Drugs

Beswick, Daniel; Gray, Stacey; Smith, Timothy

doi: 10.1007/s40265-017-0803-4pmid: 28853058

Chronic rhinosinusitis (CRS) is an inflammatory sinonasal condition with multiple etiologic factors that is associated with a vast economic cost. Treatment is most frequently pharmacologic and has centered on agents that ameliorate inflammation, decrease bacterial or pathogen load, and facilitate egress of mucus or purulence from the sinonasal cavity. Nasal saline irrigations, topical nasal steroids, certain antibiotics, and systemic steroids have shown some efficacy in the management of CRS. Recently, biologic therapeutics that target specific inflammatory pathways associated with subsets of CRS have been developed and evaluated. Early data evaluating these biologic treatments suggest a potential role in treating a subset of CRS with refractory, poorly controlled disease. Additional studies are necessary to identify which patients would benefit most from biologic therapies and to assess the cost of these therapies compared with the benefit they provide. This review describes the pathophysiology of CRS and summarizes both established and novel biologic pharmacologic treatments.

Mukerji, Geetha; Feig, Denice

doi: 10.1007/s40265-017-0807-0pmid: 28864965

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes in the setting of poor glycemic control. The initial management for GDM includes intensive lifestyle modification, which often requires behavioral and nutritional changes to optimize glycemic control. Pharmacotherapy for GDM is initiated when glycemic targets are not met. The rapid-acting bolus analogues aspart and lispro achieve postprandial targets with less hypoglycemia compared to regular insulin, with similar fetal outcomes. The long-acting insulin analogues glargine and detemir appear safe with similar maternal/fetal outcomes compared to NPH. While insulin has been the mainstay therapy for women with GDM to improve glycemic control when lifestyle modifications are insufficient, certain oral antihyperglycemic drugs (OADs) can be considered as alternative treatment options for GDM but continue to be controversial for use as first-line treatment options compared to insulin by many professional bodies. Metformin has good efficacy and short-term safety data but it freely crosses the placenta and long-term safety data are lacking. Glyburide has good efficacy and short-term data but it also crosses the placenta and may be associated with increased rates of large-for-gestational-age (LGA) infants and neonatal hypoglycaemia when compared with insulin. This review aims to give an overview of the pharmacological treatment for women with GDM including some of the known safety profiles of current therapeutic options.

Costa, Francesco; Windecker, Stephan; Valgimigli, Marco

doi: 10.1007/s40265-017-0806-1pmid: 28853033

Dual antiplatelet therapy (DAPT) prevents recurrent ischemic events after an acute coronary syndrome (ACS) as well as stent thrombosis (ST) in patients with prior stent implantation. Nevertheless, these benefits are counterbalanced by a significant bleeding hazard, which is directly related to the treatment duration. Although DAPT has been extensively studied in numerous clinical trials, optimal treatment duration is still debated, mostly because of apparent inconsistencies among studies. Shortened treatment duration of 6 or 3 months was shown to mitigate bleeding risk compared with consensus-grounded 12-month standard duration, without any apparent excess of ischemic events. However, recent trials showed that a >12-month course of treatment reduces ischemic events but increases bleeding compared with 12 months. The inconsistent benefit of a longer DAPT course compared with shorter treatment durations is puzzling, and requires a careful appraisal of between-studies differences. We sought to summarize the existing evidence aiming at reconciling apparent inconsistencies among these studies, as well as thoroughly discuss the possible increased risk of fatal events associated with long-term DAPT. Benefits and risks of prolonging or shortening DAPT duration will be discussed, with a focus on treatment individualization. Finally, we will provide an outlook for possible future directions in the field.

Comi, Giancarlo; Hartung, Hans-Peter; Bakshi, Rajesh; Williams, Ian; Wiendl, Heinz

doi: 10.1007/s40265-017-0814-1pmid: 28905255

Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit–risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.

Domingo, Christian

doi: 10.1007/s40265-017-0810-5pmid: 28948572

Among the monoclonal antibodies (mAbs) developed for severe asthma treatment, three have already been marketed. Omalizumab was the first, more than 10 years ago; today, mepolizumab and reslizumab are also available in the European Union and the US. Omalizumab blocks free immunoglobulin E (IgE), mepolizumab and reslizumab block an interleukin (IL-5). In the near future, dupilumab and benralizumab are expected to emerge as two new alternatives. Benralizumab blocks the receptor for IL-5 (IL5-Rα) and has a direct cytotoxic effect on eosinophils, and dupilumab blocks the α-unit of the heterodimeric receptor for IL-4 and IL-13 (IL-4Rα); as a result, dupilumab can block both IL-4 and IL-13. The purpose of this manuscript is to present the pathophysiology of some immunological aspects of severe asthma, describe the adaptive and innate immunity arms as well as their interrelations (stressing the subordination of the adaptive arm to the innate arm), outline the pharmacologic effects of these mAbs, clarify the overlapping effects of the different mAbs, and discuss the differences between mAbs based on their target molecules. Based on the data presented, I propose omalizumab for patients with an allergic phenotype regardless of their peripheral eosinophilic count, and anti-IL-5 as an alternative in allergic patients with blood eosinophilia in which omalizumab has failed; anti-IL5 for patients with an eosinophilic phenotype and omalizumab as an alternative in patients in whom anti-IL5 fails and IgE ≥30 IU/mL (compassionate use). Omalizumab is also proposed for patients with severe chronic asthma allergic to seasonal allergens.

Deeks, Emma D.

doi: 10.1007/s40265-017-0827-9pmid: 29071467

A once-daily tablet formulation (Isentress® HD; Isentress® 600 mg) of the integrase strand transfer inhibitor raltegravir is now available for the treatment of HIV-1 infection. The 600 mg tablet has improved bioavailability versus the existing twice-daily 400 mg tablet (due, at least in part, to differences in tablet dissolution) and the recommended dosage is 1200 mg (i.e. two 600 mg tablets) once daily. In combination with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve adults, once-daily raltegravir 1200 mg provided virological suppression non-inferior to that seen with twice-daily raltegravir 400 mg over 48 and 96 weeks in the phase 3 ONCEMRK trial. The once-daily raltegravir regimen was also generally well tolerated in this study, displaying a tolerability profile similar to that of the twice-daily regimen. The once-daily tablet simplifies and improves the convenience of raltegravir regimens, although its impact on adherence has yet to be determined. Thus, once-daily raltegravir tablets are a convenient alternative to twice-daily raltegravir tablets for the treatment of HIV-1, further expanding the therapeutic options available to meet the diverse needs of this patient population.

Lamb, Yvette

doi: 10.1007/s40265-017-0817-ypmid: 28929412

A fixed-dose combination tablet of the hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) glecaprevir and the HCV NS5A inhibitor pibrentasvir [glecaprevir/pibrentasvir; MAVIRET™ (EU); MAVYRET™ (USA)] has been developed by AbbVie. Oral glecaprevir/pibrentasvir 300 mg/120 mg (three 100 mg/40 mg tablets) taken once daily has been approved by the EMA for the treatment of all major genotypes (genotypes 1–6) of chronic HCV infection in adults. It has also been approved by the US FDA for the treatment of adult patients with chronic HCV genotype 1–6 infection without cirrhosis and with compensated cirrhosis, and for the treatment of adult patients with HCV genotype 1 infection who previously have been treated with a regimen containing either an HCV NS5A inhibitor or an NS3/4A PI, but not both. This article summarizes the milestones in the development of glecaprevir/pibrentasvir leading to its first global approval in the EU and subsequent approval in the USA for chronic HCV infection.

Blair, Hannah

doi: 10.1007/s40265-017-0818-xpmid: 28929345

Pemafibrate (Parmodia®) is a novel, highly selective peroxisome proliferator-activated receptor (PPAR)-α modulator (SPPARM). It acts by binding to PPAR-α and regulating the expression of target genes that modulate lipid metabolism, thereby decreasing plasma triglyceride levels and increasing high-density lipoprotein cholesterol levels. Developed by Kowa Company, Ltd., oral pemafibrate has been approved in Japan for the treatment of hyperlipidaemia (including familial hyperlipidaemia). This article summarizes the milestones in the development of pemafibrate leading to this first global approval for hyperlipidaemia.

Al-Salama, Zaina T.

doi: 10.1007/s40265-017-0820-3pmid: 28940154

Elsulfavirine (Elpida®) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) being developed by Viriom for the treatment and prevention of human immunodeficiency virus (HIV) infections. It is the prodrug of the active compound VM-1500A, a small molecule selective NNRTI, which prevents HIV replication. In June 2017, elsulfavirine received its first global approval in Russia for the treatment of HIV-1 infections in combination with other antiretroviral medicines. Other formulations of this drug are also being evaluated in preclinical and phase II studies for the treatment of HIV infections and/or pre-exposure and post-exposure prophylaxis. This article summarizes the milestones in the development of elsulfavirine leading to this first approval in HIV-1 treatment.

Syed, Yahiya

doi: 10.1007/s40265-017-0826-xpmid: 29019107