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D Iakovidis

Publications and source records attributed to D Iakovidis.

16 recordsLinked to original sources
PubMed2000

Role of beta-adrenergic receptor subtypes in lipolysis.

In vitro lipolysis stimulated by low (-)-isoprenaline concentrations (< or =30 nM) in epididymal white adipocytes from Sprague-Dawley rats was inhibited at least 60-80% by the specific beta1-antagonists LK 204-545 and CGP 20712A (1 microM), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via beta1-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for beta1-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, beta3-adrenergic receptors were fully activated and were the dominant beta-adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the beta1-antagonists, demonstrating that the beta3-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively beta2-selective agonist formoterol in the presence of beta1-blockade (1 microM CGP 20712A) demonstrated the inability of the beta2-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551 < or = 1 microM. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (approximately 500-fold lower than its beta2-adrenergic receptor pA2, 7.80 +/- 0.21), suggesting that formoterol was not acting via beta2-adrenergic receptors. These data are consistent with beta1-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that beta2-adrenergic receptors play no obvious direct role in mediating beta-adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a beta3-selective antagonist), was found to be a nonselective antagonist at the three beta-adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.

Adipocytes↗
PubMed1999

beta(1)- and beta(2)-Adrenoceptor antagonist activity of a series of para-substituted N-isopropylphenoxypropanolamines.

To further explore the structure-activity relationships of beta-adrenoceptor (beta-AR) antagonists, a series of 25 para-substituted N-isopropylphenoxy-propanolamines were synthesised, nine of which are new compounds. All have been examined for their ability to antagonise beta(1)-ARs in rat atria and beta(2)-ARs in rat trachea. Substitution in the para-position of the phenyl ring is thought to confer beta(3)-specificity and the selectivity of these compounds for the beta(1)-AR ranges from 1.5-234. None of the compounds tested were selective for the beta(2)-AR. Of the 25 compounds studied, 22 had reasonable (pA(2) > 7) potencies for the rat beta(1)-AR. Only compound 1 displayed reasonable (pA(2) > 7) potency for the rat beta(2)-AR. Twenty two compounds were used as the training set for comparative molecular field analysis (CoMFA) of antagonist potency (pA(2)) at the rat beta(1)- and beta(2)-ARs. The inclusion of a number of additional physical characteristics improved the QSAR analysis over models derived solely using the CoMFA electrostatic and steric fields. The final models predicted the beta(1)- and beta(2)-AR potency of the compounds in the training set with high accuracy (r(2) = 0.93 and 0.86 respectively). The final beta(1)-AR model predicted the beta(1)-potencies of two out of the three test compounds, not included in the training set, with residual pA(2) values < -0.14, whereas the test compounds were not as well predicted by our final beta(2)-AR model (residual pA(2) values < -0.38).

Journal Article↗
PubMed1999

LK 204-545, a highly selective beta1-adrenoceptor antagonist at human beta-adrenoceptors.

LK 204-545 ((+/-)-1-(2-(3-(2-cyano-4-(2-cyclopropyl-methoxy-ethoxy)phenoxy)-2-hydro xy-propyl-amino)-ethyl)-3-(4-hydrxy-phenyl) urea), an antagonist that possesses high beta1-/beta2-selectivity in the rat, and a range of cardio-selective and non-selective beta-adrenoceptor antagonists were examined to compare their radioligand binding affinities for human beta1-, beta2- and beta3-adrenoceptors transfected into CHO cells. LK 204-545 and CGP 20712A displayed the highest beta1-/beta2- (approximately 1800 and approximately 650, respectively) and beta1-/beta3-selectivity (approximately 17000 and approximately 2200, respectively) at human beta-adrenoceptors with LK 204-545 being approximately 2.75-fold more beta1-/beta2-selective and approximately 8-fold beta1-/beta3-selective than CGP 20712A. The high potency of LK 204-545 at transfected human beta1-adrenoceptors and in functional models of rat beta1-adrenoceptors together with its high selectivity, identify it as a useful ligand for studying beta1-adrenoceptors and suggest that it may be the preferred ligand for human beta-adrenoceptor studies.

Adrenergic beta-Agonists↗
PubMed1998

[3H]Rilmenidine-labelled imidazoline-receptor binding sites co-localize with [3H]2-(benzofuranyl)-2-imidazoline-labelled imidazoline-receptor binding sites and monoamine oxidase-B in rabbit, but not rat, kidney.

The distribution and relative densities of imidazoline-receptor binding sites (I-RBS) and monoamine oxidase (MAO)-A and -B enzyme(s) in rat and rabbit kidney were compared autoradiographically using fixed nanomolar concentrations of [3H]rilmenidine and [3H]2-(benzofuranyl)-2-imidazoline ([3H]2-BFI) to label I-RBS, and [3H]RO41-1049 and [3H]RO19-6327 to label MAO-A and -B isoenzymes, respectively. In rat kidney, high densities of I-RBS labelled by [3H]rilmenidine were observed in the cortex and outer stripe (120-280 fmol/mg tissue), in contrast to low I-RBS densities labelled by [3H]2-BFI (<4 fmol/mg). A relatively high density of [3H]RO41-1049 binding to MAO-A enzyme was present in all regions of the rat kidney (160-210 fmol/mg) compared with a low density of [3H]RO19-6327 binding to MAO-B (< 25 fmol/mg). Comparison of MAO-A and -B distributions with that of [3H]rilmenidine-labelled I-RBS strongly suggests a lack of association in rat kidney. Similarly, the extremely low densities of [3H]2-BFI-labelled I2-RBS in rat kidney contrasts with the density of MAO-A, but is consistent with the low density of MAO-B. Rabbit kidney cortex and outer stripe contained high relative densities of [3H]rilmenidine-labelled I-RBS (200-215 fmol/mg) and [3H]2-BFI-labelled I2-RBS (45-60 fmol/mg) with lower densities in the inner stripe and inner medulla (< or = 100 and 30 fmol/mg respectively). A high density of MAO-A binding was observed in the inner stripe (515 fmol/mg) with lower levels in the cortex and outer stripe (100-240 fmol/mg), while high densities of MAO-B binding were observed in the cortex and outer stripe (290-450 fmol/mg) with lower levels in the inner stripe (65 fmol/mg). The correlation between the localization of [3H]rilmenidine-labelled I-RBS and [3H]RO19-6327-labelled MAO-B in rabbit kidney (r = 0.87, P = 0.057) suggest that [3H]rilmenidine may label a binding site co-existent with MAO-B, but not MAO-A (n.s.), in this tissue, but rilmenidine did not inhibit [3H]RO41-1049 or [3H]RO19-6327 binding. The distribution of [3H]2-BFI-labelled I2-RBS overlapped the combined distributions of both MAO-A and -B isoenzymes, suggesting that [3H]2-BFI may label sites on both enzymes in the rabbit, but [3H]2-BFI binding only correlated with [3H]RO19-6327 (r = 0.84, P = 0.07), not [3H]RO41-1049 binding (n.s.). Moreover, 2-BFI only inhibited [3H]RO19-6327, not [3H]RO41-1049 binding. These data are consistent with reports that I2-RBS are located on MAO-B and allosterically influence the catalytic site. The relationship of [3H]rilmenidine- and [3H]2-BFI-labelled I-RBS and the identity of non-MAO-associated [3H]rilmenidine-labelled I-RBS requires further investigation.

Adrenergic alpha-Agonists↗
PubMed1994

Radiopacity of elastomeric impression materials.

The purpose of this study was to measure and classify the radiopacity of various elastomeric impression materials available on the open market and to compare their appearance in radiographs of the oral tissues. In order to measure and classify their radiopacity, twenty-eight specimens of various materials were placed and exposed on film together with an aluminium stepwedge. A dummy head was used to investigate the radiographic density of the above specimens in comparison with that of simulated oral tissues.

Absorptiometry, Photon↗
PubMed1993

Partial agonist activity of celiprolol.

Celiprolol given intravenously (i.v.) to pithed rats in the dose range of 0.1-10,000 micrograms/g produced a dose-dependent increase in heart rate (HR) which was greatest (123 beats/min) at 1,000-3,000 micrograms/kg. This partial agonist effect was blocked by the selective beta 1-adrenoceptor antagonist CGP 20712A. Celiprolol also produced a vasodepressor effect in this dose range which was abolished by the relatively selective beta 2-adrenoceptor antagonist ICI 118551 but not CGP 20712A. The magnitude of this intrinsic sympathomimetic activity (ISA) response was not significantly altered by reserpine pretreatment. Celiprolol also antagonised the effects of isoprenaline 0.05 microgram/kg on HR and blood pressure (BP). The beta 1 selectivity of celiprolol as an antagonist in pithed rats (beta 1/beta 2 = 340:1) was similar to that observed in studies with isolated guinea pig atria and trachea (beta 1/beta 2 = 63:1), both being considerably greater than that observed with atenolol. Celiprolol, however, like atenolol, potentiated the bronchoconstrictor responses to histamine (3 micrograms/kg). Metabolic studies of rats and human urine failed to show significant amounts of potentially vasoactive metabolites. These data are consistent with celiprolol acting as both a beta 1- and beta 2- adrenoceptor partial agonist.

Adrenergic beta-Antagonists↗
PubMed1992

Computer-aided mapping of the beta-adrenoceptor. 1. Explanation for effect of para substitution on blocking activity at the beta-1-adrenoceptor.

Anomalously low affinities for the beta-1-adrenoceptor are seen for members of a series of para-substituted N-isopropylphenoxypropanolamines in which the substituent is able to conjugate with the aromatic ring. The energy of conjugation was calculated using the AM1 semiempirical molecular orbital method and appears to correlate with the loss of binding energy, and hence affinity for the receptor. This suggests that binding is associated with movement of the substituent out of the plane of the aromatic ring due to steric interference with the receptor. A previously unrecognized binding site for aromatic groups off the para position is also identified.

Adrenergic beta-Antagonists↗
PubMed1991

[Histiocytosis X: roentgenological findings in 23 cases].

The authors describe the clinical, roentgenological findings, especially the oral manifestation and differential diagnosis of histiocytosis X in 23 cases. It is shown that the clinical and roentgenological differential diagnosis is problematically.

Adolescent↗
PubMed1990

[Clinical and roentgenographic follow-up study of tricalcium phosphate ceramic in bone cavities of apicoectomized teeth].

In 8 patients aged 16-30 years with periapical osteolytic areas (1,5-2 cm) of anterior maxillary and mandibular teeth root canal treatment and apicoectomy were performed. The bone cavity following apicoectomy was filled with tricalcium phosphate ceramic (small spheres diameter more than 1 mm and less than 2 mm). Patients were re-examined the following day as well as on the 4th, 7th, and 15th postoperative day. Follow up at the 1, 3, 6, 12 and 18 postoperative months did not show any problem of the healed wood nor any rejection of the implanted material. Radiographically, some resorption of the material as well as new bone formation were noticed 12 and 18 month after the operation.

Adolescent↗
PubMed1990

Biliary excretion and conjugation of diacid angiotensin-converting enzyme inhibitors.

The metabolism and biliary excretion of the diacid angiotensin-converting enzyme inhibitors enalapril, lisinopril, perindopril and ramipril have been studied in an isolated perfused rat liver model. Inhibitors were presented to the livers at a dose of 100 micrograms. The hepatic clearance of lisinopril was very low (0.072 ml/min) and was hardly excreted into the bile. The clearances of enalapril, perindopril and ramipril were higher at 0.63, 0.87 and 9.9 ml/min, respectively, and were excreted into bile. The amounts of ester prodrugs excreted in bile were 4.0, 6.1 and 14%, respectively, whereas the diacid forms were excreted to the extent of 46, 27 and 71% of the administered dose, respectively, over 4 hr. Glucuronide metabolites were only detected in bile in significant concentrations for perindopril and ramipril. Base hydrolysis of the perfusate samples showed that lisinopril was not significantly metabolized to conjugates and that little metabolism of enalapril occurred other than rapid conversion to the diacid form. However, both perindopril and ramipril were extensively metabolized beyond the diacid form. These differences in hepatic handling can in part be explained by their octanol-buffer partition coefficients but may also be related to the introduction of a bicyclic ring in perindopril and ramipril which increases their ability to be metabolized and excreted into bile. These differences in hepatic handling of angiotensin-converting enzyme are likely to influence their clinical usefulness, particularly in renal and hepatic disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

[Arterial pressure variation following an intravenous and submucous injection of local anaesthetic solutions with vasoconstrictor].

This paper deals with the control, registration and statistical evaluation of blood pressure variations (systolic, diastolic and average) after an i.v. and submucous injection of fixed quantity local anaesthetic solutions (0.05 ml) in white hamsters. The solutions used were: lidocaine 2% with adrenaline 1/80,000, lidocaine 3% with noradrenaline 1/25,000. The intravenous injection of all three local anaesthetic solutions has caused an increase of the arterial pressure parameters which was statistically significant (P less than 0.01). The submucous injection of lidocaine 2% solution with adrenaline 1/80,000 and lidocaine 2% with noradrenaline 1/80,000 has not caused mentionworthy arterial pressure variations. On the contrary, the submucous injection of lidocaine 3% solution with noradrenaline 1/25,000 has led to an increase of the arterial pressure which is statistically important (P less than 0.05). The research results have led to the following conclusions: 1) Intravascular injection of local anaesthetics with adrenaline or noradrenaline has immediate negative consequences on the circulatory system, a fact which renders necessary a test respiration prior to any stem anaesthesia. 2) The submucous injection of lidocaine solutions with adrenaline or noradrenaline 1/80,000 may be described as harmless with respect to cardiovascular toxicity, and 3) The 3% lidocaine solution with noradrenaline 1/25,000 has proved to be capable of producing significant increase of the arterial pressure following a submucous injection. Anaesthetic solutions with 1/25,000 noradrenaline concentration should not be used, while they must be considered as extremely hazardous for patients with cardiovascular problems.

Administration, Buccal↗
PubMed1988

Biotransformation studies of di-acid angiotensin converting enzyme inhibitors.

The biotransformation of di-acid angiotensin converting enzyme inhibitors (I) to cyclized lactam metabolites was studied in the urine of rats using gas chromatography-mass spectrometry. Chemical synthesis of the corresponding piperazine-dione metabolite (III) was achieved by reaction of enalapril, perindopril or ramipril with acetic acid anhydride followed by hydrolysis of the ester group by sodium in ethanol or by acid hydrolysis. Electron impact and chemical ionization mass spectra confirmed the structure of these potential novel metabolites. Selected ion monitoring of urinary extracts demonstrated small amounts (less than 5%) of these lactams for all three inhibitors, however, it was shown that the majority of these lactams were formed as a result of sample treatment rather than due to biotransformation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1980

In vitro activity of RO363, a beta1-adrenoceptor selective agonist.

1 The beta-adrenoceptor stimulant effects of RO363 and (--)-isoprenaline have been compared in a variety of isolated tissue preparations. 2 RO363 is approximately half as potent as (--)-isoprenaline in tissues where actions are due to beta1-receptor activation (guinea-pig atrial and ileal preparations and ventricular strips from the rabbit, rat and guinea-pig. 3 In uterine and lung strip preparations from the guinea-pig, where responses are due to beta2-receptor stimulation. RO363 is 100 to 350 times less active than (--)-isoprenaline and has a low intrinsic activity. 4 In spontaneously contracted tracheal preparations from the guinea-pig, RO363 is a full agonist and is approximately half as potent as (--)-isoprenaline. These effects of RO363 are due to the activation of a population of beta1-receptors in the tissue since RO363 and (--)-isoprenaline have the same relative potencies in trachea, cardiac and ileal preparations. In addition the Kb values for practolol are similar in all these preparations when RO363 is used as the agonist. 5 The results show that RO363 is a potent and highly selective beta1-receptor agonist.

Adrenergic beta-Agonists↗