Background: The mechanism by which astrocytes contribute to disease progression in mutant SOD1 mouse models of ALS is not known.Results: Mutant SOD1 astrocytes release mutant SOD1-containing exosomes that are toxic for motor neurons.Conclusion: Astrocyte-derived exosomes may have a role in disease spreading and motor neuron pathology.Significance: New therapeutic approaches should target exosomes to contain disease progression.

Changes in the homeostasis of tumor necrosis factor a (TNFa) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFa to the development of ALS is still debated. TNFa is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFa and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2À/À mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFa as Abbreviations used: ALS, amyotrophic lateral sclerosis; Ara-C, arabinoside; BDNF, brain-derived neurotrophic factor; ChAT, choline acetyl transferase; CSF, cerebrospinal fluid; DIV, days in vitro; GFAP, glial fibrillary acidic protein; HBSS, Hank's balanced salt solution; IFNc, interferon c; IL-1b, interleukin 1b; IL-6, interleukin 6; iNOS, inducible NO synthase; LPS, lipopolysaccharides; mTNFa, membrane TNFa; NGS, normal goat serum; NMJ, neuromuscular junctions; PBS, phosphate-buffered saline; PFA, paraformaldehyde; qPCR, quantitative polymerase chain reaction; SDS, sodium dodecyl sulphate; SOD1, superoxide dismutase 1; sTNFa, soluble TNFa; sTNFR2, soluble TNFR2; TBS, tris-buffered solution; TBS-T, tris-buffered solution with Tween; TDP-43, TAR DNA-binding protein 43; Teff, T effector cells; TNFa, tumor necrosis factor a; TNFR1, tumor necrosis factor receptor 1; TNFR2, tumor necrosis factor receptor 2; Treg, regulatory T cells. an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology.

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Un rapido accesso ai nuovi trattamenti efficaci rimane una priorità dell'Agenzia Italiana del Farmaco (AIFA) e del Servizio Sanitario Nazionale (SSN) e un importante traguardo per le aziende farmaceutiche. 1 Poiché molti dei nuovi farmaci sono approvati a livello centralizzato dalla European Medicines Agency (EMA), l'accesso ai nuovi trattamenti riveste anche un carattere di equità comunitario. Proprio per questo, la Legge 189/2012 ha istituito la classe C NN , in cui è previsto che i farmaci approvati con procedura centralizzata sono automaticamente classificati entro 60 giorni dall'ottenimento dell'AIC europea. 2 Questo ne consente la commercializzazione, nonostante non abbiano concluso la procedura negoziale con AIFA (" NN " sta per

Objective. To compare the time-to-reimbursement of the last two committees of the Italian Medicines Agency (AIFA), respectively appointed in 2015 and in 2018. Methods. The analysis was run through a specific internal database created by MA-Provider. The database was populated with information regarding European Medicines Agency (EMA) approved new drugs, including each step of the Italian Price and Reimbursement (P&R) process reported in the monthly outcomes of Technical Scientific Committee (CTS) and Price and Reimbursement Committee (CPR) meetings from September 2015 to April 2020. Results. The 2015 and the 2018 committees have reimbursed respectively 39 and 28 drugs by comparing their initial 19 months of activity. Significant differences have been observed in negotiated economic conditions, in particular an increase in the number of drugs with confidential discount (2018-committee: 96.4% vs 2015-committee: 64.1%; p = 0.003) and a reduction in the application of Managed Entry Agreements (MEAs) (2018-committee: 10.7% vs 2015-committee: 33.3%; p = 0.036). The average duration of the P&R procedure managed by the 2018-committee has increased by 45 days compared to the 2015-committee (287 days vs 242 days; p = 0.071) and this trend of delay is associated to the active scientific/economic assessment phase by CTS and CPR (particularly by the latter) and not to administrative phases (e.g. Official Journal publications). Conclusions. The observed differences between committees may be explained by the higher number of oncological and/or innovative drugs assessed by the 2018-committee (regarding the time delay, probably linked to greater difficulties in finding a win-win agreement able to satisfy both AIFA and Pharmaceutical Company).

The use of eltrombopag in HCV patients with thrombocytopenia is cost-effective as it leads to a reduction in disease progression and thus a drop in the number of patients with advanced liver disease.

, were collected and categorized according to: i) kind of innovativeness: full, conditional or no innovativeness; ii) orphan designation; iii) therapeutic area: oncological vs non-oncological drugs. For each single indication assessed for innovativeness, the ranking of the three criteria (therapeutic unmet need maximum to absent, added therapeutic value maximum to absent, and quality of evidences high to very low) was analyzed. Sub-analyses according to the three categories were also run. Results: Out of forty-one indications assessed by AIFA for innovativeness (and corresponding to 30 drugs), 12 (29%) were granted full innovative status, 14 (34%) obtained the conditional innovativeness and the remaining 15 (37%) were assessed as not innovative (7 orphan and 8 oncological indications). 50% of full innovative indications referred to orphan drugs (6/12) and 42% to oncological diseases (5/12); regarding conditionally innovative indications, 29% were for orphan drugs (4/14) and 79% (11/14) for oncological ones. Analysing innovativeness criteria application, AIFA have never recognized the maximum grading for added therapeutic value; moreover, focusing on fully innovative indications, 9 out of 12 (75%) did not meet all the three criteria thresholds stated by AIFA decree. Conclusions: This analysis highlighted that there is no strict matching between AIFA criteria (as reported by AIFA decree) and the granting of full innovative status. In fact, most of the analysed cases are borderline situations (full vs. conditional innovativeness) and have been assessed case-by-case, leaving a shade of subjectivity that gives innovativeness decision-making process a margin of flexibility. The limited sample does not let us make conclusions on the impact of orphan designation or oncological setting.

Objectives: For a recent health technology appraisal in the treatment of chronic idiopathic constipation, direct evidence of the effectiveness of a new intervention (lubiprostone) against the standard of care (prucalopride) was not available. The aim of this study was to review the available data from clinical trials and perform indirect comparisons between the two treatments where possible. MethOds: A literature search (in Medline and other databases) was conducted in December 2013 for trials of lubiprostone or prucalopride. Data for any comparable endpoints were extracted from the papers, and indirect comparisons performed using the Bucher method. Results: Four clinical trials for lubiprostone were identified (three company-sponsored, and a small clinician-led trial), as well as three companysponsored clinical trials for prucalopride. After data extraction, indirect comparisons were possible for seven different endpoints, including the primary efficacy parameter of the lubiprostone studies (Spontaneous Bowel Movements; the relative risk was 1.12 in favour of lubiprostone, 95% CI 0.77-1.64). Other endpoints included the primary efficacy parameter of the prucalopride studies (Spontaneous Complete Bowel Movements), and a range of symptom comparisons. In total, five of the seven indirect comparisons favoured lubiprostone, with statistical significance reached in favour of lubiprostone once and prucalopride once. cOnclusiOns: The indirect comparisons showed that lubiprostone is likely to be at least as effective as prucalopride, with numerical superiority in five out of seven comparisons. However, the number of feasible indirect comparisons on a range of endpoints raises a wider question: which to use in cost-effectiveness modelling? Although analyses generally have a 'base case', each of the indirect comparisons adds different information about the relative efficacy of the two products. Given the range of endpoints with associated relative risks, to reduce these to a single comparison (as is current practice) may omit important and relevant information about relative efficacy. PGI50 hIGh theraPeutIc eFFIcIency WIth soFosbuVIr For the treatMent oF chronIc hePatItIs c