Umeclidinium for treating COPD: an evaluation of pharmacologic properties, safety and clinical use.

INTRODUCTION: Umeclidinium (UMEC) is a long-acting inhaled antagonist of muscarinic cholinergic receptors. The FDA approved UMEC for maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 and it became available for commercial use as a single agent in 2014. After tiotropium, this is the only other once daily LAMA available for COPD patients. AREAS COVERED: In this article, we have comprehensively reviewed the pharmacokinetic properties and analyzed the currently available randomized controlled trials on the efficacy and safety profile of UMEC. We have discussed the current clinical application of UMEC and its future implication. EXPERT OPINION: UMEC is the newer long-acting antimuscarinic agent (LAMA) that has demonstrated significant improvement in lung function and improved the quality of life in moderate-to-severe COPD patients. It is suitable for once daily dosing, has low anticholinergic side effects and is well tolerated. Overall, it is a safe, effective and convenient LAMA for maintenance therapy in COPD patients.

Pulmonary nodule: a comprehensive review and update.

The incidental detection of solitary pulmonary nodules and ground-glass nodules has increased substantially with the use of computed tomography as a diagnostic modality and is expected to rise exponentially as lung cancer screening guidelines are more widely implemented by primary care physicians. The lesions should then be classified as low, indeterminate, or high risk for malignancy, depending on the clinical and radiological characteristics. Once classified, these lesions should be evaluated and managed as per expert consensus-based recommendations for performing follow-up computed tomography scans and tissue sampling depending on the pretest probability. When weighing the risks and benefits of further investigations, patient preference and suitability for surgery should be taken into consideration as well.

Acquired thrombotic thrombocytopenic purpura associated with reversible severe renal failure requiring hemodialysis.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon hematologic disorder characterized by microangiopathic hemolytic anemia (MHA) and thrombocytopenia with or without fever, renal failure, and neurologic manifestations. Although the full pentad was required for the diagnosis of TTP until recently, because of the high mortality of untreated TTP and the varying manifestations of the disease itself, diagnostic criteria for TTP have been relaxed since the emergence of plasma exchange as effective treatment for TTP. The occurrence of MHA and thrombocytopenia without an alternate cause is now sufficient to initiate therapy. Renal dysfunction in acquired TTP, when it occurs, is transient and responds to therapeutic plasma exchange readily. Here we report a patient with acquired TTP who had no preexisting renal pathology but developed severe prolonged renal failure requiring multiple rounds of hemodialysis with eventual complete recovery of renal function. We adopted an intensive approach including steroids, rituximab, cyclosporine, twice daily plasma exchange, and hemodialysis. We believe that this was responsible for complete recovery of the patient. However, the reason for this unusually severe renal manifestation needs further study.

Disseminated Mycobacterium gordonae infection in an immunocompetent host.

Mycobacterium gordonae is a slow-growing mycobacterium that is the least pathogenic of the mycobacteria. Infection with M. gordonae is most commonly reported in immunocompromised patients. We present a rare case of M. gordonae infection in an immunocompetent individual. A 37-year-old woman was found to have a pulmonary nodule in the left upper lobe. The patient denied any respiratory symptoms, including cough, sputum production, fever, chest pain, or shortness of breath. The patient was a lifetime nonsmoker. Physical examination was normal. Computed tomography (CT) scan of the chest revealed several discrete pleural-based inflammatory infiltrates bilaterally. The patient was treated with oral amoxicillin-clavulinic acid initially and a repeat CT scan chest was scheduled after 2 weeks. Laboratory data were nonsignificant. Repeat CT scan did not show any resolution. Patient positron emission tomography scan revealed marked hypermetabolic uptake involving bilateral parenchymal nodules, mediastinal lymph nodes, and the spleen. A thoracotomy with biopsy of the left upper lobe nodule revealed necrotizing granulomatous pneumonitis with rare acid-fast bacilli. Cultures were positive for M. gordonae. The patient was started on a multidrug regimen of azithromycin, rifampin, and ciprofloxacin, based on drug sensitivities, for 12 months. Repeat CT scan and positron emission tomography scan after treatment showed complete resolution. The patient has remained disease-free 5 years after treatment. Instead of always dismissing M. gordonae as a contaminant, we should include it in our differential diagnosis of pulmonary infection in both immunocompetent and immunocompromised hosts. Further studies are needed to understand the pathogenesis of M. gordonae infection in humans.

Major adverse cardiac events at follow-up after bare-metal stenting versus drug-eluting stenting in ST-elevated myocardial infarction.

After thrombolytic therapy with tenecteplase for ST-segment elevation acute myocardial infarction, 376 patients were transferred from their hospital to Westchester Medical Center for percutaneous coronary intervention with stenting. Of 376 patients, 102 (27%) received bare-metal stents and 274 (73%) received drug-eluting stents with sirolimus-eluting or paclitaxel-eluting stents. At 43 months of follow-up, major adverse cardiac events occurred in 25 (25%) of 102 patients treated with bare-metal stents versus 40 (15%) of 274 patients treated with drug-eluting stents (p = 0.024). Cox regression analysis showed that significant independent prognostic factors for major adverse cardiac events were previous coronary artery bypass surgery (hazard ratio 2.2, p = 0.019), width of stent (hazard ratio 0.44, p = 0.006), and bare-metal stent (hazard ratio 1.8, p = 0.019). In conclusion, patients with bare-metal stents had a 1.8 times greater risk of developing major adverse cardiac events than did those using drug-eluting stents after controlling the confounding effects of previous coronary artery bypass surgery and stent width.

Targeting endothelial cells with heme oxygenase-1 gene using VE-cadherin promoter attenuates hyperglycemia-mediated cell injury and apoptosis.

Risk factors for cardiovascular diseases include hyperglycemia, TNF, and reactive oxygen species (ROS), which collectively contribute to vascular endothelial cell dysfunction and apoptosis. We examined, in vascular endothelial cells, whether the selective expression of heme oxygenase-1 (HO-1) offers cytoprotection against glucose- and TNF-mediated cell death. An adenoviral vector expressing human HO-1 was constructed using a VE-cadherin (VECAD) promotor fragment, and cell-specific expression of the recombinant adenovirus was examined using endothelial and vascular smooth muscle cells. The effects of HO-1 transduction (Ad-VECAD-HO-1 gene) on HO-1 expression, HO activity, and the response to TNF and hyperglycemia were studied. Human HO-1 gene was selectively expressed in endothelial cells after infection with the Ad-VECAD-HO-1 vector. Selective expression of HO-1 prevented TNF- and hyperglycemia-mediated superoxide (O2-) formation, DNA degeneration, and upregulation of caspase, but increased the expression of pAkt and Bcl-xL, proteins responsible for endothelial dysfunction in diabetes. These results demonstrate that endothelial cell survival after oxidative stress injury may be enhanced by targeting HO-1 expression, thus blocking inflammation, apoptosis, and thereby attenuating cardiovascular risk factors.

Heme oxygenase -1 gene therapy: recent advances and therapeutic applications.

Heme oxygenase-1 (HO-1) is regarded as a sensitive and reliable indicator of cellular oxidative stress. Studies on carbon monoxide (CO) and bilirubin, two of the three (iron is the third) end products of heme degradation have improved the understanding of the protective role of HO against oxidative injury. CO is a vasoactive molecule and bilirubin is an antioxidant, and an increase in their production through an increase in HO activity assists other antioxidant systems in attenuating the overall production of reactive oxygen species (ROS), thus facilitating cellular resistance to oxidative injury. Gene transfer is used to insert specific genes into cells that are either otherwise deficient in or that underexpress the gene. Successful HO gene transfer requires two essential elements to produce functional HO activity. Firstly, the HO gene must be delivered in a safe vector, e.g., adenoviral, retroviral or leptosome based vectors, currently being used in clinical trials. Secondly, with the exception of HO gene delivery to either ocular or cardiovascular tissue via catheter-based delivery systems, HO delivery must be site and organ specific. This has been achieved in rabbit ocular tissues, rat liver, kidney and vasculature, SHR kidney, and endothelial cells [Abraham et al., 1995a; Abraham et al., 1995b; Abraham et al., 2002c; Quan et al., 2004; Sabaawy et al., 2000; Sabaawy et al., 2001; Yang et al., 2004]. In this review, we discuss the functional significance of the HO system in various pathophysiological conditions and the beneficial therapeutic applications of human HO gene transfer and gene therapy in a variety of clinical circumstances.