Investigation of creep phenomenon on composite material for bolt connections

One of the main target in the automotive design is the weight reduction. This reduction leads to the reduction of the gas emissions. The designers tend to use innovative materials for the automotive field such as plastics and composites. To use the right material for the right application, multi material solutions are increasingly adopted. To join dissimilar materials, solutions like adhesive, bolt and nuts, riveting are necessary. It is necessary to know the behaviour of the materials to be joined, under different loading conditions to ensure the joint. In this work, a bolt connection between composite and aluminium plates has been considered. The behaviour of a carbon fibre reinforced material under compression load, taking into account creep is studied. A specific experimental equipment has been design and built. A series of experimental compressive tests, in the laminate thickness direction, have been done on carbon fibre reinforced material specimens. Different set-up in terms of temperature, compression load and surface roughness have been investigated. The obtained results are presented and discussed. A mathematical model will be proposed for interpolation of the obtained results. Finally, a possible strategy for reducing the tight loss in the initial phase of the joint life is propose

JAK-Inhibitors for the Treatment of Rheumatoid Arthritis : A Focus on the Present and an Outlook on the Future

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use

CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions

Palbociclib, ribociclib, and abemaciclib belong to the third generation of cyclin-dependent kinases inhibitors (CDKis), an established therapeutic class for advanced and metastatic breast cancer. Interindividual variability in the therapeutic response of CDKis has been reported and some individuals may experience increased and unexpected toxicity. This narrative review aims at identifying the factors potentially concurring at this variability for driving the most appropriate and tailored use of CDKis in the clinic. Specifically, concomitant medications, pharmacogenetic profile, and pathophysiological conditions could influence absorption, distribution, metabolism, and elimination pharmacokinetics. A personalized therapeutic approach taking into consideration all factors potentially contributing to an altered pharmacokinetic/pharmacodynamic profile could better drive safe and effective clinical use

An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug–drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients’ plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment

Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure

The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (Cmin) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy

Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk

Preemptive targeted pharmacogenetic testing of candidate variations in DPYD is currently being used to limit toxicity associated with fluoropyrimidines. The use of innovative next generation sequencing (NGS) approaches could unveil additional rare (minor allele frequency <1%) genetic risk variants. However, their predictive value and management in clinical practice are still controversial, at least partly due to the challenges associated with functional analyses of rare variants. The aim of this study was to define the predictive power of rare DPYD variants burden on the risk of severe fluoropyrimidine-related toxicity. The DPYD coding sequence and untranslated regions were analyzed by NGS in 120 patients developing grade 3–5 (NCI-CTC vs3.0) fluoropyrimidine-related toxicity and 104 matched controls (no-toxicity). The functional impact of rare variants was assessed using two different in silico predictive tools (i.e., Predict2SNP and ADME Prediction Framework) and structural modeling. Plasma concentrations of uracil (U) and dihydrouracil (UH2) were quantified in carriers of the novel variants. Here, we demonstrate that the burden of rare variants was significantly higher in patients with toxicity compared to controls (p = 0.007, Mann-Whitney test). Carriers of at least one rare missense DPYD variant had a 16-fold increased risk in the first cycle and an 11-fold increased risk during the entire course of chemotherapy of developing a severe adverse event compared to controls (p = 0.013 and p = 0.0250, respectively by multinomial regression model). Quantification of plasmatic U/UH2 metabolites and in silico visualization of the encoded protein were consistent with the predicted functional effect for the novel variations. Analysis and consideration of rare variants by DPYD-sequencing could improve prevention of severe toxicity of fluoropyrimidines and improve patients’ quality of life

CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients

Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure

FARMAPRICE: A Pharmacogenetic Clinical decision support system for precise and Cost-Effective Therapy

Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of clinical decision support system (CDSS) tools to aid health providers in managing PGx information in the clinical context. The present study aimed to describe the first Italian endeavor to develop a PGx CDSS, called FARMAPRICE. FARMAPRICE prototype was conceived for integration of patient molecular data into the clinical prescription process in the Italian Centro di Riferimento Oncologico (CRO)-Aviano Hospital. It was developed through a coordinated partnership between two high-tech companies active in the computerization of the Italian healthcare system. Introducing FARMAPRICE into the clinical setting can aid physicians in prescribing the most efficacious and cost-effective pharmacological therapy available