A new and very small European species of terrestrial enchytraeids is described, Enchytronia pygmaea sp. nov. (Enchytraeidae, Oligochaeta). It differs from all enchytraeids known so far in the chaetal ...pattern: lateral bundles have 2 chaetae from segment II to V, 0 from segment VI to XII–XV, and only 1 chaeta in lateral postclitellar bundles; ventral bundles have 2 chaetae. A further peculiarity is the presence of only 1 pair of preclitellar nephridia. The species must be considered as widespread as it is recorded here from 17 different localities distributed over seven European countries ranging from the Atlantic to the Mediterranean zone.
The use of herbs for treating various ailments dates back several centuries. Usually, herbal medicine has relied on tradition that may or may not be supported by empirical data. The belief that ...natural medicines are much safer than synthetic drugs has gained popularity in recent years and led to tremendous growth of phytopharmaceutical usage. Market driven information on natural products is widespread and has further fostered their use in daily life. In most countries there is no universal regulatory system that insures the safety and activity of phytopharmaceuticals. Evidence-based verification of the efficacy of HMPs (herbal medicinal products, botanicals) is still frequently lacking. However, in recent years, data on evaluation of the therapeutic and toxic activity of herbal medicinal products became available. The advances in analytical technology have led to discovery of many new active constituents and an ever-increasing list of putatively active constituents. Establishing the pharmacological basis for efficacy of HMPs is a constant challenge. Of particular interest is the question of bioavailability to assess to what degree and how fast compounds are absorbed after administration of HMPs. Of further interest is the elucidation of metabolic pathways (yielding potentially new active compounds), and the assessment of elimination routes and their kinetics. These data become an important issue to link data from pharmacological assays and clinical effects. Of interest are currently also interactions of herbal medicinal products with synthetically derived drug products. A better understanding of the pharmacokinetics and bioavailability of phytopharmaceuticals can also help in designing rational dosage regimens. In this review, pharmacokinetic and bioavailability studies that have been conducted for some of the more important or widely used phytopharmaceuticals are critically evaluated. Furthermore, various drug interactions are discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived active pharmaceutical ingredients.
Abstract
Background
Evaluation of disease severity (DS) in the Inflammatory Bowel Diseases (IBD) requires comprehensive consideration of disease course and health status of individual patients. It is ...not clear how well physician assessment covers disease impact as perceived by patients. We compared patient and physician global assessment of disease severity in relation to standardized assessment using a clinical disease severity score (DSI, Siegel 2018).
Methods
Patients with ulcerative colitis (UC) and Crohn’s disease (CD) were prospectively recruited from the national patient organization (DCCV) and by participating physicians. Physicians (IBD experts) were approached via the DCCV advisory board and other professional contacts. Both groups graded disease severity for a random selection of written standard short cases (1 page, maximum 5 CD, 3 UC) on a simple visual analogue scale (VAS) (online survey). For analysis, VAS were transferred to a 0 (minimal severity) to 100 (maximal severity) scale, in analogy to the range of the DSI. We present graphs of mean scores by rater group with 95% CI. Differences between mean patient and physician assessments were calculated per case. In addition, we examined the difference from the DSI.
Results
We included 824 ratings from 319 patients (168 CD, 151 UC), and 143 ratings from 34 physicians (20 ISS, 14 external)(recruitment ongoing). UC cases received on average 124 patient ratings (range 122–125), and 21 physician ratings (range 17–26). Means from both rater groups discriminated well between disease severity as scored by the DSI. Mean physician ratings were consistently and substantially lower than patient ratings for all three UC cases. Differences between means ranged from 8.5 (95% CI 0.5 to 16.5) for mild disease to 10.1 (95% CI 1.3 to 18.9) for moderate disease (p < 0.001) (Figure 1). In contrast, deviations from the DSI did not show a clear pattern.
CD cases were rated by a mean of 91 patients (77–125) and 16 physicians (13–21). Mean physician and mean patient ratings were very close, in particular in those with medium DSI (Figure 2).
Conclusion
Physicians agreed, on average, very well with patient grading on disease severity grading of exemplary cases of CD. Lower scores were given for UC cases, and mild CD, but the overall trend remained intact. In contrast, correlation with DSI scores was poor and will need further analysis.
Abstract
Background
The VEDOibd I study is an investigator initiated, ongoing, non-interventional trial on biologics in IBD-patients (Crohn′s disease (CD) and ulcerative colitis (UC)) in Germany with ...consecutive recruitment and prospective documentation of effectiveness in induction and maintenance therapy of biologics, especially vedolizumab (VEDO). The aim of this analysis was to compare steroid-free remission rates in CD- and UC-patients after a 14-week-long induction phase of VEDO (bio-naïve and bio-experienced) vs. other biologics (infliximab (IFX), adalimumab (ADA), Golimumab (GLM), Ustekinumab (UST)) in bio-naïve patients.
Methods
From 10/2017 to 07/2019 750 IBD-patients (CD: 414; UC: 336) from 45 gastroenterology practices and hospitals with IBD-experience from all over Germany were recruited in the VEDOibd I study of whom 232 CD- and 184 UC-patients completed induction phase (week 14) in this interim analysis. At week 14 we compared clinical response (CD: reduction of Harvey Bradshaw Index HBI from baseline to week 14 by >3 points or HBI < 4 in week 14; UC: reduction of partial Mayo score pMayo from baseline to week 14 by >3 points or a reduction of at least 30% compared with baseline) and steroid-free remission rates (CD: HBI < 4 and no systemic use of steroids or budesonide at week 14; UC: pMayo ≤1 plus a bleeding subscore = 0 and no systemic use of steroids or budesonide at week 14) in patients with VEDO vs. other biologics.
Results
Ninety-two CD- and 111 UC-patients started a first-time VEDO therapy; of these 40 CD- (43%) and 57 UC-patients (51%) were bio-naïve. Furthermore 140 CD-patients (IFX 48.6%; ADA 47.1%; UST 4.3%) and 73 UC-patients (IFX 58.9%; ADA 24.7%; GLM 16.4%) started treatment with another biologic than VEDO and all of these were bio-naïve. Baseline characteristics were well balanced between both naïve groups (VEDO/other biologics; p > 0.05): males %: CD 38/41, UC 37/51; age years: CD 46 ± 15/42 ± 15, UC 43 ± 19/39 ± 15; disease duration years: CD 15 ± 11/9 ± 11, UC 9 ± 9/6 ± 7; extraintestinal manifestations %: CD 23/20, UC 7/15. Response/steroid-free remission rates after induction phase in biologic-naïve patients with VEDO and other biologics were 74.4%/57.5% vs. 78.4%/64.3% in CD (p>0.05) and 60.0%/21.1% vs. 56.0%/13.7% in UC (p>0.05), respectively.
Conclusion
In this real-world setting we could show that in CD the effectiveness of VEDO vs. other biologics was very similar in bio-naïve patients and that in UC patients, VEDO treatment tended to be numerically superior to other biologics with respect to response and steroid-free remission rates. Further follow-up data of this interim-analysis including the whole planned study population of 1.200 IBD-patients will be shown in the near future.
To determine how long pathological findings persist after burial and which factors play a role in decomposition of a corpse, we evaluated all bodies exhumed under the auspices of the Institute of ...Legal Medicine at the Hannover Medical School between 1978 and 1997. A total of 87 exhumations (54 men, 33 women) were performed in this period. The time bodies remained buried varied between 5 days and 16.8 years (mean 1.5 years, median 2.3 months). Fifty-six percent of the bodies were exhumed after at most 3 months, 10% remained buried for greater than 3 years. Pathomorphological changes of the soft tissues and the internal organs remained evident after several months, in some cases after several years of burial. Overall, it was possible to evaluate internal organs after 5 years of burial. Bodies became mostly decomposed after approximately 8 years at the earliest, although it was still possible to evaluate some soft tissue remnants after 16.8 years. In stepwise logistic regression, both the length of time the body was buried (
p
<
0.00005) and the time of year (
p
<
0.0019) clearly affected the rate of physical change. The variables of sex (
p
=
0.33), age (
p
=
0.61) and changes in the integrity of the body before burial (trauma, autopsy before burial;
p
=
0.15) did not influence the physical state of the body after exhumation. Our data show that much information may be gained from an exhumation even after significant time has passed since burial.
Co-administration of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) with pioglitazone may improve glycemic control in patients with Type 2 diabetes due to their complementary mechanisms ...of action. This study aimed to investigate any potential pharmacokinetic interaction between linagliptin and pioglitazone, a CYP 2C8 substrate.
20 (10 male and 10 female) healthy subjects, between 22 and 65 years of age with a BMI range of > = 18.5 and < =29.9 kg/m2, took part in this single center open-label, randomized,two-way cross-over study. The subjects were administered linagliptin 10 mg/day and/orpioglitazone 45 mg/day until steady state was reached.
Co-administration of pioglitazone did not significantly affect linagliptin Cmax,ss (geometric mean ratio(GMR) 107.3; 90% confidence interval (CI);92.3 – 124.8) or AUC tau,ss (GMR 113.4; 90%CI 103.0 – 124.9). Co-administration of linagliptin did not significantly affect pioglitazoneAU tau,ss (GMR 94.4; 90% CI 87.1 –102.2), but reduced Cmax,ss by 14% (GMR85.6; 90% CI 78.1 – 93.8). As expected, linagliptin and pioglitazone were well tolerated,whether administered alone or concomitantly.There were no reported serious adverse events. The investigator defined 5 adverse events as drug-related with linagliptin,and 4 with pioglitazone.
Linagliptinand pioglitazone have no clinically relevant pharmacokinetic interaction and may be co-administered without dose adjustment.These data further confirm that linagliptin is not an inhibitor of CYP2C8 in vivo.As the pharmacokinetic profiles of linagliptin and pioglitazone are similar in Type 2 diabetes patients and healthy subjects, it is reasonable to assume that they may be administered together to Type 2 diabetes patients without dose adjustment.
Objectif La Linagliptine (LINA) puissant I-DPP4 est principalement éliminée par voie non rénale. Cas unique parmi les I-DPP4 actuellement disponibles. L’objectif de cette étude était d’évaluer ...l’influence de l’Insuffisance Rénale (IR) à différents stades, sur la pharmacocinétique (PK) de la LINA Matériels et méthodes Sujets avec différents degrés d’IR : légère (clairance créatinine (ClCr) 51-80 ml/min ; n = 6), modérée (ClCr 31-50 ml/min ; n = 6), sévère (ClCr30 ml/min ; n = 6), terminale (n = 6), et chez Volontaires Sains (VS) (ClCr > 80 ml/min ; n = 6). Egalement, patients DT2 avec IR sévère (n = 10), patients DT2 avec fonction rénale normale (n = 11). Posologie LINA 5 mg 1/j, en dose unique (groupes : IR sévère, terminale) ou pendant 7 jours (groupes : VS, IR légère, modérée) ou pendant 10 jours (groupes : DT2). L’analyse principale comparait l’exposition à la LINA : • à l’Etat d’Equilibre (EE) (IR légère ou modérée vs VS et patients DT2 avec IR sévère vs DT2 normorénaux) • ou a Résultats Exposition totale à LINA à l’EE (AUCt, EE) et concentrations maximales à EE (Cmax, EE) étaient comparables entre sujets avec IR légère et groupe témoin, et augmentation modérée si IR modérée et sévère, respectivement de 71 % et 42 %. Après 1 dose, tous les patients IR ont présenté une augmentation de 30 à 60 % de l’exposition totale (AUC0-24) vs groupes témoins. Pas d’augmentation de la demi-vie terminale selon stade IR. Demi-vies d’accumulation comprises entre 14-15 h dans groupes témoins vs 18 h pour IR sévère. Faible corrélation observée entre ClCr et exposition à EE. L’excrétion rénale du médicament inchangé à l’EE était < 7 % de la dose dans tous les groupes. L’IR n’a pas altérée la liaison aux protéines plasmatiques ni la corrélation entre PK et inhibition DPP-4. Conclusion L’altération de la fonction rénale n’a qu’un effet mineur sur l’élimination de la Linagliptine. Les variations d’exposition observées (∼40% dans IR sévère) ne justifient pas d’adaptation posologique de la Linagliptine chez le DT2 insuffisant rénal.
We analysed samples of Sparganophilus taken at the corners of its distribution area in Europe (UK, Germany and Italy). No mitochondrial genetic divergence within and amongst them was found, neither ...in COI nor in 16S. Further, the COI haplotype was also identical to two sequences from Ontario, Canada in the Barcoding of Life Data System (BOLD) database. Our European COI and 16S sequences showed only minimal differentiation (only 1 or 2 substitutions) from specimens newly collected in Illinois and Washington states (USA), as well as from a COI haplotype from Tennessee (USA) in BOLD. An additional COI haplotype from Illinois (found in BOLD) is 2.1% different from the other haplotypes but clearly belongs to the same lineage of Sparganophilus . This geographically broad but genetically compact group fits the morphological diagnosis of S. tamesis Benham, 1892 as revised by Jamieson (1971) and is seen as evidence that all European populations 1) belong to the same species, 2) derive from a recent introduction, 3) are conspecific with the most widespread species of Sparganophilus in North America, and that 4) S. tamesis is a senior synonym of S. eiseni Smith, 1895. The single European haplotype does not refute the possibility of its spread from a single introduced source population.
To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate.
This open-label, 2-period, ...fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose.
The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0-∞ and Cmax for (linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had o clinically relevant effect on the AUC0-168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0-168 for (linagliptin + warfarin)/ warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 15.1 (94.3 -140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated.
Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin.
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