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Background Compassionate use programs (CUP) for medicines respond to the ethical imperative of providing access to medicines before marketing approval to patients not recruited in trials. The economic impact of clinical trials has previously been investigated. No evidence on the net economic benefit of CUP exists. This research aims to address this information gap by estimating the economic consequences of 11 CUP in Italy conducted between March 2015 and December 2020 from the perspective of public health care system in Italy (National Health Service). Eight programs concern cancer treatments, two refer to spinal muscular atrophy, and one is indicated for multiple sclerosis. Methods Since CUP medicines are covered by the industry, the net economic benefit includes: (i) avoided costs of the Standard of Care (SoC) the patients would have received had they not joined the CUP, (ii) costs not covered by the pharmaceutical industry sponsor, but instead sustained by payers, such as those associated with adverse events (only severe side effects resulting in hospitalisation and attributable to CUP medicines), and (iii) costs for combination therapies and diagnostic procedures not used with the SoC. The SoC costing relied on publicly available data. Information on adverse events and diagnostic procedures was retrieved from the CUP and monetized using the relevant fee for episode or service. One CUP was excluded since a SoC was not identified. Results 2,713 patients were treated in the 11 CUP where a SoC was identified. The SoC mean cost per patient ranged from €11,415 to €20,299. The total cost of the SoC ranged between €31.0 and €55.1 million. The mean cost per patient covered by hospitals hosting CUP was equal to €1,646, with a total cost of €4.5 million. The net economic benefit ranged €26.5 million - €50.6 million. Conclusions Despite research limitations, this paper illustrates for the first time the net economic impact of CUP from a public payer perspective. It is important to integrate these estimates with the prospective effects of CUP implementation, i.e., the economic value of the comparative benefit profile of medicines used in CUP versus the SoC, including effects from a societal perspective.

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Poly(ADP-ribose)polymerase (PARP-1), a nuclear enzyme activated by DNA strand breaks, is involved in DNA repair, aging, inflammation, and neoplastic transformation. In diabetes, reactive oxygen and nitrogen species occurring in response to hyperglycemia cause DNA damages and PARP-1 activation. Because circulating mononuclear cells (MNCs) are involved in inflammation mechanisms, these cells were chosen as the experimental model to evaluate PARP-1 levels and activity in patients with type 2 diabetes. MNCs were isolated from 25 diabetic patients (18 M, 7 F, age, 63.5 +/- 10.2 years, disease duration 17.7 +/- 8.2 years) and 11 age and sex matched healthy controls. PARP-1 expression and activity were analyzed by semi-quantitative PCR, Western and activity blot, and immunofluorescence microscopy. PARP-1-mRNA expression was increased in MNCs from all diabetic patients versus controls (P < 0.01), whereas PARP-1 content and activity were significantly lower in diabetic patients (P < 0.0001). To verify whether low PARP-1 levels and activity were due to a proteolytic effect of caspase-3 like, the latter activation was measured by a fluorimetric assay. Caspase-3 activity in MNCs was significantly higher in diabetic patients versus control subjects (P < 0.0001). The different PARP-1 behavior in MNCs from patients with type 2 diabetes could therefore be responsible for the abnormal inflammation and infection responses in diabetes.

Background/Aim: Extracellular matrix alterations are involved in the pathogenesis of diabetic nephropathy. We evaluated the effects of high glucose concentrations and inhibition of angiotensin-converting enzyme on the laminin and fibronectin production by glomerular epithelial cells. Methods: Glomerular epithelial cells were cultured in 5 and 30 mmol/l glucose, with and without enalaprilat (0.3 mmol/l). Laminin and fibronectin were measured (³⁵S-methionine, immunoprecipitation), and their mRNA expression was evaluated (RT-PCR). Results: The laminin concentration was higher in the cells than in the medium, where an increase of its content was observed under high-glucose conditions (p < 0.01). Fibronectin, found only in the medium, was not modified by the high glucose concentration. Following enalaprilat administration, the laminin concentration was decreased under high-glucose conditions, both in the cell and in the medium (p < 0.001), whereas the fibronectin concentration was increased under high-glucose conditions (p < 0.001). The mRNA expression of laminin and fibronectin under high-glucose conditions only slightly increased. Enalaprilat decreased the fibronectin mRNA synthesis dramatically (>50%, p < 0.0001) under high-glucose conditions. Conclusions: Enalaprilat normalizes the abnormal, high-glucose-induced concentration of laminin, while it decreases the fibronectin synthesis. The improvement of the renal function in diabetic patients treated with angiotensin-converting enzyme inhibitors may, in part, be due to a modulator effect on extracellular matrix content and composition.