Population pharmacokinetic/ pharmacodynamic modelling of eltrombopag in healthy volunteers and subjects with chronic liver disease

Aims

To characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of eltrombopag in chronic liver disease (CLD).

Methods

The PK/PD model was developed using data from 79 CLD patients using nonlinear mixed-effects modelling.

Results

The PK of eltrombopag were described by a two-compartment model with dual sequential first-order absorption. Gender, race and severity of CLD were predictors of the apparent clearance of eltrombopag. The PD of eltrombopag in CLD were adequately described by a four-compartment lifespan model, in which eltrombopag stimulated platelet precursor production rate. East Asian CLD patients were less sensitive to the stimulatory effect of eltrombopag. Following a daily dose regimen of 50 mg eltrombopag, the time to achieve peak platelet counts was longer for the CLD population compared with patients who had immune thrombocytopenic purpura, but was comparable to patients with hepatitis C. Likewise, it took a longer time for platelet counts to rebound back to baseline once eltrombopag treatment was discontinued.

Conclusions

The time course of the platelet response in CLD was different from that in immune thrombocytopenic purpura but comparable to that in hepatitis C.     

Altered Interhemispheric and Temporal Lobe White Matter Microstructural Organization in Severe Chronic Schizophrenia

Diffusion MRI investigations in schizophrenia provide evidence of abnormal white matter (WM) microstructural organization as indicated by reduced fractional anisotropy (FA) primarily in interhemispheric, left frontal and temporal WM. Using tract-based spatial statistics (TBSS), we examined diffusion parameters in a sample of patients with severe chronic schizophrenia. Diffusion MRI data were acquired on 19 patients with chronic severe schizophrenia and 19 age- and gender-matched healthy controls using a 64 gradient direction sequence, (b=1300 s/mm²) collected on a Siemens 1.5T MRI scanner. Diagnosis of schizophrenia was determined by Diagnostic and Statistical Manual for Mental Disorders 4th Edition (DSM-IV) Structured Clinical Interview for DSM disorder (SCID). Patients were treatment resistance, having failed to respond to at least two antipsychotic medications, and had prolonged periods of moderate to severe positive or negative symptoms. Analysis of diffusion parameters was carried out using TBSS. Individuals with chronic severe schizophrenia had significantly reduced FA with corresponding increased radial diffusivity in the genu, body, and splenium of the corpus callosum, the right posterior limb of the internal capsule, right external capsule, and the right temporal inferior longitudinal fasciculus. There were no voxels of significantly increased FA in patients compared with controls. A decrease in splenium FA was shown to be related to a longer illness duration. We detected widespread abnormal diffusivity properties in the callosal and temporal lobe WM regions in individuals with severe chronic schizophrenia who have not previously been exposed to clozapine. These deficits can be driven by a number of factors that are indistinguishable using in vivo diffusion-weighted imaging, but may be related to reduced axonal number or packing density, abnormal glial cell arrangement or function, and reduced myelin.     

Increased training of general practitioners in Ireland may increase the frequency of exercise counselling in patients with chronic illness: A cross-sectional study

Background: Recent systematic reviews have established that brief interventions in primary care are effective and economic at promoting physical activity. Lack of training has previously been identified as a barrier to lifestyle counselling in Ireland.

Objectives: This study evaluates frequency of exercise counselling (EC), in patients with six chronic illnesses (type 2 diabetes mellitus, stable coronary heart disease, hypertension, depression, obesity, osteoarthritis) and healthy adults, by general practitioners (GPs) in the mid-west of Ireland, as well as, whether training in EC influences the frequency of EC.

Methods: A questionnaire survey of GPs based in the mid-west of Ireland was conducted during February and March 2012. The questionnaire was distributed to 39 GPs at two continuing medical education meetings and posted to 120 other GPs in the area. The questionnaire assessed the frequency of EC, use of written advice and frequency of recommending resistance exercise in the above patient groups. It also assessed training in EC.

Results: 64% of GPs responded (n = 102). Frequency of EC varied among the chronic illnesses evaluated. Use of written advice and advice on resistance exercise in EC was low. Only 17% of GPs had previous training in EC. If available, 94% of GPs would use guidelines to prescribe exercise in chronic illness. The association of previous training in EC with frequency of EC was variable, with significantly higher counselling rates found in T2DM, obesity and healthy adults.

Conclusion: Improved training of GPs and development of guidelines may increase the frequency of EC in Ireland.     

IFNL cytokines do not modulate human or murine NK cell functions

The interferon-lambda (IFNL) cytokines have been shown to be important in HCV infection with SNPs in the IFNL3 gene associated with both natural and treatment induced viral clearance. We have recently shown that rs1299860 (an IFNL3 associated SNP) and an NK cell gene, KIR2DS3, synergised to increase the odds of chronic infection in a homogenous cohort of Irish women infected with HCV. To characterise a biological basis for the genetic synergy, we investigated for any evidence that IFNL cytokines regulate NK cell functions. Using a range of functional responses, we did not find any evidence of NK cell activation by IFNL3, IFNL1 or IFNL2 cytokines. Similar results were found using human and murine NK cells. In addition, and in contrast to our preliminary study, we did not find any evidence that IFNL cytokines inhibited NK cell cytokine production; thus, the biological basis for the genetic synergy remains to be discovered.     

Prostate cancer derived prostatic acid phosphatase promotes an osteoblastic response in the bone microenvironment

Approximately 90 % of patients who die of prostate cancer (PCa) have bone metastases, often promoting osteoblastic lesions. We observed that 88 % of castration-resistant PCa (CRPC) bone metastases express prostatic acid phosphatase (PAP), a soluble secreted protein expressed by prostate epithelial cells in predominately osteoblastic (n = 18) or osteolytic (n = 15) lesions. Additionally, conditioned media (CM) of an osteoblastic PCa xenograft LuCaP 23.1 contained significant levels of PAP and promoted mineralization in mouse and human calvaria-derived cells (MC3T3-E1 and HCO). To demonstrate that PAP promotes mineralization, we stimulated MC3T3-E1 cells with PAP and observed increased mineralization, which could be blocked with the specific PAP inhibitor, phosphonic acid. Furthermore, the mineralization promoted by LuCaP 23.1 CM was also blocked by phosphonic acid, suggesting PAP is responsible for the mineralization promoting activity of LuCaP 23.1. In addition, gene expression arrays comparing osteoblastic to osteolytic CRPC (n = 14) identified betacellulin (BTC) as a gene upregulated during the osteoblastic response in osteoblasts during new bone formation. Moreover, BTC levels were increased in bone marrow stromal cells in response to LuCaP 23.1 CM in vitro. Because new bone formation does occur in osteoblastic and can occur in osteolytic CRPC bone metastases, we confirmed by immunohistochemistry (n = 36) that BTC was highly expressed in osteoblasts involved in new bone formation occurring in both osteoblastic and osteolytic sites. These studies suggest a role for PAP in promoting the osteoblastic reaction in CRPC bone metastases and identify BTC as a novel downstream protein expressed in osteoblasts during new bone formation.     

Cardiovascular effects at multi-detector row CT colonography compared with those at conventional endoscopy of the colon

PURPOSE: To compare the cardiovascular effects of computed tomographic (CT) colonography and conventional endoscopy in a group of patients undergoing both procedures. MATERIALS AND METHODS: A total of 144 patients underwent CT colonography followed by flexible sigmoidoscopy (40 patients) or colonoscopy (104 patients). Pulse, blood pressure, and oxygen saturation were measured before, during, and after the procedures. Forty patients also underwent continuous Holter electrocardiographic (ECG) monitoring. Periprocedural pain was assessed by using a handheld counting device. Outcome variables were assessed by using a combination of paired t testing and multilevel linear regression. RESULTS: When a spasmolytic was not used, CT colonography was associated with only a small increase in oxygen saturation (P =.03), while use of a spasmolytic caused an increase in pulse (mean increase, 19.9 beats per minute; P <.001) and diastolic blood pressure (mean increase, 5 mm Hg; P <.001). Compared with that at CT, oxygen saturation decreased significantly during and after colonoscopy and sigmoidoscopy (mean decrease after colonoscopy with sedation, 1.0%; P <.001). Systolic and diastolic blood pressure also decreased during and after colonoscopy (mean systolic decrease after colonoscopy with sedation, 16.6 mm Hg, P <.001; mean diastolic decrease after colonoscopy with sedation, 7.5 mm Hg, P <.001). Patients were 30.3 times more likely to develop bradycardia after endoscopy (95% CI: 2.65, 346; P =.006). Ventricular couplets were significantly higher at endoscopy than at CT in patients with a history of cardiac disease (odds ratio: 72.5 and 95% CI: 4.56, 1,153 at CT vs odds ratio: 14.6 and 95% CI: 0.96, 222 at endoscopy; P =.002). Patients were 1.89 times more likely to register pain during colonoscopy than during CT (95% CI: 1.06, 3.38; P =.03). CONCLUSION: CT colonography had no significant cardiovascular effect other than spasmolytic-induced tachycardia. Endoscopy-and colonoscopy in particular-causes cardiovascular effects that are largely related to sedation. CT colonography is less painful than colonoscopy and is comparable to flexible sigmoidoscopy.