Lyophilization Process Design and Development: A Single-Step Drying Approach

High-throughput lyophilization process was designed and developed for protein formulations using a single-step drying approach at a shelf temperature (T_s) of ≥40°C. Model proteins were evaluated at different protein concentrations in amorphous-only and amorphous-crystalline formulations. Single-step drying resulted in product temperature (T_p) above the collapse temperature (T_c) and a significant reduction (of at least 40%) in process time compared to the control cycle (wherein T_p < T_c). For the amorphous-only formulation at a protein concentration of ≤25 mg/mL, single-step drying resulted in product shrinkage and partial collapse, whereas a 50 mg/mL concentration showed minor product shrinkage. The presence of a crystallizing bulking agent improved product appearance at ≤25 mg/mL protein concentration for single-step drying. No impact to other product quality attributes was observed for single-step drying. Vial type, fill height, and scale-up considerations (i.e., choked flow, condenser capacity, lyophilizer design and geometry) were the important factors identified for successful implementation of single-step drying. Although single-step drying showed significant reduction in the edge vial effect, the scale-up considerations need to be addressed critically. Finally, the single-step drying approach can indeed make the lyophilization process high throughput compared to traditional freeze-drying process (i.e., 2-step drying).     

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

System x_c⁻ (Sx_c⁻), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sx_c⁻. However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood–brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure–activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sx_c⁻ antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sx_c⁻ inhibitory activity following in vitro Sx_c⁻ inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.     

Cone beam computed tomography in Endodontics – a review of the literature

The use of cone beam computed tomography (CBCT) in the diagnosis and/or management of endodontic problems is increasing and is reflected in the exponential rise in publications on this topic in the last two decades. The aim of this paper is to: (i) Review current literature on the endodontic applications of CBCT; (ii) Based on current evidence make recommendations for the use of CBCT in Endodontics; (iii) Highlight the areas in which more research is required.     

Positive Airway Pressure Adherence in Patients with Obstructive Sleep Apnea with Schizophrenia

Introduction

To determine the 1-year and 3-year adherence rates with Positive Airway Pressure (PAP) therapy in patients with schizophrenia compared to matched controls.

Methods

A case–control retrospective analysis was performed in a Veterans Affairs hospital. All symptomatic patients with schizophrenia ever started on PAP therapy between 2007 and 2015 were compared with controls matched for severity of sleep apnea based on AHI, BMI, and age at the time of diagnosis.

Results

Total number of subjects in both groups was 39. Mean AHI among cases and controls was 27.63 ± 22.16 and 33.59 ± 44.04 (p = 0.32), mean BMI was 34.91 ± 5.87 and 33.92 ± 5.21 (p = 0.43), and mean age at diagnosis was 53.6 ± 11.75 and 55.97 ± 11.92 (p = 0.36), respectively. There was no statistically significant difference in PAP use between patients with schizophrenia and controls at 1-year (percent days device use > 4 h—36.43% ± 31.41 vs. 49.09% ± 38.76; p = 0.17) and 3-year (percent days device use > 4 h—42.43 ± 35.50 vs. 60.53 ± 38.56; p = 0.089) visits

Conclusions

PAP adherence and usage is not significantly different among patients with schizophrenia compared to matched controls. Therefore, schizophrenia does not appear to influence CPAP compliance.

     

A multi-institutional comparison of mitoxantrone,etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.