α-Tocopherol Pharmacokinetics in Adults with Cystic Fibrosis: Benefits of Supplemental Vitamin C Administration.

BACKGROUND: Numerous abnormalities in cystic fibrosis (CF) could influence tocopherol absorption, transportation, storage, metabolism and excretion. We hypothesized that the oxidative distress due to inflammation in CF increases vitamin E utilization, which could be positively influenced by supplemental vitamin C administration. METHODS: Immediately before and after receiving vitamin C (500 mg) twice daily for 3.5 weeks, adult CF patients (n = 6) with moderately advanced respiratory tract (RT) disease consumed a standardized breakfast with 30% fat and a capsule containing 50 mg each hexadeuterium (d6)-α- and dideuterium (d2)-γ-tocopheryl acetates. Blood samples were taken frequently up to 72 h; plasma tocopherol pharmacokinetics were determined. During both trials, d6-α- and d2-γ-tocopherols were similarly absorbed and reached similar maximal plasma concentrations ~18-20 h. As predicted, during vitamin C supplementation, the rates of plasma d6-α-tocopherol decline were significantly slower. CONCLUSIONS: The vitamin C-induced decrease in the plasma disappearance rate of α-tocopherol suggests that vitamin C recycled α-tocopherol, thereby augmenting its concentrations. We conclude that some attention should be paid to plasma ascorbic acid concentrations in CF patients, particularly to those individuals with more advanced RT inflammatory disease and including those with severe exacerbations.

The pharmacotherapeutic options in patients with catecholamine-resistant vasodilatory shock.

INTRODUCTION: Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure. AREAS COVERED: VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP. EXPERT OPINION: Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given.

Quantitative assessment of cyanide in cystic fibrosis sputum and its oxidative catabolism by hypochlorous acid.

RATIONALE: Cystic fibrosis (CF) patients are known to produce cyanide (CN-) although challenges exist in determinations of total levels, the precise bioactive levels, and specificity of its production by CF microflora, especially P. aeruginosa. Our objective was to measure total CN- levels in CF sputa by a simple and novel technique in P. aeruginosa positive and negative adult patients, to review respiratory tract (RT) mechanisms for the production and degradation of CN-, and to interrogate sputa for post-translational protein modification by CN- metabolites. METHODS: Sputa CN- concentrations were determined by using a commercially available CN- electrode, measuring levels before and after addition of cobinamide, a compound with extremely high affinity for CN-. Detection of protein carbamoylation was measured by Western blot. MEASUREMENTS AND MAIN RESULTS: The commercial CN- electrode was found to overestimate CN- levels in CF sputum in a highly variable manner; cobinamide addition rectified this analytical issue. Although P. aeruginosa positive patients tended to have higher total CN- values, no significant differences in CN- levels were found between positive and negative sputa. The inflammatory oxidant hypochlorous acid (HOCl) was shown to rapidly decompose CN-, forming cyanogen chloride (CNCl) and the carbamoylating species cyanate (NCO-). Carbamoylated proteins were found in CF sputa, analogous to reported findings in asthma. CONCLUSIONS: Our studies indicate that CN- is a transient species in the inflamed CF airway due to multiple biosynthetic and metabolic processes. Stable metabolites of CN-, such as cyanate, or carbamoylated proteins, may be suitable biomarkers of overall CN- production in CF airways.

Safety and Clinical Utility of Flexible Bronchoscopic Cryoextraction in Patients With Non-neoplasm Tracheobronchial Obstruction: A Retrospective Chart Review.

BACKGROUND: Airway obstruction from blood clots, airway secretions, and foreign bodies is a potentially life-threatening condition. Optimal management of this problem, whether by rigid or flexible bronchoscopy, has not been well studied. We report our single-center experience on the safety and clinical utility of cryoprobe extraction for this indication. METHODS: We performed a retrospective chart review from January 2006 to November 2014 of all subjects aged 18 and older who underwent flexible bronchoscopic cryoprobe extraction. Subjects with obstruction due to benign or malignant neoplasm or airway stenosis were excluded. RESULTS: A total of 38 cryotherapy sessions performed on 30 subjects were identified for inclusion. Cryoprobe extraction was successful in reestablishing airway patency in 32/38 (84%) sessions overall and in 24/26 (92%) for blood clots, 4/6 (67%) for mucous plugging, 2/4 (50%) for foreign bodies, and 2/2 (100%) for plastic bronchitis. Twenty-one of 31 (68%) sessions resulted in improvement in oxygenation or ventilation. There was 1 complication related to sedation. CONCLUSIONS: We conclude that flexible bronchoscopic cryoprobe extraction of blood clots, mucous secretions, plastic bronchitis, and foreign bodies is a safe and effective option. It can be safely performed at the bedside and in many cases eliminates the need for rigid bronchoscopy.

Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive form of lung disease of unknown etiology for which a paucity of therapies suggest benefit, and for which none have demonstrated improved survival. Acute exacerbation of IPF (AE-IPF) is defined as a sudden acceleration of the disease or an idiopathic acute injury superimposed on diseased lung that leads to a significant decline in lung function. An AE-IPF is associated with a mortality rate as high as 85% with mean survival periods of between 3 to 13 days. Under these circumstances, mechanical ventilation (MV) is controversial, unless used a as a bridge to lung transplantation. Judicious fluid management may be helpful. Pharmaceutical treatment regimens for AE-IPF include the use of high dose corticosteroids with or without immunosuppressive agents such as cyclosporine A (CsA), and broad spectrum antibiotics, despite the lack of convincing evidence demonstrating benefit. Newer research focuses on abnormal wound healing as a cause of fibrosis and preventing fibrosis itself through blocking growth factors and their downstream intra-cellular signaling pathways. Several novel pharmaceutical approaches are discussed.

Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis.

Cystic fibrosis (CF) represents one of a number of localized lung and non-lung diseases with an intense chronic inflammatory component associated with evidence of systemic oxidative stress. Many of these chronic inflammatory diseases are accompanied by an array of atherosclerotic processes and cardiovascular disease (CVD), another condition strongly related to inflammation and oxidative stress. As a consequence of a dramatic increase in long-lived patients with CF in recent decades, the specter of CVD must be considered in these patients who are now reaching middle age and beyond. Buttressed by recent data documenting that CF patients exhibit evidence of endothelial dysfunction, a recognized precursor of atherosclerosis and CVD, the spectrum of risk factors for CVD in CF is reviewed here. Epidemiological data further characterizing the presence and extent of atherogenic processes in CF patients would seem important to obtain. Such studies should further inform and offer mechanistic insights into how other chronic inflammatory diseases potentiate the processes leading to CVDs.

Cerebral gas embolism in a case of Influenza A-associated acute respiratory distress syndrome treated with high-frequency oscillatory ventilation.

A 22-year-old obese asthmatic woman with Influenza A (H1N1)-associated acute respiratory distress syndrome died from cerebral artery gas emboli with massive cerebral infarction while being treated with High-Frequency Oscillatory Ventilation in the absence of a right to left intracardiac shunt. We review and briefly discuss other causes of systemic gas emboli (SGE). We review proposed mechanisms of SGE, their relation to our case, and how improved understanding of the risk factors may help prevent SGE in positive pressure ventilated patients.

The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.

Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15-25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.

Omics approaches in cystic fibrosis research: a focus on oxylipin profiling in airway secretions.

Cystic fibrosis (CF) is associated with abnormal lipid metabolism, intense respiratory tract (RT) infection, and inflammation, eventually resulting in lung tissue destruction and respiratory failure. The CF RT inflammatory milieu, as reflected by airway secretions, includes a complex array of inflammatory mediators, bacterial products, and host secretions. It is dominated by neutrophils and their proteolytic and oxidative products and includes a wide spectrum of bioactive lipids produced by both host and presumably microbial metabolic pathways. The fairly recent advent of "omics" technologies has greatly increased capabilities of further interrogating this easily obtainable RT compartment that represents the apical culture media of the underlying RT epithelial cells. This paper discusses issues related to the study of CF omics with a focus on the profiling of CF RT oxylipins. Challenges in their identification/quantitation in RT fluids, their pathways of origin, and their potential utility for understanding CF RT inflammatory and oxidative processes are highlighted. Finally, the utility of oxylipin metabolic profiling in directing optimal therapeutic approaches and determining the efficacy of various interventions is discussed.

Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients.

Retained respiratory tract (RT) secretions, infection, and exuberant inflammatory responses are core abnormalities in cystic fibrosis (CF) lung disease. Factors contributing to the destructive CF airway inflammatory processes remain incompletely characterized. The pro-oxidative inflammatory CF RT milieu is known to contain enzymatically and nonenzymatically produced regulatory lipid mediators, a panel of structurally defined oxidized metabolites of polyunsaturated fatty acids known to play a role in pathology related to inflammation. Using an extraction protocol that maximizes recoveries of sputum-spiked deuterated standards, coupled with an LC/MS/MS detection system, this study presents a metabolomic method to assess a broad spectrum of regulatory lipid mediators in freshly obtained sputum from CF patients. A broad range of both proinflammatory and anti-inflammatory lipid mediators was detected, including PGE2, PGD2, TXB2, LTB4, 6-trans-LTB4, 20-OH-LTB4, 20-COOH-LTB4, 20-HETE, 15-HETE, 11-HETE, 12-HETE, 8-HETE, 9-HETE, 5-HETE, EpETrEs, diols, resolvin E1, 15-deoxy-PGJ2, and LXA4. The vast majority of these oxylipins have not been reported previously in CF RT secretions. Whereas direct associations of individual proinflammatory lipid mediators with compromised lung function (FEV-1) were observed, the relationships were not robust. However, multiple statistical analyses revealed that the regulatory lipid mediators profile taken in aggregate proved to have a stronger association with lung function in relatively stable outpatient adult CF patients. Our data reveal a relative paucity of the anti-inflammatory lipid mediator lipoxin A4 in CF sputum. Patients displaying detectable levels of the anti-inflammatory lipid mediator resolvin E1 demonstrated a better lung function compared to those patients with undetectable levels. Our data suggest that comprehensive metabolomic profiling of regulatory lipid mediators in CF sputum should contribute to a better understanding of the molecular mechanisms underlying CF RT inflammatory pathobiology. Further studies are required to determine the extent to which nutritional or pharmacological interventions alter the regulatory lipid mediators profile of the CF RT and the impact of potential modulations of RT regulatory lipid mediators on the clinical progression of CF lung disease.

Are fluoroquinolones superior antibiotics for the treatment of community-acquired pneumonia?

Various guidelines for the antibiotic treatment of community-acquired pneumonia (CAP) are presented that include fluoroquinolone antibiotics. The efficacy of current fluoroquinolone antibiotics in the treatment of CAP is summarized. Healthcare resource utilization and shortened duration of clinical symptoms have been shown in some, but not all of CAP trials utilizing fluoroquinolone antibiotics. Although evidence for both the clinical and microbiological efficacy of fluoroquinolone antibiotics is abundant, no convincing data demonstrates that they are superior to other standard antibiotics included in CAP guidelines.

The critically ill asthmatic--from ICU to discharge.

Status asthmaticus (SA) is defined as an acute, severe asthma exacerbation that does not respond readily to initial intensive therapy, while near-fatal asthma (NFA) refers loosely to a status asthmaticus attack that progresses to respiratory failure. The in-hospital mortality rate for all asthmatics is between 1% to 5%, but for critically ill asthmatics that require intubation the mortality rate is between 10% to 25% primarily from anoxia and cardiopulmonary arrest. Timely evaluation and treatment in the clinic, emergency room, or ultimately the intensive care unit (ICU) can prevent the morbidity and mortality associated with respiratory failure. Fatal asthma occurs from cardiopulmonary arrest, cerebral anoxia, or a complication of treatments, e.g., barotraumas, and ventilator-associated pneumonia. Mortality is highest in African-Americans, Puerto Rican-Americans, Cuban-Americans, women, and persons aged ≥ 65 years. Critical care physicians or intensivists must be skilled in managing the critically ill asthmatics with respiratory failure and knowledgeable about the few but potentially serious complications associated with mechanical ventilation. Bronchodilator and anti-inflammatory medications remain the standard therapies for managing SA and NFA patients in the ICU. NFA patients on mechanical ventilation require modes that allow for prolonged expiratory time and reverse the dynamic hyperinflation associated with the attack. Several adjuncts to mechanical ventilation, including heliox, general anesthesia, and extra-corporeal carbon dioxide removal, can be used as life-saving measures in extreme cases. Coordination of discharge and follow-up care can safely reduce the length of hospital stay and prevent future attacks of status asthmaticus.

Occupational asthma.

Occupational asthma is the most common occupational lung disease. Work-aggravated asthma and occupational asthma are two forms of asthma causally related to the workplace, while reactive airways dysfunction syndrome is a separate entity and a subtype of occupational asthma. The diagnosis of occupational asthma is most often made on clinical grounds. The gold standard test, specific inhalation challenge, is rarely used. Low molecular weight isocyanates are the most common compounds that cause occupational asthma. Workers with occupational asthma secondary to low molecular weight agents may not have elevated specific IgE levels. The mechanisms of occupational asthma associated with these compounds are partially described. Not all patients with occupational asthma will improve after removal from the workplace.

Evaluation of thiol-based antioxidant therapeutics in cystic fibrosis sputum: Focus on myeloperoxidase.

Neutrophil-dependent reactions catalysed by myeloperoxidase (MPO) are thought to play important roles in the pulmonary pathobiology of cystic fibrosis (CF). Aerosolized thiol antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC) are currently being utilized as therapeutics to modify CF respiratory tract oxidative processes. This study hypothesized that MPO in CF airway lining fluids may be a target of such therapeutics. MPO activity in sputum from 21 adult CF patients was found to be inversely associated with lung function (FEV(1)). In contrast, systemic inflammation (assessed by plasma C-reactive protein) was not correlated with lung function. Ex vivo studies revealed that GSH and NAC effectively scavenged N-chloramines in sputum and inhibited sputum MPO activity with potency exquisitely dependent upon MPO activity levels. Detailed kinetic analyses revealed that NAC and GSH inhibit MPO by distinct mechanisms. Activation of the key pro-inflammatory transcription factor NF-κB in cultured HBE1 cells was inhibited by GSH. The findings reveal that MPO activity and its reactive products represent useful predictors of the doses of inhaled thiol antioxidants required to ameliorate airway oxidative stress and inflammation in CF patients and provide mechanistic insight into the antioxidative/anti-inflammatory mechanisms of action of GSH and NAC when administered into the CF lung.

Myeloperoxidase-dependent oxidative metabolism of nitric oxide in the cystic fibrosis airway.

BACKGROUND: Decreased expired nitric oxide (eNO) is commonly observed in cystic fibrosis (CF) patients and is usually explained by dysregulation of NO synthase (NOS) isoforms in respiratory tract epithelium. Later stages of this disease are accompanied by intense airway infiltration of phagocytes with high NOS activity, abundant levels of the hemoprotein myeloperoxidase (MPO) and significant production of significant reactive oxygen species. METHODS: This study characterizes the contribution of the high airway levels of MPO to decreased eNO levels in adult CF patients. NO metabolites (NO(x)) and MPO levels in fresh sputum of control and adult CF patients were determined and related to measurements of eNO and to in vitro consumption of NO in CF sputum. RESULTS: Despite essentially equal levels of NO(x) in sputum, eNO was 2- to 3-fold lower in CF patients compared to healthy controls. In CF patients, eNO levels were negatively associated with sputum peroxidase activity. In vivo correlations were confirmed by ex vivo studies of NO consumption by MPO in CF sputum. Immunodepletion studies confirmed MPO as the major heme peroxidase in CF sputum contributing to the hydrogen peroxide (H(2)O(2))-dependent consumption of NO. CONCLUSIONS: In CF airways MPO acts as a phagocyte-derived NO oxidase that diminishes NO bioavailability at airway surfaces, possibly identifying this peroxidase as a potential target for therapeutic intervention.

Pathogenesis of bronchiectasis.

Cystic fibrosis (CF) typically follows a more severe clinical course than non-CF bronchiectasis. Despite this recognized difference, the underpinnings of respiratory biology support a common pathogeneses of the anatomic deformations of bronchiectasis. This article reviews the observed manifestations among the related diseases of bronchiectasis and CF and discusses some of their similarities and differences. As more details of the mechanisms of bronchiectasis are unveiled, more parallels among the seemingly disparate causes of CF and non-CF bronchiectasis are recognized. With these insights, more opportunities to halt the vicious circle have become apparent.

Differentiation of the roles of NO from airway epithelium and inflammatory cells in ozone-induced lung inflammation.

Mice lacking inducible nitric oxide synthase (NOS2-/-) are more susceptible to ozone-induced lung inflammation and injury than their isogenic wild-type (NOS2+/+) counterparts, demonstrating an apparent protective effect for NOS2 in murine lungs. We hypothesized that nitric oxide (NO) generated from either NOS2 in the airway epithelial cells or the bone-marrow-derived inflammatory cells was responsible for the protective effect of NOS2. To test this hypothesis, we prepared chimeric mice by killing their endogenous bone marrow cells by whole body irradiation followed by bone marrow transplantation from a heterologous donor mouse. We exposed C57BL/6 (NOS2+/+), NOS2-/-, and chimeric NOS2 mice (NOS2-/+, NOS2+/-) to 1 ppm of ozone for 3 consecutive nights. NOS2-/- mice were more severely injured after exposure to ozone than C57BL/6 mice, including a more robust inflammatory cell influx (4.14 x 10(5) +/- 2.19 x 10(5) vs. 2.78 x 10(5) +/- 1.36 x 10(5) cells respectively; P = 0.036) and greater oxidation of total protein sulfhydryls (R-SH) in their blood plasma. Chimeric NOS2-/+ mice, which had bone marrow from NOS2-/- mice transplanted into C57BL/6 recipients, had a significantly greater response to ozone (increased numbers of neutrophils in lung lavage and decreased concentrations of exhaled NO) as compared to the reciprocal chimeric strain (NOS2+/-). We conclude that NOS2 has a protective effect against acute lung injury caused by ozone inhalation, which may be mediated, in part, by NO generated by NOS2 from inflammatory cells, predominantly neutrophils, recruited into the lung.

L-arginine supplementation enhances exhaled NO, breath condensate VEGF, and headache at 4,342 m.

We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4,342 m through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NO-dependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.