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Introduction: Tablets are commonly produced by internally adding particulate lubricants, which are known to possibly lower the mechanical strength of tablets. This reduction is caused by the coverage of matrix forming components by lubricant particles, resulting in decreased interparticulate interactions. The known incompatibilities with some active compounds of the predominantly used lubricant, magnesium stearate, call for the in-depth characterization of alternative lubricants., Purpose: Investigation of the dispersion behavior of five commonly applied pharmaceutical lubricants by mathematically modeling the dispersion kinetics for short and extended mixing times., Methods: The dispersion behavior of five different pharmaceutical lubricants were examined by systematically varying lubricant concentration and mixing time of binary formulations and evaluating the kinetic of tensile strength reduction by theoretically estimating the surface coverage based on particle sizes., Results: For short mixing times, a unifying relationship between compactibility reduction and theoretical surface coverage was identified. Subsequently, for extended mixing times, distinct differences in the shear strength and dispersion kinetics of the investigated lubricants were found., Conclusions: The lubricant particle size controls the tensile strength reduction if short mixing times are applied. For extended mixing times, the investigated lubricants can be divided into two groups in terms of dispersion kinetics. Possible underlying reasons are discussed in detail in order to enhance the general understanding of lubricant dispersions in tablet formulations., (© 2023. The Author(s).)

The majority of tablets manufactured contain lubricants to reduce friction during ejection. However, especially for plastically deforming materials, e.g., microcrystalline cellulose (MCC), the internal addition of lubricants is known to reduce tablet tensile strength. This reduction is caused by the surface coverage by lubricant particles, the extent of which depends on both process and formulation parameters. Previously published models to predict the lubrication effect on mechanical strength do not account for changes in the excipient particle size. In this study, the impact of both lubricant concentration and mixing time on the tensile strength of tablets consisting of three different grades of MCC and four grades of magnesium stearate (MgSt) was evaluated. By taking into account the particle size of the applied excipients, a unifying relationship between the theoretically estimated surface coverage and compactibility reduction was identified. Evaluating the dispersion kinetics of MgSt as a function of time reveals a substantial impact of the initial surface coverage on the dispersion rate, while the minimal tensile strength was found to be comparable for the majority of formulations. In summary, the presented work extends the knowledge of lubricant dispersion and facilitates the reduction of necessary experiments during the development of new tablet formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

We report the case of a 28-year-old female patient who complained of extreme neck pain when giving birth to a child. Magnetic resonance imaging (MRI) of the cervical spine demonstrated an osteolytic lesion at the second cervical vertebral body (C2). In this presentation, we highlight a transoral surgical approach in order to prevent instability of this osteolytic lesion. To the best of our knowledge, this is the first time that such a route of access has been described for this tumor entity. A histopathologic examination led to the diagnosis of epithelioid hemangioendothelioma. During a follow-up period of 33 months, the patient had no complaints.

Modeling of structural and mechanical tablet properties consisting of multiple components, based on a minimum of experimental data is of high interest, in order to minimize time- and cost-intensive experimental trials in the development of new tablet formulations. The majority of commonly available models use the compressibility and compactibility of constituent components and establish mixing rules between those components, in order to predict the tablet properties of formulations containing multiple components. However, their applicability is limited to single materials, which form intact tablets (e.g. lactose, cellulose) and therefore, they cannot be applied for lubricants. Lubricants are required in the majority of industrial tablet formulations and usually influence the mechanical strength of tablets. This study combines the multi-component compaction model of Reynolds et al. (2017) with a recently published lubrication model (Puckhaber et al. 2020) to describe the impact of multiple components on a formulation consisting of two diluents and a lubricant. By that, this model combination displays a meaningful extension of existing compaction models and allows the systematic prediction of properties of lubricated multi-component tablets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In rotary tablet presses, the powder flow into the dies is typically facilitated by paddle feeder. For internally lubricated formulations, the shear forces exerted by the paddle rotation can result in a considerable decrease in tablet strength due to the dispersion of lubricant agglomerates. Available models to describe the lubricant dispersion in paddle feeder allow only a limited quantitative description and transferability of the process. This study introduces an empirical dispersion kinetic which is able to precisely describe the reduction of compactibility due to the shear stresses inside the paddle feeder, even for inhomogeneously flowing material. Additionally, by blending different grades of magnesium stearate at three levels of lubricant concentration with two different grades of microcrystalline cellulose, the impact of bulk properties on the lubrication dispersion in the feed frame was investigated. It was shown, that for a given formulation, the kinetics of compactibility reduction are comparable for different magnesium stearate concentrations. Additionally, the bulk properties of the applied magnesium stearate grade critically affect the dispersion kinetics as well as the maximum compactibility reduction inside the feed frame. In summary, the developed model represents a meaningful extension of the currently available process models for pharmaceutical tablet lubrication., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The tableting of most pharmaceutical formulations requires the addition of lubricants to reduce ejection forces, prevent tooling damage and tablet defects. The internal addition of lubricants is known to reduce tablet tensile strength, especially of mainly plastically deforming materials. To date, available models show only limited quantitative predictive accuracy for the influence of lubricant concentration on the mechanical strength of tablets. This study aims to fill this gap and present a model based on the Ryshkewitch-Duckworth equation that can estimate the compactibility profiles of lubricated formulations. Binary mixtures of different diluents (microcrystalline cellulose and lactose) were prepared with common lubricants (magnesium stearate and sodium stearyl fumarate) and subsequently tableted. The resulting compactibility profiles were fitted using the Ryshkewitch-Duckworth equation and the derived fit parameters (k b and σ 0 ) were correlated with the lubricant concentration. Subsequently, an empirical model was established which requires a minimum of experimental data and is able to predict the tensile strength of lubricated diluent tablets. Consequently, the developed empirical model is an interesting and valuable addition to the existing multi-component compacting models available and offers the opportunity to accelerate experimentation in the development of new tablet formulations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Compaction simulators are frequently used in the formulation and process development of tablets, bringing about the advantages of flexibility, low material consumption, and high instrumentation to generate the most possible process understanding. However, their capability of resembling general aspects of rotary press compaction and their precision in simulating or mimicking sub-processes such as feeding and filling need to be systematically studied. The effect of material deformation behavior, blend composition, and feeding on tensile strength and simulation precision as compared with rotary presses of different scales is evaluated in this study. Generally, good simulation performance was found for the studied compaction simulator. Compaction profile-sensitivity was demonstrated for highly visco-plastic materials while shear-sensitivity in feeding was demonstrated for lubricated blends of ductile particles. Strategies for the compensation of both in compaction simulator experiments are presented by careful investigation of the compaction stress over time profiles and introduction of a compaction simulator-adapted shear number approach to account for differences in layout and operation mode between compaction simulator and rotary press, respectively. These approaches support the general aim of this study to provide a more straightforward determination of scaling process parameters between rotary press and compaction simulator and facilitate a quicker and more reliable process transfer.

Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This study focuses on the residence time distribution (RTD) of two commonly applied excipients (microcrystalline cellulose, MCC; dicalcium phosphate, DCP), which exhibit different flow properties inside rotary tablet presses. To realistically depict the powder flow inside rotary tablet presses, custom-made tracer powder was developed. The applied method was proven to be appropriate as the tracer and bulk powder showed comparable properties. The RTDs of both materials were examined in two differently scaled rotary tablet presses and the influence of process parameters was determined. To analyze RTDs independent of the mass flow, the normalized variance was used to quantify intermixing. Substantial differences between both materials and tablet presses were found. Broader RTDs were measured for the poorer flowing MCC as well as for the production scale press. The obtained results can be used to improve the general understanding of powder flow inside rotary tablet presses and amplify scale-up and continuous production process development.

A post hoc analysis of the PALLAS trial suggested life-threatening interactions of digitalis and dronedarone. Thus, there is concern about an interplay between digitalis and other drugs that influence cardiac electrophysiology. We therefore investigated the interaction between digitalis and flecainide or ranolazine. Twenty-five rabbit hearts were Langendorff-perfused and treated with flecainide (2 µM, 12 hearts) or ranolazine (10 µM, 13 hearts). Infusion of flecainide prolonged mean action potential duration [APD 90 , from 153 ms (interquartile range (IQR): 29.7 ms) to 159 ms (IQR: 24.9 ms, p = 0.04)] and effective refractory period [ERP, 170 ms (IQR: 40 ms) vs. 200 ms (IQR: 32.5 ms, p < 0.01)]. Administration of ranolazine prolonged APD 90 [144 ms (IQR: 34.3 ms)) vs. 157 ms (IQR: 31.2 ms, p < 0.01)] and ERP [180 ms (IQR: 40 ms) vs. 200 ms (IQR: 30 ms, p < 0.01)]. Additional infusion of the digitalis glycoside ouabain (0.2 µM) abbreviated APD 90 and ERP in both groups (flecainide: APD 90 : to 128 ms (IQR: 19 ms), ERP: to 170 ms (IQR: 20 ms), p < 0.01 each; ranolazine: APD 90 : to 141 ms (IQR: 40 ms), ERP: to 160 ms (IQR: 30 ms), p < 0.01 each). Ventricular vulnerability was assessed by a pacing protocol employing premature extra stimuli and burst stimulation. No proarrhythmic effect was observed with flecainide (1 vs. 3 episodes at baseline) or ranolazine (3 vs. 11 episodes at baseline). However, further infusion of ouabain had a proarrhythmic effect for both drugs (flecainide: 15 episodes, p = 0.04; ranolazine: 21 episodes, p = 0.09). Concomitant treatment of the sodium channel blockers flecainide or ranolazine with digitalis seems to be proarrhythmic. Abbreviation of repolarization and refractoriness that can facilitate re-entry was found as underlying mechanism.

Magnesium stearate (MgSt) is a common tablet lubricant. As variations in MgSt properties are known to influence tablet attributes, the impact of MgSt fatty acid composition, particularly the significance of the stearate and palmitate contents, and its effects on tablet properties warrant further investigation. This study investigated the effect of MgSt with different stearate and palmitate contents but comparable physical properties (e.g. particle size, crystallinity, specific surface area and morphology) on lubrication performance and resulting tablet quality attributes, including mechanical strength, disintegratability and drug release. The influence of MgSt concentration and blending duration on the resulting tablet properties was also examined. Tablets produced using the lower stearate content MgSt had slightly higher tensile strength. The effect of MgSt stearate content was more apparent in the disintegration time and drug release, whereby MgSt of lower stearate content resulted in tablets with longer disintegration time and slower drug release. The lower stearate content also resulted in a lower lubrication performance, leading to a lesser reduction in tablet ejection force. As expected, a longer blending time of the tablet formulation blend with MgSt yielded tablets with reduced tensile strength, shorter disintegration time and slower drug release. Tablets with higher MgSt concentration showed a greater reduction in tensile strength, longer disintegration time and faster drug release. The study findings reinforced observations by other researchers and provided a better understanding of the fatty acid composition effects of MgSt on lubrication performance and the resulting tablet properties., (© 2024. The Author(s).)

Background: A post hoc analysis of the PALLAS trial suggested possible interactions of dronedarone and digitalis glycosides. The aim of the present study was to compare the effects dronedarone or amiodarone in combination with digitalis glycosides., Methods and Results: Eleven female rabbits underwent chronic oral treatment with amiodarone (50mg/kg/d for 6weeks). Ten rabbits were treated with dronedarone (50mg/kg/d for 6weeks). Ten rabbits were used as controls. Hearts were isolated and Langendorff-perfused. Monophasic action potentials and ECG showed a moderate prolongation of QT interval and action potential duration (APD). Both drugs also increased effective refractory period. Additional application of ouabain (0.2μM) resulted in a significant decrease of QT interval, APD, and ERP in all groups. Ventricular arrhythmias were induced by programmed ventricular stimulation and aggressive burst stimulation. Reproducible occurrence was defined as occurrence of at least 3 episodes. Under baseline conditions in control hearts, ventricular fibrillation (VF) was inducible in 1 of 10 hearts (7 episodes). After the application of 0.2μM ouabain, 4 of 10 control hearts were inducible (24 episodes). One of 10 dronedarone-pretreated hearts (3 episodes) and 2 of 11 amiodarone-pretreated hearts (6 episodes) showed VF before ouabain infusion. After the application of 0.2μM ouabain, 7 of 10 dronedarone-pretreated hearts were inducible (73 episodes). By contrast, only 4 of 11 amiodarone-pretreated hearts (13 episodes) showed VF., Conclusion: In the present study, additional treatment with ouabain resulted in an increased ventricular vulnerability in al study groups. Of note, chronically dronedarone-pretreated hearts were significantly more vulnerable than amiodarone-pretreated hearts., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Additive manufacturing (AM) processes, such as fused deposition modelling (FDM), have emerged as transformative technologies in pharmaceutical manufacturing, enabling the production of drug delivery systems with complex and customised geometries. These advancements provide precise control over drug release profiles and facilitate the development of patient-specific medicines. This study investigates the dissolution behaviour of AM-fabricated tablets made from polyvinyl alcohol (PVA), a hydrophilic and biocompatible polymer widely used in drug delivery systems. The influence of the initial mass, surface area, and surface-area-to-volume ratio (S/V) on dissolution kinetics is evaluated for tablets with intricate geometries. Our findings demonstrate that these parameters, while critical for conventional tablet shapes, are insufficient to fully predict the dissolution behaviour of complex geometries. Furthermore, this study highlights how geometric modifications can enable the administration of the same drug dosage through sustained or immediate release profiles, offering enhanced versatility in drug delivery. By leveraging the geometric design freedom provided by AM technologies, this research underscores the potential for optimising drug delivery systems to improve therapeutic outcomes and patient compliance. [ABSTRACT FROM AUTHOR]

Aims Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. Methods and results We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]. Conclusion Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org [ABSTRACT FROM AUTHOR]

Modern pharmaceutical manufacturing based on Quality by Design and digitalisation is revolutionising the pharmaceutical industry. Continuous processes are promoted as they increase efficiency and improve quality control. Compared to batch blending, continuous blending is easier to scale and provides advantages for achieving blend homogeneity. One potential challenge of continuous blending is the risk of over-lubrication. In this study, blending homogeneity and lubricant sensitivity are investigated for both batch and continuous processes. Given their distinct chemical structures and morphologies, anhydrous lactose and granulated lactose are expected to exhibit varying sensitivities to changes in process settings across both technologies. The findings suggest that both lactose grades provide highly stable blends that can be safely utilised in both batch and continuous modes. Optimisation should focus on process variables, such as the quality of loss-in-weight feeders used for dosing low doses of ingredients. The most significant process parameter for lubricant sensitivity was the type of lactose used. Anhydrous lactose produced harder tablets than the more porous granulated lactose but was more sensitive to lubrication at the same settings. The magnesium stearate content and its interaction with the type of lactose are also critical factors, with magnesium stearate having a counterproductive impact on tabletability. [ABSTRACT FROM AUTHOR]

The aim of this paper was to describe the influence of high-shear wet granulation process parameters on tablet tensile strength and compaction behavior of a powder mixture and granules containing hydralazine. The hydralazine powder mixture and eight types of granules were compacted into tablets and evaluated using the Heckel, Kawakita and Adams analyses. The granules were created using two types of granulation liquid (distilled water and aqueous solution of polyvinylpyrrolidone), at different impeller speeds (500 and 700 rpm) and with different wet massing times (without wet massing and for 2 min). Granulation resulted in improved compressibility, reduced dustiness and narrower particle-size distribution. A significant influence of wet massing time on parameters from the Kawakita and Adams analysis was found. Wet massing time had an equally significant effect on tablet tensile strength, regardless of the granulation liquid used. Granules formed with the same wet massing time showed the same trends in tabletability graphs. Tablets created using a single-tablet press (batch compaction) and an eccentric tablet press showed opposite values of tensile strength. Tablets from granules with a higher bulk density showed lower strength during batch compaction and, conversely, higher strength during eccentric tableting. [ABSTRACT FROM AUTHOR]

The aim of this feasibility study was to investigate the possibility of producing industrial-scale relevant, robust, high drug-loaded (90.9%, w/w) 100 mg dose immediate-release tablets of isoniazid and simultaneously meet the biowaiver requirements. With an understanding of the real-life constrictions on formulation scientists during product development for the generic industry, this study was done considering a common set of excipients and manufacturing operations, as well as paying special attention to the industrial-scale high-speed tableting process as one of the most critical manufacturing operations. The isoniazid substance was not applicable for the direct compression method. Thus, the selection of granulation method was logically justified, and it was fluid-bed granulated with an aqueous solution of Kollidon® 25, mixed with excipients, and tableted with a rotary tablet press (Korsch XL 100) at 80 rpm (80% of the maximum speed) in the compaction pressure range 170–549 MPa monitoring of ejection/removal forces, tablet weight uniformity, thickness, and hardness. Adjusting the main compression force, the Heckel plot, manufacturability, tabletability, compactability, and compressibility profiles were analysed to choose the main compression force that resulted in the desirable tensile strength, friability, disintegration, and dissolution profile. The study showed that highly robust drug-loaded isoniazid tablets with biowaiver requirements compliance can be prepared with a common set of excipients and manufacturing equipment/operations incl. the industrial-scale high-speed tableting process. [ABSTRACT FROM AUTHOR]

Significant improvements in the wettability and dissolution rate of celecoxib (CEL), a poorly soluble selective cyclooxygenase-2 (COX-2) inhibitor, have been shown by Huyn et al., 2019 by combining the binary pharmaceutical compositions including CEL and one of the two co-formers, adipic acid (ADI) and saccharin (SAC), into eutectic mixtures (EM). Purpose: In this study, we developed a therapeutic eutectic system for CEL which is a promising approach for oral delivery to enhance bioavailability. CEL EM were synthesized by novel techniques including supercritical CO2 techniques and new tablet formulations were purposed. Methods: CEL EM were synthesized by evaporation crystallization method, spray drying, supercritical fluid (SCF) techniques. The CEL EM particles were then characterized by differential scanning calorimetry, powder X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscope, and particle size analysis. Dissolution studies were carried out. With a quality by design approach, a statistical method through design of experiment and data analysis by JMP® (SAS institute) was applied to CEL EM immediate release tablet formulation development. Results: CEL EM produced by spray drying technique, supercritical fluid (SCF) techniques were identified and characterized. The enhancement of dissolution was observed for SCF processed samples. The design space for CEL-ADI EM IR tablet and control limits for individual parameters were determined. [ABSTRACT FROM AUTHOR]

The ability to predict formulation behaviour at production scale during formulation design can reduce the time to market and decrease product development costs. However, it is challenging to extrapolate compaction settings for direct compression formulations between tablet press models during scale-up and transfer from R&D to commercial production. The aim of this study was to develop statistical process models to predict tablet tensile strength, porosity and disintegration time from compaction parameters (pre-compression and main compression force, and press speed), for three formulations, with differing deformation characteristics (plastic, brittle and elastic), on three tablet press models (one pilot-scale tablet press (KG RoTab) and two production-scale presses (Fette 1200i and GEA Modul P)). The deformation characteristics of yield pressure and elastic recovery were determined for the model placebo formulations investigated. To facilitate comparison of dwell time settings between tablet press models, the design of experiments (DoE) approach was 9 individual 16-run response surface DoEs (3 formulation × 3 press models), whose results were combined to create a polynomial regression model for each tablet property. These models predicted tablet tensile strength, porosity and disintegration time and enabled the construction of design spaces to produce tablets with specified target properties, for each formulation on each press. The models were successfully validated. This modelling approach provides an understanding of the compaction behaviour of formulations with varying deformation behaviour on development and commercial tablet press models. This understanding can be applied to inform achievable production rates at a commercial scale, during the formulation development. [ABSTRACT FROM AUTHOR]

We investigate fabrication of compacts using polytetrafluoroethylene (PTFE) and polyethylene (PE), and the effect of compaction conditions on their terahertz transmission properties. The conditions used to fabricate compressed powder samples for terahertz time-domain spectroscopy (THz-TDS) can impact the accuracy of the measurements and hence the interpretation of results. This study investigated the effect of compaction conditions on the accuracy of the THz-TDS analysis. Two polymers that are commonly used as matrix materials in terahertz spectroscopy studies were explored using a compaction simulator and a hydraulic press for sample preparation. THz-TDS was used to determine the refractive index and loss coefficient to compare the powder compacts (pellets) to the values of solid material. Sample porosity, axial relaxation and tensile strength were measured to assess the material's suitability for terahertz spectroscopy. It was found that PTFE is the preferable material for creating THz-TDS samples due to its low porosity and high tensile strength. PE was found to show significant porosity at all compaction pressures, making it an unsuitable material for the accurate determination of optical parameters from THz-TDS spectroscopy measurements. The larger particle sizes of PE resulted in compacts that exhibited significantly lower tensile strength than those made from PTFE making handling and storage difficult. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa is a genetically heterogenous skin fragility disorder with multiorgan involvement appearing already in newborn children. Severe progressive fibrosis follows skin blistering, mucosa lesions, and wound healing, favouring development of highly aggressive squamous cell carcinomas. Losartan potassium (LP) has been described to show positive effects; therefore, it was of clinical interest to develop 2 mm mini-tablets with LP for treatment of the affected children. Several challenges emerged during development: limited flowability and sticking to punches were observed in the first tableting experiments due to a high drug load, and a bitter taste of the LP was reported. Sticking to punches was reduced by using SMCC 50 and a combination of different lubricants; however, direct compression trials on a Korsch XM 12 rotary press were not successful due to compaction phenomena in the hopper. Thus, an intermediate dry granulation was successfully introduced. Two final formulations of the mini-tablets complied with the requirements of the European Pharmacopoeia regarding disintegration times (<15 min) and friability (<1.0%); mean tensile strengths amounted to about 1 MPa as a compromise between manufacturability and sufficient mechanical strength for further coating studies. The subsequent coating step succeeded delaying the initial drug release for more than 2 min. An acceptance value ≤15 was matched for the coated mini-tablets, and stability studies showed a promising shelf life. [ABSTRACT FROM AUTHOR]

Plenty of non-cardiovascular drugs alter cardiac electrophysiology and may ultimately lead to life-threatening arrhythmias. In clinical practice, measuring the QT interval as a marker for the repolarization period is the most common tool to assess the electrophysiologic safety of drugs. However, the sole measurement of the QT interval may be insufficient to determine the proarrhythmic risk of non-cardiovascular agents. Several other markers are considered in pre-clinical safety testing to determine potential harm on cardiac electrophysiology. Besides measuring typical electrophysiologic parameters such as repolarization duration, whole-heart models allow the determination of potential predictors for proarrhythmia. Spatial and temporal heterogeneity as well as changes of shape of the action potential can be easily assessed. In addition, provocation manoeuvers (either by electrolyte imbalances or programmed pacing protocols) may induce sustained arrhythmias and thereby determine ventricular vulnerability to arrhythmias. Compared with the human heart, the rabbit heart possesses a similar distribution of ion currents that govern cardiac repolarization, resulting in a rectangular action potential configuration in both species. In addition, similar biophysical properties of rabbit and human cardiac ion channels lead to a comparable pharmacologic response in human and rabbit hearts. Of note, arrhythmia patterns resemble in both species due to the similar effective size of human and rabbit hearts. Thus, the rabbit heart is particularly suitable for testing the electrophysiologic safety of drugs. Several experimental setups have been developed for studying cardiac electrophysiology in rabbits, ranging from single cell to tissue preparations, whole-heart setups, and in vivo models. [ABSTRACT FROM AUTHOR]

The contributions in this Special Issue address powder processing in granulation [1,2], capsule filling [3], tableting [4-7], and along whole process chains [8], which powders mostly experience in industrial applications. Effects of insufficient die filling and powder densification are described and differentiated regarding the effects of powder properties and process parameters on these. Besides presenting methods to produce tracers with the properties of the investigated powder, the influence of different setups and scales of paddle feeders integrated in rotary presses, as well as of powder properties on the residence time distribution within rotary presses, is evaluated [7]. [Extracted from the article]

Several case reports suggest QT prolongation leading to ventricular arrhythmias with fatal outcome after intoxication with the μ-opioid receptor agonist and anti-diarrheal agent loperamide. The number of cases of loperamide misuse are growing due to its potential stimulating effects. Loperamide intoxications can be treated by naloxone. However, previous reports described a further QT prolongation associated with naloxone administration. Therefore, the aim of this study was to investigate the effects of loperamide and naloxone on the cardiac electrophysiology in a sensitive whole-heart model. Twenty-six hearts of New Zealand White rabbits were retrogradely perfused in a modified Langendorff apparatus. Monophasic action potentials were recorded by endo- and epicardially positioned catheters. Hearts were stimulated at different cycle lengths, thereby obtaining action potential duration at 90% of repolarization (APD90) and QT intervals. Programmed ventricular stimulation was used to assess ventricular vulnerability. Fourteen hearts were perfused with ascending concentrations of loperamide (0.2 μM, 0.35 μM, and 0.5 μM) after obtaining baseline data. Another 12 hearts were treated with naloxone (0.1 μM, 0.5 μM, 2 μM). Loperamide led to a significant increase in QT interval, APD90, and ventricular tachycardia (VT) episodes. In contrast, naloxone led to a decrease in QT interval and APD90. Accordingly, the number of VT episodes was unaltered. To the best of our knowledge, this is the first experimental study that investigated the effects of loperamide and naloxone in a whole-heart model. Loperamide led to a significant increase in action potential duration and QT interval. Simultaneously, the number of ventricular tachycardias was significantly increased. In contrast, naloxone led to a shortening of the action potential duration without altering arrhythmia susceptibility. [ABSTRACT FROM AUTHOR]

Recent experimental studies showed a protective effect of the renin inhibitor aliskiren regarding atrial structural remodeling. Purpose of this study was to assess acute electrophysiologic effects of aliskiren in a whole-heart model of atrial fibrillation (AF) and to investigate its impact on the ventricle. Twelve rabbit hearts were excised, retrogradely perfused, and paced at different cycle lengths. To enhance atrial vulnerability, a combination of acetylcholine (ACh) and isoproterenol (Iso) was infused and significantly reduced atrial action potential duration (aAPD90) and atrial effective refractory period (aERP). Additional infusion of aliskiren prolonged aAPD90 but did not alter aERP. A triangulation of action potential with ACh/Iso and a further triangulation after treatment with aliskiren were noted. Vulnerability to AF was tested by employing trains of burst pacing. Administration of ACh/Iso provoked more episodes of AF (baseline: 26 episodes, Iso/Ach: 48 episodes). Additional treatment with aliskiren induced AF significantly more often (108 episodes). Another nine hearts were perfused with aliskiren to examine its ventricular effects. Infusion with aliskiren abbreviated ventricular APD90 and ERP. Utilizing programmed ventricular stimulation, a trend towards more ventricular arrhythmias in aliskiren-treated hearts was observed. Though aliskiren did not reduce aAPD90 or aERP, acute treatment with aliskiren promoted AF. Triangulation of atrial action potentials, which is an established risk factor for ventricular proarrhythmia, may contribute to the increased atrial vulnerability. This effect may interfere with its recently demonstrated beneficial properties in atrial remodeling. Of note, aliskiren might have a proarrhythmic effect on the ventricular level. [ABSTRACT FROM AUTHOR]

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment. [ABSTRACT FROM AUTHOR]

Background: Digitalis glycosides are employed for rate control of atrial fibrillation. Recent studies suggested potential harmful effects of digitalis monotherapy and combination with antiarrhythmic drugs. The aim of the present study was to assess the prevalence and potential impact of digitalis therapy on outcome in patients undergoing catheter ablation of supraventricular arrhythmias. Methods and results: The German Ablation Registry is a nationwide, prospective registry with a 1-year follow-up investigating 12,566 patients receiving catheter ablations of supraventricular arrhythmias in 52 German centres. The present analysis focussed on pharmacotherapy in 8608 patients undergoing catheter ablation of atrial tachycardia, atrial fibrillation, or atrial flutter. Patients receiving digitalis therapy (n = 417) were older and presented a significantly increased prevalence of comorbidities including coronary artery disease, heart failure, diabetes, and pulmonary disease. One-year mortality was significantly higher in digitalis-treated patients (4.7% vs. 1.3%, p < 0.001), most strikingly in patients undergoing ablation of atrial flutter. This effect was maintained after adjustment for important risk factors. Similar results were obtained for as the combined endpoint of death, myocardial infarction, stroke and major bleeding (6.6% vs. 2.7%, p < 0.001), and non-fatal rehospitalisations (54.1% vs. 45.1%, p = 0.001). Conclusion: In the present study of patients undergoing catheter ablation of supraventricular arrhythmias, an association of digitalis therapy with increased mortality and an increased rate of other severe adverse events were observed. The results from this 'real-life' registry are consistent with previously published studies. However, whether digitalis therapy promotes a poorer prognosis or may just serve as a marker for this aspect cannot be thoroughly interpreted. [ABSTRACT FROM AUTHOR]

Summary: The natural polyphenol resveratrol and its analogue piceatannol have various beneficial effects including antiarrhythmic properties. The aim of the present study was to examine potential electrophysiologic effects in an experimental whole‐heart model of atrial fibrillation (AF). Simultaneous infusion of resveratrol (50 μmol/L) or piceatannol (10 μmol/L) in rabbit hearts resulted in an increase in atrial refractory period. Both agents induced a significant slowing of atrial conduction and of intrinsic heart rate. In both groups, a trend toward a reduction in AF and a regularization of AF was observed. [ABSTRACT FROM AUTHOR]

The Dietary Supplements and Health Education Act (DSHEA), passed by the United States Congress in October of 1994, definesherbal productsas nutritional supplements, not medications. This opened the market for diverse products made from plants, including teas, extracts, essential oils, and syrups. Mexico and the United States share an extensive border, where diverse herbal products are available to the public without a medical prescription. Research undertaken in the neighboring cities of Ciudad Juarez, Mexico, and El Paso, Texas, USA, shows the use of herbs is higher in this border area compared to the rest of the United States. A portion of the population is still under the erroneous impression that “natural” products are completely safe to use and therefore lack side effects. We review the dangers of ingesting the toxic seed ofThevetiaspp. (family Apocynaceae), commonly known as “yellow oleander” or “codo de fraile,” misleadingly advertised on the Internet as an effective and safe dietary supplement for weight loss. Lack of proper quality control regarding herbs generates a great variability in the quantity and quality of the products' content. Herb–drug interactions occur between some herbal products and certain prescription pharmaceuticals. Certain herbs recently introduced into the U.S. market may not have been previously tested adequately for purity, safety, and efficacy. Due to the lack of reliable clinical data regarding the safe use of various herbal products currently available, the public should be made aware regarding the possible health hazards of using certain herbs for therapeutic purposes. The potentially fatal toxicity of yellow oleander seed is confirmed by cases reported from various countries, while the purported benefits of using it for weight loss have not been evaluated by any known clinical trials. For this reason, the use of yellow oleander seed as a dietary supplement should be avoided. [ABSTRACT FROM PUBLISHER]

The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (−34 ms, p < 0.05) and action potential duration (APD90; −27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; −27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 μM). Of note, this did not exert significant effects on QT interval (−4 ms, p = ns) or APD90 (−15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 μM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 μM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine. [ABSTRACT FROM AUTHOR]

Presents a medical case of woman with hypercalcemic crisis and primary multifocal lymphoma of bone. Medical history; Incidence of primary lymphoma of bone; Suppressed parathyroid hormone and calcitrol levels; Cause of hypercalcemia.

With the emergence of quality by design in the pharmaceutical industry, it becomes imperative to gain a deeper mechanistic understanding of factors impacting the flow of a formulation into tableting dies. Many flow characterization techniques are present, but so far only a few have shown to mimic the die filling process successfully. One of the challenges in mimicking the die filling process is the impact of rheological powder behavior as a result of differences in flow field in the feeding frame. In the current study, the rheological behavior was investigated for a wide range of excipients with a wide range of material properties. A new parameter for rheological behavior was introduced, which is a measure for the change in dynamic cohesive index upon changes in flow field. Particle size distribution was identified as a main contributing factor to the rheological behavior of powders. The presence of fines between larger particles turned out to reduce the rheological index, which the authors explain by improved particle separation at more dynamic flow fields. This study also revealed that obtained insights on rheological behavior can be used to optimize agitator settings in a tableting machine. [ABSTRACT FROM AUTHOR]

In pharmaceutical manufacturing, the utmost aim is reliably producing high quality products. Simulation approaches allow virtual experiments of processes in the planning phase and the implementation of digital twins in operation. The industrial processing of active pharmaceutical ingredients (APIs) into tablets requires the combination of discrete and continuous sub-processes with complex interdependencies regarding the material structures and characteristics. The API and excipients are mixed, granulated if required, and subsequently tableted. Thereby, the structure as well as the properties of the intermediate and final product are influenced by the raw materials, the parametrized processes and environmental conditions, which are subject to certain fluctuations. In this study, for the first time, an agent-based simulation model is presented, which enables the prediction, tracking, and tracing of resulting structures and properties of the intermediates of an industrial tableting process. Therefore, the methodology for the identification and development of product and process agents in an agent-based simulation is shown. Implemented physical models describe the impact of process parameters on material structures. The tablet production with a pilot scale rotary press is experimentally characterized to provide calibration and validation data. Finally, the simulation results, predicting the final structures, are compared to the experimental data. [ABSTRACT FROM AUTHOR]

We previously reported a novel method for the precise prediction of tablet properties (e.g., tensile strength (TS)) using a small number of experimental data. The key technique of this method is to compensate for the lack of experimental data by using data of placebo tablets collected in a database. This study provides further technical knowledge to discuss the usefulness of this prediction method. Placebo tablets consisting of microcrystalline cellulose, lactose, and cornstarch were prepared using the design of an experimental method, and their TS and disintegration time (DT) were measured. The response surfaces representing the relationship between the formulation and the tablet properties were then created. This study investigated tablets containing four different active pharmaceutical ingredients (APIs) with a drug load ranging from 20–60%. Overall, the TS of API-containing tablets could be precisely predicted by this method, while the prediction accuracy of the DT was much lower than that of the TS. These results suggested that the mode of action of APIs on the DT was more complicated than that on the TS. Our prediction method could be valuable for the development of tablet formulations. [ABSTRACT FROM AUTHOR]