Search PubMed⌕ Search

Biomedical subjects

G M Fanelli

Publications and source records attributed to G M Fanelli.

13 recordsLinked to original sources
PubMed1979

Urate excretion: drug interactions.

A derivative of probenecid, 2-nitroprobenecid, was studied in chimpanzees and Cebus monkeys. The uricosuria induced by the drug could be diminished by the infusion of p-aminohippurate (chimpanzee) or hippurate (monkey). Both hippurates inhibited the secretion of the drug and it is likely that the diminished response was the result of decreased access of 2-nitroprobenecid to its site of action. In contrast, pyrazinoate diminished the response to 2-nitroprobenecid without disturbing its renal disposition (both species). This action of pyrazinoate is attributed to its ability to inhibit the secretory flux of urate. The effect of pyrazinoate is diminished at high levels of 2-nitroprobenecid, i.e., it appears as if pyrazinoate causes a shift to the right of the concentration-response curve of 2-nitroprobenecid. A mathematical model is developed which seems to explain this apparent shift in the concentration-response curve. This model requires that the transepithelial fluxes for urate be very large. In the chimpanzee the action of salicylate resembles that of pyrazinoate but it is less prominent.

Animals↗
PubMed1979

A new platelet aggregation inhibitor which possesses hypolipemic and uricosuric properties, 2-[3-(2-thiazolylthio)phenyl]propionic acid (TPA).

In vitro, 2-[3-(2-thiazolylthio)phenyl]propionic acid (TPA) at plasma concentrations ranging from 0.02 to 1.0 microgram/ml prevents aggregation of human platelets induced by various aggregating agents. Oral administration of TPA to guinea pigs inhibits platelet aggregation; the estimated dose to reduce aggregation by 50% is 0.3 mg/kg. TPA protects rabbits against arachidonate-induced thromboembolic death (50% protection at 0.79 mg/kg i.p.). TPA is a potent hypotriglyceridemic agent in rats when present in the diet in concentrations as low as 0.003%. In chimpanzees, TPA is uricosuric at oral doses of 0.625 and 2.5 mg/kg. This rare combination of pharmacological properties suggests that TPA is a potentially useful antithrombotic agent.

Adenosine Diphosphate↗
PubMed1979

Diuretic and antihypertensive effects of 2-aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK-447).

2-Aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride or MK-447, is a chemically novel diuretic agent which produced diuretic and saluretic effects in rats, dogs and chimpanzees. At doses ranging from 0.1 to 10 mg/kg p.o. (0.32-32 mumol/kg) MK-447 was more effective then furosemide at the same or higher doses in increasing the excretion of Na+, K+ and Cl- in rats and dogs. At single oral doses, MK-447 had antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs. Other diuretics are known to lower arterial pressure in these models only by repeated administration. The antihypertensive and diuretic effects of MK-447 in spontaneously hypertensive rats were reduced by indomethacin.

Animals↗
PubMed1978

Does intracellular sodium regulate sodium transport across the mucosal surface of frog skin?

A method has been devised to functionally remove the serosal membrane of frog skin. Skins treated in this way have no spontaneous potential. However, if sodium gradients are placed across the tissues diffusion potentials and hence short-circuit currents of either sign, depending on the direction of the gradient, could be recorded. These short-circuit currents were completely imhibited by amiloride only from the mucosal face. However, the concentration of amiloride causing 50% inhibition of the short-circuit curent (Km) in treated skins was 2.3 . 10(-3)M, when a sodium gradient was applied from serosa to mucosa, whereas both in untreated skins without a sodium gradient and in treated skins with a mucosal to serosal sodium gradient, the Km of amiloride was 2 . 10(-7)-4 . 10(-7)M. The mechanism by which amiloride is able to inhibit the short-circuit currents of either sign is discussed.

Amiloride↗
PubMed1978

(Acylaryloxy)acetic acid diuretics. 2. (2-Alkyl-2-aryl-1-oxo-5-indanyloxy)acetic acids.

The introduction of an aryl group at the 2 position of the uricosuric diuretics, (1-oxo-2-alkyl-5-indanyloxy)acetic acids, provided compounds with markedly increased potency over their monosubstituted precursors. These compounds were synthesized either by arylation of the corresponding 2-alkyl-5-methoxy-1-indanones with diaryliodonium salts or by alkylation of the 2-aryl-5-methoxy-1-indanones which were cleaved to the corresponding phenols and then converted to the desired oxyacetic acids. Systematic structural variation of the 2-arylindanyloxyacetic acids provided aryl-substituted compounds with varying degrees of uricosuric and diuretic activity.

Acetates↗
PubMed1978

Effects of some pyrazinecarboxamides on sodium transport in frog skin.

1 The inhibitory effect of amiloride (N-amidino-3,5-diamino-6-chloropyrazinecarboxamide) on sodium transport in isolated skin of frog has been compared with 17 of its analogues. The dissociation constant of amiloride for passive sodium channels was 181.9 +/- 8.9 nM, and the maximal percentage inhibition of sodium transport was 101.3 +/- 0.4% (means of 123 measurements) when measured at a sodium concentration of 111 mM. 2 The N-benzylamidino and N-o-chlorobenzylamidino compounds had affinities approximately 20 times larger than those for amiloride, and produced maximal inhibition of transport. 3 Substitution of chlorine in the 6-position by other halogens showed that the bromo-compound was equally active to amiloride, whereas the iodo derivative had an affinity equal to 15% of that for amiloride. 4 Substitution in the 5-amino group in 10 compounds reduced the affinities to less than 1% of that of amiloride, without affecting their ability to produce complete inhibition of transport. 5 N-Amidino-3,5-diaminopyrazinecarboxamide was unique in that it produced an unusual concentration-response relationship.

Amiloride↗
PubMed1977

Urate excretion.

Explore the source record for details and available documents.

Acetohexamide↗
PubMed1977

Saluretic and uricosuric effects of (6, 7-dichloro-2-methyl=1-oxo-2-phenyl-5-indanyloxy) acetic acid (MK-196) in the chimpanzee.

The saluretic and uricosuric responses elicited by a novel agent, MK-196, have been studied in a great ape, the chimpanzee. This agent is orally active at very low doses and has a prolonged duration of action. Probenecid does not appear to influence the saluretic and uricosuric properties of MK-196. Net tubular secretion of urate was reduced by MK-196. Urinary pH changes did not compromise the efficacy of this new agent. On a dose basis, MK-196 was more saluretic (and uricosuric) than ethacrynic acid or furosemide and possessed a longer duration of action. Because of the marked natriuresis caused by MK-196, some increase in potassium excretion occurred.

Animals↗
PubMed1977

Renal excretion of a slauretic-uricosuric agent (MK-196) and interaction with a urate-retaining drug, pyrazinoate, in the chimpanzee.

The excretory pattern for MK-196 is ocmpatible with that of other weak organic acids such as salicylate and probenecid. Tubular secretion of MK-196 is strongly inhibitied by probenecid and high loads of p-aminohippurate. Urinary excretion of MK-196 is increased 10-fold when the urine is alkaline. Clearances of MK-196 were not corrected for plasma protein binding of the drug which is very high (greater than 99%). Bidirectional transport processes are operative in that MK-196 is secreted by the renal tubule and passively back diffuses across the tubular epithelium by a pH-dependent process. MK-196 is able to overcome pyrazinoate-induced urate retention, whereas probenecid is not when studied by conventional clearance techniques. The uricosuric activity of MK-196 appears to be somewhat less with pyrazinoate than in its absence. When MK-196 is administered prior to pyrazinoate an attenuated uricosuric response was observed. This finding cannot be ascribed to a temporal decline in uricosuric action. Diuresis and saluresis produced by MK-196 are not influenced by pyrazinoate. The interaction of MK=196 and pyrazinoate on urate excretion is in direct contrast to results obtained with probenecid and pyrazinoate. A model has been proposed to explain this unique finding.

Acetazolamide↗
PubMed1975

Renal urate excretion in animal models.

Several aspects of the comparative physiology and pharmacology of renal urate handling are considered; with special attention to bidirectional transport, the existence of intrarenal urate synthesis and degradation in certain species, and the nature and sites of the reabsorptive and secretory processes. Interspecies variations in the sensitivity of the kidney to uricosuric agents and the degree of specificity of the secretory mechanism are discussed. A variety of techniques, especially as applied in certain nonhuman primates, have led to a concept of very rapid trans-tubular fluxes of urate--a concept which may apply in man.

Allopurinol↗
PubMedDate not supplied

Uricosuric agents.

Explore the source record for details and available documents.

Benzofurans↗
PubMedDate not supplied

The biotransformation of (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy) acetic acid (MK-196) in the chimpanzee.

The metabolism of a novel polyvalent saluretic agent (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196) was studied in the chimpanzee. Following oral administration, 50% of the radioactive dose was recovered in the urine in four days; 8-14% of the dose was excreted as unchanged drug. The fecal specimens accounted for 5-9% of the dose. Following intravenous administration an initial rapid elimination of drug from the plasma was observed [(t1/2)alpha approximately 0.4 hr, (t1/2)beta approximately 4 hr]. The data are consistent with the rapid elimination of radioactivity, approximately 30% of dose, in the urine during the first 24 hr, followed by a much slower rate of excretion of drug and metabolites. These findings are congruous with the high affinity (greater than 98%) of MK-196 and the major metabolite with plasma proteins. The urinary metabolites were isolated and identified by the following techniques: solvent extraction, column, thin-layer, and gas-liquid chromatography, derivatization, and mass and nuclear magnetic resonance spectroscopy. The major metabolite, which resulted from para-hydroxylation of the 2-phenyl substitutent, accounted for about 40% of the urinary radioactivity. Reduction of the ketone group, methylation of the p-hydroxy group, and additional phenyl ring hydroxylation were also shown to occur. There was no evidence for glucuronide formation nor did SKF-525-A inhibit the metabolism of the drug in the chimpanzee. Under conditions of induced metabolic alkalosis, the urinary levels of MK-196 increased from 11 to 40%. Probenecid and p-aminohippurate administered during metabolic alkalosis decreased the clearance of drug (40 to 15%).

Administration, Oral↗