Bronchodilator activity of (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino] carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407), a potent, long-acting, and selective muscarinic M3 receptor antagonist.

The novel quaternary ammonium salt (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino]carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407) showed subnanomolar affinities for human muscarinic M1 (hM1), M2 (hM2), and M3 (hM3) receptors and dissociated very slowly from hM3 receptors (t(½) = 166 min) with a large part of the receptorial complex (54%) remaining undissociated at 32 h from radioligand washout. In contrast, [(3)H]CHF5407 dissociated quickly from hM2 receptors (t(½) = 31 min), whereas [(3)H]tiotropium dissociated slowly from both hM3 (t(½) = 163 min) and hM2 receptor (t(½) = 297 min). In the guinea pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC(50) = 9.0-9.6) and long-lasting (up to 24 h) inhibition of M3 receptor-mediated contractile responses to carbachol. In the guinea pig electrically driven left atrium, the M2 receptor-mediated inhibitory response to carbachol was recovered more quickly in CHF5407-pretreated than in tiotropium-pretreated preparations. CHF5407, administered intratracheally to anesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED(50) value of 0.15 nmol/kg. The effect was sustained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmol/kg. In conscious guinea pigs, inhaled CHF5407 inhibited Ach-induced bronchoconstriction for at least 24 h as did tiotropium at similar dosages. Cardiovascular parameters in anesthetized guinea pigs were not significantly changed by CHF5407, up to 100 nmol/kg i.v. and up to 1000 nmol/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, caused by a very slow dissociation from M3 receptors. In contrast, CHF5407 is markedly short-acting at M2 receptors, a behavior not shared by tiotropium.

Typical and atypical carcinoid tumours: 20-year experience with 89 patients.

AIM: The aim of this study was to conduct a retrospective clinical and pathological analysis of the authors' 20-year experience on treatment of typical and atypical carcinoid tumours. METHODS: A retrospective clinical and pathological analysis was conducted on 89 patients treated for bronchial carcinoid neoplasms at the Division of Thoracic Surgery, Hospital of Florence (Italy) between January 1986 and January 2006. They were 47 male (52.8%) and 42 female patients, age ranging from 22 to 77 years (average: 55.5 years). Diagnosis was made with radiological methods such as plain chest roentgenography, computed tomography (CT), and bronchoscopy. On the basis of bronchoscopic findings 63 carcinoids (70.8%) were centrally located and 26 (29.2%) were classified as peripheral. In 38 cases of central lesion the diagnosis was obtained by endobronchial biopsy. A correct pathological diagnosis was obtained before surgery in 58 patients; in the others resected cases the correct diagnosis was determined by intraoperative histology during surgery. All operation were performed through a thoracotomy, with sparing muscle in last ten years. Surgical procedures utilized were lobectomy, pneumonectomy, segmentectomy, wedge resections, sleeve resections and bronchoplastic procedures. A radical mediastinal lymphadenectomy was performed in every operation. RESULTS: There were 63 (70.8%) typical carcinoid (TC) and 26 (29,2%) atypical carcinoid (AC). No operative or postoperative mortality was seen. Ten patients (11.7%) experienced complications: 4 prolonged air leaks, 2 bleeding requiring re-operation, 1 chylothorax, 1 pulmonary embolism, 2 late cicatricial bronchial stenosis after sleeve lobectomy treated successfully by laser therapy. Four patients (4.5%) were treated with endoscopy plus surgery. In all that patients a Laser Nd-YAG coagulation and excision of the lesion was performed. Four patients (4.5%) were treated only with endoscopy, overall because of bad general condition. On the basis of the hystopatological documentation of all patients operated before 1999 (60 patients) the authors observed that in 4 cases (6.6%) the diagnosis has changed from AC to TC while only 1 case (1.6%) of AC was classified as TC with new criterias. During median 122-month follow-up 7 relapses (8.2%) were diagnosed in operated patients; recurrent cancer developed preferentially in AC (N=4, 16.6%) than TC (N=3, 4.9%). The overall survival at 10 and 15 years was 92% and 82% respectively. CONCLUSIONS: Anatomical resection, including formal lobectomy (or pneumonectomy when indicated) and radical mediastinal lymphadenectomy, should be performed in carcinoid tumours.

Lack of correlation between the expression of herpes simplex virus type 1 (HSV-1) glycoprotein C and both the maintenance of persistence in vitro and the capacity to establish latency in vivo.

The possible involvement of herpes simplex virus type 1 (HSV-1) glycoprotein C (gC) in the maintenance of persistence in vitro and the establishment of latency in the mouse was investigated by the use of virus mutans which do not express glycoprotein C (gC-). A persistent infection of MDBK cells could be established with 3 of 3 gC- mutans derived from HSV-1 (MP) and with 1 of 2 gC- mutans derived from HSV-1 (HFEM)H6; cells infected with the other gC- mutant derived from HSV-1(HFEM)H6 survived for 25 days only. Of the 4 lines of persistence obtained, only one showed the appearance of revertants expressing gC (gC+). gC+ revertants, which appeared also in the "short term infection", rapidly became the majority population once they had arisen. gC- mutans could establish latency in mice, and the virus recovered from the latently infected ganglia maintained its gC- phenotype. The results show that expression of gC is not essential for the maintenance of persistence in MDBK cells and for the establishment of latency in the mouse. In addition, the results indicate that MDBK cells could offer a model to study the role of gC in the virus replication cycle in vitro.

[Compliance problems in the oral anticoagulant treatment of patients wearing heart valve prostheses]. / Problemi di "compliance" nel trattamento anticoagulante orale dei portatori di protesi valvolari cardiache.

The need for and the efficacy of oral anticoagulation in patients who have undergone prosthetic valve replacement is widely demonstrated. The aim of this study is to assess how dicumarolic treatment is understood and actually accomplished by patients. A 30-question form was sent to 292 patients discharged following valve replacement, 5 to 45 months (mean: 19 months) after surgery. All of the 220 patients who submitted their answers, were effectively on oral anticoagulants. More than 95% of them knew exactly the suggested optimal prothrombin activity range. About one fifth of the patients has laboratory tests performed weekly, and nearly one half does so every 10-15 days. One fourth of the patients does not consult a physician for decision making about drug dosage. Difficulties in maintaining anticoagulation in the desired range, occurring at least once every month, are reported by 18.6% of patients. Haemorrhage was never experienced by 83.18%; in one single case thromboembolism was apparent. A few patients (2.27%) think of oral anticoagulation as a "difficult" treatment. We conclude that complete information is needed, about the aim, the modality, and the potential hazard of oral anticoagulation, so that a better understanding of the treatment and an improved cooperation between physicians and patients can result in benefits, in terms of the safety and efficacy of life-long antithrombotic therapy.