Drugs

Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel; Recarti, Chiara; Steckelings, Ulrike; Unger, Thomas

doi: 10.1007/s40265-015-0509-4pmid: 26631237

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin–angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired.

Airody, Archana; Heath, Greg; Lightman, Susan; Gale, Richard

doi: 10.1007/s40265-015-0502-ypmid: 26645222

Non-infectious uveitis mainly affects the working-age population and can contribute to significant social and economic burden. It comprises a heterogeneous group of conditions with varied aetiology. Precise and early diagnosis, excluding masquerade syndromes, is the key to early therapeutic intervention. Treatment should be appropriately selected according to the anatomical sites of inflammation, the diagnosis and known prognosis, and whether there is a systemic inflammatory drive. Corticosteroids in the form of local or systemic therapy form the mainstay of treatment; however, due to unacceptable side effects, the need for long-term use or suboptimal response, corticosteroid-sparing medications may need to be considered early on in the management of non-infectious uveitis. With newer insights into the immunopathology of uveitis and the availability of biologic agents, treatment can be tailored according to individual needs. Many patients have systemic involvement, and hence a multidisciplinary approach is often required to achieve the best outcome in an individual. Patient involvement in the management of non-infectious uveitis, ensuring compliance, and continual monitoring of both the treatment and therapeutic response are the key to achieving optimal outcomes.

Hermansen, Kjeld; Bohl, Mette; Schioldan, Anne

doi: 10.1007/s40265-015-0500-0pmid: 26607485

Limiting excessive postprandial glucose excursions is an important component of good overall glycemic control in diabetes mellitus. Pharmacokinetic studies have shown that insulin aspart, which is structurally identical to regular human insulin except for the replacement of a single proline amino acid with an aspartic acid residue, has a more physiologic time–action profile (i.e., reaches a higher peak and reaches that peak sooner) than regular human insulin. As expected with this improved pharmacokinetic profile, insulin aspart demonstrates a greater glucose-lowering effect compared with regular human insulin. Numerous randomized controlled trials and a meta-analysis have also demonstrated improved postprandial control with insulin aspart compared with regular human insulin in patients with type 1 or type 2 diabetes, as well as efficacy and safety in children, pregnant patients, hospitalized patients, and patients using continuous subcutaneous insulin infusion. Studies have demonstrated that step-wise addition of insulin aspart is a viable intensification option for patients with type 2 diabetes failing on basal insulin. Insulin aspart has shown a good safety profile, with no evidence of increased receptor binding, mitogenicity, stimulation of anti-insulin antibodies, or hypoglycemia compared with regular human insulin. In one meta-analysis, there was evidence of a lower rate of nocturnal hypoglycemia compared with regular human insulin and, in a trial that specifically included patients with a history of recurrent hypoglycemia, a significantly lower rate of severe hypoglycemic episodes. The next generation of insulin aspart (faster-acting insulin aspart) is being developed with a view to further improving on these pharmacokinetic/pharmacodynamic properties.

Collins, Sean; Grant, Philip; Shafer, Robert

doi: 10.1007/s40265-015-0515-6pmid: 26677129

HIV-1-infected patients with suppressed plasma viral loads often require changes to their antiretroviral (ARV) therapy to manage drug toxicity and intolerance, to improve adherence, and to avoid drug interactions. In patients who have never experienced virologic failure while receiving ARV therapy and who have no evidence of drug resistance, switching to any of the acceptable US Department of Health and Human Services first-line therapies is expected to maintain virologic suppression. However, in virologically suppressed patients with a history of virologic failure or drug resistance, it can be more challenging to change therapy while still maintaining virologic suppression. In these patients, it may be difficult to know whether the discontinuation of one of the ARVs in a suppressive regimen constitutes the removal of a key regimen component that will not be adequately supplanted by one or more substituted ARVs. In this article, we review many of the clinical scenarios requiring ARV therapy modification in patients with stable virologic suppression and outline the strategies for modifying therapy while maintaining long-term virologic suppression.

Garnock-Jones, Karly

doi: 10.1007/s40265-015-0518-3pmid: 26628294

Prucalopride (Resolor®), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC.

Syed, Yahiya

doi: 10.1007/s40265-015-0521-8pmid: 26628293

Sumatriptan/naproxen sodium (Treximet®) is a fixed-dose combination of a serotonin 5-HT1B/1D receptor agonist (sumatriptan) and an NSAID (naproxen sodium), approved in the USA for the acute treatment of migraine with or without aura in adolescents and adults. In a randomized, phase 3 trial in adolescents, significantly more sumatriptan/naproxen sodium than placebo recipients were pain-free at 2 h. Similarly, in a pair of randomized phase 3 trials in adults, significantly more sumatriptan/naproxen sodium than placebo recipients had relief from migraine symptoms at 2 h, and the combination was more effective than individual components in terms of sustained (2–24 h) pain-free response rate. Sumatriptan/naproxen sodium was generally well tolerated, with ≤11 % of adolescents and ≤22 % of adults reporting treatment-related adverse events in the key clinical trials. The most common adverse reactions were nasopharyngitis, hot flushes and muscle tightness in adolescents, and dizziness, pain or pressure sensations, nausea, somnolence, dry mouth, dyspepsia and paraesthesia in adults. Based on current data, sumatriptan/naproxen sodium is a useful option for the acute treatment of migraine in adolescents and adults. The fixed-dose combination may reduce pill burden and improve adherence in some patients.

Burness, Celeste; McCormack, Paul

doi: 10.1007/s40265-015-0520-9pmid: 26666418

The capsaicin 8 % patch (QUTENZA®) is an adhesive patch containing a high concentration (8 % w/w) of synthetic capsaicin, a selective agonist of transient receptor potential vanilloid 1 channel. It is approved for treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain in the EU; it is only approved to treat postherpetic neuralgia (PHN) in the USA. In patients with painful diabetic peripheral neuropathy (PDPN), a single 30-min application of the capsaicin 8 % patch significantly improved pain relief and sleep quality compared with placebo in a 12-week double-blind trial. In a 52-week, randomized trial, up to seven consecutive 30-min treatments with the capsaicin 8 % patch (≤7 treatments each at least 8 weeks apart) plus standard of care therapy was associated with sustained pain relief and no negative neurological safety consequences compared with standard of care. In two randomized trials, a single 60-min application of the capsaicin 8 % patch reduced pain scores significantly more than a low-concentration (0.04 %) capsaicin control patch in patients with PHN. Capsaicin 8 % patch treatment was noninferior to pregabalin (optimized dosage) in a randomized trial in patients with nondiabetic peripheral neuropathic pain. Results in two trials in patients with HIV-AN were equivocal, with a significant improvement in pain intensity observed in one trial, but not in the other. The capsaicin 8 % patch was associated with expected, transient, capsaicin-related application-site adverse events such as erythema and pain.

Dhillon, Sohita

doi: 10.1007/s40265-015-0527-2pmid: 26683033

Tiotropium/olodaterol (Stiolto™ Respimat®, Spiolto™ Respimat®) is a fixed-dose combination of the long-acting antimuscarinic agent tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β2-adrenoreceptor agonist olodaterol delivered via the Respimat® Soft Mist™ inhaler. It is indicated for the maintenance treatment of airflow obstruction in adults with COPD. Several randomized, phase III studies of 6–52 weeks’ duration evaluated the efficacy of once-daily tiotropium/olodaterol in patients with GOLD stage 2–3 or 2–4 COPD. Tiotropium/olodaterol maintenance therapy improved lung function to a greater extent than the individual components or placebo and provided clinically meaningful improvements in health-related quality of life and dyspnoea in 12- and 52-week studies. Tiotropium/olodaterol consistently improved 24-h lung function in 6-week studies, providing greater benefits than the monotherapies, placebo or twice-daily fixed-dose fluticasone propionate/salmeterol. Inspiratory capacity and exercise endurance were also improved with tiotropium/olodaterol following 6 or 12 weeks’ treatment. The tolerability profile of tiotropium/olodaterol in the phase III studies was generally similar to that of the component monotherapies. The most common adverse events and serious adverse events during 52 weeks’ therapy were respiratory in nature, with COPD exacerbation, unsurprisingly, reported most frequently with tiotropium/olodaterol and component monotherapies. Although additional data assessing the effect of tiotropium/olodaterol on exacerbations and comparative studies with other recommended therapies are needed to definitively position tiotropium/olodaterol, current evidence indicates that tiotropium/olodaterol is a useful treatment option for patients with COPD.

Greig, Sarah

doi: 10.1007/s40265-015-0522-7pmid: 26620366

Talimogene laherparepvec (Imlygic™) is an oncolytic viral therapy that is being developed by BioVex (a subsidiary of Amgen) for the intralesional treatment of various cancers, including malignant melanoma. Talimogene laherparepvec is a genetically modified, live, attenuated, herpes simplex virus type 1 that is designed to promote an antitumour response through selective viral replication in tumour cells and stimulation of systemic antitumour immunity. In October 2015, talimogene laherparepvec was the first genetically modified, oncolytic viral therapy to be approved in the USA for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery, although it has not been shown to improve overall survival or have an effect on visceral metastases. Talimogene laherparepvec has been recommended for approval in adults with unresectable metastatic melanoma in the EU, and is being evaluated in several countries for use as neoadjuvant or combination therapy in malignant melanoma; it is also in development for soft tissue sarcoma and liver cancer in the USA. This article summarizes the milestones in the development of talimogene laherparepvec leading to this first approval in malignant melanoma.