Efficacy and safety of moxidectin, synriam, synriam-praziquantel versus praziquantel against schistosoma haematobium and S. mansoni infections: a randomized, exploratory phase 2 trial

Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies.; We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d'Ivoire. Our primary endpoints were cure rates (CRs) and egg reduction rates (ERRs) based on geometric mean and safety. Each subject was asked to provide two stool samples (S. mansoni trial) for Kato-Katz analysis or three urine samples (S. haematobium trial) for urine filtration and one finger prick for malaria screening at baseline and follow-up. Participants were randomly assigned to either moxidectin, Synriam, Synriam plus praziquantel or praziquantel.; 128 adolescents (age: 12-17 years) were included in each study. Against S. haematobium moxidectin and Synriam revealed low efficacy. On the other hand, Synriam plus praziquantel and praziquantel yielded CRs of 60.0% and 38.5% and ERRs of 96.0% and 93.5%, respectively. CRs observed in the treatment of S. mansoni were 13.0%, 6.7%, 27.0%, and 27.6% for moxidectin, Synriam, Synriam plus praziquantel and praziquantel, respectively. ERRs ranged from 64.9% (Synriam) to 87.5% (praziquantel).; Synriam and moxidectin show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to corroborate our findings that moxidectin and Synriam show moderate ERRs against S. mansoni

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

Modulation of transendothelial permeability and expression of ATP-binding cassette transporters in cultured brain capillary endothelial cells by astrocytic factors and cell-culture conditions

Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vitro cell culture model of the blood-brain barrier. The present study describes the influence of cell-culture conditions on tight junctions, filamentous-actin cytoskeleton, and expression of ATP-binding cassette (ABC) transporters in primary cell cultures of porcine BCEC. Astrocyte as well as C6 glioma-conditioned cell culture medium was used in combination with retinoic acid, dexamethasone, cyclic adenosine monophosphate (cAMP) analogs, or 1,25-dihydroxyvitamin D3. It was shown that C6-conditioned medium led to a reorganization of filamentous actin and to an improved staining of zonula occludens-associated protein-1 (ZO-1). Further optimization of these culture conditions was achieved with cAMP analogs and dexamethasone. Retinoic acid, as well as 1,25-dihydroxyvitamin D3, did not improve cellular tight junctions as judged by filamentous actin, ZO-1 rearrangement, and transcellular electrical resistance (TER) measurements. However, these morphological changes did not influence the paracellular permeability of the extracellular marker sucrose. Expression of ABC transporters such as P-glycoprotein, multidrug resistance-associated protein-1( MRP1), and MRP2 were compared by measuring messenger RNA (mRNA) levels in whole-brain tissue, isolated brain capillaries, and cultured cells. In freshly isolated BCEC, mRNA levels of MRP2 and P-glycoprotein dropped by two- to sevenfold, respectively, whereas MRP1 mRNA levels were slightly increased. During cell culture, mRNA levels of MRP1 and MRP2 decreased by up to fivefold, while P-glycoprotein levels remained constant. These results were unaltered by different cell-culture conditions. In conclusion, the present study suggests that paracellular permeability, as well as mRNA expression of the studied ABC transporters in primary cultures, of porcine BCEC are insensitive toward changes in cell-culture condition

In Vivo Evaluation of a Gastroretentive Drug Delivery System Based on Enteric-Coated Floating Tablets

Floating dosage forms are supposed to exhibit an enhanced gastric residence time. Their development is challenging as the prediction of the retention potential in humans based on in vitro studies and animal models is difficult. A strategy to determine the stomach residence time of a floating dosage form with an inherently low density in human without using imaging techniques was explored in a self-experiment. Floating tablets and non-floating controls were prepared containing caffeine as a model drug. The compacts had a pH-dependent entericcoating to assess their stomach residence time. Since caffeine is rapidly absorbed in the gastrointestinal tract, the prolonged gastric retention of tablets can be demonstrated by a delayed systemic exposure. Caffeine and paraxanthine were determined in capillary blood by liquid chromatography coupled to tandem mass spectrometry. An increase in caffeine and paraxanthine blood levels was observed in human volunteers after 90 to 180 min for the non-floating controls. For the floating tablets, no elevated blood concentrations were found in two out of three participants during 8 h of sample collection. The results demonstrate the technical feasibility of the proposed clinical study protocol. Follow-up clinical trials will be needed to confirm the preliminary data on stomach residence time of our floating dosage form

The extended clearance model and its use for the interpretation of hepatobiliary elimination data

Hepatic elimination is a function of the interplay between different processes such as sinusoidal uptake, intracellular metabolism, canalicular (biliary) secretion, and sinusoidal efflux. In this review, we outline how drugs can be classified according to their in vitro determined clearance mechanisms using the extended clearance model as a reference. The approach enables the determination of the rate-determining hepatic clearance step. Some successful applications will be highlighted, together with a discussion on the major consequences for the pharmacokinetics and the drug-drug interaction potential of drugs. Special emphasize is put on the role of passive permeability and active transport processes in hepatic elimination

Functionalized Calcium Carbonate as a Novel Pharmaceutical Excipient for the Preparation of Orally Dispersible Tablets

Purpose: To overcome the limitation of insufficient hardness during the production of rapidly disintegrating orally dispersible tablets (ODTs). Furthermore, we investigated the properties and usefulness of functionalized calcium carbonate (FCC) as a new pharmaceutical excipient for the production of ODTs. Methods: A highly sensitive tensiometer-based method was developed to measure kinetics of weight loss during tablet disintegration. With this method we were able to determine the residence time of tablets placed on a basket immersed into a test medium. The shapes of tensiometer plots allowed us to categorize substances into four different types of disintegration. Results: At the same volume and hardness, the tablet formulations with FCC showed a significantly higher porosity (over 60%) than all other formulations. Residence time depended mainly on the tablet composition rather than on porosity. When combined with disintegrants, FCC formulations exhibited favorable disintegration properties, comparable to those of the marketed drug risperidone oro (disintegration time ca. 10s). Conclusions: Oral dosage forms - based on the new pharmaceutical excipient FCC - can be designed to have a short disintegration time combined with good mechanical strength. Due to these properties, FCC can be used for the preparation of ODT

Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins

Background: During drug development, it is an important safety factor to identify the potential of new molecular entities to become a victim of drug-drug interactions (DDIs). In preclinical development, however, anticipation of clinical DDIs remains challenging due to the lack of in vivo human pharmacokinetic data. Methods: We applied a recently developed in vitro-in vivo extrapolation method, including hepatic metabolism and transport processes, herein referred to as the Extended Clearance Concept Classification System (ECCCS). The human hepatic clearances and the victim DDI potentials were predicted for atorvastatin, cerivastatin, fluvastatin, lovastatin acid, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid. Results: Hepatic statin clearances were well-predicted by the ECCCS with six out of eight clearances projected within a two-fold deviation to reported values. In addition, worst-case DDI predictions were projected for each statin. Based on the ECCCS class assignment (4 classes), the mechanistic interplay of metabolic and transport processes, resulting in different DDI risks, was well-reflected by our model. Furthermore, predictions of clinically observed statins DDIs in combination with relevant perpetrator drugs showed good quantitative correlations with clinical observations. Conclusions: The ECCCS represents a powerful tool to anticipate the DDI potential of victim drugs based on in vitro drug metabolism and transport data

Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics

Despite huge need in the medical domain and significant development efforts, artificial cells to date have limited composition and functionality. Whereas some artificial cells have proven successful for producing therapeutics or performing in vitro specific reactions, they have not been investigated in vivo to determine whether they preserve their architecture and functionality while avoiding toxicity. Here we overcome these limitations and achieve customizable cell mimic - molecular factories (MFs) - by supplementing giant plasma membrane vesicles derived from donor cells with nanometer-sized artificial organelles (AOs). MFs inherit the donor cell's natural cytoplasm and membrane, while the AOs house reactive components and provide cell-like architecture and functionality. We demonstrate that reactions inside AOs take place in a close-to-nature environment due to the unprecedented level of complexity in the composition of the MFs. We further demonstrate that in a zebrafish vertebrate animal model these cell mimics showed no apparent toxicity and retained their integrity and function. The unique advantages of highly varied composition, multi-compartmentalized architecture, and preserved functionality in vivo open new biological avenues ranging from the study of bio-relevant processes in robust cell-like environments to the production of specific bioactive compounds

A Scoping Review on the Therapeutic Potential of Resin From the Species Larix decidua Mill. [Pinaceae] to Treat Ulcerating Wounds.

Malignant ulcerating wounds or neoplastic lesions are a considerable burden for patients suffering from advanced cancer. These wounds have no effective treatment and are very difficult to manage. The present review summarizes evidence in support of a hypothesis put forward in anthroposophic medicine, which suggests a beneficial role of resin from the species Larix decidua Mill. [Pinaceae] for treating such wounds. A systematic search strategy was performed using the databases PubMed, EMBASE and SciFinder. The included publications described the chemical composition of this species, as well as in vitro, in vivo, and ex vivo experiments using plant extracts and isolated compounds. The results show that among the phytochemical classes, terpenoids were the major components of this species, especially in the resin. The summarized biological experiments revealed antimicrobial, antioxidant and anti-inflammatory effects, with promising potential for the extracts and isolated compounds. However, the molecular mechanisms and toxicological effects are as of yet not conclusively evaluated. From the data of our study, we can conclude that L. decidua might indeed have a promising potential for the treatment of malignant wounds, but definitive information that can prove its effectiveness is still lacking. We therefore suggest that future efforts should be dedicated to the evaluation of L. decidua resin's therapeutic use considering its antiseptic action and proposed wound healing properties

Incorporation of phosphatidylserine improves efficiency of lipid based gene delivery systems

The essential homeostatic process of dead cell clearance (efferocytosis) is used by viruses in an act of apoptotic mimicry. Among others, virions leverage phosphatidylserine (PS) as an essential "eat me" signal in viral envelopes to increase their infectivity. In a virus-inspired biomimetic approach, we demonstrate that PS can be incorporated into non-viral lipid nanoparticle (LNP) pDNA/mRNA constructs to enhance cellular transfection. The inclusion of the bioactive PS leads to an increased ability of LNPs to deliver nucleic acids in vitro to cultured HuH-7 hepatocellular carcinoma cells resulting in a 6-fold enhanced expression of a transgene. Optimal PS concentrations are in the range of 2.5 to 5% of total lipids. PS-decorated mRNA-LNPs show a 5.2-fold enhancement of in vivo transfection efficiency as compared to mRNA-LNPs devoid of PS. Effects were less pronounced for PS-decorated pDNA-LNPs (3.2-fold increase). Incorporation of small, defined amounts of PS into gene delivery vectors opens new avenues for efficient gene therapy and can be easily extended to other therapeutic systems