Factors correlated with transmural healing in patients with Crohn's disease in long-term clinical remission on anti-TNF medication.

BACKGROUND & AIMS: Transmural healing is a long-term target for patients with Crohn's disease. Factors contributing to its promotion are poorly understood. This study assessed factors correlating with transmural healing based on intestinal ultrasound, in patients in long-term clinical remission on anti-TNF. METHODS: 68 consecutive Crohn's patients on adalimumab (50) or infliximab (18) therapy with clinical remission ≥1 year were recruited and assessed for clinical features, trough serum levels of anti-TNF and intestinal ultrasound findings. Univariate analysis and multivariate binary logistic regression analysis identified variables independently associated with bowel wall thickening behavior. RESULTS: Sixty eight patients were in remission for a mean of 4.1 years. Thirty-six patients (52.9 %) showed anti-TNF trough levels below the normal threshold. Twenty-two patients (38.4 %) showed transmural healing, 32 (47.1 %) transmural response, and 26 (38.2 %) no treatment response. Transmural healing correlated with higher BMI and lower baseline bowel wall thickening; transmural response correlated with short Crohn's disease duration, high drug levels, and with non-stricturing phenotype. Treatment non-response correlated with lower BMI, lower drug levels, higher baseline bowel wall thickening, and stricturing phenotype. CONCLUSIONS: Lack of transmural healing in stable remission Crohn's patients on anti-TNF therapy is multifactorial, mainly due to low anti-TNFs trough levels, development of strictures, and higher baseline bowel wall thickening at treatment initiation.

Two Years of Active Pharmacovigilance Surveillance and Therapeutic Reconciliation in Frail Populations: The MEAP 3.0 Study.

Awareness related to the risk/benefit profile of therapies used in paediatric and elderly patients is limited. We carried out a study, called the MEAP 3.0 study, to collect and analyse evidence of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) that occurred in frail populations under polypharmacy in a real-world setting. Data were retrieved from reports of ADRs and pharmacological counselling from patients treated in hospitals and territorial health services. We collected 2977 ADRs reports and identified 'anti-infectives for systemic use' and 'cardiovascular system' as the most frequently implicated pharmacological classes in under-18 and over-65 patients, respectively. We detected 2179 DDIs, of which 10.7% were related to at least one ADR: 22 were classified as 'contraindicated' (7 in the paediatric group and 15 in the elderly one), and 61 as 'major' (6 in the paediatric patients and 55 in the geriatric ones), while 151 DDIs were classified as 'moderate' (10 referred to paediatric population, and 109 to elderly patient) and as 'minor' (1 in paediatric patients, and 31 in the elderly ones). The MEAP 3.0 project demonstrates that pharmacovigilance surveillance and therapeutic reconciliation are valid strategies to avoid potential DDIs and the occurrence of ADRs, allowing for personalised medicine.

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping.

The application of pharmacogenetics in oncology is part of the routine clinical practice. In particular, genotyping of dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase (UGT1A1) is crucial to manage the treatment of patients taking fluoropyrimidines and irinotecan. The unique approach of our laboratory to the pharmacogenetic diagnostic service in oncology is to combine two real-time PCR methods, LightSNiP assay (TIB MOLBIOL), and more recently FRET (Fluorescent Resonance Energy Transfer) probes technology (Nuclear Laser Medicine), plus TaqMan assay (Thermo Fisher) for the confirmation of the presence of variant alleles on DNA from a second extraction. We found that both the FRET and LightSNiP assays, where detection occurs by melting curve analysis, offer an advantage over the competing TaqMan technology. Whereas unexpected genetic variants may be missed using a mutation-specific TaqMan assay, the information thus obtained can be useful to adjust the therapy in case of unexpected post-treatment toxicity. The combination of TaqMan and FRET assays helped us to achieve more accurate genotyping and a correct result for the patient. The added value of the DPYD FRET assay is the possibility of detecting, with the same amplification profile of the polymorphisms detailed in the guidelines, also the c.2194G>A (*6 rs1801160), cited in the recommendations as a variant to be investigated in case of severe toxicity. Regarding the UGT1A1 (TA)n promoter polymorphism (rs3064744), the distinctive and positive feature of the FRET assay is to allow clearly identifying all those potential variant alleles, including the (TA)5 and (TA)8 alleles, that are frequent in African Americans. Our clinical practice emphasizes the importance of not only rapid and easy-to-use assays, such as the new FRET ones, but also of accurate and comprehensive genotyping for good pharmacogenetic diagnostic activity.

Cryopreserved placental biopsies maintain mitochondrial activity for high-resolution respirometry.

BACKGROUND: High-resolution respirometry (HRR) of human biopsies can provide useful metabolic, diagnostic, and mechanistic insights for clinical research and comparative medical studies. Fresh tissues analysis offers the potential best condition, the drawback being the need to use them shortly after dissection for mitochondrial respiratory experiments. The development of effective long-term storage protocols for biopsies that allow the assessment of key Electron Transport System (ETS) parameters at later stages is thus a major need. METHODS: We optimised a cryopreservation protocol that preserves mitochondrial membranes intactness, otherwise affected by direct tissue freezing. The protocol is based on a gradual freezing step from on-ice to liquid nitrogen and - 80 °C storage using a specific DMSO-based buffer. RESULTS: Placenta is a suitable tissue to design and test the effectiveness of long-term storage protocols being metabolically active foetal tissue with mitochondrial dysfunctions contributing to placental disease and gestational disorders. Here we designed and tested the effectiveness of the cryopreservation protocol using human placenta biopsies; we measured the ETS activity by HRR of placenta specimens comparing fresh, cryopreserved, and snap frozen conditions. CONCLUSIONS: By this protocol, Oxygen Consumption Rate (OCR) measurements of fresh and cryopreserved placental specimens are comparable whereas snap frozen procedure impairs mitochondrial activity.

One year of experience with combined pharmacokinetic/pharmacogenetic monitoring of anti-TNF alpha agents: a retrospective study.

Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (-308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged.

On the potential of drug repurposing in dysphagia treatment: New insights from a real-world pharmacovigilance study and a systematic review.

Background: Polypharmacy is common in patients with dysphagia. Routinely used drugs may influence swallowing function either improving or worsening it. We aimed to explore the potential effects of three commonly used drug classes on dysphagia and aspiration pneumonia through a systematic review and a real-world data analysis to probe the possibility of drug repurposing for dysphagia treatment. Material and Methods: Five electronic databases were searched. Studies on adults at risk for dysphagia, treated with Dipeptidyl-Peptidase IV Inhibitors (DPP-4i), Adrenergic Beta-Antagonists (beta-blockers), or Angiotensin-Converting Enzyme Inhibitors (ACEi), and reporting outcomes on dysphagia or aspiration pneumonia were included. A nested case/non-case study was performed on adverse events recorded in the FDA Adverse Event Reporting System (FAERS) on patients >64 years. Cases (dysphagia or aspiration pneumonia) were compared between patients only treated with Levodopa and patients who were concomitantly treated with the drugs of interest. Results: Twenty studies were included in the review (17 on ACEi, 2 on beta-blockers, and 1 on DPP-4i). Contrasting findings on the effects of ACEi were found, with a protective effect mainly reported in Asian studies on neurological patients. Beta-blockers were associated with a reduced dysphagia rate. The study on DPP-4i suggested no effect on dysphagia and an increased risk of aspiration pneumonia. The FAERS analysis showed a reduction of the risk for dysphagia/aspiration pneumonia with ACEi, beta-blockers, and DPP-4i. Conclusion: Our study explores the potential drug repurposing of ACEi, beta-blockers and DPP-4i in neurological patients with dysphagia to improve swallowing function and reduce aspiration pneumonia risk. Future randomized controlled studies should confirm these results and clarify the underlying mechanisms of action.

Pesticides groundwater modelling relies on input data characterised by a high intrinsic variability: Is the resulting risk for groundwater credible?

In the framework of Regulation (EC) 1107/2009, concerning the placing of plant protection products (PPP) on the market, FOCUS models are used to predict active substances concentration in groundwater. The predicted environmental concentration in groundwater (PECGW) are influenced by active substance specific parameters, namely DT50, KOM and Freundlich coefficient (1/n), whose minimal variation in certain combinations of intervals significantly affects PECGW output. Considering that minimal variation are intrinsic in all laboratory studies, this approach may lead to not acceptable variations in the results for regulatory purposes. In the present article, PECGW were calculated for all maize crop scenarios, using 808 dummy active substances with different combinations of DT50, KOM and 1/n values, in order to quantify the influence of each single parameter on the final result of PEARL and PELMO models. The results obtained were used to create a classification system for the input parameters KOM and DT50 in order to minimise the input uncertainty effects. Even if this approach is scientifically viable yet, due to its conservative nature, it cannot be considered suitable in the regulatory framework, where acceptability of an active substance is strictly related to the limit value of 0.1 µg/L. Nevertheless, this classification system could represent an important screening or preliminary assessment to plan pesticide monitoring programmes. Based on the results of this analysis, it is believed that the assessment of pesticide leaching into groundwater should be revised to take into account this variability. Considering that both PEARL and PELMO FOCUS models deal with interaction between a chemical and a complex system like soil and weather, the selection of input data cannot pretend to rely on single specific number. Considering that intrinsic uncertainty cannot be eliminated from experimental work, a revision of the criteria used to identify the proper input data and a thorough revision of the actual groundwater modelling is recommended.

Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype.

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells' differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.

The impact of anti-TNFα agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database.

INTRODUCTION: Studies in patients with immune-mediated inflammatory diseases (IMIDs) have inconsistently suggested that anti-TNFα therapy may be associated with excessive weight gain. AREAS COVERED: We performed a nested case/non-case analysis to investigate the anti-TNF-α inhibitor-associated body-changes in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The risk was expressed as a measure of disproportionality using the reporting odds ratio (ROR) while adjusting for sex, drugs known to cause weight gain and reporter type. We also performed a time-to-onset (TTO) analysis of body weight-related events. RESULTS: Infliximab was the most commonly involved TNF-α inhibitor in body weight-related changes, reaching an aROR of 1.42 (95%CI:1. 26; 1.59). An increased risk was especially found in patients affected by rheumatic disorders, both in the adult and pediatric population. The median TTO after the start of anti- TNFα therapy was about 6-7 months for both children and adults. CONCLUSIONS: Given the potential effect of these agents on the excess weight gain in IMIDs patients, continuous attention for this side effect with appropriate counseling regarding lifestyle modifications are warranted, especially in those at high risk for obesity.

Single nucleotide polymorphisms to predict taxanes toxicities and effectiveness in cancer patients.

Taxanes are used in the treatment of several solid tumours. Adverse events (AEs) might be influenced by single nucleotide polymorphisms (SNPs) in genes encoding proteins responsible for pharmacokinetic and pharmacodynamic. In this prospective, monocentric, observational study we explored the effect of SNPs in the main genes involved in taxanes metabolism and transport, on toxicity and efficacy in 125 patients (pts) treated with paclitaxel, nab-paclitaxel, or docetaxel for neoplasms. There was no statistically significant association between the investigated SNPs and AEs. The heterozygous genotype of CYP3A4*22 showed a trend of association with skin reactions in pts treated with paclitaxel and nab-paclitaxel (RR = 6.92; 95% CI 0.47, 99.8; p = 0.0766). CYP2C8*3/*4 variant carriers showed a trend of association with overall AEs in pts treated with paclitaxel and nab-paclitaxel (RR = 1.28; 95% CI 0.96, 1.67; p = 0.0898). No statistically significant relationship with treatment efficacy was found. ABCB1 3435TT showed a trend of association with a higher treatment response (RR = 0.22; 95% CI 0.03, 1.51; p = 0.0876). Despite the population was heterogeneous, CYP3A4*22 and CYP2C8 SNPs may influence paclitaxel and nab-paclitaxel toxicity and ABCB1 c.3435 may affect taxanes effectiveness, even if any statistically significant was found.

Drug Use in Pediatric Patients Admitted to Rehabilitation For Severe Acquired Brain Injury: Analysis of the Associations With Rehabilitation Outcomes.

INTRODUCTION: Patients with severe acquired brain injuries require drug therapies in intensive care for life support and injury treatment. Patients who then access rehabilitation usually maintain their drug treatments long term, with a potential influence on the rehabilitation course. Whereas drug effects have been reported for specific drugs and clinical issues in adults, comprehensive data on pediatric patients with traumatic and non-traumatic injuries are scant. OBJECTIVES: The aims of this study were to describe the therapeutic classes and groups of drugs prescribed to pediatric inpatients recovering from severe acquired brain injury when they enter rehabilitation; to assess whether clinical variables may determine the use of drug classes; and to assess whether the use of drug classes may be associated with differences in rehabilitation outcomes. METHODS: We carried out a retrospective chart review, following a previous study on the clinical-epidemiological characteristics of our patients. We collected information on drug therapies present at admittance to rehabilitation and analyzed their distribution according to therapeutic classes and groups. We verified the associations of drug groups with clinical variables (putatively antecedents to drug use) and with rehabilitation outcomes (putatively resultant of drug use and of clinical variables) in regression models. The clinical variables considered were injury etiology, Glasgow Outcome Score (GOS) at admittance to rehabilitation, sex, age at injury, plus two aggregate factors resulting from the previous work, 'neurological dysfunction' regarding the use of devices and 'injury severity' regarding the neurological status. The rehabilitation outcomes used were death after rehabilitation, persistence of a vegetative/minimally conscious state, coma duration, duration of the rehabilitation stay, rehabilitation efficiency (GOS at discharge minus GOS at admittance, divided by the length of rehabilitation stay). RESULTS: We described the distribution of drug classes and groups among pediatric patients with severe acquired brain injuries. Regarding the associations between drug classes and clinical variables, we found greater use of cardiovascular agents with higher patient age, 'neurological dysfunction' score, and with an etiology of hypoxic brain injury. The use of antithrombotic agents was greater with higher patient age and 'neurological dysfunction' score. Glucocorticoid use was greater with higher GOS at admittance and with several etiologies: brain tumor, infective encephalitis, and autoimmune encephalitis. Regarding drug classes and rehabilitation outcomes, we found that the use of cardiovascular drugs was associated with increased occurrence of death after rehabilitation. The use of antispastic drugs was associated with a more frequent permanence in vegetative/minimally conscious states. The use of antispastic drugs and melatonin was associated with longer coma duration. The use of glucocorticoid drugs was associated with decreased rehabilitation efficiency. CONCLUSIONS: We provided a description of drug use in pediatric rehabilitation after severe acquired brain injuries, which was lacking in the literature. Prospective studies should verify our associative observations regarding clinical variables, drugs use, and outcomes, to assess causality.

We Really Need Clear Guidelines and Recommendations for Safer and Proper Use of Aripiprazole and Risperidone in a Pediatric Population: Real-World Analysis of EudraVigilance Database.

Background: Although aripiprazole and risperidone are used widespread in pediatrics, there are still limited pieces of evidence on their actual safety profile. By using the EudraVigilance database, we carried out an analysis to perform a comprehensive overview of reported adverse events among children and adolescents treated with aripiprazole and risperidone. Methods: Descriptive analysis was performed of all individual case safety reports (ISCRs) submitted to EudraVigilance associated with aripiprazole and risperidone and related to the pediatric population from 2016 to 2018. Results: A total of 855 and 2,242 ISCRs for aripiprazole and risperidone, respectively, were recorded for a total of 11,042 suspected adverse drug reactions (2,993 for aripiprazole and 8,049 for risperidone). Most ISCRs were related to male patients (65.0 and 86.3% for aripiprazole and risperidone, respectively) and were serious (81.0 and 94.1% for aripiprazole and risperidone, respectively). Schizophrenia spectrum and other psychotic disorders, such as disruptive, impulse-control, and conduct disorders, and autism spectrum disorder were the top three clinical indications for aripiprazole (19.0, 16.1, and 11.6%, respectively). For risperidone, attention-deficit/hyperactivity disorder (25.4%), disruptive, impulse-control, and conduct disorders (17.1%), and bipolar and related disorders (14.2%) were more commonly reported as clinical indications. Data also showed a high proportion of use for clinical conditions not authorized in children. Psychiatric disorders were the main related adverse events for aripiprazole (20.2%), and among these, suicidal behavior was one of the most reported (14.9%). Reproductive system and breast disorders were the main related adverse events for risperidone (19.8%), and gynecomastia was the most reported event; metabolism and nutrition disorders, mainly reported as weight gain disorders, were more reported in children (3-11 years) than in adolescents (12-17 years). Conclusions: Our results demonstrate that spontaneously reported adverse events associated with aripiprazole and risperidone reflect what is already known in terms of safety profile, although with about 90% of them being serious. This analysis stresses the need for further studies and effective training and information activities to better define the actual benefit/risk ratio of these drugs in pediatric patients.

Changes in Anthropometric Parameters After Anti-TNFα Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Tumour necrosis factor (TNF)-α inhibitors have been widely used for the treatment of moderate-to-severe inflammatory bowel disease (IBD). TNFα also plays an important role in the regulation of weight homeostasis and metabolism and has been linked to variations in anthropometric responses. This relationship in patients with IBD has yet to be determined. OBJECTIVES: Our objective was to evaluate the effects of TNFα inhibitors on changes in anthropometric measures in both adults and children with IBD through a systematic review and meta-analysis. METHODS: Multiple database searches identified studies involving children and adults with IBD and treated with TNFα inhibitors and reporting at least one primary outcome measure. Where possible, data were combined for meta-analysis. The primary outcomes included weight, body mass index (BMI), waist circumference, height, height/velocity, and fat and lean mass. Secondary outcomes included surrogate markers of disease activity. A random-effects model was used to estimate the standardised mean difference (SMD). RESULTS: In total, 23 cohort studies (total 1167 participants) met the inclusion criteria. Meta-analysis was performed on 13 of these studies. In children, 6-29.3 months of anti-TNFα therapy had a small but statistically significant effect on weight (SMD 0.31; 95% confidence interval [CI] 0.12-0.49; P = 0.001) with a mean gain in z score of 0.30 (standard error [SE] 0.12). In adults, 2-22.4 months of treatment had a moderate effect on BMI (SMD 0.72; 95% CI 0.17-1.26; P = 0.010; mean gain 1.23 kg/m2; SE 0.21). A small but statistically significant increase in BMI z score was found in children (SMD 0.28; 95% CI 0.03-0.53; P = 0.026; mean change 0.31 ± standard deviation [SD] 0.14) after 12-29.3 months of therapy. A meta-analysis of four studies found a negligible but statistically significant increase in height (SMD 0.16; 95% CI 0.06-0.26; P = 0.002; mean change 0.17 z score [SE 0.05]). A negligible effect on fat mass (SMD 0.24; 95% CI -0.19-0.66; P = 0.272) was found in a meta-analysis of five studies. Of note, despite the high heterogeneity among the studies that addressed the issue, these results were also consistently supported by findings from studies not included in the meta-analysis and reviewed in the systematic review. Unfortunately, a lack of data meant we were unable to perform moderator analysis on observed heterogeneity. CONCLUSION: Anti-TNFα treatment appears to be associated with an increase in body weight, BMI, and other anthropometric parameters. Given the differing courses of IBD between children and adults, this association should be considered before initiating biologics for undernourished, overweight, and obese patients. Registration: PROSPERO registration number CRD42020163079.

Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?

In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection.

Acid Sphingomyelinase Downregulation Enhances Mitochondrial Fusion and Promotes Oxidative Metabolism in a Mouse Model of Melanoma.

Melanoma is the most severe type of skin cancer. Its unique and heterogeneous metabolism, relying on both glycolysis and oxidative phosphorylation, allows it to adapt to disparate conditions. Mitochondrial function is strictly interconnected with mitochondrial dynamics and both are fundamental in tumour progression and metastasis. The malignant phenotype of melanoma is also regulated by the expression levels of the enzyme acid sphingomyelinase (A-SMase). By modulating at transcriptional level A-SMase in the melanoma cell line B16-F1 cells, we assessed the effect of enzyme downregulation on mitochondrial dynamics and function. Our results demonstrate that A-SMase influences mitochondrial morphology by affecting the expression of mitofusin 1 and OPA1. The enhanced expression of the two mitochondrial fusion proteins, observed when A-SMase is expressed at low levels, correlates with the increase of mitochondrial function via the stimulation of the genes PGC-1alpha and TFAM, two genes that preside over mitochondrial biogenesis. Thus, the reduction of A-SMase expression, observed in malignant melanomas, may determine their metastatic behaviour through the stimulation of mitochondrial fusion, activity and biogenesis, conferring a metabolic advantage to melanoma cells.

Efficacy of Tumour Necrosis Factor-alpha therapy in paediatric Crohn's disease patients with perianal lesions: a systematic review.

Introduction: Anti-Tumor Necrosis Factor-alpha (TNF-α) therapy, primarily infliximab and adalimumab, are now increasingly used to induce and maintain disease remission in the pediatric perianal Crohn's disease (CD) population, however, their optimal use has not yet been defined in the pediatric setting.Areas covered: In accordance with a published protocol (PROSPERO no. CRD42019118838), we systematically and critically evaluated all published evidence on the efficacy and safety of anti-TNF-α in children with perianal CD, in the PubMed, MEDLINE, Embase, Cochrane and clinicalTrials.gov databases until October, 18th, 2018. We included in our systematic review 29 articles yielding a total of 565 perianal CD patients aged between 9 months to 18 years.Expert opinion: According to low-quality evidence from small, uncontrolled and heterogeneous descriptive studies, and very few randomized controlled trial, nearly three-fifths children with perianal CD achieved remission with anti-TNF-α treatment and in approximately 40% remission was maintained after 12 months, with practically low discontinuation rate due to serious adverse events. More than half of the patients achieved complete fistula closure. There is still a need for more robust evidence adequately assessing the efficacy and safety of anti-TNF-α therapy in pediatric perianal CD, as well as in comparison with other therapies.

Impact of Therapeutic Drug Monitoring of Antiretroviral Drugs in Routine Clinical Management of People Living With HIV: A Narrative Review.

BACKGROUND: The treatment of HIV infection has evolved significantly since the advent of highly active antiretroviral therapy. As a result, a response rate of 90%-95% now represents a realistically achievable target. Given this background, it is difficult to imagine the additional benefits that therapeutic drug monitoring (TDM) could provide in the management of HIV infection. METHODS: This article is not intended to provide a systematic literature review on TDM of antiretroviral agents; rather, the authors aim to discuss the potential added value of TDM in the optimal management of people living with HIV (PLWH) in selected real-life clinical scenarios based on data collected over 10 years by their TDM service. RESULTS: Some clinical situations, in which the selection of the optimal antiretroviral therapy is challenging, have been identified. These include poorly compliant patients, suboptimal antiretroviral therapies (in terms of both efficacy and toxicity), polypharmacy with a high risk of drug-drug interactions, and different patient populations, such as pregnant women. CONCLUSIONS: The transformation of HIV infection from a near-universally fatal illness to a lifelong chronic disease has resulted in an HIV population that is growing and aging, placing new and increasing demands on public programs and health services. Increasingly, the management of comorbidities, polypharmacy, and drug-drug interaction, and their impact on antiretroviral therapy will have to be undertaken. These clinical settings represent some of the new frontiers for the use of TDM with the goal of achieving optimal prescription and outcome for PLWH.

XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death.

X-linked inhibitor of apoptosis protein (XIAP) is an emerging crucial therapeutic target in cancer. We report on the discovery and characterisation of small organic molecules from Piper genus plants exhibiting XIAP antagonism, namely erioquinol, a quinol substituted in the 4-position with an alkenyl group and the alkenylphenols eriopodols A-C. Another isolated compound was originally identified as gibbilimbol B. Erioquinol was the most potent inhibitor of human cancer cell viability when compared with gibbilimbol B and eriopodol A was listed as intermediate. Gibbilimbol B and eriopodol A induced apoptosis through mitochondrial permeabilisation and caspase activation while erioquinol acted on cell fate via caspase-independent/non-apoptotic mechanisms, likely involving mitochondrial dysfunctions and aberrant generation of reactive oxygen species. In silico modelling and molecular approaches suggested that all molecules inhibit XIAP by binding to XIAP-baculoviral IAP repeat domain. This demonstrates a novel aspect of XIAP as a key determinant of tumour control, at the molecular crossroad of caspase-dependent/independent cell death pathway and indicates molecular aspects to develop tumour-effective XIAP antagonists.