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R M Gaion

Publications and source records attributed to R M Gaion.

At least 19 recordsLinked to original sources
PubMed2004

Disposition of 4,6,4'-trimethylangelicin in mice maintained in the dark and after UVA irradiation.

The disposition of the furocoumarin 4,6,4'-trimethylangelicin (4,6,4'-TMA) was studied in mice. After oral administration of (3)H 4,6,4'-TMA, radioactivity measured in serum shows fast absorption and slow elimination. Serum protein binding is higher as compared to 8-methoxypsoralen (8-MOP), currently used in photochemotherapy (PUVA) and linearly declines from 30 min to 6 h after administration. Distribution in the various organs was similar to that of 8-MOP and was relatively uninfluenced by UVA radiation, required for the biological effects of 4,6,4'-TMA. Mice eliminate (3)H 4,6,4'-TMA mostly through the urine, but also through the faeces. Two metabolites were identified in the urine and serum of the treated mice, one of which proved to be a derivative of 4,6,4'-TMA, formed by hydrogenation of the double 4',5' bond of the furocoumarin nucleus.

Animals↗
PubMed2001

Effects of daily oral administration of rifaximin and neomycin on faecal aerobic flora in rats.

The aim of this study was to compare the influence of rifaximin and neomycin on faecal flora in rats. The study was performed on 18 Wistar rats (three groups of six male animals). Group 1 received rifaximin (50 mg kg(-1)/day), group 2, neomycin (50 mg kg(-1)/day) and group 3 was used as control. Drugs were administered orally, once daily for 3 days. Faecal specimens, collected from each rat on day 3, were cultured for the quantitative and qualitative determination of aerobic microorganisms. Rifaximin treatment produced a marked reduction in the number of total aerobic bacteria and Salmonellae; neomycin caused reduction in Salmonellae, but did not cause statistically significant changes in total aerobic bacterial count. The binding of neomycin with faeces could explain this limited activity, which does not correlate with the in vitro susceptibility of the organism affected. These results confirm that rifaximin is suitable for topical treatment to reduce selected bacterial load in the gut intestines.

Administration, Oral↗
PubMed1999

Involvement of P1 receptors in the effect of forskolin on cyclic AMP accumulation and export in PC12 cells.

In PC12 cells, forskolin as well as the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased intracellular adenosine-3',5'-cyclic monophosphate (cyclic AMP) levels, which peaked at 45-60 minutes and declined thereafter. Maximum levels were 3000 and 1700 pmol/10(6) cells during treatment with 10 microM forskolin or 0.1 microM NECA, respectively. Extracellular cyclic AMP rose with time, at mean rates of 24.7 (forskolin) and 11.3 (NECA) pmol/min/10(6) cells. With either drug, a linear correlation was obtained between the calculated time integral of intracellular cyclic AMP and the measured extracellular cyclic AMP levels, indicating that the outflow of cyclic AMP was sustained by a nonsaturated transport system. The ability of forskolin to increase intracellular and extracellular cyclic AMP levels was hindered in a concentration-dependent manner by 8-(p-sulfophenyl)theophylline (8-SPT). A similar inhibition was exerted by other two adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine. The concentration-response curve to adenosine was shifted to the right by 25 microM 8-SPT, whereas that of forskolin was shifted downwards. Adenosine deaminase (ADA, EC 3.5.44, 1 U/mL) reduced the intracellular cyclic AMP response to forskolin by 68%, whereas the adenosine transport inhibitor, dipyridamole (10 microM), significantly increased 1 and 10 microM forskolin-dependent cyclic AMP accumulation. Erythro-9-(2-hydroxy-3-nonyl)adenine (10 microM), an inhibitor of ADA, and alpha,beta-methyleneadenosine 5'-diphosphate (100 microM), an inhibitor of ecto-5'-nucleotidase, did not alter forskolin activity. These results demonstrate that a cyclic AMP extrusion system operates in PC12 cells during adenylyl cyclase stimulation by forskolin and that this stimulation involves a synergistic interaction with endogenous adenosine. However, extruded cyclic AMP does not appear to significantly contribute to the formation of the endogenous adenosine pool.

Adenosine↗
PubMed1999

Amplification of the cyclic AMP response to forskolin in pheochromocytoma PC12 cells through adenosine A(2A) purinoceptors.

In this study, we present evidence on the ability of endogenous adenosine to modulate adenylyl cyclase activity in intact PC12 cells. The adenosine receptor antagonists PD 115199, xanthine amine congener, 8-cyclopentyl-1,3-dipropylxanthine, 8-(p-sulfophenyl)theophylline, and 3,7-dimethyl-1-propargylxanthine inhibited 10 microM forskolin-induced cyclic AMP (cAMP) accumulation, with IC(50) values of 2.76 +/- 1.16 nM, 17.4 +/- 1.08 nM, 443 +/- 1. 03 nM, 2.00 +/- 1.01 microM, and 2.25 +/- 1.05 microM, respectively. Inhibition by 2.5 nM PD 115199 was only partially reversed by increasing forskolin concentrations up to 100 microM. The addition of PD 115199 with or 60 min after forskolin caused a comparable inhibition of forskolin effect over the next hour. Both exogenous adenosine (0.1 microM) and its precursor, AMP (10 and 100 microM), significantly enhanced forskolin-induced cAMP accumulation, whereas inosine was ineffective. Forskolin activity was also potentiated by the hydrolysis-resistant adenosine receptor agonists 5'-N-ethylcarboxamido adenosine and CGS 21680 (8.9- and 12.2-fold increase, respectively). Adenosine deaminase (1 U/ml) and 8-SPT (25 microM), which nearly abolished the response to 1 microM adenosine, also reduced cAMP accumulation caused by AMP (-78 and -54%, respectively). These results demonstrate that in PC12 cells, activation of adenylyl cyclase by forskolin is highly dependent on the occupancy of A(2A) adenosine receptors and that AMP potentially contributes to the amplification of forskolin response.

Adenosine↗
PubMed1997

New inotropic agents: milrinone analogs.

1. Two new milrinone analogs, 3-acetyl-6-phenyl-2(1H)-pyridone (SF 348) and 3-acetyl-7-methyl-7,8-dihydro-2,5(1H, 6H) quinolinone (SF 349), increase the contractile activity of spontaneously beating and electrically driven atria isolated from reserpine-treated guinea-pigs. 2. Propranolol 0.1 microM drastically inhibits the contractile effect of SF 348, whereas that of SF 349 is unaffected. Preincubation of the atria with adenosine-deaminase suppresses the cardiac activity of SF 349, but does not affect that of SF 348. 3. SF 349 competitively antagonizes the negative inotropic effect induced by N6-(R-phenylisopropyl)-adenosine (R-PIA) and displaces N6-cyclohexyl[3H]-adenosine (3H-CHA) from its binding sites to A1 receptors in the guinea-pig heart. 4. The positive inotropic effect of SF 348 is largely sustained by activation of beta-adrenoceptors, whereas SF 349 acts by displacing endogenous adenosine from its inhibitory (A1) receptors in the atria.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Chemical and pharmacological characterization of Erythrophleum lasianthum alkaloids.

Two alkaloids 1 and 2 were isolated from the seeds of Erythrophleum lasianthum. Their structures were assigned by spectroscopic and chemical means as 3 beta-hydroxynorerythrosuamine (1) and its 3-O-beta-D-glucopyranoside (2). In spontaneously beating atria, both compounds 1 and 2 showed a marked and concentration-dependent positive inotropic activity and a weak negative chronotropic activity. The positive inotropic effect induced by 1 and 2 was not modified by propranolol, prazosin, carbachol, and ranitidine plus pyrilamine. Both 1 and 2 were very active in inhibiting the Na+/K(+)-ATPase isolated from bovine cardiac sarcolemmal vesicles.

Alkaloids↗
PubMed1994

[Interferon-alpha. Results of a pharmaco-epidemiologic study].

In the present study we evaluated the use of alpha-IFN in the ULSS 21 of Veneto Region. All outpatients treated with interferon during the period June-July 1992 (114 subjects) were interviewed using a standard questionnaire which was meant to collect information about therapy, side effects and quality of life. Alpha-IFN was mostly prescribed for chronic non-A non-B hepatitis (as approved by the FDA in the USA and by the Ministero della Sanità in Italy), while 35% of the patients were suffering from diseases for which interferon use is approved by Ministero della Sanità but not by FDA. In most cases, independently of the specific disease, a standard dose of 9 MU/week was used, which often resulted to be below the recommended doses reported in the literature. Adverse effects were frequently reported. The most common include fever, chills, headache, fatigue, myalgia. Mild mental disturbances (irritability and/or depression) and thyroid dysfunction were also reported but were less frequent. Finally, a negative influence of alpha-IFN therapy on the quality of life was reported by about half of the interviewed patients.

Dose-Response Relationship, Drug↗
PubMed1994

Pharmacological characterization of a new milrinone analogue.

In a new series of milrinone analogues (esters of 2-substituted 5-acetyl-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids), ethyl 5-acetyl-1,6-dihydro-6-oxo-2-phenyl-3-pyridinecarboxylate (compound 2f) has been found to be more potent and more effective than milrinone as a positive inotropic agent while affecting only marginally the frequency rate of guinea-pig isolated atria. This finding prompted us to study the mechanism of cardiac action of compound 2f in electrically driven left atrium from reserpine-treated guinea pigs. Compound 2f induced a statistically significant increase in the contractile force at a concentration as low as 1 microM, while the minimum effective concentration of milrinone was 10 microM. The beta-blocker propranolol (0.1 microM) caused a marked inhibition of the inotropic effect of compound 2f. Adenosine deaminase (1 and 2 U/ml) inhibited significantly and in a concentration-dependent manner the increase in inotropism induced by compound 2f and the adenosine deaminase-resistant response was abolished by 0.1 microM propranolol. In the presence of 0.1 microM propranolol, compound 2f (5 to 30 microM) antagonised in competitive manner the negative inotropic effect induced by N6-(R-phenylisopropyl) adenosine (R-PIA) (0.01-1.0 microM), a stable adenosine receptor agonist. Schild regression analysis gave in fact a slope of 1.02 +/- 0.06 and the pA2 value for compound 2f was 5.41 +/- 0.28. Compound 2f also inhibited phosphodiesterase (PDE) III isolated from calf heart, this inhibition being quantitatively significant only at the highest concentrations tested (0.5 M to 1 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Deaminase↗
PubMed1993

A pharmacological, crystallographic, and quantum chemical study of new inotropic agents.

The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.

Amrinone↗
PubMed1992

Antagonism towards endogenous adenosine and inhibition of cGI-PDE in the cardiac effects of amrinone, milrinone and related analogues.

1. The effect of amrinone, milrinone and of three milrinone analogues was tested on spontaneous chronotropic and inotropic activity of guinea-pig isolated atria, on the activity of cGMP-inhibited phosphodiesterase (cGI-PDE) from guinea-pig heart and on specific binding of N6-cyclohexyl[3H]adenosine ([3H]CHA) to Ri adenosine receptors in guinea-pig atria. 2. The Ki-values towards [3H]CHA binding to Ri receptors were linearly related to the EC50S for the increase in force of contraction but not to the EC50S for the increase in frequency of the atria. The Ki values towards cGI-PDE were linearly related to the EC50S for the positive chronotropic effect.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1992

Synthesis and cardiotonic activity of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids and their methyl or ethyl esters.

The synthesis of ethyl or methyl esters of 5-cyano-1,6-dihydro-6-oxo-3- pyridinecarboxylic acids carrying as 2-substituent a polar group such as CO2C2H5, (CH2)2CO2CH3, (CH2)3CO2C2H5, CH2OCH3, or CF3 group is described. Also 2-[5-cyano-1,6-dihydro-2-(1,1-dimethylethyl)-6-oxo-3-pyridyl]-2- oxoacetic acid and 2,5,6,8-tetrahydro-2,5-dioxo-1H-thiopyrano[3,4-b]pyridine-3-carbon itrile were prepared. Nearly all the above esters gave routinely the corresponding carboxylic acids by alkaline hydrolysis followed by acidification. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria from reserpine-treated guinea-pigs. 5-Cyano-2-trifluoromethyl-1,6- dihydro-6-oxo-3-pyridinecarboxylic acid and, in a lesser degree, the relative ethyl ester showed an appreciable positive inotropic activity, although inferior to that of milrinone.

Animals↗
PubMed1991

An analysis of the mechanism of the inotropic action of some milrinone analogues in guinea-pig isolated atria.

1. It has been reported previously that the milrinone analogues, ethyl 5-cyano-1,6-dihydro-2-methyl-6-oxo-3 pyridine carboxylate (I) and ethyl 5-cyano-1,6-dihydro-2-ethyl-6-oxo-3 pyridine carboxylate (II) exert a positive inotropic effect (EC50 = 15.6 +/- 0.2 microM and 40.3 +/- 0.1 microM) both on spontaneously beating and on electrically driven atria from reserpine-treated guinea-pigs. In the present study the mechanism of the inotropic action of these two agents was investigated. 2. In electrically driven left atrium from reserpine-treated guinea-pigs the EC50 values for inotropic activity for compounds (I) and (II) corresponded to that of milrinone (EC50 = 25 +/- 0.1 microM) but compound (I) induced a greater maximum effect. This corresponded to a percentage increase in developed tension over control of 63 +/- 0.3 whereas the maximum inotropic effect of milrinone was 48 +/- 0.3 and that of compound (II) was 47 +/- 0.2. 3. The inotropic activity of compounds (I) and (II) (10-100 microM) was resistant to propranolol (0.1 microM), thus excluding the involvement of beta-adrenoceptors. 4. Since the inotropism induced by compounds (I) and (II) was not reduced by carbachol (1 nM-0.5 microM), an action involving changes in adenosine 3':5'-cyclic monophosphate (cyclic AMP) can be excluded. 5. The inotropic action of compounds (I) and (II) was blocked selectively by 8-phenyltheophyline (10 microM) or adenosine deaminase (2 u ml-1). 6. Both (I) and (II) inhibited, in an apparently competitive manner, the negative inotropic effect induced by N6-(L-phenylisopropyl) adenosine (L-PIA), a stable adenosine agonist. The pA2 values for (I) and (II) were 4.79 and 4.36, respectively.7. In rat brain compounds (I) and (II) inhibited the specific binding of N6-cyclohexyl[3H]-adenosine- ([3H]-CHA) with an IC50 of 0.18 + 0.01 mM and 0.25 + 0.02 mm, respectively, which were similar to their IC50 values for blocking the PIA-induced negative inotropic effect and which are also in the range of concentrations that are effective in inducing positive inotropism in guinea-pig atria.8. The results from the present study suggest that antagonism of endogenous purines causes positive inotropism without affecting intracellular cyclic AMP levels.

Adenosine↗
PubMed1991

Modulation of cholinergic profile of acetylcholine through its cyclovinylogues.

The o-, m- and p-acetoxymethyl-N,N,N-trimethylbenzenemethanaminium iodide (2a-c) as cyclovinilogues of acetylcholine are described. This structural modification allows to modulate the cholinergic activity of the natural neurotransmitter along the sequence: agonist----partial agonist----antagonist, which is referred to meta (2b), para (2c) and ortho (2a) regioisomers, respectively.

Acetylcholine↗
PubMed1991

Studies on 8-methoxypsoralen tolbutamide interactions in vitro and in vivo.

The present study aimed at characterizing the influence of tolbutamide on the distribution of 8-methoxypsoralen (8-MOP) in mouse serum and organs. Experiments performed in vitro clearly showed that tolbutamide causes competitive displacement of 8-MOP from its binding sites on human serum albumin. Similarly, the amount of labelled compound(s) bound in serum after oral administration of 3H-8-MOP to mice was significantly reduced when tolbutamide was given by the same route. The quantitative distribution of radioactivity from 3H-8-MOP in mouse tissues varied according to organ (liver, intestine, skin, etc.,), and was maximum in the organs of elimination. In all the organs studied, the administration of tolbutamide 2 hours after that of 3H-8-MOP caused a dose-dependent reduction of the radioactive compound(s) present in tissues, suggesting that tolbutamide may accelerate the excretion of 8-MOP and/or its metabolites from the body.

Animals↗
PubMed1990

Involvement of purine compounds in the inotropic action of milrinone.

In spontaneously beating atria from reserpine-treated guinea pigs, milrinone (1-100 micrograms/ml) induced a positive inotropic and chronotropic effect but was ineffective in preparations preincubated with adenosine deaminase (1 U/ml). Both in spontaneously beating and in electrically driven atria, ATP and adenosine evoked a dual effect: a first negative phase characterized by a reduction in contractile force, followed by a positive phase of increased inotropism. In these preparations milrinone inhibited the early negative influence exerted by purine compounds and amplified the following positive phase. These data suggest that the positive inotropic and chronotropic effect of milrinone may originate from its interference with endogenous purines.

Adenosine↗
PubMed1990

Comparison between the cardiac effects induced by muzolimine and furosemide in guinea-pig atria.

Muzolimine (10-500 microM) induced a concentration-dependent reduction of both the contractile force and frequency in spontaneously beating atria and in electrically driven left atrium from reserpine-treated guinea pigs. This negative inotropic response was unaffected by the addition of atropine to the perfusion fluid, and it was highly sensitive to changes in external Ca2+ concentration. Both in spontaneously beating and in electrically driven atrium, muzolimine (50-400 microM) antagonized, in an apparently competitive manner, the increase in contractile force induced by cumulative addition of CaCl2 (0.68-9.59 mM) to the bathing fluid. Muzolimine (50-100 microM) reduced the inotropic response to low (5-30 nM), but not high (50-100 nM) concentrations of Bay K 8644, a calcium-channel agonist. The inotropic effects of 8-phenyltheophylline and of ouabain were antagonized by muzolimine (10-100 microM) in a noncompetitive manner, while the response to noradrenaline was not altered. Similar to muzolimine, verapamil at a concentration suitable to block calcium channels inhibited, in a noncompetitive way, the inotropic effect induced by 8-phenyltheophylline and by ouabain without altering the contractile response to noradrenaline. Furosemide (10 and 100 microM) did not influence the contractile force or the frequency of spontaneously beating atria, nor the inotropic effect induced by CaCl2, 8-phenyltheophylline, ouabain, or noradrenaline. These results indicate that the influence of muzolimine on guinea-pig atria originates from an inhibition of Ca2+ influx into cardiac cells and that furosemide does not mimic the effect of muzolimine at this level.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Different action of milrinone analogs in guinea-pig atria.

1. Three new milrinone analogs, esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridine carboxylic acids [compounds I, II and III] displaced 3H-CHA (N6-cyclohexyl[3H]-adenosine) from its binding sites to Ri receptors in the rat brain. 2. When tested on the contractile activity of electrically driven left atrium from reserpine-treated guinea-pigs, I induced marked positive inotropic activity, whereas the most lipophilic compounds II and III, induced negative inotropic effects. 3. These results suggest that the positive inotropic agent may act by displacing endogenous adenosine from its Ri inhibitory receptors in the atria, whereas the negative inotropic agents may act as agonists at the same adenosine receptor.

Adenosine↗