Exploring the Effect of Solution Speciation on Crystallization Outcome

In the field of pharmaceuticals, the crystallization process significantly impacts the purity, morphology and polymorphism of active pharmaceutical ingredients (API), all of which are important in drug development. Polymorphism is the existence of more than one solid-state form of the same chemical entity. Tolfenamic acid (TFA), a Non-Steroid Anti-inflammatory drug (NSAID), has been shown to exhibit a unique physical phenomenon called concomitant polymorphism, whereby two polymorphs crystallize from the solution simultaneously. From previous work, it has been established that solution speciation i.e. the presence of monomers or dimers of TFA in solution is concentration and temperature dependent. This study correlates this existing solution speciation with the crystallization outcome by analyzing the ratio of polymorphs obtained at different temperatures at a fixed concentration. Polymorphic purity was examined using powder X-ray diffraction. Crystallization experiments were performed at 10°C, 37°C, and 55°C at a constant supersaturation ratio of 1.95. Samples were taken at various time points in the recrystallization process. These samples were examined using Infrared spectroscopy for solid-state composition and quantified using a calibration curve. Pure polymorphs of TFA have been obtained and a calibration curve to quantify phase composition has been established. The initial recrystallization results suggest that the conformation of the crystals in solution is decided by the composition of the initial crystals formed, however more experimentation is necessary. Ongoing work involving recrystallization experiments under different temperature conditions would lead to a much better understanding of the role of solution speciation in the nucleation and crystallization processes

Clinical Study Crevicular Fluid and Serum Concentrations of Progranulin and High Sensitivity CRP in Chronic Periodontitis and Type 2 Diabetes

Introduction. This study was designed to correlate the serum and gingival crevicular fluid (GCF) levels of progranulin (PGRN) and high sensitivity C-reactive protein (hs CRP) in chronic periodontitis and type 2 diabetes mellitus (DM). Design. PGRN and hs CRP levels were estimated in 3 groups: healthy, chronic periodontitis, and type 2 DM with chronic periodontitis. Results. The mean PGRN and hs CRP concentrations in serum and GCF were the highest for group 3 followed by group 2 and the least in group 1. Conclusion. PGRN and hs CRP may be biomarkers of the inflammatory response in type 2 DM and chronic periodontitis

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Investigating the Crystallization Propensity of Structurally Similar Organic Molecules From Amorphous State

Combinatorial chemistry and high-throughput screening approaches utilized during drug discovery have resulted in many potent pharmacologically active molecules with low aqueous solubility and consequently poor bioavailability. Enabling technologies, such as amorphous solid dispersions (ASD’s), can obviate these challenges and provide an efficient route to formulate the drug as an oral solid dosage form. However, high-energy amorphous materials have an inherent tendency to crystallize and in doing so can negate the apparent solubility advantage achieved by using such formulations. Crystallization can occur during (1) cooling the drug molecule from the melt state (such as during hot melt extrusion); (2) during storage of an amorphous formulation; (3) during pharmaceutical processing unit operations such as compression, granulation etc. Current knowledge with regards to the relationship between crystallization propensity of an active pharmaceutical ingredient (API) from the amorphous state (supercooled liquid and glass) and its thermodynamic, kinetic and molecular properties is limited. Furthermore, examining the mechanistic steps involved in crystallization of organic molecules under conditions of supercooling provides an opportunity to examine supramolecular aggregation events occurring during early stages of crystallization. Studying crystallization mechanism from amorphous state is important for pharmaceutical formulation development because a molecular-level understanding of the crystallization process would provide clues regarding the intermolecular interactions at the early stages of nucleation and help in rational selection of polymeric excipients to hinder such events. The primary goal of this research is to develop an understanding of phase transition from amorphous pharmaceuticals, specifically focusing on the role of thermodynamic, kinetic and molecular properties of a series of structurally similar compounds. It is hypothesized that the there exists a link between thermodynamics quantities, kinetic properties, molecular interactions and glass forming ability. Furthermore, it is hypothesized that the molecular heterogeneity in supercooled liquids and glassy state, manifested through intermolecular interactions and conformational flexibility impacts the observed crystallization behavior. Understanding the phase transition kinetics and mechanism of crystallization from amorphous pharmaceuticals is critical for development of stable formulations for drug delivery. The specific goals of this research include: (1) Investigating the link between thermodynamic and kinetic factors affecting the crystallization propensity of organic compounds from supercooled liquid state. (2) Evaluating the role of intermolecular interactions and conformational distribution on glass forming ability and stability. (3) Examining the relationship between supramolecular aggregates present in glassy state and polymorphic outcome. It is believed that successful completion of this research will provide a fundamental understanding of amorphous solid-state chemistry as well as provide useful tools for the implementation of ASD’s as solid oral dosage forms

The effect of yoga on cardiovascular disease risk factors: A meta-analysis

Yoga has been increasingly popular yet has shown inconsistent benefits on cardiovascular disease (CVD) risk factors. We aimed to systematically analyze the effect of yoga on modifiable CVD risk factors. We systematically searched Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception in 1966 through June 2022 for studies evaluating the association between yoga and blood pressure, lipid profile, HbA1c and body mass index (BMI). Two investigators independently reviewed data. Conflicts were resolved through consensus. Random-effects meta-analyses were used. 64 RCTs including a total of 16,797 participants were eligible for inclusion in the meta-analysis. Yoga therapy improved both systolic as well as diastolic blood pressure (weight mean difference [WMD] (95% Confidence interval [CI]) of -4.56 [-6.37, -2.75] mm Hg, WMD [95% CI] - 3.39 [-5.01, -1.76] mm Hg respectively). There was also an improvement in BMI as well as hemoglobin A1c (HbA1c) (WMD [95% CI] of -0.57 [-1.05, -0.10] kg/m2, WMD [95% CI] of -0.14 [-0.24, -0.030] mmol/L respectively) . In addition, all parameters of the lipid profile, including low-density lipoprotein cholesterol (LDL-C) showed a significant improvement with yoga therapy (WMD [95% CI] -7.59 [-12.23, -2.95] mg/dL for LDL-C). Yoga has a modest yet positive effect on blood pressure, BMI, lipid profile and HbA1c and, therefore, may play an ancillary role in primary prevention of CVD

The Effect of Yoga on Cardiovascular Disease Risk Factors: A Meta-Analysis

Yoga has been increasingly popular yet has shown inconsistent benefits on cardiovascular disease (CVD) risk factors. We aimed to systematically analyze the effect of yoga on modifiable CVD risk factors. We systematically searched Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception in 1966 through June 2022 for studies evaluating the association between yoga and blood pressure, lipid profile, HbA1c and body mass index (BMI). Two investigators independently reviewed data. Conflicts were resolved through consensus. Random-effects meta-analyses were used. 64 RCTs including a total of 16,797 participants were eligible for inclusion in the meta-analysis. Yoga therapy improved both systolic as well as diastolic blood pressure (weight mean difference [WMD] (95% Confidence interval [CI]) of -4.56 [-6.37, -2.75] mm Hg, WMD [95% CI] - 3.39 [-5.01, -1.76] mm Hg respectively). There was also an improvement in BMI as well as hemoglobin A1c (HbA1c) (WMD [95% CI] of -0.57 [-1.05, -0.10] kg/m, WMD [95% CI] of -0.14 [-0.24, -0.030] mmol/L respectively) . In addition, all parameters of the lipid profile, including low-density lipoprotein cholesterol (LDL-C) showed a significant improvement with yoga therapy (WMD [95% CI] -7.59 [-12.23, -2.95] mg/dL for LDL-C). Yoga has a modest yet positive effect on blood pressure, BMI, lipid profile and HbA1c and, therefore, may play an ancillary role in primary prevention of CVD

A Recommended Preclinical Extracorporeal Cardiopulmonary Resuscitation Model for Neurological Outcomes: A Scoping Review

Background: Despite the high prevalence of neurological complications and mortality associated with extracorporeal cardiopulmonary resuscitation (ECPR), neurologically-focused animal models are scarce. Our objective is to review current ECPR models investigating neurological outcomes and identify key elements for a recommended model. Methods: We searched PubMed and four other engines for animal ECPR studies examining neurological outcomes. Inclusion criteria were: animals experiencing cardiac arrest, ECPR/ECMO interventions, comparisons of short versus long cardiac arrest times, and neurological outcomes. Results: Among 20 identified ECPR animal studies (n = 442), 13 pigs, 4 dogs, and 3 rats were used. Only 10% (2/20) included both sexes. Significant heterogeneity was observed in experimental protocols. 90% (18/20) employed peripheral VA-ECMO cannulation and 55% (11/20) were survival models (median survival = 168 hours; ECMO duration = 60 minutes). Ventricular fibrillation (18/20, 90%) was the most common method for inducing cardiac arrest with a median duration of 15 minutes (IQR = 6–20). In two studies, cardiac arrests exceeding 15 minutes led to considerable mortality and neurological impairment. Among seven studies utilizing neuromonitoring tools, only four employed multimodal devices to evaluate cerebral blood flow using Transcranial Doppler ultrasound and near-infrared spectroscopy, brain tissue oxygenation, and intracranial pressure. None examined cerebral autoregulation or neurovascular coupling. Conclusions: The substantial heterogeneity in ECPR preclinical model protocols leads to limited reproducibility and multiple challenges. The recommended model includes large animals with both sexes, standardized pre-operative protocols, a cardiac arrest time between 10–15 minutes, use of multimodal methods to evaluate neurological outcomes, and the ability to survive animals after conducting experiments

Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State

Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid–pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid–acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid–pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid–pyridine chains. Conversely, for the compounds that form acid–acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization