Pharmacokinetic study of praziquantel enantiomers and its main metabolite R-trans-4-OH-PZQ in plasma, blood and dried blood spots in Opisthorchis viverrini-infected patients

Praziquantel (PZQ) is the treatment of choice for infections with the liver fluke Opisthorchis viverrini, a major health problem in Southeast Asia. However, pharmacokinetic (PK) studies investigating the disposition of PZQ enantiomers (R- and S-PZQ) and its main metabolite, R-trans-4-OH-PZQ, in diseased patients are lacking. The implementation of a dried blood spot (DBS) sampling technique would ease the performance of PK studies in remote areas without clinical facilities. The aim of the present study is to provide data on the disposition of PZQ enantiomers and R-trans-4-OH-PZQ in opisthorchiasis patients and to validate the use of DBS compared to plasma and blood sampling.; PZQ was administered to nine O. viverrini-infected patients at 3 oral doses of 25 mg/kg in 4 h intervals. Plasma, blood and DBS were simultaneously collected at selected time points from 0 to 24 h post-treatment. PK parameters were determined using non-compartmental analysis. Drug concentrations and areas under the curve (AUC0-24h) measured in the 3 matrices were compared using Bland-Altman analysis. We observed plasma AUC0-24hs of 1.1, 9.0 and 188.7 μg/ml*h and half-lives of 1.1, 3.3 and 6.4 h for R-PZQ, S-PZQ and R-trans-4-OH, respectively. Maximal plasma concentrations (Cmax) of 0.2, 0.9 and 13.9 μg/ml for R-PZQ, S-PQZ and R-trans-4-OH peaked at 7 h for PZQ enantiomers and at 8.7 h for the metabolite. Individual drug concentration measurements and patient AUC0-24hs displayed ratios of blood or DBS versus plasma between 79-94% for R- and S-PZQ, and between 108-122% for R-trans-4-OH.; Pharmacodynamic (PD) in vitro studies on PZQ enantiomers and R-trans-4-OH-PZQ are necessary to be able to correlate PK parameters with efficacy. DBS appears to be a valid alternative to conventional venous sampling for PK studies in PZQ-treated patients

Membranoproliferative glomerulonephritis and C3 glomerulopathy in children: change in treatment modality? A report of a case series

Background Membranoproliferative glomerulonephritis (MPGN) with immune complexes and C3 glomerulopathy (C3G) in children are rare and have a variable outcome, with some patients progressing to end-stage renal disease (ESRD). Mutations in genes encoding regulatory proteins of the alternative complement pathway and of complement C3 (C3) have been identified as concausative factors. Methods Three children with MPGN type I, four with C3G, i.e. three with C3 glomerulonephritis (C3GN) and one with dense deposit disease (DDD), were followed. Clinical, autoimmune data, histological characteristics, estimated glomerular filtration rate (eGFR), proteinuria, serum C3, genetic and biochemical analysis were assessed. Results The median age at onset was 7.3 years and the median eGFR was 72 mL/min/1.73 m. Six children had marked proteinuria. All were treated with renin-angiotensin-aldosterone system (RAAS) blockers. Three were given one or more immunosuppressive drugs and two eculizumab. At the last median follow-up of 9 years after diagnosis, three children had normal eGFR and no or mild proteinuria on RAAS blockers only. Among four patients without remission of proteinuria, genetic analysis revealed mutations in complement regulator proteins of the alternative pathway. None of the three patients with immunosuppressive treatment achieved partial or complete remission of proteinuria and two progressed to ESRD and renal transplantation. Two patients treated with eculizumab revealed relevant decreases in proteinuria. Conclusions In children with MPGN type I and C3G, the outcomes of renal function and response to treatment modality show great variability independent from histological diagnosis at disease onset. In case of severe clinical presentation at disease onset, early genetic and biochemical analysis of the alternative pathway dysregulation is recommended. Treatment with eculizumab appears to be an option to slow disease progression in single cases

Impact of osteosynthesis in fracture care : a cost comparison study

Aim: To estimate the health economic impact of osteosynthesis (OS) in fracture care over six decades in 17 high-income countries. Patients & methods: Applying a decision tree model, we assumed a hypothetical absence of OS and compared OS (intervention) with conservative treatment (CONS; comparator). We included patients with femur, tibia and radius fractures (age <65 years) and for proximal femur fractures also elderly patients (≥70 years). Results: We estimated savings in direct and indirect costs of 855 billion Swiss francs in the working age population in addition to 4.6 million years of life gained. In the elderly population, 69 billion Swiss francs were saved in direct costs of proximal femur fractures in addition to 73 million years of life gained. Conclusion: OS contributed to maximize health gains of society

STATTLAND PLANER

AUFTRAGGEBER Der Verein StattLand bietet in Bern thematische, auf Bern bezogene Stadtführungen an. Diese Masterarbeit ist im Auftrag von StattLand an der HSR Hochschule für Technik in Rapperswil, der Universität Basel und der Fachhochschule Nordwestschweiz im Rahmen des Lehrgangs Master of Advanced Studies in Human Computer Interaction Design (MAS HCID) entstanden. AUSGANGSLAGE UND ZIELSETZUNG StattLand plant seine Ressourcen und Rundgänge heute auf umständliche Weise. Die Planung ist unübersichtlich und fehleranfällig. Eine einfach zu bedienende und UCD-optimierte Rundgangplanung Lösung soll den Verantwortlichen eine Übersicht über die Planung aller Rundgänge geben, indem die Applikation Ressourcen und Kalenderdaten mit den Rundgängen visuell verknüpft. VORGEHEN UND ANALYSE Mayhews „Usability Engineering Lifecycle“ diente als Rahmen für das Vorgehen. Für das Erarbeiten der Projektziele wurde er angepasst und mit weiteren UCDMethoden ergänzt. RESULTATE oo Der Planungsablauf ist effizienter und übersichtlicher oo Die eruierten Fehlerquellen können in der neuen Lösung eliminiert werden oo Die Anwendung lässt sich nach kurzer Einführungszeit von ungeübtem Personal bedienen oo Die Benutzergruppen sind definiert und homogenisiert mit anderen Rundgangsanbietern der Schweiz oo Die Anwendung lässt sich aufgrund der zusätzlich erfolgten externen Analysen und Tests in gleicher Weise von anderen Institutionen verwenden oo Konzeptionelles Modell und Screen Design Standards sind definiert oo Die Anbindung an Umsysteme kann modular und dynamisch erfolgen FAZIT Das erarbeitete Konzept entspricht den Vorstellungen des Auftraggebers, aber auch den involvierten Institutionen von Basel und Thun. Aufgrund der vorliegenden Arbeit hat der Auftraggeber sein Fundraising forciert und plant, die Entwicklungsphase des neuen SL-Planers zu starten. Es sind bereits Gespräche zur Zusammenarbeit unter den Rundgangsanbietern im Gange. Die Analyse einer innovativen Kalendersystematik hat viele Steine ins Rollen gebracht und motiviert zu weiterem Research

Population pharmacokinetic modeling of tribendimidine metabolites in opisthorchis viverrini-Infected adults

There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.)

Single ascending dose pharmacokinetic study of tribendimidine in Opisthorchis viverrini-infected patients

Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (Tmax) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) of dADT to the AUC0- 24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (Cmax) and AUC0-24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.)