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Biomedical subjects

T Colombo

Publications and source records attributed to T Colombo.

At least 37 records · Page 2Linked to original sources
PubMed1986

Comparison between VP 16 and VM 26 in Lewis lung carcinoma of the mouse.

The antitumoral activity and pharmacokinetics of VP 16 and VM 26 were comparatively investigated in Lewis lung carcinoma (3LL)-bearing mice. When the two drugs were given at equitoxic doses, in single or repeated treatment, the superior antitumoral activity of VM 26 was clear. Compared to VP 16, VM 26 had a different pattern of distribution, with a larger volume of distribution, a longer elimination half-life time and a lower clearance. The tissue to plasma AUC ratios indicated that VM 26 concentrated more in tumor and heart while VP 16 gave highest concentrations in liver and intestine. Flow cytometry studies showed that VM 26 was more potent than VP 16 in causing cell cycle perturbation of 3LL cells growing in primary culture. VM 26 displayed cytotoxic activity at a concentration in the medium one-tenth that of VP 16. The uptake of VM 26 by 3LL cells was 15 times that of VP 16.

Animals↗
PubMed1985

Metabolic studies of a podophyllotoxin derivative (VP16) in the isolated perfused liver.

The metabolism of VP16 was studied in isolated perfused rat liver. The rate of elimination into the medium and excretion in bile were determined by h.p.l.c. with u.v. detection. With high VP16 concentrations (180 micrograms/ml medium), the elimination half-life of the compound was prolonged markedly (156 v. 45 min for lower doses), the percentage recovered in bile was more than halved and drug accumulation in the hepatic tissue was three times greater. These findings indicate saturation of metabolism and of biliary elimination during high-dose treatment. The presence of glucuronides in the bile of VP16 perfused livers indicates that VP16 undergoes conjugation with glucuronic acid. Formation of picro isomer of VP16 in the liver also occurs.

Animals↗
PubMed1985

[Reinterventions on cardiac valve prosthesis].

From January 1978 to December 1984, 214 patients underwent a total of 243 reoperations for repair or replacement of a prosthetic heart valve. On the basis of the number of valve reoperations in the same anatomic position within the heart, the patients were divided into three groups. Overall hospital mortality was 23.4% (CL 20.3-26.7) in Group I (214 patients), 48% (CL 36.1-60.1) in Group II (25 patients), 25% (CL 3.3-62.6) in Group III (4 patients). Hospital mortality appeared to be related to urgency of reoperation (p less than 0.001 in Group I; p = 0.037 in Group II), primary indication for reoperation (p = 0.034 in Group I; p = 0.022 in Group II), association with other cardiac surgical procedures (p = 0.00253 in Group I). Hospital mortality in Group I was significantly higher (p = 0.0056) when reoperation was performed within one year after valve replacement. No significant differences in urgency and emergency rate were noted between reoperations on mechanical heart valves and bioprostheses. No significant differences in bleeding complications were noted between reoperations and initial valve replacement. Mean follow-up is 37.4 +/- 21.8 months (range 2 to 85 months). Actuarial survival rate is 82.8 +/- 3.1% at 1 year, 78.7 +/- 3.5% at 2 years and 71.5 +/- 5.1% at 5 years; 90.9% (CL 87.4-93.6) of the followed patients are in I or II NYHA class. The results appear to suggest that when significant (on clinical or instrumental criteria) prosthetic disfunction is diagnosed, reoperation should be undertaken early to minimize operative risk. The Authors point out that surgery in such patients also ensures satisfying long-term results.

Follow-Up Studies↗
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↗
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↗
PubMed1978

The effect of outreach workers' services on the medical care utilization of a disadvantaged population.

An original goal of the Kaiser-Permanente Neighborhood Health Center Project was to organize the project so that a medically indigent population would be able to utilize fully and appropriately the services of a complex medical care program. A special program of outreach services was designed as the principal means to achieve this goal. This study was made to determine the effects of these outreach services on (1) the use of or nonuse of ambulatory care services; (2) the volume and type of services used; (3) the patterns of use; and (4) the appointment-keeping behavior of the project population for a 12-month period. Outreach and medical care services were provided to an average of 7,000 persons in 1,500 low-income families who were enrolled as health plan members in the Kaiser-Permanente Medical Care Program. Project participants were randomly divided into two groups, one with and one without services, and utilization data were collected from their medical and administrative records. The findings suggest that outreach intervention had a positive effect on access to care. Persons who received outreach services were more likely to contact the medical care system; these persons also showed a substantial difference in the volume of services they used, when compared to those without outreach services. Outreach workers were less successful in changing utilization patterns, although slight differences were found in the direction of more appropriate use. Persons with outreach services were more likely to have made contacts with their regular physician, to have made a smaller proportion of walk-in contacts, to have had a higher proportion of regularly scheduled contacts, and to have made a higher proportion of continuing visits. Outreach workers also had little or no effect on appointment-keeping behavior.

Adolescent↗
PubMed1978

Distribution and antitumor activity of adriamycin given in a high-dose and a repeated low-dose schedule to mice.

Experimental studies on the distribution of adriamycin (AM) under different treatment conditions and possible correlations between tissue and plasma levels and chemotherapeutic activity are discussed. C57BL/6J mice bearing im Lewis lung carcinoma and (C3H x O2O)F1 mice bearing mammary carcinoma were injected iv with AM at a single dose of 15 mg/kg or with the same total amount of drug administered in spaced doses of 3.75 mg/kg for 4 consecutive days. In the two experimental systems studied, the drug reached approximately the same value in the tumor and spleen with both types of treatment, but with the 3.75-mg/kg x 4 schedule much lower AM concentrations were observed in the heart than with the single high-dose treatment. The therapeutic activity of the two treatments also differed: the antitumor and antimetastatic effect was the same in the two tumor systems, but with the 3.75-mg/kg x 4 schedule, increased survival and somewhat lower toxicity were observed. Daunorubicin, tested in the mammary carcinoma system with the two schedules of treatment, behaves very similarly to AM in terms of both distribution and chemotherapeutic effect.

Animals↗
PubMed1977

Differential distribution of antitumor agents in primary and secondary tumors.

The differential distribution of a series of antineoplastic agents in metastatic tissues compared to their respective primary tumors has been investigated in one rat and two mouse experimental tumor systems, ie, the intramuscular Lewis lung carcinoma (3LL) of C57BL/6 mice, which gives rise to spontaneous lung metastases, the intratibial Sarcoma 180 (S180) of CD1 mice, which induces macroscopic metastases to the lymph nodes, and the Walker 256 carcinosarcoma of CD rats, which also metastasizes to the lymph nodes. The results described in this paper show that the concentrations of adriamycin, daunorubicin, cyclophosphamide and its alkylating metabolites, hydroxyurea, 1-methyl-1-nitrosourea, and 6-mercaptopurine are much higher in the pulmonary metastases of 3LL and/or in the lymph node metastases of S180 than the concentrations measured in the primary tumor. In the Walker 256 tumor system the distribution of adriamycin appears to follow the same pattern observed for the mouse tumors. Only for methotrexate (in the 3LL tumor) is the difference in the concentrations at the two sites not so evident. These findings are discussed in relation to the comparatively greater sensitivity of metastases to chemotherapy.

Animals↗
PubMed1976

Effect of phenobarbital on cyclophosphamide metabolism in rats.

1. The pharmacokinetics of cyclophosphamide and its alkylating metabolites have been studied in rats whose liver microsomal enzymes had been induced by phenobarbital pre-treatment. 2. Serum levels of cyclophosphamide were determined using a new g.l.c. method. The half-life of cyclophosphamide in blood of rats pre-treated with phenobarbital was shorter than in control rats. This change is closely related to higher rates of production of p-nitrobenzylpyridine-positive alkylating metabolites of cyclophosphamide, which in turn is followed by their more rapid disappearance from the circulation. 3. Urinary excretion reflects this situation; lower amounts of cyclophosphamide and higher concentrations of its alkylating metabolites are present in the urine of phenobarbital-treated rats. 4. Perfusion of livers isolated from phenobarbital-pre-treated rats confirmed the results in vivo. With this preparation, too, disappearance of cyclophosphamide was more rapid and formation of its alkylating metabolites was accelerated after phenobarbital treatment.

Alkylating Agents↗
PubMed1976

Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect.

Pharmacokinetic studies on cyclophosphamide (CP) and its alkylating metabolites produced by hepatic biotransformation have been performed in vivo in animals and in vitro in the perfused liver. CP levels were determined by a gas-chromatographic method combined with mass-spectrometry, and production of alkylating metabolites was assayed by the 4-(4-nitrobenzyl)pyridine reaction for alkylating compounds. Differenes in serum drug levels between normal rats and rats bearing Walker 256 carcinosarcoma were observed in vivo and were confirmed by the liver-perfusion technique. Pharmacokinetic parameters and enzyme kinetic data both in normal and in tumor-bearing animals will be presented. The disappearance of CP and the corresponding formation of CP metabolites was significantly modified when (a) CP was given after previous treatment with a compound which alters its biotransformation (ie, phenobarbital, an inducer of microsomal metabolism), (b) CP was given after previous treatment with CP (which inhibits microsomal metablism), or (c) CP was given with competitive substrates of aldehyde oxidase or dehydrogenase (glyceraldehyde, chloral hydrate, and disulfiram). Results obtained in animals or in the perfused liver will be discussed. The significance of this modified CP metabolism in influencing its cytotoxic effect will be discussed and correlations between drug levels and activity will be presented.

Animals↗