PubMed Health⌕ Search

Biomedical subjects

D Ukena

Publications and source records attributed to D Ukena.

At least 73 records · Page 4Linked to original sources
PubMed1990

Management of chronic airway obstruction: theophylline--is it still necessary?

Theophylline is a second-line drug for the symptomatic treatment of obstructive pulmonary diseases. It appears to be of particular value in the treatment of the more severe cases of airway obstruction. The likelihood of a therapeutic benefit and the safety of drug therapy can be increased markedly by an individually optimized theophylline therapy, that is, individual dosage and time of dosing, and monitoring the serum concentrations.

Airway Resistance↗
PubMed1990

Beta 2-adrenergic receptors on eosinophils. Binding and functional studies.

We have studied the binding characteristics and functional effects of beta-adrenoceptors on human and guinea pig eosinophils. We determined the binding of the beta-antagonist radioligand [125I]pindolol (IPIN) to intact eosinophils obtained from the peritoneal cavity of guinea pigs and from blood of patients with eosinophilia. Specific binding was saturable, and Scatchard analysis showed a single binding site with a dissociation constant (Kd) of 24.6 pM and maximal number of binding sites (Bmax) of 7,166 per cell. ICI 118,551, a beta 2-selective antagonist, inhibited IPIN binding with a Ki value of 0.28 nM and was approximately 5,000-fold more effective than the beta 1-selective antagonist, atenolol. Isoproterenol increased cAMP levels about 5.5-fold above basal levels (EC50 = 25 microM); albuterol, a beta 2-agonist, behaved as a partial agonist with a maximal stimulation of 80%. Binding to human eosinophils gave similar results with a Kd of 25.3 pM and a Bmax corresponding to 4,333 sites per cell. Incubation of both human and guinea pig eosinophils with opsonized zymosan (2 mg/ml) or with phorbol myristate acetate (PMA) (10(-8) and 10(-6) M) resulted in superoxide anion generation and the release of eosinophil peroxidase; albuterol (10(-7) to 10(-5) M) had no inhibitory effect on the release of these products. Thus, eosinophils from patients with eosinophilia and from the peritoneal cavity of guinea pigs possess beta-receptors of the beta 2-subtype that are coupled to adenylate cyclase; however, these receptors do not modulate oxidative metabolism or degranulation. The possible therapeutic consequences of these observations to asthma are discussed.

Adenylyl Cyclases↗
PubMed1990

[Characterization of platelet-activating factor (PAF)-receptors in neutrophilic and eosinophilic granulocytes].

It has recently been shown that the triazolodiazepine WEB 2086 inhibits the platelet-activating factor (PAF)-induced platelet aggregation, bronchoconstriction (J. Pharmacol. Exp. Therap. 1987; 241:974) and microvascular leakage (Br. J. Pharm. 1987; in press) in guinea pigs. In the present study we have determined the PAF antagonistic properties of WEB 2086 in human neutrophil and eosinophil leukocytes. In addition, we have characterized [3H] WEB 2086 as a radioligand in direct binding experiments with these cell types. PAF increased the beta-glucuronidase release from neutrophils with an EC50 of 138 nM. WEB 2086 caused a concentration-dependent inhibition of this PAF effect with an inhibition constant (Ki) of 11.9 nM. Binding of [3H] WEB 2086 to neutrophils was specific, reversible and saturable with a dissociation constant (KD) of 18.9 nM and a maximal number of binding sites of 40000 sites per cell. The characteristics of the binding sites were identical to those of PAF receptors. In human eosinophils PAF induced an increase in lucigenin-enhanced chemiluminescence with an EC50 of 2.5 nM. WEB 2086 competitively inhibited this response with a Ki of 16.4 nM. [3H] WEB 2086 bound to eosinophils with a KD of 18.5 nM, which is in good agreement with the Ki from the functional studies. Our results show that WEB 2086 is a potent and specific antagonist of PAF in human neutrophils and eosinophils. Also, [3H] WEB 2086 appears to be a suitable antagonist radioligand for labelling of PAF receptors in these inflammatory cells. WEB 2086 should be of value in further elucidation of the role of endogenous PAF in asthma through activation of inflammatory cells recruited to the lung.

Azepines↗
PubMed1990

First-time treatment with steroids in bronchial asthma: comparison of the effects of inhaled beclomethasone and of oral prednisone on airway function, bronchial reactivity and hypothalamic-pituitary-adrenal axis.

In a double-blind cross-over study of 12 asthmatic patients the effects of 1,000 micrograms.day-1 beclomethasone dipropionate (BDP) on airway function, bronchial reactivity and hypothalamic-pituitary-adrenal (HPA) axis have been compared to those of 15 mg.day-1 oral prednisone (PRD). None of the patients had ever received corticosteroids before. Fourteen days treatment with either of both steroids improved airway function, both subjectively and objectively. Both steroids slightly reduced the responsiveness to histamine. PRD suppressed the corticotrophin-releasing factor (CRF) stimulated cortisol release more than BDP did, whereas there was no significant change in adrenocorticotrophic hormone (ACTH) release. The results indicate that short-term treatment with 1,000 micrograms.day-1 BDP reduces bronchial hyperreactivity (BHR) in asthmatic patients, whilst having subtle effects on HPA axis.

Administration, Inhalation↗
PubMed1989

[3H]WEB 2086 labels platelet activating factor receptors in guinea pig and human lung.

The radiolabelled platelet activating factor (PAF) receptor antagonist, [3H]WEB 2086, bound to specific sites on membrane fractions from homogenised guinea pig and human lungs. The sites on guinea pig and human membranes bound [3H]WEB 2086 with dissociation constants (KD) of 16.8 and 22.6 nM and binding capacities (Bmax) of 203 and 157 fmol/mg protein, respectively. In both species, binding was displaced competitively by PAF, suggesting that the sites labelled by [3H]WEB 2086 are PAF receptors.

Animals↗
PubMed1989

Characterization of PAF receptors on human neutrophils using the specific antagonist, WEB 2086. Correlation between receptor binding and function.

The antagonism of PAF effects by WEB 2086 and the receptor binding of [3H]WEB 2086 were investigated in isolated human neutrophils. WEB 2086 inhibited PAF-induced beta-glucuronidase release and [3H]WEB 2086 bound specifically to high-affinity sites on the cells. Close concordance between affinity constants for WEB 2086 from functional and radioligand-binding studies suggests that WEB 2086 interacts with the neutrophil PAF receptors and that [3H]WEB 2086 may be a useful ligand in investigation of these receptors.

Azepines↗
PubMed1989

Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions.

The effects of 8-phenyl and 8-cycloalkyl substituents on the activity of theophylline, caffeine, 1,3-dipropylxanthine, 1,3-dipropyl-7-methylxanthine, 3-propylxanthine, and 1-propylxanthine at A1 adenosine receptors of rat brain and fat cells and at A2 adenosine receptors of rat pheochromocytoma PC12 cells and human platelets are compared. An 8-phenyl substituent has little effect on the activity of caffeine or 1,3-dipropyl-7-methylxanthine at adenosine receptors, while markedly increasing activity of theophylline, 1,3-dipropylxanthine, 1-isoamyl-3-isobutylxanthine, 1-methylxanthine, and 3-propylxanthine. 8-Phenyl-1-propylxanthine is potent (Ki = 20-70 nM) at all receptors. A p-carboxy or p-sulfo substituent, which is introduced on the 8-phenyl ring to increase water solubility, in most cases decreases the activity and selectivity for the A1 receptor. Among the 8-p-sulfo analogues, only 8-(p-sulfophenyl)theophylline and 1,3-dipropyl-8-(p-sulfophenyl)xanthine are selective for the A1 receptors. 8-p-Sulfophenyl derivatives of caffeine, 1,3-dipropyl-7-methylxanthine, and 3-propylxanthine are somewhat selective for the A2 receptors. 8-Cycloalkyl substituents (cyclopentyl, cyclohexyl) markedly increase activity of caffeine and 1,3-dipropyl-7-methylxanthine at the A2 receptor. 8-Cyclohexylcaffeine is potent (Ki = 190 nM) and very selective for the human platelet A2 receptors, but is not as selective for the rat PC12 cell A2 receptor. Such A2 selectivity is in contrast to the marked A1 selectivity of 8-cycloalkyltheophyllines and 8-cycloalkyl-1,3-dipropulxanthines. The apparent selectivity of certain xanthines is dependent on the assay systems that are compared.

Adenylyl Cyclases↗
PubMed1989

Effect of nedocromil sodium on down-regulation of pulmonary beta-adrenoceptors.

1. We have studied the effect of the anti-inflammatory anti-asthma drug, nedocromil sodium, on down-regulation of pulmonary beta-adrenoceptors in guinea-pig lung. 2. Incubation of minced lung with isoprenaline (10 mumol/l) resulted in a reduction in maximum binding capacity of [125I]iodocyanopindolol to lung membranes from 246 +/- 4 to 169 +/- 6 fmol/mg of protein (mean +/- SEM, P less than 0.01, n = 18). 3. Nedocromil sodium, which had no direct effect on [125I]iodocyanopindolol binding, prevented isoprenaline-induced down-regulation, giving complete protection at a dose of 100 mumol/l. 4. The mechanism of this effect is not certain, but nedocromil sodium may interfere with the internalization of beta-adrenoceptors in pulmonary parenchymal cells. This may have some therapeutic relevance.

Animals↗
PubMed1989

Effect of theophylline and adenosine on eosinophil function.

Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced superoxide anion (O2-) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10(-3) M) inhibited O2- release by 27.6 +/- 9.4% (mean +/- SEM, p less than 0.05), whereas at clinically relevant concentrations (10(-6) and 10(-5) M), it significantly potentiated this by 26.8 +/- 9.9% (p less than 0.05) and 36.9 +/- 6.3% (p less than 0.01), respectively. 8-phenyltheophylline (10(-7) to 10(-3) M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2- release by 72.4 +/- 15.2% (p less than 0.01), whereas addition of adenosine (3 x 10(-8) to 10(-6) M) reversed the potentiation induced by theophylline (10(-5) M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2- release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.

Adenosine↗
PubMed1988

Non-xanthine heterocycles: activity as antagonists of A1- and A2-adenosine receptors.

A variety of non-xanthine heterocycles were found to be antagonists of binding of [3H]phenylisopropyladenosine to rat brain A1-adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxamidoadenosine with A2-adenosine receptors in human platelet and rat phenochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A1- and A2-adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N6-substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A1 and A2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A1- and A2-adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and beta-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak non-competitive adenosine antagonist.

Adenosine↗
PubMed1988

Radioligand binding of antagonists of platelet-activating factor to intact human platelets.

Two new antagonists of platelet-activating factor (PAF), the pyrrolothiazole derivative 52770 RP and the triazolodiazepine WEB 2086, have been studied as radioligands in intact human platelets. [3H]52770 RP and [3H]WEB 2086 bound specifically to high-affinity sites with dissociation constants (Kd) of 14.8 and 6.1 nM, respectively. The maximal number of sites for [3H]52770 RP binding was approx. 15-fold higher than for [3H]PAF and [3H]WEB 2086. In addition, C16-PAF, lyso-PAF, WEB 2086 and 52770 RP had Ki values which were nearly identical for both [3H]PAF and [3H]WEB 2086, whereas only 52770 RP competed for [3H]52770 RP-binding sites. These results demonstrate that in human platelets the sites of [3H]WEB 2086 binding are identical to [3H]PAF-binding sites, whereas those of [3H]52770 RP are not. [3H]WEB 2086 appears, therefore, to be a suitable antagonist radioligand for labelling PAF receptors.

Azepines↗