In situ modification of nanostructure configuration through the manipulation of hydrogen bonded amphiphile self-association

Herein, we report the synthesis of a novel amphiphilic salt containing a number of hydrogen bond donating (HBD) and accepting (HBA) functionalities. This amphiphile has been shown to self-associate via hydrogen bond formation in a DMSO solution, confirmed through a combination of NMR, UV-Vis and dynamic light scattering and supported by X-ray diffraction studies. The combination of different HBD and HBA functionalities within the amphiphile structure gives rise to a variety of competitive, self-associative hydrogen bonding modes that result in the formation of ‘frustrated’ hydrogen bonded nanostructures. These nanostructures can be altered through the addition of competitive HBD arrays and/or HBA anionic guests. The addition of these competitive species modifies the type of self-associative hydrogen bonding modes present between the amphiphilic molecules, triggering the in situ formation of novel hydrogen bonded nanostructures

Expert consensus document: A 'diamond' approach to personalized treatment of angina.

In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease

Optimizing choice of oral interferon-free treatment for genotype 1 hepatitis C virus using testing for NS5A resistance: a cost-utility analysis from the perspective of the Italian National Health Service

Kirsten Y Westerhout,1 Walter Bouwmeester,1 Inge Duchesne,2 Marta Pisini,2 Marjanne A Piena,1 Francesco Damele,3 Beatrice Gueron,2 Maarten Treur,1 Jonathan Belsey4 1Pharmerit BV, Marten Meesweg, Rotterdam, the Netherlands; 2Janssen EMEA, Turnhoutseweg, Beerse, Belgium; 3Janssen-Cilag SpA, Via Michelangelo Buonarroti, Cologno Monzese, Italy; 4JB Medical Ltd, Old Brickworks, Little Cornard, United Kingdom Background: Patients with genotype-1 hepatitis C virus infection who have failed to respond to standard therapy or who relapse following treatment may be considered for an interferon-free regimen incorporating a nonstructural protein 5A (NS5A) inhibitor. Sustained virologic response (SVR) with these regimens is typically >90%, but this is reduced in patients with NS5A resistance. European Association for Study of the Liver guidelines recommend simeprevir + sofosbuvir ± ribavirin (SMV+SOF±R) for re-treating patients failing an NS5A inhibitor-containing regimen. An alternative strategy would be to test for NS5A resistance prior to treatment, with therapy optimized based on the results. This study investigates the cost-effectiveness of this strategy.Materials and methods: A Markov model was used to estimate disease progression for treatment-experienced genotype 1 patients with severe fibrosis or compensated cirrhosis. Targeted treatment with either SMV+SOF±R or sofosbuvir + ledipasvir ± ribavirin (SOF+LDV±R) based on pretreatment NS5A resistance testing was compared to routine SOF+LDV±R without testing. Treatment duration was 12 or 24 weeks for patients with severe fibrosis or compensated cirrhosis (Metavir F3/F4). SVR data for the treatment options were based on the results of published clinical trials. The analysis was carried out from the perspective of the Italian National Health Service.Results: Optimized treatment using NS5A resistance testing yielded 0.163 additional QALYs and increased costs of €2,789 per patient versus no testing. The incremental cost-effectiveness ratio (ICER) was €17,078/QALY. Sensitivity analysis identified the SVR attributable to each of the treatment regimens as the most sensitive determinant of ICER (range: €10,055/QALY–€43,501/QALY across plausible range). Probabilistic sensitivity analysis demonstrated that, at a willingness-to-pay threshold of €30,000/QALY, the probability that NS5A-directed treatment will be cost-effective is 81.4%.Conclusion: Optimizing therapy with either SMV+SOF±R or SOF+LDV±R based on pretreatment NS5A resistance testing was cost-effective from the perspective of the Italian National Health Service, in treatment-experienced patients with severe fibrosis or compensated cirrhosis. Keywords: hepatitis C, NS5A inhibitor, simeprevir, sofosbuvir, ledipasvir, health economic