A global strategy for prevention and detection of blood doping with erythropoietin and related drugs.
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Blood Chemical Analysis↗
Biomedical subjects
M Cazzola
Publications and source records attributed to M Cazzola.
Potential role of macrolides in the treatment of asthma.
A body of evidence highlights the fact that macrolides may not only enhance the host defence system through increased cytokine synthesis by host cells but also exhibit anti-inflammatory activity by including anti-inflammatory cytokines. Several authors have stressed the possibility that macrolides are useful in the treatment of asthma because of their antimicrobial activity rather than any anti-inflammatory action. However, the mechanism of action of macrolides in improving asthma and reducing airway responsiveness is speculated not to be due to their antibiotic properties, especially when these agents are active in noninfectious asthma. The steroid-sparing effect of macrolide antibiotics has been postulated to contribute to their beneficial actions in the treatment of asthma. Nevertheless, a number of studies have shown that macrolides antibiotics have an anti-inflammatory effect which is independent of their antibiotic action or any influence on corticosteroid metabolism. Macrolides may be useful in the treatment of patients with steroid-dependent asthma, probably because they inhibit eosinophilic inflammation. It has also been suggested that the effect of macrolides on bronchial hyperresponsiveness is mediated by their inhibitory action on superoxide production and chemotaxis of polymorphonuclear neutrophils and the mixed lymphocyte reaction. In any case, it is clear that the mechanism of action of macrolides in asthmatic syndrome is not unequivocal. Only well-designed and -conducted clinical studies are capable of assessing the efficacy and safety of immunosuppressive macrolides in the treatment of asthma.
Anti-Asthmatic Agents↗
Haematologica's impact factor
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Journal Article↗
Alternatives to conventional or myeloablative chemotherapy in myelodysplastic syndrome.
At present, the only 2 treatments that can prolong survival in patients with myelodysplastic syndrome (MDS) are allogeneic stem cell transplantation and intensive chemotherapy. Alternatives to myeloablative or conventional chemotherapy include: (1) supportive therapy, (2) stimulation of normal residual hematopoietic progenitors, and (3) manipulation of myelodysplastic hematopoiesis. These alternative therapeutic strategies can be accomplished using various therapeutic tools. Supportive therapy remains the mainstay in the management of MDS patients and desferrioxamine should be administered to individuals who have a regular need for blood transfusion. The only hematopoietic growth factors that can be useful in the treatment of selected MDS patients are recombinant human erythropoietin (rhEpo) and granulocyte colony-stimulating factor (G-CSF). Overall, 15% to 20% of patients with MDS respond to rhEpo treatment. Factors predicting response include serum erythropoietin levels <100 to 200 mU/mL, low-risk MDS, and no or low need for transfusion. G-CSF alone should be used only for short-term treatments during severe infection episodes that do not respond to conventional therapy. About 40% of MDS patients respond to a combined treatment of rhEpo plus G-CSF with amelioration of anemia. Cytoprotective antiapoptotic agents such as amifostine, alone or in combination, may improve blood values in occasional MDS patients. MDS patients with immunologically mediated myelosuppression may respond favorably to antithymocyte globulin or cyclosporin A (CyA). Although rhEpo and CyA may be used in individual patients who appear likely to respond, the remaining therapeutic tools must be considered strictly experimental; phase III clinical trials are required to establish whether they can be useful in the treatment of MDS patients. More generally, because of the current uncertainties concerning MDS treatment, participation of patients in clinical trials should be always encouraged.
Antineoplastic Agents↗
Mechanisms of anaemia in patients with malignancy: implications for the clinical use of recombinant human erythropoietin.
Anaemia is a frequent finding in cancer and may be due to different causes. In untreated subjects, the most common type is the so-called anaemia of chronic disease, a condition characterised by excessive release of cytokines such as interleukin-1 and tumour necrosis factor. These peptides both inhibit erythroid marrow proliferation and blunt the normal exponential relationship between haematocrit and serum erythropoietin. Chemotherapy may cause or worsen anaemia in cancer patients. Cisplatin appears to be peculiar in that this drug can blunt erythropoietin production and cause prolonged anaemia. Controlled studies have demonstrated that recombinant human erythropoietin (rHuEPO) can ameliorate anaemia in patients with malignancy and prevent chemotherapy-induced anaemia. However, improvement of anaemia following rHuEPO treatment is seen in only a portion of cancer patients, and significant improvements of quality of life cannot be demonstrated in all responsive patients. Therefore, an important issue remains whom to treat.
Anemia↗
Current thinking and treatment practices in anaemia--an interactive poll.
At the recent EHA meeting in Birmingham, UK, an expert audience of haematologists and oncologists were polled using keypad technology on current thinking and treatment practices in anaemia in cancer patients. More than 76% of the audience thought that anaemia had a significant negative impact on the quality of life of cancer patients. The majority (> 60%) would institute treatment on the basis of appropriate symptoms rather than haemoglobin level, although among those who would use haemoglobin levels, there was no consensus on the concentration at which they would start treatment. The majority of respondents (54%) chose not to use the serum erythropoietin level as a guide as to when to institute therapy with recombinant human erythropoietin (rHuEPO) but, of those who would use it, 55% would use onlythe haemoglobin or haematocritto identify those responding within thefirst 2-4weeks of treatment. The remainder of the session used three case studies to investigate current treatment practices.
Anemia↗
Cord blood-derived hematopoietic progenitor cells: in vitro response to hematopoietic growth factors and their recruitment into the S-phase of the cell cycle.
BACKGROUND AND OBJECTIVES: In the recent years many studies on the expansion of cord blood (CB)-derived progenitor cells have been performed, whereas less information is available on their cycling status. The objective of this study was to evaluate the cycling status of CB-derived colony-forming cells (CFC) and long-term culture-initiating cells (LTC-IC), and their recruitment into the S-phase of the cell cycle in response to a combination of cytokines. DESIGN AND METHODS: CB-derived CFC and LTC-IC were first quantified by standard clonogenic assay and long-term culture, respectively. In a second set of experiments, CB-derived progenitor cells were incubated with interleukin(IL)-3, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) and their cell cycle status assessed both by the cytosine arabinoside (Ara-C) suicide approach and by flow cytometric DNA analysis. RESULTS: We found that only small proportions of both CFC and LTC-IC were in the S-phase of the cell cycle. These estimates were confirmed by flow cytometric DNA analysis, which showed that 96% +/- 2% of CB-derived CD34+ cells were in G0/G1 and only 1.6% +/- 0.4% in the S-phase. Staining of CD34+ cells with an anti-statin monoclonal antibody, a marker of the G0 phase, indicated that among CD34+ cells with a flow cytometric DNA content typical of the G0/G1 phase, 68% +/- 7% of cells were in the G0 phase of the cell cycle. Twenty-four hour incubation with IL-3, SCF and G-CSF significantly increased the proportion of cells in the S-phase for both CFC and LTC-IC without inducing any loss in their number. Flow cytometric DNA analysis also showed an increase of CD34+ cells in the S-phase upon continuous exposure to these cytokines. INTERPRETATIONS AND CONCLUSIONS: Our findings indicate that: i) a small number of CB-derived CFC and LTC-IC are in the S-phase of the cell cycle; ii) a substantial number of CD34+ cells with a flow cytometric DNA content typical of the G0/G1 fraction are cycling, as they are found in the G1 phase of the cell cycle; iii) 24-hour incubation with IL-3, SCF and G-CSF can drive a proportion of progenitor cells into the S-phase without reducing their number.
Cells, Cultured↗
Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome.
Hereditary hyperferritinemia-cataract syndrome (HHCS) is a novel genetic disorder characterized by elevated serum ferritin and early onset cataract formation. The excessive ferritin production in HHCS patients arises from aberrant regulation of L-ferritin translation caused by mutations within the iron-responsive element (IRE) of the L-ferritin transcript. IREs serve as binding sites for iron regulatory proteins (IRPs), iron-sensing proteins that regulate ferritin translation. Previous observations suggested that each unique HHCS mutation conferred a characteristic degree of hyperferritinemia and cataract severity in affected individuals. Here we have measured the in vitro affinity of the IRPs for the mutant IREs and correlated decreases in binding affinity with clinical severity. Thermodynamic analysis of these IREs has also revealed that although some HHCS mutations lead to changes in the stability and secondary structure of the IRE, others appear to disrupt IRP-IRE recognition with minimal effect on IRE stability. HHCS is a noteworthy example of a human genetic disorder that arises from mutations within a protein-binding site of an mRNA cis-acting element. Analysis of the effects of these mutations on the energetics of the RNA-protein interaction explains the phenotypic variabilities of the disease state.
Base Sequence↗
Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.
X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband's maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance of HFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.
5-Aminolevulinate Synthetase↗
Prescribing habits of general practitioners in choosing an empirical antibiotic regimen for lower respiratory tract infections in adults in Sicily.
The survey was carried out, between September 1995 and May 1996, in order to describe the prescriptive behaviour among Sicilian general practitioners (GPs) in choosing an empirical antibiotic regimen for LRTIs in adult patients and begin an educational process which involves the same GPs in decisions regarding their prescriptions and in performing local guidelines. Each practitioner filled out a questionnaire for each therapeutic intervention which ended with an antibiotic prescription. The questionnaire also enquired into the patient's characteristics, diseases to be treated and drug prescription. Doctors were asked to give an opinion about the severity assessment of the infectious disease before choosing the antibiotic treatment, in order to evaluate the prescriptive behaviour of physicians related to the patient's symptoms. Of all Sicilian GPs approached, 76 physicians from 25 Sicilian towns, with a patient population of 96,630, agreed to participate. The GPs used 49 different molecules and six different associations of two antibiotics. The most frequently used antibacterial agents were cephalosporins (55.0%). Penicillins (11.7%), fluoroquinolones (11. 4%), macrolides (10.1%) and combinations of penicillins with beta-lactamase inhibitors (7.9%), together, represented 41.1% of the remaining antibiotic prescriptions. The choice of the route of administration was significantly influenced by age of the patients, by symptoms and signs of the disease and by the presence of concurrent diseases rather than by bacteria suspected of causing the disease. The rather marked variation in antibiotic prescribing pattern for LRTIs among Sicilian GPs reflects lack of availability or knowledge of any local or national guidelines about the management of these diseases.
Adolescent↗
Incremental benefit of adding oxitropium bromide to formoterol in patients with stable COPD.
The effects of the long-acting beta(2)-agonist formoterol, the anticholinergic drug oxitropium bromide, and their combination were compared in 16 patients with partially reversible stable COPD. On each of 4 study days patients inhaled both drugs separated by 180 min in alternate sequence, with formoterol being administered in two doses (formoterol 12 microg + oxitropium bromide 200 microg; oxitropium bromide 200 microg + formoterol 12 microg; formoterol 24 microg + oxitropium bromide 200 microg; oxitropium bromide 200 microg + formoterol 24 microg). FEV(1)and FVC were measured baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. In terms of onset of action, formoterol performed better than oxitropium bromide. Within the first 180 min after inhalation formoterol 24 microg was the most effective drug (maximal change in FEV(1): formoterol 24 microg = 25.6%, formoterol 12 microg = 21.1%, oxitropium bromide = 18.2%). Increased bronchodilation was obtained when the second drug was added, the sequence formoterol 24 microg + oxitropium bromide being the most effective (maximal change in FEV(1)over baseline: formoterol 24 microg + oxitropium bromide 28.8%, oxitropium bromide + formoterol 24 microg 20.9%, formoterol 12 microg + oxitropium bromide 26.6%, oxitropium bromide + formoterol 12 microg 22.5%). Significant improvement in pulmonary function may be achieved by giving two different bronchodilators in stable COPD patients. The sequence formoterol 24 microg + oxitropium bromide 200 microg seems to be the most effective.
Administration, Inhalation↗
Oral bambuterol compared to inhaled salmeterol in patients with partially reversible chronic obstructive pulmonary disease.
OBJECTIVE: There is now good evidence that inhaled salmeterol is an effective agent in chronic obstructive pulmonary disease (COPD),but, at the present time, data on the effects of bambuterol, which is an oral tarbutaline pro-drug, in patients with COPD are scarce. Moreover, no comparative study between bambuterol and salmeterol in patients with chronic obstructive airway disorders has been published. The objective of this research was, consequently, to compare the efficacy and safety of 20 mg oral bambuterol and 50 microg inhaled salmeterol in patients with partially reversible COPD. METHODS: The speed and length of bronchodilation with 20 mg bambuterol and 50 microg inhaled salmeterol were compared in 16 patients with partially reversible COPD. The investigation and designed as a double-blind, double-dummy, cross-over, placebo controlled and randomised study. Lung function (FEV1, FVC) and systemic variables (subjective tremor, heart rate, blood pressure) were monitored prior to the administration of the drug and for 12 h after each agent on 3 non-consecutive days. RESULTS: Inhalation of salmeterol induced a significant (P < 0.05) increase of lung function when compared with placebo. In addition, oral bambuterol elicited good bronchodilation, with its maximum slightly later than for salmeterol. The mean (+/- SE) AUC(0-12h)S for all patients were 3.134 1 +/- 0.553 for salmeterol and 1963 1 +/- 0.573 for bambuterol. Both AUC(0-12h)S were significantly greater than for placebo (P < 0.05), but there was no significant difference (P = 0.077) between the salmeterol and bambuterol AUC(0-12h)S. Bambuterol, but not salmeterol, caused tremor in four patients. Moreover, it induced a higher heart rate when compared with salmeterol at each considered time after the administration of the drug; differences after 9 and 12 h were statistically significant (P < 0.05). CONCLUSION: Both oral bambuterol and inhaled salmeterol resulted in good bronchodilation in patients with stable COPD. However, bambuterol, but not salmeterol, caused tremor in several subjects and elicited a more pronounced tachycardia.
Administration, Inhalation↗
Should long-acting beta 2-agonists be considered an alternative first choice option for the treatment of stable COPD?
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Adrenergic beta-Agonists↗
Influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in COPD.
We examined the influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in patients with partially reversible stable COPD. Twenty outpatients inhaled one or two puffs of formoterol (12 microg puff(-1)), or placebo. Two hours after inhalation, a dose-response curve to inhaled oxitropium bromide (100 microg puff(-1)) or placebo was constructed using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 microg oxitropium bromide. Doses were given at 20-min intervals and measurements made 15 min after each dose. On six separate days, all patients received one of the following: (1) formoterol 12 microg + oxitropium bromide 600 microg, (2) formoterol 12 microg + placebo, (3) formoterol 24 microg + oxitropium bromide 600 microg, (4) formoterol 24 microg + placebo, (5) placebo + oxitropium bromide 600 microg, or (6) placebo + placebo. Both formoterol 12 microg and 24 microg induced a good bronchodilation (formoterol 12 microg, 0.19-0.20 l; formoterol 24 microg 0.22-0.24 l). The dose-response curve of oxitropium, but not placebo, showed an evident increase in FEV1, with a further significant increase of respectively 0.087 l and 0.082 l after the formoterol 12 microg and formoterol 24 microg pre-treatment. This study shows that improved pulmonary function in patients with stable COPD may be achieved by adding oxitropium 400-600 microg to formoterol. There is not much difference in bronchodilation between combining oxitropium with formoterol 12 microg or 24 microg. In any case, formoterol 24 microg alone seems sufficient to achieve the same bronchodilation induced by oxitropium 600 microg alone in most patients.
Administration, Inhalation↗
Periodic breathing during sleep in patients affected by fibromyalgia syndrome.
Seventeen patients affected by fibromyalgia syndrome (FMS) (16 females and one male) and 17 matched healthy subjects underwent formal polysomnography, a sleep questionnaire and lung function tests. FMS patients slept significantly less efficiently than the healthy controls (p<0.01), had a higher proportion of stage 1 sleep (mean+/-SD, 21+/-6% versus 11+/-4%; p<0.001), less slow wave sleep (p<0.01) and twice as many arousals per hour of sleep (p<0.001). The respiratory pattern of FMS patients showed a high occurrence of periodic breathing (PB) (15+/-8% of total sleep time) in 15/17 patients, versus 2/17 control subjects. The short length of apnoeas and hypopnoeas did not affect the apnoea/hypopnoea index (5.1+/-3.5 versus 3.2+/-1.6; NS), but FMS patients had a greater number of desaturations per hour of sleep (8+/-5 versus 3+/-3; p<0.01). Pulmonary volumes did not differ between the two groups, but FMS patients had a lower transfer factor of the lung for carbon monoxide (TL,CO (5.8+1 versus 7.7+1 mmol x min(-1) x kPa(-1); p=0.001). PB occurrence correlated with TL,CO (r=-0.62; p=0.01), number of desaturations (r=0.76, p=0.001) and carbon dioxide tension in arterial blood (Pa,CO2) (r=-0.50; p=0.05). Stepwise multiple linear regression analysis showed desaturation frequency (p=0.0001) and TL,CO (p=0.029) to be the best predictors of PB percentage (R2 0.73; p=0.0001). Patients complaining of daytime hypersomnolence had a higher number of tender points, about twice as many arousals per hour and a lower sleep efficiency than patients who did not report this symptom. TL,CO was more impaired and the occurrence of PB was higher. The occurrence of periodic breathing in fibromyalgia syndrome patients, which was previously unreported, and is shown to be linked to a reduction of transfer factor of the lung for carbon monoxide could play a major role in the symptoms of poor sleep of these patients.
Disorders of Excessive Somnolence↗
A model for analysing the cost of autologous peripheral blood progenitor cell (PBPC) transplantation.
Data from autologous peripheral blood progenitor cell (PBPC) transplant recipients were used for cost analysis and modelling so as to link the main intervention procedures and clinical events to resource use and costs. This cohort consisted of 64 patients from 4 to 62 years old at transplantation (mean, 36.9 years) who underwent a first transplant between August 1994 and May 1997. The main indications for transplantation were non-Hodgkin's lymphomas (47%), multiple myeloma (30%) and Hodgkin's lymphomas (15%). The course of a patient during the whole transplant procedure was modelled using a Markov chain of six states of health: (1) mobilisation and recovery of PBPC; (2) post-mobilisation phase; (3) conditioning and transplant; (4) critical haematological reconstitution; (5) non-critical haematological reconstitution; (6) death. The probability of transition between the different health states, together with the estimated costs, were the input for the Markov model. The model also managed transition probabilities depending both on the current health state and on various demographic, clinical and procedure-related covariates unique to the patient. The expected time spent in each clinical state and the expected total cost were, therefore, estimated. This analysis gave an actual total cost per transplanted patient of $26,600 (95% range: $24,700 to $43,500) while mean duration was 197 days. The expenses for in-hospital stay accounted for 80% of the costs. Both the probability of staying in the different states, and the consequent cost were dependent on the number of CD34-positive cells collected, the phase and the type of the disease, the subset of patients (either children or adults), and the post-transplant G-CSF prophylaxis. The sensitivity of the estimates to alternative assumptions was studied, and the method of comparing alternative future scenarios by the model was explored.
Adolescent↗
Normal primitive haemopoietic progenitors are more frequent than their leukaemic counterpart in newly diagnosed patients with chronic myeloid leukaemia but rapidly decline with time.
We carried out studies to quantify Ph-negative progenitors both in steady state and during regeneration after chemotherapy and G-CSF in 23 newly diagnosed chronic myeloid leukaemia (CML) patients (group A) and in 14 individuals more than a year from diagnosis (nine in chronic and five in accelerated phase, group B). In steady-state bone marrow, Ph-negative long-term culture initiating cells (LTC-IC) and Ph-negative colony-forming-cells (CFC) were detected in 18/23 and 14/23 patients of group A versus 3/14 and 3/14 patients of group B (P<0.001 and P<0.02, respectively). The absolute number of mobilized Ph-negative progenitors was markedly higher in group A versus group B (P<0.02 for LTC-IC, P<0.003 for CFC). 12/16 newly diagnosed patients mobilized Ph-negative LTC-IC only and the yield was in the range of normal allogeneic donors. Overall the frequency of Ph-negative LTC-IC in the bone marrow predicted the yield of Ph-negative LTC-IC mobilized into peripheral blood (P<0.001). The bone marrow frequency of Ph-positive LTC-IC was considerably lower than the normal counterpart. Taken together, these findings suggest that normal progenitors are relatively well preserved in newly diagnosed CML patients, but tend to rapidly decline with time. This observation helps in the understanding of the pathogenesis of CML and has potential implications for autografting. The optimal time for a successful collection of Ph-negative circulating progenitors would appear to be soon after diagnosis.
Adult↗
Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis.
Congenital anaemias due to ineffective erythropoiesis may be associated with excessive iron absorption and progressive iron loading. We investigated whether the soluble transferrin receptor (TfR) level was related to the degree of iron overload in 20 patients with thalassaemia intermedia, six patients with congenital dyserythropoietic anaemia type II (CDA II) and four patients with X-linked congenital sideroblastic anaemia (XLSA). All but two patients had increased serum ferritin levels (median 601 microgram/l, range 105-2855 microgram/l). Multiple regression analysis showed that 62% (P < 0.0001) of the variation in serum ferritin was explained by age and by changes in soluble TfR.
Adolescent↗