Anthony A. Floreani

The role of cigarette smoke in the pathogenesis of asthma and as a trigger for acute symptoms.

Although it has been long believed that cigarette smoke is injurious to the lower respiratory tract, the exact early mechanisms and early events responsible for this injury remain unclear. Maternal smoking, particularly in utero, is clearly associated with an increased risk for the later development of childhood atopy and asthma. Smoking is known to increase the inflammatory burden of the lower respiratory tract through a number of related but separate mechanisms. These include the recruitment of increased numbers of inflammatory cells, alteration in cell subtypes, enhancement of some cellular functions, and proinflammatory mediator release. In addition, cigarette smoking in vitro and in animal models appears to promote neurogenic inflammation, increase oxidative stress and lead to the elevation of cysteinyl leukotrienes, all of which could potentially lead to an amplification of the airway inflammation already present in asthmatics. Greater and more consistent effort must be given to encourage the young asthmatic not to smoke. In addition, greater effort must be spent on smoking cessation, especially in pregnant women and young asthmatics.

Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma.

BACKGROUND Although inhaled glucocorticoids are recommended for all stages of persistent asthma, compliance with long-term therapy is often poor, leading to significant morbidity and mortality. A simplified, once-daily dosing regimen may foster improved compliance. OBJECTIVE To compare the efficacy and safety of once-daily (AM) administration of mometasone furoate dry powder inhaler (MF DPI) 200 microg and 400 microg with placebo in patients with asthma previously maintained only on short-acting inhaled beta-adrenergic receptor agonists. METHODS This was a 12-week, double-blind, placebo-controlled, parallel group study. The mean change from baseline to endpoint (last treatment visit) for FEV1 was the primary efficacy variable. RESULTS At endpoint, both doses of MF DPI were significantly more effective than placebo (P < or = .05) in improving FEV1. Based on morning peak expiratory flow rate, once-daily MF DPI 400 microg was more effective than placebo (P < or = .001) at endpoint. Both active treatments also demonstrated improvement at endpoint in asthma symptom scores, physician-evaluated response to therapy and use of rescue medication. Although both MF DPI dosages were efficacious, MF DPI 400 microg provided additional improvement in some measures of pulmonary function (eg, morning PEFR) when these agents were administered once daily in the morning. Both doses of MF DPI were well tolerated and treatment-related adverse events occurred at a similar incidence among the three treatment groups. CONCLUSIONS The results of this study indicate that once-daily (AM) MF DPI provides a convenient and effective treatment option for patients with mild or moderate persistent asthma.

Evaluation of subclinical respiratory tract inflammation in heavy smokers who switch to a cigarette-like nicotine delivery device that primarily heats tobacco

Cigarette smoking remains a major public health problem. For smokers who cannot or do not wish to quit, few options exist to reduce health risks. A cigarette-like nicotine delivery device that heats rather than burns tobacco might deliver nicotine with fewer toxins. The current study was designed to determine whether asymptomatic heavy smokers who did not wish to quit had improvement in lower respiratory tract inflammation after switching to Eclipse, a cigarette-like nicotine delivery device that primarily heats rather than burns tobacco. Twelve smokers of at least 40 cigarettes daily, asymptomatic and in good health, underwent paired bronchoscopies, bronchoalveolar lavages and endobronchial biopsies before and after 2 months of using Eclipse. Eight normal non-smoking individuals were evaluated on one occasion for comparison. Inflammation was assessed by direct inspection and by cytological parameters. Goblet cell metaplasia was assessed histologically. Compared to non-smokers, smokers had increased visible inflammation, increased recovery of inflammatory cells and increased percentage of goblet cells. There were significant reductions in all these parameters following a switch to Eclipse use, although the improvement did not reach the normal range. No significant differences were observed in peripheral blood measures. Nicotine levels were generally maintained, and exhaled carbon monoxide (CO) levels trended strongly upward. One individual experienced a transient twofold increase in CO and concurrently experienced transient headaches. Eclipse use may be a strategy to reduce the health risks for heavy smokers unwilling or unable to quit.

Protein kinase c-α mediates cigarette smoke extract- and complement factor 5a-stimulated interleukin-8 release in human bronchial epithelial cells

Background Cigarette smoke extract (CSE) activates protein kinase C (PKC) and augments complement factor 5a (C5a)-stimulated release of the proinflammatory cytokine IL-8 in human bronchial epithelial cells (HBEC). We hypothesized that PKC activation by alternative PKC activators will also mediate C5a-stimulated IL-8 release in HBEC. Methods HBEC were treated with phorbol myristate acetate (100 ng/mL), calcium ionophore A23187 (2 nM), or 10 nM cholesterol-3-sulfate in the presence or absence of C5a. Interleukin-8 (IL-8) release was measured by enzyme-linked immunoadsorbent assay. Results IL-8 release by PKC activators alone was significantly higher than in unstimulated cells and was further augmented in the presence of C5a. Preincubation with the PKC inhibitor calphostin C (1 μM) significantly suppressed IL-8 release in HBEC treated with CSE and C5a. Preincubation with 10 μM TMB-8 (an intracellular calcium sequester) also significantly suppressed IL-8 release in CSE- and C5a-treated HBEC, suggesting that intracellular calcium is required for CSE- and C5a-mediated IL-8 release. When HBEC were preincubated with 30 nM of the PKCβ-specific inhibitor LY363196, CSE- and C5a-mediated IL-8 release was not inhibited. However, with higher concentrations of LY363196 (>600 nM), which exceeds the IC50 for PKCβ greater than 100 fold, CSE- and C5a-mediated IL-8 release was significantly suppressed. Preincubation of HBEC with 100 nM of Gö 6976, a specific PKCα inhibitor, significantly inhibited CSE- and C5a-mediated stimulation of IL-8 release. Conclusions Collectively, these data suggest that PKC activators in addition to CSE augment C5a-stimulated IL-8 release from HBEC and that CSE and C5a stimulate IL-8 release in HBEC by activating the calcium-dependent PKCα isoform.

Novel C5a Agonist-Based Dendritic Cell Vaccine in a Murine Model of Melanoma

A novel method to improve targeting and presentation of poorly immunogenic tumor-related antigens was investigated. This was performed with a molecular adjuvant constructed by covalently linking a response selective peptide agonist of C5a (YSFKDMP(MeL)aR) to known melanoma tumor-related antigens. C57Bl/6J mice were injected subcutaneously with bone marrow derived dendritic cells (DCs) pulsed with a melanoma epitope (TRP2-P2/Agonist), melanoma epitope tyrosinase (TYR/Agonist), a nonfunctional reverse conformation C5a agonist bound to TYR(reverse peptide) or DMSO-PBS vehicle. Mice were injected with the pulsed DCs and cytokines IL-2 and GM-CSF three times prior to subcutaneous challenge with B16-F10 melanoma cells. All groups subsequently received DC vaccine boosters twice per week. Tumor growth was reduced and survival enhanced in mice immunized with the combination of TRP2-P2/Agonist and TYR/Agonist compared to mice receiving reverse peptide or vehicle.

Experimental treatments for asthma

There has been increased recognition of the importance of inflammatory cells and their products in the pathogenesis of asthma. From this recognition has evolved a number of new approaches to treat the various components of the asthmatic inflammatory response. Nonselective anti-inflammatory agents such as cyclosporine and gold appear to decrease symptoms and allow a steroid-sparing effect in many cases, though side effects from cyclosporine often necessitate dose reduction. Novel oral compounds as the 5-lipoxygenase inhibitors have been effective in controlling asthma symptoms triggered by various stimuli, and the cysteinyl leukotriene receptor antagonists have shown promise in this regard as well. Neurokinin antagonists, inhaled loop diuretics, and lidocaine may play significant roles in asthma therapy through inhibition of neurogenic inflammation and possibly mast cell function. Inhibition of mast cell products by existing drugs such as heparin or the development of specific inhibitors of mast cell tryptase may also be effective agents, as are selective phosphodiesterase inhibitors, which appear to have anti-inflammatory properties. Finally, specific cytokine antagonists, agonists, inhibitors of T-cell function, selective inducible nitric oxide synthase inhibitors, and even gene-directed strategies may provide not only insights into the pathogenesis of asthma but also novel therapeutic approaches to treat the inflammation in this disease.

Staggered Transition to Epoprostenol from Treprostinil in Pulmonary Arterial Hypertension

OBJECTIVE: To describe a successful transition process from subcutaneous treprostinil to intravenous epoprostenol after the failure of treprostinil in a patient with idiopathic pulmonary arterial hypertension and present an algorithm to achieve the conversion without significant adverse reactions. CASE SUMMARY: A 25-year-old white female receiving subcutaneous treprostinil 97 ng/kg/min was admitted to the intensive care unit for transition from subcutaneous treprostinil to a target intravenous epoprostenol dose of 72 ng/kg/min via a staggered interval dose adjustment approach. The patient experienced facial flushing, hot flashes, and headache when dose adjustments of the drugs were made simultaneously; however, when dose adjustments were staggered, the adverse reactions did not occur and larger adjustments could be achieved. DISCUSSION: This case demonstrates a suboptimal therapeutic response to treprostinil for the treatment of idiopathic pulmonary arterial hypertension. The transition of treprostinil to epoprostenol is rare; however, in the event therapy change is needed, dosing information is minimal. A staggered transition dosing regimen that accounts for the pharmacokinetic differences between epoprostenol and treprostinil was successfully used in this case. CONCLUSIONS: The approach in this case demonstrates the success of staggered-interval dose adjustments to minimize supratherapeutic symptoms and coincides with the pharmacokinetic profile of the 2 medications.