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2.
Respir Med ; 108(8): 1153-62, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24953015

ABSTRACT

The FORWARD study is a randomised, double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate (BDP/FOR), 100/6 µg pMDI, 2 inhalations BID, vs. FOR 12 µg pMDI, 1 inhalation BID, in severe COPD patients with a history of exacerbations. Co-primary endpoints were exacerbation rate over 48 weeks and pre-dose morning FEV(1) at 12 weeks. The ITT population included 1186 patients (69% males, mean age 64 years) with severe airflow limitation (mean post-bronchodilator FEV(1) 42% predicted). Salbutamol as rescue therapy, theophylline and tiotropium (if stable regimen prior to screening) were allowed. Compared to FOR, BDP/FOR: (1) reduced the exacerbation rate (rate ratio: 0.72 [95% confidence interval 0.62-0.84], p < 0.001); (2) improved pre-dose morning FEV(1) (mean difference: 0.069 L [0.043-0.095] p < 0.001); (3) prolonged the time to first exacerbation; (4) improved the SGRQ total score. The percentage of patients with adverse events was similar (52.1% with BDP/FOR and 49.2% with FOR). Pneumonia incidence was low, slightly higher with BDP/FOR (3.8%) than with FOR (1.8%). No difference for laboratory values, ECG or vital signs. Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of patients with severe COPD and history of exacerbations as compared to FOR alone.


Subject(s)
Beclomethasone/administration & dosage , Bronchodilator Agents/administration & dosage , Ethanolamines/administration & dosage , Glucocorticoids/administration & dosage , Pulmonary Disease, Chronic Obstructive/drug therapy , Beclomethasone/adverse effects , Bronchodilator Agents/adverse effects , Double-Blind Method , Ethanolamines/adverse effects , Female , Forced Expiratory Volume/drug effects , Formoterol Fumarate , Glucocorticoids/adverse effects , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Seasons , Treatment Outcome , Vital Capacity/drug effects
3.
Respir Med ; 104(12): 1858-68, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20965712

ABSTRACT

OBJECTIVES: To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol (non-inferiority) and versus formoterol (superiority) in patients with severe stable chronic obstructive pulmonary disease (COPD). METHODS: A double-blind, double-dummy, randomised, active-controlled, parallel-group study. After 4 weeks run-in with ipratropium/salbutamol (40/200 µg, three times daily) patients were randomised to receive beclomethasone/formoterol (200/12 µg pressurised metered dose inhaler), budesonide/formoterol (400/12 µg dry powder inhaler) or formoterol (12 µg dry powder inhaler) twice daily for 48 weeks. Co-primary efficacy variables were change from baseline to 48 weeks in pre-dose morning forced expiratory volume in 1 s (FEV(1)) and mean rate of COPD exacerbations. RESULTS: Of 718 patients randomised, 703 (232 beclomethasone/formoterol, 238 budesonide/formoterol, 233 formoterol) were in the ITT analysis. Improvement in pre-dose morning FEV(1) was 0.077 L, 0.080 L and 0.026 L for beclomethasone/formoterol, budesonide/formoterol and formoterol respectively (LS mean from the ANCOVA model). Beclomethasone/formoterol was not inferior to budesonide/formoterol (95% CI of the difference -0.052, 0.048) and superior to formoterol (p = 0.046). The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments (beclomethasone/formoterol 0.414, budesonide/formoterol 0.423 and formoterol 0.431). Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased. Safety profiles were as expected and treatments well-tolerated. CONCLUSIONS: Beclomethasone/formoterol (400/24 µg) treatment for 48 weeks improved pulmonary function, reduced symptoms compared to formoterol, was safe and well-tolerated in patients with severe stable COPD. Neither of the long-acting ß2-agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population.


Subject(s)
Albuterol/therapeutic use , Beclomethasone/therapeutic use , Bronchodilator Agents/therapeutic use , Ethanolamines/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Double-Blind Method , Drug Combinations , Female , Forced Expiratory Volume/physiology , Formoterol Fumarate , Humans , Male , Metered Dose Inhalers , Middle Aged , Pulmonary Disease, Chronic Obstructive/physiopathology , Quality of Life
4.
Thorax ; 59(8): 679-81, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15282388

ABSTRACT

BACKGROUND: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC. METHODS: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell. RESULTS: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype. CONCLUSIONS: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.


Subject(s)
Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Squamous Cell/etiology , Lung Neoplasms/etiology , Pulmonary Disease, Chronic Obstructive/complications , Smoking/adverse effects , Aged , Analysis of Variance , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Case-Control Studies , Female , Humans , Lung Neoplasms/pathology , Male , Regression Analysis , Risk Factors
5.
Cancer ; 89(8): 1714-9, 2000 Oct 15.
Article in English | MEDLINE | ID: mdl-11042565

ABSTRACT

BACKGROUND: This randomized trial was designed to investigate the feasibility, toxicity, and activity of two different schedules of gemcitabine plus cisplatin in previously untreated patients with advanced (International Union Against Cancer (UICC) Stage IIIB-IV) nonsmall cell lung carcinoma (NSCLC). METHODS: From February 1997 to September 1998, 82 patients with advanced NSCLC were entered onto the study and were randomized to gemcitabine 1000 mg/m(2) on Days 1, 8, and 15 plus cisplatin 80 mg/m(2) on Day 2 (arm A) or Day 15 (arm B) every 28 days. RESULTS: All the patients were assessable for toxicity (arm A/arm B: 151/177 cycles; median, 4 of 5 cycles per patient), and the following Grade 3-4 toxicities were reported (percentage of cycles in arm A vs. arm B): anemia, 7.9% and 2.3% (P < 0.05); leukopenia, 6.0% and 6.7%; thrombocytopenia, 15.0% and 1.6% (P < 0.01); no World Health Organization (WHO) Grade 3-4 nonhematologic toxicities were observed. These side effects led to gemcitabine dose reductions in 35.1% of courses in arm A and 22.0% of courses in arm B (P < 0.05) and to gemcitabine omissions in 28.5% of courses in arm A versus 7.3% of courses in arm B (P < 0.01). Dose intensities (DIs) of gemcitabine were 607.5 mg/m(2)/week in arm A and 711.6 mg/m(2)/week in arm B (P < 0.01); DIs of cisplatin were 18. 1 mg/m(2)/week in arm A and 18.8 mg/m(2)/week in arm B. The total delivered doses of gemcitabine were 9315.5 mg/m(2) in arm A and 12, 631.0 mg/m(2) in arm B (P < 0.01); the total delivered doses of cisplatin were 277.1 mg/m(2) in arm A and 333.0 mg/m(2) in arm B (P < 0.01). Response rates according to intention to treat were 40.4% (95% confidence interval [CI], 25.5-55.3) in arm A and 45% (95% CI, 29.5-60.5) in arm B. The overall median duration of response was 7.4 months; the median time to disease progression was 6 months (95% CI, 3-9) in arm A and 9 months (95% CI, 4-14) in arm B (P < 0.02); the median overall survival was 10 months (95% CI, 7.0-12.5) in arm A and 17 months (95% CI, 13.0-21.6) in arm B (P < 0.01); the 1-year survival rates were 34% and 63%, respectively. CONCLUSIONS: Our data show that arm B (cisplatin on Day 15) is less toxic than arm A (cisplatin on Day 2) and allows the administration of significantly higher total doses and dose intensities of chemotherapy. No significant differences in response rates were observed between the two schedules; patients on arm B experienced a significantly more prolonged progression free and overall survival; however, the study was not powered to detect differences in these outcomes.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/administration & dosage , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Gemcitabine
6.
Lung Cancer ; 27(2): 75-80, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10688490

ABSTRACT

BACKGROUND: This trial investigated the activity and toxicity of gemcitabine in previously untreated elderly (> 70 years) patients with advanced (stage IIIB-IV) non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From January 1997 to July 1998, 46 patients with advanced NSCLC aged over 70 years with a performance status of 0-2 were entered into the study. Gemcitabine 1000 mg/m2 was administered as a 30-min infusion once a week for 3 weeks followed by a week of rest; cycles were repeated every 4 weeks. RESULTS: Forty-four patients were evaluable for response. One complete response and nine partial responses were observed, for an overall response rate of 22.2% (95% C.I.: 11.3-37.5). The median time to disease progression was 5.1 months (95% C.I.: 3.5-6.7), the median duration of response was 6.3 months, and the median overall survival time 6.75 months (95% C.I.: 5.3-8.2). All patients were evaluable for toxicity (184 cycles, median = 3 cycles/patient) and no grade 4 hematologic toxicities were reported. WHO grade 3 leukopenia, neutropenia and anemia occurred in 3.3, 0.5 and 1.1% of cycles, respectively. Grade 3 skin rash occurred in 4.3% of patients. These side effects led to treatment discontinuation in two patients. CONCLUSION: Our data show that gemcitabine is active and well tolerated in patients aged over 70 years with advanced NSCLC.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Disease Progression , Female , Humans , Infusions, Intravenous , Lung Neoplasms/pathology , Male , Survival Analysis , Treatment Outcome , Gemcitabine
7.
Nicotine Tob Res ; 2(4): 345-50, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11197314

ABSTRACT

Twenty healthy, asymptomatic long-term cigarette smokers (8 males, 12 females; mean age: 43 +/- 9 years) were selected at random from a larger series receiving nicotine replacement therapy (NRT) for 12 weeks to study the effects of NRT on plasma markers of oxidative stress. Plasma aliquots, obtained at baseline (T0) and after 12 weeks (T12) of NRT, were used to measure malondialdeyde (MDA) and total Trolox-equivalent antioxidant capacity (TEAC). In subjects who completely quit smoking ('quitters', n = 10), MDA was higher at T0 (1.08 mumol/l, interquartile range 0.85-1.16) than at T12 (0.71 mumol/l, range 0.32-0.92; p < 0.01), and TEAC was lower at T0 (1.20 mM, range 1.11-1.31) than at T12 (1.43 mM, range 1.31-1.49; p < 0.05). In subjects who had only reduced the number of cigarettes smoked per day ('reducers', n = 10), differences between the T0 and T12 levels of MDA (0.81 [0.75-0.96] vs. 0.76 [0.58-0.84] mumol/l) and TEAC (1.28 [1.05-1.50] vs. 1.25 [1.09-1.42] mM) were not significant. At T0, MDA and cotinine levels correlated in reducers (r = 0.79, p < 0.05) and, though not significantly, in quitters (r = 0.50, p = 0.12). At T12 this relationship between MDA and cotinine was still present in the reducers (r = 0.70, p < 0.05), while the scatter of points in quitters was completely dispersed (r = (0.09). These results show that smoking cessation but not smoking reduction is associated with decreased markers of oxidative stress in the plasma of active cigarette smokers.


Subject(s)
Ganglionic Stimulants/pharmacology , Nicotine/pharmacology , Oxidative Stress , Smoking Cessation , Smoking/adverse effects , Adult , Biomarkers/analysis , Female , Ganglionic Stimulants/therapeutic use , Humans , Male , Nicotine/therapeutic use
8.
Am J Physiol ; 277(3): L465-71, 1999 09.
Article in English | MEDLINE | ID: mdl-10484453

ABSTRACT

Intercellular adhesion molecule-1 (ICAM-1) is the only inducible adhesion receptor for neutrophils identified in bronchial epithelial cells. We stimulated human airway epithelial cells with various agonists to evaluate whether ICAM-1-independent adhesion mechanisms could be elicited. Phorbol 12-myristate 13-acetate (PMA) stimulation of cells of the alveolar cell line A549 caused a rapid, significant increase in neutrophil adhesion from 11 +/- 3 to 49 +/- 7% (SE). A significant increase from 17 +/- 4 to 39 +/- 6% was also observed for neutrophil adhesion to PMA-stimulated human bronchial epithelial cells in primary culture. Although ICAM-1 expression was upregulated by PMA at late time points, it was not affected at 10 min when neutrophil adhesion was already clearly enhanced. Antibodies to ICAM-1 had no effect on neutrophil adhesion. In contrast, antibodies to the leukocyte integrin beta-chain CD18 totally inhibited the adhesion of neutrophils to PMA-stimulated epithelial cells. These results demonstrate that PMA stimulation of human airway epithelial cells causes an increase in neutrophil adhesion that is not dependent on ICAM-1 upregulation.


Subject(s)
Bronchi/physiology , Intercellular Adhesion Molecule-1/physiology , Neutrophils/physiology , Pulmonary Alveoli/physiology , Tetradecanoylphorbol Acetate/pharmacology , Bronchi/cytology , Bronchi/drug effects , Cell Adhesion/drug effects , Cell Adhesion Molecules/physiology , Energy Metabolism/physiology , Epithelial Cells/drug effects , Epithelial Cells/physiology , Humans , Ions , Metals/pharmacology , Neutrophils/drug effects , Protein Synthesis Inhibitors/pharmacology , Pulmonary Alveoli/cytology , Pulmonary Alveoli/drug effects
9.
Cancer Res ; 58(18): 4122-6, 1998 Sep 15.
Article in English | MEDLINE | ID: mdl-9751623

ABSTRACT

Polycyclic aromatic hydrocarbons (PAHs) are almost ubiquitous pollutants that may interact with metabolic systems in human tissues and eventually cause cancer. PAH-adducted DNA becomes antigenic and antibodies anti-benzo(a)pyrene diol epoxide (BPDE)-DNA may be found in serum of PAH-exposed subjects. The presence of serum antibodies anti-BPDE-DNA adduct was investigated in 1345 individuals from family clusters of the general population of a small area in central Italy in whom information about smoking habits, site of residence, and personal and family history of lung diseases, including cancer, were obtained. Anti-BPDE-DNA antibodies in the sera were detected with a direct ELISA and the association of anti-BPDE-DNA antibodies with subjects' data from a standardized respiratory questionnaire including age, occupation, tobacco smoking habits, respiratory symptoms, and family history of respiratory diseases was subsequently tested by multivariate logistic regression analysis. The overall prevalence of subjects with anti-BPDE-DNA antibodies was 21.0% (n=283), with no differences between males and females. Anti-BPDE-DNA positivity was associated with living in the urban area [odds ratio (OR), 1.49; 95% confidence interval (CI), 1.16-1.92], with active tobacco smoking (OR, 1.25; 95% CI, 1.06-1.48), and with family history of lung cancer (OR, 1.30; 95% CI, 0.90-1.88), and positivity increased with the number of members in the family cluster positive to anti-BPDE-DNA antibodies (OR, 1.30; 95% CI, 1.03-1.65). This study on a large general population sample indicates that serum anti-BPDE-DNA antibodies may be considered as biomarkers of exposure to environmental carcinogens and of DNA damage. The genetic and familial components of their association with tobacco smoking lend further support to the argument about the familial predisposition to lung cancer.


Subject(s)
Antibodies/blood , Benzo(a)pyrene/analysis , DNA Adducts/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Child , DNA Adducts/blood , Environmental Exposure , Family , Female , Humans , Italy/epidemiology , Male , Middle Aged , Regression Analysis , Smoking/epidemiology , Suburban Health/statistics & numerical data , Urban Health/statistics & numerical data
10.
Appl Environ Microbiol ; 64(3): 1161-2, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9501456

ABSTRACT

A new method for screening microbial colonies endowed with antiviral activity is described. It is based on close contact between microbial agar cultures and agar-covered virus-infected-cell monolayers and allows the screening of large numbers of colonies in just a few months.


Subject(s)
Antiviral Agents/analysis , Bacteria/metabolism , Environmental Microbiology , Fungi/metabolism , Animals , Chlorocebus aethiops , Vero Cells
12.
Am J Respir Crit Care Med ; 156(6): 1902-7, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9412573

ABSTRACT

Peroxynitrite has been associated with increased oxidative reactions and DNA damage in inflamed tissues as it may cause a reduction of plasma antioxidants as well. Nitration of tyrosine residues of proteins leads to the production of 3-nitrotyrosine (NTYR), which may be considered as a marker of NO.-dependent oxidative damage. We developed a highly sensitive method to detect NTYR in human plasma and tested it in cigarette smokers and in healthy control subjects. Peripheral venous blood (10 ml) was obtained in 20 healthy, asymptomatic cigarette smokers (13 males, 7 females; age: 49 +/- 11 yr) and in 18 healthy nonsmokers (10 males and 8 females; age: 36 +/- 6 yr). In smokers, plasma nicotine, cotinine, and expired CO levels were measured. NTYR was determined with a sequential HPLC/gas chromatography-thermal energy analysis (GC-TEA) technique. The total plasma Trolox-equivalent antioxidant capacity (TEAC) was also measured using metmyoglobin as peroxidase and a phenothiazine as a radical donor. NTYR was detectable (detection limit: 0.02 ng/injection) in 11 smokers (mean +/- SD: 1.60 +/- 1.24 ng/mg protein) and in two nonsmokers (1.10 and 1.20 ng/mg protein, respectively). NTYR was not associated with nicotine and cotinine levels or expired CO in smokers. Plasma TEAC in smokers was significantly lower (0.43 +/- 0.38 mM) than in nonsmokers (1.42 +/- 0.3 mM; p < 0.001) and showed a biphasic, negative relationship with NTYR (r = 0.96, p < 0.001). This highly sensitive HPLC/GC-TEA method for detection and quantitation of plasma NTYR may be used for monitoring oxidative reactions associated with tobacco smoking. This assay might be incorporated into molecular epidemiologic studies for lung chronic inflammatory and neoplastic disorders in which exposure to oxidants may be an important risk factor.


Subject(s)
Smoking/blood , Tyrosine/analogs & derivatives , Adult , Aged , Antioxidants/analysis , Chromans/analysis , Chromatography, High Pressure Liquid , Cotinine/blood , Female , Humans , Male , Middle Aged , Nicotine/blood , Tyrosine/blood
13.
Microb Drug Resist ; 3(3): 271-5, 1997.
Article in English | MEDLINE | ID: mdl-9270998

ABSTRACT

Twenty-five high-level gentamicin resistant (HLGR) Enterococcus faecalis strains were isolated from three different University laboratories in Italy. The resistant strains were variously distributed in the three centers with percentages of prevalence ranging from about 3% up to 14%. Almost all strains shared high-level resistance to streptomycin (23 out of 25). Ribotyping and restriction analysis of the 16S-23S rRNA intergenic spacer sequences were used to genetically differentiate the various strains and to study their spreading in the university hospitals serviced by the three laboratories. At least three ribotypes were identified, which showed a peculiar distribution in the various centers. Only the ribotype B was isolated from the University of Padua. In Cagliari, most strains belonged to ribotype A (4/6), whereas in Genoa there was an equal distribution of the ribotypes A and B. A clonal spreading of some HLGR strains is suggested by these findings. The restriction analysis of the 16S-23S rRNA intergenic-spacer sequences gave comparable results with classical ribotyping and, in addition, was quicker and easier to perform than the latter.


Subject(s)
Enterococcus faecalis/genetics , Gentamicins/pharmacology , RNA, Ribosomal, 16S/genetics , RNA, Ribosomal, 23S/genetics , Drug Resistance, Microbial/genetics , Polymerase Chain Reaction , Restriction Mapping
14.
FEMS Immunol Med Microbiol ; 18(1): 61-6, 1997 May.
Article in English | MEDLINE | ID: mdl-9215588

ABSTRACT

In total 34 strains of Gardnerella vaginalis were analyzed with various molecular techniques in order to find the possibility of dividing this single species into different genotypes. Classical ribotyping, PCR-ribotyping and restriction analysis of 16S-23S rRNA intergenic spacer sequences were all unsuccessful in genotype differentiation of these bacteria. Only amplified ribosomal DNA restriction analysis (ARDRA) was suitable in recognizing different G. vaginalis genotypes. At least 3-4 genotypes were identified with different restriction enzymes, some of which showed a prevalent distribution in certain of the centers from which they were collected. Although in this study no correlation was found between bacterial vaginosis and any of the genotypes identified, the ARDRA method could prove to be a useful tool for studying the etiopathology and epidemiology of G. vaginalis.


Subject(s)
DNA, Bacterial/analysis , DNA, Ribosomal/analysis , Gardnerella vaginalis/classification , Gardnerella vaginalis/genetics , DNA Restriction Enzymes , Genotype , Molecular Sequence Data
15.
Int J Cancer ; 70(2): 145-9, 1997 Jan 17.
Article in English | MEDLINE | ID: mdl-9009151

ABSTRACT

Among biomarkers of tobacco smoke (TS)-induced genotoxic damage, benzo[a]pyrene diolepoxide-DNA adducts (BPDE-DNA) are extensively studied. Adducted DNA becomes antigenic and antibodies anti-BPDE-DNA (BPDE-DNA-Abs) may be found in serum of exposed subjects. Little is known about the persistence of BPDE-DNA, and no study has been performed to evaluate the persistence of BPDE-DNA-Abs after cessation of exposure. Fifty heavy smokers, enrolled in a smoking cessation program with nicotine patch substitution therapy, were evaluated for the presence of BPDE-DNA-Abs before (w0) and 1, 3, 6 and 12 weeks (w1-12) after the start of the program. Nicotine or placebo patches were randomly assigned to the subjects. BPDE-DNA-Abs were determined in serum by non-competitive ELISA. After the start of the cessation program, 28 subjects quit smoking (group Q) and the other 22 reduced by about 75% the number of cigarettes smoked per day (group R). At the start of the program (w0) 8% of subjects were positive. At w1 the prevalence of positivity had increased both in subjects who quit smoking (Q: 21%) and in subjects who had reduced the number of cigarettes per day (R: 27%). Positivity remained stable up to w12 (21%) for group Q, whereas it increased to 41% in group R. Serum BPDE-DNA-Abs can be detected in smokers, and their persistence for months after smoking cessation suggests their usefulness for relatively long-term surveys. The low percentage of positivity in actual heavy smokers and the increase in antibody positivity with smoking cessation or reduction must be taken into account when interpreting serum BPDE-DNA-Ab measurement in exposed individuals.


Subject(s)
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide , Antibodies, Antinuclear/immunology , DNA Adducts/immunology , Smoking Cessation , Smoking/immunology , Biomarkers , DNA Damage , Humans , Nicotine/administration & dosage , Nicotine/therapeutic use , Single-Blind Method , Smoking/genetics , Smoking/metabolism
16.
Am J Respir Cell Mol Biol ; 15(2): 216-23, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8703477

ABSTRACT

Alkylating agents may cause DNA damage in different human cells and tissues, including lungs. For instance, tobacco-specific N-nitrosamines are known to produce methyl-DNA adducts, such as N7-methyldeoxyguanosine, and to induce lung tumors. We applied a combined high-performance liquid chromatography (HPLC)/32P-postlabeling technique for measurement of N7-methyldeoxyguanosine in human pulmonary alveolar cells (HPAC). Thirty patients (13 males, 17 females; mean age 51 +/- 17 yr) undergoing bronchoalveolar lavage for diagnosis of nonmalignant lung diseases were studied. DNA was extracted from HPAC, digested to 2'-deoxyribonucleotide 3'-monophosphates and HPLC separated to obtain deoxyguanosine (dGp) and N7-methyldeoxyguanosine (N7-MedGp) monophosphates. Fractions corresponding to normal (1:10,000) and N7-methylated dGp were subsequently 32P-postlabeled by T4 polynucleotide kinase with high specific activity 32P-ATP, resolved by two-dimensional thin-layer chromatography (TLC) and autoradiographed after 3 to 18 h exposure. Spots corresponding to dGp and N7-MedGp were scraped off the plates and quantitated by liquid scintillation counting to calculate direct molar ratios. Recovered HPAC (14.4 +/- 10.0 x 10(6)) were predominantly macrophages (73.8 +/- 16.4%) and lymphocytes (9.8 +/- 11.6%). N7-MedGp was detected in 11 patients, the level ranging from 0.10 to 48.03 fmol/micrograms DNA which corresponded to 0.31-79.00 x 10(-6) N7-MedGp/dGp ratios. Detection of N7-MedGp in HPAC was associated with the smoking habit of patients: N7-MedGp was present in 7 of 10 smokers, 2 of 10 ex-smokers, and 2 of 10 nonsmokers (P < 0.05). These results show that HPAC may be used for molecular dosimetry of DNA damage by alkylating agents, including tobacco-specific N-nitrosamines, in cigarette smokers and thus used for cancer risk assessment.


Subject(s)
Deoxyguanine Nucleotides/analysis , Pulmonary Alveoli/cytology , Adult , Aged , Alkylating Agents , Bronchoalveolar Lavage Fluid/chemistry , Chromatography, High Pressure Liquid , DNA/drug effects , DNA/radiation effects , DNA Adducts/analysis , Dose-Response Relationship, Radiation , Electrophoresis, Gel, Two-Dimensional , Epithelium/chemistry , Female , Humans , Male , Middle Aged , Phosphorus Radioisotopes , Pulmonary Alveoli/chemistry , Smoking/adverse effects
19.
Chest ; 107(1 Suppl): 21S-24S, 1995 Jan.
Article in English | MEDLINE | ID: mdl-7813324

ABSTRACT

Pulmonary embolism (PE) is largely undiagnosed because clinical suspicion is not raised in most instances, and thus, patients with PE go undetected. In this paper, we try to define the role of clinical assessment (including chest radiography, electrocardiogram, arterial blood gas analysis) in making the diagnosis early, accurate, and at low cost, and propose a flow chart to be used in clinical practice. All patients with otherwise unexplained dyspnea or chest pain should be sent for perfusion lung scintigraphy; accordingly, underdetection of PE and mortality of PE should be reduced. If, within 1 h after the clinical suspicion has been raised, the above-mentioned simple and noninvasive examinations are available, they may be employed to reduce the number of unnecessary procedures, without losing patients actually affected by PE. Finally, when diagnostic tools are not promptly available, noninvasive techniques may be employed to identify patients with the highest probability of PE where to start with heparin coverage while waiting for definitive diagnosis.


Subject(s)
Pulmonary Embolism/diagnosis , Clinical Protocols , Humans , Pulmonary Embolism/diagnostic imaging , Radionuclide Imaging , Sensitivity and Specificity
20.
Respiration ; 62(4): 201-4, 1995.
Article in English | MEDLINE | ID: mdl-8578015

ABSTRACT

We studied 196 patients with suspicion of pulmonary embolism (PE), subsequently confirmed in 98 by positive pulmonary angiography and excluded in 98 by normal or near-normal perfusion lung scan. Patients had a clinical questionnaire for history, and, soon after. a radiograph, blood gas analysis, and an ECG. Clinical and instrumental signs were matched in patients with confirmed and unconfirmed PE to find those more frequent in embolic patients and, thus, more characteristic of PE. The following were: previous PE, immobilization and thrombophlebitis (p < 0.05); dyspnea and cough (p < 0.05); enlarged descending pulmonary artery (DPA), enlarged right heart, pulmonary infarction, Westermark sign (p < 0.001), and elevated diaphragm (p < 0.05); hypoxemia. No ECG sign was more frequent in PE. Thereafter, all variables were processed separately with a logistic multiple regression analysis and those significantly associated to PE were tested in a final logistic model that was able to predict the actual result of angiography or scintigraphy; accordingly, previous PE, immobilization, thrombophlebitis, enlarged DPA, pulmonary infarction, Westermark sign, hypoxemia were significantly associated with a high risk of PE (from 2.8 to 15 times greater than in patients without these signs). Therefore, we may conclude that clinical assessment and noninvasive tests may help to detect patients at higher risk for PE where heparin coverage should be started while waiting for conclusive diagnostic procedures.


Subject(s)
Patient Selection , Pulmonary Embolism/epidemiology , Adult , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Risk Factors
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