Probing Molecular Packing of Amorphous Pharmaceutical Solids Using X-ray Atomic Pair Distribution Function and Solid-State NMR.

The structural investigation of amorphous pharmaceuticals is of paramount importance in comprehending their physicochemical stability. However, it has remained a relatively underexplored realm primarily due to the limited availability of high-resolution analytical tools. In this study, we utilized the combined power of X-ray pair distribution functions (PDFs) and solid-state nuclear magnetic resonance (ssNMR) techniques to probe the molecular packing of amorphous posaconazole and its amorphous solid dispersion at the molecular level. Leveraging synchrotron X-ray PDF data and employing the empirical potential structure refinement (EPSR) methodology, we unraveled the existence of a rigid conformation and discerned short-range intermolecular C-F contacts within amorphous posaconazole. Encouragingly, our ssNMR 19F-13C distance measurements offered corroborative evidence supporting these findings. Furthermore, employing principal component analysis on the X-ray PDF and ssNMR data sets enabled us to gain invaluable insights into the chemical nature of the intermolecular interactions governing the drug-polymer interplay. These outcomes not only furnish crucial structural insights facilitating the comprehension of the underlying mechanisms governing the physicochemical stability but also underscore the efficacy of synergistically harnessing X-ray PDF and ssNMR techniques, complemented by robust modeling strategies, to achieve a high-resolution exploration of amorphous structures.

Predictive and Accelerated Formulation Design Using Synchrotron Methods.

Predictive formulation design and accelerated formulation design can lead to the discovery of useful formulations to support drug clinical studies and successful drug approval. Predictive formulation design can also lead to discovery of a path for commercialization, especially for poorly soluble drugs, when the target product profile is well defined and a "learning before doing" approach is implemented. One of the key components of predictive/accelerated formulation design is to understand and leverage the material properties of drug substance including solubility, BCS classification, polymorphs, salt formation, amorphous form, amorphous complex, and stability. In addition, utilizing synchrotron-based PDF (pair distribution function) analysis can provide important structural information for the formulation. This knowledge allows control of physical and chemical stability of the designed product. Finally, formulation design should link to process development following Quality by Design principles, and solid-state chemistry should play a critical role in many of the steps required to achieve Quality by Design, which can lead to successful product development.

Antiracism and mental health recovery: Bridging the gap to improve health disparities among veteran populations.

Viewing the Substance Abuse and Mental Health Services Administration's recovery principles through an antiracist lens has guided the authors' vision of recovery-oriented systems for all. In this brief letter, they present some considerations arising from their application of recovery principles to areas affected by racial bias. They are also identifying best practices for incorporating micro and macro antiracism efforts into recovery-oriented health care. These are important steps in promoting recovery-oriented care, but there is much more to do. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Acoustic levitation and high-resolution synchrotron X-ray powder diffraction: A fast screening approach of niclosamide amorphous solid dispersions.

The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents.

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg(-1)·day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1ß, IL-2, IL-6, MCP-1, IFNγ, and TNFα) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents.

Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration.

Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.

Leadership for learning: a literature study of leadership for learning in clinical practice.

AIM: To report a literature study of leadership for learning in clinical practice in the United Kingdom. Background Previous research in the United Kingdom showed that the ward sister was central to creating a positive learning environment for student nurses. Since the 1990s, the ward mentor has emerged as the key to student nurses' learning in the United Kingdom. METHODS: A literature study of new leadership roles and their influence on student nurse learning (restricted to the United Kingdom) which includes an analysis of ten qualitative interviews with stakeholders in higher education in the United Kingdom undertaken as part of the literature study. RESULTS: Learning in clinical placements is led by practice teaching roles such as mentors, clinical practice facilitators and practice educators rather than new leadership roles. However, workforce changes in clinical placements has restricted the opportunities for trained nurses to role model caring activities for student nurses and university based lecturers are increasingly distant from clinical practice. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Leadership for learning in clinical practice poses three unresolved questions for nurse managers, practitioners and educators - what is nursing, what should student nurses learn and from whom? IMPLICATIONS FOR NURSING MANAGEMENT: Leadership for student nurse learning has passed to new learning and teaching roles with Trusts and away from nursing managers. This has implications for workforce planning and role modelling within the profession.

Biological activity of AC3174, a peptide analog of exendin-4.

Exenatide, the active ingredient of BYETTA (exenatide injection), is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. Exenatide binds to and activates the known GLP-1 receptor with a potency comparable to that of the mammalian incretin GLP-1(7-36), thereby acting as a glucoregulatory agent. AC3174 is an analog of exenatide with leucine substituted for methionine at position 14, [Leu(14)]exendin-4. The purpose of these studies was to evaluate the glucoregulatory activity and pharmacokinetics of AC3174. In RINm5f cell membranes, the potency of AC3174 for the displacement of [(125)I]GLP-1 and activation of adenylate cyclase was similar to that of exenatide and GLP-1. In vivo, AC3174, administered as a single IP injection, significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge in both non-diabetic (C57BL/6) and diabetic db/db mice (P<0.05 vs. vehicle-treated). The magnitude of glucose lowering of AC3174 was comparable to exenatide. The ED(50) values of AC3174 for glucose lowering (60 minute post-dose) were 1.2 microg/kg in db/db mice and 1.3 microg/kg in C57BL/6 mice. AC3174 has insulinotropic activity in vivo. Administration of AC3174 resulted in a 4-fold increase in insulin concentrations in normal mice following an IP glucose challenge. AC3174 was also shown to inhibit food intake and decrease gastric emptying in rodent models. AC3174 was stable in human plasma (>90% of parent peptide was present after 5 h of incubation). In rats, the in vivo half-life of AC3174 was 42-43 min following SC administration. In summary, AC3174 is an analog of exenatide that binds to the GLP-1 receptor in vitro and shares many of the biological and glucoregulatory activities of exenatide and GLP-1 in vivo.

Scientific evidence for the identification of an Aboriginal massacre at the Sturt Creek sites on the Kimberley frontier of north-western Australia.

Archival research into episodes of frontier violence in the Kimberley region of Western Australia indicate that the bodies of Aboriginal victims of massacres were frequently incinerated following the event. This paper presents the results of a scientific investigation of a reported massacre at Sturt Creek where burnt bone fragments were identified in two adjacent sites and documents the archaeological signatures associated with the sites. The methodology used to undertake the project brought together three systems of knowledge: the oral testimonies of the descent group originating from a sole adult survivor of the massacre; archival, historical and scientific research. An archaeological survey defined the two distinct sites containing hundreds of fragile bone fragments; a third site was found to be highly disturbed. Scientific investigations included macroscopic and microscopic examination of selected bone fragments by an anatomical pathologist and a zooarchaeologist and X-ray diffraction analysis of sixteen bone fragments. The anatomical pathologist and zooarchaeologist undertook macroscopic and microscopic examinations of selected bone samples to identify morphological evidence for human origin. It was concluded that three bone fragments examined may have been human, and two of the fragments may have been from the vault of a skull. It was concluded that the likelihood of them being human would be strengthened if it was found that the three samples had been subjected to high temperatures. X-ray diffraction analysis of 16 bone fragments provided this evidence. All fragments showed sharp hydroxylapatite peaks (crystallite sizes 9882nm and 597nm respectively) and all had been subjected to extreme temperatures of either 600°C for more than 80h, 650°C for more than 20h, 700°C for more than 4h or 800°C for more than 1h. XRD analyses were also done on bone samples collected from three cooking hearths at three different archaeological sites. It was found that two of the three samples had been exposed to substantially lower temperatures for a short time period. It was concluded that there was strong pathological and archaeological evidence that the bone fragments were human in origin, but that the evidence was not conclusive. This research also identified archaeological signatures for the identification of massacre sites in similar Australian environments and circumstances.

Nutrition, hydration, and dysphagia in long-term care: Differing opinions on the effects of aspiration.

OBJECTIVES: This study examined the management of aspiration in skilled nursing settings, by determining speech-language pathologists' and nursing staff members' agreement about aspiration, interventions, and impact on residents' nutrition and hydration status, as determined by agreement scores on a questionnaire. DESIGN: Cross sectional descriptive. SETTING: Health care; skilled nursing facility. PARTICIPANTS: Seventy-eight speech-language pathologists (SLPs) and 83 nursing caregivers. INTERVENTION: Participants completed a survey questionnaire requesting a level of agreement with statements about aspiration and interventions for aspiration. Questionnaires also included demographic questions for analysis purposes. MEASUREMENTS: Agreement scores on a modified Likert scale. RESULTS: There were no significant differences in agreement scores for SLPs by formal training or years of experience. Nurses showed differences by experience for 2 statements, and by level of certification for 3 statements. There were significant differences between responses for nurses and SLPs for 7 of the 10 items. Both groups demonstrated content knowledge that conflicts with principles documented in the medical literature. CONCLUSION: Results suggest that both SLP and nursing training programs should include more evidence from multidisciplinary sources, specifically the medical literature, to improve the knowledge base of clinicians providing care to residents with swallowing disorders.

Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight.

The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin sensitivity, and beta-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 wk of treatment, ad libitum-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, hemoglobin A(1c) (HbA(1c)), and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats, compared with ad libitum-fed vehicle control (CON) rats (P < 0.001). The increases in HbA(1c) and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats, compared with CON rats (P < 0.001). The insulin sensitivity index (ISI; glucose infusion rate to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats (P < 0.001) and 61% higher in EX rats than PF rats (P < 0.004). The latter difference was despite comparable HbA(1c), fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, beta-cell mass was hyperbolically related to ISI (beta-cell mass * ISI was constant). Analogous to the disposition index, the beta-cell mass * ISI product was 63% greater in EX than PF rats (P < 0.05). Thus, exenatide increased beta-cell mass to a greater extent than would be expected in animals of comparable insulin resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/fa rats independent of body weight and glycemia.

Characterization of char from the pyrolysis of tobacco.

Pyrolysis of tobacco was studied in oxidative and nonoxidative (inert) environments at atmospheric pressure and temperatures ranging from 150 to 750 degrees C. The objective was to study the effect of pyrolysis conditions on the characteristics of the solid residue, i.e., char. The char was characterized using cross-polarization (13)C nuclear magnetic resonance (CPMAS NMR), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), the Brunauer-Emmett-Teller (BET) surface area, and the elemental composition. The char yield from pyrolysis (i.e., nonoxidative) decreased sharply with an increase in temperature to ca. 22% (dry, ash-free basis) at high temperatures. In oxidative pyrolysis, i.e., in 5% oxygen, the char was completely oxidized above 600 degrees C. The gaseous product from pyrolysis at high temperatures contained a significant concentration of hydrogen. The surface area of the char was low, with a maximum of 8 m(2)/g at 400 degrees C. SEM analysis indicated that pyrolysis of the tobacco led to a gradual accumulation of inorganic crystals on the exposed surfaces, and some constituents also melted, resulting in the formation of vesicles by evolving gas. NMR analysis showed significant changes in pectin and sugar constituents of the tobacco and breaking of glycosidic bonds of cellulose at 300-500 degrees C before the char became predominantly aromatic at high temperatures. FTIR results showed a continuous decrease in the intensity of the OH stretch with temperature and the aromatic character to be at maximum at 550-650 degrees C. The H/C ratio of the char decreased continuously with temperature, while the O/C ratio became constant above 300 degrees C due to the presence of oxides and carbonates in the char. The results are consistent with the analysis of the evolved gases.

Attention, working memory, and grammaticality judgment in typical young adults.

PURPOSE: To examine resource allocation and sentence processing, this study examined the effects of auditory distraction on grammaticality judgment (GJ) of sentences varied by semantics (reversibility) and short-term memory requirements. METHOD: Experiment 1: Typical young adult females (N = 60) completed a whole-sentence GJ task in distraction (Quiet, Noise, or Talk). Participants judged grammaticality of Passive sentences varied by sentence (length), grammaticality, and reversibility. Reaction time (RT) data were analyzed using a mixed analysis of variance. Experiment 2: A similar group completed a self-paced reading GJ task using the similar materials. RESULTS: Experiment 1: Participants responded faster to Bad and to Nonreversible sentences, and in the Talk distraction. The slowest RTs were noted for Good-Reversible-Padded sentences in the Quiet condition. Experiment 2: Distraction did not differentially affect RTs for sentence components. Verb RTs were slower for Reversible sentences. CONCLUSIONS: Results suggest that narrative distraction affected GJ, but by speeding responses, not slowing them. Sentence variables of memory and reversibility slowed RTs, but narrative distraction resulted in faster processing times regardless of individual sentence variables. More explicit, deliberate tasks (self-paced reading) resulted in less effect from distraction. Results are discussed in terms of recent theories about auditory distraction.

An orthotopic model of metastatic nasopharyngeal carcinoma and its application in elucidating a therapeutic target that inhibits metastasis.

To define and therapeutically target mechanisms that mediate nasopharyngeal carcinoma (NPC) metastasis, we have developed a unique orthotopic xenograft mouse model that accurately recapitulates the invasive and metastatic behavior of human disease. Based on clinical and laboratory evidence that the PI3K/Akt/mTOR axis is involved in aggressive NPC tumor behavior, we chose it as a therapeutic target to test the utility of our orthotopic system for evaluating the effectiveness of a targeted treatment for metastatic NPC. Demonstrated herein, we have shown that both the development and growth of metastatic lesions are markedly reduced by the mTOR inhibitor sirolimus. Thus, this orthotopic model provides a platform to study potential therapeutics for advanced NPC and demonstrates that targeting the PI3K/Akt/mTOR pathway is a promising intervention against disseminated disease.

Thermal inkjet application in the preparation of oral dosage forms: dispensing of prednisolone solutions and polymorphic characterization by solid-state spectroscopic techniques.

The utility of thermal inkjet (TIJ) technology for preparing solid dosage forms of drugs was examined. Solutions of prednisolone in a solvent mixture of ethanol, water, and glycerol (80/17/3 by volume) were dispensed onto poly(tetrafluoroethylene)-coated fiberglass films using TIJ cartridges and a personal printer and using a micropipette for comparison. The post-dried, TIJ-dispensed samples were shown to contain a mixture of prednisolone Forms I and III based on PXRD analyses that were confirmed by Raman analyses. The starting commercial material was determined to be Form I. Samples prepared by dispensing the solution from a micropipette initially showed only Form I; subsequent Raman mapping of these samples revealed the presence of two polymorphs. Raman mapping of the TIJ-dispensed samples also showed both polymorphs. The results indicate that the solvent mixture used in the dispensing solution combined with the thermal treatment of the samples after dispensing were likely the primary reason for the generation of the two polymorphs. The advantages of using a multidisciplinary approach to characterize drug delivery systems are demonstrated using solid state mapping techniques. Both PXRD and Raman spectroscopy were needed to fully characterize the samples. Finally, this report clarifies prednisolone's polymorphic nomenclature existent in the scientific literature.