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1.
J Biol Inorg Chem ; 16(3): 491-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21181484

ABSTRACT

Gold metallodrugs form a class of promising antiproliferative agents showing a high propensity to react with proteins. We exploit here X-ray absorption spectroscopy (XAS) methods [both X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS)] to gain insight into the nature of the adducts formed between three representative gold(I, III) metallodrugs (i.e., auranofin, [Au(2,2'-bipyridine)(OH)(2)](PF(6)), Aubipy, and dinuclear [Au(2)(6,6'-dimethyl-2,2'-bipyridine)(2)(µ-O)(2)](PF(6))(2), Auoxo6) and two major plasma proteins, namely, bovine serum albumin (BSA) and human serum apotransferrin (apoTf). The following metallodrug-protein systems were investigated in depth: auranofin/apoTf, Aubipy/BSA, and Auoxo6/apoTf. XANES spectra revealed that auranofin, upon protein binding, conserves its gold(I) oxidation state. Protein binding most probably takes place through release of the thiosugar ligand and its subsequent replacement by a thiol (or a thioether) from the protein. This hypothesis is independently supported by EXAFS results. In contrast, the reactions of Aubipy with serum albumin and of Auoxo6 with serum apoTf invariantly result in gold(III) to gold(I) reduction. Gold(III) reduction, clearly documented by XANES, is accompanied, in both cases, by release of the bipyridyl ligands; for Auoxo6 cleavage of the gold-gold dioxo bridge is also observed. Gold(III) reduction leads to formation of protein-bound gold(I) species, with deeply modified metal coordination environments, as evidenced by EXAFS. In these adducts, the gold(I) centers are probably anchored to the protein through nitrogen donors. In general, these two XAS methods, i.e., XANES and EXAFS, used here jointly, allowed us to gain independent structural information on metallodrug/protein systems; detailed insight into the gold oxidation state and the local environment of protein-bound metal atoms was achieved in the various cases.


Subject(s)
Apoproteins/chemistry , Gold Compounds/chemistry , Serum Albumin, Bovine/chemistry , Transferrin/chemistry , X-Ray Absorption Spectroscopy/methods , Animals , Auranofin/chemistry , Cattle , Humans
2.
Ultrasonics ; 49(6-7): 569-76, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19278707

ABSTRACT

The structural effect induced by therapeutic ultrasound on proteins in aqueous solution has been investigated with FTIR spectroscopy, UV-VIS spectroscopy, circular dichroism and light scattering. Six proteins (cytochrome, lysozyme, myoglobin, bovine serum albumin, trypsinogen, and alpha-chymotrypsinogen A) with different molecular weight and secondary structure have been studied. The experiment has been performed using an ultrasound source at resonant frequency of 1 MHz and sonication times of 10, 20, 30, 40, 50, and 60 min. A different behaviour of proteins under sonication depends on the dominant secondary structure type (alpha-helix or beta-sheets) and on the grade of the ordered structure. The results suggest that the free radicals, produced by water sonolysis, have an important role in the changes of structural order.


Subject(s)
Proteins/chemistry , Ultrasonics , Circular Dichroism , Free Radicals , Molecular Weight , Protein Conformation , Protein Structure, Secondary , Scattering, Radiation , Signal Processing, Computer-Assisted , Spectroscopy, Fourier Transform Infrared , Ultrasonic Therapy
4.
Int J Clin Pharmacol Ther ; 33(11): 612-8, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8688986

ABSTRACT

An international multicentric study was conducted with the aim of demonstrating that erdosteine improves the efficacy of amoxycillin in the treatment of infective exacerbation of chronic bronchitis mainly on the clinical symptomatology (primary objective), on spirometric tests and body temperature, without negatively influencing the tolerance (secondary objectives). The study was conducted as a prospective evaluation, with 2 comparative groups treated with erdosteine (300 mg x 2/day) or placebo in association with amoxycillin (1500 mg/day) for a maximum of 10 days. The design of the trial was double-blind and parallel group with 2 subgroups. The treatments have been assigned randomly to a population of chronic bronchitic patients in exacerbation phase of n = 237 subjects. The study was conducted according to the principles of the Declaration of Helsinki and its amendments (Hong Kong, September 1989). The primary end-point used to determine effectiveness in this study was the global clinical assessment (GCA) which was choosen as a general indication of activity with objective/subjective evaluation of the clinical picture. Secondary endpoints of efficacy are sputum parameters, functional signs of chronic obstructive bronchitis, spirometric tests and overall judgement of efficacy. Safety was evaluated with adverse drug reactions reporting, arterial blood pressure, heart rate and laboratory tests monitoring. The obtained values have been analyzed with two-way and factorial ANOVA, Least Squares Catmod-SAS, Wilcoxon and Chi-square tests. The number of patients included in the effectiveness analysis is of n = 226 subjects, due to the fact that 11 patients were lost due to different reasons. In term of results as far as the primary objective of the study was concerned, erdosteine resulted more active than placebo. The analysis evidenced a very significant difference for treatment, time and interaction time x treatment. No difference on the contrary was observed for center and the interaction center x treatment. Sputum volume, body temperature and spirometric parameters were not significantly influenced by both treatments. Viscosity, appearance as well as functional signs evidenced a modification over time in favour of erdosteine. As safety is concerned the majority of adverse events, both in the erdosteine and in the placebo group, were related to the gastrointestinal area. For erdosteine, of 9/17 side-effects, 3 were epigastralgias, 3 nauseas, 1 diarrhoea, 1 taste loss, 1 hemorrhoids. For placebo of 13/17 related events 3 were epigastralgias, 4 nauseas, 4 diarrhoeas, 1 pyrosis, 1 dry mouth. In terms of severity they have been all defined as mild or moderate degree. Also from a qualitative perspective it is clear that there are no relevant differences between the 2 treatments under evaluation, concerning safety. In conclusion of particular interest is the datum arising from the efficacy/safety evaluation, which indicates that the clinical picture is modified earlier and at deeper degree by the synergistic activity of erdosteine and of the antibiotic without the risk of an augmentation of side-effects incidence.


Subject(s)
Amoxicillin/therapeutic use , Bronchitis/drug therapy , Expectorants/therapeutic use , Penicillins/therapeutic use , Thioglycolates/therapeutic use , Thiophenes/therapeutic use , Aged , Chronic Disease , Double-Blind Method , Expectorants/adverse effects , Female , Humans , Male , Middle Aged , Prospective Studies , Thioglycolates/adverse effects , Thiophenes/adverse effects
5.
Life Sci ; 54(7): 463-9, 1994.
Article in English | MEDLINE | ID: mdl-8309349

ABSTRACT

MR889 is a synthetic inhibitor of human neutrophil elastase with potential in clinical conditions characterized by a high load of this proteolytic enzyme, mainly chronic obstructive pulmonary disease. On the basis of its mechanism of inhibition, it has been suggested that MR889, upon reaction with elastase, would generate new free thiol groups. The aim of this study was to investigate whether MR889, upon reaction with elastase, may modify rheologic properties, i.e. apparent viscosity and elasticity, of both human sputum and porcine stomach mucus, in ex-vivo and in vitro experiments. MR889 10(-4) M alone had no effect on rheologic properties of samples, whereas an agent with free thiol group, n-acetylcysteine 10(-4) M reduced both viscosity and elasticity. MR889 10(-4) M upon reaction with elastase 0.03 nMol (giving 83% of elastase inhibition) had no effect on rheologic properties of samples, whereas upon reaction with elastase 0.15 nMol (49% inhibition) yielded a marked decrease in viscosity. This result would suggest that MR889, in the presence of a high load of elastase, may acquire direct mucus modifying capacity, likely because of its greater utilization upon reaction with the enzyme.


Subject(s)
Bronchitis/enzymology , Mucus/drug effects , Pancreatic Elastase/antagonists & inhibitors , Sputum/drug effects , Thiophenes/pharmacology , Animals , Bronchitis/drug therapy , Chronic Disease , Elasticity/drug effects , Gastric Mucosa/enzymology , Humans , In Vitro Techniques , Leukocyte Elastase , Mucus/enzymology , Sputum/enzymology , Swine , Viscosity/drug effects , alpha 1-Antitrypsin/pharmacology
6.
J Chemother ; 5(6): 517-20, 1993 Dec.
Article in English | MEDLINE | ID: mdl-8195848

ABSTRACT

Brodimoprim is a new diaminopyridine derivative suitable for oral therapy which shows good in-vitro activity against most Gram-positive and Gram-negative pathogens. The efficacy and tolerability of brodimoprim in acute lower respiratory tract infections was tested in controlled clinical trials in comparison with different classes of antibiotics. Acute bacterial infections or infective exacerbations of chronic obstructive bronchitis were included in the studies. Brodimoprim in a single dose was compared to different oral treatments which included co-trimoxazole (trimethoprim 160 mg+sulphamethoxazole 800 mg every 12 hours) and erythromycin (600 mg three times a day). In the studies criteria of efficacy such as daily temperature curve, intensity and frequency of cough, degree of dyspnea, intensity of thoracic pain, difficulty of expectoration, sputum production, thoracic semiology were examined. Brodimoprim was more effective than cotrimoxazole and erythromycin at the end of the treatment, induring a more significant and prompt reduction of axillary temperature, daily sputum volume, degree of dyspnea. There was no difference among treatments in the mean period of therapy to obtain the resolution of the infective process (8 days on average). Brodimoprim had a significantly lower percentage of side effects during the treatment in comparison with cotrimoxazole or erythromycin. Hence brodimoprim was better accepted by patients.


Subject(s)
Respiratory Tract Infections/drug therapy , Trimethoprim/analogs & derivatives , Adult , Erythromycin/adverse effects , Erythromycin/therapeutic use , Female , Gram-Negative Bacterial Infections/drug therapy , Humans , Male , Middle Aged , Trimethoprim/adverse effects , Trimethoprim/therapeutic use , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use
7.
Minerva Med ; 84(6): 307-12, 1993 Jun.
Article in Italian | MEDLINE | ID: mdl-8336838

ABSTRACT

It is well known that the incidence of cardiac arrhythmia is particularly high in patients with chronic respiratory insufficiency (CRI). This study examines the prevalence, incidence and prognostic clinical importance of arrhythmia occurring during the course of CRI on the basis of data taken from the literature and the authors' personal experience using dynamic electrocardiographic diagnosis (24-hour Holter monitoring). The majority of arrhythmias observed in these patients appeared to take the form of premature ventricular and/or supraventricular beats and less frequently of atrial fibrillation and/or attacks of supraventricular paroxysmal tachycardia. Cardiac rhythm alterations were observed using Holter monitoring in 70-90% of patients. No cardiac rhythm disorder is specific to this pathological condition. The aim of this study was to formulate, as far as was possible, a rational therapeutic approach which took account of the electrogenesis of arrhythmic phenomena, variations in the type of arrhythmia and the hemodynamic conditions under which they occur. The etiopathogenesis of arrhythmias within the framework of CRI is relatively complex and probably multifactorial since there are a number of concomitant pathological conditions able to trigger off arrhythmogenic processes both inducing the onset of reflux circuits and enhancing cardiac automatism centres. Many studies correlate the presence of arrhythmia with hypoxemia, hypercapnia and both respiratory and metabolic alkalosis. Even the combined effect of hypoxia with respiratory acidosis and the integrity or otherwise of cardiac function (chronic pulmonary heart, right ventricular hypertrophy, ischemic cardiopathy) have a notable pro-arrhythmic effect. Hypokalemia induced by both respiratory alkalosis and by drugs used during the course of CRI (eg diuretics and/or steroids) may induce a marked dispersion of refractory periods of the various fibrocells thus encouraging the onset of arrhythmia. With regard to drugs, it has been observed that both digitalis and theophylline and beta-2 stimulants if frequently used during the course of CRI may possibly induce arrhythmia. It is therefore important to underline that they should be used with particular caution. As far as concerns the use of beta-2 adrenergic compounds, it is advised that they be administered using an aerosol rather than systemic route. Digitalis has limited indications; the molecules of the methylxanthine classes require careful pharmacological dose monitoring. Arrhythmic therapy should also be seen in terms of prophylaxis and the correction of predisposing and decisive factors such as hypoxemia, hypercapnia, hemoglobin and electrolyte levels, and alterations in blood pH following the obstruction of small airways.(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Arrhythmias, Cardiac/etiology , Respiratory Insufficiency/complications , Arrhythmias, Cardiac/classification , Arrhythmias, Cardiac/drug therapy , Humans
8.
Int J Clin Pharmacol Res ; 13(5): 275-80, 1993.
Article in English | MEDLINE | ID: mdl-8200722

ABSTRACT

Seaprose is a semialkaline proteinase endowed with proteolytic effect and antiinflammatory activity tested in different clinical trials. There is clinical evidence that seaprose reduces sputum viscoelastic properties in chronic hypersecretory bronchitis. The present study evaluated (in a double-blind design vs. placebo) the activity of seaprose on bronchial inflammation, mucus glycoprotein secretion and bronchial humoral defence mechanism in chronic bronchitic patients clinically stable (10 per group). Markers of bronchial inflammation (albumin, albumin/total protein ratio) and bronchial infection (DNA), of mucus glycoproteins (fucose and N-acetylneuraminic acid) and of humoral defence mechanism (secretory-IgA) were tested in sputum. We found that ten-day treatment with seaprose (90 mg/day) reduced sputum albumin during the observation period, the difference being statistically significant at the 18th day. The sputum albumin/total protein ratio also decreased by 50% at the end of the study. In the same group, sputum DNA, secretory-IgA, fucose and N-acetylneuraminic acid remained unchanged after treatment. The placebo group did not show any significant changes in the sputum marker substances. This study provides experimental evidence for the antiinflammatory activity of seaprose on bronchial mucosa in chronic bronchitic patients studied in a stable phase of their disease. Furthermore the drug does not seem to affect mucus glycoprotein secretion or secretory-IgA production.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Bronchitis/drug therapy , Serine Endopeptidases/therapeutic use , Sputum/drug effects , Aged , Biomarkers/analysis , Chronic Disease , Double-Blind Method , Female , Humans , Male , Middle Aged , Sputum/chemistry
9.
Pediatr Med Chir ; 14(5): 523-7, 1992.
Article in Italian | MEDLINE | ID: mdl-1488311

ABSTRACT

At present current knowledges on OIT are controversial. We studied the effectiveness and the possible immunological mechanisms of this therapy. We followed a group of 56 children affected by allergic asthma due to Dermatophagoides during their treatment with OIT. Many clinical parameters were investigated and also immunoallergological and spirometric values in a subgroup. We observed a particularly satisfying clinical and respiratory improvement, while immunoallergological parameters did not suffer significant changes.


Subject(s)
Allergens/adverse effects , Asthma/etiology , Asthma/therapy , Desensitization, Immunologic/methods , Mites/immunology , Animals , Asthma/immunology , Asthma/physiopathology , Child , Child, Preschool , Chronic Disease , Desensitization, Immunologic/statistics & numerical data , Evaluation Studies as Topic , Female , Follow-Up Studies , Humans , Male , Respiration
10.
Riv Eur Sci Med Farmacol ; 12(6): 347-57, 1990 Dec.
Article in Italian | MEDLINE | ID: mdl-2132289

ABSTRACT

Sixty patients, 33 men and 27 women (mean age about 45 years; range 25-60), affected by acute influenza syndrome of the upper airways were admitted to a controlled single-blind study with three drugs under parallel conditions. According to a balanced randomized sequence, the subjects were treated over a 7-10 day period with morniflumate sachets (700 mg bid) or with tiaprofenic acid sachets (300 mg bid) or with paracetamol (10 ml syrup equivalent to 500 mg tid). The efficacy of the test drugs was assessed by determining the local and general signs and symptoms before starting the treatments, in basal conditions, and on the 3rd, 5th and last day of treatment. At the doses and formulations used, morniflumate proved to be equivalent to paracetamol and more effective than tiaprofenic acid as for its antipyretic action in the first days of treatment. On the other hand, both morniflumate and tiaprofenic acid showed a significantly higher antiinflammatory effect compared to paracetamol. Pain was effectively and equally controlled in all the treatment groups. The drugs administered were generally well tolerated. A greater incidence of adverse GI events was reported in the group treated with tiaprofenic acid.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Influenza, Human/complications , Niflumic Acid/analogs & derivatives , Respiratory Tract Diseases/drug therapy , Adolescent , Adult , Female , Humans , Male , Middle Aged , Niflumic Acid/therapeutic use , Respiratory Tract Diseases/etiology
11.
Clin Ter ; 135(2): 105-13, 1990 Oct 31.
Article in Italian | MEDLINE | ID: mdl-2149543

ABSTRACT

The therapeutic efficacy and tolerability of the association paracetamol-sobrerol in comparison with paracetamol alone, was tested in a double-blind, randomized clinical trial, carried out on 287 out-patients, suffering from diseases of the respiratory tree with fever. The treatment was performed for up to five days. At the end of the treatment, both treatments lead to an important improvement of all considered clinical parameters; furthermore, the association paracetamol-sobrerol showed a statistically important difference versus paracetamol alone as to cough and difficulty to expectorate. As to body temperature, both paracetamol and paracetamol-sobrerol showed a good antipyretic activity; furthermore, the association compared to paracetamol alone obtained a statistically significant differences in times x treatments. These data fully confirm the results obtained from recent studies: the simultaneous administration of paracetamol and sobrerol obtains a better antipyretic action than paracetamol alone. This synergism allows to reduce paracetamol doses and, consequently, to eliminate the already low incidence of adverse reactions, without decreasing the antipyretic activity.


Subject(s)
Acetaminophen/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Expectorants/administration & dosage , Respiratory Tract Infections/drug therapy , Terpenes/administration & dosage , Adult , Double-Blind Method , Drug Combinations , Female , Humans , Male , Middle Aged , Time Factors
12.
Lung ; 168(5): 285-93, 1990.
Article in English | MEDLINE | ID: mdl-2126836

ABSTRACT

Erdosteine is a new thioderivative endowed with mucokinetic, mucolytic, and free-radical-scavenging properties. This study evaluated (in a double-blind design vs. placebo) its efficacy on biochemical and rheologic properties of sputum and on some indices of respiratory function in chronic patients with chronic bronchitis (10 per group), while receiving basic treatment with a controlled-release theophylline preparation. The pharmacokinetics of erdosteine and theophylline were also studied. We found that a 2 week treatment with erdosteine (300 mg 3 times daily) was able to reduce significantly (p less than 0.05) the sputum apparent viscosity, fucose content, and macromolecular dry weight (MDW) with no statistically significant influence on sputum elasticity, DNA, albumin, total proteins, total IgA, lactoferrin, and lysozyme content. The treatment caused a significant increase in the following ratios: total IgA/albumin, lactoferrin/albumin, and lysozyme/albumin. The pharmacokinetics of erdosteine, its metabolites, and theophylline were the same after 1 or 14 days of treatment, evidence both of absence of an enzymatic induction and of an accumulation process. Further confirmation that there was no interference between erdosteine and theophylline was obtained from the data available on the group of patients receiving only theophylline, since its plasma levels and related pharmacokinetic parameters were identical to those obtained in patients receiving both drugs. In conclusion, 2 weeks of therapy with erdosteine reduced the marker of mucus glycoproteins (fucose) in patients with chronic bronchitis but did not interfere with the pharmacokinetics of xanthine derivatives. We also suggest that the significant increment in the IgA/albumin ratio might be related to a sum of other local effects such as reduction of the inflammatory process and enhancement of the humoral defense mechanism.


Subject(s)
Bronchitis/drug therapy , Expectorants/therapeutic use , Sputum/chemistry , Thioglycolates/therapeutic use , Thiophenes/therapeutic use , Bronchitis/metabolism , Chronic Disease , Double-Blind Method , Expectorants/pharmacokinetics , Humans , Male , Rheology , Theophylline/pharmacokinetics , Theophylline/therapeutic use , Thioglycolates/pharmacokinetics , Thiophenes/pharmacokinetics
13.
Clin Ter ; 129(6): 429-36, 1989 Jun 30.
Article in Italian | MEDLINE | ID: mdl-2526704

ABSTRACT

The above study was carried out in 30 patients, 22 males, 8 females, aged between 30 and 66 years, average age 57.17 +/- 1.43 years, 19 of whom with flare-ups of chronic or asthmatic bronchitis, 6 suffering from flare-ups of chronic bronchoectasic bronchitis, and 5 with acute tracheobronchitis. Treatment with two 300 mg tablets of enoxacin daily lasted from 10 to 15 days. The clinical result was good in 95% of the cases, and microbiological results were also satisfactory in that the micro-organisms isolated were sensitive to the antibiotic. Tolerance was good both locally and generally, only two patients complained of slight stomach discomfort. Both symptoms and laboratory findings improved progressively, and the result was considered excellent in four cases, good in 25 and only fair in one.


Subject(s)
Bacterial Infections/drug therapy , Bronchitis/drug therapy , Enoxacin/therapeutic use , Tracheitis/drug therapy , Adult , Aged , Bronchitis/microbiology , Drug Evaluation , Female , Humans , Male , Middle Aged , Tracheitis/microbiology
14.
Respiration ; 50 Suppl 2: 160-4, 1986.
Article in English | MEDLINE | ID: mdl-2951797

ABSTRACT

The response to an aerosol preparation containing 100 micrograms fenoterol and 40 micrograms ipratropium bromide per puff (Duovent) was compared with a placebo in 18 asthmatic patients in a double-blind cross-over fashion. We measured changes in lung function tests and pulse rate. Duovent induced a significant improvement in lung tests with statistical relevance for VEMS and Raw in comparison with placebo. The combination of fenoterol and ipratropium bromide also provided a long-lasting bronchodilatation without side effects.


Subject(s)
Atropine Derivatives/therapeutic use , Bronchodilator Agents/therapeutic use , Fenoterol/therapeutic use , Ipratropium/therapeutic use , Aerosols , Clinical Trials as Topic , Drug Combinations/therapeutic use , Drug Therapy, Combination , Female , Humans , Male , Respiratory Function Tests
15.
Eur J Respir Dis ; 65(5): 365-70, 1984 Jul.
Article in English | MEDLINE | ID: mdl-6745338

ABSTRACT

Nineteen patients with chronic mucus hypersecretion and reversible airway obstruction were studied during an acute exacerbation. One group of patients was treated with antibiotics and aminophylline, the other, additionally, with gradually decreasing doses of methylprednisolone, starting with 80 mg/day. The sputum specimens were collected on the day of admission and 2 weeks later. In whole sputum, we examined macromolecular components both transudated from serum and locally secreted: albumin, fucose, N-acetylneuraminic acid, total protein, IgA, IgM, IgG. At the end of the second week albumin (marker of serum transudate), and fucose (marker of mucus glycoproteins), were significantly lower in the group treated with corticosteroids. IgG and albumin behaved in the same way suggesting a marked IgG serum exudation. IgM was partially reduced by corticosteroids while IgA remained unchanged.


Subject(s)
Bronchitis/drug therapy , Methylprednisolone/therapeutic use , Sputum/drug effects , Adult , Aged , Aminophylline/therapeutic use , Anti-Bacterial Agents/therapeutic use , Bronchitis/metabolism , Female , Fucose/analysis , Humans , Immunoglobulins/analysis , Male , Middle Aged , N-Acetylneuraminic Acid , Proteins/analysis , Serum Albumin/analysis , Sialic Acids/analysis , Sputum/analysis
19.
Quad Sclavo Diagn ; 15(2): 170-82, 1979 Jun.
Article in Italian | MEDLINE | ID: mdl-400029

ABSTRACT

A case of bilateral neoplastic pulmonary amyloidosis is presented and discussed. The diagnosis was based on the results of a lung biopsy; and laboratory methods of great utility in this pathology were used. Of particular importance are the indications which can be obtained through subcutaneous biopsies and the biochemical test for digoxinemia.


Subject(s)
Amyloidosis/diagnosis , Digoxin/blood , Lung Diseases/diagnosis , Lung/pathology , Amyloidosis/diagnostic imaging , Amyloidosis/pathology , Biopsy, Needle , Humans , Lung Diseases/diagnostic imaging , Lung Diseases/pathology , Male , Medigoxin/metabolism , Middle Aged , Radionuclide Imaging
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