Felix Schneider

Predictors for long‐term seizure outcome in juvenile myoclonic epilepsy: 25–63 years of follow‐up

Purpose:  The long‐term seizure outcome of juvenile myoclonic epilepsy (JME) is still controversial; the value of factors that are potentially predictive for seizure outcome remains unclear. The aim of this study was both to investigate the long‐term seizure outcome in patients with JME after a follow‐up of at least 25 years and to identify factors that are predictive for the seizure outcome.

Linking MRI postprocessing with magnetic source imaging in MRI‐negative epilepsy

MRI‐negative (MRI–) pharmacoresistant focal epilepsy (PFE) patients are most challenging for epilepsy surgical management. This study utilizes a voxel‐based MRI postprocessing technique, implemented using a morphometric analysis program (MAP), aiming to facilitate detection of subtle focal cortical dysplasia (FCD) in MRI– patients. Furthermore, the study examines the concordance between MAP‐identified regions and localization from magnetic source imaging (MSI).

Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants

&NA; The 3D printing technique of fused deposition modeling® (FDM) has lately come into focus as a potential fabrication technique for pharmaceutical dosage forms and medical devices that allows the preparation of delivery systems with nearly any shape. This is particular promising for implants administered at application sites with a high anatomical variability where an individual shape adaption appears reasonable. In this work different polymers (Eudragit®RS, polycaprolactone (PCL), poly(L‐lactide) (PLLA) and ethyl cellulose (EC)) were evaluated with respect to their suitability for FDM of drug loaded implants and their drug release behaviour was evaluated. The fluorescent dye quinine was used as a model drug to visualize drug distribution in filaments and implants. Quinine loaded filaments were produced by solvent casting and subsequent hot melt extrusion (HME) and model implants were printed as hollow cylinders using a standard FDM printer. Parameters were found at which model implants (hollow cylinders, outer diameter 4–5 mm, height 3 mm) could be produced from all tested polymers. The drug release which was examined by incubation of the printed implants in phosphate buffered saline solution (PBS) pH 7.4 was highly dependent on the used polymer. The fastest relative drug release of approximately 76% in 51 days was observed for PCL and the lowest for Eudragit® RS and EC with less than 5% of quinine release in 78 and 100 days, respectively. For PCL further filaments were prepared with different quinine loads ranging from 2.5% to 25% and thermal analysis proved the presence of a solid dispersion of quinine in the polymer for all tested concentrations. Increasing the drug load also increased the overall percentage of drug released to the medium since nearly the same absolute amount of quinine remained trapped in PCL at the end of drug release studies. This knowledge is valuable for future developments of printed implants with a desired drug release profile that might be controlled by the choice of the polymer and the drug load. Graphical abstract Figure. No caption available. Highlights3D‐printing of quinine loaded implants was established for 4 different polymers.Drug release is highly dependent on the choice of the polymer.Solid quinine dispersions in polycaprolactone formed for all tested drug loadings.

Navigating the human gastrointestinal tract for oral drug delivery: Uncharted waters and new frontiers☆

Many concepts of oral drug delivery are based on our comprehension of human gastrointestinal physiology. Unfortunately, we tend to oversimplify the complex interplay between the various physiological factors in the human gut and, in particular, the dynamics of these transit conditions to which oral dosage forms are exposed. Recent advances in spatial and temporal resolution of medical instrumentation as well as improved access to these technologies have facilitated clinical trials to characterize the dynamic processes within the human gastrointestinal tract. These studies have shown that highly relevant parameters such as fluid volumes, dosage form movement, and pH values in the lumen of the upper GI tract are very dynamic. As a result of these new insights into the human gastrointestinal environment, some common concepts and ideas of oral drug delivery are no longer valid and have to be reviewed in order to ensure efficacy and safety of oral drug therapy.

Intragastric pH and pressure profiles after intake of the high-caloric, high-fat meal as used for food effect studies.

The intraluminal conditions of the fed stomach are critical for drug release from solid oral dosage forms and thus, often associated with the occurrence of food effects on oral bioavailability. In this study, intragastric pH and pressure profiles present after the ingestion of the high-caloric, high-fat (964 kcal) FDA standard breakfast were investigated in 19 healthy human subjects by using the telemetric SmartPill® capsule system (26 × 13 mm). Since the gastric emptying of such large non-digestible objects is typically accomplished by the migrating motor complex phase III activity, the time required for recurrence of fasted state motility determined the gastric emptying time (GET). Following the diet recommendations of the FDA guidance on food effect studies, the mean GET of the telemetric motility capsule was 15.3 ± 4.7 h. Thus, the high caloric value of the standard breakfast impeded gastric emptying before lunch in 18 out of 19 subjects. During its gastric transit, the capsule was exposed to highly dynamic conditions in terms of pH and pressure, which were mainly dependent on further meal and liquid intake, as well as the intragastric capsule deposition behavior. Maximum pH values in the stomach were measured immediately after capsule intake. The median pH value of the 5 min period after capsule ingestion ranged between pH 3.3 and 5.3. Subsequently, the pH decreased relatively constantly and reached minimum values of pH 0-1 after approximately 4 h. The maximum pressure within the stomach amounted to 293 ± 109 mbar and was clearly higher than the maximum pressure measured at the ileocaecal junction (60 ± 35 mbar). The physiological data on the intraluminal conditions within the fed stomach generated in this study will hopefully contribute to a better understanding of food effects on oral drug product performance.

Neuroimaging characteristics of MRI‐negative orbitofrontal epilepsy with focus on voxel‐based morphometric MRI postprocessing

The orbitofrontal (OF) region is one of the least explored regions of the cerebral cortex. There are few studies on patients with electrophysiologically and surgically confirmed OF epilepsy and a negative magnetic resonance imaging (MRI) study. We aimed to examine the neuroimaging characteristics of MRI‐negative OF epilepsy with the focus on a voxel‐based morphometric MRI postprocessing technique.

Resolving the physiological conditions in bioavailability and bioequivalence studies: comparison of fasted and fed state.

In the present study temperature, pH and pressure profiles of nine healthy human volunteers were investigated after ingestion of the SmartPill® under conditions simulating the fasted state treatment in bioavailability and bioequivalence studies. In a previously published study the same subjects received the SmartPill® under fed conditions as recommended by the FDA. Since large non-digestible objects are mainly emptied during phase III of the interdigestive migrating motor complex, the gastric residence time of the SmartPill® was found to be clearly shorter under fasting conditions. Intragastric pH values during the initial 5min were similar with an identical median value of pH 4.6. Interestingly, the median lowest observed intragastric pH value in fasted state was about one pH unit higher than that under fed conditions. Highest pressure activity was observed within the stomach, in relation to gastric emptying. In fasted state, pressure values upon gastric emptying varied strongly between 30mbar and 304mbar, whereas after fed state ingestion values of at least 240mbar could always be observed. The data showed highly variable gastrointestinal parameters even under fasting conditions which must be considered when evaluating clinical studies and developing biorelevant in vitro test methods especially for large non-disintegrating dosage forms.

Effects of Propofol on Electrocorticography in Patients With Intractable Partial Epilepsy

BackgroundPropofols potential to trigger generalized tonic-clonic seizures and epileptic discharges is still controversial. The aim of this study was to investigate the incidence of epileptic discharges and epileptic seizures in epilepsy patients anesthetized with propofol. MethodsThirty three patients with intractable partial epilepsy selected for video electrocorticography-monitoring were studied. Twenty-three of them had epilepsy surgery with at least one year of followup. Subdural electrodes were surgically removed under propofol anesthesia. Video electrocorticography recordings were classified into two phases (Phase-A, ≥2 min without propofol, followed by Phase-P, starting 20 s after propofol injection) and visually analyzed concerning the occurrence of spikes, and spike-burst-suppression-patterns. ResultsNo seizures were detected. Spikes were recorded in Phase-P, but without a significant change in frequency compared to Phase-A. Spike-burst-suppression-patterns occurred in 8 of the 33 patients (24.2%). Five of those patients (62.5%) had epilepsy surgery, 3 (60%) became seizure-free. ConclusionsOur results do not contraindicate the use of propofol in patients with partial epilepsy. While spike-burst-suppression-patterns were recorded under propofol, the small number of surgically treated patients limits conclusions concerning their predictive value for improved epilepsy surgery outcome.

Gastric Emptying and Small Bowel Water Content after Administration of Grapefruit Juice Compared to Water and Isocaloric Solutions of Glucose and Fructose: A Four-Way Crossover MRI Pilot Study in Healthy Subjects

Grapefruit juice (GFJ) is known to affect the bioavailability of drugs in different ways. Despite the influence on gastrointestinal enzymes and transporters, the influence on gastrointestinal fluid kinetics is regarded to be relevant for the absorption of several drugs. Thus, it was the aim of this pilot study to investigate the gastric and intestinal volumes after intake of GFJ compared to isocaloric fructose and glucose solutions and water. The gastric and small intestinal volume kinetics after intake of 240 mL of GFJ, 10.6% fructose solution, 10.6% glucose solution, and water were investigated with magnetic resonance imaging in a four-way crossover study in six healthy human volunteers. The carbohydrate content of the administered beverages was quantified by high-performance liquid chromatography. Even with the small sample size of this pilot study, the gastric emptying of GFJ and the glucose solution was significantly slower than that of water. The fructose solution had only a slightly delayed gastric emptying. Small bowel water content was increased by administration of GFJ and fructose solution, whereas it was decreased by glucose compared to the administration of pure water. At 80 min the small bowel water content after GFJ was twice as high as the small bowel water content after administration of water. The observed influence of GFJ on gastrointestinal fluid kinetics may explain certain phenomena in drugs pharmacokinetics. The effect is double edged, as the slower gastric emptying and increased intestinal filling can lead to enhanced or altered absorption. Due to the comparability of fruit juices, a general effect of fruit juices on gastrointestinal volumes is likely.

Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools

This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated.