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Biomedical subjects

G Antonelli

Publications and source records attributed to G Antonelli.

At least 73 records · Page 4Linked to original sources
PubMed1996

Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of phosphorylation of thymidine kinase.

The purpose of this study was to investigate the mechanism of acquired cellular resistance to AZT, a mechanism that has been described as a potential source of drug resistance in addition to viral mutations. To study this phenomenon the kinetics parameters of thymidine kinase (TK) activity have been defined in CEMazt, a cell line previously selected for resistance to AZT, in comparison with the parental AZT-sensitive CEM cells. The results revealed that the value of the maximum velocity (Vmax) of TK activity for deoxythymidine (dThd) phosphorylation is decreased in CEMazt as compared to the wild-type cell line (Vmax: CEM = 105.3 +/- 17.6 nmol/hr/mg of protein; CEMazt = 0.3 +/- 0.02 nmol/hr/mg of protein; p < 0.001). Furthermore, the enzyme affinity versus dThd is lower in CEMazt as compared to CEM (Km: CEM = 0.9 +/- 0.2 microM; CEMazt = 1.6 +/- 0.2 microM; p < 0.01). Consequently phosphorylation efficiency, expressed as the ratio between Vmax and Km, is also reduced in CEMazt (p < 0.001). To evaluate whether such a phenomenon may also occur in patients, ex vivo experiments were carried out by using PBMCs from HIV-infected patients, treated or not treated with AZT. The results (mean values from 10 patients for each group) indicate that a prolonged treatment (> 6 months) with AZT may modify the enzymatic kinetics of TK, leading to a significant reduction in the phosphorylation efficiency of the enzyme (4.07 +/- 1.7 in treated patients versus 13.5 +/- 1.7 in untreated patients; p < 0.001). These results indicate that AZT treatment can also induce a defect in TK activity in patients.

Cell Line↗
PubMed1996

New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase.

A series of pyridobenzothiodiazepindioxides such as the 11-ethyl-6,8,9-trimethyl-6,11-dihydro-pyrido[2,3-f] [2,1,5]benzothiodiazepine-5,5-dioxide and arylpiridodiazepines such as the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b] pyrido(2',3'-4,5]furo[2,3-f][1,4]diazepin-6(12H)-thio and the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido- [2,3-4,5]thieno[2,3-f][1,4] diazepin-6(12H)-thione were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.003-0.04 microM without being cytotoxic at a 3,000- to 15,000-fold higher concentration. These compounds proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3' deoxythymidine (AZT), but not against HIV-2, simian immunodeficiency virus or herpes simplex virus. An HIV-1 strain containing the 188 Tyr-->His mutation in the reverse transcriptase displayed severely reduced sensitivity to the compounds. The specificity of these compounds is due to an interaction with the reverse transcription process. The 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido [2,3-4,5]thieno[2,3-f][1,4]diazepin-6(12H)-thione (MEN 10979) enhanced the anti-HIV-1 activity of AZT and dideoxyinosine (ddI) in a synergistic manner. The new arylpyrido-diazepine and -thiodiazepine derivatives appear to be drug candidates for the treatment of HIV-1 infection.

Antiviral Agents↗
PubMed1996

Antibodies to interferon (IFN) in hepatitis C patients relapsing while continuing recombinant IFN-alpha2 therapy.

A number of trials have demonstrated that IFN-alpha is effective in chronic hepatitis C virus infection. It is known, however, that a number of chronic hepatitis C patients experience, after an initial response to IFN, disease reactivation or relapse (also called 'breakthrough') while IFN therapy is still ongoing. Since in a number of clinical conditions a significant correlation between development of antibodies to IFN and failure of therapy has been established, we addressed the possibility that the development of antibodies to IFN may take part in the relapse occurring in hepatitis C patients during recombinant IFN-alpha (rIFN-alpha) therapy. The prevalence of neutralizing (NA) and binding antibodies (BA) to rIFN-alpha2 has been evaluated in 45 patients with chronic hepatitis C treated with rIFN-alpha2a who first normalized aminotransferase (ALT) levels, and subsequently showed disease reactivation while on treatment. The presence of NA and BA was tested before therapy, during the response to IFN treatment, and at the time when ALT started to rise again to abnormal levels. The results showed that no patients had detectable antibodies to IFN before therapy and during the period of response to the therapy, while most of them (88.9%) developed NA and/or BA to IFN-alpha2 concomitantly with disease reactivation. In particular, in 29 of the 45 patients (64.4%) ALT normalized on treatment and rose to abnormal levels when NA appeared in their serum, while in 11 of the 16 (68.8%) remaining patients the relapse was associated with BA development. The frequency of seroconversion in these patients is significantly higher than that observed in the control group. These data indicate that antibodies to IFN may be responsible for breakthrough in the majority of patients showing disease reactivation while rIFN-alpha therapy is still ongoing.

Adolescent↗
PubMed1996

Geometry of the carotid arteries and tilt-up hypotension in subjects with essential arterial hypertension.

Dysfunction of the baroreceptor structures located in the carotid bulb is considered responsible for hypotensive responses to orthostatic posture in hypertensive subjects. Because of a recurrent vascular impairment in essential hypertensives, the authors hypothesized that in these cases the baroreceptive dysfunction could be related to some peculiar vascular disarrangement of the carotid arteries, at the level of the bulb. To test this, they compared two groups of mild essential hypertensives, divided into group A--15 subjects considered hyporeacting because of a decrease in mean blood pressure > or = 10 mmHg at the first minute of a passive orthostatic stress--and group B--15 subjects considered normoreacting because of an increase in mean blood pressure > or = 5 mmHg. They evaluated by high definition echo Doppler ultrasonography: (1) an arterial compliance index, (2) the volume of the carotid bulb, and (3) a score expressing the degree of arteriopathy at the level of the carotid arteries. In group A, results demonstrated a significant impairment of the carotid artery structure, expressed by an increase in volume of the carotid bulb (389.4 +/- 134.7 vs 233.2 +/- 116.5 mm3, P < 0.05) and a higher vascular score (2.7 vs 1, P < 0.001), while the index of arterial compliance was similar in the two groups. In conclusion, in mild essential hypertension a baroreceptor dysfunction could be strictly linked to a derangement of the carotid artery structure, while arterial compliance does not seem to involve the baroreceptor function.

Adult↗
PubMed1996

Effects of interferon-alpha treatment on neutrophil oxidative metabolism, lymphocyte proliferation and monocyte HLA class I antigen expression in patients with chronic hepatitis C.

Polymorphonuclear cell (PMN) oxidative metabolism, lymphocyte polyclonal proliferation and monocyte HLA class I antigen expression were evaluated at different intervals of time in patients with chronic hepatitis C (CH-C) subjected to a 6 month interferon alpha (IFN-alpha) treatment and divided into Responder ('R') and Nonresponder ('NR') subsets according to clinical outcome. Before therapy, all subjects exhibited multiple immune alterations even if to a different extent between 'R' and 'NR' subsets: an elevated superoxide anion (O2-) generation by suspended PMN, a failure to further increase neutrophil oxidative responsiveness under adherence conditions, an augmented phytohaemagglutin-induced lymphocyte proliferative capacity and an enhanced HLA class I antigen expression on CD14+ cells. IFN-alpha administration gave rise to a modulation of oxidative response in 'R' group only, since these individuals displayed an O2- release by suspended and adherent PMN which fell within normal values. At the same time, a decrease of lymphocyte proliferation occurred in both groups of patients during IFN-alpha therapy, even if it reached statistical significance in 'R' group only. Finally, a more marked difference between 'R' and 'NR' individuals was noted in terms of HLA class I antigen induction on CD14+ cells at the end of therapy, as a consequence of a reduced expression of these structures in 'NR' subjects. Altogether, these findings suggest the occurrence of a strict relationship between immunoresponsiveness and IFN-alpha induced therapeutical effects in CH-C patients.

Adult↗
PubMed1995

Treatment with natural IFN of hepatitis C patients with or without antibodies to recombinant IFN.

The purpose of this study was to evaluate if a retreatment with natural human interferon alpha could lead to a recovery of the therapeutic responsiveness in non-responder patients with chronic hepatitis C who did (9 cases) or did not (14 cases) develop anti-interferon neutralizing antibodies while on treatment with recombinant interferon alpha2a. During retreatment, no patient developed detectable levels of neutralizing antibodies to natural interferon. At the end of retreatment, 6/9 positive patients showed a complete response to natural interferon therapy, while only 1/14 negative patients had a partial response. These data suggest that a second course of treatment with the natural preparation may be useful in patients who failed to respond to an earlier course of recombinant interferon, particularly the anti-interferon positive patients who showed hepatitis reactivation after an initial response concomitantly with antibody appearance. Conversely, a second course of natural interferon therapy might be useless in cases in which the lack of response is not associated to antibody development.

Antibodies↗
PubMed1995

Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection: prevalence, etiology, and management.

Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the treatment, in spite of a complete initial response (breakthrough). We studied 191 HCV Ab-positive patients with histologically proven chronic hepatitis. All of them were treated with r-IFN alpha 2 (3 MU three times a week). A complete response was seen in 54.4%. However, 12 of 104 responders experienced a breakthrough. At the time of breakthrough, neutralizing IFN antibodies were positive in 6 of 12 patients. Binding IFN antibodies were positive in all of these 12 patients. Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients.

Adolescent↗
PubMed1994

Development of neutralizing and binding antibodies to interferon (IFN) in patients undergoing IFN therapy.

Since the 1970's, people started to use interferon as a therapeutic agent against infectious and neoplastic diseases. Since the beginning of its therapeutical use, it was demonstrated that some patients produce, when treated with interferon, antibodies able to neutralize its biological activity. This paper will review and discuss what it is currently known about the technical, biological, and clinical aspects of these antibodies.

Hepatitis, Viral, Human↗
PubMed1994

Infectious virus with reduced cytopathogenicity resulting from persistent infection of normal lung fibroblasts by HIV type 1 strains.

We asked whether HIV-1 had the capacity to establish a persistent infection of cultured human diploid fibroblasts. Human strains of normal diploid embryo lung fibroblasts were infected with HIV-1 of the HTLV-IIIB and HIV-1P1 strains. Infection was followed over time, to analyze HIV expression. Virus production (intra- and extracellular virus) was evaluated as follows: ability to form syncytia in the C8166 T cell line, production of p24 and other viral antigens (ELISA and indirect immunofluorescence), search for a gag sequence in cell DNA by the polymerase chain reaction followed by hybridization to an HIV-1-specific probe (SK19). Cell-free culture supernatant was used as a virus source to infect de novo fibroblasts and C8166 T cells. Infection of cultured fibroblasts with either the HTLV-IIIB or HIV-1P1 strain led regularly to the establishment of persistently infected cultures. Fibroblast cells were capable of continuous virus production for at least 10 months. The released virus was capable of reinfecting cultured fibroblasts and of producing cytopathic effects in the C8166 T cell line. However, when compared to wild-type strains, the infectious virus derived from fibroblasts showed a prolonged replication cycle and a decreased ability to form syncytia in the T cell line. Therefore, HIV-1 can establish a persistent and productive infection in normal lung fibroblasts. The data are consistent with the hypothesis that in vivo, at least in the lung, fibroblasts may represent a virus reservoir and that infection of these cells may lead to the production of attenuated variants of HIV.

Cell Line↗
PubMed1994

Zidovudine induces the expression of cellular resistance affecting its antiviral activity.

We have previously shown that multidrug-resistant cells expressing the multidrug transporter P-glycoprotein are less sensitive to the antiviral activity of AZT. Subsequently, we addressed the question whether AZT itself is able to induce cellular resistance to the drug. Indeed, CEM cells propagated in the presence of increasing concentrations of AZT become resistant to the antigrowth and antiviral activity of AZT but do not express detectable level of P-glycoprotein. Sensitivity of these cells to other compounds, such as vinblastine, vincristine, ddI, and ddC remained unchanged, indicating that, in contrast to P-glycoprotein-positive cells, AZT-induced resistance is specific for AZT. Interestingly, in AZT-induced resistant cells the intracellular accumulation of AZT and exogenous deoxythymidine, as well as thymidine kinase activity, are significantly reduced when compared with the parental cell line. Our findings show that AZT itself may directly induce the expression of cellular mechanisms leading to the acquisition of specific cellular resistance that can affect its antiviral activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Biological and clinical significance of neutralizing and binding antibodies to interferon-alpha (IFN-alpha) during therapy for chronic hepatitis C.

It is known that IFN therapy can induce the development of anti-IFN antibodies. In order to evaluate the biological and clinical significance of both neutralizing (NA) and non-neutralizing (binding) antibodies, 123 patients with chronic hepatitis C treated with recombinant IFN-alpha were examined. Among them, 15 were positive for NA and 24 for binding antibodies. The kinetics of NA appearance show that, in general, they develop early during the first 3 months of treatment. Moreover, NA seem to be clinically relevant, since they may be responsible for non-responsiveness to treatment in 53% of patients who develop them. The evaluation of the clinical significance of binding antibodies is more difficult. They appear significantly earlier in non-responders than in responders, but no differences were observed in the overall percentage of seroconversion between responders and non-responders. Thus, it is not possible at the moment to establish their possible role in inducing non-responsiveness.

Alanine Transaminase↗
PubMed1994

Identification of an amino acid substitution involved in the reduction of sensitivity of HIV-1 to an inhibitor of viral proteinase.

Clones derived from HIV variants previously characterized as resistant to Ro31-8959, an inhibitor of viral proteinase (PR), were sequenced. Substitution of glycine by valine at position 48 of the PR protein was found. None of the 20 clones derived from wild type HTLV-IIIB contain this mutation. Since such a position is located in a conserved region of PR, it is possible that the substitution can affect the interaction of the enzyme with the inhibitor.

Base Sequence↗
PubMed1994

[The echocardiographic assessment of the functional variations in the left ventricle induced by isometric stress in subjects with primary cardiomyopathy in the pre-dilated phase].

The aim of this study was to assess whether a sudden increase in left ventricular (LV) afterload in a pre-dilated condition of idiopathic cardiomyopathy, in associated with some non-invasively detectable impairment of LV function. Ten subjects (Group A, 7 males, 3 females, mean age 36.7 +/- 11.4 years), submitted to cardiac catheterization because of severe symptoms related to ventricular arrhythmias, were found to have normal coronary arteries and left ventricular function, but histological features suggestive of congestive cardiomyopathy at endomyocardial biopsy. Echocardiography was performed during handgrip for 5 min at 30% of the maximal effort, in order to obtain a sharp increase in systolic LV pressure of more than 40 mm Hg. Ten healthy subjects were used as controls (Group B). Results in Group A showed a significant decrease in LV ejection fraction (from 62.4 +/- 6.9 to 57 +/- 7; p < 0.005) and LV shortening fraction (from 34.2 +/- 5.1 to 31 +/- 4.3; p < 0.01); a significant increase in LV systolic volume (from 48.2 +/- 9.1 to 60.0 +/- 12.0; p < 0.005) and systolic stress (from 114.6 +/- 33.2 to 178.8 +/- 58.2; p < 0.001). At the first minute of recovery LV function normalized quickly while LV systolic volume remained moderately increased (52.5 +/- 10.2). In conclusion, in pre-congestive dilated cardiomyopathy a latent impairment in LV function can be detected during a sharp increase of LV afterload. Isometric stress is particularly useful in eliciting these transient changes, as the method allows a reliable echocardiographic examination during maximal stress and not only during the recovery phase, as in dynamic stress.

Adult↗
PubMed1993

Antibodies to interferon alpha in patients.

A massive amount of information on interferons (IFNs) has been gathered since their original description as antiviral agents in 1957. Human IFNs have now been used clinically for over a decade and their therapeutic efficacy has been well established for some human neoplasias and viral diseases. During these studies, it has also been documented that some of the patients treated with IFNs can develop antibodies to IFNs which can affect their therapeutic efficacy. Here, it is summarized what is currently known on the biological and clinical aspects of these antibodies.

Antibodies↗