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Biomedical subjects

C G Persson

Publications and source records attributed to C G Persson.

At least 181 records · Page 10Linked to original sources
PubMed1985

Relaxation of lower esophageal sphincter and stimulation of gastric secretion and diuresis by antiasthmatic xanthines. Role of adenosine antagonism.

The study was designed to obtain information on selected extrapulmonary effects of enprofylline, an adenosine-non-blocking alkylxanthine that is about 5 times more potent as a bronchodilator than the adenosine receptor antagonist theophylline. Effects of theophylline (5.0 mg/kg) on lower esophageal sphincter pressure (LESP), gastric secretion, and diuresis and of enprofylline (1.5 mg/kg intravenously producing about 2 micrograms/ml plasma) were examined in 8 healthy volunteers. Enprofylline and theophylline decreased LESP (by 5.0 +/- 2.6 mm Hg, mean +/- SD, p less than 0.001, and by 5.8 +/- 2.7 mmHg, p less than 0.001, respectively), but only theophylline stimulated gastric secretion (volume p less than 0.01 and acidity p less than 0.01) and urine production (volume p less than 0.01 and sodium chloride excretion p less than 0.01). Neither xanthine affected plasma gastrin. Enprofylline and theophylline can be expected to have a similar ability to reduce the barrier to gastroesophageal reflux, but only the latter would have additional stimulant effects on gastric secretion and diuresis. These findings may have clinical significance and suggest a role for adenosine in regulating gastric secretion (and diuresis) but not LESP.

Adult↗
PubMed1984

Substance P antagonists and the role of tachykinins in non-cholinergic bronchoconstriction.

Electrical field stimulation of guinea-pig isolated hilus bronchi induced tetrodotoxin-sensitive contractions of which only a minor part could be inhibited by atropine. The remaining non-cholinergic bronchoconstriction was antagonized by a heptapeptide and an undecapeptide substance P (SP) analogue (Arg5, D-Trp7,9) SP5-11, IC50 = 24.0 microM and (D-Pro2, D-Trp 7,9) SP, IC50 = 10.0 microM. Of the exogenously added tachykinins, both eledoisin (8 times) and physalaemin (3 times) were more potent bronchoconstrictors than SP. Pretreatment with the SP-analogues shifted concentration-response curves to the tachykinins to the right, eledoisin being most readily antagonized. (Arg5, D-Trp 7,9) SP 5-11 also antagonized the neural response more readily than that of SP. In addition, in the frog isolated sciatic nerve preparation the two SP-analogues were found to possess potent lidocaine-like neurodepressant actions which further complicated the interpretation of the neural inhibitory effects of these compounds. It is concluded that if a tachykinin contributes to non-cholinergic bronchoconstriction, an eledoisin-like peptide is a more likely candidate than SP itself. Since SP-antagonists may have local anaesthetic properties their value as tools in neurophysiology seems limited. Inferentially, the non-cholinergic bronchoconstrictive neurotransmitter remains to be identified.

Animals↗
PubMed1984

Absorption of enprofylline from the gastrointestinal tract in healthy subjects.

Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1-4 mg/l, i.e. in the assumed "therapeutic interval" according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean +/- SEM) were 32.5 +/- 8.7, 13.3 +/- 2.5, and 157 +/- 23 min.

Adult↗
PubMed1984

Increase in plasma free fatty acids and natriuresis by xanthines may reflect adenosine antagonism.

The hypothesis has been examined that adenosine is involved in the diuretic and free fatty acid (FFA) - releasing action of xanthines. The effects of theophylline (T), a potent adenosine antagonist, were compared with those of enprofylline (3-propyl xanthine, E), which exerts negligible antagonism of adenosine. Eight healthy male volunteers were given E 1.5 mg/kg, T 5.0 mg/kg or placebo 0.9% saline (P) intravenously in a double-blind, randomized, cross-over investigation. Blood samples were analyzed for E, T, catecholamines (CA: adrenaline, noradrenaline and dopamine), FFA, renin, glucose, glucagon and insulin, and urine was collected at 2-h intervals. T (plasma concentration 53 +/- 8 mumol/l) but not E (11 +/- 2 mumol/l) caused an increase in FFA from 0.42 to 0.86 mmol/l after 90 min. Without affecting the urinary excretion of potassium, T doubled natriuresis and the urine volume as compared to E and P. Neither T nor E had any effect on plasma CA, or on any other of the metabolic parameters studied. E, but not T, produced a small but statistically significant decrease in diastolic blood pressure (5 mmHg) and an increase in heart rate (3 beats/min). It is suggested that the difference between E and T in terms of stimulation of FFA-release and natriuresis may be related to their different ability to antagonize adenosine.

Adenosine↗
PubMed1984

Effects on aggregation of human platelets of two xanthines and their interactions with adenosine.

Adenosine receptor antagonism has been suggested to be the cellular basis for many extrapulmonary actions of xanthine derivatives, such as theophylline. Enprofylline (3-propylxanthine) is a poor adenosine antagonist but is five times as potent as theophylline as a bronchodilator in man. Adenosine is a potent inhibitor of platelet aggregation, but also xanthines are considered to exert this action. In the present study, effects of theophylline and enprofylline on ADP-induced aggregation of human platelets were studied in vitro. Theophylline alone in concentrations exceeding 280 microM inhibited platelet aggregation concentration-dependently. Enprofylline alone mimicked this effect but was about five times more potent than theophylline. At the lowest concentrations used, corresponding to upper therapeutic levels, neither of the two xanthines affected platelet aggregation by ADP. The interactions between these low concentrations of the xanthines and adenosine were then evaluated. In the presence of theophylline 110 microM the inhibitory effect of adenosine 4 microM was attenuated, whereas the presence of enprofylline 21 microM enforced the inhibitory effect of adenosine. Thus, at low concentrations where neither theophylline nor enprofylline inhibits platelet aggregation theophylline antagonizes the antiaggregatory effect of adenosine, whereas enprofylline acts in synergy with this nucleoside.

Adenosine Diphosphate↗
PubMed1984

Neither vasoactive intestinal peptide (VIP) nor purine derivatives may mediate non-adrenergic tracheal inhibition.

Neurogenic responses in isolated electrical field stimulated guinea-pig tracheas include a prominent relaxation that is only partially inhibited by propranolol. The possibility that either purine derivatives or VIP could be a non-adrenergic inhibitory neurotransmitter was examined. Relaxant characteristics of adenosine, ATP, adenine and VIP in tracheas with different degrees of contraction were compared to those of maximal non-adrenergic nerve stimulation. Spontaneous tone and carbachol (5.5 microM and 55 microM)-contracted tracheas were inhibited 77.5 +/- 5.0% (n = 9), 24.7 +/- 2.8% (n = 11) and 14.5 +/- 5.0% (n = 10), respectively, by electrical nerve stimulation. At the three states of contraction exogenous VIP, but not adenosine, ATP, or adenine, produced relaxations similar to those of electrical nerve stimulation. In carbachol-contracted tracheas with maximally effective concentrations present of adenosine (3 mM), adenine (3 mM) or VIP (23.3 microM), the non-adrenergic neurogenic inhibitory response remained intact. The neurogenic inhibitory response was also unaffected by the presence of theophylline and indomethacin which blocked relaxatory effects of adenosine and ATP, respectively. The results suggests that neither the purine derivatives, nor VIP are involved in the non-adrenergic, neurogenic inhibition in the guinea-pig trachea.

Adenine↗
PubMed1984

Elimination pathways of terbutaline.

The main elimination pathways of tritium-labelled terbutaline have been investigated in the rat, the dog, and man. In the rat, 25% of an intravenous dose is excreted unchanged in the urine. Terbutaline is extensively metabolized to the glucuronic acid conjugate which is eliminated via bile (40% of the dose) and urine (25% of the dose). After oral administration, a high first-pass metabolism (70%) was found. In contrast, in the dog, more than 90% of a parenteral dose is excreted renally, largely as unchanged terbutaline together with a small amount of the sulphate conjugate. Only 1.7% of the dose is excreted via bile. The first-pass metabolism amounted to 13%. The elimination of terbutaline in man exhibits a pattern intermediate between rat and dog. Thus, more than 90% of a parenteral dose is eliminated in the urine, of which about 2/3 is unchanged drug. The main metabolite is the sulphate conjugate which is excreted renally. Less than 1% of the dose is excreted in the bile. A large first-pass metabolism (69%) was confirmed in man.

Animals↗
PubMed1984

Intravenous enprofylline in asthma patients.

Enprofylline is a novel xanthine derivative with negligible adenosine antagonizing ability. It is eliminated almost exclusively by renal clearance with a half-life of about 2 h. Enprofylline was given i.v. to 8 patients with partially reversible chronic airway obstruction in a double blind cross-over trials with placebo. Three infusions of drug (1 mg/kg in 10 min) were given at hourly intervals. Spirometry (FEV1x0 and FVC) and drug analyses showed that enprofylline produced significant and concentration-dependent bronchodilation between plasma levels of 1 and 4 mg/L. The maximum effect obtained was similar to that produced by 5 doses of terbutaline aerosol. Heart rate was significantly increased by enprofylline. No change in tremor of hand and no subjective side effects were recorded. It is concluded that enprofylline given i.v. is well tolerated and produces marked and dose-dependent bronchodilation.

Adult↗
PubMed1983

Enprofylline kinetics in healthy subjects after single doses.

The kinetics of enprofylline, a novel antiasthmatic xanthine derivative, were studied. Eight healthy subjects received three different single enprofylline doses, 0.5, 1, and 1.5 mg/kg, injected as an infusion over 10 min. Plasma and urine levels of unchanged enprofylline were observed 3 to 7 and 21 to 24 hr after dosing. Plasma t 1/2 varied among individuals from 1.2 to 1.9 hr. Volume of distribution (V beta or area) and volume of distribution at steady state (V ss) averaged 0.57 and 0.511 X kg-1. Total clearance averaged 0.25 l X hr-1 X kg-1. Renal clearance ranged from 200 to 400 ml X min-1, indicating a large contribution by active tubular secretion. The mean recovery of unchanged drug in the urine was 89%. Thus, unlike theophylline, enprofylline was eliminated mainly by the kidney.

Adult↗
PubMed1983

Evidence against vasoactive intestinal polypeptide (VIP) as a dilator and in favour of substance P as a constrictor in airway neurogenic responses.

Propranolol-resistant neurogenic relaxation persisted in (carbachol-contracted) guinea-pig tracheae already relaxed by supramaximal concentrations of vasoactive intestinal polypeptide (VIP). Also, VIP relaxed preparations that were under neurogenic inhibition. In hilus bronchi, about 60% of a neurogenic contraction was atropine-resistant. (Arg5, D-Trp7.9) SP 5-11 specifically antagonized this contraction and those produced by exogenous substance P. Substance P, but not VIP, seems to be involved in nerve-mediated effects on guinea-pig airway tone.

Animals↗
PubMed1983

Tolerance and some circulatory effects of intravenous and oral enprofylline in healthy volunteers.

Enprofylline (3-propylxanthine), a novel bronchodilating xanthine derivative that seems to lack adenosine antagonistic potency was given intravenously to eight recumbent healthy male volunteers in the doses 0.5, 1 and 1.5 mg/kg body-weight and to six of them also orally in the doses 2, 4 and 6 mg/kg. Mean enprofylline plasma levels ranged between 1.6 and 4.4 mg/1 (8.2-22.2 mumol/1) after intravenous, and between 1.9 and 5.5 mg/1 (9.8-27.9 mumol/1) after oral administration. Enprofylline was rapidly and completely absorbed and had an elimination half-life of approximately 2 hrs. About 90% of the dose given by either route was recovered as unchanged drug in the urine. A slight but significant increase in heart rate was seen at peak plasma levels after each of the highest intravenous and oral doses. At these dose levels the heart rate response to orthostatic tests was significantly increased by enprofylline. Adverse reactions were mild and short-lasting and occurred most frequently after the two highest intravenous and oral doses. Headache and nausea were noted in 5 of the 24 intravenous experiments and in 9 of the 17 times that enprofylline was given orally. In conclusion, the circulatory effects of enprofylline were small and the adverse reactions mild. Further clinical studies with enprofylline seem warranted.

Administration, Oral↗
PubMed1983

A novel bronchodilator xanthine apparently without adenosine receptor antagonism and tremorogenic effect.

Enprofylline is a potent bronchodilating xanthine derivative that has been shown to have little or no ability to antagonize adenosine in a variety of cell types. In eight patients with chronic obstructive lung disease, a single dose of enprofylline (3.5 mg/kg) was given orally. A double blind, randomized, crossover comparison was made with oral theophylline (9.5 mg/kg) which is a potent and general adenosine receptor antagonist. Forced expiratory volume (FEV1), vital capacity, tremor of hands, heart rate, and blood pressure were followed for 6 h. Plasma concentrations of both drugs were monitored. At doses producing significant bronchodilation, theophylline caused a significant increase in tremor of hands whereas enprofylline did not. There were no significant changes in heart rate or blood pressure after either drug. It is suggested that the lack of tremorogenic effect of enprofylline is related to its lack of CNS-stimulating behavioural effects and, hence, may reflect its low tendency to antagonize neuro-depressant actions of adenosine. The adenosine-blocking mechanism may not be important for the bronchodilating effects of xanthines.

Adult↗
PubMed1982

Tracheal relaxant and cardiostimulant actions of xanthines can be differentiated from diuretic and CNS-stimulant effects. Role of adenosine antagonism?

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.

Adenosine↗