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Biomedical subjects

A Zaccara

Publications and source records attributed to A Zaccara.

51 records · Page 3Linked to original sources
PubMed1981

A differential interaction of doxorubicin and daunorubicin with human serum proteins.

The results of a comparative investigation on the interaction of doxorubicin (adriamycin) and daunorubicin with serum proteins are reported. Whereas a strong interaction occurs in vitro between doxorubicin and human serum proteins, no appreciable binding to proteins could be detected for daunorubicin under similar experimental conditions. Since the protein-bound drug is only partially dissociated by physical procedures including gel-electrophoresis, column-chromatography and solvent extraction, the formation of a covalent bond is suggested. The doxorubicin binding to serum proteins is apparently nonselective for a class of proteins; it is strongly reduced in acid conditions and slightly dependent on the ionic strength. Two tentative reaction mechanisms have been considered.

Blood Proteins↗
PubMed1980

The interaction of daunorubicin and doxorubicin with DNA and chromatin.

Isotherms that describe the binding of anthracycline antibiotics (including daunorubicin and doxorubicin (adriamycin)) to calf thymus DNA and chromatin have been obtained by means of fluorescence measurements. As expected for charged ligands, the association constants for the interaction of all drugs examined with DNA were found to be dependent on the ionic strength. However, in the case of the daunorubicin-DNA interaction, a marked decrease in the number of binding sites was also observed when the ionic strength was increased. It is suggested that the effect of salt concentration on the number of potential binding sites of daunorubicin molecules to DNA may be the result of some salt-induced alterations in the DNA conformation. This interpretation is also supported by binding data obtained with calf thymus chromatin; Whereas at low salt concentration the binding parameters for the doxorubicin-chromatin interaction are similar to those expected by neutralization of the phosphate groups by histones, modifications of the DNA structure in chromatin are invoked to account for the reduction and heterogeneity of daunorubicin binding sites. The side chain at C-9 could play an important role in determining the strength and specificity of the anthracycline-DNA interaction.

Animals↗
PubMed1979

Molecular structural effects involved in the interaction of anthracyclines with DNA.

Changes in DNA binding ability of daunomycin following structural modifications in the aglycone moiety have been studied by the fluorescence quenching method and by thermal denaturation of the complex. Removal of the methoxyl group at position 4 leads to a slightly stronger binding. Changes in the position of the glycosidic linkage result in a markedly weaker binding. Removal of the hydroxyl group at position 9, with the concomitant formation of a 9,10-anhydro derivative, decreases the binding ability. Methylation of hydroxyl groups at C-6 and C-11 leads to an inactive derivative and makes the binding affinity disappear almost completely. Structure-activity correlations for the DNA binding reaction deduced from these studies are in agreement with earlier findings that relate to the biological activity and confirm the general picture of the binding mechanism.

Anthracenes↗
PubMed1977

The interaction of adriamycin and its beta anomer with DNA.

The results of thermal denaturation, fluorescence, calorimetric and viscosimetric studies on the interaction of adriamycin and its beta anomer with DNA are reported. Whereas all equilibrium, hydrodynamic and thermodynamic measurements are consistent with the proposed intercalative binding model for the adriamycin-DNA complex, the binding mechanism for the reaction of the beta anomer with DNA remains uncertaian. All DNA binding properties of this stereoisomer are substantially different from those of the parent compound. The results suggest that the amino sugar residue of the natural antibiotic may interact stero-specifically with the DNA helix, thus dictating the orientation of the tetracvclic chromophore within the intercalation site. The alteration in the DNA binding capacity and the changes in interactions with DNA following in inversion of configuration at C-1', parallel a lack of biological activity observed for the beta anomer.

Binding Sites↗
PubMed1977

Changes of activity of daunorubicin, adriamycin and stereoisomers following the introduction or removal of hydroxyl groups in the amino sugar moiety.

The results of a study of the effects of hydroxyl groups at positions, 2, 4 and 6 of the amino sugar on the activity of daunorubicin, adriamycin, and stereoisomers are presented. While the 4'-deoxy derivatives showed a slightly increased biological activity as compared with the parent compounds, the derivatives containing an additional hydroxyl group were less active. It is suggested that the changes in the polarity and in the DNA binding ability of these derivatives are the main factors accounting for the difference in the in vivo activity. The possible relations among the pKa values, the DNA binding properties, and the cellular uptake of the compounds are discussed with particular reference to their therapeutic effectiveness.

Animals↗
PubMed1975

DNA polymerases of rat liver. Partial characterization and effect of various inhibitors.

Three distinct DNA-dependent DNA polymerase activities have been partially purified from normal rat liver. Soluble activities are separable into two distinct fractions (P1 and P2) by phosphocellulose chromatography. A low-molecular-weight DNA polymerase was isolated from purified nuclei. The enzymes were characterized according to chromatographic and sedimentation behavior, enzymological properties, and response to various inhibitors. The results indicate that fraction P1 corresponds to the high-molecular-weight enzyme and suggest that polymerase P2 may be derived from partial dissociation of the high-molecular-weight enzyme. The molecular weight of polymerase P1 was estimated to be about 250 000 by Sephadex column chromatography. Both fraction P2 and nuclear DNA polymerase appeared to be low-molecular-weight enzymes. However, the molecular size of these activities was apparently different. The estimated molecular weights of nuclear and P2 enzyme are about 40 000 and 25 000, respectively. As with the nuclear enzyme, polymerase P2 (but not P1) appeared to be free of detectable exonuclease activity. All of these polymerases showed a marked preference for initiated polydeoxyribonucleotide templates. The rat liver polymerases differed in their ability to use poly[d(A-T)-A1 primer-template, as is shown by the ratios of their activity with this synthetic polymer to that with activated DNA: 0.5, 2.75, and 1.34 for P1, P2, and nuclear polymerase, respectively. Denatured DNA was a poor template for both enzymes P1 and P2, but it was inert as template for the nuclear enzyme. Although each of these polymerases required all four deoxynucleoside triphosphates for maximal activity, they catalyzed a high rate of synthesis in the absence of one or more deoxynucleoside triphosphates. Such a 'limited' synthesis was much more extensive for polymerase P2 and nuclear enzyme than for P1 was the most sensitive of the three to sulphydryl reagents, ehtidium bromide, heparin, and single-stranded DNA. The responses of P2 and nuclear enzymes to various inhibitors were very similar. However, these two enzymes respond differently to heat and high ionic strength.

Animals↗
PubMed1975

A comparison of the effects of daunomycin and adriamycin on various DNA polymerases.

The effects of the anthracycline antiboties, daunomycin and adriamycin, on the DNA-directed activities of DNA polymerases from murine sarcoma virus, rat liver (high-molecular-weight species), Escherichia coli, and Micrococcus luteus were determined. Under all conditions tested, these compounds had greater inhibitory effect against the viral polymerase than against cellular polymerase. The inhibition of murine sarcoma virus DNA polymerase by daunomycin was competitive with respect to DNA. For viral DNA polymerase it was concluded that the inhibition was predominatly caused by the interaction of duanomycin with the primer-template DNA. Also, an appreciable reversal of the daunomycin-induced inhibition of this polymerase by an increase in Mg-2+ concentration is consistent with the conclusion derived by competition experiments. In contrast, the inhibition of both rat liver and M. luteus DNA polymerases was essentially noncompetitive with DNA. Also, bacterial enzymes wer e less sensitive to inhibition by these drugs than the virion polymerase. The strong and preferential inhibiton of viral DNA polymerase is discussed in relation to a differential sensitivity of normal as compared to tumor cells observed in some cell lines.

Animals↗
PubMedDate not supplied

Experience with a drug formulary in a large Italian city hospital.

The preparation and distribution of a drug formulary, providing some 377 pharmacological entities together with significant general information, in a large city hospital, enabled the collection of data on the pattern of drug use in this setting. Out of the 377 selected drugs, 27 were never used in the course of one year: most notable among these were the cephalosporin cephalothin, the antifungal griseofulvin, piperazine and the leading anti-H1-blocker terfenadine. Thirteen pharmaceutical preparations were used in over 50,000 doses; among these were the amiloride + hydrochlorothiazide combination, co-trimoxazole and lorazepam. Examination of specific drug series, e.g. of cephalosporins, showed a clear preference for the longer acting ceftriaxone versus a minor use for oral agents, e.g. cefadroxil. There was a wide choice of cardiovascular agents and a relative stability in the preference for major and minor antipsychotics. Outside of the formulary list, only a small number of preparations were requested, among these some traditional analgesic combinations and some extractive products. The provision of a hospital formulary may, in some way, modify drug choice in the hospital, although some established patterns of use are difficult to change. On the other hand, some interesting information was provided on the criteria of choice of hospital physicians.

Formularies, Hospital as Topic↗
PubMedDate not supplied

Fetal monolateral urinoma and neonatal renal function outcome in posterior urethral valves obstruction: the pop-off mechanism.

The "fetal urinoma" is a clinical and diagnostic entity due to urinary extravasation, early diagnosed in fetal and/or neonatal period. Both urinoma and urinary ascites, whose pathogenesis is not clear, are recognized associations of uterero-pelvic junction obstruction (UPJO) and neonatal posterior urethral valves (PUV) related with a protected fetal and neonatal renal function. Clinical and experimental studies have demonstrated that fetal urinary tract obstruction results in severe renal parenchymal injury. The so called "pop-off" valve mechanism has been advocated to justify the upper tract function preservation. Protective "pop-off" mechanisms, such as a unilateral reflux and dysplasia, urinary extravasation and congenital bladder diverticula are present in about 30% of patients with PUV. Their presence correlates with better overall long-term renal function. This mechanism has been justified as a sort of self derivation, to explain the renal function preservation in fetal and neonatal period. In the last two years we observed three cases of fetal monolateral urinoma, prenatally detected in fetuses with diagnosis of PUV. All three cases did well for that concerning renal function despite some current opinions suggesting the necessity of a bilateral urinary extravasation in order to preserve upper urinary tract function.

Female↗
PubMedDate not supplied

Impalpable testis and laparoscopy: when the gonad is not visualized.

The diagnostic accuracy of laparoscopy for impalpable testis is well recognized. However, in some cases, laparoscopic findings may be misleading, and a viable gonad may be missed with significant medico-legal implications. From January 1993 to December 2000, 202 patients with 219 impalpable testes were evaluated. In 95 cases, the gonad was immediately visualized, and in 5, the presence of a testis was documented by inserting the scope into the processus vaginalis. In the 119 remaining cases, no gonad was seen while entering the abdomen with the laparoscope. All patients with documented vas and vessels exiting the inguinal ring were surgically explored. Ten testes were found, 8 ectopic, with significant changes in shape and position, and 2 were canalicular. In the absence of hormone stimulation, no testes were found while exploring patients with cord structures coursing a closed inguinal ring and with contralateral hypertrophy. In 1 patient with absent vas and vessels, the testis was found at the lower renal pole while removing a dysplastic kidney. Despite technical refinements and an increase in clinical practice, a small percentage of viable testes may be missed with laparoscopic findings consistent with absent/vanished inguinal testis. Therefore, inguinal exploration is mandatory in all these cases.

Child↗