Strategies for early prediction and timely recognition of drug-induced liver injury: The case of cyclin-dependent kinase 4/6 inhibitors

The idiosyncratic nature of drug-induced liver injury (Dili) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized Dili potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of Dili, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of Dili and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of Dili signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences

Clinically Significant Drug Interactions Between Psychotropic Agents and Repurposed COVID-19 Therapies

As many patients with underlying psychiatric disorders may be infected with COVID-19, and COVID-19-affected subjects may frequently experience a new onset of psychiatric manifestations, concomitant use of psychotropic medications and COVID-19 therapies is expected to be highly likely and raises concerns of clinically relevant drug interactions. In this setting, four major mechanisms responsible for drug interactions involving psychotropic agents and COVID-19 therapies may be identified: (1) pharmacokinetic drug–drug interactions mainly acting on cytochrome P450; (2) pharmacodynamic drug–drug interactions resulting in additive or synergistic toxicity; (3) drug–disease interactions according to stage and severity of the disease; and (4) pharmacogenetic issues associated with polymorphisms of cytochrome P450 isoenzymes. In this review, we summarise the available literature on relevant drug interactions between psychotropic agents and COVID-19 therapies, providing practical clinical recommendations and potential management strategies according to severity of illness and clinical scenario

The very faint hard state of the persistent neutron star X-ray binary SLX 1737-282 near the Galactic centre

We report on a detailed study of the spectral and temporal properties of the neutron star low mass X-ray binary SLX 1737-282, which is located only ~1degr away from Sgr A. The system is expected to have a short orbital period, even within the ultra-compact regime, given its persistent nature at low X-ray luminosities and the long duration thermonuclear burst that it has displayed. We have analysed a Suzaku (18 ks) observation and an XMM-Newton (39 ks) observation taken 7 years apart. We infer (0.5-10 keV) X-ray luminosities in the range 3-6 x10^35erg s-1, in agreement with previous findings. The spectra are well described by a relatively cool (kTbb = 0.5 keV) black body component plus a Comptonized emission component with {\Gamma} ~1.5-1.7. These values are consistent with the source being in a faint hard state, as confirmed by the ~ 20 per cent fractional root mean square amplitude of the fast variability (0.1 - 7 Hz) inferred from the XMM-Newton data. The electron temperature of the corona is >7 keV for the Suzaku observation, but it is measured to be as low as ~2 keV in the XMM-Newton data at higher flux. The latter is significantly lower than expected for systems in the hard state. We searched for X-ray pulsations and imposed an upper limit to their semi-amplitude of 2 per cent (0.001 - 7 Hz). Finally, we investigated the origin of the low frequency variability emission present in the XMM-Newton data and ruled out an absorption dip origin. This constraint the orbital inclination of the system to 65 degr unless the orbital period is longer than 11 hr (i.e. the length of the XMM-Newton observation).Comment: 7 pages, 4 figures, 1 table. Accepted for publication in MNRA

Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: Insight from a pharmacovigilance study

Background: The management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections. Methods: Three spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999-2008 vs. 2009-2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009-2017) was investigated for both Italy and UK. Results: A total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found. Conclusion: KPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues

Probing variability patterns of the Fe K line complex in bright nearby AGNs

The unprecedented sensitivity of current X-ray telescopes allows for the first time to address the issue of the Fe K line complex variability patterns in bright, nearby AGNs. We examine XMM-Newton observations of the brightest sources of the FERO sample of radio-quiet type 1 AGNs with the aim of characterizing the temporal behaviour of Fe K complex features. A systematic mapping of residual flux above and below the continuum in the 4-9 keV range is performed in the time vs energy domain, with the purpose of identifying interesting spectral features in the three energy bands: 5.4-6.1 keV, 6.1-6.8 keV and 6.8-7.2 keV, corresponding respectively to the redshifted, rest frame and blueshifted or highly ionized Fe Kalpha line bands. The variability significance is assessed by extracting light curves and comparing them with MonteCarlo simulations. The time-averaged profile of the Fe K complex revealed spectral complexity in several observations. Red- and blue-shifted components (either in emission or absorption) were observed in 30 out of 72 observations, with an average ~90 eV for emission and ~ -30 eV for absorption features. We detected significant line variability (with confidence levels ranging between 90% and 99.7%) within at least one of the above energy bands in 26 out of 72 observations on time scales of ~6-30 ks. Reliability of these features has been carefully calculated using this sample and has been assessed at ~3sigma confidence level. This work increases the currently scanty number of detections of variable, energy shifted, Fe lines and confirms the reliability of the claimed detections. We found that the distribution of detected features is peaked at high variability significances in the red- and blue-shifted energy bands, suggesting an origin in a relativistically modified accretion flow.Comment: Accepted for publication in Astronomy & Astrophysic

Injection Pattern Investigation for Gasoline Partially Premixed Combustion Analysis

Nowadays, compression-ignited engines are considered the most efficient and reliable technology for automotive applications. However, mainly due to the current emission regulations, that require increasingly stringent reductions of NOx and particulate matter, the use of diesel-like fuels is becoming a critical issue. For this reason, a large amount of research and experimentation is being carried out to investigate innovative combustion techniques suitable to simultaneously mitigate the production of NOx and soot, while improving engine efficiency. In this scenario, the combined use of compression-ignited engines and gasoline-like fuels proved to be very promising, especially in case the fuel is directly-injected in the combustion chamber at high pressure. The presented study analyzes the combustion process produced by the direct injection of small amounts of gasoline in a compression-ignited light-duty engine. The engine under investigation has been modified to guarantee a stable engine operation over its whole operating range, that is achieved controlling boost pressure and temperature, together with the design of the injection pattern. Experimental tests have been performed to highlight the impact of several control variables on the combustion effectiveness, i.e. on combustion efficiency and ignition delay. To identify the main mechanisms which impact the start of the combustion process and the sensitivity to the variation of the main control parameters, several tests have been run, directly-injecting constant amounts of gasoline in a compression ignited engine. These tests have been performed changing intake pressure and temperature (when suitable to maintain combustion stability), fuel pressure and injection timing within the cycle

Dapagliflozin and cardiovascular outcomes: anything else to DECLARE?

Introduction: Individuals with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk with regulatory agencies requiring cardiovascular outcome trials (CVOTs) for the approval of new antidiabetic drugs. Areas covered: In this paper, the authors critically discuss the background, trial design, results and implications of a recent CVOT [NCT01730534; DECLARE-TIMI 58 study], which demonstrated that dapagliflozin was non-inferior to placebo in terms of major adverse cardiovascular events, and superior for the occurrence of hospitalization for heart failure (HF) and composite renal endpoints, thus confirming the cardiovascular benefit of sodium-glucose co-transporter-2 (SGLT2) inhibitors. No statistically-significant effects were found for amputations, fractures, and stroke (debated safety issues having emerged in previous CVOTs). Expert opinion: DECLARE-TIMI 58 is the longest (4.2 years of follow up), largest (>17,000 participants) and most inclusive (only 41% of individuals with established atherosclerotic cardiovascular disease) CVOT raising the debate towards SGLT2 inhibitor therapy in primary prevention and the potential use of these drugs also in patients with HF without T2DM and other subpopulations

The value of case reports and spontaneous reporting systems for pharmacovigilance and clinical practice

Non present

Investigation of Gasoline Partially Premixed Combustion with External Exhaust Gas Recirculation

The stringent emission regulations for Internal Combustion Engines (ICEs) spawned a great amount of research in the field of innovative combustion approaches characterized by high efficiency and low emissions. Previous research demonstrate that such promising techniques, named Low-Temperature Combustion (LTC), combine the benefits of Compression Ignition (CI) engines, such as high compression ratio and unthrottled lean mixture, with low engine-out emissions using a properly premixed air-fuel mixture. Due to longer ignition delay and high volatility compared to diesel, gasoline-like fuels show good potential for the generation of a highly premixed charge, which is needed to reach LTC characteristics. In this scenario, gasoline Partially Premixed Combustion (PPC), characterized by the high-pressure direct injection of gasoline, showed good potential for the simultaneous reduction of pollutants and emissions in CI engines. However, previous research on gasoline CI highlight that a key factor for the optimization of both efficiency and pollutants is the proper management of Exhaust Gas Recirculation (EGR). This work presents the experimental investigation performed running a light-duty CI engine, operated with gasoline PPC, and varying the mass of recirculated gases trapped in the combustion chamber. To guarantee the stability of gasoline autoignition in all the tested conditions, a specific experimental layout has been developed to accurately quantify the amount of trapped residual gases due to the internal and external EGR. The obtained results clearly highlight the impact of EGR on the combustion process and emissions, demonstrating that optimization of charge dilution with EGR is fundamental to guarantee the optimal compromise between efficiency and emissions over the whole operating range