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Biomedical subjects

M Palumbo

Publications and source records attributed to M Palumbo.

At least 73 records · Page 4Linked to original sources
PubMed1997

Growth after recombinant human growth hormone (rhGH) treatment in transplanted thalassemic patients.

The aim of this study was to evaluate the treatment effects with recombinant human growth hormone (rhGH) in a group of patients after bone marrow transplantation for thalassemia major. At the end of treatment we divided the subjects into two groups according to the outcome of the therapy: responder and nonresponder. Responder group: after 24 months of rhGH administration, growth rate was still significantly higher in respect to start of treatment (P < 0.0001). Plasma levels of IGF-I rose significantly (P < 0.003). The serum levels of serum asparate aminotransferase (SGOT) and alanine aminotransferase (SGPT) were higher compared to normal values but improved in non-responder patients. There was no difference in the mean concentration of these parameters before and after treatment (P = NS). Non-responder group: these patients had a worsening of the growth rate during rhGH administration. There was no increase of the IGF-I levels. Single values of transaminase and ferritin levels were higher than in responder patients before and after treatment. There was a significant correlation between IGF-I, SGOT, SGPT and ferritin in all patients before and after therapy. It appears from these data that rhGH administration is worth serious consideration in patients after BMT for thalassemia major presenting impaired growth hormone secretion. This treatment can offer good results only in cases where the normal hepatic synthesis of IGF-I is conserved and where liver damage has not reached irreversible conditions, as we have seen in the responder group.

Adolescent↗
PubMed1997

Liquid-crystalline structure of nucleic acids: effect of antracycline drugs and copper ions.

The formation of liquid-crystalline dispersions (L.C.D.) from double-stranded DNA and polynucleotide (NA) molecules complexed with a number of anthracycline derivatives was investigated. These drugs form two types of complexes (complex I and complex II) with NA, which differ in the mode of drug orientation in respect to the NA helical axis. When complex II forms, addition of copper ions causes bridging of neighboring NA molecules through polymeric copper-anthracycline links (Figure 1). This results in an extra-increase in the amplitude of the intense CD band, characteristic for complex II, in the drug absorption region. Comparison of data obtained for different analogs and derivatives of daunomycin, has shown that the presence of 4 coordinating oxygen atoms at positions 5,6 and 11,12 (or 1,12) of the anthracycline ring system represents the basic prerequisite for the formation of a long polymeric chelate bridge after addition of copper ions. A second requirement relates to the chemical and stereochemical properties of sugar residues at position 7. These are important for proper positioning of the neighboring anthracycline aglycones in the polymeric chelate bridges and for spatial fixation of Cu2+ ions. Base sequence of double-stranded polynucleotides plays, if any, a minor role in polymeric chelate bridge formation. The question concerning the sterical orientation of two neighbouring antracyclines in the linking bridges, formed between NA molecules fixed in the liquid-crystalline structure, remains open.

Anthracyclines↗
PubMed1997

High dosage alpha-interferon for treatment of children and young adults with chronic hepatitis C disease.

BACKGROUND: There are limited data on the use of high interferon (IFN) dosage for treatment of children and young adults with hepatitis C virus infection and in those affected by thalassemia major (TM). OBJECTIVES: To assess the response of children and young adults with chronic hepatitis C disease, including those affected by TM, to high dose natural alpha-interferon (IFN-alpha). To evaluate the effect of iron overload in response to high dose IFN-alpha in young chronic hepatitis C virus thalassemia patients. METHODS: We conducted a therapeutic trial of natural IFN-alpha, using 10 million units/m2 three times a week for 6 months in 14 chronic hepatitis C patients ages 5 to 28 years; 7 also had TM. The follow-up period lasted 12 months. RESULTS: Ten patients (73%) showed normal or nearly normal alanine aminotransferase values at the end of follow-up (biochemical response), but only five (35%) were negative for serum hepatitis C virus-RNA (complete responders). Four of the patients (57%) with TM were sustained complete responders. No correlation was found between the initial serum concentration of ferritin and response to IFN therapy. Patients infected with genotype 1b showed a poor response although high dose of natural IFN was used. CONCLUSIONS: These results indicate that IFN-alpha can be used in children and young patients with chronic hepatitis C disease as well as in those affected by TM. Treatment with high dosage natural IFN-alpha in children and young adults with hepatitis C infection does not appear to be more effective than dosages previously used.

Adolescent↗
PubMed1997

Amido analogs of mitoxantrone: physico-chemical properties, molecular modeling, cellular effects and antineoplastic potential.

To assess the effects of amido substitution in the side-chains of the anticancer drug mitoxantrone (MX) two analogs were synthesized, having hydroxyethylaminoacetyl- and hydroxyethylaminopropionyl- substituents at the nitrogens located at positions 1, 4 of the anthracenedione ring system. The novel derivatives exhibit DNA-affinity and redox properties similar to the parent drug. However, unlike MX, they are not able to stimulate DNA cleavage, as shown by alkaline elution experiments. Molecular modeling studies using ab initio quantum mechanical methods show that, while the stereochemistry of the drug molecule is not appreciably affected when an amide group replaces the aromatic amino function, the reverse is true for the electrostatic properties. Indeed, overlapping of electron density of MX with its analogs is very poor. Moreover, a reversal in the direction of MX dipole moment occurs in the amido congeners. This may explain the lack of recognition of the cleavable topoisomerase II-DNA complex and loss of cleavage stimulation. However, the new derivatives exhibit pharmacological activity comparable to that found for MX, as they are remarkably cytotoxic and are active in vivo against P388 murine leukemia. Hence, amido substitution may lead to a different mechanism of cytotoxicity, not related to classical protein or free radical-mediated DNA damage, which points to a novel type of antineoplastic pharmacophore.

Animals↗
PubMed1996

Potent 6-desfluoro-8-methylquinolones as new lead compounds in antibacterial chemotherapy.

In a furtherance of our SAR study on the C-6 position of quinolone antibacterials, a series of 6-desfluoro-8-methylquinolones were synthesized and evaluated for their in vitro antimicrobial activity. As a result of this study, compounds with strong activity against Gram-positive bacteria, including ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus, were identified. The best Gram-positive antibacterial activity was exhibited by piperidinyl derivative 6c, which was 17 times more potent than ciprofloxacin and displayed extremely high activity against Streptococcus pneumoniae with an MIC value of <0.016 microg/mL. Thus, we have shown that substituent combinations in the quinolone ring, excluding the C-6 fluorine atom, might produce powerful antibacterial agents.

Anti-Bacterial Agents↗
PubMed1996

Peptidyl anthraquinones as potential antineoplastic drugs: synthesis, DNA binding, redox cycling, and biological activity.

A series of new compounds containing a 9,10-anthracenedione moiety and one or two peptide chains at position 1 and/or 4 have been synthesized. The amino acid residues introduced are glycine (Gly), lysine (Lys), and tryptophan (Trp), the latter two in both the L- and D-configurations. The peptidyl anthraquinones maintain the ability of intercalating efficiently into DNA, even though the orientation within the base-pair pocket may change somewhat with reference to the parent drugs mitoxantrone (MX) and ametantrone (AM). The interaction constants of the mono-, di-, and triglycyl derivatives are well comparable to those found for AM but 5-10 times lower than the value reported for MX. On the other hand, the glycyl-lysyl compounds bind DNA to the same extent as (L-isomer) or even better than (D-isomer) MX. As for the parent drugs without peptidyl chains, the new compounds prefer alternating CG binding sites, although to different extents. The bis-Gly-Lys derivatives are the least sensitive to base composition, which may be due to extensive aspecific charged interactions with the polynucleotide backbone. As far as redox properties are concerned, all peptidyl anthraquinones show a reduction potential very close to that of AM and 60-80 mV less negative than that of MX; hence, they can produce free-radical-damaging species to an extent similar to the parent drugs. The biological activity has been tested in human tumor and murine leukemia cell lines. Most of the test anthraquinones exhibit cytotoxic properties close to those of AM and considerably lower than those of MX. Stimulation of topoisomerase-mediated DNA cleavage is moderately present in representatives of the glycylanthraquinone family, whereas inhibition of the background cleavage occurs when Lys is present in the peptide chain. For most of the test anthraquinones, the toxicity data are in line with the DNA affinity scale and the topoisomerase II stimulation activity. However, in the lysyl derivatives, for which lack of cytotoxicity cannot be related to poor binding to DNA, the steric and electronic properties of the side-chain substituent must impair an effective recognition of the cleavable complex.

Animals↗
PubMed1996

Adjustable 'cross-linking' of neighboring DNA molecules in liquid-crystalline dispersions through (daunomycin-copper) polymeric chelate complexes.

The interaction of daunomycin molecules with double-stranded DNA in the liquid-crystalline state was investigated. It was shown that at a certain extent of daunomycin binding a change of the mechanism of anthracycline orientation with reference to the DNA chain occurs. This is testified by the alteration of the sense of spatial packing of the DNA molecules in liquid-crystalline dispersions formed as a result of phase separation in poly(ethyleneglycol)-containing solutions, as well as by the onset of the reaction of daunomycin with divalent copper ions. Using this reaction, polymeric (daunomycin-copper) chelate cross-links between the DNA molecules fixed in the liquid-crystalline dispersions were formed. The length of such cross-links as adjusted by the distance between the DNA molecules, which, in turn, depends on the concentration of poly(ethyleneglycol) used for phase separation. The above molecular building mechanism may lead to new interesting applications.

Animals↗
PubMed1996

Aza-bioisosteres of 9, 10-anthracenedione: a modulation of DNA sequence specificity.

The sequence specificity of DNA-binding by monoaza- and diaza-anthracenedione analogues of mitoxantrone (MX) has been investigated by DNase 1 footprinting and spectroscopic techniques. More than 100 sites cut by the enzyme were sequenced on three pBR 322 and simian virus 40 DNA restriction fragments. Different inhibition and stimulation effects were observed as a function of the structural properties of each drug. A gradual change was found from MX to monoaza derivatives and from these to diaza derivatives, corresponding to a broader distribution of drug-inhibited regions. In addition to almost all sites found with MX (38 of 44), 29 new inhibition sites were observed using the diaza compound BBR 2894. The sequence analyses in terms of base doublets or triplets confirm the preference of MX for alternating pyrimidine-purine sites, the most significant triplet sequences being (5' to 3') CTA, GCA, TAC, ACT, CAC and TTA. In addition to MX sites, BBR 2894 seemed to bind efficiently to pyrimidine-pyrimidine-pyrimidine or purine-pyrimidine-pyrimidine triplets containing CT or TC motifs. Differential cleavage plots essentially confirmed the above results. Spectrophotometric and chiroptical studies showed a decreased DNA-binding affinity and a modified geometry of intercalation when nitrogen replaces carbon in the anthraquinone ring. These results can be useful for understanding the substantially different biological responses exhibited by aza-substituted anthracenedlones when compared with their non-substituted, pharmacologically relevant congeners.

Anthraquinones↗
PubMed1995

Chromophore-modified antitumor anthracenediones: synthesis, DNA binding, and cytotoxic activity of 1,4-bis[(aminoalkyl)amino]benzo[g]-phthalazine-5,10-diones.

As part of a program aimed at exploring the effect of the introduction of heteroatoms into the anthracene-9,10-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)amino]-benzo[g]phthalazine-5,10-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[g]phthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,10-dihydroxybenzo[g]phthalazine-1,4-dione (8). The 1-[(aminoalkyl)amino]-4-amino congeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo[g]phthalazine-5,10-diones 1 and 2 exhibited cytotoxic activity comparable or even superior to that of mitoxantrone. In compounds 1, structure-activity relationships different than those operative in the carbocyclic series appeared to emerge. DNA-binding studies with the ametantrone-like compound 1c and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,10-dione chromophore reduces the affinity of the drug for DNA in comparison with ametantrone. On the other hand, the number of side-chain groups does not affect binding to a great extent. These findings seem to suggest mechanisms of cell death other than those induced by simple interaction of the 1,4-BPDs 1 and 2 with DNA.

Cell Survival↗
PubMed1995

Continuous mitoxantrone infusion in pretreated epithelial ovarian cancer.

Mitoxantrone has shown moderate activity in advanced epithelial ovarian cancer following intermittent i.v. administration. Experiments and clinical data suggest that long-term continuous drug infusion may achieve a better therapeutic result with less toxicity. This hypothesis was tested in patients with advanced ovarian cancer who had been pretreated with other agents. Mitoxantrone was infused continuously in 21-day courses beginning every 6 weeks. If severe toxicity did not occur, the infusion rate was increased by 0.1-0.2 mg/m2 per day. The mitoxantrone solution proved to be stable over the 21-day infusion period. For ethical reasons an optimal two-stage design was employed. The trial was interrupted at the end of the first recruitment stage because the target of 3 responses out of 13 patients had not been achieved (only 1 patient had a partial response). Hematologic toxicity was observed in 11 patients, and 2 of them had a catheter occlusion. In conclusion, we found that 21-day of infusion of mitoxantrone apparently has no clinical benefit as compared with bolus administration in patients with advanced ovarian cancer.

Adult↗
PubMed1995

Effects of tacrine upon murine neuroblastoma cells.

Tacrine [9-amino-1,2,3,4-tetrahydroacridine] (THA), a potent acetylcholinesterasic inhibitor, is utilized in the pharmacological treatment of Alzheimer's disease (Birne and Arie, 1994). Cytopharmacology of THA is still largely to be discovered. In the present paper we report some effects produced by THA on murine neuroblastoma cells (N2A) used as an experimental model. N2A cells treated with THA at low concentration (1 mu M) showed a reduced cell's mitosis and a remarkable reduction of protein synthesis. Eventually, a marked reduction on the phosphorylation of proteins associated to neurofilaments 200 kD, is observed using specific antibody.

Alzheimer Disease↗
PubMed1995

Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives.

The cytotoxic activity of mitoxantrone and related anthracenediones has been ascribed to the ability of these compounds to interfere with DNA topoisomerase II function, resulting in DNA cleavage stimulation. The molecular details of enzyme inhibition by these intercalating agents remain to be defined. In an attempt to identify the structural determinants for optimal activity, the molecular and cellular effects of a series of heteroanalogues bearing different side-chains were examined in relation to the physico-chemical and DNA binding properties of these compounds. The results indicated that substitution of a pyridine ring for the dihydroxyphenylene ring in the planar chromophore caused a marked reduction of cytotoxic activity and of the ability to stimulate topoisomerase II-mediated DNA damage in intact cells and with simian virus 40 DNA in vitro. Although all tested derivatives were shown to intercalate into DNA, their DNA binding affinities were appreciably lower than that of mitoxantrone. The behavior of 2-aza derivatives more closely resembled that of ametantrone, suggesting that the potency of agents of this class is influenced more by the presence of hydroxyl groups than by the phenylene ring. The observation that a dramatic reduction (or loss) of the ability of aza derivatives to stimulate DNA cleavage is associated with a marked reduction of cytotoxic potency supports a primary role of topoisomerase II-mediated effects in the mechanism of action of the effective agents of this class. Because appreciable cytotoxic activity and significant in vivo antitumor efficacy are retained by compounds inactive (or poorly active) in inhibition of topoisomerase II, these results are consistent with multiple effects of anthracenediones at the cellular level.

Antineoplastic Agents↗
PubMed1995

Growth and endocrine function following bone marrow transplantation for thalassemia.

Twenty two patients with thalassemia major who received successful bone marrow transplantation (BMT) were followed to verify the impact of the transplant procedure on subsequent growth and development. The transplant preparative regimen consisted of busulphan and cyclophosphamide. Growth and endocrinological function were assessed during the first 4 years following BMT. At the time of transplant most patients showed growth retardation. The median difference between chronological age and bone age was -9.5 months for the boys and -8.5 months for the girls. Patients > 7 years old at the time of BMT showed a significant worsening of their growth delay at 48 months following BMT compared with 12 months before transplantation. Patients < 7 years at the time of BMT had their growth retardation constant over time span after transplantation. Moreover six of 11 younger patients showed an improvement of their growth delay compared with one of 11 older patients. The outcome of height standard deviation score at 24 and 48 months following BMT was strictly correlated with the level of serum transaminases and ferritin. Sixteen patients had impaired growth hormone secretion after a provocative test evaluated at 24 months after transplant. At 48 months there was no significant increase in the mean peak GH levels. This study confirms that the growth retardation of patients with thalassemia major is multifactorial.

Adolescent↗