Aims
To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1) inhibitor, after single‐ and repeated‐dose ...administration.
Methods
The single‐dose study included open‐label administration of 200 mg BI 135585 in healthy volunteers, while in the multiple‐dose study, we carried out randomized, double‐blind administration of 5–200 mg BI 135585 or placebo once daily over 14 days in patients with type 2 diabetes (T2DM). Assessments included 11β‐HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus‐pituitary‐adrenal (HPA) axis hormone levels.
Results
No major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5–200 mg BI 135585, exposure (area under the curve) increased dose‐proportionally and half‐life was 55–65 h. The urinary THF/THE ratio decreased, indicating liver 11β‐HSD1 inhibition. Median 11β‐HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14 days of continuous treatment.
Conclusions
BI 135585 was safe and well tolerated over 14 days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11β‐HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.
Aims To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11 beta -hydroxysteroid dehydrogenase-1 (11 beta -HSD1) inhibitor, after single- and ...repeated-dose administration. Methods The single-dose study included open-label administration of 200mg BI 135585 in healthy volunteers, while in the multiple-dose study, we carried out randomized, double-blind administration of 5-200mg BI 135585 or placebo once daily over 14days in patients with type 2 diabetes (T2DM). Assessments included 11 beta -HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus-pituitary-adrenal (HPA) axis hormone levels. Results No major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5-200mg BI 135585, exposure (area under the curve) increased dose-proportionally and half-life was 55-65h. The urinary THF/THE ratio decreased, indicating liver 11 beta -HSD1 inhibition. Median 11 beta -HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14days of continuous treatment. Conclusions BI 135585 was safe and well tolerated over 14days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11 beta -HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.
To identify the role of hyperleptinaemia in mediating the effects of early postnatal overfeeding in a rat strain known to be prone to manipulations of the early environment which result in ...predispositions for obesity and associated metabolic and cardiovascular disturbance in later life.
Wistar rats were reared in normal litters (NL, 10--12 pups) or small litters (SL, four pups) from postnatal day 3 and killed for determination of body composition and plasma leptin and insulin concentrations on day 7 or day 21 after having been treated with recombinant leptin (2 x 50 (pmol/g)/day) or saline from day 1.
Rearing in SL doubled the body fat content and plasma leptin levels in comparison to NL pups by 21 days of age. Under leptin-treatment throughout suckling age, NL pups remained leptin responsive, ie the difference in body fat content was progressively reduced relative to the controls. Until 7 days of age, despite the body fat content of untreated SL pups being 2-fold higher and their plasma leptin level 7-fold higher than that of NL pups, leptin treatment caused the same percentage decreases in body fat in SL than in NL pups. But in contrast to NL pups, the SL pups became leptin resistant thereafter. Plasma insulin levels in 7-day-old leptin-treated SL pups were 3-fold higher than in untreated littermates and 5-fold higher than in the NL groups.
Prophylactic leptin treatment does not prevent hyperinsulinaemia and excessive fat deposition in SL pups. On the other hand, selective hyperleptinaemia during suckling age does not trigger leptin resistance and obesity in NL pups. Rather than hyperleptinaemia per se, other factors associated with early postnatal overnutrition, for example, the concurrent hyperinsulinaemia, seem to play a pivotal role for the development of leptin-resistance and life-long obesity risk in SL rats.
Aims To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor, after single- and ...repeated-dose administration. Methods The single-dose study included open-label administration of 200mg BI 135585 in healthy volunteers, while in the multiple-dose study, we carried out randomized, double-blind administration of 5-200mg BI 135585 or placebo once daily over 14days in patients with type 2 diabetes (T2DM). Assessments included 11beta-HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus-pituitary-adrenal (HPA) axis hormone levels. Results No major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5-200mg BI 135585, exposure (area under the curve) increased dose-proportionally and half-life was 55-65h. The urinary THF/THE ratio decreased, indicating liver 11beta-HSD1 inhibition. Median 11beta-HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14days of continuous treatment. Conclusions BI 135585 was safe and well tolerated over 14days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11beta-HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.
Circulating tumour cells (CTC) in the blood have been accepted as a prognostic marker in patients with metastatic colorectal cancer (CRC). Only limited data exist on the prognostic impact of CTC in ...patients with early stage CRC using standardised detection assays. The aim of this study was to elucidate the role of CTC in patients with non-metastatic CRC.
A total of 287 patients with potentially curable CRC were enrolled, including 239 patients with UICC stage I-III. CTC were measured in the blood using the CellSearch system preoperatively and on postoperative days 3 and 7. The complete patient group (UICC I-IV) and the non-metastatic cohort (UICC I-III) were analysed independently. Patients were followed for 28 (0-53) months. Prognostic factors for overall and progression-free survival were analysed using univariate and multivariate analyses.
CTC were detected more frequently in patients with metastatic disease. No clinicopathological variables were associated with CTC detection in non-metastatic patients. CTC detection (⩾1 CTC per 7.5 ml blood) in the blood was significantly associated with worse overall survival (49.8 vs 38.4 months; P<0.001) in the non-metastatic group (UICC I-III), as well as in the complete cohort (48.4 vs 33.6 months; P<0.001). On multivariate analysis CTC were the strongest prognostic factor in non-metastatic patients (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.3-13.6) as well as in the entire study group (HR 5.6; 95% CI 2.6-12.0).
Preoperative CTC detection is a strong and independent prognostic marker in non-metastatic CRC.
Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed ...to evaluate the prognostic role of PTS in patients with IBD-CRC.
All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence–free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS.
A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98).
In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.
•This the first study to investigate the prognostic value of primary tumor sidedness in patients with IBD-CRC.•The results diverge from the findings of most studies that assessed primary tumor sidedness in sporadic CRC.•The prognostic role of primary tumor sidedness in IBD-CRC is at the very least less pronounced than in sporadic CRC.
Zusammenfassung
Das jahrzehntealte Dogma, dass die akute Appendizitis ausschließlich und unverzüglich operativ behandelt werden muss, ist inzwischen in mehreren randomisierten Studien widerlegt ...worden. So konnte gezeigt werden, dass ein konservativer, antibiotischer Therapieversuch bei nichtperforierter Appendizitis sicher ist und keine erhöhte Morbidität und Mortalität nach sich zieht. Gleichzeitig ist die Effektivität der konservativen Therapie der Operation jedoch deutlich unterlegen: Im ersten Jahr nach konservativer Therapie der Appendizitis werden ca. 30 % der Patienten doch operiert, im weiteren Verlauf bis zu 40 % – langfristig sind noch höhere Raten zu erwarten. Vorteile der konservativen Therapie sind die schnellere Rekonvaleszenz und der fehlende Wundschmerz. Alle verfügbaren Studien vergleichen die konservative Therapie jedoch nahezu ausschließlich mit der konventionellen Appendektomie, zur laparoskopischen Appendektomie sind aktuell keine Daten verfügbar. Vor diesem Hintergrund und aufgrund der Tatsache, dass die laparoskopische Appendektomie als gut etabliertes und sicheres Verfahren in Deutschland flächendeckend verfügbar ist, kann keine generelle Empfehlung zum konservativen Therapieversuch der unkomplizierten Appendizitis ausgesprochen werden. Als zwar weniger effektives, jedoch sicheres Therapieverfahren kann ein solcher Versuch jedoch ausgewählten Patienten angeboten werden.
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