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Biomedical subjects

T Colombo

Publications and source records attributed to T Colombo.

At least 91 records · Page 5Linked to original sources
PubMed1985

[Replacement of the mitral and aortic valves with bioprostheses. Long-term results].

The purpose of the study was to analyze the medium-term results (late mortality, thromboembolism, valve failure) in patients who underwent bioprosthetic valve replacement at "A. De Gasperis" Cardiovascular Surgery Division. From October 1975 to December 1982, 195 patients were consecutively operated on and discharged (118 with mitral prosthesis, 54 with aortic prosthesis, 22 with mitral and aortic prosthesis, 1 with mitral and tricuspid prosthesis). We reviewed 115 (97.45%) of 118 patients with mitral prosthesis (mean follow-up 46.61 months) and 54 (100%) patients with aortic prosthesis (mean follow-up 38 months). Eleven late deaths (2.4%/pt-yr) and 13 thromboembolic events (2.8%/pt-yr) occurred in patients with mitral prosthesis, 6 late deaths (3.5%/pt-yr) and 5 thromboembolic events (2.9%/pt-yr) occurred in patients with aortic prosthesis. Actuarial survival curves and actuarial incidence of thromboembolic event-free patients at 5 years are, respectively, 91.2% and 87.3% in patients with mitral prosthesis, 82.8% and 86.3% in patients with aortic prosthesis. The risk factors for thromboembolism were analyzed. Reoperation was requested in 14 cases (10 mitral and 4 aortic prostheses) for prosthetic leak (6 patients) or valve failure (8 patients). In linearized terms, the rate of valve failure requiring reoperation is 1.3%/pt-yr for mitral prostheses and 1.1%/pt-yr for aortic prostheses. The medium-term results suggest that the bioprostheses are, at the present time, an effective choice to the mechanical prostheses, nevertheless they are not free from risks of thromboembolic complications.

Adolescent↗
PubMed1984

Biochemical studies on the ability of pentamethylmelamine to interact in vivo with DNA and proteins in a sensitive murine ovarian reticular cell sarcoma.

The metabolism of 14C-PMM and its irreversible interaction with DNA and proteins were studied in M5076/73A reticular cell sarcoma, a murine solid tumor previously shown to be sensitive to the drug. Metabolism and irreversible binding were determined 0.25, 1, 8 and 104 hours after a single i.p. injection of radiolabelled PMM, tumor and liver macromolecular binding were compared with two differently 14C-labelled PMM, i.e. ring- and methyl-PMM. Ring-PMM derived macromolecular binding appeared to have more relevance in vivo and had a similar time profile in both liver and tumor. Ring-PMM derived DNA binding was then related to metabolic steps between PMM and 2,2,4,6 TMM and 2,2,4,6 TMM itself and 2,4,6 TriMM.

Altretamine↗
PubMed1984

Comparison of the antitumor activity of DTIC and 1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt on murine transplantable tumors and their hematological toxicity.

This study describes a comparison of 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazeno) (DTIC) with reference to antitumor activity on different murine tumors and hematological toxicity. DM-COOK appeared comparably or slightly more effective in L1210, P388, and M5 tumors in the mouse. However, when the treatment of mice bearing M5 with DM-COOK was combined with surgical removal of the primary tumor, the host's life-span was highly significantly prolonged. The two drugs showed similar activity in an M5 variant selected for resistance to cyclophosphamide. In L1210 Ha, a leukemia that is spontaneously resistant to DTIC, DM-COOK was not effective. Both DM-COOK and DTIC caused transient leukopenia with a maximum WBC fall of 57% and 71% compared with control values. DM-COOK's greater chemical stability might be an advantage, as the decomposition of DTIC is thought to lead to products responsible for some toxic effects in humans. Like other phenyldimethyltriazenes DM-COOK, is a good candidate for clinical trials because its water solubility eliminates formulation problems.

Animals↗
PubMed1984

Activity and distribution of iv and oral 4-demethoxydaunorubicin in murine experimental tumors.

The antitumor activity of 4-demethoxydaunorubicin ( 4DDM ) compared to its parent compound daunorubicin (DM) was investigated in C57BL/6 mice bearing a T-cell lymphoma, the EL-4, chosen because of its sensitivity to this compound. 4DDM was moderately effective against Lewis lung carcinoma and M5076 ovarian reticulosarcoma tumor systems. Against the EL-4 tumor, after either iv or oral treatment, 4DDM had a good therapeutic effect (survival time in treated mice was almost double that in untreated mice) which was comparable to that of iv doxorubicin. Serum and tissue distribution of 4DDM and its reduced metabolite 4- demethoxydaunorubicinol , given either iv or orally at therapeutic doses to EL-4-bearing mice, was then compared with iv DM using a high-performance liquid chromatography technique with fluorimetric detection. DM seemed to be cleared faster and to a greater extent by metabolism than 4DDM , with half-lives after iv treatment of 23 hrs for 4DDM versus 4.6 hrs for DM. The reduced metabolite in serum amounted to greater than 100% of the concentration of the native compound for DM and less than 20% for 4DDM . By both the iv and oral routes, 4DDM appeared to be concentrated and retained in tissues to a proportionally higher extent than DM, with drug exposure being at least twice as high with correspondingly longer half-lives in almost all tissues investigated, including the tumor. Moreover, this demethoxy analog appeared to be somewhat more selective than DM, since the relative capacity of the tumor tissue to accumulate this compound seemed higher than that of other organs (eg, heart and spleen) reported to be targets of toxicity. Oral administration gave more favorable distribution, resulting in the highest tumor to heart and spleen concentration ratio; this suggests a superiority of this route of administration.

Administration, Oral↗
PubMed1983

Flow-cytometric analysis of DNA distribution after VP16-213 treatment of Lewis lung carcinoma.

The two dosage schedules of VP16 that gave the least and the greatest efficacy in Lewis lung carcinoma of the mouse were selected for evaluation of the cytokinetic effects observable in vivo at different intervals after treatment (schedule A: 40 mg/kg IV, on day 8 after transplant; schedule B: 13 mg/kg IV, repeated on days 8, 11, and 14 after transplant). After the single dose and after each repeated dose there was a marked increase in the percentage of cells in the LS-G2-M phases, with a corresponding decrease in the percentage of cells in G0-G1. The number of neoplastic tetraploid cells compared with normal diploid cells in the tumor was reduced after the single IV dose, and more markedly so after repeated doses. This study suggests that the more marked delay of cancer cell growth and greater effectiveness observed with schedule B is related to repeated blockage of the LS-G2-M phases.

Animals↗
PubMed1983

Distribution, metabolism, and irreversible binding of hexamethylmelamine in mice bearing ovarian carcinoma.

The covalent binding of hexamethylmelamine (HMM) and its metabolites was studied in liver, tumor, blood, kidney, spleen, lung, brain, heart, and small intestine after a single IP injection of 2,4,6-14C-hexamethylmelamine (50 mg/kg) to C57Bl/6J female mice bearing 20-day-old M5076/73A ovarian cancer. Covalent binding to tissue macromolecules was measured 2, 10, and 40 h after injection of the drug. At 2 h liver and small intestine showed the highest levels of irreversibly bound metabolites, the lowest being found in brain and heart. Except in the small intestine, where a decrease was observed between 2 and 10 h, the level of covalent binding was constant up to 40 h. HMM metabolism was also studied. Tissue distribution of pentamethylmelamine (PMM), 2,2,4,6-tetramethylmelamine (TMM), and 2,4,6-trimethylmelamine (TriMM) was determined at the three times considered. At 2 h the drug was already extensively metabolized, TriMM being the major metabolite among those determined.

Altretamine↗
PubMed1983

Influence of adriamycin on growth kinetics of Lewis lung carcinoma and its lung metastases.

Using a Gompertzian pharmacodynamic model, we have studied the changes induced by graded doses of adriamycin (AM) on the growth of intramuscular Lewis lung carcinoma (3LL) and its lung metastases in C57Bl/6 mice. An interpretation of the drug's effects on free growth of the tumor cells is given in the Appendix. Unlike other tumors (1-6), in which AM treatment induces no long-term change in growth parameters, in the 3LL model after an initial phase of inhibited growth following treatment with AM, the theoretically attainable plateau value is lowered. This is dose dependent for the primary tumor and even more so for metastases. In order to investigate whether the drug effect was irreversible or whether the host's weakened condition was a factor in the altered growth conditions, the tumor and its metastases were removed from AM-treated mice and transplanted in healthy animals in which its growth was then observed over time. For transplants of the primary intramuscular tumor no differences could be seen between treated and nontreated mice, but for the metastases the growth was markedly slowed. However, after a 'lag' period, the tumors arising from metastases returned to a growth pattern whose kinetic parameters, analyzed statistically, were not different from controls.

Animals↗
PubMed1983

Activity and pharmacokinetics of teniposide in Lewis lung carcinoma-bearing mice.

The antitumor activity of teniposide (VM26) was investigated in Lewis lung carcinoma (3LL) of the mouse after a single dose of 20 mg/kg iv (given 8 or 14 days after tumor transplant) or after three doses of 6.5 mg/kg iv (given on Days 8, 11, and 14 after tumor transplant) (total dose, 19.5 mg/kg). The single dose resulted in only 25% primary tumor reduction but had marked antimetastatic activity. The repeated doses (6.5 mg/kg x 3) were much more effective, with 85% primary tumor reduction and the apparent disappearance of all metastatic deposits. The pharmacokinetics of VM26 was investigated in 3LL-bearing mice by a high-performance liquid chromatographic assay. At both of the above doses VM26 disappeared from mouse plasma biphasically, with an elimination half-life of about 70 mins. The concentrations in metastases were higher than in primary tumor, where very low levels were found. The highest VM26 levels were found in liver, small intestine, and kidney, and the lowest levels were found in the brain. Excretion of VM26 in urine amounted to less than 5% of the dose.

Animals↗
PubMed1982

Studies of the mode of action of antitumour triazenes and triazines-III. Metabolism studies on hexamethylmelamine.

These is good evidence that the antitumour agent hexamethylmelamine (HMM) undergoes oxidative metabolic activation which might occur in the liver and/or extrahepatically. The hepatic microsomal N-methylmelamine metabolizing enzymes were investigated in mice and exhibited different affinities for different melamine derivatives. The apparent Km values are 0.09 mM for HMM, 0.23 mM for pentamethylmelamine, 0.91 mM for 2,2,4,6-tetramethylmelamine and 1.7 mM for trimethylmelamine. HMM inhibited its own metabolism in vitro at substrate concentrations greater than 0.05 mM. Its hepatic microsomal N-demethylation rate was reduced when the mice were pretreated with the hepatic glutathione depleting agent methyliodide. Injection of hexaethylmelamine, a derivative of HMM without antineoplastic properties against the M5076 sarcoma in mice, lead to plasma concentrations of drug and metabolite pentaethylmelamine which were only a fraction of the drug and metabolite levels achieved after a similar dose of HMM.

Altretamine↗
PubMed1982

Pharmacokinetics of VP16-213 in Lewis lung carcinoma bearing mice.

The pharmacokinetics of VP16 have been investigated in Lewis lung bearing mice after i.v. doses of 13 and 40 mg/kg. At both doses the plasma elimination of half-life was around 30 min. The lowest VP16-213 levels were in brain and primary tumor. Drug concentrations were much higher in metastases than in primary tumor. The highest concentrations were in small intestine, liver and kidney. Drug levels in the liver were disproportionally higher after 40 mg/kg, and AUC value being approximately 12 times greater than after 13 mg/kg. Urinary excretion of VP16-213 as unchanged drug accounted for 20-30% of the administrated dose in the 60 h after treatment. The concentration cytotoxicity curve was very steep and apparently similar for cells derived from primary tumor or metastases grown in vitro.

Animals↗
PubMed1982

Routes of elimination of hexamethylmelamine and pentamethylmelamine in the rat.

1. In the rat 40% of a dose of 25 mg/kg of hexamethylmelamine or pentamethylmelamine was excreted in the urine as metabolites, more than 95% of which were N2N4-dimethylmelamine and monomethylmelamine. 2. Biliary excretion of hexamethylmelamine or pentamethylmelamine and their N-demethylated metabolites accounted for less than 2% of the administered dose. Only 0 X 3% was excreted with the faeces, suggesting that there is intestinal reabsorption of a portion of the methylmelamines passing into the bile. 3. Conjugates of methylmelamines with glucuronic acid or sulphate were found only in minute quantities in the urine or bile of rats treated with hexamethylmelamine or pentamethylmelamine. However a conjugation product of pentamethylmelamine, of as yet unknown nature, is a major metabolite after pentamethylmelamine treatment.

Altretamine↗
PubMed1982

Activity of 1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt in M 5076/73A ovarian reticular cell sarcoma of the mouse.

1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt (DM-COOK) was tested on M 5076/73A (M5) mouse sarcoma at a dose of 40 or 50 mg/kg/day (Days 6--14) after im transplant of 7 x 10(5) cells, with or without surgical removal of the primary tumor on Day 14. Treatment at either dose level resulted in reduction of the primary tumor weight to around 50% of that in the controls, and striking antimetastatic effects were observed. When a dose of 40 or 50 mg/kg of DM-COOK was followed by surgery, there were 14% and 40% long-term survivors, respectively, but the higher dose caused about 30% toxic deaths. After iv injection of 10(3) or 10(5) M5 tumor cells, no artificial metastases appeared in DM-COOK-treated mice, whereas all control animals had metastatic involvement in the liver, spleen, ovaries, and kidneys.

Animals↗
PubMed1982

Hexamethylmelamine and pentamethylmelamine tissue distribution in M5076/73A ovarian cancer-bearing mice.

The distribution of hexamethylmelamine (HMM), pentamethylmelamine (PMM), and their metabolites N2,N2,N4,N6-tetramethylmelamine (TMM) and N2,N4,N6-trimethylmelamine (TriMM) was investigated in different tissues of M5076/73A ovarian cancer-bearing mice given 100 mg/kg ip of either drug. The area-under-the-curve (AUC) values of HMM and PMM, expressed in microgram/g x min after these drug treatments, were 2432 and 1296 in tumor, 6290 and 8141 in liver, 9779 and 21,294 in spleen, 6840 and 10,800 in kidney, 4003 and 4295 in heart, 1569 and 1327 in brain, 163,689 and 50,809 in adipose tissue, 88,725 and 45,070 in lymph nodes, 15,033 and 18,992 in small intestine, and 393 and 351 in plasma, respectively. The elimination rate of HMM for the different organs was similar, with a half-life of 37-48 mins; PMM disappeared with more variability, the half-life being 19-46 mins. While TMM concentrations were not very different from those of HMM or PMM, TriMM was much higher in all organs evaluated, particularly the brain, where AUC values were 21-24 times those of the administered drug.

Altretamine↗
PubMed1982

Results of valve replacement surgery with mechanical prostheses.

The clinical study is reported of the results of heart valve replacement surgery with a new pyrolytic carbon tilting disc prosthesis manufactured in Italy. From March 1977 to January 1981, at the "De Gasperis" Cardiosurgery Center, this prosthesis has been implanted in 644 patients: 283 for mitral valve replacement, 240 for aortic valve replacement, and 121 for the replacement of both mitral and aortic valves. To have a sufficiently long period of post-surgery follow-up, we considered the results of 207 patients (124 cases of isolated mitral valve replacement and 83 cases of isolated aortic valve replacement), who underwent surgery consecutively from March 1977 to December 1979. The hospital mortality was 10.5% for mitral valve replacement and 4.8% for aortic valve replacement. All patients who were discharged from hospital, except 2, were subjected to clinical, electrocardiographic, phonocardiographic, echocardiographic and radiological checks. The average follow-up period was approximately 20 months: clinical results were satisfactory. The probability of survival, expressed by actuarial curve, was, three years after surgery, 94% for patients who underwent mitral valve replacement and 97.5% for those who underwent aortic valve replacement. The probability of embolism was, three years after surgery, 8.5% for patients with mitral replaced and 5% for aortic. Even if further confirmations are needed the mortality rate and the probability of embolism related to this new prosthesis, are lower, over the same period of follow-up, than that found in the groups of patients who underwent valve replacement surgery, at the same Center, with Starr-Edwards and Björk-Shiley prostheses. The phonocardiographic and echocardiographic characteristics of this new prosthesis were also investigated.

Adolescent↗
PubMed1982

[Discrete subaortic stenosis. Considerations on 64 cases surgically treated].

The AA. reviewed our experience concerning 64 patients operated on for discrete subaortic stenosis due to a fibrous membrane, between 1975 and 1981 at the Department on Cardiac Surgery "A. De Gasperis" in Milan. The clinical and hemodynamic features, the indication for operation, the surgical management and the immediate and long-term results are described. No patients died at surgery or afterwards. Only in three cases complications were noted (2 atrioventricular block, 1 pleural empyema). Of all the patients 95% were asymptomatic after operation; only three cases presented symptoms correlated with the cardiac malformation, but still they were greatly improved, compared to their preoperative status. As discrete subaortic stenosis is a progressive disorder, the operative risk is poor and the results are good, surgical treatment is recommended in symptomatic patients and if the haemodynamic gradient is 50 mmHg or greater.

Adolescent↗
PubMed1982

[Ventricular septal defect associated with aortic insufficiency: observations on 40 patients surgically treated].

Since 1970, forty patients with ventricular septal defect (VSD) and aortic insufficiency (AI) have undergone surgical treatment in our institution. In the majority of the patients (60%) the VSD was subcristal. In sixteen cases the aortic valve was replaced, whereas in 9 patients the valve was repaired and in 15 subjects simple closure of the VSD was deemed to be sufficient to correct the AI. There have been 2 hospital and 4 late deaths. The A.I. seems to be due to two different pathogenetic mechanisms in supra- and subcristal V.S.D., with the faster progression in the supracristal ones. With simple patch closure of the V.S.D. we had the best late results, good results were obtained with the plasty of the aortic leaflets while the worst late results were found in the group which had undergone aortic valve replacement. For this reason the Authors recommend surgical intervention as soon as AI shows up.

Adolescent↗
PubMed1981

Dose-dependent pharmacokinetics of PMM in the rat.

Concentrations of pentamethylmelamine (PMM) and some metabolites were determined in plasma of rats treated with 10 and 50 mg PMM/kg IV. The areas under the plasma levels curve after these doses were 241 and 1,827 mu g/ml X min; plasma clearances were 0.042 and 0.027 l . kg(-1) . min(-1), respectively. These data suggest that PMM pharmacokinetics is dose-dependent in the rat. The N-demethylated metabolite levels were not proportional to the administered dose.

Altretamine↗