Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.

Does Preoperative Platelet Function Predict Bleeding in Patients Undergoing Off Pump Coronary Artery Bypass Surgery?

OBJECTIVE: We sought to examine the relationship between preoperative platelet function and perioperative bleeding in patients undergoing CABG. BACKGROUND: There are many ways to measure platelet aggregability. Little is known about their correlations with one another, or with bleeding. METHODS: We prospectively studied 50 patients undergoing a first isolated off-pump CABG. Thirty-four were exposed to a thienopyridine prior to surgery; 16 were not. Preoperative platelet function was measured by VerifyNow®, TEG®, AggreGuide™, Plateletworks®, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and light transmission aggregometry. Bleeding was assessed 2 ways: drop from pre- to nadir postoperative hematocrit, and chest tube drainage. Correlation coefficients were calculated using Spearman's rank-order correlation. RESULTS: Mean age was 62 years. Patient characteristics and surgical details were similar between the thienopyridine-exposed and non-exposed patients. The correlation coefficients between the 4 point-of-care platelet function measurements and hematocrit change ranged from -0.2274 to 0.2882. Only Plateletworks® correlated with drop in hematocrit (r = 0.2882, P = 0.0470). The correlation coefficients between each of the 4 point-of-care platelet function tests and the chest tube drainage were also poor, ranging from -0.3073 to 0.2272. Both AggreGuide™ (r = -0.3073, P = 0.0317) and VASP (r = -0.3187, P = 0.0272) were weakly but significantly correlated with chest tube drainage. The correlation among the 4 point-of-care platelet function measurements was poor, with coefficients ranging from -0.2504 to 0.1968. CONCLUSIONS: We observed little correlation among 4 platelet function tests, and between those assays and perioperative bleeding defined 2 different ways. Whether any of these assays should be used to guide decision making in individual patients is unclear.

Allergic reactions to clopidogrel and cross-reactivity to other agents.

Clopidogrel is a widely used antiplatelet agent, particularly after coronary stent implantation. About 1% of patients have allergic or hematologic adverse reactions to clopidogrel. This has important therapeutic implications, as premature discontinuation of clopidogrel is the strongest risk factor for stent thrombosis. Clopidogrel allergy most commonly manifests as a rash. It is important to distinguish this from other causes of rash occurring in patients who have had a recent coronary stent. Although antihistamines and short-term oral corticosteroids are effective in treating most clopidogrel hypersensitivity reactions, some persistent reactions may require discontinuation of clopidogrel. When discontinuation of clopidogrel is required, substitution with an alternative thienopyridine such as ticlopidine traditionally has been performed. However, a recent study suggests that there may be as high as a 27% risk of recurrence of non-life-threatening allergic reactions in such patients, which are usually similar to the allergic reactions that occurred with clopidogrel. No data are available regarding the frequency of cross-reactivity to prasugrel and ticagrelor; these may be potential therapeutic options in some patients.

Hormonal determinants of bone turnover before and after attainment of peak bone mass.

INTRODUCTION: Bone turnover decreases from adolescence into adulthood, but does not reach a nadir until the fourth decade. Biochemical markers of bone turnover reflect different processes before and after peak bone mass, so hormonal influences on bone turnover may differ before and after peak bone mass. OBJECTIVES: To describe the changes in bone turnover and hormones relevant to bone metabolism from adolescence into adulthood, and to identify which hormones correlate with bone turnover before and after peak bone mass. DESIGN/PARTICIPANTS: Two measurements of bone turnover markers and hormones were obtained 5-9 years apart in 116 healthy males and females recruited from secondary schools and general practices. Correlations were examined cross-sectionally and longitudinally. RESULTS: Dehydroepiandrosterone sulphate (DHEAS) correlated negatively with bone turnover cross-sectionally and longitudinally (r-0.59 to -0.69) in males and females under the age of 25 years. IGF-1 correlated positively with aminoterminal propeptide of type I procollagen (PINP) cross-sectionally and longitudinally (r 0.35) in women over the age of 25 years. After correction for change in BMI, there were significant longitudinal correlations between DHEAS and bone turnover in women under 25 years (r-0.62, -0.66) and IGF-1 and PINP in women over 25 years (r 0.56). CONCLUSIONS: We have described changes in bone turnover and hormones from adolescence into adulthood. Dehydroepiandrosterone sulphate correlates with bone turnover before peak bone mass which may represent a direct effect on bone metabolism or the role of dehydroepiandrosterone sulphate as a substrate for conversion to other sex steroids. IGF-1 is correlated with aminoterminal propeptide of type I procollagen in women after peak bone mass, which may reflect an influence on cortical modelling.

Impact of Switching From Prasugrel to Clopidogrel Shortly After a Percutaneous Coronary Intervention Without a Loading Dose of Clopidogrel.

OBJECTIVE: To determine the safety and efficacy of administering prasugrel at the time of percutaneous coronary intervention (PCI), and switching to clopidogrel, without reloading. BACKGROUND: Prasugrel has faster onset of action and appears to be of greater benefit than clopidogrel, particularly early after PCI. However, long-term prasugrel increases bleeding. Many physicians at Geisinger Medical Center (GMC) administer prasugrel before PCI and switch to clopidogrel afterward. The safety and efficacy of this strategy has not been studied. METHODS: We performed a retrospective study using electronic medical records and identified patients at GMC who underwent PCI between February 1, 2009 and January 31, 2012 and received a loading dose of prasugrel with a subsequent switch to clopidogrel, without reloading. The primary endpoint was major adverse cardiovascular event (MACE), defined as death, myocardial infarction (MI), stroke, or stent thrombosis, 7 days after the first dose of clopidogrel. Secondary endpoints included MACE at 30 days, individual MACE components at 7 and 30 days post procedure, and bleeding as defined by the Bleeding Academic Research Consortium (BARC) at 1 day and 30 days. RESULTS: A total of 151 patients met inclusion criteria. One patient suffered a MACE on day 7 (0.7%; 95% confidence interval, 0.03%-3.33%). One patient had an MI between 8-30 days. Two patients had BARC bleeding (type 2 and type 3b) 30 days post PCI. CONCLUSIONS: In this small, retrospective analysis, the results of loading patients with prasugrel for PCI and switching them to clopidogrel without a loading dose appear to be encouraging.

The effect of antiplatelet and anticoagulant therapy on the clinical outcome of patients undergoing ureteroscopy.

OBJECTIVE: To determine if there is any difference in the clinical outcome for patients receiving aspirin, clopidogrel, and warfarin undergoing ureteroscopy and laser lithotripsy for urolithiasis compared with patients on no antithrombotic medication. METHODS: We retrospectively reviewed patients who underwent ureteroscopy for urolithaisis from July 1, 2005 to October 1, 2010. If patients continued aspirin, clopidogrel, or warfarin within 48 hours of surgery, they were considered to be on antithrombotic therapy. Patients not on these medications or those who discontinued the medications atleast 5 days before surgery comprised the control group. Six hundred forty-six patients met our inclusion criteria for analysis including 137 on aspirin alone, 17 on clopidogrel, 22 on warfarin, and 470 in the control group. RESULTS: Patients on antiplatelet and anticoagulants were older and were more likely to have risk factors for thromboembolism. When comparing patients on aspirin, clopidogrel, or warfarin with patients not on these medications, there was no difference in bleeding complications or need for an unplanned repeat ureteroscopy. There was also no difference in complications within 30 days of surgery. CONCLUSION: Among patients undergoing elective ureteroscopy and laser lithotripsy on the antithrombotic medications aspirin, clopidogrel, and warfarin, the procedure was as successful, and complications were not increased, compared with patients on no antithrombotic medications.

Preoperative aspirin is safe in patients undergoing urologic robot-assisted surgery.

PURPOSE: To determine the impact of preoperative aspirin on bleeding and other complications in patients undergoing robot-assisted radical prostatectomy and nephrectomy. PATIENTS AND METHODS: We identified all patients who underwent robot-assisted radical prostatectomy or robot-assisted nephrectomy by a single surgeon between August 2008 and August 2010. We compared patients in whom aspirin had not been administered for 7 days with those who received aspirin the morning of surgery. Patients on other antiplatelet agents or anticoagulants were excluded. RESULTS: Forty-four patients underwent prostatectomy without recent aspirin, and 51 received preoperative aspirin. There were no significant differences between the two groups in terms of age, body mass index, American Society of Anesthesiologists score, prostate-specific antigen level, or highest Gleason score. Operative time (182 vs 174 min, P=0.19), median blood loss (175 vs 100 mL, P=0.12), and duration of hospital stay (1 vs 1 day, P=0.08) were similar between the two groups, respectively. No patient received a transfusion. Three patients who had not received aspirin and one who had were readmitted within 30 days. In the nephrectomy cohort, 12 patients had not received aspirin and 14 had. There were no differences in median blood loss (65 vs 50 mL, P=0.96), median operative time (176 vs 140 min, P=0.14), or median hospital stay (2 vs 2 days, P=0.74). No patient received a transfusion. CONCLUSIONS: The administration of aspirin to patients undergoing robot-assisted radical prostatectomy and nephrectomy appears to be safe. The risk of cardiovascular complications resulting from stopping aspirin may exceed the risk of perioperative bleeding and associated complications.

Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density.

The age at which peak bone mineral content (peak BMC) is reached remains controversial and the mechanism underlying bone mass "consolidation" is still undefined. The aims of this study were to investigate; (1) the timing of peak BMC by studying bone size and volumetric BMD (vBMD) as separate entities and (2) to determine the relative contributions of bone size and vBMD to bone mass "consolidation". A total of 132 healthy Caucasian children (63 boys and 69 girls, ages 11-19 years) and 134 healthy Caucasian adults (66 men and 68 women, ages 20-50 years) were studied. BMC was measured by DXA at the AP and lateral lumbar spine (LS) femoral neck (FN) and ultradistal radius (UDR). vBMD and bone volume (size) were estimated. Bone mass "consolidation" was examined between age 16 years to the age peak bone values were attained. During growth, BMC and bone size increased steeply with age and approximately 80-90% of peak values were achieved by late adolescence. vBMD at the spine and UDR (in women) increased gradually, but vBMD at the FN and UDR in men remained almost constant. During "consolidation", bone size continued to increase with little change in vBMD. Peak vBMD at the lumbar spine was reached at 22 and 29 years in men and women, respectively, but earlier at the FN at 12 years. At the UDR peak vBMD was achieved at age 19 years in women, with little change in men. In conclusion, peak vBMD and bone size are almost fully attained during late adolescence. Although speculative, the lack of change in vBMD during consolidation implies that the continued increase in bone mass may primarily be due to increases in bone size rather than increases in either trabecular volume, cortical thickness or the degree of mineralisation of existing bone matrix (vBMD). Skeletal growth and maturation is heterogeneous, but crucial in understanding how the origins of osteoporosis may begin during childhood and young adulthood.