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S Vella

Publications and source records attributed to S Vella.

At least 109 records · Page 6Linked to original sources
PubMed1995

HIV pathogenesis and treatment strategies.

HIV infection is a chronic progressive illness. This virus has a multiplicity of cellular targets and the virus-host relationship changes over time. The high daily rate of virus production is initially controlled by the immune system, but eventually the immune system fails to contain viral replication and individuals become susceptible to a range of opportunistic infections. The course of the disease is improved by chemotherapeutic intervention with antiretroviral drugs, but the major limiting factor in the effective control of viral replication is the emergence of resistance of these agents. Using the phenomenon of "resistance reversal" in which resistance mutations to one drug reverse the effect of resistance mutations to another drug, researchers have identified promising combinations of antiretrovirals for clinical use. Application of the scientific understanding of HIV pathogenesis is essential if new and successful therapeutic approaches are to be developed. A wide range of antiretroviral drugs is now available for combination therapy studies. The criteria for their selection and combination should include synergy, different sites of activity in the body, lack of cross- resistance, resistance reversal, and no overlapping toxicities. Ultimately, there must be consensus in initiating treatment during the early stages of infection while the immune system is still functional, and treatment should involve the use of a combination of antiretroviral agents.

Antiviral Agents↗
PubMed1995

Rationale and experience with reverse transcriptase inhibitors and protease inhibitors.

The majority of antiretroviral agents used in the treatment of HIV are targeted at the HIV reverse transcriptase (RT) enzyme. In a continuing effort to develop more effective antiviral regimens, drugs that target other specific enzymes in the virus replication cycle are under development. A promising new class of drugs is the protease inhibitors. These antiviral agents are potent and highly specific, giving excellent inhibition of viral replication. Unfortunately, the high level of inhibition may not be maintained in vivo because of the rapid emergence of resistance to these agents when they are used as monotherapy. However, the combination of protease inhibitors with reverse transcriptase inhibitors may represent a major advance in the treatment of HIV infection.

Drug Therapy, Combination↗
PubMed1995

Clinical experience with saquinavir.

BACKGROUND: Saquinavir, a peptide-based, transition-state analogue of a characteristic HIV proteinase cleavage site, is a potent and highly specific inhibitor of HIV-1 and HIV-2 proteinases. COMBINATION THERAPY: Combination therapy with saquinavir at 600 mg and zidovudine at 200 mg, both three times a day, has been shown to provide greater and more sustained increases in CD4 cell counts and decreases in HIV-1 RNA plasma levels than treatment with either agent alone in antiretroviral-naive patients with symptomatic HIV infection. In previously antiretroviral-treated patients, triple combination therapy with saquinavir at 600 mg, zidovudine at 200 mg and zalcitabine at 0.75 mg three times a day was associated with greater immunological and virological responses than either saquinavir+zidovudine or zidovudine+zalcitabine, as demonstrated by 48 weeks of follow-up data. TOLERABILITY: Clinical experience to date has shown that saquinavir is well tolerated, even in patients with advanced disease, alone and in combination with zidovudine or zidovudine+zalcitabine. ONGOING STUDIES: Phase III studies to support these data and determine the effects of saquinavir on clinical end-points are continuing.

Antiviral Agents↗
PubMed1994

Survival differences in European patients with AIDS, 1979-89. The AIDS in Europe Study Group.

OBJECTIVES: To examine the pattern of survival and factors associated with the outcome of disease in patients with AIDS. DESIGN: Inception cohort. Data collected retrospectively from patients' charts. SETTING: 52 clinical centres in 17 European countries. SUBJECTS: 6578 adults diagnosed with AIDS from 1 January 1979 to 31 December 1989. MAIN OUTCOME MEASURES: Survival after the time of diagnosis. RESULTS: The median survival after diagnosis was 17 months, with an estimated survival at three years of 16% (95% confidence interval 15% to 17%). Patients diagnosed in southern Europe had a shorter survival, particularly immediately after the time of diagnosis, compared with patients diagnosed in central and northern Europe (survival at one year (95% confidence interval) 54% (52% to 56%) 66% (64% to 68%), 65% (63% to 66%), respectively. The three year survival, however, was similar for all regions. The regional differences in survival were less pronounced for patients diagnosed in 1989 compared with earlier years. Improved survival in recent years was observed for patients with a variety of manifestations used to define AIDS but was significant only for patients diagnosed with Pneumocystis carinii pneumonia. The three year survival, however, remains unchanged over time. CONCLUSIONS: Survival of AIDS patients seems to vary within Europe, being shorter in southern than central and northern Europe. The magnitude of these differences, however, has declined gradually over time. Short term survival has improved in recent years, but the long term prognosis has remained equally poor, reflecting the fact that the underlying infection with HIV and many of the complicating diseases remains essentially uncontrolled.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Differential survival of patients with AIDS according to the 1987 and 1993 CDC case definitions.

OBJECTIVE: To evaluate the impact of the 1993 Centers for Disease Control and Prevention (CDC) revised classification system for human immunodeficiency virus and expanded surveillance case definition for acquired immunodeficiency syndrome (AIDS) on the number of cases and on survival of patients with AIDS. DESIGN: Retrospective analysis of data from a prospective cohort study of patients treated with zidovudine. PATIENTS: A total of 3515 patients enrolled in the Italian National Registry of Zidovudine-Treated Patients between July 1987 and December 1991 were analyzed. MAIN OUTCOME MEASURES: Numbers and survival probability estimates (using the Kaplan-Meier method) for patients satisfying the 1993 CDC case definition compared with patients fulfilling the 1987 CDC classification. Multiple regression analysis was also used to analyze the combined effect of independent variables on survival. RESULTS: According to the new classification system, the number of AIDS cases in the study population would increase by 188%. While the median survival of patients meeting the 1987 definition was 24 months, at the end of 57 months 53% of patients meeting the 1993 definition were still alive. Among the patients meeting the laboratory criteria for AIDS diagnosis using the new definition (CD4+ lymphocyte count < 0.20 x 10(9)/L [200/microL]), the presence of an AIDS-defining illness was a strong independent predictor of death. CONCLUSIONS: The application of the new definition results in a considerable increase in the number of cases. Survival for patients classified according to the 1993 definition is much longer than for those classified with the 1987 definition. Clinical status plays a major role in predicting survival outcome among patients whose CD4+ lymphocyte counts meet the new case definition.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Comparison of long-term prognosis of patients with AIDS treated and not treated with zidovudine. AIDS in Europe Study Group.

OBJECTIVE: To determine the association between elapsed time since starting zidovudine and survival in patients with acquired immunodeficiency syndrome (AIDS). DESIGN: Inception cohort and observational study of patients treated and not treated with zidovudine. SETTING: Fifty-one centers in 17 European countries. PATIENTS: A total of 4484 patients diagnosed as having AIDS from 1979 to 1989 who survived their initial AIDS-defining event and who had not started zidovudine before AIDS diagnosis. MAIN OUTCOME MEASURES: Use of zidovudine and mortality. RESULTS: Among patients who did not receive zidovudine, the death rate was approximately constant for the first 5 years after AIDS diagnosis. For patients treated with zidovudine, the death rate within the first year since starting zidovudine was markedly lower than for untreated patients who had developed AIDS at the same time (relative rate, 0.47; 95% confidence interval [CI], 0.42 to 0.51). For longer times since starting zidovudine, the association with reduced mortality rate was diminished, and for patients surviving more than 2 years since starting zidovudine, the death rate was greater than for untreated patients who had developed AIDS at the same time (relative rate, 1.35; 95% CI, 1.15 to 1.58). Adjustment for other prognostic factors failed to substantially affect this observation. CONCLUSIONS: When initiated after the time of AIDS diagnosis, zidovudine was associated with improved prognosis but for no more than 2 years after starting therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1994

HIV therapy advances. Update on a proteinase inhibitor.

HIV PROTEINASE INHIBITORS: The HIV proteinase enzyme has been identified as a potential target for antiretroviral therapy, as inhibition of this enzyme leads to the generation of immature, non-infectious virions. There are several proteinase inhibitors in development; the first to enter clinical trials was saquinavir. DEVELOPMENT OF SAQUINAVIR: Saquinavir, a transition-stage analogue of an HIV proteinase cleavage site, was developed using computer-led rational design techniques. It is a highly specific inhibitor of HIV-1 and -2 proteinases, with antiviral activity at concentrations 1000-fold less than those causing cytotoxicity. EUROPEAN CLINICAL EXPERIENCE WITH SAQUINAVIR: Three European clinical studies involving 202 patients have been conducted with saquinavir at doses of 25, 75, 200 and 600 mg three times a day. Two studies were dose-ranging monotherapy trials, one in asymptomatic or mildly symptomatic patients not previously treated with zidovudine, the other in patients with advanced HIV infection who had been treated with zidovudine. The third study was a combination therapy trial with zidovudine in previously untreated patients with advanced infection. Saquinavir was well tolerated either alone or in combination with zidovudine. In the monotherapy studies, CD4 cell counts and estimates of viral load showed the best results with the 600-mg dose. The combination of saquinavir and zidovudine resulted in higher and more sustained increases in CD4 cell counts than with either drug alone. The CD4 cell counts favoured saquinavir at 200 and 600 mg in combination with zidovudine, although plasma viraemia and the RNA polymerase chain reaction indicated that the 600-mg dose (in combination) produced better responses.

Aspartic Acid Endopeptidases↗
PubMed1994

Long-term follow-up of zidovudine therapy in asymptomatic HIV infection: results of a multicenter cohort study. The Italian Zidovudine Evaluation Group.

In 1990 the results of a placebo-controlled study conducted within the AIDS Clinical Trials Group (ACTG 019) showed that in the short term, zidovudine was effective in slowing progression to advanced disease in HIV-infected asymptomatic patients with low CD4 cell counts. More recently, the preliminary results of the Concorde Trial suggested that while the data at 1 year agreed with those of ACTG 019, no sustained clinical benefit was detectable at 3 years for early versus deferred therapy. Therefore, the length of the clinical usefulness of zidovudine in this population is still to be determined. We evaluated the 2-year outcome of zidovudine therapy in asymptomatic patients through the prospective follow-up of a cohort of 936 subjects with low CD4+ (< 500/mm3) counts who strictly satisfied, at enrollment, the inclusion and exclusion criteria of the ACTG 019 trial. The clinical end point of the analysis was the development of AIDS. The majority (72.2%) of the individuals in the cohort acquired HIV infection through intravenous drug use; 26.6% were women. The median baseline CD4 cell count was 308/mm3. At 55 weeks of mean follow-up, the progression rate to AIDS (3.2 events per hundred person-years) appears to be comparable to that already reported at the same mean follow-up time for the ACTG 019 zidovudine-treated asymptomatic patients. After 124 weeks of mean follow-up, the overall rate of progression to AIDS was 5.2 per hundred person-years.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1994

High rate of HIV isolation from plasma of asymptomatic patients through polyethylene glycol (PEG) treatment.

The usefulness of traditional methods of HIV plasma titration has been limited by poor detection capacity in the asymptomatic phase of HIV disease. We analyzed plasma samples from asymptomatic seropositive or early symptomatic patients, comparing the classic plasma culture method with the following techniques: phorbol 12-myristate 13-acetate treatment of target cells, centrifugal inoculation of the virus, heat treatment of cultures, addition of monocyte/macrophages to cultures, and polyethylene glycol (PEG) treatment of the plasma. Only PEG treatment significantly increased the percentage of HIV isolation. The increase of HIV isolation after PEG treatment is more evident in patients with higher CD4+ cell counts and those without detectable levels of p24 antigen. In the p24-negative samples, HIV was isolated in 17 of 24 (71%) with PEG treatment versus nine of 24 (37%) with the classic method (p < 0.01). A number of discordant samples were found using the classic and PEG methods. Combining the positive results obtained with either technique, we obtained an overall HIV detection rate of 76%. The increased sensitivity of the combination of PEG and classic methods may allow a wider use of plasma viremia as part of the virological evaluation of anti-HIV drug efficacy in asymptomatic patients.

Cells, Cultured↗
PubMed1992

Survival of zidovudine-treated patients with AIDS compared with that of contemporary untreated patients. Italian Zidovudine Evaluation Group.

OBJECTIVE: To assess the long-term effectiveness of zidovudine (AZT) in patients with acquired immunodeficiency syndrome (AIDS). This assessment has never been adequately done because controlled clinical trials were stopped early and survival comparisons were made with historical controls. DESIGN: Nonrandomized contemporary observational study of patients treated and not treated with zidovudine. SETTING: Twenty-three AIDS treatment centers throughout Italy that reported cases to the National Registry of AIDS Cases between July 1987 and March 1988. PATIENTS: One hundred fifty-nine zidovudine-treated and 112 untreated patients with AIDS, the majority of whom had acquired human immunodeficiency virus (HIV) infection through intravenous drug use. OUTCOME MEASURES: Median survival and 1- and 2-year survival for treated and untreated groups, as estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was also used to identify independent predictors of survival among the variables studied. RESULTS: Patients were similar with respect to CD4/CD8 ratio, age, sex, clinical and immunological status at diagnosis, and source of HIV infection. After 24 months, survival was 45.9% (95% confidence interval [CI], 36.1% to 55.7%) in the treated group and 20.5% (95% CI, 12.6% to 28.3%) in the untreated group, with median survival of 21.2 and 9.6 months, respectively. CONCLUSIONS: Possible biases of this study include imperfect matching for clinical status and better overall medical care of treated patients. Nevertheless, we believe that the observed differences in survival were primarily due to zidovudine treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1992

The effects of AZT and DDI on pre- and postimplantation mammalian embryos: an in vivo and in vitro study.

This study reports the effects of the nucleoside analogs dideoxyinosine (DDI) and 3'-azido-3'-deoxythymidine (AZT) on mammalian embryonic development. When administered to pregnant mice (at concentrations ranging from 10 to 300 mg/kg/day), through all or part of gestation, AZT and DDI did not result in any visible effect on mouse embryos nor did they cause any obvious malformation or defect at birth or during postnatal growth. Similarly, when embryonic or fetal mouse or human cells (from brain, limb buds, or different organ rudiments) were exposed to AZT or DDI in vitro, cytotoxicity was observed only in the mM range, with AZT showing slightly higher cytotoxicity and brain cells appearing slightly more sensitive to both nucleosides. However, even in cultures treated with very high concentrations of AZT or DDI, the reduction in the number of terminally differentiated skeletal myotubes, cardiocytes, neurons, and chondrocytes was similar to the reduction in the total number of cells, indicating that AZT and DDI did not selectively inhibit differentiation of any of the above-mentioned cell types. Finally, preimplantation mouse embryos (at the 2-cell or 4-cell stage), treated in vitro with micromolar concentrations of AZT, were arrested at the 4-cell stage. DDI or other nucleoside analogs tested did not have this effect.

Animals↗
PubMed1989

Adrenocorticotropin is a specific mitogen for mammalian myogenic cells.

Peptides derived from proopiomelanocortin (POMC) have been found to stimulate the proliferation of murine myogenic cells. Among these peptides, adrenocorticotropin (ACTH) and alpha-, beta-, and gamma-melanocyte-stimulating hormones (MSH) were found to be active, whereas the opioid peptides were not. At clonal density, both ACTH and MSH caused a three- to fourfold increase in the average number of cells per clone in myogenic but not in fibroblast colonies. At high cell density, ACTH and MSH caused a three- to fourfold increase in proliferation of myogenic cells, reflected by an increased accumulation of skeletal myosin. On the other hand mouse embryo skin or muscle fibroblasts or vertebral chondroblasts did not increase proliferation in response to POMC-derived peptides. The half-maximal dose at which ACTH stimulated myoblast proliferation was around 5 nM, and the mitogenic effect was doubled by suboptimal doses of fibroblast growth factor. The possible physiological significance of the mitogenic effect of ACTH on myogenic cells is discussed.

Adrenocorticotropic Hormone↗
PubMed1988

A three-year diagnostic and epidemiological study on viral infantile diarrhoea in Rome.

Rotavirus infection was demonstrated in 168 (29.3%) of 573 children hospitalized for acute diarrhoea in Rome between January 1982 and December 1984. Laboratory diagnosis of these infections was made by transmission electron microscopy and enzyme immunoassay techniques with an overall agreement of 91.3%. Astroviruses, adenoviruses and small round viruses were detected in the faeces of 36 patients (6.4%). Whereas in 1982 rotavirus positive patients were clustered in the winter and following spring, in the following years cases were recorded all year round. The median age of patients with rotavirus infections was 17, 10 and 11.5 months in 1982, 1983 and 1984, respectively. In addition, a smaller number of rotavirus positive cases were admitted in 1983 when compared to those admitted during the previous as well as the subsequent years. It is suggested that a herd immunity was induced in the population by epidemic spread of rotavirus in the first half of 1982.

Adenovirus Infections, Human↗
PubMed1982

Antigen-specific human T-cell hybridomas with helper activity.

Human T cell hybridomas were produced by fusing the hypoxanthine phosphoribosyltransferase-deficient line of the human T cell lymphoma Jurkat with a continuous line of normal human T cells specific for tetanus toxoid (TeT). The hybridomas were selected for their ability to produce interleukin 2 after exposure to TeT on semiautologous monocytes and for their ability to bind to TeT-pulsed semiautologous monocytes. These antigen-specific T hybridomas demonstrated potent helper activity for semiautologous B cells as determined by the production of high levels of anti-TeT antibody in vitro.

Antibody Formation↗