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Matera, Maria; Calzetta, Luigino; Cazzola, Mario
doi: 10.1007/s40265-013-0120-5pmid: 24127222
The common coexistence of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) presents several therapeutic constraints that have not been comprehensively investigated. Pharmacologic modulation of β-adrenoceptor (β-AR) function is one of the critical issues in the treatment of these patients because inhaled β2-AR agonists may induce adverse events in patients with COPD, mainly in those with coexisting CVD. Moreover, the use of β-AR blockers has traditionally been contraindicated in COPD, mainly because of the potential for acute bronchospasm and increased airway hyperresponsiveness after their administration. However, there now appears to be good evidence that β-AR blockers are not only safe but may have benefits in COPD that extend beyond a reduction in cardiovascular mortality. This article starts with a succinct outline of the evolution in our understanding of β-AR modulation in COPD, touching on treatment of COPD with β-AR agonists and the issues of β-AR blockade and cardioselectivity in patients with comorbid CVD. We then summarize the current evidence for a COPD benefit from β-AR blockers and hypothesize on the mode of action. Finally, we provide a view of the future landscape in terms of therapeutic possibilities and what still needs to be resolved, based on our opinion.
Harbeck, Nadia; Wuerstlein, Rachel
doi: 10.1007/s40265-013-0118-zpmid: 24127221
With the advent of the monoclonal antibody trastuzumab over 2 decades ago for breast cancer therapy, the outcome of patients with human epidermal growth factor receptor (HER) 2-positive disease has improved dramatically. Based on its substantial efficacy and good tolerability, trastuzumab has become the therapeutic gold standard for early as well as advanced breast cancer. Nevertheless, despite adjuvant trastuzumab, patients do experience recurrence and require further anti-HER2-targeted therapy. Next to the small molecule tyrosine kinase inhibitor lapatinib, which was the first approved therapy option after trastuzumab failure, several new anti-HER2 agents are currently already available for clinical use [i.e. pertuzumab, T-DM1 (trastuzumab emtansine)] or are still being evaluated (e.g. afatinib, neratinib). Recent evidence from neoadjuvant as well as metastatic therapy suggests that dual blockade may be superior to single-agent HER2 blockade. While the number of available or potential therapies has increased considerably, no additional predictive biomarkers beyond HER2 have been validated for the use of the different anti-HER2 therapies. Moreover, novel therapeutic concepts such as the antibody-drug conjugate T-DM1 warrant excellent determination methodology for HER2 and suggest re-evaluation of tumor biology upon first metastasis. The clinical challenge remains to optimally choose, utilize, and sequence anti-HER2 therapy in early as well as metastatic breast cancer. This article will provide evidence-based guidance for sequencing anti-HER2 therapy throughout the continuum of breast cancer therapy.
Ferri, Nicola; Corsini, Alberto; Bellosta, Stefano
doi: 10.1007/s40265-013-0126-zpmid: 24114622
The P2Y12 receptor is a key player in platelet activation and represents an effective pharmacological target for the inhibition of platelet aggregation and prevention of atherothrombotic events. Indeed, the clinical use of the P2Y12 receptor inhibitor clopidogrel is an effective strategy for inhibiting platelet activity in patients with acute coronary syndrome, and for preventing thrombotic events in those undergoing percutaneous coronary intervention with stenting. However, clopidogrel has several drawbacks, which include delayed onset of action, large inter-individual variability in platelet response, genetic polymorphism of the metabolizing enzyme, drug–drug interactions (DDIs), and the two-step activation process catalyzed by a series of cytochrome P450 (CYP) isoenzymes. For these reasons, new P2Y12 receptor inhibitors have been developed in an attempt to improve on the pharmacological and clinical profile of clopidogrel. Three new P2Y12 receptor inhibitors—prasugrel, cangrelor, and ticagrelor—have arrived, and more are coming into clinical use. Each of these antagonists has individual properties and, according to their mechanism of inhibition, can be divided into irreversible (prasugrel) and reversible inhibitors (ticagrelor, cangrelor). These agents also have different metabolic pathways: prasugrel is a prodrug that requires metabolic activation through a cytochrome-dependent pathway, while ticagrelor and cangrelor do not require metabolic conversion. However, ticagrelor is a CYP3A4 substrate/inhibitor and thus it can be involved in DDIs. Indeed, ticagrelor significantly increases the plasma levels of CYP3A4 substrates such as statins. Moreover, concomitant use with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, clarithromycin, ritonavir, telithromycin, etc.) is contraindicated, while the co-administration of ticagrelor with potent CYP3A inducers (carbamazepine, rifampicin, phenytoin, phenobarbital) is discouraged. Prasugrel and ticagrelor determine a faster, greater, and more consistent adenosine diphosphate (ADP)-receptor inhibition than clopidogrel, with a near complete inhibition of platelet aggregation between 1–2 h after administration of an oral loading dose, while cangrelor shows a rapid and potent platelet inhibitory effect with intravenous infusion. Thus, the different pharmacokinetic and pharmacodynamic characteristics of the P2Y12 receptor inhibitors enable clinicians to personalize therapy according to patient-specific medical requirements for better prevention of atherothrombotic events. In the present review, we describe the pharmacological properties, the pharmacokinetic and pharmacodynamic differences, and the clinical efficacy of the currently available P2Y12 receptor inhibitors.
doi: 10.1007/s40265-013-0129-9pmid: 24127223
Enzalutamide (MDV3100, XTANDI®) is an androgen receptor inhibitor that is indicated for the treatment of metastatic, castration-resistant, prostate cancer (mCRPC) that has progressed despite treatment with docetaxel. This article reviews the pharmacology, efficacy and tolerability of enzalutamide relevant to this indication. In a randomized, double-blind, placebo-controlled, multinational, phase III trial in patients with mCRPC progressing after docetaxel therapy, enzalutamide significantly prolonged overall survival (OS), delayed prostate specific antigen progression and prolonged radiographic progression-free survival and time to the first skeletal event. The median OS was 18.4 months in the enzalutamide group and 13.6 months in the placebo group, which represents a 37 % reduction in the mortality risk in the enzalutamide group. Enzalutamide was also associated with significant benefits in health-related quality of life and in pain palliation. Enzalutamide was generally as well tolerated as placebo during the trial, with most adverse events at a mild or moderate level of severity. Enzalutamide carries a small increased risk of seizures that appears to be dose-dependent. Enzalutamide is an efficacious and well tolerated treatment for this severe, rapidly progressive disease.
doi: 10.1007/s40265-013-0134-zpmid: 24136090
Oral fidaxomicin (Dificid®; Dificlir®) is a first-in-class macrocyclic antibacterial that is approved in several countries for the treatment of adult patients with Clostridium difficile-associated diarrhoea. Fidaxomicin 200 mg twice daily for 10 days was an effective and generally well tolerated treatment in adult patients with a first episode or first recurrence of C. difficile infection. In two multinational phase III trials, fidaxomicin treatment was noninferior to vancomycin treatment with regard to clinical cure rates and was associated with statistically significantly lower C. difficile infection recurrence rates and statistically significantly higher global cure rates than vancomycin. The drug has a favourable pharmacological profile, including having a narrow spectrum of activity that targets relevant pathogens, minimal impact on normal faecal microflora, a convenient treatment regimen and attainment of very high faecal concentrations. Albeit further clinical experience is required to fully define the position of fidaxomicin, it is a valuable emerging option for the treatment of first episode and recurrent episodes of C. difficile-associated diarrhoea.
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