Biomedical subjects
Publications and source records attributed to L E Edholm.
Diastereomers of 5-S-cysteinyldopa formed from D-dopa and L-cysteine or from L-dopa and D-cysteine can be separated from 5-S-cysteinyldopa formed from L-dopa and L-cysteine by liquid chromatography. The diastereomers have a great potential as internal standards in the analysis of 5-S-cysteinyldopa. They can be used as reference substances in the differentiation of stereospecific enzymatic oxidation of dopa from non-specific oxidation.
Theophylline (1, 3-dimethylxanthine) and enprofylline (3-propylxanthine) have been examined for effects in the rat. Enprofylline was 3.8 times as potent as theophylline as a tracheal relaxant in vitro, and 1.3 times as potent as theophylline to increase the rate of isolated perfused hearts. An oral dose (5 mg/kg) of enprofylline to rats was almost completely recovered in the urine as unchanged drug, showing that this xanthine is well absorbed and negligibly metabolised. Theophylline (10 and 30 mg/kg p.o.) significantly and dose-dependently increased locomotor activity in rats whereas the same doses of enprofylline were without effect on behaviour. Theophylline ( 5-20 mg/kg p.o.) produced significant and dose-dependent natriuretic and volume diuretic effect with little augmentation of potassium excretion. Enprofylline up to 10 mg/kg was without diuretic effects. At the large dose of 20 mg/kg enprofylline decreased sodium excretion and produced some volume diuresis. It is suggested that lack of diuretic and CNS-stimulant behavioural effects by enprofylline is due to its low ability to antagonise adenosine receptor stimulation. Pharmacodynamic differences between enprofylline and the potent adenosine antagonist theophylline may indicate a functional importance of endogenous adenosine.
Rats under pentobarbitone anaesthesia, pancuronium relaxation and artificial ventilation with constant volume, were given methacholine (MeCh) 4, 6, and 9 micrograms intravenously at 2 min. intervals; the rise in intratracheal pressure indicated bronchoconstriction. The heights of peak responses (PIPR), response areas (RA), and blood pressure and heart rate were recorded, and theophylline (THEO) concentrations in plasma and lung tissue were measured. THEO (5, 10, or 20 mg/kg intravenously) proved a weak bronchodilator agent with pronounced effects on circulation. Terbutaline (TER) (10, 20, or 40 microgram/kg intravenously) shifted dose dependently the airways MeCh dose-response curves to the right, with minor stimulation of the heart. THEO 5+TER 20, and THEO 20+TER 20 enhanced the bronchodilator action of each other in an additive manner. Ipratropium bromide (IPRA) (5 micrograms/kg intravenously) eliminated MeCh bronchoconstriction without any inhibition of MeCh bradycardia and with partial inhibition of MeCh hypotonia. THEO 20+IPRA 0.5 provided a supra-additive bronchodilation. Injection of TER 20 promoted the penetration of THEO into the lungs thus increasing THEO concentrations in the lung tissue. The present results suggest that in this animal model combinations of low doses of THEO with TER/IPRA provide enhanced bronchodilation but reduced cardiovascular effects, in comparison with single therapy. Further, a pharmacokinetic interaction between THEO and a beta 2-agonist was evident within certain doses.
The objective of monitoring theophylline plasma levels in therapeutic work is well established, and the consequences of using unspecific analytical methods are obvious. For the determination of pharmacokinetic parameters, concentrations far below the therapeutic range must often be measured. Interferences acceptable in therapeutic monitoring of theophylline could cause severe inaccuracy at these drug levels. The term specificity and its meaning are discussed in general and in relation to the different steps of the analytical procedure (e.g., sampling and sample work-up). Different analytical methods for theophylline are discussed in terms of specificity. Plasma concentrations of paraxanthine (1,7-dimethylxanthine)--a metabolite of caffeine--as high as 3 microgram/ml have been observed, and the compound can interfere in various theophylline assay methods. An example is given of the pharmacokinetic consequences.
The catecholic amino acids, dopa, 2-S- and 5-S-cysteinyldopa, and 2,5-S,S-dicysteinyldopa were determined qualitatively in serum from patients with malignant melanoma by reversed-phase high-performance liquid chromatography, using electrochemical detection. In urine the catecholamines dopamine, noradrenaline and adrenaline were also determined qualitatively, as well as the above-mentioned compounds, in a single chromatographic run. The conditions were optimized by changing the pH of the mobile phase and by the addition of methanesulphonic acid. A comparison was made between the performance of four commercial reversed-phase packing materials containing chemically bonded octadecyl groups, using a standard mixture of catecholic amino acids. The influence of ionic strength, pH and amount of methanesulphonic acid on retention was investigated.
A method is described for quantitative determination of 5-S-cysteinyldopa and Dopa in serum involving high-pressure liquid chromatographic analysis (HPLC) and electrochemical detection. The chromatographic system allows estimation of injected amounts corresponding to 25 pg of 5-S-cysteinyldopa and Dopa. In normal subjects the mean serum 5-S-cysteinyldopa concentration was 2.8 ng/ml (range 0.4--12 ng/ml) and the mean serum Dopa 6.3 ng/ml (range 4--10 ng/ml). Patients with melanoma metastases showed increased serum concentrations of 5-S-cysteinyldopa.
This work demonstrates the high selectivity and sensitivity obtainable in bioanalysis using the supported liquid membrane (SLM) technique coupled on line with capillary zone electrophoresis (CZE) through a micro-column liquid chromatography (CLC) interface. The system utilizes two selective, sequential enrichment steps before the third analyte focusing and separation step with double-stacking CZE. The enantiomers of bambuterol in human plasma can be concentrated about 40,000 times (approx. 6 times by the SLM treatment, approx. 17 times by micro-CLC focusing, and approx. 400 times by double-stacking CZE) on their way through the system, and extremely high selectivity is obtained. Determinations in the subnanomolar region are achievable for the enantiomers despite relatively weak UV absorbance. Good performance of the entire procedure is demonstrated and a method to increase the sample throughput is presented.
The potential of using the supported liquid membrane (SLM) technique for pretreatment of plasma samples before analysis with capillary zone electrophoresis (CZE) has been investigated. A basic drug, bambuterol, was used as a model substance in a system, where either 6-undecanone or a mixture of di-n-hexyl ether (DHE) and tri-n-octyl phosphine oxide (TOPO) was used as membrane liquids. It was found that the electropherograms obtained after SLM enrichment of bambuterol in plasma samples were as clean as when aqueous samples containing the same substance were processed in the same way. The low ionic strength of the SLM treated blood plasma samples permitted subsequent sample stacking in the CZE step. The linearity of the detector signal for different concentrations of bambuterol in plasma was satisfactory from 50 to 1000 nmol/L with regression co-efficients of 0.997 using 6-undecanone as membrane liquid and 0.999 with the other liquid. In both systems, the confidence interval of the intercept included the origin. The detection limit was about 50 nmol/L. The long-term stability of the two membrane liquids proved adequate as a membrane lasted at least through the working day.