Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes.

Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes.

1,8-Naphthyridines IV. 9-substituted N,N-dialkyl-5-(alkylamino or cycloalkylamino) [1,2,4]triazolo[4,3-a][1, 8]naphthyridine-6-carboxamides, new compounds with anti-aggressive and potent anti-inflammatory activities.

The title compounds (8) were synthesized through the cyclocondensation of the corresponding N-substituted 4-amino-2-chloro-1,8-naphthyridine-3-carboxamides (4) with the proper hydrazides, in order to evaluate their anti-inflammatory and anti-aggressive properties. Several compounds 8 exhibited high anti-inflammatory activity (carrageenin-induced paw edema assay in the rat) along with appreciable anti-aggressive properties (isolation-induced aggressiveness test in mice). With respect to anti-inflammatory activity, the most active compounds (8n and 8c) produced a 61% edema inhibition at the 25 mg/kg dose, and 50 or 35% inhibition, respectively, at the 12.

4-Dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols: synthesis and evaluation of analgesic, anti-inflammatory and platelet anti-aggregating activities.

A number of 4-dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols 2a-n were synthesized and tested in vivo for anti-inflammatory and analgesic activities and in vitro for platelet anti-aggregating activity. Dimethylaminoderivatives 2b, e, g showed good analgesic activity; almost all of them had strong platelet anti-aggregating properties at a final concentration of 1 x 10(-3) M; pyrazoles 2c, d, f-h showed weak anti-inflammatory activity.

Induction of micronuclei and of enzyme-altered foci in the liver of female rats exposed to progesterone and three synthetic progestins.

Progesterone (PG) and three structurally similar synthetic progestins-norethisterone (NE), allylestrenol (AE), and dydrogesterone (DG)-have been compared for their ability to induce the formation of micronuclei and of enzyme-altered foci in the liver of female rats. In the micronucleus assay, carried out in rats given a single p.o.

Acid-catalysed hydrolysis and benzodiazepine-like properties of 5-(dialkylamino)- and 5-(alkylthio)-substituted 8-chloro-6-phenyl-6H-[1,2,4]triazolol[4,3-a][1,5]benzodiazepines in mice.

The in-vitro and in-vivo hydrolysis of two benzodiazepine compounds has been studied to evaluate their in-vivo activity in mice. Compounds RL 218 and RL 236, selected as representative examples of N,N-dialkyl-8-chloro-6-phenyl-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiaz epin-5-amines (1) and of their 5-(alkylthio) substituted analogues (2), were rapidly hydrolysed to the corresponding 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5(6H )-one 3 (RL 214) in aqueous acidic solution at pH 1.5.

Effects of reduced glutathione and n-acetylcysteine on lidocaine metabolism in cimetidine treated rats.

The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N-acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (i.p.

Penetration of oral cefuroxime axetil into the human aqueous humor.

The purpose of this study was to investigate the penetration into the aqueous humor of cefuroxime after a single oral dose as cefuroxime axetil. Fourteen patients scheduled for cataract extraction received a single oral dose of cefuroxime axetil corresponding to 500 mg of cefuroxime 2-8 h preoperatively. Aqueous humor samples were obtained at the beginning of the cataract surgery and blood samples were drawn at the time of anesthesia.

1,8-Naphthyridines. III. N,N-dialkyl-5-chloro[1,2,4]-triazolo[4,3-a][1,8]naphthyridine-6-carboxa mides with anti-inflammatory activity.

Fifteen N,N-dialkyl-5-chloro[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxami des (7a-o) were synthesized through the cyclocondensation of the corresponding N,N-dialkyl-2,4-dichloro-1,8-naphthyridine-3-carboxamides with proper hydrazides, in order to evaluate their anti-inflammatory, antiaggressive, and analgesic properties. Four of the compounds tested showed a statistically significant and dose-dependent anti-inflammatory activity.

A possible medium-term assay for detecting the effects of liver and colon carcinogens in rats.

The aim of the present study was to verify whether the tumorigenic effect of a rat liver carcinogen, 2-acetylaminofluorene (AAF), and of a promoter of rat colon carcinogenesis, chenodeoxycholic acid (CDCA), could be detected with a single medium-term assay using as markers gamma-glutamyltranspeptidase (GGT)-positive foci in the liver and aberrant crypt foci (ACF) in colon mucosa. In rats given in the first 2 weeks of treatment both N-nitrosodiethylamine (NDEA), as initiator of liver carcinogenesis, and azoxymethane (AOM), as initiator of colon carcinogenesis, the subsequent 6-week feeding on a diet containing AAF (0.01%) produced a significant marked increase of the number and area of GGT-positive foci which is consistent with the results of long term assays.

Inhibition of the development of rat liver preneoplastic lesions by verapamil and dexverapamil.

The effect of verapamil and dexverapamil on the development of liver preneoplastic foci was investigated in male Sprague-Dawley rats initiated with N-nitrosodiethylamine (200 mg/kg i.p.), fed on a diet containing 0.

Comparative study of DNA repair induced by cyproterone acetate, chlormadinone acetate and megestrol acetate in primary cultures of human and rat hepatocytes.

Cyproterone acetate (CPA), a synthetic progestin recently found to induce genotoxic effects in hepatocytes from female rats and from humans of both genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for their capacity to induce DNA repair synthesis as measured by quantitative autoradiography. Exposure of primary human hepatocytes for 20 h to concentrations of CPA, CMA and MGA ranging from 2 to 50 microM induced positive responses in cultures from donors of both genders and the amounts of DNA repair elicited by the three progestins were similar. Under the same experimental conditions substantial differences were observed in the amounts of DNA repair elicited by the three progestins in primary hepatocytes from female rats, their potency decreasing in the following order CPA > CMA > MGA, and the three compounds failed to induce DNA repair in hepatocytes from male rats.

Evaluation of the potential carcinogenic activity of Senna and Cascara glycosides for the rat colon.

Anthraquinone glycosides of Senna and Cascara were investigated for their ability to induce aberrant crypt foci (ACF) in the rat colon mucosa, which are considered putative preneoplastic lesions. Dietary exposure to high doses of these glycosides for 56 successive days did not cause the appearance of ACF or increase in incidence of ACF induced by 1,2-dimethyl-hydrazine (DMH). However, in rats treated with both DMH and the highest dose of glycosides, the average number of aberrant crypts per focus, considered a consistent predictor of tumor outcome, was higher than in rats given DMH alone.

Induction of micronuclei and initiation of enzyme-altered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate, or megestrol acetate.

The synthetic anti-androgen and progestin cyproterone acetate (CPA), recently found to be genotoxic for the liver, and two structurally similar progestins, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for clastogenic and tumor-initiating activities in female rats. In the micronucleus assay, carried out in rats given a single p.o.

Inhibitory properties of triethylphosphine goldlupinylsulfide in adjuvant-induced arthritis in rats.

A new gold coordination compound (triethylphosphine goldlupinylsulfide: TP-Au-LS) was tested in adjuvant-induced arthritis in the rat, by oral administration at doses of 5, 10 and 20 mg/kg/day of gold for 17 consecutive days, in comparison with auranofin and betamethasone. TP-Au-LS produced a dose dependent reduction of both the injected and uninjected hind paw volume. Gold levels in serum (measured on day 18 by inductively coupled plasma atomic emission spectrometry) were also found to be dose related.

Increased frequency of N-methyl-N'-nitro-N-nitrosoguanidine-induced nuclear anomalies in the forestomach of rats pretreated with sodium chloride.

The frequency of nuclear anomalies (micronuclei, pyknosis, and karyorrhexis) in the forestomach mucosa was examined in Sprague-Dawley male rats given a single oral dose of 50 or 150 mg/kg of the gastric carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) 17 h after the administration of 2 ml of a 3 M NaCl solution. Rats pretreated with NaCl displayed an incidence of nuclear anomalies approximately 3-fold greater than the one observed in rats given MNNG alone, and micronucleated cells accounted to a significant extent for this increase. These findings confirm that NaCl presumably acts as co-carcinogen in the initial phase of gastric carcinogenesis, and suggest that its administration before the carcinogen might increase the sensitivity of short-term tests for the preliminary screening of potential gastric carcinogens.

Evaluation of DNA-damaging, clastogenic, and promoting activities of metoclopramide and procainamide in rats.

The DNA-damaging and clastogenic activities of metoclopramide (MCA) and procainamide (PCA), two substituted benzamides not systematically tested for genotoxicity before clinical use, were investigated in rats given a single high oral dose (500 mg/kg) of these drugs. Neither MCA nor PCA induced DNA fragmentation in liver, kidney, gastric mucosa, spleen, and bone marrow, as detected by the alkaline elution technique. Moreover, neither drug increased the frequency of micronucleated hepatocytes and the frequency of micronucleated polychromatic erythrocytes in the bone marrow of partially hepatectomized rats.

In vitro and in vivo testing of hydralazine genotoxicity.

Hydralazine (HDZ), a p.o. effective antihypertensive drug, was evaluated for its genotoxic effects in both rodent and human cultured cells and in the intact rat.

Cinnamaldehyde-induced micronuclei in rodent liver.

Cinnamaldehyde, a widely used flavoring agent, has so far been subjected to a limited range of genotoxicity tests, mainly carried out in vitro, which produced contradictory results. Therefore we have examined cinnamaldehyde using additional in vivo genotoxicity end-points. In Sprague-Dawley rats, a single oral dose equal to 1/2 LD50 did not induce DNA fragmentation in liver and gastric mucosa as evaluated by the alkaline elution technique, increased the frequency of micronucleated hepatocytes but not of bone marrow micronucleated polychromatic erythrocytes, and gave rise to a significantly higher incidence of total nuclear anomalies but not of micronucleated cells in forestomach mucosa.

Effect of aspirin on incidence and growth of aberrant crypt foci induced in the rat colon by 1,2-dimethylhydrazine.

The aim of this work was to investigate if the possible chemopreventive effect of aspirin (ASA) on rat colon carcinogenesis could be detected with a medium-term assay. The end-point chosen was the inhibition of incidence and growth of putative preneoplastic lesions, the aberrant crypt foci (ACF) induced in the rat colon by two administrations of 1,2-dimethylhydrazine (DMH, 25 mg/kg p.o.

1,8-naphthyridines II. 2,4-disubstituted N,N-dialkyl-1,8-naphthyridine-3-carboxamides with anti-inflammatory and/or antiaggressive activities.

The preparation of the novel N,N-dialkyl-2,4-dichloro-1,8-naphthyridine-3-carboxamides 1c, e and N,N-dialkyl-2-(alkylamino or cycloalkylamino)-4-chloro-1,8-naphthyridine-3- carboxamides 2b, d-g, j-p is described. These compounds and the previously obtained analogs 1a, b, d, f and 2a, c, h, i have been tested for their anti-inflammatory and antiaggressive activities, as well as for their gross behavioral effects and acute toxicity. Nine of the twenty-two tested compounds exhibited a statistically significant anti-inflammatory activity in the carrageenin-induced edema assay in the rat (1e, f and 2h, o were the most active compounds).

Lack of evidence of omeprazole genotoxicity in Sprague-Dawley rats.

Omeprazole is a proton pump inhibitor of increasingly wide use in the treatment of peptic ulcers. Although omeprazole has been subjected to an extensive range of genotoxicity tests, which have all been concluded as negative, the ability of this compound to interact with DNA and elicit unscheduled DNA synthesis in the rat gastric mucosa has been the subject of debate. Therefore, we have examined omeprazole using other genotoxicity end-points.

Genotoxic activity of 1,3-dichloropropene in a battery of in vivo short-term tests.

The genotoxic activity of 1,3-dichloropropene, which has been classified as possibly carcinogenic to humans, was investigated in rats given high single doses of this chloroolefin. A dose-related amount of DNA fragmentation was observed at doses ranging from 62.5 to 250 mg/kg in liver and gastric mucosa, both of which are targets of DCP carcinogenic activity, as well as in the kidney.

Cytotoxic and genotoxic activity of 1,3-dichloropropene in cultured mammalian cells.

1,3-Dichloropropene (DCP), a widely used soil fumigant previously found to be carcinogenic in both mice and rats, was evaluated for its cytotoxic and genotoxic effects in cultured rodent and human cells. A reduction of cell viability that was dependent on the dose and the length of treatment was observed with the trypan blue and the neutral red assay in both V79 cells and rat hepatocytes exposed to DCP concentrations ranging from 0.18 to 5.

Effects of ethinyl estradiol and epidermal growth-factor on DNA-synthesis in human cultured-hepatocytes.

It has been demonstrated that the liver tumor promoter ethinyl estradiol (EE) potentiates the DNA synthetic response of cultured rat hepatocytes to epidermal growth factor (EGF), probably acting as a comitogen with a growth factor of the EGF/TGF family. The present study investigated the effects of EE and EGF on DNA synthesis in cultures of rat and human hepatocytes obtained from 5 female donors. The cultures were given the following treatments: a.

Post-operative analgesia with tramadol: a controlled study compared with an analgesic combination.

The analgesic action of tramadol in the post-operative period was compared with that of an analgesic combination (Nisidin) in a sample of 60 patients (31 male, 29 female) aged between 20 and 70 years undergoing surgical operations on the abdomen involving opening of the peritoneum. The study was carried out according to a controlled and randomized experimental design. Tramadol in 100 mg/2 ml vials and Nisidin in 2 ml vials were administered parenterally at a dosage of three vials a day during the first three days of the post-operative period.