Core Evidence最新文献

Chronic bacterial respiratory-tract infections are a major driving force in the pathogenesis of cystic fibrosis (CF) lung disease and promote chronic lung-function decline, destruction, and progression to respiratory failure at a premature age. Gram-negative bacteria colonizing the airways in CF are a major problem in CF therapy due to their tendency to develop a high degree of resistance to antibiotic agents over time. Pseudomonas aeruginosa is the dominating bacterial strain infecting the CF lung from early childhood on, and multiresistant strains frequently develop after years of therapy. Colistin has been used for treating pulmonary bacterial infections in CF for decades due to its very good Gram-negative activity. However, drawbacks include concerns regarding toxicity when being applied systemically, and the lack of approval for application by inhalation in the USA for many years. Other antibiotic substances for systemic use are available with good to excellent Gram-negative and anti-Pseudomonas activity, while there are only three substances approved for inhalation use in the treatment of chronic pulmonary infection with proven benefit in CF. The emergence of multiresistant strains leaving nearly no antibiotic substance as a treatment option, the limited number of antibiotics with high activity against P. aeruginosa, the concerns about increasing the risk of antibiotic resistance by continuous antibiotic therapy, the development of new drug formulations and drug-delivery devices, and, finally, the differing treatment strategies used in CF centers call for defining the place of this "old" drug, colistimethate, in today's CF therapy. This article reviews the available evidence to reflect on the place of colistimethate sodium in the therapy of chronic pulmonary infection in CF.

Advances in knowledge regarding the pathogenesis of psoriasis have allowed the development of a new class of agents known as biologic drugs. Data confirm that T helper (Th)17 and interleukin (IL)-17 signaling has a crucial role in the pathogenesis of the disease. High levels of IL-17 and Th17-related cytokines have been reported in psoriasis, leading to the suggestion of agents targeting IL-17 as a potential therapeutic strategy in psoriasis. Brodalumab is a human monoclonal antibody that targets IL-17 receptor A, blocking the effects of IL-17A, IL-17F, and IL-17E. Data from Phase I and Phase II clinical trials indicate that brodalumab has a favorable safety and tolerability profile, with strong clinical activity, suggesting that it is a potential tool for use in the treatment of moderate-to-severe psoriasis.

Hepatocellular carcinoma (HCC) is the second-most common cause of cancer-related death in the world. In spite of HCC surveillance with repeated imaging, about 50% of patients are diagnosed at an advanced stage and are not amenable to curative treatment options. Sorafenib, a multikinase inhibitor, remains the standard of care for advanced HCC. Over the last 5 years, several other medications have been tested in Phase III trials. However, they have not shown any added benefit over sorafenib. Regorafenib, another multikinase inhibitor, has demonstrated inhibition of a broader range of kinases, along with higher inhibition potential in preclinical models. After its safety and pharmacological properties was studied in Phase I trials, a Phase II study evaluating the role of Regorafenib in patients with advanced HCC who progressed on sorafenib therapy demonstrated efficacy and a manageable safety profile. A Phase III trial is ongoing, and its result will help us better evaluate the role of Regorafenib in patients with advanced HCC.

Pulmonary arterial hypertension (PAH) remains a progressive disease without a cure, despite the development of several treatment options over the past several decades. Its management strategy consists of the endothelin receptor antagonists (ambrisentan, bosentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), and prostacyclin analogs (epoprostenol, treprostinil, iloprost). Treprostinil, a stable prostacyclin analog, displays vasodilatory effects in the pulmonary vasculature, as well as antiplatelet aggregation properties. Clinical practice guidelines recommend oral endothelin receptor antagonist or phosphodiesterase inhibitor therapy in mild to moderate PAH. Epoprostenol is specifically suggested as first-line therapy in moderate to severe PAH patients (ie, World Health Organization/New York Heart Association functional class III-IV). However, treprostinil may be an alternative option in these severe PAH patients. The longer half-life and stability at room temperature with treprostinil may be associated with lower risk of pulmonary hemodynamic worsening as a result of abrupt infusion discontinuation and less frequent drug preparation. These characteristics make treprostinil an attractive alternative to continuous infusion of epoprostenol, due to convenience and patient safety. The purpose of this review is to evaluate the safety and efficacy of continuous infusion of treprostinil as well as the inhaled and oral routes of administration in PAH.

Cabozantinib (XL184) is a multitargeted receptor tyrosine kinase with predominantly MET and vascular endothelial growth factor inhibition properties. It is currently approved by the US Food and Drug Administration for the treatment of progressive metastatic medullary thyroid cancer. The agent has a convenient once-daily oral dosing schedule and has demonstrated encouraging activity in metastatic castrate-resistant prostate cancer (CRPC). A Phase I/II trial demonstrated responses in soft tissue, visceral disease, and bone metastases in CRPC. An objective response rate of 5%, a stable disease rate of 75%, and a median progression-free survival of 6 months was observed. As compared with the 140 mg daily dose used in thyroid cancer, a lower dose of 60 mg daily is currently being utilized in prostate cancer studies due to the fact that toxicity could be reduced without compromising efficacy. Randomized trials are ongoing in comparison with prednisone or with mitoxantrone and prednisone in pretreated metastatic CRPC. Cabozantinib has demonstrated a unique mechanism of action and preliminary efficacy in the crowded therapeutic field of prostate cancer. Since multiple therapies have recently demonstrated overall survival benefit in metastatic CRPC, cabozantinib will likely face some challenges in clinical application. At present, in this rapidly evolving field, it is unclear what proportion of patients with prostate cancer will be eligible to receive this therapy. The cost of cabozantinib is likely to be another deterrent, especially if it remains more expensive than other oral therapies, such as abiraterone and enzalutamide. Defining the role of MET overexpression and RET mutations as biomarkers in prostate cancer may help to guide patient selection, and enrich and enhance the future applications of this targeted novel agent.

Vitreomacular traction is a multicategory entity that may cause substantial visual loss due to the formation of a macular hole or traction-induced tissue distortion. The advent of optical coherent tomography (OCT) has demonstrated the anatomic features of persistent vitreomacular attachment (VMA) more definitively, including in many asymptomatic or minimally symptomatic patients. The indications for intervention are unclear, since it is not possible to predict which eyes might be likely to develop progressive visual loss. This has been especially important since for many years, the only treatment option involved surgical intervention (vitrectomy) to release the persistent VMA. Recently, a pharmacolytic agent, ocriplasmin, has become available after many years of development and investigation, and may offer a feasible alternative to surgery, or even a risk/benefit ratio sufficiently favorable to offer intervention at an earlier stage of VMA. Several studies, including a large, prospective clinical trial, have established the foundation of its rationale and efficacy, providing the basis of its approval. The role for ocriplasmin in clinical practice is in the process of being determined. This paper summarizes current knowledge and status of investigations regarding ocriplasmin-induced pharmacologic vitreolysis, and offers some evidence-based considerations for its use.

Rheumatoid arthritis (RA) management has greatly improved with the development of biologic disease modifying antirheumatic drugs, but a proportion of patients do not improve despite the biologic drugs currently available. We need new biologic agents with novel mechanisms of action for the treatment of refractory patients. Recent evidence has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is involved in the pathogenesis of RA. GM-CSF can exacerbate RA and elevated levels of this cytokine have been observed in synovial fluid from RA patients. Antagonism of GM-CSF can strikingly reduce established disease in mouse models of arthritis. Mavrilimumab, a human monoclonal antibody to GM-CSF receptor α, is a competitive antagonist of GM-CSF signaling. Phase I and II studies have shown good clinical response with a good safety profile in patients with mild to moderate RA, suggesting encouraging effects of mavrilimumab for the treatment of RA. This paper reviews the preclinical and clinical data evaluating the safety, tolerability, and efficacy of mavrilimumab in the treatment of RA.

Invasive fungal infections have increased throughout the world. Many of these infections occur in patients with multiple comorbidities who are receiving medications with the potential for interactions with antifungal therapy that could lead to renal and hepatic dysfunction. The second marketed echinocandin, micafungin, was approved in 2005 for the treatment of esophageal candidiasis and prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation. The indication for use was later expanded to include candidemia, acute disseminated candidiasis, Candida abscesses, and peritonitis. Like other echinocandins it is fungicidal against Candida species, including those that are polyene- and azole-resistant and fungistatic against Aspergillus species. Its formulation is by the intravenous route only and it is dosed once daily without a loading dose as 85% of the steady state concentration is achieved after three daily doses. It has a favorable tolerability profile with no significant drug interactions and does not need adjustment for renal or hepatic insufficiency.