SGLT2-inhibitors: Should they be considered anti-remodeling drugs?

Heart failure (HF) is a complex syndrome characterized by multiple aetiologies and a progressive clinical course with a strong impact in terms of morbidity, mortality and public health costs. According to the neurohormonal hypothesis, HF with reduced ejection fraction (HFrEF) is considered a neurohormonal disease and HF patients benefit from the use of medications that interfere with and modulate the negative effects of neurohormonal systems (i.e. permanent renin–angiotensin–aldosterone system activation). The foundation of HF treatment includes the combination of well-known neurohormonal antagonists such as angiotensin receptor neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. However, recently, Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2-i) have emerged as a new additional cornerstone of HF treatment – they are now regarded as one of the four keystone drugs to be introduced as first line therapy in HFrEF (class I recommended drug). Moreover, SGLT2-i have been shown to decrease combined endpoints of cardiovascular mortality and worsening HF regardless of ejection fraction (EF), and also to prevent the onset of HF in patients who are at high cardiovascular risk. The pathophysiologic mechanisms that may explain the benefit in clinical outcomes of the SGLT2-i in patients with HF are still incompletely understood. Therefore, it is of great interest to analyze the biological changes, which may occur in patients taking SGLT2-i because this may be helpful to elucidate how SGLT2-i may lead to improved cardiovascular outcomes. In this context, the metanalysis published in the European Journal of Internal Medicine by Fan et al. is timely and relevant because it evaluates the potential structural and functional impact of SGLT2-i in human heart giving possible translational understandings of the biologic consequences caused by SGLT2-i

Therapeutic drug monitoring of antimicrobial drugs in neonates. An opinion paper

Neonatal infections are associated with high morbidity and mortality rates. Optimal treatment of these infections requires knowledge of neonatal pharmacology and integration of neonatal developmental pharmacokinetics (PKs) of antimicrobial drugs in the design of dosing regimens for use with different gestational and postnatal ages. Population PK and pharmacodynamic models are used to personalize the use of these drugs in these fragile patients. The final step to further minimize variability in an individual patient is therapeutic drug monitoring (TDM), where the same population PK/pharmacodynamic models are used in concert with optimally drawn blood samples to further fine-tune therapy. The purpose of this article is to describe the present status and future role of model-based precision dosing and TDM of antimicrobial drugs in neonates. METHODS: PubMed was searched for clinical trials or clinical studies of TDM in neonates. RESULTS: A total of 447 articles were retrieved, of which 19 were concerned with antimicrobial drugs. Two articles (one aminoglycoside and one vancomycin) addressed the effects of TDM in neonates. We found that, in addition to aminoglycosides and vancomycin, TDM also plays a role in beta-lactam antibiotics and antifungal drugs. CONCLUSIONS: There is a growing awareness that, in addition to aminoglycosides and vancomycin, the use of beta-lactam antibiotics, such as amoxicillin and meropenem, and other classes of antimicrobial drugs, such as antifungal drugs, may benefit from TDM. However, the added value must be shown. New analytical techniques and software development may greatly support these novel developments

Solitons on H-bonds in proteins

A model for soliton dynamics on a hydrogen-bond network in helical proteins is proposed. It employs in three dimensions the formalism of fully integrable Toda lattices which admits phonons as well as solitons along the hydrogen-bonds of the helices. A simulation of the three dimensional Toda lattice system shows that the solitons are spontaneously created and are stable and moving along the helix axis. A perturbation on one of the three H-bond lines forms solitons on the other H-bonds as well. The robust solitary wave may explain very long-lived modes in the frequency range of 100 cm$^{-1}$ which are found in recent X-ray laser experiments. The dynamics parameters of the Toda lattice are in accordance with the usual Lennard-Jones parameters used for realistic H-bond potentials in proteins.Comment: 6 pages, 7 figure

Heart failure outcomes in patients with type 2 diabetes mellitus: findings from the cardiovascular outcome trials of antidiabetes agents

Type 2 diabetes mellitus (T2DM) is a recognised risk factor for several cardiovascular (CV) conditions including heart failure (HF). Findings that reflect CV risk associated with T2DM medications have led to regulatory requirement of conducting CV outcome trials (CVOTs) for new antidiabetes drugs. Over the years, several CVOTs using different glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors have reported neutral or improved CV risks or hospitalisation for HF. However, these studies included only a small proportion of the patients with baseline HF thus limiting the available evidence. Ongoing trials such as EMPEROR programme and DAPA-HF in large patient populations with chronic HF could potentially broaden the use of these drugs beyond their conventional therapeutic indication