The landscape of idiopathic pulmonary fibrosis (IPF) has changed. The significant progress regarding our knowledge on the pathogenesis of the disease together with the experience achieved after a series of negative trials has led to the development of two drugs for the treatment of IPF. Both pirfenidone and nintedanib can slow significantly the rate of disease progression. They are safe with side effects that can be either prevented by close collaboration between health care professionals and patients or treated successfully when they occur, rarely leading to treatment discontinuation. However, there are still few unanswered questions regarding the application of the beneficial results of pharmaceutical trials in the general population of IPF patients. Long-term “real-life” studies are being undertaken to answer these questions. In this article, we focus on the advances that have led to the development of the antifibrotic agents with particular focus on pirfenidone.
Atrial fibrillation is the most common arrhythmia in the elderly. It is responsible for significant morbidity and mortality from cardioembolic complications like stroke. As a result, atrial fibrillation patients are risk-stratified using the CHADS2or CHA2DS2-VASc scoring systems. Those at intermediate-to-high risk have traditionally been treated with therapeutic anticoagulation with warfarin for stroke prevention. Although effective, warfarin use is fraught with multiple concerns, such as a narrow therapeutic window, drug–drug and drug–food interactions, and excessive bleeding. Novel oral anticoagulant agents have recently become available as viable alternatives for warfarin therapy. Direct thrombin inhibitor dabigatran and factor Xa inhibitors like rivaroxaban and apixaban have already been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation. Edoxaban is the latest oral direct factor Xa inhibitor studied in the largest novel oral anticoagulant trial so far: ENGAGE AF-TIMI 48. Treatment with a 30 mg or 60 mg daily dose of edoxaban was found to be noninferior to dose-adjusted warfarin in reducing the rate of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a lower incidence of bleeding complications and cardiovascular deaths. Edoxaban was recently reviewed by an FDA advisory committee and recommended as a stroke-prophylaxis agent. Once approved, it promises to provide another useful alternative to warfarin therapy.
Pulmonary arterial hypertension (PAH) is a chronic and disabling condition characterized by an elevated pulmonary vascular resistance and an elevated mean pulmonary arterial pressure. Despite recent improvements in treatment availability, PAH remains challenging to treat, burdensome for patients, and ultimately incurable. Tadalafil is a phos-phodiesterase-5 inhibitor that is administered once daily by mouth for the treatment of PAH. Current treatment guidelines recommend tadalafil as an option for patients with World Health Organization functional class II or III PAH. In a placebo-controlled clinical trial, patients taking tadalafil demonstrated significantly improved exercise capacity as measured by the 6-minute walk distance. Patients also experienced decreased incidence of clinical worsening, increased quality of life, and improved cardiopulmonary hemodynamics. Uncontrolled studies and smaller trials have indicated a possible role for tadalafil as a suitable alternative to sildenafil and as a beneficial add-on option when used in combination with other treatments for PAH. Tadalafil is generally safe and well tolerated. Adverse events are typically mild-to-moderate in intensity, and discontinuation rates are usually low. The purpose of this review is to provide an evidence-based evaluation of the clinical utility of tadalafil in the treatment of PAH.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs. Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone, another antifibrotic drug, was shown to limit the decline in pulmonary function in patients with IPF in the ASCEND trial. Combination therapy with nintedanib and pirfenidone is anticipated, although further evaluation of its long-term safety is needed. There is limited evidence for the safety of the combination therapy although a Phase II trial conducted in Japan demonstrated that combination therapy with nintedanib and pirfenidone was tolerable for 1 month. Available antifibrotic agents (ie, pirfenidone andN-acetylcysteine) have limited efficacy as single therapies for IPF; therefore, further study of combination therapy with antifibrotic agents is needed.
Introduction:The second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist palonosetron is effective in the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy (HEC and MEC, respectively). In addition, palonosetron has been the first and, at present, the only 5-HT3receptor antagonist to have a specific indication for the prevention of delayed CINV associated with MEC. The unique pharmacology of this antagonist is thought to partly explain its improved efficacy against delayed symptoms.
Luliconazole is an imidazole antifungal agent with a unique structure, as the imidazole moiety is incorporated into the ketene dithioacetate structure. Luliconazole is the R-enantiomer, and has more potent antifungal activity than lanoconazole, which is a racemic mixture. In this review, we summarize the in vitro data, animal studies, and clinical trial data relating to the use of topical luliconazole. Preclinical studies have demonstrated excellent activity against dermatophytes. Further, in vitro/in vivo studies have also shown favorable activity againstCandida albicans, Malassezia spp., andAspergillus fumigatus. Luliconazole, although belonging to the azole group, has strong fungicidal activity againstTrichophyton spp., similar to that of terbinafine. The strong clinical antifungal activity of luliconazole is possibly attributable to a combination of strong in vitro antifungal activity and favorable pharmacokinetic properties in the skin. Clinical trials have demonstrated its superiority over placebo in dermatophytosis, and its antifungal activity to be at par or even better than that of terbinafine. Application of luliconazole 1% cream once daily is effective even in short-term use (one week for tinea corporis/cruris and 2 weeks for tinea pedis). A Phase I/IIa study has shown excellent local tolerability and a lack of systemic side effects with use of topical luliconazole solution for onychomycosis. Further studies to evaluate its efficacy in onychomycosis are underway. Luliconazole 1% cream was approved in Japan in 2005 for the treatment of tinea infections. It has recently been approved by US Food and Drug Administration for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis. Topical luliconazole has a favorable safety profile, with only mild application site reactions reported occasionally.
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 aeruginosais 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-Pseudomonasactivity, 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 againstP. 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.
The emergence of resistance to glycopeptide antibiotics such as vancomycin and teicoplanin among Gram-positive bacteria has spurred the search for second-generation drugs of this class. Oritavancin, a promising novel, second-generation, semisynthetic lipoglycopeptide, is distinguished by two mechanisms of action: inhibition of cell wall synthesis and disruption of the cell membrane. This dual mechanism of action has increased the activity of oritavancin against vancomycin-resistant Gram-positive bacteria compared to other glycopeptides. Oritavancin has a concentration-dependent and rapid bactericidal activity against Gram-positive bacteria, particularly enterococci, contrary to vancomycin and teicoplanin, which exhibit bacteriostatic activity. It has a long half-life of about 195.4 hours and is slowly eliminated by the liver and kidneys, allowing once-daily dosing. Oritavancin has demonstrated preliminary safety and efficacy in Phase I and Phase II clinical trials. It was recently shown to be noninferior to vancomycin in a large Phase III randomized, double-blind clinical trial. To date, adverse events have been mild and limited, the most common being administration site complaints, headache, and nausea. Oritavancin appears to be a promising antimicrobial alternative to vancomycin with additional activity againstStaphylococcusandEnterococcusisolates resistant to vancomycin and a more convenient way of administration.
Tumor lysis syndrome (TLS) is a potentially life-threatening complication of cancer therapy characterized by two or more of the following laboratory abnormalities: hyperuricemia, hyperkalemia, hypocalcemia, and hyperphosphatemia, with resultant end-organ damage, eg, renal failure, seizures, or cardiac arrhythmias. High-risk patients include those with highly proliferative cancers and/or large tumor burdens, particularly in the setting of highly effective chemotherapy, among other risk factors. Before 2002, antihyperuricemic drug therapy was limited to allopurinol, a xanthine oxidase inhibitor. Rasburicase, a recombinant urate oxidase, was approved by the US Food and Drug Administration for children in 2002 and adults in 2009, ushering in a new era in TLS therapy. We attempted to critically appraise the available evidence supporting the perceived benefits of rasburicase in the management of TLS. A Medline search yielded 98 relevant articles, including 26 retrospective and 22 prospective studies of rasburicase for the treatment of TLS, which were then evaluated to determine the best available evidence for the effectiveness of rasburicase in terms of disease-oriented, patient-oriented, and economic outcomes. Rasburicase is now a standard of care for patients at high risk of TLS despite continuing debate on the correlation between its profound and rapid lowering of plasma uric acid levels with hard patient outcomes, eg, need for renal replacement therapy and mortality. Rasburicase is dramatically effective in lowering plasma uric acid levels. The mortality and cost-effectiveness benefits of this expensive drug remain to be conclusively proven, and well designed, randomized controlled trials are needed to answer these fundamentally important questions.
Metastatic castration-resistant prostate cancer is the lethal form of cancer of the prostate. Five new agents that prolong survival in this group have emerged in the past 5 years, and sipuleucel-T is among them. Sipuleucel-T is the only immunotherapy shown to improve survival in prostate cancer. It is currently indicated in asymptomatic or mildly symptomatic patients, as it has never shown a direct cancer effect. This paper describes the process of creating the sipuleucel-T product from the manufacturing and patient aspects. It discusses the four placebo-controlled, randomized clinical trials (RCTs) of sipuleucel-T, focusing on survival and adverse events. There are three RCTs in metastatic castration-resistant prostate cancer, all of which showed improved overall survival without meaningful decreases in symptoms, tumor volumes, or prostate-specific antigen levels. One RCT in castration-sensitive, biochemically relapsed prostate cancer attempted to find a decrease in biochemical failure, but that endpoint was not reached. Adverse events in all four of these studies centered around cytokine release. This paper also reviews a Phase II study of sipuleucel-T given neoadjuvantly that speaks to its mechanism of action. Additionally, there is a registry study of sipuleucel-T that has been used to evaluate immunological parameters of the product in men ≥80 years of age and men who had previously been treated with palliative radiation. Attempts to find early markers of response to sipuleucel-T are described. Further ongoing studies that explore the efficacy of sipuleucel-T in combination with immune checkpoint inhibitors and second-generation hormonal therapies that are summarized. Finally, the only published economic analysis of sipuleucel-T is discussed.
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.
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.