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Biomedical subjects

G L Biagi

Publications and source records attributed to G L Biagi.

At least 55 records · Page 3Linked to original sources
PubMed1987

The influence of physicochemical parameters on the biliary excretion of a series of nitroimidazoles.

The relationship between physicochemical parameters and biliary excretion of nitroimidazoles was investigated. The unmetabolized form of each drug was detected in the bile by means of a UV procedure. A highly significant reversed parabolic relationship was shown between the Rm values and the biliary excretion of the test compounds. In other words, the compounds closer to the optimal Rm value are excreted less than those characterized by higher or lower Rm values. Since the Rm values seem to account for both the lipophilic and polar character of nitroimidazoles, the reversed parabola could be due to plasma protein binding and/or some protein binding within the hepatocyte. In fact, both the lipophilic and polar character seem to play an important role in protein binding of chemicals.

Animals↗
PubMed1986

The direct-acting mutagenicity of nitroimidazo[2,1-b]thiazoles in Salmonella typhimurium.

A series of nitroimidazo[2,1-b]thiazole derivatives was investigated for direct-acting mutagenic potency with the Salmonella assay. All of the nine derivatives tested were mutagenic. The compounds induced predominantly base displacements resulting in frame-shift mutations. The mutagenic activity did not require the S9 fraction but was largely dependent on "classical" bacterial nitroreductase. The primary basis of the mutagenic activity of nitroimidazo[2,1-b]thiazoles appears to be a reduction of the nitro-function to the corresponding hydroxylamine. Mutagenicity seems to be paralleled by an increase of the nitro groups: dinitroderivatives were more active than nitroderivatives. Other electrophiles and sterically constrained nitro groups could account for differences in genotoxicity.

Mutagenicity Tests↗
PubMed1986

Structure-activity relationship of nitroimidazo (2,1-b) thiazoles in the Salmonella mutagenicity assay.

The mutagenic activity of a series of nitroimidazo (2,1-b) thiazoles was determined in Salmonella typhimurium TA-100 strain by means of the Ames test. A multiple regression analysis showed a highly significant parabolic relationship between mutagenic activity and the Rm values as an expression of the lipophilic character of molecules. The lipophilic character should be important in determining an optimal cell permeation. However when the lipophilic character was expressed by means of the sigma pi values the equation was much less satisfactory. This could be due to the fact that the Rm values of nitroheterocyclic compounds actually represent a measure both of lipophilic and polar character.

Mutagenicity Tests↗
PubMed1986

Relationship between lipophilic character and urinary excretion of nitroimidazoles and nitrothiazoles in rats.

Many processes are involved in the renal excretion of drugs, but very little is known about their quantitative structure-activity relationship. The relationship between urinary excretion and lipophilic character of a series of nitroimidazoles and nitrothiazoles was studied. The unmetabolized forms of the drugs were detected in the urine by means of UV and HPLC procedures. The urinary excretion of unmetabolized forms is parabolically related with the log P, as an expression of lipophilic character of molecules.

Animals↗
PubMed1985

The organospecific activity of metronidazole and azanidazole in the intrasanguineous host-mediated assay.

The genotoxicity of nitroimidazoles and, in particular, their potential carcinogenicity has been demonstrated. In order to investigate the specific target organ(s) for these drugs or their metabolites, a method for measuring mutations in microorganisms, with reference to the metabolism of mammals, was used in mice. Metronidazole and azanidazole were tested for their ability to induce genetic effects in a diploid strain (D7) of Saccharomyces cerevisiae in the Intrasanguineous Host-Mediated Assay. The test compounds showed dose-related increases of point mutation and mitotic gene conversion frequencies in liver, kidney and lung. Azanidazole seemed to favour the kidney and the liver, although increases in genotoxicity were observed also in the lung. Metronidazole was toxic and induced both point mutation and mitotic gene conversion when recovered from the liver. Yeast recovered from the kidney and the lung showed an increase especially in point mutation. This work provides more information about the mechanisms involved in the mutagenicity of nitroimidazoles at the site of action.

Animals↗
PubMed1984

NADPH-generating system: influence on microsomal mono-oxygenase stability during incubation for the liver-microsomal assay with rat and mouse S9 fractions.

Activity levels of 7-ethoxycoumarin O-deethylase (ED), aminopyrine N-demethylase (APD), p-nitroanisole O-demethylase (p-NAD) and glucose-6-phosphate dehydrogenase (G-6-PDH) were determined in incubation mixtures for the liver-microsomal assay (LMA) at time 0 and after 1 and 2 h incubation under conditions for mutagenic assay. The experiments were performed with S9 liver fractions from mice (induced with Na-phenobarbital and beta-naphthoflavone) and rats (induced with Aroclor 1254) with and without G-6-PDH in the incubation mixtures. In the absence of G-6-PDH the activities were significantly lower at time 0 in the mouse. The pattern of stability, however, was similar for the activities, with an increase of stability after 1 and 2 h of pre-incubation (an exception for p-NAD). Only ED activity showed a similar behaviour in the rat. No differences were present for APD and p-NAD activities at time 0 in the rat, but the enzyme stabilities were significantly decreased after 2 h of incubation (about 15% and 10% for APD and p-NAD respectively) in the absence of G-6-PDH. At time 0, the amounts of G-6-PDH differed between mouse and rat fractions; however, during the incubations for LMA they decreased by about 57% and 53% for the two species, respectively. In addition to the above biochemical results, the presence of exogenous G-6-PDH in the incubations for the mutagenic assay, significantly increased the mitotic gene conversion and mitotic crossing-over of dimethylnitrosamine (DMN) and AR2MNFN (a nitroimidazo[2,1-b]thiazole) in the D7 strain of Saccharomyces cerevisiae.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1983

Mutagenicity of a series of 25 nitroimidazoles and two nitrothiazoles in Salmonella typhimurium.

Twenty-five 5-nitroimidazole and two 5-nitrothiazole derivatives were tested for mutagenicity as well as for antibacterial activity in Salmonella typhimurium TA-100 strain. Many of these compounds such as metronidazole, azanidazole, nimorazole, carnidazole, ornidazole, tinidazole, etc are extensively used in human chemotherapy, and some of them were recently synthetized for possible clinical trials as hypoxic cell specific radiosensitizers. Both mutagenic and antibacterial activity were shown for 22 of the test compounds. The high correlation between mutagenic and antibacterial activity supports the hypothesis of a same mechanism for both activities. The present results confirm that the mutagenicity of the nitroheterocyclic compounds is not separated from other biological activities, such as antimicrobial activity.

Mutagenicity Tests↗
PubMed1983

Quantitative relationship between structure and mutagenic activity in a series of 5-nitroimidazoles.

The mutagenic activity of 20 5-nitroimidazoles was tested in Salmonella typhimurium TA-100 strain by means of the Ames test. A multiple regression analysis using the interaction term MR2 X Hb and the chromatographic Rm values yielded the equation: (formula see text); where C is the molar concentration (1 M X 10(-6) of each drug increasing the revertants by five times in the Ames test. The interaction term MR2 X Hb takes into account the positive effect exerted by substituents characterized by higher molar refractivity (MR2) and capable of hydrogen bonding (Hb). It was found that when the electroreduction potentials (EIc.p.) were included, the correlation was not improved.

Chemical Phenomena↗
PubMed1980

Rm values and structure-activity relationship of benzodiazepines.

Quantitative structure-activity relationships (QSAR) have been formulated for the activities of a series of benzodiazepines in rats. The lipophilic character of molecules was expressed by means of the chromatographic Rm values which were very well correlated with experimental or calculated log P values. The ideal lipophilic character for activity of benzodiazepines in the exploratory behavior test is not far from that of compounds acting in the central nervous system as unspecific depressant agents. The results of both the conflict and exploratory behavior studies might support the hypothesis of different sites of action for the antianxiety and sedative effects of benzodiazepines.

Animals↗
PubMed1979

RM values of naphthols and acetophenones in structure-activity studies.

The RM values of naphthols obtained in a chromatographic system where the stationary phase consisted of a silica gel G layer impregnated with silicone oil are much more closely related to the log P values in an octanol-water system than the RM values determined on polyamide layers. Similarly, the RM values of a series of acetophenones in the silicone system are closely related to their log P values. The equations describing the structure-activity relationship indicate the importance of lipophilic character and halogen substitution in determining the hemolytic activity and the acute toxicity of compounds.

Acetophenones↗
PubMed1977

Antiinflammatory activity of four isomers of 2-(4-biphenylyl)-3-hydroxybutyric acid.

The degree of stereospecificity of the antiinflammatory activity of four isomers of 2-(4-biphenylyl)-3-hydroxybutyric acid was investigated in three different tests. The erythro compounds were the most active ones. As the "optical isomers effect" was not significant, this could indicate that the "diastereoisomer effect" is more important than optical isomerism.

Administration, Oral↗