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Biomedical subjects

M Cazzola

Publications and source records attributed to M Cazzola.

At least 199 records · Page 11Linked to original sources
PubMed1990

Penetration of cefonicid into human lung tissue and lymph nodes.

The present study was undertaken in order to investigate the penetration of cefonicid, a long-acting parenteral cephalosporin, with enhanced activity against most gram-positive and gram-negative pathogens, into human lung tissue and lymph nodes in patients undergoing open thoracotomy. Samples of lung tissue, lymph nodes and serum were obtained at various times after a single intramuscular dose of 1 g. The concentration of cefonicid was assayed by an agar diffusion method with Bacillus subtilis used as the test organism. The mean concentrations of cefonicid in serum at 2, 4, 8, 12 and 24 h after the injection were 91.5, 66.1, 35.7, 21.8 and 2.9 micrograms/ml, respectively. The mean levels of cefonicid into the hilar lymph nodes at the same times were 22.3, 18.7, 12.0, 6.9 and 1.5 micrograms/ml, respectively, while its concentrations in lung tissue were lower than those in lung lymph nodes up to the 12th hour (12.1, 14.6, 7.8, 5.4 and 1.9 micrograms/ml, respectively). Our results show that cefonicid was well distributed in interstitial fluid from which pulmonary lymph is formed and that its concentrations in lung tissue and lymph nodes were sufficient to inhibit most pathogens involved in respiratory tract infections. This finding was considered important, because it demonstrated that the high binding by plasma protein of cefonicid did not prevent it from entering lung tissue and fluids in useful quantities.

Adult↗
PubMed1990

Acute respiratory and cardiovascular effects of inhaled ketanserin in chronic obstructive pulmonary disease. A comparative study with intravenously administered ketanserin.

In a double-blind, crossover study, nebulized ketanserin, a 5-HT2 receptor antagonist, and a placebo were given to eight patients with moderate to severe nonasthmatic COPD. Intravenous ketanserin had rapid onset of action and induced a longer lasting bronchial response than inhaled ketanserin. These results confirm that ketanserin acts as a mild bronchodilator in patients with COPD and demonstrate that the inhaled route has no advantage over the intravenous route in terms of effectiveness. Thus, 5-HT may play a role in bronchomotor tone, at least in patients with chronic airway obstruction.

Administration, Inhalation↗
PubMed1990

Clinical, laboratory and radiographic features in early rheumatoid arthritis.

We evaluated disease status in relation to age, sex and disease duration using some short term indices of disease activity, laboratory tests, and radiological features in 315 patients with rheumatoid arthritis of duration varying from 3 to 36 months (mean 12 months). No differences were observed among various age groups in disease duration, female/male ratio, incidence of radiologic lesions and other indices of disease process. Some clinical markers of the disease process such as involvement of the flexor tendons of the hands and Ritchie's index (score greater than 9) were significantly more frequent in the women (p less than 0.0013 and p less than 0.04, respectively). In the patients with disease of recent onset women were slightly more numerous (56%) than men; however, in those with disease duration of 36 months there were significantly more women (72%) (p less than 0.039), suggesting a greater tendency to chronic disease in this sex. Radiological lesions of the small joints of the hands, feet, and/or wrists were found in 37% of the cases with disease duration of up to 4 months and in 91% at 36 months (p less than 0.0001). The lesions were associated significantly more frequently with Ritchie index (p less than 0.02) and with laboratory indices of inflammatory activity (erythrocyte sedimentation rate greater than or equal to 25 mm/h) (p less than 0.001) and immune response (latex test greater than or equal to 80) (p less than 0.0001). Logistic regression analysis showed that the duration of illness is the most important factor correlating with radiologic lesions.

Adolescent↗
PubMed1990

Tumor necrosis factor alpha down-regulates c-myc mRNA expression and induces in vitro monocytic differentiation in fresh blast cells from patients with acute myeloblastic leukemia.

We have studied tumor necrosis factor alpha (TNF-alpha) for its capacity to induce differentiation and to modulate c-myc and c-fms protooncogene mRNA expression in fresh blasts from 10 patients with acute myeloblastic leukemia (AML). Bone marrow blast cells were grown in suspension cultures in the presence of 500 U/ml (62 ng/ml) of TNF-alpha for 7 days. Induction of differentiation was assessed by means of morphology, cytochemistry, immunophenotyping (CD11b, CD13, CD14, CD33), and nitroblue tetrazolium reduction. In all cases, exposure of leukemic blasts to TNF-alpha resulted in phenotypic changes consistent with induction of differentiation, although a marked variability in degree and type of response was observed. The majority of cases developed monocytic morphology and showed significant increases (chi 2 test, p less than 0.05) in phagocytic activity and/or expression of ANAE and myelomonocytic differentiation antigens (CD11b, CD14). TNF-alpha reduced c-myc mRNA level over a period of 24 hr in four of six cases studied: the two cases with no down-regulation were the least responsive in terms of myelomonocytic differentiation. These results confirm those obtained with leukemic cell lines, suggesting that TNF-alpha can induce differentiation of fresh AML blasts, mainly toward the monocytic lineage, and that induction of differentiation seems to be closely linked to down-regulation of c-myc mRNA expression over the first 24 hr rather than to attenuation of cellular proliferation per se.

Bone Marrow↗
PubMed1989

Growth of human hematopoietic colonies from patients with myelodysplastic syndromes in response to recombinant human granulocyte-macrophage colony-stimulating factor.

The in vitro effect of recombinant human GM-CSF (rHuGM-CSF) was tested on bone marrow-derived multilineage (CFU-GEMM) as well as megakaryocytic (CFU-Mk), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitors in a group (n = 16) of patients with myelodysplastic syndromes (MDS). Hematopoietic progenitor cell growth was markedly impaired in MDS patients as compared to normal controls (p less than 0.05, at least). Recombinant HuGM-CSF supported the growth of CFU-GEMM, CFU-Mk, and BFU-E at lower, equivalent, or slightly higher frequencies that those found in cultures plated with medium conditioned by peripheral blood leukocytes (PHA-LCM), but it was invariably ineffective in improving growth values. Recombinant HuGM-CSF supported the growth of granulocyte-macrophage colonies in 15 of 16 cases. The overall incidence (mean +/- SEM) of CFU-GM in cultures containing rHuGM-CSF (5 ng/ml) was significantly higher than the one found in cultures stimulated with PHA-LCM (40 +/- 15 vs. 17 +/- 7, p less than 0.05). Upon culture with rHuGM-CSF (5 ng/ml), in 5 of 15 patients de novo colony formation was observed (8 +/- 4) and in 4 of 15 patients CFU-GM growth (129 +/- 33) fell within normal range. Doses of rHuGM-CSF higher than 5 ng/ml did not result in a further increase of MDS-derived colony formation. It is concluded that rHuGM-CSF (a) does not improve the growth of CFU-GEMM, CFU-Mk, and BFU-E; (b) may completely restore the growth of CFU-GM in a subgroup of MDS patients; (c) while ineffective in improving anemia and thrombocytopenia, its in vivo in MDS may correct leukopenia through an effect at the level of granulocyte-macrophage progenitor cell compartment, at least in a subset of highly responsive patients.

Adult↗
PubMed1989

The effects of cefonicid on the pharmacokinetics of a once-a-day theophylline formulation.

The authors have explored the effects of cefonicid on the steady-state pharmacokinetics of a new sustained-release theophylline formulation in 12 adult patients suffering from chronic obstructive lung disease, by comparing the pharmacokinetic data obtained following four days of medication with theophylline alone with those found at the end of seven days of combined treatment with the same theophylline preparation plus cefonicid. Blood theophylline levels were assessed in duplicate by polarized immunofluorescence with a TDx analyser. Theophylline kinetics were totally unaffected by simultaneous cefonicid treatment, showing that the two drugs may be administered together without any need for adjustment of the theophylline dosage.

Adult↗
PubMed1989

Evidence of muscarinic receptor subtypes in airway smooth muscle of normal volunteers and of chronic obstructive pulmonary disease patients.

Since there have been only a few studies on muscarinic receptor subtypes in airway smooth muscle, the effect was investigated of pirenzepine on airways of patients with chronic obstructive pulmonary disease (COPD) and the functional responses compared from these patients with those from healthy subjects. Our data demonstrated that the therapy with pirenzepine significantly improved ventilatory function in patients with COPD. The data also suggested that this drug exerts its action on small airways, but not larger airways in normal subjects. It is possible that in healthy human beings pirenzepine produces mild bronchodilation by means of a vagal efferent blockade, while in patients with COPD, it may be effective because it not only decreases the activity of the vagal efferent pathway, but also decreases the sensitivity of vagal sensory endings and causes a vagal afferent blockade.

Atropine↗
PubMed1989

Muscarinic M-1 receptors mediate the bronchial hyperresponsiveness during methacholine inhalation.

Several data suggest that muscarinic M-1 receptors are located on airway smooth muscle of human beings and dogs. Muscarinic M-1 receptors, whose stimulation is associated with enhancement of acetylcholine release, may also be located in the airway parasympathetic ganglia. To determine if postsynaptic muscarinic M-1 receptors mediate airway constriction, the action was compared of pirenzepine, that antagonizes selectively muscarinic M-1 receptors, and atropine, that blocks both muscarinic M-1 and M-2 receptors, on bronchial responses to methacholine inhalation in seven asthmatic patients. Pirenzepine and atropine gave protection against methacholine; however, the degree of protection by pirenzepine was significantly less than that given by atropine. Some inhibitory effect was obtained in all the patients studied after pirenzepine administration, even though some patients were only slight responders. The significant finding of the study is that pirenzepine partially inhibits the bronchospastic response to methacholine. This result suggests that muscarinic receptors on airway smooth muscle are also of the M-1 subtype.

Administration, Inhalation↗
PubMed1989

Effects of desferrioxamine on normal and leukemic human hematopoietic cell growth: in vitro and in vivo studies.

The iron chelator desferrioxamine (DFO) has been previously shown to be an S-phase inhibitor of cell proliferation. To investigate its potential as an antileukemic drug, we first studied the effects of DFO on the in vitro growth of normal human hematopoietic progenitors (CFU-GM and BFU-E) and clonogenic cells from human leukemic cell lines. Then we evaluated the effects of DFO on progression of leukemia refractory to conventional therapy in two individuals. Micromolar concentrations of DFO determined a dose-dependent inhibition of normal progenitor growth, with inhibitory dose 50% (ID50) for CFU-GM and BFU-E being 6.7 and 5.5 microM/liter, respectively. Marked inhibitory effects were observed on clonogenic cells from HL-60 (ID50 = 1.4 microM/liter) and U-937 (ID50 = 3.6 microM/liter) human leukemic cell lines grown in semisolid medium. When DFO was given intravenously to a patient with lymphoid blast crisis of chronic myelogenous leukemia, a marked reduction in circulating blast count was observed. On the contrary, no in vivo effect was observed in a patient with acute nonlymphocytic leukemia having transfusional iron overload. We conclude that: (a) DFO is an inhibitor of both normal and leukemic myeloid cell proliferation in vitro; (b) our limited in vivo observations and a previous case study suggest that intravenous administration of DFO to patients with normal to low plasma iron may result in leukemic cytoreduction in vivo.

Anemia, Refractory, with Excess of Blasts↗
PubMed1988

Effects of recombinant human H-subunit and L-subunit ferritins on in vitro growth of human granulocyte-monocyte progenitors.

We have studied the influence of purified recombinant human H-subunit (rHF, acidic) and L-subunit (rLF, basic) ferritins on in vitro colony formation by normal human granulocyte-macrophage progenitor cells (CFU-GM). Whereas rLF had no significant effect, rHF produced significant decrease in colony formation: mean inhibition of CFU-GM was 38% +/- 13% at 10(-8) M and 22% +/- 13% at 10(-9) M. The inhibitory activity of rHF was lost at 10(-10) M, and was inactivated with a monoclonal antibody recognizing the H subunit, but not with a monoclonal antibody recognizing the L subunit. Although H-type isoferritins were found in normal and leukaemic cells, their concentration in peripheral blood plasma and bone marrow plasma from normal subjects and patients with different haematological disorders including acute leukaemia were 10(-11) M or lower, i.e. levels showing no activity in vitro. We conclude that: (i) acidic H-subunit-rich isoferritins have inhibitory effects on in vitro growth of granulocyte-macrophage progenitors; (ii) levels of these isoferritins in peripheral blood and bone marrow plasma are 2-3 orders of magnitude lower than the effective concentrations in vitro, indicating that these molecules do not behave as circulating regulatory or suppressive factors in vivo.

Bone Marrow Cells↗
PubMed1988

Killing of K562 cells with conjugates between human transferrin and a ribosome-inactivating protein (SO-6).

Cellular iron uptake is mediated by binding of transferrin with specific surface receptors and internalization of the Fe-transferrin-receptor complex. This has been examined as a possible pathway for carrying into leukaemic cells a ribosome-inactivating protein (RIP), SO-6, derived from Saponaria officinalis. Purified human differic transferrin was conjugated with SO-6 and a pool of proteins was obtained, with variable numbers of SO-6 molecules linked to a single transferrin molecule. Human erythroleukaemic K562 cells were grown in the presence of human transferrin, SO-6 and human transferrin conjugated with SO-6. The conjugate was found to be internalized via binding with transferrin receptor. Whereas the presence of unconjugated human transferrin and SO-6 in the medium did not significantly influence K562 cell growth, the conjugated proteins displayed an inhibitory activity on cell proliferation. This was maximal after 72 h at a transferrin concentration of 10(-9) M, with about 50% of cells being killed. Bovine transferrin, present in fetal calf serum, did not appear to compete with human diferric transferrin in binding to K562 cells in suspension culture. In a clonogenic assay, colony formation by leukaemic cells was not influenced by free SO-6 or transferrin, whereas the conjugated proteins were markedly inhibitory (about 100% at 10(-9) M). Our findings indicate that SO-6 can be efficiently carried into mammalian cells via the transferrin-transferrin receptor cycle and exert its ribosome inactivating activity. This is in keeping with the existence of an alternative pathway of transferrin endocytosis in addition to the classic acidic endosome pathway. From a practical viewpoint, conjugates between transferrin and SO-6 can be useful tools for studying the expression of transferrin receptors, and deserve also to be investigated for a possible use in cancer therapy.

Humans↗
PubMed1988

Prognostic parameters in myelodysplastic syndromes: a multiple regression analysis.

The influence on survival of 21 basic clinical and hematologic parameters was evaluated in 72 patients with previously untreated myelodysplastic syndromes (MDS). Only five parameters were significant by both survival curves and multiple regression analyses: hemoglobin level, bone marrow (BM) cellularity (estimated from trephine BM biopsies), BM blast percentage, age and BM erythro/myeloid (E/M) ratio. Using these parameters, multiple regression analysis enabled us to predict 34% of the survival of all MDS patients (p less than 0.002), 38% of that of patients who had stable disease (p less than 0.04) and over 80% of that of patients who developed acute leukemia (p less than 0.02). High BM cellularity was the most predictive factor for the development of leukemia. No factor was predictive for patients who died of cytopenic or other complications.

Humans↗
PubMed1988

Ferrokinetic measurement of erythropoiesis.

Ferrokinetic measurements have proved useful because of the dominant role of the erythron in tissue iron uptake. Detailed measurements of the plasma iron disappearance curve coupled with in vivo counting have defined the major pathways of iron utilization and early refluxes of iron into plasma. Recent studies have disclosed two separate plasma kinetic pools consisting of mono- and diferric transferrin, and have demonstrated the effect of their relative abundance on tissue iron uptake. Allowance for the amount of each has made possible the calculation of iron-bearing transferrin uptake, which is independent of plasma iron concentration as long as receptors are saturated. This refinement permits the measurement of functional erythron transferrin receptors, and thereby the relative number of immature erythroid cells.

Anemia↗
PubMed1988

Recombinant gamma-interferon induces in vitro monocytic differentiation of blast cells from patients with acute nonlymphocytic leukemia and myelodysplastic syndromes.

gamma-Interferon (IFN-gamma) has previously been found to induce monocytic differentiation in established leukemic cell lines, such as HL-60 and U937. The aim of the present study was to evaluate the differentiative effect of highly purified recombinant (r)IFN-gamma on fresh bone marrow cells from patients with acute nonlymphocytic leukemia (n = 11) or myelodysplastic syndromes (n = 3). Blast cells were cultured in suspension in the presence or absence of rIFN-gamma (10-10(3) U/ml). While 6 out of 14 cases were unresponsive to rIFN-gamma in vitro, the remaining 8 patients showed a significant increase (0.05 greater than p greater than 0.001) in the percentage of cells expressing C3bi receptors, detected by OKM1 (median value in control cell, 9.5; median value in rIFN-gamma-treated cells, 31) and Mo1 (8.5 vs. 36), and in the percentage of cells expressing the monocytic antigens detected by Mo2 (8 vs. 28) and MY4 (6.5 vs. 32.5). In the responsive patients morphologic changes consistent with monocytic maturation, as well as a strong increase of alpha-naphthyl acetate esterase activity and of nitroblue tetrazolium reducing capability were observed upon culture with rIFN-gamma. We conclude that (a) rIFN-gamma may induce in vitro monocytic differentiation of blasts from acute nonlymphocytic leukemia and myelodysplastic syndrome patients, and that (b) this agent should be investigated for its capacity to be active in vivo.

Acute Disease↗
PubMed1988

Synergistic antiproliferative effect of recombinant interferon-gamma with recombinant interferon-alpha on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM).

Recombinant interferons, alpha (rIFN-alpha) and gamma (rIFN-gamma), have been demonstrated to have significant antitumor activity as single agents in the treatment of chronic myelogenous leukemia (CML). Due to their possible synergistic efficacy, a combination rIFN therapy in CML has been proposed. To establish a biologic basis for this, we have studied the suppressive effects of rIFN-alpha and rIFN-gamma on the in vitro growth of CML-derived progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, CFU-GM), the optimal conditions for rIFN synergism, and the possible role of hematopoietic accessory cells (T-lymphocytes and monocytes-macrophages) in mediating rIFN-induced growth inhibition. When added to unseparated bone marrow cells, rIFN-alpha and rIFN-gamma significantly reduced colony formation, with 50% inhibition occurring at 71 and 186 U/mL for CFU-GEMM, 40 and 152 U/mL for CFU-Mk, 222 and 1,458 U/mL for BFU-E, and 119 and 442 U/mL for CFU-GM, respectively. A small amount of rIFN-gamma (5 U/mL) acted synergistically with increasing doses of rIFN-alpha, and the values of 50% inhibitory concentrations fell outside the lower limit (10 U/mL) used in our experiments. This synergy was evident even when rIFN-gamma was added 72 hours after the initiation of cultures; however, it was completely lost when the target cells were depleted of accessory cells. When a low dose of rIFN-alpha (5 U/mL) was added to rIFN-gamma, the 50% inhibitory concentration values were decreased up to tenfold. These studies (1) confirm that CML-derived hematopoietic progenitors are responsive to the suppressive activity of both rIFN-alpha and rIFN-gamma in vitro, (2) demonstrate that different mechanisms are responsible for the suppressive activity of the two rIFNs, and (3) characterize their synergistic interaction, providing a basis for future clinical trials aimed at investigating combination rIFN therapy in CML.

Bone Marrow↗