Premature Ventricular Contractions and Cardiomyopathy while on Ofatumumab for Treatment of Chronic Lymphocytic Leukaemia

Ofatumumab is a monoclonal antibody used in the treatment of recurrent and progressive chronic lymphocytic leukaemia (CLL) and was recently approved for the treatment of multiple sclerosis. We describe the case of a 68-year-old man who presented with complaints of irregular pulse readings while undergoing ofatumumab treatment for recurrent CLL. Electrocardiograms (ECGs) demonstrated premature ventricular contractions (PVCs) which eventually caused cardiomyopathy and failed to resolve despite ablative therapy. Ofatumumab-induced PVCs are confirmed in this case by the existence of documented PVCs on ECGs and the disappearance of these PVCs after the completion of ofatumumab treatment. To the best of our knowledge, there have been no previously reported cases of PVCs associated with ofatumumab in the literature

A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets

Purpose. The fabrication of a ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing. Methods. Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of drug and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus. Results. Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication immediate release tablets at temperatures as low as 110oC. The integrity of two models drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern. Conclusions. Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms

On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing

A method for the production of liquid capsules with the potential of modifying drug dose and release is presented. For the first time, the co-ordinated use of fused deposition modelling (FDM), 3D printing and liquid dispensing to fabricate individualised dosage form on demand in a fully automated fashion has been demonstrated. Polymethacrylate shells (Eudragit EPO and RL) for immediate and extended release were fabricated using FDM 3D printing and simultaneously filled using a computer-controlled liquid dispenser loaded with model drug solution (theophylline) or suspension (dipyridamole). The impact of printing modes: simultaneous shell printing and filling (single-phase) or sequential 3D printing of shell bottom, filling and shell cap (multi-phase), nozzle size, syringe volume, and shell structure has been reported. The use of shell thickness of 1.6 mm, and concentric architecture allowed successful containment of liquid core whilst maintaining the release properties of the 3D printed liquid capsule. The linear relationship between the theoretical and the actual volumes from the dispenser reflected its potential for accurate dosing (R  = 0.9985). Modifying the shell thickness of Eudragit RL capsule allowed a controlled extended drug release without the need for formulation change. Owing to its low cost and versatility, this approach can be adapted to wide spectrum of liquid formulations such as small and large molecule solutions and obviate the need for compatibility with the high temperature of FDM 3D printing process. In a clinical setting, health care staff will be able to instantly manufacture in small volumes liquid capsules with individualised dose contents and release pattern in response to specific patient's needs. [Abstract copyright: Copyright © 2017. Published by Elsevier B.V.

Cardio oncology: Digital innovations, precision medicine and health equity

The rapid emergence of cardio-oncology has resulted in a rapid growth of cardio-oncology programs, dedicated professional societies sections and committees, and multiple collaborative networks that emerged to amplify the access to care in this new subspecialty. However, most existing data, position statements and guidelines are limited by the lack of availability of large clinical trials to support these recommendations. Furthermore, there are significant challenges regarding proper access to cardio-oncology care and treatment, particularly in marginalized and minority populations. The emergence and evolution of personalized medicine, artificial intelligence (AI), and machine learning in medicine and in cardio-oncology provides an opportunity for a more targeted, personalized approach to cardiovascular complications of cancer treatment. The proper implementation of these new modalities may facilitate a more equitable approach to adequate and universal access to cardio-oncology care, improve health related outcomes, and enable health care systems to eliminate the digital divide. This article reviews and analyzes the current status on these important issues

Cardiovascular Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: From Pretransplantation to Survivorship: A Scientific Statement From the American Heart Association

Hematopoietic stem cell transplantation can cure various disorders but poses cardiovascular risks, especially for elderly patients and those with cardiovascular diseases. Cardiovascular evaluations are crucial in pretransplantation assessments, but guidelines are lacking. This American Heart Association scientific statement summarizes the data on transplantation-related complications and provides guidance for the cardiovascular management throughout transplantation. Hematopoietic stem cell transplantation consists of 4 phases: pretransplantation workup, conditioning therapy and infusion, immediate posttransplantation period, and long-term survivorship. Complications can occur during each phase, with long-term survivors facing increased risks for late effects such as cardiovascular disease, secondary malignancies, and endocrinopathies. In adults, arrhythmias such as atrial fibrillation and flutter are the most frequent acute cardiovascular complication. Acute heart failure has an incidence ranging from 0.4% to 2.2%. In pediatric patients, left ventricular systolic dysfunction and pericardial effusion are the most common cardiovascular complications. Factors influencing the incidence and risk of complications include pretransplantation therapies, transplantation type (autologous versus allogeneic), conditioning regimen, comorbid conditions, and patient age. The pretransplantation cardiovascular evaluation consists of 4 steps: (1) initial risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiovascular reserve. Clinical risk scores could be useful tools for the risk stratification of adult patients. Long-term cardiovascular management of hematopoietic stem cell transplantation survivors includes optimizing risk factors, monitoring, and maintaining a low threshold for evaluating cardiovascular causes of symptoms. Future research should prioritize refining risk stratification and creating evidence-based guidelines and strategies to optimize outcomes in this growing patient population

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry

Pretransplant Cardiac Evaluation Using Novel Technology

Hematopoietic stem-cell transplantation (HSCT) is a complex procedure that has been increasingly successful in treating malignant and nonmalignant conditions. Despite its effectiveness, it can be associated with potentially life-threatening adverse effects. New onset heart failure, ischemic disease, and arrhythmias are among the most notable cardiovascular complications post-HSCT. As a result, appropriate cardiac risk stratification prior to transplant could result in decreased morbidity and mortality by identifying patients with a higher probability of tolerating possible toxicities associated with HSCT. In this review, we aim to discuss the utility of cardiac screening using novel modalities of imaging technology in the pre-HSCT phase

Can Filaments be stored as a shelf-item for on-demand manufacturing of oral 3D printed tablets? An initial stability assessment

3D printing of oral solid dosage forms is a recently introduced approach for dose personalisation. Fused deposition modelling (FDM) is one of the promising and heavily researched 3D printing techniques in the pharmaceutical field. However, the successful application of this technique relies greatly on the mass manufacturing of physically and chemically stable filaments, that can be readily available as a shelf item to be 3D printed on-demand. In this work, the stability of methacrylate polymers (Eudragit EPO, RL, L100-55 and S100), hydroxypropyl cellulose (HPC SSL) and polyvinyl pyrrolidone (PVP)-based filaments over 6 months were investigated. Filaments manufactured by hot melt extrusion (HME) were stored at either 5 oC or 30 oC + 65 %RH with/without vacuuming. The effects of storage on their dimensions, visual appearance, thermal properties, and ‘printability’ were analysed. Theophylline content, as well as in vitro release from the 3D printed tablets were also investigated. The filaments were analysed before storage, then after 1, 3 and 6 months from the manufacturing Storing filaments at these conditions had a significant effect on their physical properties such as shape, dimensions, flexibility and hence compatibility with FDM 3D printing. In general, the methacrylate-based filaments were more physically stable and compatible with FDM 3D printing following storage. Owing to their hygroscopic nature, cellulose- and PVP-based filaments demonstrated a reduction in their glass transition temperature upon storage, leading to increased flexibility and incompatibility with FDM 3D printer. Theophylline contents was not significantly changed during the storage. This work provides preliminary data for the impact of polymer species on the long-term stability of the filaments. In general, storage and packaging conditions have major impact on the potential of on-demand manufacturing of 3D printed tablets using hot melt extruded filaments