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Biomedical subjects

G Castello

Publications and source records attributed to G Castello.

At least 37 records · Page 2Linked to original sources
PubMed1997

Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion.

BACKGROUND: Cisplatin (DDP) and carboplatin (CBDCA) are two of the most effective drugs in a locoregional approach. Since simultaneous combined treatment with intrapleural DDP and CBDCA has not been reported in humans, we investigated its use in patients with malignant effusions, focusing on pharmacokinetics. PATIENTS AND METHODS: The pharmacokinetics of DDP and CBDCA were studied in 10 patients with malignant pleural effusion treated intrapleurally with a combination of DDP (60 mg/m2) and CBDCA (270 mg/m2) and in additional patients who received the same doses of drugs administered intravenously as single agents or in combination. Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP) and intact CBDCA in plasma and pleural fluid ultrafiltrates were measured by means of high performance liquid chromatography and atomic absorption spectrometry. RESULTS: Both in the plasma and pleural fluid, the total levels of free Pt represented the additive result of the individual concentrations of CBDCA and Pt-species derived from DDP. After intrapleural combination, high pleural-plasma ratios of the peak concentrations and AUCs were observed both for CBDCA and DDP-derived Pt species, highlighting a distinct local pharmacological advantage. However, the Pt species originating from DDP were absorbed more rapidly from the pleural cavity than CBDCA (Ka = 86 x 10(-3) vs. 37 x 10(-3) min-1, P < 0.05). Intrapleural combination of CBDCA and DDP produced therapeutic plasma levels of reactive (free) DDP species and increased the extent of their residence time (MRT) compared with single intravenous DDP treatment [peak concentration: 1.1 +/- 0.1 (SD) vs. 1.6 +/- 0.2 microgram/ml; MRT: 5.2 +/- 1.9 vs. 0.5 +/- 0.06 h]. Furthermore, the plasma AUC of free CBDCA after intrapleural combined treatment (2.1 +/- 0.5 mg/ ml x min) was similar to that after intravenous administration of CBDCA alone (2.1 +/- 0.2 mg/ml x min). The intrapleural treatment was well tolerated by all patients. Toxicity consisted of mild nausea and vomiting (grade 1-2 according to the WHO scale) in four patients. Myelosuppression (grade 1-2) was remarkable only in two heavily pretreated patients. No evidence of recurrence of the pleural effusion was observed in six patients (complete response), while an asymptomatic minimal fluid reaccumulation not requiring drainage (partial response) was observed in four patients. CONCLUSIONS: The pharmacologic results seem to exclude a pharmacokinetic interaction between CBDCA and DDP and suggest that a dose of CBDCA 2-fold higher than that used in this study associated intrapleurally with 60 mg/m2 DDP could induce an acceptable and predictable myelosuppression.

Aged↗
PubMed1997

The soluble interleukin-2 receptor as an indicator of clinical evolution in patients with ulcerative colitis.

BACKGROUND/AIMS: The soluble interleukin-2 receptor is a useful, non-specific marker of in-vivo activated cellular immune functions. The aim of this study was to evaluate the correlation between this marker and clinical evolution of ulcerative colitis. METHODS: Serum soluble interleukin-2 receptor levels were determined, by an enzyme immune assay, in 105 patients affected by ulcerative colitis with different extent and activity of disease. Forty-six of these patients were restaged in a follow-up study, and their serum-soluble interleukin-2 receptor concentrations were measured again. RESULTS: Serum soluble interleukin-2 receptor level is higher in pan-ulcerative colitis than in left ulcerative colitis (P = 0.050) and much higher in active than in quiescent stage of disease (P = 0.029). Clinical relapse of disease is accompanied by a serum soluble interleukin-2 receptor rise (P = 0.0697), whereas clinical and histological improvement in disease is accompanied by its significant decrease (P = 0.0009). CONCLUSION: In ulcerative colitis the serum determination of soluble interleukin-2 receptor is a useful and non-invasive marker of activity, and also extension and evolution of the disease.

Adult↗
PubMed1997

In vitro synergistic inhibition of human bone marrow hemopoietic progenitor growth by a 3'-azido-3'-deoxy-thymidine, 2',3'-dideoxycytidine combination.

In vitro growth of human normal bone marrow granulocyte-macrophage colony forming units (CFU-GMs) and erythroid burst forming units (BFU-Es) was dose-dependently inhibited by 3'-azido-3'deoxythymidine (AZT) (from 0.1 microM to 4 microM) and 2',3'-dideoxycytidine (ddC) (from 0.01 microM to 1.0 microM). These ranges included minimum in vitro inhibitory concentrations to HIV-1 and concentrations corresponding to plasma level achievable in vivo. A synergistic inhibitory effect, statistically highly significant, was observed when combinations of the two drugs were added to cultures. This severe in vitro toxicity of ddC and the synergistic toxicity of AZT-ddC combinations on hemopoietic progenitor cells should be considered when the two drugs are administered in concurrent or alternating regimens.

Bone Marrow Cells↗
PubMed1996

In vitro activity on myeloid progenitors of a combination of 2-chloro-2'-deoxyadenosine and interferon alpha: the effects of IL-1 and GM-CSF.

The toxic effects of a combination of 2-chloro-2'-deoxyadenosine (CDA) and interferon alpha (IFN-alpha), with and without addition of interleukin 1 (IL-1) and/or granulocyte macrophage colony stimulating factor (GM-CSF), on the in vitro growth of peripheral blood granulocyte macrophage committed progenitors (CFU-GM) from 10 normal subjects were investigated. CDA concentration ranged from 15.6 nmol/l to 1 mumol/l, IFN-alpha sole concentration was 10 IU/ml. IL-1 and/or GM-CSF were added at concentrations of 2000 pg/ml and 10 ng/ml, respectively. CDA induced a dose dependent inhibitory effect on CFU-GM growth. Addition of IFN-alpha increased CFU-GM inhibition induced by CDA only at lower concentrations of the latter. IL-1 and GM-CSF, separately or in combination, did not counteract the inhibitory activity of the CDA-IFN-alpha combination.

Antineoplastic Agents↗
PubMed1996

Correlation of soluble interleukin-2 receptor levels with severity of chronic hepatitis C virus liver injury and development of hepatocellular cancer.

BACKGROUND: Patients with acute and chronic hepatitis B virus infection have elevated serum levels of soluble interleukin-2 receptor. This study examined patients with chronic hepatitis C virus infection to determine whether serum soluble interleukin-2 receptor levels were elevated and whether the degree of these elevations in serum levels correlated with histologic severity of hepatitis-related liver injury. METHODS: Percutaneous liver biopsies were performed on 123 patients with chronic hepatitis C virus infection. Serum levels of soluble interleukin-2 receptor in these 123 patients were measured by means of specific enzyme-linked immunoassay and were compared with levels in 174 subjects in a hepatitis-free control group. RESULTS: Soluble interleukin-2 receptor levels were significantly higher in the patients with hepatitis C than in subjects in a control group (p < 0.0001). A progressive and significant increase occurred in soluble interleukin-2 receptor levels with increasing severity of liver injury (p < 0.001). The highest levels of soluble interleukin-2 receptor occurred in patients who had hepatocellular cancer. CONCLUSIONS: Soluble interleukin-2 receptor levels correlate with the histologic severity of liver damage in patients with chronic hepatitis C virus infection and may be useful as a marker in patients at high risk of getting hepatocellular cancer.

Adolescent↗
PubMed1996

Interferon-alpha inhibits CFU-GM mobilization following chemotherapy and G-CSF administration.

Changes in routine hematologic data and in circulating granulocyte-macrophage colony-forming units (CFU-GM) during granulocyte colony-stimulating factor (G-CSF) administration were evaluated in non-small cell lung carcinoma (NSCLC) patients treated with a combination of 5-fluorouracil (5-FU) and cisplatin (DDP) with and without the addition of interferon-alpha (IFN-alpha). The patterns of leukocyte changes following chemotherapy plus G-CSF were similar in both the IFN-alpha-inclusive and the IFN-alpha-devoid courses. However, the twofold increase in CFU-GM observed in patients receiving chemotherapy plus G-CSF was completely absent following the course including IFN-alpha. The activity of G-CSF on the hematologic pattern is seemingly affected by its combination with IFN-alpha treatment. Mechanisms of the possible in vivo interaction among IFNs and hematopoietic growth factors remain to be elucidated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Producton of tumor necrosis factor and granulocyte colony stimulating factor by bone marrow accessory cells in myelodysplastic patients.

This paper reports on the production of tumor necrosis factor (TNF) and granulocyte macrophage colony-stimulating factor (GM-CSF) by cultured mononuclear adherent cells derived from bone marrow of 25 patients affected by myelodysplastic syndrome (MDS) of different FAB subtypes. Mean production of GM-CSF was much lower than in controls, without significant differences among different subtypes. Mean production of TNF was similar in MDS patients and in controls, but noteworthy differences were observed between patients with RA, RAEB and RAEB-t and patients with RARS and CMML. Growth of bone marrow granulocyte macrophage and erythroid progenitors did not correlate with TNF and GM-CSF production, although in MDS subtypes with higher GM-CSF levels, colony growth was slightly higher than in subtypes with lower GM-CSF production.

Aged↗
PubMed1996

[Alpha interferon in the therapy of polycythemia vera].

In previous researches recombinant interferon alpha (IFN-alpha) has been demonstrated to significantly control red cell mass and thrombocytemia in patients with polycythemia vera (PV). Further evaluation of drug effectiveness and of modalities of maintenance therapy is warranted. We treated four patients with PV according to PVSG criteria with IFN-alpha (3 MU subcutaneously three times a week) for five months. Thereafter the starting dose was reduced to 1.5 MU three times a week. Treatment with IFN-alpha at the higher dosage induced regression in sizes of the spleen and a return to normal levels of peripheral blood platelets and leukocytes. Phlebotomies, previously performed to keep under control hematocrit values, were no more needed. During maintenance treatment with IFN-alpha reduced dose platelet level remained in the normal range, spleen size did not show further variation but hematocrit slowly rose and phlebotomies had to be resumed. These results confirm IFN-alpha effectiveness in PV, but suggest the need of relatively high dosages of the drug and difficulties in switching to a maintenance treatment.

Aged↗
PubMed1995

Circulating hematopoietic progenitor cells in polycythemia vera: the in vivo effect of hydroxyurea.

The in vivo effects of hydroxyurea (HU) on circulating erythroid (BFU-E) and granulocyte-macrophage progenitors (CFU-GM) in patients with polycythemia vera (PV) have been evaluated. HU induced a strong decrease of both BFU-E and CFU-GM in the first month of treatment. During the following 4 months of treatment the level of circulating progenitors remained at very low values, until the end of the period of observation. HU activity involved both erythroid and myeloid committed progenitors and both erythropoietin-stimulated (normal) and endogenous (derived from the abnormal PV clone) BFU-E.

Aged↗
PubMed1995

Azidothymidine and interferon-alpha in vitro effects on hematopoiesis: protective in vitro activity of IL-1 and GM-CSF.

Preclinical and clinical studies with an azidothymidine (AZT)/interferon-alpha (IFN-alpha) combination resulted in a marked and synergistic antiretroviral activity. The administration of the two drugs in HIV-seropositive patients affected with Kaposi's sarcoma, however, induced neutropenia, thrombocytopenia, and, in some cases, anemia. A possible means to improve the therapeutic index of AZT and/or IFN-alpha in AIDS patients could be the addition of hematopoietic growth factors. In vitro activity of cytokines on the hematotoxicity of the AZT-IFN-alpha association has not yet been studied. We have performed an in vitro study to evaluate the toxicity of AZT, IFN-alpha, or both on peripheral blood hematopoietic progenitors (CFU-GM and BFU-E) and to assess the activity of interleukin 1 (IL-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), or both in modifying AZT-IFN-alpha hematotoxicity. Results indicate that AZT, IFN-alpha, and combinations of the two have a dose-dependent inhibitory effect on the in vitro growth of peripheral blood hematopoietic progenitors. Combinations of AZT and IFN-alpha inhibited CFU-GM and BFU-E proliferation in an additive manner. Neither IL-1 nor GM-CSF alone was able to induce a significant reduction of AZT-induced damage. Only the addition to the cultures of both cytokines partially curbed the antiproliferative activity of AZT at low dosages.

Antimetabolites↗
PubMed1994

The in vitro and in vivo effect of recombinant interferon alpha-2a on circulating haemopoietic progenitors in polycythaemia vera.

In four patients with polycythaemia vera (PV) who received interferon alpha (IFN-alpha) (3 MU subcutaneously three times a week) for 5 months, peripheral blood levels of granulocyte-macrophage colony-forming units and erythroid burst-forming units were assessed monthly. Circulating progenitors significantly decreased throughout the treatment period. Moreover, we observed an inhibitory activity of IFN-alpha on haemopoietic progenitor cells (HPC) from patients with PV in vitro. The data presented confirm previous research which has shown an inhibitory effect of IFN-alpha on HPC from patients with myeloproliferative disorders. Significant improvement in the patients' clinical and haematological conditions should encourage larger studies on IFN-alpha administration in PV patients.

Aged↗
PubMed1994

[Interferon-alpha in the treatment of myeloproliferative syndromes].

In these last years the use of alpha-interferon (alpha-IFN) has received increasing attention especially in the onco-haematological field. alpha-IFN is particularly useful in the treatment of hairy cell leukemia, cryoglobulinemia, multiple myeloma and myeloproliferative syndromes (SMP). Among these latter conditions alpha-IFN must be considered as the treatment of choice of the early chronic phase of chronic myelogenous leukemia (LMC) in patients not eligible for allogenic bone marrow transplantation because its ability to induce a greater number of clinical remission and cytogenetic responses when compared to the classical chemotherapeutic agents. A myelosuppressive, non-leukemogenic effect and a more selective activity on the neoplastic hemopoiesis appear to be the most important advantages of alpha-IFN therapy. Based on the results obtained in LMC the use of alpha-IFN has been extended to the other SMP, essential thrombocytemia (TE), polycythemia vera (PV), idiopathic myelofibrosis with myeloid metaplasia (MMM). alpha-IFN is able to control thrombocytosis which often characterize the SMP so it appears to be particularly effective in TE. Actually a relatively limited literature is available about the alpha-IFN treatment of PV and MMM and so it is difficult to draw a final conclusion about the effectiveness of the treatment in these disorders. However, especially in PV, the use of this cytokine appears to be promising. The latest reports of the literature are here summarized and discussed.

Humans↗
PubMed1994

Serum erythropoietin increase in patients receiving adjuvant therapy with 5-fluorouracil and leucovorin.

High-dose anticancer drugs have been shown to induce an increase in serum erythropoietin (sEpo) levels not mediated by hypoxia. In this study, sEpo was assessed in seven patients who had been administered a course of 5-day leucovorin-modulated 5-fluorouracil (5-FU-LV) as an adjuvant therapy after the removal of colon cancer. During this study, the mean hemoglobin (Hb) concentration stayed at a constant level, peripheral blood (PB) reticulocytes showed an early, sharp decline, and sEpo levels progressively increased for 15 days after the start of chemotherapy. These results appear to indicate that the increase in sEpo, which was not related to anemia, may have followed from the administration of a cytotoxic drug at doses used in routine, clinical practice.

Aged↗
PubMed1993

Immunological and clinical effects of intramuscular rIFN alpha-2a and low dose subcutaneous rIL-2 in patients with advanced malignant melanoma.

Fifteen patients with tumour recurrence following radical surgical excision of malignant melanoma were treated with a combination of interferon alpha-2a (rIFN alpha-2a) and interleukin-2 (rIL-2). Immunological monitoring (performed prior to therapy and on days 7, 21, and 28, of each course of treatment) showed significant changes of several parameters after rIFN alpha-2a and rIL-2 administration. A significant increase in cells expressing CD16 (cells bearing Fc receptor), CD25 (cells bearing IL-2 receptor), and CD56 (NK cells, activated lymphocytes), as well in levels of soluble IL-2 receptor, beta 2-microglobulin and neopterin was observed. Immunological changes were closely related to the injection of the biological agent and were more relevant during the first than the second cycle of treatment. rIFN alpha-2a and rIL-2 exerted a clear synergistic activity on the same immunological parameters. No major response was seen with the present approach: four subjects showed rapid progression of decrease during the first month of therapy, while of 11 patients who completed two courses of treatment, only five were considered in stable disease. In conclusion, our results suggest that a combination of rIFN alpha-2a and rIL-2, at dosages and schedules, used in this trial, was well-tolerated and immunologically active, but was clinically ineffective in the management of advanced melanoma.

Adult↗
PubMed1991

[Active specific immunotherapy of cancer using anti-idiotypic monoclonal antibodies].

Innovative approaches to cancer treatment have been made possible today by genetic engineering and hybridoma technologies. In this paper, attention is focused on the use of anti-idiotypic monoclonal antibodies such as internal tumor-associated antigens. These MoAbs may be able to overcome the immunosuppression in cancer patients by stimulating "silent" clones, or by allowing T cell help to become active, thus enhancing the overall immune response which the nominal antigen is unable to do. Preliminary experiences of active specific immunotherapy with monoclonal antiidiotypic antibodies in cancer patients are reported.

Animals↗
PubMed1989

Modulation of erythrocyte Ca2+-ATPase by selective calpain cleavage of the calmodulin-binding domain.

The activity of the membrane-bound and the purified erythrocyte Ca2+-ATPase in the absence of calmodulin was stimulated by calpain digestion but could be further increased to maximal levels by calmodulin (CaM). Thus, CaM sensitivity was retained by the digested ATPase, at least at short times of incubation. In membranes digested at higher temperatures and in the purified ATPase digested at higher calpain/ATPase ratios, the ATPase became fully activated. The membrane-bound and the purified 138-kDa ATPase were converted by calpain to a fragment of approximately 124 kDa which still bound CaM and could be isolated on CaM columns when proteolysis occurred slowly but not when it occurred rapidly. Carboxypeptidase digestion of the purified enzyme and of its fragment of about 124 kDa has shown that calpain attacked the CaM-binding domain near the C terminus of the ATPase. This has also been supported by digestion of the purified enzyme and of its fragment of about 124 kDa. A first cut occurred in the middle of the domain producing a fragment of about 14 kDa and a (CaM-binding) fragment of about 124 kDa. A second cut closer to the N terminus of the domain also produced a fragment of about 124 kDa and accounted for the loss of CaM binding at prolonged times of incubation of the ATPase with calpain.

Amino Acid Sequence↗