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Objective Non-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥20% or to values <12 mm Hg). Design Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80–160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25–50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. Results 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): −19±10% versus −12±11% (p<0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. Conclusions Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.

Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart-gut-brain axis, which could be therapeutically targeted in patients with heart failure and obesity.

Purpose To evaluate the prevalence of lower urinary tract symptoms (LUTS) in men with liver cirrhosis. Methods In total, 128 men with known liver cirrhosis were prospectively evaluated using the validated German version of the International Prostate Symptom Score (IPSS) questionnaire. In parallel, all men underwent a detailed examination including medical history; physical examination; Child-Pugh liver function score (CPS) assessment; and measurement of blood levels of prostate-specific antigen (PSA), total and free testosterone, sexual hormone-binding globulin (SHBG), prolactin, luteotropic hormone (LH), and follicle-stimulating hormone (FSH). Results Mean patient age and mean IPSS was 56 ± 9 years and 8 ± 6, respectively. Mild (IPSS: 1–7), moderate (IPSS: 8–19), and severe (IPSS: 20–35) LUTS were present in 60.2 % (77/128), 31.3 % (40/128), and 7.0 % (9/128) of the patients, respectively. Storage symptoms increased with the CPS ( p  = 0.04). Voiding symptoms and overall IPSS did not differ between the CPS groups ( p  = 0.93 and p  = 0.67). No correlation was found between ascites volume and IPSS, storage symptoms, voiding symptoms, or quality of life (QoL) ( p  = 0.46, p  = 0.26, p  = 0.81, p  = 0.87). From CPS groups A to C, mean PSA levels ( p  = 0.04), total and free testosterone levels ( p  < 0.001 and p  < 0.001), and SHBG levels decreased ( p  = 0.03); however, prolactin levels increased ( p  = 0.03). LH and FSH levels did not differ between the CPS groups ( p  = 0.15 and p  = 0.35). Conclusions Men with liver cirrhosis commonly have LUTS, with a predominance of storage symptoms. Liver cirrhosis may also affect PSA-based prostate cancer risk assessment. Accurate diagnosis and therapy strategies are warranted to improve the QoL of these patients.

Aims: To investigate tumor and patient characteristics of individuals with mismatch repair (MMR)-deficient colorectal carcinomas. Methods: We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins (hMLH1, hMSH2, hMSH6, hPMS2) and those with mutations further for microsatellite instability (MSI) and BRAF V600E mutations. Results: 32/308 (10.4%) tumors showed MMR deficiency. Seventy five percent (n = 24) had loss of hMLH1 and hPMS2 expression, 3% (n = 1) of hPMS2 alone, 18.8% (n = 6) of hMSH6 and hMSH2, 3% (n = 1) of hMSH2 alone. All MMR-deficient tumors showed high MSI. These tumors occurred preferably in the right-sided colon, in women and showed specific histological features. We obtained the family history of 18/32 patients; 2 (11.1%) met Amsterdam Criteria, 5 (27.8%) Bethesda Guidelines and 6 (33.3%) revised Bethesda Guidelines. BRAF V600E mutations were found in 16 (67%) of hMLH1 and none of the hMSH2 deficient tumors. Conclusion: We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis, which may be justified as a screening method for MMR deficiency in colorectal cancer, since it identifies patients with possibly hereditary defects and unalike response to chemotherapy.

As with other widely used antibacterials, the abundant use of macrolides for management of ambulant infections has promoted emergence of resistance against them. Ketolides are structurally related to macrolides and were developed to overcome macrolide resistance, while sharing pharmacodynamic and pharmacokinetic characteristics. However, until now, there have been no comprehensive reviews of the comparative pharmacokinetics of macrolides and ketolides. This article reviews the pharmacokinetic parameters in plasma and relevant tissues of telithromycin, the only approved ketolide, and cethromycin, which is currently in phase III of clinical development. For comparison, the 14-membered macrolides clarithromycin and roxithromycin and the 15-membered azalide azithromycin were chosen as representatives of their class. While telithromycin achieves higher plasma concentrations than cethromycin, both antimicrobials display comparable elimination half-lives and clearance. Repeated dosing rarely influences the pharmacokinetic parameters of ketolides. Despite substantially higher maximum plasma concentrations and area under the plasma concentration-time curve (AUC) values of telithromycin, the higher antimicrobial activity of cethromycin leads to similar ratios between the AUC from 0 to 24 hours (AUC 24 ) and the minimum inhibitory concentration (MIC) for relevant pathogens, suggesting comparable antimicrobial activity of both antimicrobials in plasma. Although telithromycin and cethromycin show plasma-protein binding of 90%, they have excellent tissue penetration, as indicated by volumes of distribution of about 500 L and high intracellular concentrations. Besides enhancing killing of intracellular pathogens, the high concentrations of macrolides, azalides and ketolides in leukocytes have been associated with increased delivery of the antimicrobial agent to the site of infection. Although telithromycin has been shown to accumulate in alveolar macrophages and epithelial lining fluid by 380- and 15-fold, respectively (relative to plasma concentrations), its concentration in the interstitium of soft tissues is comparable to the free fraction in plasma. Thus the pharmacokinetics of ketolides may help to explain their good activity against a wide range of respiratory tract infections, although pharmacokinetic/pharmacodynamic calculations based on plasma pharmacokinetics would indicate only minor activity against pathogens except streptococci. In contrast, AUC 24 /MIC ratios achieved in soft tissue may be considered insufficient to kill extracellular pathogens causing soft tissue infections, except for Streptococcus pyogenes . Although ketolides and macrolides share relevant pharmacokinetic properties, the pharmacokinetics of both antimicrobial classes are not considered interchangeable. With a volume of distribution similar to that of azithromycin but plasma concentrations and an elimination half-life reflecting those of clarithromycin, the pharmacokinetics of ketolides may be considered ‘intermediate’ between those of macrolides and azalides. Thus the pharmacokinetics of ketolides can be considered similar but not identical to those of macrolides.

Objective: The present study aimed at testing the effect of S- and R-ibuprofen on thromboxane B 2 (TXB 2 ), collagen-epinephrine closure time (CEPI-CT) and collagen-adenosine 5′-diphosphate closure time (CADP-CT) in lipopolysaccharide (LPS)-stimulated and non-stimulated human whole blood. Materials and Methods: Whole blood was incubated with S- or R-ibuprofen with and without prior stimulation with LPS. To verify ibuprofen’s potential effects on TXB 2 , varying ratios of concentrations of S- and R-ibuprofen ranging from 0 to 100% were used. TXB 2 levels were measured by ELISA. The effects of S- and R-ibuprofen enantiomers on platelet aggregability were tested utilizing a PFA-100 apparatus. Results: In non-stimulated and LPS-stimulated whole blood, S-ibuprofen markedly decreased TXB 2 levels at concentrations ranging from 10 to 200 µg/ml. R-ibuprofen showed its inhibiting effect at concentrations >100 µg/ml. In inflammatory and non-inflammatory conditions, CEPI-CT was prolonged at concentrations of 12.5 and 75 µg/ml for S-ibuprofen and at a concentration of 150 µg/ml of combined R- and S-ibuprofen. S-ibuprofen was significantly more effective than R-ibuprofen (p < 0.05). The combined use of S- and R-ibuprofen did not additively or synergistically prolong CEPI-CTs. CADP-CTs remained unaffected by both enantiomers. Conclusions: S-ibuprofen was more effective than the R-ibuprofen enantiomer in inhibiting TXB 2 plasma levels and aggregability of thrombocytes in non-inflammatory and inflammatory conditions.