Migraine burden and costs in France: a nationwide claims database analysis of triptan users.

Objectives: To estimate the burden of migraine in the population of French patients identified as specific migraine acute treatment users compared to a control group. Methods: A cross-sectional retrospective analysis was performed on the Echantillon Généraliste des Bénéficiaires claims database, a 1/97 random sample of the French public insurance database. A representative sample of all adults with at least one delivery of triptans, ergot derivatives or acetylsalicylic acid/metoclopramide (all drugs with a specific label in migraine acute treatment - SMAT) in 2014 was selected with a control group matched on age, gender and geographic region. Among triptan users, a sub-group of over-users was defined according to their level of triptan uptake expressed in defined daily doses (DDD - a standard daily dose of treatment of acute migraine) per month over 3 months and more, was also compared with controls. The cost analysis was performed in a societal perspective for direct costs. Sick leave indirect costs were estimated using the human capital approach. Results: In total 8639 SMAT users (mean age: 44.6 years; 78.7% women) were selected representing a crude prevalence rate of 1.7%. The annual per capita total healthcare expenditures were higher by €280 in this group compared to controls (€2463 vs. €2183). Triptans contributed 47.8% to this extra cost. They used significantly (p < .0001) more frequently than controls antidepressants (20.8% vs. 11.0%), anxiolytics (29.4% vs. 18.8%) and analgesics (53.8% vs. 35.8%). The per capita annual productivity loss associated with sick leave was higher by €295 (€1712 vs. €1417). Among triptan users, there were 2.9% over-users. This last group was characterized by substantially higher per capita annual extra direct (+ €1805) and indirect costs (productivity loss +€706) compared to controls. Conclusions: Due to its high prevalence, migraine costs generate a significant societal burden. The group of over-users concentrates high per capita direct and indirect costs.

In Vivo FRET Imaging to Predict the Risk Associated with Hepatic Accumulation of Squalene-Based Prodrug Nanoparticles.

Förster resonance energy transfer (FRET) is used here for the first time to monitor the in vivo fate of nanoparticles made of the squalene-gemcitabine prodrug and two novel derivatives of squalene with the cyanine dyes 5.5 and 7.5, which behave as efficient FRET pair in the NIR region. Following intravenous administration, nanoparticles initially accumulate in the liver, then they show loss of their integrity within 2 h and clearance of the squalene bioconjugates is observed within 24 h. Such awareness is a key prerequisite before introduction into clinical settings.

Circulating Lipoproteins: A Trojan Horse Guiding Squalenoylated Drugs to LDL-Accumulating Cancer Cells.

Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells in vivo.

Conjugation of squalene to gemcitabine as unique approach exploiting endogenous lipoproteins for drug delivery.

Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression. In vitro and in vivo experiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content and in silico simulations further display their incorporation into the hydrophobic core of LPs. To the best of our knowledge, the use of squalene to induce drug insertion into LPs for indirect cancer cell targeting is a novel concept in drug delivery. Interestingly, not only SQGem but also other squalene derivatives interact similarly with lipoproteins while such interaction is not observed with liposomes. The conjugation to squalene represents a versatile platform that would enable efficient drug delivery by simply exploiting endogenous lipoproteins.

In vitro investigation of multidrug nanoparticles for combined therapy with gemcitabine and a tyrosine kinase inhibitor: Together is not better.

Combined therapy with gemcitabine and tyrosine-kinase inhibitors (i.e., sunitinib) has already demonstrated important benefits in pancreatic cancer treatment. Further therapeutic advantage could be achieved by their co-loading in a single nanoscale system, which enables (i) the co-existence of drugs with different mechanisms of action and pharmacokinetic profiles and (ii) the fine tuning of their release rate overcoming the rapid clearance often observed with free drugs. In this context, the already validated squalenoylation approach has been applied to the design of a multidrug nanoparticle (NP) made by co-self-assembly of the squalene-based prodrugs of gemcitabine (SQGem) and sunitinib (SQSun). We hypothesized that co-delivering of SQGem and SQSun in a single nanoparticle was capable to increase their cytotoxicity on MIA PaCa-2 pancreatic cancer cells compared to the monodrug NPs. Nevertheless, multidrug NPs (i.e., SQGem/SQSun NPs) were as efficient as the physical mixture of the individual monodrug NPs (SQGem NPs + SQSun NPs) thus suggesting that the cytotoxicity raised from the exposure of the cells simultaneously to the two bioconjugates rather than to their original loading into a single or two different nanoparticles. To be noted that the lack of differences in static 2D cultures does not exclude a different behavior in dynamic conditions in vivo.