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Biomedical subjects

A K Pedersen

Publications and source records attributed to A K Pedersen.

70 records · Page 4Linked to original sources
PubMed1983

Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man.

The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0 microM) in platelet-rich plasma as well as both aggregation and nucleotide release induced by collagen (95 micrograms/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1 alpha (PGI-M). PGI-M excretion was increased by dazoxiben; it rose a mean 2.4-fold from predosing control values at 0-6 h after administration of the highest dose studied (200 mg).

Adult↗
PubMed1982

A comparative investigation of nimorazole and misonidazole as hypoxic radiosensitizers in a C3H mammary carcinoma in vivo.

The hypoxic cell radiosensitizing properties of nimorazole have been investigated in a C3H mammary carcinoma transplanted to the feet of C3D2F1. The results have been compared with those obtained with misonidazole (MISO) in the same animal tumour system. For single-dose irradiation in air, nimorazole gives an enhancement ratio (ER) of approximately 1.4, independent of the dose of drug administered over the range 0.1-1.0 mg/g. MISO yields a similar ER at the 0.1 mg/g level but, unlike nimorazole, shows a steep dose-response curve with an ER of 2.2 when given in a concentration of 1.0 mg/g. No such dose-response relationship is seen with nimorazole despite the fact that tumour and plasma concentrations of the 2 drugs have an identical dose relationship. With irradiation given in 5 daily fractions, nimorazole and MISO at a dose of 0.3 mg/g per fraction both show an ER of approximately 1.3. The high drug doses used in single-fraction radiation experiments in animals bear little relation to those applicable to clinical practice since these would result in unacceptable toxicity. The results of the present studies are therefore of interest as nimorazole is potentially less toxic than MISO in humans but demonstrates similar radiosensitizing properties at clinically relevant dose levels.

Animals↗
PubMed1982

Binding of sulfinpyrazone and its metabolites in human serum and in solutions of human serum albumin.

The binding of sulfinpyrazone its sulfone metabolite and its sulfide metabolite to serum protein was studied by equilibrium dialysis. At 20 micrograms/ml 99.1% of the parent compound was bound in serum, whereas 99.8% of the sulfide and 98.3% of the sulfone were bound at this concentration. The binding of the three compounds were studied in diluted serum and in solutions of human serum albumin (HSA). There was no evidence of binding to proteins other than albumin. The association constants to primary and secondary binding sites and the number of binding sites were calculated. For the sulfide a lower K1-value in serum (0.76 . 10(6)M-1) than in the HSA solution (1.8 . 10(6)M-1) indicated the possible presence of a competitively bound substance in serum. In undiluted serum no displacing effect of the sulfide on sulfinpyrazone binding was found when both compounds were present in a concentration of 20 micrograms/ml, but in a HSA solution a pronounced sulfide induced displacement of the sulfinpyrazone from its primary binding site was shown. Acetylation of HSA depressed the binding of sulfinpyrazone but in undiluted serum there was no other effect on sulfinpyrazone binding by the addition of acetylsalicylic acid than could be explained by the displacing effect of salicylic acid. At concentrations of 20 micrograms/ml of sulfinpyrazone and above 50 micrograms/ml of the displacing agent significant displacement was demonstrated with phenylbutazone, tolbutamide and salicylic acid.

Acetylation↗
PubMed1982

Systemic availability of acetylsalicylic acid in human subjects after oral ingestion of three different formulations.

Systemic availability of acetylsalicylic acid (ASA) in normal human subjects after oral ingestion of 1 g in three different formulations was determined by using high-pressure liquid chromatography for ASA assay. For an effervescent, a plain and a sustained release preparation systemic availabilities expressed in percent of the ingested dose were 16.9 +/- 3.2, 8.6 +/- 1.2 and 2.6 +/- 0.4%, respectively. All subjects had clearly measureable amounts of ASA in plasma after oral intake of a sustained release preparation with an average peak concentration of 15 mumol/l. Peak concentration after an effervescent and plain formulation was on the average 80 and 40 mumol/l, respectively. Half-life of ASA in plasma was 18.1 +/- 1.2 min. for the effervescent and 28.7 +/- 5.3 min. for the plain preparation, while the elimination phase was too ill defined for the sustained release formulation. Average plasma half-life of salicylic acid (SA) was similar after the three different administration forms with values between 3.0 and 3.7 hrs. Further, no difference in SA distribution volumes or amounts of SA absorbed was found. The present study demonstrates that oral ingestion of ASA in effervescent, plain and sustained release formulations gives rise to significant amounts of ASA in plasma. Concentrations found indicate that long-term antithrombotic therapy with ASA in a sustained release formulation may be possible.

Administration, Oral↗
PubMed1981

Sulphinpyrazone metabolism during long-term therapy.

1 The plasma concentrations of sulphinpyrazone and four of its metabolites are reported together with the amounts excreted in urine. Eight insulin-requiring diabetics were investigated, all treated with sulphinpyrazone 600-800 mg day-1 for 2.5 years or more. 2 Blood samples were drawn before the first morning dose and 2 h later. The mean plasma concentrations were (t=0 h-t=2 h): sulphinpyrazone 7.1-16.0 microgram ml-1; sulphone 1.7-4.8 microgram ml-1; p-OH-sulphide 0.67-0.89 microgram ml-1; p-OH-sulphinpyrazone 0.10-0.16 microgram ml-1. Statistically significant correlations were found between the plasma concentrations at t=0 of the sulphide and the p-OH-sulphide and that of sulphinpyrazone. 3 In urine, a very wide range in excretion of unconjugated compounds was observed. Sulphinpyrazone were excreted in amounts corresponding to 1-30% of the daily dose. The metabolites were generally excreted to amounts corresponding to less than 1% of the daily dose; however, up to 3% was found as the sulphone. 4 Increases of the concentration of all compounds in urine were found after treatment with beta-glucuronidase indicating 0-conjugation with glucuronic acid. 5 Since both the sulphide and the sulphone were found more active as inhibitors of platelet function in vitro than their parent compound, they may together constitute the major part of the platelet inhibitory drug activity in plasma during long-term therapy with sulphinpyrazone.

Adult↗
PubMed1981

Two metabolites of sulphinpyrazone and their identification and determination by mass spectrometry.

Sulphinpyrazone is an antiplatelet in vivo and in vitro. Two active metabolites, a sulphide (S) and a hydroxylated sulphide (S-OH) have been identified in rabbit and human plasma and a selective and sensitive g.c.-m.s.-method for quantitative determination of the sulphide and hydroxylated sulphide in plasma and urine has been evolved which allows concentrations down to 5 ng ml-1 for the sulphide and 30 ng ml-1 for the hydroxylated sulphide to be detected. The time course of the metabolite concentrations in plasma corresponds to the biological findings, suggesting that the metabolites contribute significantly to the in vivo effects of the drug.

Animals↗
PubMed1979

Determination of sulfinpyrazone and two of its metabolites in human plasma and urine by gas chromatography and selective detection.

A selective and sensitive gas chromatographic method for simultaneous determination of sulfinpyrazone and two of its metabolites (the para-hydroxylated metabolite and the sulfone metabolite) in biological fluids using alkali flame ionization detection (AFID), electron capture detection (ECD) and mass fragmentographic detection is described. The compounds are extracted from the samples, methylated and separated on 2% OV-17 or 3% OV-225 columns. Phenylbutazone is used as internal standard. Standard curves are linear. The coefficient of variation at 10 microgram/ml of sulfinpyrazone in plasma was shown to be 1.8% (AFID), and the detection limits were 0.1 microgram/ml (AFID) and 10 ng/ml (ECD). Mass spectra of the methylated compounds are shown and serum concentration curves after oral administration of 100 mg sulfinpyrazone to two persons are determined together with the excreted amounts of drug and metabolites.

Flame Ionization↗
PubMed1979

Pharmacokinetics of dipyridamole.

Dipyridamole, though originally introduced as a coronary vasodilator, has lately been increasingly investigated in the treatment of thromboembolic diseases because of its inhibitory influence upon blood platelet function. The compound is eliminated from the organism by hepatic biotransformation to the monoglucuronide, which almost exclusively is subjected to biliary and faecal excretion with simultaneous partial enterohepatic circulation taking place. Only minute amounts are excreted through the kidneys. In experiments on four normal human volunteers it was found that the serum concentration curve after intravenous administration of dipyridamole rather closely fits the pharmacokinetics of an open two-compartment model with first order, linear disposition kinetics and elimination taking place from the central compartment. Experiments with oral ingestion of the compound could be described by the use of a corresponding pharmacokinetic model with two consecutive first order input steps, representing the dissolution and absorption processes. The disposition rate constants (beta) were within the range of 0.0051--0.0083 min.-1 corresponding to biological half-lives of 84--145 min. The absorption rate constant was about 0.07 min.-1, and the systemic availability of an oral dose of 100 mg dipyridamole in tablets varied from 37 to 66%.

Administration, Oral↗
PubMed1978

Simultaneous and specific determination of proxyphylline, theophylline and other xanthine derivatives in serum by high pressure liquid chromatography.

A HPLC-method for rapid, simultaneous and specific determination of proxyphylline, theophylline, glyphylline, theobromine, caffeine and 3-methylxanthine using 8-chlorotheophylline as internal standard is presented. Using 20 microliter deproteinised serum samples for injection, the the detection limits for theophylline and proxyphylline are about 0.040 and 0.055 microgram per ml serum or plasma, respectively, and the corresponding sensitivities are about 0.033 and 0.048 microgram compound for 0.0044 absorbance units at 280 nm. In duplicate analyses the coefficient of variation is less than 3%. A number of frequently used drugs did not interfere in the analyses of serum samples from patients under treatment or in experiments with drug additions to serum samples.

Caffeine↗
PubMed1978

Myocardial pharmacokinetics of lithium in vitro.

The myocardial pharmacokinetics of ionised lithium were investigated in isolated, intact rabbit hearts, which were retrogradely perfused with a modified Krebs-Henseleit solution containing lithium in a concentration of 5 mM. The rate of myocardial accumulation of lithium as a function of time was indirectly followed at constant coronary flow by means of determination of the lithium content of fractional samples of the coronary output of perfusate collected during the lithium perfusion period. The disposition rate of lithium from the myocardium was similarly determined with respect to the time lapse after the perfusion had been switched over to a lithium-free liquid. The accumulation and disposition processes were found to fit bi-exponential functions, as an expression of the myocardium behaving as a two-compartment system obeying apparently first order, linear kinetics with respect to ionised lithium. A pronounced decrease of the uncomposite elimination rate constants k10 and especially k21 was observed after continuous perfusion with 5 mM lithium perfusion liquid for about 30 min. During this perfusion period at steady state, an absolute increase of myocardial lithium accumulation obviously took place. A possible correlation of these findings to the cardiac effects of lithium is discussed.

Animals↗
PubMed1978

Myocardial effects of lithium in vitro.

The myocardial effects of increasing concentrations of ionic lithium were investigated in isolated, spontaneously beating rabbit hearts, which were retrogradely perfused with a modified Krebs-Henseleit solution containing lithium in concentration of 1, 5 or 10 mM. The following functional parameters were continuously recorded: heart rate, amplitude and rate of contraction, coronary flow, myocardial oxygen consumption and ECG. The lowest concentration of 1 mM lithium did not cause any measurable changes in these parameters. A concentration of 5 mM lithium produced a rather slowly developed increase in amplitude and rate of contraction of about 22% without any concomitant increase of oxygen consumption. A delayed increase in the oxygen consumption of about 21%, but accompanied by a significant decrease in contractility however, occurred much later in the experiments, probably as an expression of a decrease in myocardial efficiency. The highest lithium concentration produced similar effects. None of the other parameters measured were markedly influenced by lithium. The positive inotropic effect of lithium on myocardial contractility was very convincingly verified in isolated electrically stimulated rabbit papillary muscles by isometric measurements of the maximum tension produced and the rate of its development. An inhibitory influence of lithium on the positive inotropic effect of increasing frequency of stimulation was observed. Adrenergic beta-receptor blockade did not abolish the positive inotropic effect of lithium. A possible causative influence of lithium on the cellular calcium metabolism is discussed.

Adrenergic beta-Antagonists↗