Limited Sampling Strategies to Monitoring Mycophenolic Acid Exposure in a Heterogeneous Population of Heart Transplant Recipients: A Pilot Study

Mycophenolate mofetil (MMF) represents a cornerstone in heart transplant (HTx) treatment. The area under the 12-hour concentration-time curve (AUC0-12h) of mycophenolic acid (MPA) -MMF’s active drug- is associated with treatment outcome. Nonetheless, therapeutic drug monitoring (TDM) of MPA AUC0-12h is impractical to assess in clinical practice and Limited Sampling Strategies (LSSs) represent a consolidated tool to estimate AUC0-12h. Two LSSs were previously generated in a selected cohort of HTx recipients treated with MMF and cyclosporine (CsA). This pilot study aimed to test these LSSs in a cohort of non-selected HTx recipients treated with MMF combined with CsA or tacrolimus (TAC). Complete PK profile was performed in 40 adults HTx recipients. MPA-AUC0-12h was estimated by two algorithms, LSS3 and LSS4, based on 3 and 4 time-points. The evaluation was made through linear regression and Bland-Altman analyses. Both LSS3 and LSS4 tended to underestimate the value of MPA-AUC0-12h (mean percentage prediction error, MPE%: −6.0%; and −4.8%, respectively). Nonetheless, high correlations (r: 0.92 and 0.94, respectively) and goodness of fit of linear regression models (R2: 0.84 and 0.88, respectively) emerged for both LSSs. A study with a wider and more homogenous sample size should be performed to support these results

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/β-catenin signaling pathway. The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 (Ki = 6.8 nM) suppressed the Wnt/β-catenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved caspase-3. Compound 15 showed strong inhibition of viability in a panel of cancer cells, including colorectal cancer and triple-negative breast cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15 is a novel dual-targeting compound with activity against hCA and Wnt/β-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines

Metabolic Syndrome and Heart Transplantation: An Underestimated Risk Factor?

Metabolic Syndrome (MetS), a multifactorial condition that increases the risk of cardio-vascular events, is frequent in Heart-transplant (HTx) candidates and worsens with immunosuppressive therapy. The aim of the study was to analyze the impact of MetS on long-term outcome of HTx patients. Since 2007, 349 HTx patients were enrolled. MetS was diagnosed if patients met revised NCEP-ATP III criteria before HTx, at 1, 5 and 10 years of follow-up. MetS was present in 35% of patients pre-HTx and 47% at 1 year follow-up. Five-year survival in patients with both pre-HTx (65% vs. 78%, p < 0.01) and 1 year follow-up MetS (78% vs 89%, p < 0.01) was worst. At the univariate analysis, risk factors for mortality were pre-HTx MetS (HR 1.86, p < 0.01), hypertension (HR 2.46, p < 0.01), hypertriglyceridemia (HR 1.50, p=0.03), chronic renal failure (HR 2.95, p < 0.01), MetS and diabetes at 1 year follow-up (HR 2.00, p < 0.01; HR 2.02, p < 0.01, respectively). MetS at 1 year follow-up determined a higher risk to develop Coronary allograft vasculopathy at 5 and 10 year follow-up (25% vs 14% and 44% vs 25%, p < 0.01). MetS is an important risk factor for both mortality and morbidity post-HTx, suggesting the need for a strict monitoring of metabolic disorders with a careful nutritional follow-up in HTx patients

New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer

Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study

Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures

COVID-19 in rheumatic diseases in Italy: first results from the Italian registry of the Italian Society for Rheumatology (CONTROL-19)

OBJECTIVES: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance. METHODS: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry. RESULTS: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death. CONCLUSIONS: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments

Implantable Ventricular Assist Devices in the Deutsches Herzzentrum Experience Special Reference to Gender Differences

Background: Over the past 20 years the use of ventricular assist devices (VADs) in patients with chronic end-stage or acute heart failure has led to improved survival. There is very little literature about gender differences in mechanical assist devices implantation while different gender characteristics in heart failure exist. The aim of our study was to review the large experience of Deutsches Herzzentrum in mechanical assist devices implantation as bridge to recovery, bridge to transplant or destination therapy, specifically concerning gender differences. Methods: We analyzed data from the database of Deutsches Herzzentrum Berlin, which contains the demographic, preoperative, postoperative, and long-term follow-up data of patients who have received mechanical circulatory support (MCS) devices between July 1987 and May 2009. We collected survival data of patients implanted only with long-term MCS with a left-ventricular or a bi-ventricular assist configuration. We excluded patients implanted with short-term devices, total artificial heart devices and isolated right ventricular assist devices. We analyzed differences between men and women. Results: A total of 889 patients were implanted with long-term VADs: 492 left ventricular assist devices (LVAD) (55.3%) and 397 biventricular assist devices (BVAD) (44.7%). The mean age of the patients was 49.2 years (range 17 to 76 years) (mean age men 50.0 years ± 12.4; mean age women 44.8 years ± 13.7), 84.8% were male. Mean time of VAD was 4.48 (± 0.24) months with longer support (p 0.001) in men (4.7 months ± 0.2) than in women (3.0 months ± 0.5). Also in the two subgroups of LVAD and BVAD, mean support time was longer in men than in women (p< 0.001): 6.22 months ± 0.41 in LVAD men and 4.2 months ± 1.25 in LVAD women, 2.64 months ± 0.26 in BVAD men and 2.38 months ± 0.38 in BVAD women. Survival analysis showed that in patients needing mechanical circulatory support the 30 days survival is 88% and the p50 (= median survival) is 2.6 months. LVAD (p50 3.99 months) permit better survival than BVAD (p50 1.28 months) (p<0.0001) and there is a trend (p 0.73) of worst survival in women (p50 1.38 months) than in men (p50 2.56 months), most of all in the first month after implant. In 55 patients (45 male) the device could be removed after myocardial recovery. In this subgroup of patients women had a survival near to significantly worse than men (p50 women 9.33 months vs. p50 men 77.42; p 0.08). A total of 260 patients were successfully bridged to heart transplantation (219 male). Also in this subgroup LVADs performed better than BVADs (p<0.0001) and men better than women, even if not statistically significant. Conclusion: VAD implantation is an effective therapy in patients with advanced heart failure, but early mortality is still high. LVADs perform much better, last longer and have lower mortality than BVADs. In percentage men are more often implanted with LVAD and have better survival with VAD than women.Introduzione: Negli ultimi 20 anni l'uso di dispositivi di assistenza ventricolare (VAD) in pazienti con insufficienza cardiaca cronica in fase terminale o acuta ha portato ad un miglioramento della sopravvivenza. La letteratura sulle differenze tra i due sessi nell’ impianto di VAD è molto scarsa, mentre esistono delle diverse caratteristiche di sesso nell’insufficienza cardiaca. Lo scopo del nostro studio era quello di analizzare la grande esperienza del Deutsches Herzzentrum nella terapia con VAD come ponte al recovery del miocardio, come ponte al trapianto cardiaco o come destination therapy, specificamente riguardo alle differenze tra i due sessi. Metodi: Abbiamo analizzato i dati provenienti dal database del Deutsches Herzzentrum di Berlino, che contiene le caratteristiche demografiche, preoperatorie, postoperatorie e il follow-up a lungo termine dei pazienti che hanno ricevuto dispositivi meccanici di assistenza circolatoria nel periodo compreso tra luglio 1987 e maggio 2009. Abbiamo raccolto i dati di sopravvivenza solo dei pazienti trattati con supporto meccanico di circolo (MCS) a lungo termine mediante un’assistenza ventricolare sinistra (LVAD) o un’assistenza biventricolare (BVAD). Abbiamo escluso i pazienti a cui erano stati impiantati dispositivi d’emergenza a breve termine, un cuore artificiale totale o un’assistenza ventricolare destra isolata. Abbiamo quindi analizzato le differenze tra uomini e donne. Risultati: Un totale di 889 pazienti hanno ricevuto un VAD a lungo termine: 492 LVADs (55,3%) e 397 BVADs (44,7%). L'età media dei pazienti era di 49,2 anni (range 17-76 anni) (età media uomini 50,0 anni ± 12,4; età media donne 44,8 anni ± 13,7), l’84,8% erano maschi. Il tempo medio di assistenza ventricolare è stato di 4,48 (± 0,24) mesi con supporto più lungo (p <0,001) negli uomini (4,7 mesi ± 0,2) che nelle donne (3,0 mesi ± 0,5). Anche nei due sottogruppi di tempo in LVAD e BVAD, la durata media era più lunga negli uomini che nelle donne (p <0,001): 0,41 mesi ± 6,22 gli uomini con LVAD e 4,2 mesi ± 1,25 le donne con LVAD; 2,64 mesi ± 0,26 gli uomini con BVAD e 2,38 mesi ± 0,38 le donne con BVAD. L'analisi di sopravvivenza ha dimostrato che nei pazienti che necessitano un MCS la sopravvivenza a 30 giorni è dell’88% e la p50 (= sopravvivenza mediana) è di 2,6 mesi. Gli LVADs (p50 3,99 mesi) consentono una migliore sopravvivenza rispetto ai BVADs (p50 1,28 mesi) (p <0,0001) e vi è una tendenza (p 0,73) di peggiore sopravvivenza nelle donne (p50 1,38 mesi) che negli uomini (p50 2,56 mesi), soprattutto nel primo mese dopo l'impianto. In 55 pazienti (45 maschi) si è potuto rimuovere il dispositivo dopo avere ottenuto un accettabile recupero della funzione contrattile del miocardio. In questo sottogruppo di pazienti le donne hanno avuto una sopravvivenza significativamente peggiore rispetto agli uomini (p50 donne 9,33 mesi vs p50 uomini 77,42 mesi; p 0,08). Un totale di 260 pazienti (219 maschi) sono stati portati con successo al trapianto di cuore. Anche in questo sottogruppo gli LVADs hanno dato una sopravvivenza migliore rispetto ai BVADs (p <0,0001) e gli uomini sono sopravvissuti più delle donne, anche se non in modo statisticamente significativo. Conclusioni: l'impianto di VAD è una terapia efficace nei pazienti con insufficienza cardiaca avanzata, ma la mortalità peri-operatoria è ancora elevata. Gli LVADs hanno una migliore performance, durano più a lungo e danno una mortalità più bassa rispetto ai BVADs. In percentuale gli uomini vengono più spesso trattati con LVAD e hanno una migliore sopravvivenza in assistenza rispetto alle donne

CXCL-13 serum levels in patients with rheumatoid arthritis treated with abatacept

Objectives: C-X-C motif chemokine 13 (CXCL-13), which is expressed by synovial follicular dendritic cells and activated mature antigen-experienced T-helper cells, has been described as a surrogate marker of lymphoid phenotype of synovitis in rheumatoid arthritis (RA). A preferential response to anti-interleukin-6 receptor (IL-6R) as compared to anti-tumour necrosis factor alpha (TNFα) monotherapy has been described in patients with increased levels of CXCL-13. We hypothesised that serum levels of CXCL-13 could be used as a biomarker of response to treatment with abatacept (ABA), a T-cell co-stimulation blocker. Methods: Serum levels of CXCL-13 and of soluble intracellular adhesion molecule 1 (sICAM-1) (a putative marker of the myeloid subtype of synovitis) were measured by indirect solid-phase enzyme immunoassays, before (T0) and after 6 months of therapy with ABA (T6) in 63 patients with RA. Circulating T follicular helper cells and B cell subpopulations were identified by flow-cytometry. Results: At T0, CXCL-13 serum levels were higher in RA patients than in healthy controls (p=0.0001) and correlated with disease activity, while no difference between the two groups was observed as far as sICAM-1 levels. Serum levels of CXCL-13 levels decreased after therapy with ABA both in patients who achieved a clinical response (p<0.01) and in non-responders (p=0.01), whereas sICAM-1 levels did not significantly change. When comparing RA patients who responded to ABA with non-responders no significant difference of baseline serum levels of CXCL-13 was observed. Conclusions: CXCL-13 serum levels are raised in RA patients and decrease after therapy with ABA. We were not able to demonstrate that serum CXCL-13 levels predict the clinical response to ABA in RA patients