Cardiomyocyte PAI-1 influences the cardiac transcriptome and limits the extent of cardiac fibrosis in response to left ventricular pressure overload.

Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid-acting inhibitor of endogenous plasminogen activators (uPA and tPA). The global PAI-1 knockout mice (PAI-1KO) develop age-dependent cardiac-selective fibrosis, and young global PAI-1KO mice exhibit augmented susceptibility to developing cardiac fibrosis in response to hypertension. Here, we tested the hypothesis that cardiomyocyte PAI-1 is necessary to provide cardioprotective effects in a left ventricular pressure overload-induced murine model of cardiac hypertrophy and fibrosis using cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) mice. The results revealed that cmPAI-1KO mice display significantly worse cardiac fibrosis than controls. To investigate the molecular mechanisms responsible for these effects, genome-wide cardiac transcriptome analysis was performed. Loss of cardiomyocyte PAI-1 led to differential expression of 978 genes compared to controls in response to left ventricular pressure overload. Pathway enrichment analysis identified the inflammatory response, cell substrate adhesion, regulation of cytokine production, leukocyte migration, extracellular matrix organization, and cytokine-mediated signaling pathways as being significantly upregulated in cmPAI-1KO hearts. Conversely, specific epigenetic repressors, cation transmembrane transport, muscle system processes, and nitric oxide signaling were significantly downregulated in cmPAI-1KO hearts compared to control hearts in response to left ventricular pressure overload. Collectively, the present study provides strong evidence of the impact of cardiomyocyte PAI-1 in regulation of the transcriptome network involved in the cardiac stress response. In response to stress, the deregulatory impact of cardiomyocyte PAI-1 loss on the cardiac transcriptome may be the underlying cause of cardiac-selective accelerated fibrogenesis in global PAI-1-deficient mice.

Clozapine Patients at the Interface between Primary and Secondary Care.

Patients receiving clozapine must undergo routine blood monitoring to screen for neutropenia, and to monitor for potential agranulocytosis. In Cork University Hospital, Cork, Ireland, clozapine is dispensed in the hospital pharmacy and the pharmacists are not aware of co-prescribed medicines, potentially impacting upon patient safety. The aim of this study was to examine the continuity of care of patients prescribed clozapine. A retrospective audit was conducted on patients attending the clozapine clinic at Cork University Hospital and assessed patients' (i) independent living, (ii) co-prescribed medicines and (iii) knowledge of their community pharmacists regarding co-prescribed clozapine. A list of prescribed medicines for each patient was obtained, and potential drug-drug interactions between these medicines and clozapine were examined using Lexicomp® and Stockley's Interaction checker. Secondary outcomes included patients' physical health characteristics, and a review of co-morbidities. Data were collected between the 29 May 2017 and 20 June 2017. Local ethics committee approval was granted. Patients were eligible for inclusion if they were receiving clozapine treatment as part of a registered programme, were aged 18 years or more, and had the capacity to provide written informed consent. Microsoft Excel was used for data analysis. Of 112 patients, (33% female; mean age (SD) 43.9 (11.3) years; 87.5% living independently/in the family home) 86.6% patients reported that they were taking other prescribed medicines from community pharmacies. The mean (SD) number of co-prescribed medicines in addition to clozapine was 4.8 (4) per patient. Two thirds of community pharmacists were unaware of co-prescribed clozapine. Interactions with clozapine were present in all but 3 patients on co-prescribed medicines (n = 97). Lexicomp® reported 2.9 drug-drug interactions/patient and Stockley's Interaction Checker reported 2.5 drug-drug interactions/patient. Secondary outcomes for patients included BMI, total cholesterol, and HbA1c levels, which were elevated in 75%, 54% and 17% respectively. Patients prescribed clozapine did not receive a seamless service, between primary and secondary care settings. Community pharmacists were not informed of clozapine, prescribed for their patients, in two thirds of cases. Patients in this study were exposed to clozapine-related drug-drug interactions and hence potential adverse effects. This study supports reports in the literature of substandard management of the physical health of this patient group. This study shows that there is an opportunity for pharmacists to develop active roles in the management of all clozapine-related effects, in addition to their traditional obligatory role in haematological monitoring. This study supports the need for a clinical pharmacist to review inpatients commencing on clozapine, monitor for drug-drug interactions and provide counselling.

Amifostine does not reduce the toxicity of the fludarabine and cyclophosphamide regimen in patients with chronic lymphocytic leukemia.

PURPOSE: Amifostine is an organic thiophosphate that may selectively protect normal tissues from the toxicities of chemotherapy. The combination of fludarabine and cyclophosphamide (FC) is highly active in patients with chronic lymphocytic leukemia (CLL). Infection is a serious toxicity of the FC regimen. METHODS: Amifostine was added to the FC regimen in a phase II study of 46 patients with CLL. Patients received FCA (fludarabine 30 mg/m(2) i.v. daily for 3 days, cyclophosphamide 300 mg/m(2) i.v. daily for 3 days, and amifostine 500 mg i.v. over 15 min daily for 3 days starting 30 min before cyclophosphamide) at intervals of 4-6 weeks for a maximum of six courses. RESULTS: Patients receiving FCA had equivalent rates of sepsis, early death, objective response and survival to those observed in a prior series of 78 patients treated with FC. Amifostine-associated toxicities included nausea, vomiting, and hypotension. CONCLUSION: The study amifostine regimen did not reduce the toxicity or activity of the FC regimen in patients with CLL.