tbuckley/cabot-search huggingface dataset:
Long-term safety of twice-daily aclidinium bromide in COPD patients: A one-year, double-blind study
Authors: Arthur Gelb, Donald Tashkin, Barry Make, Xiaoyun Zhong, Esther Garcia Gil, Cynthia Caracta
Journal: European Respiratory Journal (2012)

INTRODUCTION:

Aclidinium bromide is a novel, long-acting muscarinic antagonist currently under investigation for the maintenance treatment of COPD. Safety data from a long-term efficacy and safety trial of twice-daily (BID) aclidinium are presented here.

METHODS:

In this 52-week study, moderate-to-severe COPD patients were randomized (1:1) to receive aclidinium 200 µg or 400 µg BID. Safety was assessed via adverse events (AEs), vital signs, and 12-lead ECG.

RESULTS:

A total of 605 patients were randomized, and 602 (99.5%) were included in the safety population. Postbronchodilator FEV1 and percent predicted at screening were (mean ±SD) 1.55 ±0.54 L and 52.3±13.2 L. The incidence of AEs was similar across the aclidinium 200 µg and 400 µg groups and most were mild or moderate. The most common AE and most frequently reported AE leading to discontinuation was COPD exacerbation, with a similar percentage of patients between groups who discontinued due to exacerbations [200 µg, 9 (2.9%); 400 µg, 8 (2.7%)]. The incidence of typically expected anticholinergic AEs was low and similar between groups (e.g. dry mouth: 200 µg, 1.3%; 400 µg, 2.7%; constipation: 200 µg, 2.9%; 400 µg, 1.7%). Cardiac and cerebrovascular AEs did not occur in a dose-related manner. The 200 µg and 400 µg groups had similar incidences of serious AEs, with values [n (%)] of 29 (9.3) and 29 (10.0), respectively. One patient in each treatment group died during the study (200 µg, biliary sepsis; 400 µg, subarachnoid hemorrhage), but neither death was deemed to be related to treatment.

CONCLUSIONS:

Twice-daily aclidinium 200 µg and 400 µg were safe and well tolerated over 52 weeks with a similar safety profile for both doses.
Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline <i>versus</i> standard care in patients with pleural infection
Authors: Clare E. Hooper, Anthony J. Edey, Anthony Wallis, Amelia O. Clive, Anna Morley, Paul White, Andrew R.L. Medford, John E. Harvey, Mike Darby, Natalie Zahan-Evans, Nick A. Maskell
Journal: European Respiratory Journal (2015)

Pleural infection is increasing in incidence. Despite optimal medical management, up to 30% of patients will die or require surgery. Case reports suggest that irrigation of the pleural space with saline may be beneficial. A randomised controlled pilot study in which saline pleural irrigation (three times per day for 3 days) plus best-practice management was compared with best-practice management alone was performed in patients with pleural infection requiring chest-tube drainage. The primary outcome was percentage change in computed tomography pleural fluid volume from day 0 to day 3. Secondary outcomes included surgical referral rate, hospital stay and adverse events. 35 patients were randomised. Patients receiving saline irrigation had a significantly greater reduction in pleural collection volume on computed tomography compared to those receiving standard care (median (interquartile range) 32.3% (19.6–43.7%) reduction versus 15.3% (−5.5–28%) reduction) (p&lt;0.04). Significantly fewer patients in the irrigation group were referred for surgery (OR 7.1, 95% CI 1.23–41.0; p=0.03). There was no difference in length of hospital stay, fall in C-reactive protein, white cell count or procalcitonin or adverse events between the treatment groups, and no serious complications were documented. Saline irrigation improves pleural fluid drainage and reduces referrals for surgery in pleural infection. A large multicentre randomised controlled trial is now warranted to evaluate its effects further.
Inhaled corticosteroids and influenza A (H1N1) viral pneumonia
Authors: Rosa Malo de Molina, Myrian Aguilar, Andrea Trisan, Manuel Valle, Patricia Minguez, Antolin López, Piedad Ussetti
Journal: European Respiratory Journal (2012)

Background: Recent studies suggest that the use of inhaled corticosteroids (ICS) may be associated with a higher risk of pneumonia in patients with COPD. However it is unclear if ICS are associated with pneumonia risk in patients with influenza A (H1N1) infection.

Therefore, our aim was to examine the association of prior outpatient ICS therapy with influenza pneumonia in patients with confirmed influenza A (H1N1) 2009 infection presenting to a University Hospital in Madrid.

Methods: We included patients ≥16 yrs of age with influenza A (H1N1) virus infection diagnosed by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and assessed the association of ICS exposure with viral pneumonia using covariate-adjusted regression model.

Results: We identified 121 subjects with a diagnosis of influenza A (H1N1) virus infection who had a chest radiograph ordered. 71 (59%) had pneumonia, 17 (14%) acute exacerbation of COPD, 18 (15%) acute asthma exacerbation and 15 (12%) an influenza syndrome with no other diagnosis.

15% of subject with viral pneumonia were on previous ICS compared with 32% of the subject with influenza infection without pneumonia (p 0.03). In regression analyses, outpatient ICS therapy was associated with lower pneumonia in patients with influenza A (H1N1) infection (OR 0.29; 95% CI 0.11-0.77).

When we look for a possible class effect, the association was only found with fluticasone (OR 0.09; 95% CI 0.02-0.47, p= 0.004).

Conclusion: In our cohort viral pneumonia was quite common and the inhaled corticosteroid fluticasone may be associated with a lower risk of pulmonary infiltrates in patients with influenza A (H1N1) infection.
Assessments of protective effects of tiotropium bromide against methacholine- and neurokinin A-induced bronchoconstriction in patients with asthma
Authors: Eric Derom, Yannick Van Durme, Bihiyga Salhi, Christine Vander Stichele, Fre Bauters, Joyceline Sele, Roland Louis, Guy Joos
Journal: European Respiratory Journal (2011)

Rationale: Previous studies using short-acting anticholinergics have suggested a possible protective effect on bronchoconstriction induced by the sensory neuropeptide neurokinin A (NKA).

Aim: To assess the effect of tiotropium bromide, a longacting anticholinergic agent, on NKA-induced bronchoconstriction.

Methods: PC20 NKA and PC20 methacholine were investigated in asthmatic patients after 20 days of treatment with tiotropium bromide (18 μg/od) or placebo. PC20 was expressed in log2 doubling concentrations (DC). Values were reported as median with 25th-75th percentiles. Pairwise comparisons of the log2 PC20 values at screening and at the end of active and placebo treatments were performed.

Results: 16 patients with asthma (9 male; age: 24 (18-63) years) were included. PC20 NKA was 0.18 (0.06 - 0.29) μmol/ml at screening, 0.34 (0.09 - 3.34) μmol/ml after placebo, and 0.77 (0.08 - 3.34) μmol/ml after tiotropium bromide. PC20 methacholine was 0.5 (0.3 - 0.7) mg/ml at screening, 0.3 (0.2- 1.5) mg/ml after placebo, and 256.0 (11.7 – 256.0) mg/ml after tiotropium bromide. Differences between active treatment and screening log2PC20 were 2.4 (0.4 – 3.2) DC for NKA (p = 0.06) and 7.6 (4.8 – 9.0) DC for methacholine (p <0.0001). Differences between placebo treatment and screening for log2PC20 NKA and log2PC20 methacholine were not observed.

Conclusions: Inhaled tiotropium bromide protects against methacholine-induced bronchoconstriction, but not against bronchoconstriction induced by NKA, suggesting that cholinergic mechanisms are not involved in the contractile effects of NKA in patients with asthma.
Suiciding of Hematopoietic and Tumor Clonal Cells by Tritiated Nucleosides In Vitro: Brief Communication2
Authors: Edwin M. Uyeki, Tomoo Nishimura, Stephen Strom, Teresa U. Bisel
Journal: JNCI Journal of the National Cancer Institute (1977)

Four colony-forming cell (CFC) types were compared to determine their sensitivity in vitro to doses of tritiated nucleic acid precursors; clonal cultures used were monocytic CFC's and lymphocytic CFC's (CFC-L) from mouse explants [(C57BL/6 × DBA/2)F, mice] and P815 mastocytoma and 5178Y lymphoma CFC's from passaged mouse cell lines. Surviving colonies indicated progeny of precursor cells not suiciding from (or not incorporating) a particular tritiated nucleoside. Several general patterns of suiciding were observed. 1) [3H]Adenosine (Ado) and [3H]uridine (Urd) caused the lowest suiciding ratios (3H-treatment/control) in all four clonal cultures. [3H]Guanosine (Guo) and [3H]deoxyguanosine (dGuo) were the least inhibitory suiciding agents on colony formation in both tumor and hematopoietic cultures. 2) CFC-L development was reduced to a greater extent by [3H]Guo, [3H]dGuo, [3H]Urd, [3H]deoxyuridine, and [3H]Ado than were the other three types of CFC's. CFC-L cultures were also the only cell type that consistently was more sensitive to doses of tritiated ribosides than to doses of corresponding deoxysides. 3) When suiciding patterns were compared, a greater correlation of suiciding ratios was observed between the two tumor cell lines than between the two hematopoietic clonal lines. That is, equivalent doses of each tritiated precursor gave rise to similar suiciding ratios for both P815 and 5178Y CFC's. The combination of clonal assays with suiciding techniques described here represented a novel approach to the biochemical analysis of precursor cells.
Recruitment Maneuvers for Acute Lung Injury
Authors: Eddy Fan, M. Elizabeth Wilcox, Roy G. Brower, Thomas E. Stewart, Sangeeta Mehta, Stephen E. Lapinsky, Maureen O. Meade, Niall D. Ferguson
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

There are conflicting data regarding the safety and efficacy of recruitment maneuvers (RMs) in patients with acute lung injury (ALI).To summarize the physiologic effects and adverse events in adult patients with ALI receiving RMs.Systematic review of case series, observational studies, and randomized clinical trials with pooling of study-level data.Forty studies (1,185 patients) met inclusion criteria. Oxygenation (31 studies; 636 patients) was significantly increased after an RM (PaO2): 106 versus 193 mm Hg, P = 0.001; and PaO2/FiO2 ratio: 139 versus 251 mm Hg, P < 0.001). There were no persistent, clinically significant changes in hemodynamic parameters after an RM. Ventilatory parameters (32 studies; 548 patients) were not significantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H2O; P = 0.02). Hypotension (12%) and desaturation (9%) were the most common adverse events (31 studies; 985 patients). Serious adverse events (e.g., barotrauma [1%] and arrhythmias [1%]) were infrequent. Only 10 (1%) patients had their RMs terminated prematurely due to adverse events.Adult patients with ALI receiving RMs experienced a significant increase in oxygenation, with few serious adverse events. Transient hypotension and desaturation during RMs is common but is self-limited without serious short-term sequelae. Given the uncertain benefit of transient oxygenation improvements in patients with ALI and the lack of information on their influence on clinical outcomes, the routine use of RMs cannot be recommended or discouraged at this time. RMs should be considered for use on an individualized basis in patients with ALI who have life-threatening hypoxemia.
The Design of Vaccines Against<i>Helicobacter Pylori</i>and Their Development
Authors: Giuseppe Del Giudice, Antonello Covacci, John L. Telford, Cesare Montecucco, Rino Rappuoli
Journal: Annual Review of Immunology (2001)

Helicobacter pylori is a gram negative, spiral, microaerophylic bacterium that infects the stomach of more than 50% of the human population worldwide. It is mostly acquired during childhood and, if not treated, persists chronically, causing chronic gastritis, peptic ulcer disease, and in some individuals, gastric adenocarcinoma and gastric B cell lymphoma. The current therapy, based on the use of a proton-pump inhibitor and antibiotics, is efficacious but faces problems such as patient compliance, antibiotic resistance, and possible recurrence of infection. The development of an efficacious vaccine against H. pylori would thus offer several advantages. Various approaches have been followed in the development of vaccines against H. pylori, most of which have been based on the use of selected antigens known to be involved in the pathogenesis of the infection, such as urease, the vacuolating cytotoxin (VacA), the cytotoxin-associated antigen (CagA), the neutrophil-activating protein (NAP), and others, and intended to confer protection prophylactically and/or therapeutically in animal models of infection. However, very little is known of the natural history of H. pylori infection and of the kinetics of the induced immune responses. Several lines of evidence suggest that H. pylori infection is accompanied by a pronounced Th1-type CD4 + T cell response. It appears, however, that after immunization, the antigen-specific response is predominantly polarized toward a Th2-type response, with production of cytokines that can inhibit the activation of Th1 cells and of macrophages, and the production of proinflammatory cytokines. The exact effector mechanisms of protection induced after immunization are still poorly understood. The next couple of years will be crucial for the development of vaccines against H. pylori. Several trials are foreseen in humans, and expectations are that most of the questions being asked now on the host-microbe interactions will be answered.
Induction of Lymphocytic Neoplasms, Hepatomas, and Other Tumors After Oral Administration of Urethan to Infant Mice&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: Michael Klein
Journal: JNCI Journal of the National Cancer Institute (1962)

Strain B6AF1/J hybrid infant mice were fed repeatedly by stomach tube with 10 or 5 percent urethan dissolved in Methocel-Aerosol OT. Control mice remained untreated or were given Methocel-Aerosol OT alone. Few tumors developed among the controls during an observation period as long as 555 days. On the other hand, many neoplasms were seen among the mice treated with urethan, including lymphocytic leukemia, reticulum-cell neoplasms, hepatomas, pulmonary adenomas, and forestomach papillomas. More leukemia arose in mice treated with 10 percent than with 5 percent urethan and consequently there were fewer survivors among the former mice. Median age at death from leukemia for mice given 10 or 5 percent urethan varied little (20–22 weeks). Four of six surviving male mice that did not die from leukemia following exposure to 10 percent urethan had multiple hepatomas at 274 to 352 days of age. Compared to this, 23 males treated with 5 percent urethan and alive at 270 days all bore hepatomas at autopsy (mean age at death, 277 days). Among 22 females also treated with 5 percent urethan, only 5 were observed with hepatomas. While the males were more susceptible than the females to hepatocarcinogenesis, no sex difference was noted among the same mice in incidence of pulmonary adenomas or lymphocytic leukemia.
Communication and Choice in Dying from Heart Disease
Authors: M Mccarthy, J Addington Hall, M Ley
Journal: Journal of the Royal Society of Medicine (1997)

In heart disease palliative care has received less attention than in cancer. In the Regional Study of Care for the Dying, carers of a random sample of deaths in 20 English health districts were interviewed about 10 months after the death. There were 675 respondents for patients dying with heart disease, and we report data on 600 deaths that were not sudden. 54% of patients died in hospital, 30% in their own home, 11% in a nursing or residential home, and 4% in other places. Half the patients were said to have known, or probably known, that they were likely to die; of these, 82% were said to have worked this out for themselves rather than been told by a doctor or nurse. More than one-third of patients (39%) died without an informal carer present. Respondents said that a quarter of the patients had wanted to die earlier: this desire was associated with older age and the number and severity of symptoms. The study suggests the need for health services to give greater attention to palliative care for patients dying with heart disease.
Cyclosporine in the treatment of idiopathic nephrosis.
Authors: P Niaudet, R Habib
Journal: Journal of the American Society of Nephrology (1994)

Within the past decade, there have been numerous reports on the use of cyclosporine in idiopathic nephrosis. In this review, the results of both uncontrolled and controlled studies of the therapeutic effects of cyclosporine in steroid-sensitive/dependent idiopathic nephrosis and in steroid-resistant idiopathic nephrosis are analyzed. Cyclosporine is efficient in up to 80% of patients with steroid-sensitive/dependent idiopathic nephrosis. Most patients, however, relapse when the drug is withdrawn, thus necessitating prolonged treatments. Although cyclosporine is less efficient in patients with steroid-resistant idiopathic nephrosis, a few studies seem to indicate that this drug may be successful in some patients, especially if combined with corticosteroids. There is no evidence that cyclosporine can prevent the recurrence of nephrotic syndrome on the graft after renal transplantation. However, in patients in whom disease has recurred, high doses of cyclosporine may be effective alone or in combination with plasma exchanges. The main worrisome side effect of cyclosporine is chronic nephrotoxicity, which should be differentiated from acute or "functional" toxicity. Follow-up studies including pretreatment and posttreatment renal biopsies show a lack of correlation between structural damage and renal function, suggesting that a histologic examination of the renal parenchyma is the only reliable way of evaluating chronic cyclosporine nephrotoxicity.
Pharmacokinetic, Metabolic, and Pharmacodynamic Profiles in a Dose-Escalating Study of Irinotecan and Cisplatin
Authors: Maja J. A. de Jonge, Jaap Verweij, Peter de Bruijn, Eric Brouwer, Ron H. J. Mathijssen, Robbert J. van Alphen, Maureen M. de Boer-Dennert, Laurent Vernillet, Christian Jacques, Alex Sparreboom
Journal: Journal of Clinical Oncology (2000)

To investigate the pharmacokinetics and pharmacodynamics of irinotecan and cisplatin administered once every 3 weeks in a dose-escalating study in patients with solid tumors.Fifty-two cancer patients were treated with irinotecan administered as a 90-minute infusion at doses ranging from 175 to 300 mg/m(2) followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m(2). After reaching the maximum-tolerated dose, the sequence of drug administration was revised. For pharmacokinetic analysis, serial plasma samples were obtained on days 1 through 3 of the first cycle. Forty-five patients were assessable for irinotecan pharmacokinetics, and 46 were assessable for cisplatin pharmacokinetics.Irinotecan and cisplatin demonstrated linear pharmacokinetics comparable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasma metabolite of irinotecan, whereas 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possibly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compared with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. The percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinotecan (P =.0245) and SN-38 (P =. 0123). The severity of diarrhea was not significantly related to the AUCs of irinotecan and SN-38, nor to the systemic glucuronidation rate of SN-38.There was no apparent pharmacokinetic interaction between irinotecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. The incidence and severity of delayed-type diarrhea was not related to any of the studied parameters.
Pulmonary gas exchange differentiates pulmonary arterial from venous hypertension
Authors: Bryan Taylor, Barry Borlaug, Thomas Olson, Andrew Miller, Manda Keller, Bruce Johnson
Journal: European Respiratory Journal (2013)

Impaired gas exchange (PGX) is common in both pulmonary arterial (PAH) and venous (PVH) hypertension. We aimed to determine whether PGX measures during rest and moderate exercise (RPE ∼15) differentiate these patient groups. Pulmonary arterial pressure (PAP), wedge pressure (PWP), transpulmonary gradient (TPG) and PGX indices (end-tidal CO2, PETCO2; ventilatory efficiency, VE/VCO2; dead space/tidal volume; VD/VT) were assessed simultaneously at rest and during exercise in 10 PAH and 7 PVH patients (i.e. left heart disease). Arterial blood was drawn for measurement of PaO2, PaCO2 and SaO2. Mean PAP increased during exercise in PAH and PVH patients and was not different at end exercise (65±24 vs. 54±5 mmHg, P =0.26). Conversely, mean PWP increased during exercise in PVH but not PAH. Thus, TPG (mPAP-mPWP) was greater at end exercise in PAH vs. PVH (48±29 vs. 17±8 mmHg, P =0.02). At rest, all key PGX indices were similar between groups (Fig. 1). At end exercise, however, VD/VT, PaCO2-PETCO2 difference and VE/VCO2 ratio were higher whereas PETCO2 and SaO2 were lower in PAH vs. PAH (Fig. 1). Thus, gas exchange indices during exercise, but not rest, differentiate PAH from PVH patients, despite similar levels of exercise induced PH. These differences are consistent with greater ventilation/perfusion inhomogeneities and/or right to left shunt in PAH patients. Supported by Gilead Sciences.

![Figure][1] 



Fig. 1. * P <0.05, value significantly different vs. PAH.

 [1]: pending:yes
The Addition of Gemtuzumab Ozogamicin to Intensive Chemotherapy in Older Patients with AML Produces a Significant Improvement in Overall Survival: Results of the UK NCRI AML16 Randomized Trial
Authors: Alan K Burnett, Robert K Hills, Ann E. Hunter, Donald Milligan, William J. Kell, Keith Wheatley, John L Yin, Sahra Ali, Lars Kjeldsen, David Bowen, Nigel H. Russell
Journal: Blood (2011)
Cerebral air embolism during CT-guided lung biopsy
Authors: Rafael Dahmer Rocha, André Arantes Azevedo, Priscila Mina Falsarella, Antônio Rahal, Rodrigo Gobbo Garcia
Journal: Thorax (2015)

A patient with cirrhosis and hepatocellular carcinoma, on the waiting list for liver transplantation, presented with lung nodule during initial evaluation. A CT-guided core needle lung biopsy under general anaesthesia was performed. Pneumothorax (figure 1) and a large amount of gas within the left ventricle (figure 2) were identified during the procedure. …