From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.

BACKGROUND: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. METHODS: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100-600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. RESULTS: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 µm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). CONCLUSIONS: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016-004547-36).

Unconventional High-Energy-State Contribution to the Cooper Pairing in the Underdoped Copper-Oxide Superconductor HgBa_{2}Ca_{2}Cu_{3}O_{8+δ}.

We study the temperature-dependent electronic B_{1g} Raman response of a slightly underdoped single crystal HgBa_{2}Ca_{2}Cu_{3}O_{8+δ} with a superconducting critical temperature T_{c}=122 K. Our main finding is that the superconducting pair-breaking peak is associated with a dip on its higher-energy side, disappearing together at T_{c}. This result reveals a key aspect of the unconventional pairing mechanism: spectral weight lost in the dip is transferred to the pair-breaking peak at lower energies. This conclusion is supported by cellular dynamical mean-field theory on the Hubbard model, which is able to reproduce all the main features of the B_{1g} Raman response and explain the peak-dip behavior in terms of a nontrivial relationship between the superconducting gap and the pseudogap.

Collapse of the normal-state pseudogap at a Lifshitz transition in the Bi(2)Sr(2)CaCu(2)O(8+δ) cuprate superconductor.

We report a fine tuned doping study of strongly overdoped Bi_{2}Sr_{2}CaCu_{2}O_{8+δ} single crystals using electronic Raman scattering. Combined with theoretical calculations, we show that the doping, at which the normal-state pseudogap closes, coincides with a Lifshitz quantum phase transition where the active holelike Fermi surface becomes electronlike. This conclusion suggests that the microscopic cause of the pseudogap is sensitive to the Fermi surface topology. Furthermore, we find that the superconducting transition temperature is unaffected by this transition, demonstrating that their origins are different on the overdoped side.

Raman-scattering measurements and theory of the energy-momentum spectrum for underdoped Bi2Sr2CaCuO(8+δ) superconductors: evidence of an s-wave structure for the pseudogap.

We reveal the full energy-momentum structure of the pseudogap of underdoped high-Tc cuprate superconductors. Our combined theoretical and experimental analysis explains the spectral-weight suppression observed in the B2g Raman response at finite energies in terms of a pseudogap appearing in the single-electron excitation spectra above the Fermi level in the nodal direction of momentum space. This result suggests an s-wave pseudogap (which never closes in the energy-momentum space), distinct from the d-wave superconducting gap. Recent tunneling and photoemission experiments on underdoped cuprates also find a natural explanation within the s-wave pseudogap scenario.

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.

Evolution of the dynamical pairing across the phase diagram of a strongly correlated high-temperature superconductor.

We study the dynamics of the Cooper pairing across the T = 0 phase diagram of the two-dimensional Hubbard model, relevant for high-temperature superconductors, using a cluster extension of dynamical mean-field theory. We find that the superconducting pairing function evolves from an unconventional form in the overdoped region into a more conventional boson-mediated retarded form in the underdoped region of the phase diagram. The boson, however, promotes the rise of a pseudogap in the electron density of states rather than a superconducting gap as in the standard theory of superconductivity. We discuss our results in terms of Mott-related phenomena, and we show that they can be observed in tunneling experiments.

QTc prolongation assessment in anticancer drug development: clinical and methodological issues.

Cardiac safety assessments are commonly employed in the clinical development of investigational oncology medications. In anti-cancer drug development there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can potentially influence decision making at many levels during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Given the potential for serious and irreversible morbidity from cardiac adverse events, it is understandable that cardiac safety results can have broad impact on study conduct and patient management. The methodologies for risk management of QTc prolongation for non cardiac drugs have been developed out of experiences primarily from drugs used to treat non life-threatening illnesses in a chronic setting such as antibiotics or antihistamines. Extrapolating these approaches to drugs for treating cancer over an acute period may not be appropriate. Few specific guidelines are available for risk management of cardiac safety in the development and use of oncology drugs. In this manuscript, clinical and methodological issues related to QTc prolongation assessment will be reviewed. Discussions about limitations in phase-I design and oncology drug development will be highlighted. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. A thoughtful risk management plan generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development programme essential for oncology agents with cardiac safety concerns.

Long QT syndrome and torsade de pointes after anthracycline chemotherapy.

Anthracycline chemotherapy, which represents the treatment of choice for many hematologic and metastatic cancers, unfortunately carries with it the possibility of both early cardiotoxic phenomena, occuring during chemotherapy, and also late cardiotoxic manifestations, occuring even months or years from the completion of treatment.THE CLINICAL MANIFESTATIONS OF EARLY CARDIOTOXICITY COMMONLY INCLUDE: ventricular premature beats, supraventricular tachycardia, cardiomyopathy and sudden death.This study confirms the necessity for close cardiac monitoring of patients undergoing anthracycline therapy. Such monitoring should not only comprise echocardiographic monitoring for left ventricular systo-diastolic dysfunction, but also electrocardiographic monitoring (QTc) in order to exclude electrophysiological changes possibly related to life threatening arrhythmias (10).

Nodal-antinodal dichotomy and the two gaps of a superconducting doped Mott insulator.

We study the superconducting state of the hole-doped two-dimensional Hubbard model using cellular dynamical mean-field theory, with the Lanczos method as impurity solver. In the underdoped regime, we find a natural decomposition of the one-particle (photoemission) energy gap into two components. The gap in the nodal regions, stemming from the anomalous self-energy, decreases with decreasing doping. The antinodal gap has an additional contribution from the normal component of the self-energy, inherited from the normal-state pseudogap, and it increases as the Mott insulating phase is approached.

Cardio-oncology: a new medical issue.

Due to the increasing number of long-term cancer survivors, the ageing of the population, as well as the increased incidence and prevalence of oncologic and cardiovascular diseases, the number of patients presenting oncologic and cardiologic co-morbidities are increasing. Accordingly, there is a rapidly growing need for a comprehensive and proficient management of patients in whom the two co-morbidities exist, and for cancer patients whose clinical history and oncologic treatment put them at higher risk for developing cardiovascular problems, in order to provide the optimal treatment in every situation, and to avoid the possibility that the development of the second disease does not lead to a reduction of therapeutic opportunities for the patient. A new discipline, cardio-oncology, has been created to deal with this need. Its aim is to investigate new strategies, collect new evidence-based indications and develop interdisciplinary expertise in order to manage this growing category of patients. Cardio-oncology deals with the following main clinical and research areas: early diagnosis of cardiotoxicity, risk stratification and preventions, treatment and monitoring of cardiotoxicity.

Dynamical breakup of the fermi surface in a doped Mott insulator.

The evolution from an anomalous metallic phase to a Mott insulator within the two-dimensional Hubbard model is investigated by means of the cellular dynamical mean-field theory. We show that approaching the density-driven Mott metal-insulator transition the Fermi surface is strongly renormalized and the quasiparticle description breaks down in a very anisotropic fashion. Regions where the quasiparticles are strongly scattered (hot spots) and regions where the scattering rate is relatively weak (cold spot) form irrespective of whether the parent insulator has antiferromagnetic long-range order, while their location is not universal and is determined by the interplay of the renormalization of the scattering rate and the Fermi surface shape.

Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy.

BACKGROUND: High-dose chemotherapy (HDC) has been widely utilized in high-risk breast cancer, but it may induce cardiac toxicity. Cardiac dysfunction may become evident weeks or months after HDC and, to date, no early markers of myocardial injury that are able to predict late ventricular impairment are available. We investigated the role of plasma troponin I (TnI) in this setting. PATIENTS AND METHODS: We measured TnI plasma concentration after HDC in 211 high-risk breast cancer women (46 +/- 11 years, mean +/- SD). According to TnI value (< 0.5 or > or = 0.5 ng/ml), patients were allocated into a troponin positive (TnI+; n = 70) and a troponin negative (TnI-; n = 141) group. All patients underwent left ventricular ejection fraction (LVEF, Echo) examination during the following 12 months. RESULTS: LVEF progressively decreased in the TnI+ group but not in the TnI- group. In TnI+ patients a close relationship between the TnI increase, as well as the number of positive TnI assays, and the maximal LVEF decrement, was found (r = -0.92, P < 0.0001 and r = -0.93, P < 0.0001, respectively). CONCLUSIONS: In our population, the elevation of TnI soon after HDC accurately predicts the development of future LVEF depression. In this setting, TnI can be considered a sensitive and reliable marker of myocardial damage with relevant clinical and prognostic implications.

Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.

OBJECTIVES: We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC). BACKGROUND: High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need. METHODS: We measured, in 204 patients (45+/-10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value (< or = or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI-, n = 139) group. All patients underwent echocardiographic examination during the following seven months. RESULTS: In the cTnI- group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = -0.87, p<0.0001). CONCLUSIONS: The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.

Evaluation of acute toxicities associated with autologous peripheral blood progenitor cell reinfusion in patients undergoing high-dose chemotherapy.

Peripheral blood progenitor cell reinfusion (PBPC) in patients undergoing high-dose chemotherapy (HDC) for poor prognosis malignancies, has been described as causing possible acute gastrointestinal (nausea, vomiting), allergic (oedema, bronchospasm, anaphyl- axis), renal (proteinuria, haematuria) and/or cardiovascular (hypotension, arrhythmia, conduction disturbances, transient ischaemic phenomena) toxicities. To establish the clinical relevance of these observations and the possible relationship with different HDC regimens used, we performed a clinical and instrumental evaluation on 33 patients with advanced breast cancer, non-Hodgkin's lymphoma, Hodgkin's disease, relapsed ovarian cancer, Ewing's sarcoma, extragonadal germinal tumour and small cell lung cancer. They underwent at least one reinfusion each for a total of 51 studied procedures. No patient had a previous history of cardiovascular disease or significant intercurrent illness such as diabetes or liver, renal or neurologic impairment. All patients had totally implanted central venous catheters, through which the transplants had been collected and reinfused without technical consequences. To evaluate cardiovascular function, we continuously monitored 12-lead ECGs, with arterial pressure (AP) measurements every 5 min from the beginning of the procedure to 15 min after the reinfusion ended. We did not observe any significant differences between basal and subsequent steps in AP, heart rate, PQ and QTc time, P wave and QRS complex duration or P wave and QRS electrical axes. No patient showed any ST-T tract pathological abnormality, but one patient developed a transient ectopic atrial rhythm, without any haemodynamic disfunction and with spontaneous reversion to sinus rhythm. No patient complained of symptoms of haemodynamic failure. Gastrointestinal side-effects appeared to be strictly related to speed of reinfusion and to the number of packs reinfused, probably reflecting on the amount of dimethylsulphoxide infused. In one patient a tonic-clonic seizure occurred during a vomiting episode, but no patient developed allergic or renal toxicities. We conclude that PBPC reinfusion, if managed according to the procedure we propose in patients without organic impairment, is a safe procedure not associated either with increased risk of acute arrhythmias or ischaemic or significant systemic acute toxicities. Bone Marrow Transplantation (2000) 25, 173-177.

Intrapericardial treatment of neoplastic pericardial effusions.

Pericardial effusion and cardiac tamponade are known complications of many advanced malignancies as lung cancer, breast cancer, lymphomas and leukemias. Initial relief can be easily obtained with percutaneous echo-guided pericardiocentesis, without significant mortality and morbidity and well-tolerated even in critically ill patients. Effusion recurrences can be observed, however, in up to 40% of cases if only simple pericardial drainage is performed. Effective management can be obtained by instillation in the pericardial sac of different agents, with sclerosing or cytostatic activity, like tetracyclines, bleomycin, thiotepa or radionuclides. Intrapericardial sclerotherapy is associated to good results in terms of recurrence prevention and survival improvement. Absence of pericardial effusion at 30 days after drainage can be observed in 70 to 90% of all treated patients, without significant variations among different treatments. No significant side effects are observed, with the exclusion of chest pain during tetracyclines instillation. In our opinion pericardiocentesis associated to intrapericardial sclerotherapy with thiotepa is the best compromise in terms of recurrence prevention, tolerability and costs. Real randomized, case-control studies are moreover required to assess the gold standard of malignant pericardial effusions treatment.

Atrial fibrillation after operation for lung cancer: clinical and prognostic significance.

BACKGROUND: Atrial fibrillation is a common complication of early postoperative period in lung cancer thoracotomy. Its clinical incidence and short- and long-term impact on overall mortality has never been definitely assessed; moreover, it is unclear whether the arrhythmia represents an independent cardiac risk factor. METHODS: We prospectively studied 233 consecutive patients undergoing operation for lung cancer (170 with non-small-cell lung cancer). Postoperative atrial fibrillation incidence was related to different clinical factors possibly involved in its occurrence and to both short- and long-term survival. RESULTS: Atrial fibrillation occurred in 28 patients (12%) (same percentage in non-small-cell lung cancer); a strong relationship was observed between arrhythmia and age, history of hypertension and associated lymph node resection. The mean hospitalization time was 14 +/- 4 days in patients developing atrial fibrillation and 13 +/- 4 days in those who did not (p = not significant). No difference was observed between the two groups with regard to short- or long-term mortality or to long-term atrial fibrillation recurrences, also when considering the entire population and only non-small-cell lung cancer, separately. CONCLUSIONS: At our institution, early atrial fibrillation occurrence after operation for lung cancer does not show any negative impact on short- and long-term mortality or on recurrence rate.

Comparative analysis of isolated human bronchi contraction and biosynthesis of cysteinyl leukotrienes using a direct 5-lipoxygenase inhibitor.

Quantitation of cysteinyl leukotriene production and smooth muscle contraction upon immunological challenge of isolated human bronchi was evaluated. Analysis of picomole amounts of leukotriene C4, D4, and E4 was achieved using HPLC separation and enzyme immunoassay quantitative determination. The aim of the study was to correlate the contraction of airway smooth muscle and cysteinyl leukotriene production with and without 5-lipoxygenase inhibition. In human isolated bronchial tissue treated with indomethacin and pyrilamine to make their contractile responses leukotriene dependent only, the novel 5-lipoxygenase inhibitor 5,6-Dihydroxy-2-(N,N-Dimethylhydrazino)-1,2,3,4-tetrahydro-naph talene bromide (CHF 1909) caused a concentration-dependent inhibition of the immunologically induced contraction, showing an IC50 value of 13 +/- 2.2 microM (mean +/- CV). At the concentration of 30 microM, this compound caused more than 90% inhibition of the maximal bronchoconstriction in vitro, and inhibited cysteinyl leukotriene production by 90% as well. Contemporary measurement of immunologically induced contraction and production of cysteinyl leukotrienes in isolated human bronchi provided a direct correlation between smooth muscle contraction and synthesis of leukotriene C4, D4, and E4.

Inhibition of parathyroid hormone-stimulated resorption in cultured fetal rat long bones by the main metabolites of ipriflavone.

Ipriflavone is an isoflavone derivative used in the prevention and treatment of postmenopausal and senile osteoporosis in humans. To assess the potential contribution of the main in vivo ipriflavone metabolites (M1, M2, M3, and M5) on the pharmacological properties of the drug, we investigated their effect on osteoclastic resorption induced by the well-known stimulator of bone resorption bovine parathyroid hormone fragment 1-34 (bPTH 1-34). The study was carried out using fetal rat long bones in stationary cultures. The amount of osteoclastic resorption was determined by assaying for 5 days the release from bones in the media of previously incorporated 45Ca. All metabolites were effective at inhibiting osteoclastic resorption. Maximal potency was shown by M3, characterized by a significant effect at 10 microM (P < 0.01) and by an IC50 value of 17 microM. M2 was about threefold less potent than M3 (IC50 = 46 microM). M1 and M5 were the least active compounds with an IC50 value of 117 and 200 microM, respectively. The present evidence indicates that metabolites of ipriflavone, in particular M3 and M2, inhibit bPTH 1-34-induced bone resorption in fetal rat long bones. Accordingly, they may play an important role in the pharmacological effects of the drug.