Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers

Aims

The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination.

Methods

We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14.

Results

Clarithromycin significantly increased bosentan area under the plasma concentration–time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance.

Conclusions

Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary.     

Effect and clinical prediction of worsening renal function in acute decompensated heart failure

We aimed to establish the prevalence and effect of worsening renal function (WRF) on survival among patients with acute decompensated heart failure. Furthermore, we sought to establish a risk score for the prediction of WRF and externally validate the previously established Forman risk score. A total of 657 consecutive patients with acute decompensated heart failure presenting to the emergency department and undergoing serial creatinine measurements were enrolled. The potential of the clinical parameters at admission to predict WRF was assessed as the primary end point. The secondary end point was all-cause mortality at 360 days. Of the 657 patients, 136 (21%) developed WRF, and 220 patients had died during the first year. WRF was more common in the nonsurvivors (30% vs 41%, p = 0.03). Multivariate regression analysis found WRF to independently predict mortality (hazard ratio 1.92, p <0.01). In a single parameter model, previously diagnosed chronic kidney disease was the only independent predictor of WRF and achieved an area under the receiver operating characteristic curve of 0.60. After the inclusion of the blood gas analysis parameters into the model history of chronic kidney disease (hazard ratio 2.13, p = 0.03), outpatient diuretics (hazard ratio 5.75, p <0.01), and bicarbonate (hazard ratio 0.91, p <0.01) were all predictive of WRF. A risk score was developed using these predictors. On receiver operating characteristic curve analysis, the Forman and Basel prediction rules achieved an area under the curve of 0.65 and 0.71, respectively. In conclusion, WRF was common in patients with acute decompensated heart failure and was linked to significantly worse outcomes. However, the clinical parameters failed to adequately predict its occurrence, making a tailored therapy approach impossible.     

Annexin A2 as a differential diagnostic marker of hepatocellular tumors

While improved imaging techniques have made it possible to detect focal liver lesions smaller than 1 cm in diameter, differentiating benign lesions from hepatocellular carcinoma (HCC) still remains a challenge. To address this problem and obtain a definite diagnosis, needle core biopsies are often performed, leading to an increased need for supportive ancillary techniques in the histopathological assessment of highly differentiated hepatocellular tumors. Here we evaluate the diagnostic value of immunohistologically detected Annexin A2 (ANXA2) expression in highly differentiated liver tumors. ANXA2 is a calcium-dependent phospholipid-binding protein that has been linked to malignant transformation and HCC development. Our data show that adding sinusoidal ANXA2 expression to the already established marker panel (GPC3, GS, and HSP70) increases the accuracy for the detection of well-differentiated HCC (74% sensitivity, 100% specificity). In addition, in our series, the combinations ANXA2-GPC3 and ANXA2-GS performed better compared to the other established marker combinations. In conclusion, we suggest that adding ANXA2 to the established diagnostic marker panel increases the reliability and objectivity of HCC diagnosis in liver biopsies.     

Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure

Introduction

The accurate prediction of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel sensitive and specific marker of AKI.

Methods

A total of 207 consecutive patients presenting to the emergency department with AHF were enrolled. Plasma NGAL was measured in a blinded fashion at presentation and serially thereafter. The potential of plasma NGAL levels to predict AKI was assessed as the primary endpoint. We defined AKI according to the AKI Network classification.

Results

Overall 60 patients (29%) experienced AKI. These patients were more likely to suffer from pre-existing chronic cardiac or kidney disease. At presentation, creatinine (median 140 (interquartile range (IQR), 91 to 203) umol/L versus 97 (76 to 132) umol/L, P < 0.01) and NGAL (114.5 (IQR, 67.1 to 201.5) ng/ml versus 74.5 (60 to 113.9) ng/ml, P < 0.01) levels were significantly higher in AKI compared to non-AKI patients. The prognostic accuracy for measurements obtained at presentation, as quantified by the area under the receiver operating characteristic curve was mediocre and comparable for the two markers (creatinine 0.69; 95%CI 0.59 to 0.79 versus NGAL 0.67; 95%CI 0.57 to 0.77). Serial measurements of NGAL did not further increase the prognostic accuracy for AKI. Creatinine, but not NGAL, remained an independent predictor of AKI (hazard ratio (HR) 1.12; 95%CI 1.00 to 1.25; P = 0.04) in multivariable regression analysis.

Conclusions

Plasma NGAL levels do not adequately predict AKI in patients with AHF.     

The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer

Organic anion transporting polypeptides (OATP, SLCO genes) mediate the uptake of endobiotics and drugs. Thus, their expression levels and pattern could be of relevance for cancer therapy. This prompted us to investigate the expression of poorly characterized OATPs, namely OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic cancer of different origin. First, mRNA levels of all eleven OATPs were determined in paired (cancerous and adjacent non-cancerous) specimens from 43 patients with primary liver cancer (hepatocellular carcinoma, HCC; cholangiocellular carcinoma, CCC) and liver metastases from colon tumors (MLT). Real-time RT-PCR analysis revealed that all OATPs, except OATP1C1 and OATP6A1, are extensively expressed in nearly all samples. In contrast to downregulated OATP1B1, OATP1B3, OATP1A2 and OATP2B1 in cancerous vs. non-cancerous samples, an increase in OATP2A1, OATP3A1, OATP4A1 and OATP5A1 mRNA levels was seen in tumors (up to 40-fold for OATP5A1 in the MLT group). Therefore, OATP2A1, OATP3A1, OATP4A1 and OATP5A1 were further investigated by immunofluorescence microscopy on paraffin-embedded cancerous and non-cancerous sections (seven per group). OATP-derived immunoreactivity was observed in plasma membranes and cytosol of hepatic tumor cells, and additionally, in various cytokeratin 19 positive bile ducts. An increased percentage of immunoreactive cells and a higher staining intensity in cancerous vs. non-cancerous paraffin sections paralleled higher mRNA levels of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in cancerous tissues of HCC, CCC and MLT patients. The extensive expression of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic tumors of different origin suggests that these transporters might be further exploited for the discovery of novel anticancer agents.     

Serum lipids and risk factors for attempted suicide in patients with alcohol dependence

BACKGROUND: Alcohol dependence is a major risk factor for suicidal behavior. Although a number of risk factors have been suggested there is still no well-defined risk profile for attempted suicide in alcoholic patients. Alterations of serum lipids have been associated with completed as well as attempted suicide and with suicidal ideation. This study investigated potential demographic and clinical risk factors for attempted suicide in alcohol-dependent patients taking serum lipids additionally into consideration. METHODS: One-hundred ten alcohol-dependent patients who were admitted to a psychiatric university hospital department for inpatient treatment were grouped according to whether or not they had a lifetime history of attempted suicide. Attempters versus nonattempters as well as attempters who used a violent versus a nonviolent suicide method were compared. RESULTS: Patients who had attempted suicide at least once in their life differed significantly from those who had no history of suicide attempts. Univariate analyses showed that they were younger (41.7 years vs 46.8 years; p = 0.003), were more often smokers (97% vs 77%; p = 0.011), had more frequently coabused benzodiazepines (54% vs 17%; p = 0.002), and scored currently higher on the Montgomery and Asberg Depression Rating Scale (MADRS) global scale (26.3 vs 20.2; p = 0.005) as well as the "suicidal thoughts" item (1.8 vs 0.6; p = 0.001). Additionally, they had higher serum triglyceride levels (178.9 vs 127.5; p = 0.039). A logistic regression analysis left coabuse of benzodiazepines [odds ratio (OR), 5.26; p = 0.001], younger age (OR per year increase of age, 0.91; p = 0.006), and current MADRS item 10 ("suicidal thoughts") score (OR per point increase in MADRS item 10 score, 1.43; p = 0.019) as significant factors. Suicide attempters who had used a violent method were significantly more often male (82% vs 44%; p = 0.035), were younger (38.2% vs 45.1 years; p = 0.008), and had less frequently coabused tranquilizers (35% vs 78%; p = 0.018) than nonviolent attempters. CONCLUSIONS: These findings contribute to the development of a more specific profile of alcohol-dependent individuals at risk for suicidal behavior. Further research is required to determine the role of serum triglycerides for suicidal behavior in patients with alcohol dependence.