Local thrombolysis with recombinant tissue plasminogen activator in a high-risk patient.
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Aged↗
Biomedical subjects
G Brambilla
Publications and source records attributed to G Brambilla.
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 5.6 mM. In the absence of a metabolic activation system, a dose-dependent frequency of DNA single-strand breaks, that were only partially repaired within 24 hr, was revealed by the alkaline elution technique in V79 cells exposed to subtoxic DCP concentrations. The genotoxicity of DCP was confirmed by the results obtained in metabolically competent primary cultures of both rat and human hepatocytes which displayed similar dose-related amounts of DNA fragmentation and DNA repair synthesis, and showed, in comparison to metabolically deficient V79 cells, a somewhat greater sensitivity to the cytotoxic and DNA-damaging effects of DCP. The increase in the frequency of DNA breaks observed in rat hepatocytes after GSH depletion confirms the role of this tripeptide in DCP detoxification; its reduction in hepatocytes simultaneously exposed to metyrapone is consistent with a cytochrome P450-dependent biotransformation of DCP to more toxic metabolites.
Allyl Compounds↗
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. The frequency of DNA breaks, that were to a large extent repaired within 24 hr, was higher after po than after ip administration in the liver, while the converse occurred in the kidney. Any evidence of DNA fragmentation was, in contrast, absent in lung, bone marrow, and brain which are not sites of DCP-induced tumor development. A role of cytochrome P450 in the activation of DCP is suggested by the lower degree of liver DNA fragmentation observed in rats pretreated with methoxsalen. DCP produced a dose-dependent reduction of the liver GSH level, an effect that presumably hinders its detoxification and thus favors its DNA-damaging activity. In contrast with the satisfactory prediction of DCP carcinogenic activity provided by the results of the in vivo DNA damage/alkaline elution assay, neither the in vivo rat hepatocyte DNA repair assay nor the micronucleus assay, carried out on bone marrow, spleen, and liver cells of partially hepatectomized rats, supplied any evidence of DCP genotoxicity.
Allyl Compounds↗
Comparison of micronucleus formation in mouse bone marrow and spleen.
The frequencies of micronucleated erythrocytes were compared in bone marrow and spleen of mice killed 24 and 48 h after a single i.p. dose of one directly acting carcinogen, N-nitroso-N-ethylurea (NEU, 100 mg/kg), and two indirectly acting ones, N-nitrosodimethylamine (NDMA, 50 mg/kg) and 7,12-dimethylbenz[a]anthracene (7,12-DMBA, 50 mg/kg). The treated/control ratio of the incidence of micronucleated polychromatic erythrocytes (MnPCEs) was similar in the two tissues for NDMA at 24 h (sampling at 48 h was precluded by toxicity) and for 7,12-DMBA at 48 h, while it was higher in the bone marrow than in the spleen for NEU at both 24 and 48 h and for 7,12-DMBA at 24 h. Concerning micronucleated normochromatic erythrocytes (MnNCEs), their frequency in both tissues was always lower than that of MnPCEs; however, while in bone marrow a marked increase in their incidence was induced by NEU and 7,12-DMBA, any response was absent in spleen, thus suggesting that this organ does not sequester micronucleated erythrocytes. These results already indicate that the spleen is not a useful alternative to the bone marrow in the micronucleus assay. Moreover, counting of MnPCEs in the spleen is made more difficult and prone to error by the low frequency of PCEs, and by their greater toxicity-induced reduction. This last effect was found to be enhanced by the use of old mice.
9,10-Dimethyl-1,2-benzanthracene↗
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. In female Sprague-Dawley rats, the administration by the oral route of 100 mg/kg, either as neutral (pH 7.0) suspension or as suspension acidified to pH 1.5, which favours its transformation into the active form of sulphenamide, did not induce DNA fragmentation in gastric mucosa and liver, as detected by the alkaline elution technique. In the same experimental conditions, a frequency of total nuclear anomalies (micronuclei, pyknosis and karyorrhexis) that was significantly higher than in controls was detected with both types of suspension in forestomach and descending colon mucosa. However, in both tissues this higher frequency of nuclear anomalies was mostly due to pyknosis and karyorrhexis, which may be the outcome of a non-genotoxic effect, whereas there was no significant increase in the number of micronucleated cells, and this suggests the absence of clastogenic activity. Finally, in rats initiated with N-nitrosodiethylamine, the oral administration of 100 mg/kg omeprazole for 14 successive days produced a modest but statistically significant increase of liver gamma-glutamyltranspeptidase positive foci, which is consistent with a potential promoting activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Human hepatocyte primary cultures in toxicity assessment.
Forty-two compounds of various chemical families were tested for their cytotoxicity and for their ability to induce DNA fragmentation and DNA repair synthesis in primary cultures of hepatocytes obtained from 74 human donors, and a comparison was carried out with data provided in the same experimental conditions by rat hepatocytes. The results indicate that for the majority of chemicals the intraspecies variability was greater than the average interspecies difference. Some chemicals, however, produced quite different effects in the hepatocytes of the two species, and this suggests that rat hepatocytes might be sometimes inappropriate predictor of the human response.
Animals↗
Evaluation in a battery of in vivo assays of four in vitro genotoxins proved to be noncarcinogens in rodents.
2-Chlorethanol, 8-hydroxyquinoline, 2,6-toluenediamine, and eugenol, previously found to behave as genotoxins in in vitro systems and as noncarcinogens in rodents, were evaluated for their ability to induce genotoxic effects in vivo. Rats were given by gavage a single or two successive doses equal to one-half the corresponding LD50, killed at different times after treatment, and examined for the following end points: the frequency of both micronucleated polychromatic erythrocytes in the bone marrow and micronucleated hepatocytes (after partial hepatectomy); the in vivo-in vitro induction of DNA fragmentation, as measured by the alkaline elution technique, and of unscheduled DNA synthesis, as measured by autoradiography, in hepatocyte primary cultures. The two latter end points were also evaluated after in vitro exposure of hepatocytes to log-spaced subtoxic concentrations. 2-Chloroethanol, 8-hydroxyquinoline, and eugenol never produced effects indicative of genotoxic activity. The same happened with 2,6-toluenediamine, with the exception of a significant increase over controls in the amounts of DNA damage and repair displayed by hepatocyte cultures obtained from rats given two 1/2 LD50 separated by a 24 h interval. Our results, which, apart the above mentioned exception, are in concordance with the rodent carcinogenicity results, contribute to underline the role of in vivo short-term tests for the detection of potential genotoxic carcinogens.
Animals↗
Ipriflavone inhibits osteoclast differentiation in parathyroid transplanted parietal bone of rats.
Ipriflavone, a synthetic isoflavone-derived flavonoid, was shown to have inhibitory effect on bone resorption. In order to study its mechanism of action directly on bone, 46 female Wistar rats were divided into six groups and medicated orally for 25 days as follows: groups 1 and 2 were given 1% carboxymethylcellulose solution (vehicle), groups 3, 4, 5, and 6 were administered ipriflavone at doses of 0.178, 0.356, 0.712, and 1.424 mmol/kg/day (suspended in vehicle), respectively. On the 22nd day, parathyroid glands, taken from donor rats, were transplanted in contact with the outer surface of the periosteum of both the right and the left parietal bones of rats from groups 2, 3, 4, 5, and 6. The group 1 rats underwent sham operation. Bone histomorphometry, performed on the ectocranial periosteum of parietal bones, showed that absolute erosion boundary, absolute eroded area, absolute erosion depth, number of tartrate-resistant acid phosphatase (TRAP)-positive polynucleated osteoclasts, and number of TRAP-positive mononucleated cells decreased in ipriflavone-treated rats compared with group 2 rats. The reduction was roughly proportional to the increase of drug dosage and reached statistical significance in rats of groups 5 and 6. The same parameters were extremely low in group 1 rats. Mineral apposition rate did not differ in any of the groups. Significant increase of serum calcium and significant decrease of serum phosphate were found in group 2 rats compared with group 1 rats, whereas no differences from controls were detected in ipriflavone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The role of spontaneous portosystemic shunts in the course of orthotopic liver transplantation.
Spontaneous portosystemic shunts are commonly found in cirrhotic patients. Not yet established is their role after orthotopic liver transplantation (OLTx), especially when an increase in portal pressure develops, as during early acute rejection. In this study, 34 cirrhotic patients in a series of 70 OLTx are considered. Each patient had preoperative angiographic assessment, and, in 21 (62%), large spontaneous portosystemic shunts were evident. In 12 cases the shunts were not affected by the surgical procedure and were present during the postoperative period; in 9 the hepatectomy itself involved interruption of the shunts. The patient population was divided into two groups: patients with postoperative shunts (n = 12) and those without (n = 22). The two groups were similar in age, sex, Child's stage, transplantation variables, and number and grade of rejection episodes. However, mean transaminases (AST) values in the first 2 weeks were significantly higher levels in shunt versus nonshunt patients (421 +/- 335 vs 183 +/- 126; P less than 0.025), and this was even more evident when rejection occurred (626 +/- 375 vs 195 +/- 129; P less than 0.001). Furthermore, during an acute rejection reaction, three cases showed a true "steal phenomenon" through the large reopened shunts with ischemic damage to the grafts. The data indicate a possible detrimental effect of the spontaneous shunts on graft perfusion and suggest the prophylactic surgical interruption of the residual shunts during the transplantation.
Adult↗
Immunopharmacological activity of cefodizime in young and elderly subjects: in vitro and ex vivo studies.
The biological response modifying activities of cefodizime (CDZ), a new third-generation cephalosporin, were investigated in vitro and ex vivo. In vitro investigations using cells isolated from the blood of young healthy donors showed no stimulating activity of CDZ on peripheral blood lymphocytes, natural killer cell activity, IL-1 production by adherent mononuclear cells, PMN chemiluminescence or PMN chemotaxis. A slight but statistically insignificant increase in PMN phagocytosis and phagocytic index was observed in the same population. IL-1 production was increased in three subjects with low resting state values. In a controlled ex vivo study, 20 healthy elderly subjects selected on the basis of depressed phagocytic function were treated with CDZ 1 g i.m. b.i.d. or placebo for eight days. PMN function was determined at baseline and on the day after the last dose. In the CDZ group a significant increase in both phagocytosis and phagocytic index was found, while there were no changes in the placebo group. In conclusion, CDZ restored depressed PMN phagocytic function in a population of elderly subjects. Patients with impaired PMN function who require antibiotic treatment may benefit from this activity of CDZ.
Adult↗
Effect of ten thiocompounds on rat liver DNA damage induced by a small dose of N-nitrosodimethylamine.
The use in a chemoprevention study of high doses of the genotoxic agent might result in erroneous information because of possible nonlinearity of pharmacokinetic processes and toxicity-induced derangement of physiological defense mechanisms. According to these premises ten thiocompounds, potentially active as inhibitors of metabolic activation and/or scavengers, were examined for their capability of reducing the frequency of liver DNA lesions induced by a very small dose of N-nitrosodimethylamine (NDMA). This was accomplished by means of a viscometric technique previously found suitable to detect a minimal amount of DNA fragmentation. Rats were injected i.p. or i.v. with 1 mmol/kg of thiocompound, 0.2 mg/kg NDMA given by gavage 1 h afterwards, and killed for DNA damage assessment 14 h later. Statistically significant changes of viscometric parameters, which are considered indicative of a protective activity, were produced by disulfiram (DSF), and to a lower extent by diethyldithiocarbamate (DEDTC). Any modification of NDMA-induced DNA damage was absent in rats pretreated with glutathione reduced form (GSH) and dimethyl sulfoxide (DMSO). Allyl disulfide (ADS), L-cysteine (CYS), N-acetylcysteine (NAC), alpha-mercaptopropionylglycine (MPG), ethylxanthic acid (PEX), and 2-mercaptoethane sulfonic acid (MESNA) increased in various degree the frequency of DNA-strand breaks. In subsequent experiments the protective activity of DSF was found to be dose-related, dependent on the time of administration, and greater by oral route. Taken as a whole, these results suggest that several putative anticarcinogens might be ineffective against the DNA-damage produced by the low doses encountered in human exposure.
Administration, Oral↗
Grain counting in the in vitro hepatocyte DNA-repair assay.
The in vitro hepatocyte DNA-repair assay is a widely used useful method in assessing the genotoxic activity of both directly and indirectly acting chemical agents. This article discusses the criteria presently employed in the autoradiographic evaluation of unscheduled DNA synthesis, and suggests that the subtraction of either the average or the highest cytoplasmic grain count, usually carried out to obtain the net nuclear grain count, may represent a potential source of errors when the test compound is a weakly genotoxic or a non-genotoxic agent. As a matter of fact, a response can be classified as positive or negative depending on the procedure used to quantitate the cytoplasmic background, and the subtraction of this background from the nuclear count is not founded on a sound theoretical basis because of the following reasons: the different nature of the processes responsible for the generation of nuclear and cytoplasmic grains; and the quantitatively different effect that the test compounds may have on the nuclear and the cytosolic labelling.
Animals↗
In vitro and in vivo evaluation of the genotoxicity of N-nitrosooxprenolol.
N-nitrosooxprenolol (NO-oxprenolol) might be formed in the stomach of patients taking the beta-adrenergic blocking drug, oxprenolol. This nitroso derivative has previously been shown to induce DNA damage and repair in both rat and human cultured hepatocytes. The results of the present study show that in the presence of co-cultured rat hepatocytes, 0.03 mM NO-oxprenolol produced a significant increase in the frequency of 6-thioguanine-resistant but not of ouabain-resistant mutants. No mutagenic activity was detected in the absence of metabolic activation. In mice, NO-oxprenolol (1 g/kg) increased the incidence of micronucleated cells in the liver but not in the bone marrow and the spleen. These results suggest that NO-oxprenolol, consistent with its chemical nature of nitrosamine, is biotransformed into short-lived reactive species.
Animals↗
Health aspects of the use of beta-2 adrenergic drugs in animal production.
In the zootechnical field, there is a strong need to correlate analytical results with biological effects of beta-2 adrenergic agonist drugs on animal health, food processing and human toxicology, taking into account the peculiarity of their administration (long-term treatments with doses tenfold as high as the therapeutical ones). The opportunity to use ELISA tests to readily detect illegal treatments, suspected on the basis of clinical and inspective data, can allow appropriate preventive medicine action by monitoring the food chain during its early steps (in living animals). Sanitary implications will not be limited only to serious clinical signs confirmed by analyses, but should also lead to educational programmes intended for farmers, showing them the main obvious risks in animal production associated with beta-2 agonist side-effects.
Adrenergic beta-Agonists↗
Surgical treatment of symptomatic giant hemangiomas of the liver.
Cavernous hemangiomas are the most common benign tumors of the liver. Twenty-four patients who had hepatic resections for giant symptomatic hepatic hemangiomas during a six year period at a single institute were retrospectively reviewed to analyze indications for surgical treatment and evaluate operative mortality and morbidity. There were 18 women and six men varying in age from 41 to 69 years with an average age of 52.5 years. Moderate to severe pain, discomfort, feeling of fullness, bloating and sensation of an abdominal mass were the most commonly reported symptoms. Ten patients had moderate anemia and two had severe anemia. Tumors were visualized by ultrasonography in all patients and by computed tomography in 18. Angiography was performed in all patients with diagnostic confirmation of a benign hemangioma in all but one patient in whom an angiosarcoma was suspected. The resection was feasible in each patient: 20 minor hepatic resections (three wedge, 11 segmentectomies, six bisegmentectomies) and four right hepatic lobectomies were carried out. There were no surgical deaths. Two patients had postoperative complications: one patient had a pneumonia on the right side and one had wound infection. The benign nature of the tumors was confirmed in all. The lesions varied in size from 5.6 to 26 centimeters in diameter. Symptoms and hematologic disorders were relieved in all patients in the follow-up. The results of our experience confirm that resection for giant symptomatic hepatic hemangioma represents a safe radical curative procedure. Medical treatment is justified in smaller lesions or in asymptomatic patients.
Female↗
Formation of the N-nitroso derivatives of six beta-adrenergic-blocking agents and their genotoxic effects in rat and human hepatocytes.
Six beta-adrenergic-blocking drugs, atenolol, metoprolol, nadolol, oxprenolol, propranolol and sotalol, were found to react with sodium nitrite in HCl solution, yielding the corresponding N-nitrosamines. The genotoxic activity of the six nitrosamines was evaluated in primary cultures of both rat and human hepatocytes; DNA fragmentation was measured by the alkaline elution technique, and DNA repair synthesis by quantitative autoradiography. Positive dose-related responses were produced in cells of both species after 20 h of exposure to the following subtoxic concentrations: NO-propranolol, 0.01-0.1 mM; NO-oxprenolol, 0.03-1 mM; NO-atenolol and NO-metoprolol, 0.1-1 mM; and NO-nadolol and NO-sotalol, 0.3-3 mM. Modest but statistically significant differences between the DNA-damaging potencies for the two species were observed with NO-atenolol and NO-oxprenolol, which were both more active against rat hepatocytes, and with NO-propranolol, which was more active against human hepatocytes. At equal or higher concentrations, the six N-nitrosamines did not produce DNA fragmentation in Chinese hamster lung V79 cells; this indicates that they behave as indirectly acting compounds, which need to be transformed into reactive metabolites in order to exert a genotoxic effect.
Adrenergic beta-Antagonists↗
Biliary complications in orthotopic liver transplantation: experience with a modified technique of duct-to-duct reconstruction.
Biliary complications are described as frequent causes of morbidity during the postoperative course of orthotopic liver transplantation (OLTx), even in recent papers. The authors report here on their experience with duct-to-duct anastomosis as their method of choice for biliary reconstruction in a consecutive series of 100 OLTx in adult patients. The original technique, as described by Starzl, was modified by the authors by performing a wide, longitudinal plasty of both the donor and recipient bile ducts, joined together with two polidioxanone running sutures, producing the effect of a side-to-side anastomosis. This technique was used in all procedures, even when a significant discrepancy was evident between the ducts (n = 10). Follow-up was completed in 100% of the patients for a period of 2-40 months (mean 13.1 months). Four major complications (4%) occurred including hepatic abscesses due to ascending cholangitis, T-tube dislocation, partial occlusion by a branch of the T-tube at the anastomotic site, and disruption of the bile duct after T-tube removal. In four other patients, transient abdominal pain followed removal of the stent. Neither strictures nor fistulas were observed. Choledochocholedochostomy on a T-tube stent represents, in our experience, the technique of choice for biliary reconstruction in OLTx. The procedure, as described in the present study, proved to be safe in preventing strictures and leakages and appears to be feasible in nearly 100% of all adult patients undergoing OLTx.
Adult↗
Genotoxicity testing of chloramphenicol in rodent and human cells.
The results of this work, carried out to extend the limited information at present available on the genotoxic potential of chloramphenicol (CAP), indicate that in millimolar concentrations this antibacterial agent produced a minimal amount of DNA fragmentation in both V79 cells and metabolically competent rat hepatocytes. Moreover, a level of DNA-repair synthesis indicative of a weak but positive response was detected in primary cultures of liver cells obtained from 2 of 3 human donors, and a borderline degree of repair was present in those prepared from rats. The promutagenic character of CAP-induced DNA lesions was confirmed by a low but significant increase in the frequency of 6-thioguanine-resistant clones of V79 cells, which, however, was absent when the exposure was done in the presence of co-cultured rat hepatocytes. Finally, oral administration to rats of 1/2 LD50 CAP did not increase the incidence of either micronucleated polychromatic erythrocytes or micronucleated hepatocytes. Taken as a whole these findings suggest that CAP should be considered a compound intrinsically capable of producing a very weak genotoxic effect, but only at concentrations about 25 times higher than those occurring in patients treated with maximal therapeutic dosages.
Animals↗