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Biomedical subjects

M Cazzola

Publications and source records attributed to M Cazzola.

At least 19 recordsLinked to original sources
PubMed2001

Onset of action of single doses of formoterol administered via Turbuhaler in patients with stable COPD.

We studied 16 patients with stable COPD in a double blind, double dummy, placebo-controlled, within patient study to see if formoterol could be used as a rescue drug. We compared the of onset of bronchodilation obtained with formoterol 12 microg (metered dose corresponding to 9 microg delivered dose) and formoterol 24 microg (metered dose corresponding to 18 microg delivered dose), both delivered via Turbuhaler, with that of salbutamol 400 microg and salbutamol 800 microg delivered via pressurized metered-dose inhaler (pMDI). Patients inhaled single doses of placebo, formoterol and salbutamol on five separate days. FEV1 was measured in baseline condition and 3, 6, 9, 12, 15, 18, 21, 24, 30, 40, 50, and 60 min after inhalation of each treatment. We examined two separate criteria for deciding if a response was greater than that expected by a random variation of the measurement: (1) a rise in FEV1 of at least 15% from the baseline value; (2) an absolute increase in FEV1 of at least 200 ml. Formoterol 12 microg (15.2 min; 95% CI 9.5-21.0) and formoterol 24 microg (15.1 min; 95% CI 8.9-21.2) caused a rise in FEV1 of at least 15% from the baseline value almost rapidly as salbutamol 400 microg (13.6 min; 95% CI 7.1-20.1) and salbutamol 800 microg (14.5 min; 95% CI 7.1-21.9). No significant difference (P=0.982) in onset of action was seen between the four active treatments. According to Criterion 2, the mean time to 200 ml increase in FEV1 was 11.1 min (95% CI: 7.0-15.2) after salbutamol 400 microg, 13.0 min (95% CI: 7.9-18.1) after salbutamol 800 microg, 14.7 min (95% CI: 7.1-22.4) after formoterol 12 microg, and 12.7 min (95% CI: 7.4-18.0) after formoterol 24 microg. Again, there was no significant difference (P= 0.817) between the four active treatments. Formoterol Turbuhaler 12 microg and 24 microg caused bronchodilation as rapidly as salbutamol 400 microg and 800 microg given via pMDI.

Acute Disease↗
PubMed2001

Advances in the research and development of chemotherapeutic agents for respiratory tract bacterial infections.

The activity of existing antibiotics is diminishing due to the increasing number of resistant strains and by the increase of infections with naturally resistant microorganisms. New agents are urgently needed to meet this challenge and the molecular strategies adopted for the discovery of these compounds must focus on minimizing the emergence of future resistance to them. Novel compounds can be grouped on the basis of their mechanism of action: inhibitors of nucleic acid synthesis (fluoroquinolones), inhibitors of protein synthesis (ketolides, oxazolidinones, streptogramins, and glycylcyclines), inhibitors of peptidoglycan synthesis (beta-lactams and glycopeptides), and agents interfering with membrane function (cationic peptides, and lipopeptides). Regarding the agents that are already in the research and development pipeline, only the oxazolidinones, the cationic peptides and the lipopeptide antibiotics can be truly considered as structurally novel inhibitors because the other agents are analogues of existing compounds that have been in use for many years.

Anti-Bacterial Agents↗
PubMed2001

The role of outdoor air pollution and climatic changes on the rising trends in respiratory allergy.

Evidence suggests that allergic respiratory diseases such as hay fever and bronchial asthma have become more common world-wide in the last two decades, and the reasons for this increase are still largely unknown. A major responsible factor could be outdoor air pollution, derived from cars and other vehicles. Studies have demonstrated that urbanization and high levels of vehicle emissions and westernized lifestyle is correlated with the increasing frequency of pollen-induced respiratory allergy. People who live in urban areas tend to be more affected by pollen-induced respiratory allergy than those from of rural areas. Pollen allergy has been one of the most frequent models used to study the interrelationship between air pollution and respiratory allergic diseases. Pollen grains or plant-derived paucimicronic components carry allergens that can produce allergic symptoms. They may also interact with air pollution (particulate matter, ozone) in producing these effects. There is evidence that air pollutants may promote airway sensitization by modulating the allergenicity of airborne allergens. Furthermore, airway mucosal damage and impaired mucociliary clearance induced by air pollution may facilitate the access of inhaled allergens to the cells of the immune system. In addition, vegetation reacts with air pollution and environmental conditions and influence the plant allergenicity. Several factors influence this interaction, including type of air pollutants, plant species, nutrient balance, climatic factors, degree of airway sensitization and hyperresponsiveness of exposed subjects.

Air Pollution↗
PubMed2001

Pulmonary disposition of lomefloxacin in patients with acute exacerbation of chronic obstructive pulmonary disease. A multiple-dose study.

In this study we have measured the concentrations of lomefloxacin at steady state in serum and in the intrapulmonary region at specified intervals for 24 h following administration of the last dose of drug in patients suffering from acute exacerbation of chronic obstructive pulmonary disease (COPD). Twenty subjects were enrolled. They received lomefloxacin 400 mg orally once-daily for 5 consecutive days. All patients were divided into five groups, with 4 subjects in each group, according to sampling times (2, 4, 8, 12, and 24 h after the last dose). At bronchoscopy, bronchial biopsies and bronchoalveolar lavage (BAL) were performed. At 12 h after the last dose, serum concentration of lomefloxacin was >1.0 microg/mL and at 24 h it was still detectable, but, at all times, the concentrations in bronchial secretion, bronchial mucosa, and epithelial lining fluid (ELF) were greater than the concentrations in serum [bronchial secretions (pg/mL) = 2.5+/-1.2; 2.2+/-1.0: 2.0+/-1.1; 1.8+/-1.1; 0.6+/-0.3. bronchial mucosa (microg/g) = 5.9+/-2.1; 6.2+/-1.8; 2.6+/-2.2; 1.9+/-1.5; 1.0+/-0.9. ELF (microg/mL) = 6.9+/-2.8; 5.9+/-2.6; 3.1+/-1.9; 2.2+/-1.0; 0.8+/-1.3. serum (microg/mL) = 3.2+/-1.4; 2.8+/-0.9: 2.1+/-1.5; 1.2+/-1.1; 0.4+/-0.81. We must stress that we observed a large inter-individual variability in concentrations. Our data show that lomefloxacin once-daily induces high and sustained concentrations in the various potential sites of pulmonary infection and clearly indicate that the pharmacokinetic behavior of this fluoroquinolone permits once-daily administration in patients with acute exacerbations of COPD.

Administration, Oral↗
PubMed2001

Mechanisms and characteristics of airway sensitization to indoor allergens.

The increasing prevalence of allergic respiratory diseases, and particularly of bronchial asthma, has been linked to changes induced by human activities in outdoor and indoor environments. People living in industrialized countries spend most of their time indoors: in private homes, offices and means of transport. Indoor environments are not a refuge from outdoor air pollution. Modern systems for energy saving such as insulated windows and doors reduce the indoor natural ventilation and consequently increase the rate of indoor humidity. These conditions may determine an increase in the level of indoor pollutants (tobacco smoke, gases produced by cooling processes etc.) and of allergens derived from mites, domestic animals and cockroaches. Upholstered furniture, wall-to-wall carpets, central heating systems and/or humidifiers may also contribute to the growth of mite populations. The increasing levels of exposure to pollutants and allergens in indoor environments represents a risk factor for the development of airway sensitization, especially if these materials are inhaled early in life. The major cat allergen Fel d 1 is considered an ubiquitous allergen, since it has been found in many indoor environments where a cat has never been kept. The clothing of cat owners seems to help spread Fel d 1 in cat-free environments. Sensitization to cockroach allergens is very common in patients living in urban areas where unhygenic conditions may favour the growth of cockroach populations. Monitoring of the levels of allergens and strategies of allergen and pollutant avoidance in indoor environments are the main ways to reduce the prevalence of respiratory allergies induced by these materials.

Air Pollution, Indoor↗
PubMed2000

Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females.

X-linked sideroblastic anemia (XLSA) is caused by mutations in the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) gene. An elderly woman who presented with an acquired sideroblastic anemia is studied. Molecular analysis revealed that she was heterozygous for a missense mutation in the ALAS2 gene, but she expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation, had normal hemoglobin levels, and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia both in the proband and her grandson. All women who were analyzed in this family showed skewed X-chromosome inactivation in leukocytes, which indicated a hereditary condition associated with unbalanced lyonization. Because the preferentially active X chromosome carried the mutant ALAS2 allele, acquired skewing in the elderly likely worsened the genetic condition and abolished the normal ALAS2 allele expression in the proband. (Blood. 2000;96:4363-4365)

5-Aminolevulinate Synthetase↗
PubMed2000

Translational pathophysiology: a novel molecular mechanism of human disease.

In higher eukaryotes, the expression of about 1 gene in 10 is strongly regulated at the level of messenger RNA (mRNA) translation into protein. Negative regulatory effects are often mediated by the 5'-untranslated region (5'-UTR) and rely on the fact that the 40S ribosomal subunit first binds to the cap structure at the 5'-end of mRNA and then scans for the first AUG codon. Self-complementary sequences can form stable stem-loop structures that interfere with the assembly of the preinitiation complex and/or ribosomal scanning. These stem loops can be further stabilized by the interaction with RNA-binding proteins, as in the case of ferritin. The presence of AUG codons located upstream of the physiological start site can inhibit translation by causing premature initiation and thereby preventing the ribosome from reaching the physiological start codon, as in the case of thrombopoietin (TPO). Recently, mutations that cause disease through increased or decreased efficiency of mRNA translation have been discovered, defining translational pathophysiology as a novel mechanism of human disease. Hereditary hyperferritinemia/cataract syndrome arises from various point mutations or deletions within a protein-binding sequence in the 5'-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinemia and severity of cataract in affected individuals. Hereditary thrombocythemia (sometimes called familial essential thrombocythemia or familial thrombocytosis) can be caused by mutations in upstream AUG codons in the 5'-UTR of the TPO mRNA that normally function as translational repressors. Their inactivation leads to excessive production of TPO and elevated platelet counts. Finally, predisposition to melanoma may originate from mutations that create translational repressors in the 5'-UTR of the cyclin-dependent kinase inhibitor-2A gene.

5' Untranslated Regions↗
PubMed2000

Exclusion of ZIRTL as candidate gene of juvenile hemochromatosis and refinement of the critical interval on 1q21.

Hemochromatosis type 2 (HFE2) or juvenile hemochromatosis (JH) is a rare recessive disorder that causes iron overload, characterized by early onset and severe clinical course. The JH locus maps to chromosome 1q, in a 4-cM region encompassing markers D1S442 and D1S2347. Recently a gene named ZIRTL has been characterized and mapped to 1q21. This gene belongs to a family of divalent metal ion-transporting genes that encode for proteins involved in transport of different metals, including iron. Thus, the ZIRTL gene represents a positional and functional candidate for JH. Here we further restrict the candidate region through segregation analysis of two new polymorphic markers and haplotype analysis in JH families. Furthermore, we exclude ZIRTL as a JH candidate gene showing that it maps outside the critical interval and that its genomic sequence is normal in three patients.

Carrier Proteins↗
PubMed2000

Parenteral antibiotic therapy in the treatment of lower respiratory tract infections. Strategies to minimize the development of antibiotic resistance.

Antibiotic use is often imputed for increases in the prevalence of infections due to antibiotic-resistant bacteria. Resistance depends on the variety of genotypes in the large bacterial population and also on the selective pressures that are produced along the antibiotic concentration gradients in the body. In effect, at certain selective concentrations the antibiotic eliminates the susceptible majority, leaving a selected remainder intact. Therefore, the choice of antibiotics for the treatment of lower respiratory tract infections should take into consideration not only their effectiveness but also the pharmacokinetics of each agent and its delivery schedule. In fact, the potential therapeutic efficacy of an antibiotic depends not only on its spectrum of action, but also on the concentration it reaches at the site of infection. Most infections occur in the tissues of the body rather than in the blood and that it is accepted that appropriate antibiotic therapy requires the maintenance of significant concentrations of antibiotics at the site of infection in the lung long enough to eliminate the invading pathogen. Thus, the development of dosing schedules for most antimicrobials has been based on the postulate that drug levels need to be above the minimal inhibitory concentration (MIC) at this site for most or all the dosing interval. The selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUIC(0-24)/MIC ratio of less than 100O125. Antimicrobial regimens that do not achieve these values cannot prevent the selective pressure that leads to overgrowth of resistant bacterial subpopulations. It has been suggested that resistance can be avoided with attention to dosing, since dosing which provides an AUIC(0-24)/MIC ratio of at least 100 appears to reduce the rate of the development of bacterial resistance. Unfortunately, very different serum or lung concentration profiles can result in the same AUIC(0-24)/MIC. High doses administered sufficiently may often completely prevent any possibility of attaining a selective concentration. Alternatively, an antibiotic which has good bactericidal potency and maintains tissue and/or serum concentrations greater than the MIC or, better, minimal bactericidal concentration (MBC) throughout the dosing interval is equally effective in minimizing the development of antibiotic resistance.

Anti-Bacterial Agents↗
PubMed2000

Lung function improvement in smokers suffering from COPD with zafirlukast, a CysLT(1)-receptor antagonist.

The present study was designed to evaluate the bronchodilating role of zafirlukast, a CysLT(1)receptor antagonist, at the standard dosage currently recommended in the marketing of this agent in smokers with COPD. The study was performed using a double-blind, cross-over, randomized design and was conducted on 2 non-consecutive days. Sixteen outpatients suffering from stable COPD received 40 mg oral zafirlukast, or placebo. Lung function was controlled before drug administration and 30, 60, 120, 180, 240 min thereafter. At the end of the 4-h period, each patient received 400 microg inhaled salbutamol and spirometric testing was performed 30 min later. Zafirlukast, but not placebo, produced a significant (P<0.05) bronchodilation between 30 min and 4 h following administration, with a maximum mean increase in FEV(1)of 0.134 l (11.2%) above baseline after 2 h. Nine of 16 patients showed an increase in FEV(1)of at least 15% above baseline after zafirlukast. The maximum mean increase in FEV(1)after zafirlukast in these subjects, who were considered responders, observed after 2 h, was 0.221 (19.4%). The mean difference of post-salbutamol FEV(1)values after zafirlukast and placebo (-0.036 l) was not significant (P<0.05). In responders, the mean of differences in pre- and post-salbutamol FEV(1)values after zafirlukast was 0.077 l, whereas the mean of differences between post-salbutamol values after zafirlukast and those after placebo was -0.064 l. The mean AUC(0-4 h)for all patients was 0.121 l for placebo and 0.385 l for zafirlukast. The difference between the placebo and zafirlukast AUC(0-4 h)was significant (P<0.05). The individual FEV(1)AUC(0-4 h)after zafirlukast were higher than those after placebo in 12 out of 16 patients. These findings suggest that cysteinyl leukotrienes might be one of the causes of persistent bronchoconstriction in COPD, at least in several smokers, but do not confirm the hypothesis that the effects of zafirlukast and salbutamol are independent and additive.

Aged↗
PubMed2000

Autografting with Ph-negative progenitors in patients at diagnosis of chronic myeloid leukemia induces a prolonged prevalence of Ph-negative hemopoiesis.

OBJECTIVE: In many patients with chronic myeloid leukemia (CML), a residual population of primitive normal (Ph-negative) progenitors persists despite the marked expansion of the leukemic (Ph-positive) clone. These cells may be found in the blood of patients studied soon after diagnosis or during the period of endogenous hematopoietic recovery that follows myeloreductive therapy. Based on those observations, we have developed a clinical protocol that allows collection of Ph-negative peripheral blood progenitor cells (PBPC) with transplantable hematopoietic regenerative potential. The aim of this study is to examine changes that occur in the percentage of Ph-negative- and Ph-positive-committed progenitor cells and to determine the relationship between changes and clinical outcome. MATERIALS AND METHODS: We followed 15 patients with CML, mobilized and autografted soon after diagnosis with 85%-100% Ph-negative PBPC for a median time of 28 months (range 18-50) after transplant. At 6 months, 1 year, 2 years, and last follow-up, cytogenetic analyses were performed on fresh bone marrow cells and on colony-forming cells (CFC). RESULTS: Autologous transplantation induces a reduction in the proportion of Ph-positive CFC, from 70%-100% to 0%-25% in the majority of patients (78%). After autografting, 8 of 15 patients achieved a long-lasting cytogenetic remission (median, 24 months; range, 21-43) with a Ph-positivity ranging between 0% and 20% at the level of mature mononuclear cells and colony-forming cells (CFC). In some patients, the majority of CFC remained Ph-negative, whereas the majority of the mature cells were Ph-positive. Other patients (5/15) developed cytogenetic relapse (100% Ph-positive), although they were in hematological remission. We found that detection of Ph-positive long-term-culture initiating cells (LTC-IC) in the marrow at diagnosis was the only factor significantly associated with recurrence of the disease (p < 0.01); on the other hand, the number of Ph-negative LTC-IC infused showed a significant correlation with a better outcome (p < 0.03). CONCLUSION: We have shown that a prolonged period of complete or almost complete Ph-negative hemopoiesis can be achieved in patients with CML who undergo autografting with Ph-negative progenitors. Longer follow-up study will be needed to assess whether these changes are associated with improved survival.

Adult↗
PubMed2000

Cell cycle distribution of cord blood-derived haematopoietic progenitor cells and their recruitment into the S-phase of the cell cycle.

The objective of this study was to evaluate the cycling status of cord blood (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. By using the cytosine arabinoside (Ara-C) suicide approach, 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 antistatin 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. Incubation (24 h) with interleukin 3 (IL-3), recombinant human stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) significantly increased the proportion of cells in the S-phase for both CFC and LTC-IC without inducing any loss in numbers. Flow cytometric DNA analysis also showed an increase in CD34+ cells in the S-phase upon continuous exposure to these cytokines. Our findings indicate that: (i) very few CB-derived CFC or LTC-IC were in the S-phase of the cell cycle; (ii) a substantial amount of CD34+ cells with a flow cytometric DNA content typical of the G0/G1 fraction was cycling, as found in the G1 phase of the cell cycle; and (iii) 24-h incubation with IL-3, SCF and G-CSF could drive a proportion of progenitor cells into the S-phase without reducing their number. These data might be useful for gene transfer protocols and the ex vivo expansion of CB-derived progenitor cells.

Antigens, CD34↗
PubMed2000

Pets and cockroaches: two increasing causes of respiratory allergy in indoor environments. Characteristics of airways sensitization and prevention strategies.

The increasing prevalence of allergic sensitization to indoor allergens such as dust mites, pets and cockroaches is the result of the changes in indoor environments induced by human activities. The Westernized lifestyle and the increasing time spent indoors determine a reduction in natural air ventilation and, consequently, higher levels of allergen concentrations and longer exposure to allergens. The major cat allergen Fel d 1 is carried by small-dimension particles (< 5 microm diameter) that readily become airborne and persist immodified for a long time. Fel d 1 must be considered a ubiquitous allergen because it has been found in indoor environments and even in public places where a cat has never been kept. Recent research has demonstrated that clothing of cat owners may contribute to the dispersal of Fel d 1 in cat-free environments. Therefore, washing Fel d 1-contaminated clothes should be considered a simple and effective method for removing this allergen from clothing and, consequently, reducing the risk of Fel d 1 dispersion. Cockroach allergens constitute another important cause of environment-related respiratory allergy and may trigger asthma exacerbations in sensitized individuals. In the prevention of cockroach allergy, the use of chemical agents associated with an intensive vacuum cleaning of indoor environments is an important tool in removing cockroach material containing allergenic proteins. Early recognition of allergy-predisposed babies, monitoring indoor allergens and adequate strategies of allergen avoidance are likely to be important means for reducing the prevalence of bronchial asthma.

Allergens↗