A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort.

BACKGROUND AND AIMS: ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial. METHODS AND RESULTS: The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively. CONCLUSION: The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment. GOV IDENTIFIER: NCT02476006.

The impact of drug-drug interactions on pulmonary arterial hypertension therapy.

In clinical practice, pulmonary arterial hypertension (PAH) requires co-administration of multiple drugs to act on several pathogenic mechanisms; chronic pathologic conditions induce the onset of other concomitant diseases that need additional therapies. Combination treatment could exploit a synergism between administered drugs, increasing the effectiveness of the treatment and allowing dose reductions of the individual agents with a subsequent lower risk of toxicity. Conversely, concomitant administration of drugs may cause drug-drug interactions (DDIs), compromising treatment efficacy or increasing side effects, with a negative influence on disease progression. The choice of treatment is based on the fact that PAH is not caused by a single mechanism and that several syndromes, genetic abnormalities and environmental factors predispose to disease; therefore it is very likely that the use of treatments acting on a single pathway are not significantly effective. Moreover PAH is also frequently associated with other diseases that require concomitant clinical therapy. In this review we focused on the pharmacological treatment in PAH and related DDIs, evaluating alterations in drug transport, absorption, metabolism and excretion. This detailed analysis may be useful in clinical practice, as a better prediction of adverse events caused by DDIs in PAH improves the efficacy of combination therapy, resulting in reduced health care costs.

Ibrutinib: from bench side to clinical implications.

The activation of the B cell receptor (BCR) is nowadays known to play a primary role in the etiopathogenesis of a multitude of B cell malignancies, being one of the main factors responsible for the enhanced proliferation and survival of transformed cells. Thanks to the characterization and continuous discovery of the pathways driving B cell proliferation in consequence to BCR activation, it has been possible to develop a small molecule inhibitor specifically antagonizing the Bruton's tyrosine kinase (BTK), an enzyme located in an early strategic position within the whole pathway. Ibrutinib, formerly PCI-32765, is a first in class, potent, specific, irreversible and relatively safe BTK inhibitor, demonstrating so far an impressive efficacy in the treatment of chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), Waldenström macroglobulinemia and multiple myeloma. This review will summarize the most important pharmacological evidences available as of today and will take in consideration the latest findings regarding the mechanism of action of ibrutinib.

Antibiotics counteract the worsening of airway remodelling induced by infections in asthma.

Asthma is associated with structural remodelling processes, including basement membrane thickening, increased vascularity and smooth muscle alterations. It is known that respiratory infections are associated with asthma exacerbation; infections can worsen asthma symptoms and influence susceptibility to asthma onset. How infections affect asthma is not fully elucidated. It is possible that the immune response, due to recurrent infections, leads to the pathogen's eradication but also increases bronchial inflammation, which induces airway remodelling in asthmatic subjects. We evaluated how infection affects lung remodelling and inflammatory responses and assessed the impact of antibiotic treatment in a murine model of asthma. Ovalbumin-sensitised BALB/c mice were divided into control, mild and chronic asthmatics. A subset of animals in each group was infected with Streptococcus pneumoniae and was treated with antibiotics. The results show an increase in key lung remodelling factors in mice with chronic asthma, particularly those infected with S. pneumoniae. Notably, antibiotic therapy attenuated these effects. These findings demonstrate for the first time that prompt antibiotic therapy may be useful to reduce lung remodelling progression in infected asthmatic subjects.