. The uptake of 14C-sulphanilamide and 14C-trimethoprim, in neutrophils and mononuclear blood cells, as assessed by measurement of the cell-associated radioactivity, correlated well with that determined by the HPLC procedure. In the intracellular localization studies 14C-sulphanilamide and 14C-trimethoprim exhibited similar distribution profiles. In neutrophils, 35-40% of radiolabelled drug was located in both the microsome and cytosol fractions whereas in peripheral blood mononuclear cells 40-60% was found in the cytosol and 10-20% in the microsome fraction. The results of this study suggest that, following activation, leucocytes may actively transport these drugs and release them locally at sites of infection. The ability of neutrophils to further concentrate the drugs during phagocytosis may result in reduced survival time of some ingested bacteria. These concepts may be important in designing treatment stratagems for intracellular pathogens.

Chromatography, High Pressure Liquid↗
PubMed1986

A randomized controlled trial of hypnotherapy for smoking cessation.

A randomized controlled study in a family practice setting was conducted on the use of hypnosis in helping people quit smoking. In the hypnosis group 21 percent of patients quit smoking by the three month follow-up compared with 6 percent in the control group. By six months there were no significant differences between the two groups, and at one year 22 percent in the hypnosis group and 20 percent in the control group had quit. The only significant predictor of success with quitting was having a college education.

Adult↗
PubMed1985

High-performance liquid chromatographic determination of certain salicylates and their major metabolites in plasma following topical administration of a liniment to healthy subjects.

The liniment used is a topical analgesic and anti-inflammatory preparation containing two active constituents, 3-phenylpropylsalicylate and ethyl-5-methoxysalicylate, in solution in isobutyl decanoate. It is known that 3-phenylpropylsalicylate is metabolised to salicylic acid and salicyluric acid and ethyl-5-methoxysalicylate is metabolised to 5-methoxysalicylic acid and gentisic acid. In the present study the separation of the salicylates and their metabolites was carried out on a Waters mu Bondapak C18 column using two different mobile phases, methanol-water (80:20) for the parent drugs and methanol-5% aqueous acetic acid (27:73) for their metabolites. The salicylates and their metabolites were detected by absorption at 310 nm. The limits of detection for parent drugs and metabolites were respectively 0.2 and 0.1 microgram/ml in plasma, using a 1-ml plasma sample and a 20-microliter injection from a reconstituted volume of 250 microliter. Mean percentage coefficients of variation for intra-assay and inter-assay precision were between 3.3 +/- 1.9% to 9.1 +/- 3.7% and 6.8 +/- 2.2% to 15.7 +/- 10.1%, respectively. Linearity, as measured by the correlation coefficient of intra-assay linear regression curves, was better than 0.998 in all cases.

Administration, Topical↗
PubMed1985

Sudden death of a volunteer.

A volunteer participating in a study of eproxindine, a new antiarrhythmic agent, had a sudden cardiorespiratory arrest and died. Subsequently it became known that he had received a depot injection of flupenthixol on the day before his death; an interaction between these two drugs seems likely. This incident illustrates that it is impossible to guarantee absolute safety in volunteer studies if details of medical history are withheld.

Adult↗
PubMed1985

Gas chromatographic determination of mefloquine in human and dog plasma using electron-capture detection.

A sensitive and selective gas-liquid chromatographic method for the determination of plasma levels of mefloquine in human and dog plasma is described. The drug and internal standard were extracted from plasma at pH 9.0 into isopropyl acetate. After evaporation of the solvent, the residue was taken up in toluene and derivatised with heptafluorobutyrylimidazole. The derivative was quantified by gas-liquid chromatography on a 3% GC GE-SE30 column with electron-capture detection. The limit of detection for mefloquine in plasma was 10 ng/ml. The mean overall recovery from plasma was 102.7 +/- 3.3%. The method was shown to be specific for mefloquine without any interference from endogenous compounds in plasma or from the drugs pyrimethamine and sulfadoxine (compounds often administered in combination with mefloquine). The assay described was successfully applied to the determination of plasma levels of mefloquine in man and dog following oral and intravenous administration, respectively.

Animals↗
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↗
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 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↗