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1.
Artículo en Inglés | MEDLINE | ID: mdl-38836654

RESUMEN

STUDY DESIGN/SETTING: This retrospective study analyzed bracing outcomes in AIS patients, focusing on curve pattern changes and brace efficacy. OBJECTIVE: To analyze the effectiveness of the Chêneau brace across different curve patterns and to evaluate the tendencies in curve evolution during treatment. SUMMARY OF BACKGROUND DATA: Adolescent idiopathic scoliosis (AIS) presents diverse curve patterns, each responding differently to bracing. Understanding these variations is crucial for optimizing treatment strategies. METHODS: The study included 177 AIS patients treated with Chêneau orthoses, categorized based on curve patterns as per the main curve and modified Lenke (mLenke) classifications. We compared patients according to curve patterns and assessed changes in curve magnitude and pattern before and after treatment. RESULTS: Over an average follow-up of 28.1±10.7 months, the primary curve magnitude decreased from 28.8±6.6° to 25.9±10.5°. Significant reductions were observed in mLenke V and VI patients (P<0.05). Patients with main lumbar curves showed better initial in-brace correction and curve control compared with those with main thoracic curves (P<0.05). In single-curve patterns, binary logistic regression indicated that mLenke V patients demonstrated higher rates of curve control compared with mLenke I patients (P<0.05). No significant differences were found in double-curve patterns between mLenke III and VI (P>0.05). At the final follow-up, thoracolumbar/lumbar curves improved significantly in mLenke III and VI patients (P<0.05), while thoracic curves did not (P>0.05). Furthermore, at the last follow-up, the proportions of mLenke I, II, and IV increased, while mLenke III, V, and VI decreased. CONCLUSIONS: Bracing outcomes were more favorable in patients with main lumbar curves than those with main thoracic curves. However, no significant differences were found in patients with double-curve patterns. Thoracic curves exhibited a higher progression risk compared with thoracolumbar/lumbar curves within the same curve pattern. During bracing, a tendency for primary curves to shift proximally was noted.

2.
Nat Commun ; 15(1): 4744, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834549

RESUMEN

Developing mild photocatalytic bromination strategies using sustainable bromo source has been attracting intense interests, but there is still much room for improvement. Full utilization of redox centers of photocatalysts for efficient generation of Br+ species is the key. Herein we report heterogenous organophotocatalytic HBr oxidation coupled with oxygen reduction to furnish Br2 and H2O2 for effective bromination of arenes over Al2O3 supported perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA). Mechanism studies suggest that O-vacancy in Al2O3 can provide Lewis-acid-type anchoring sites for O2, enabling unexpected dual-electron transfer from anchored photoexcited PTCDA to chemically bound O2 to produce H2O2. The in-situ generated H2O2 and Br2 over redox centers work together to generate HBrO for bromination of arenes. This work provides new insights that heterogenization of organophotocatalysts can not only help to improve their stability and recyclability, but also endow them with the ability to trigger unusual reaction mode via cooperative catalysis with supports.

3.
BMC Vet Res ; 20(1): 191, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734611

RESUMEN

BACKGROUND: Many proteins of African swine fever virus (ASFV, such as p72, p54, p30, CD2v, K205R) have been successfully expressed and characterized. However, there are few reports on the DP96R protein of ASFV, which is the virulence protein of ASFV and plays an important role in the process of host infection and invasion of ASFV. RESULTS: Firstly, the prokaryotic expression vector of DP96R gene was constructed, the prokaryotic system was used to induce the expression of DP96R protein, and monoclonal antibody was prepared by immunizing mice. Four monoclonal cells of DP96R protein were obtained by three ELISA screening and two sub-cloning; the titer of ascites antibody was up to 1:500,000, and the monoclonal antibody could specifically recognize DP96R protein. Finally, the subtypes of the four strains of monoclonal antibodies were identified and the minimum epitopes recognized by them were determined. CONCLUSION: Monoclonal antibody against ASFV DP96R protein was successfully prepared and identified, which lays a foundation for further exploration of the structure and function of DP96R protein and ASFV diagnostic technology.


Asunto(s)
Virus de la Fiebre Porcina Africana , Anticuerpos Monoclonales , Epítopos , Ratones Endogámicos BALB C , Proteínas Virales , Animales , Femenino , Ratones , Fiebre Porcina Africana/inmunología , Fiebre Porcina Africana/virología , Virus de la Fiebre Porcina Africana/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Epítopos/inmunología , Porcinos , Proteínas Virales/inmunología
4.
Molecules ; 29(9)2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38731425

RESUMEN

Perylenetetracarboxylic dianhydride (PTCDA) derivatives have received significant attention as molecule photocatalysts. However, the poor recyclability of molecule-type photocatalysts hinders their widespread applications. Herein, immobilization of PTCDA on Al2O3 was achieved by simply physical mixing, which not only dramatically improved their recyclability, but also surprisingly improved the reactivity. A mechanism study suggested that the photo-exited state (PTCDA*) of PTCDA could promote the oxidation of thioanisole to generate PTCDA•-, which sequentially reduces oxygen to furnish superoxide radicals to achieve the catalytic cycle. Herein, the immobilization support Al2O3 was able to facilitate the strong adsorption of thioanisole, thereby boosting the photocatalytic activity. This work provides a new insight that the immobilization of organic molecular photocatalysts on those supports with proper adsorption sites could furnish highly efficient, stable, and recyclable molecular-based heterogeneous photocatalysts.

5.
Front Public Health ; 12: 1329768, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38737867

RESUMEN

Objectives: This study aimed to analyze the influencing factors of hospitalization cost of hypertensive patients in TCM (traditional Chinese medicine, TCM) hospitals, which can provide a scientific basis for hospitals to control the hospitalization cost of hypertension. Methods: In this study, 3,595 hospitalized patients with a primary diagnosis of tertiary hypertension in Tianshui City Hospital of TCM, Gansu Province, China, from January 2017 to June 2022, were used as research subjects. Using univariate analysis to identify the relevant variables of hospitalization cost, followed by incorporating the statistically significant variables of univariate analysis as independent variables in multiple linear regression analysis, and establishing the path model based on the results of the multiple linear regression finally, to explore the factors influencing hospitalization cost comprehensively. Results: The results showed that hospitalization cost of hypertension patients were mainly influenced by length of stay, age, admission pathways, payment methods of medical insurance, and visit times, with length of stay being the most critical factor. Conclusion: The Chinese government should actively exert the characteristics and advantages of TCM in the treatment of chronic diseases such as hypertension, consistently optimize the treatment plans of TCM, effectively reduce the length of stay and steadily improve the health literacy level of patients, to alleviate the illnesses pain and reduce the economic burden of patients.


Asunto(s)
Hospitalización , Hipertensión , Medicina Tradicional China , Humanos , Femenino , Hipertensión/economía , Masculino , Persona de Mediana Edad , Medicina Tradicional China/economía , Medicina Tradicional China/estadística & datos numéricos , Hospitalización/economía , Hospitalización/estadística & datos numéricos , China , Anciano , Tiempo de Internación/estadística & datos numéricos , Tiempo de Internación/economía , Adulto , Costos de Hospital/estadística & datos numéricos
6.
Org Lett ; 26(19): 4098-4103, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38708839

RESUMEN

C-1-deuterated aldehydes are essential building blocks in the synthesis of deuterated chemicals and pharmaceuticals. This has led chemists to devise mild methodologies for their efficient production. Ideally, hydrogen-deuterium exchange (HDE) is the most effective approach. However, the traditional HDE for creating C-1-deuterated aldehydes often requires a complex system involving multiple catalysts and/or ligands. In this study, we present a mild photocatalytic HDE of the formyl C-H bond with D2O. This process is facilitated by chlorine radicals that are generated in situ from low-cost FeCl3. This strategy demonstrated a broad reaction scope and high functional group tolerance, affording good yields and ≤99% D incorporation. To bridge the gap between research and industrial applications, we designed a new flow photoreactor equipped with a high-intensity light-emitting diode bucket, enabling the synthesis of C-1-deuterated aldehydes on a scale of 85 g. Finally, we successfully produced several important deuterated aldehydes that are integral to the synthesis of deuterated pharmaceuticals.

7.
Pharm Res ; 41(5): 947-958, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38589647

RESUMEN

PURPOSE: We aim to present a refined thin-film model describing the drug particle dissolution considering radial diffusion in spherical boundary layer, and to demonstrate the ability of the model to describe the dissolution behavior of bulk drug powders. METHODS: The dissolution model introduced in this study was refined from a radial diffusion-based model previously published by our laboratory (So et al. in Pharm Res. 39:907-17, 2022). The refined model was created to simulate the dissolution of bulk powders, and to account for the evolution of particle size and diffusion layer thickness during dissolution. In vitro dissolution testing, using fractionated hydrochlorothiazide powders, was employed to assess the performance of the model. RESULTS: Overall, there was a good agreement between the experimental dissolution data and the predicted dissolution profiles using the proposed model across all size fractions of hydrochlorothiazide. The model over-predicted the dissolution rate when the particles became smaller. Notably, the classic Nernst-Brunner formalism led to an under-estimation of the dissolution rate. Additionally, calculation based on the equivalent particle size derived from the specific surface area substantially over-predicted the dissolution rate. CONCLUSION: The study demonstrated the potential of the radial diffusion-based model to describe dissolution of drug powders. In contrast, the classic Nernst-Brunner equation could under-estimate drug dissolution rate, largely due to the underlying assumption of translational diffusion. Moreover, the study indicated that not all surfaces on a drug particle contribute to dissolution. Therefore, relying on the experimentally-determined specific surface area for predicting drug dissolution is not advisable.


Asunto(s)
Liberación de Fármacos , Hidroclorotiazida , Tamaño de la Partícula , Polvos , Solubilidad , Polvos/química , Difusión , Hidroclorotiazida/química , Química Farmacéutica/métodos , Modelos Químicos , Simulación por Computador
8.
Mol Pharm ; 21(4): 1884-1899, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38512389

RESUMEN

Upon dissolution, amorphous solid dispersions (ASDs) of poorly water-soluble compounds can generate supersaturated solutions consisting of bound and free drug species that are in dynamic equilibrium with each other. Only free drug is available for absorption. Drug species bound to bile micelles, polymer excipients, and amorphous and crystalline precipitate can reduce the drug solute's activity to permeate, but they can also serve as reservoirs to replenish free drug in solution lost to absorption. However, with multiple processes of dissolution, absorption, and speciation occurring simultaneously, it may become challenging to understand which processes lead to an increase or decrease in drug solution concentration. Closed, nonsink dissolution testing methods used routinely, in the absence of drug removal, allow only for static equilibrium to exist and obscure the impact of each drug species on absorption. An artificial gut simulator (AGS) introduced recently consists of a hollow fiber-based absorption module and allows mass transfer of the drug from the dissolution media at a physiological rate after tuning the operating parameters. In the present work, ASDs of varying drug loadings were prepared with a BCS-II model compound, ketoconazole (KTZ), and hypromellose acetate succinate (HPMCAS) polymer. Simultaneous dissolution and absorption testing of the ASDs was conducted with the AGS, and simple analytical techniques were utilized to elucidate the impact of bound drug species on absorption. In all cases, a lower amount of crystalline precipitate was formed in the presence of absorption relative to the nonsink dissolution "control". However, formation of HPMCAS-bound drug species and crystalline precipitate significantly reduced KTZ absorption. Moreover, at high drug loading, inclusion of an absorption module was shown to enhance ASD dissolution. The rank ordering of the ASDs with respect to dissolution was significantly different when nonsink dissolution versus AGS was used, and this discrepancy could be mechanistically elucidated by understanding drug dissolution and speciation in the presence of absorption.


Asunto(s)
Absorción Gastrointestinal , Polímeros , Solubilidad , Cristalización , Liberación de Fármacos , Polímeros/química
9.
J Org Chem ; 89(6): 4120-4127, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38439707

RESUMEN

Heteroatom-adjacent C(sp3) radical cyclization of N-arylacrylamides provides a straightforward pathway to synthesize valuable 3-functionalized oxindoles. Traditional cyclization reactions normally require harsh conditions or transition-metal catalysts. Here, we developed a metal-free, diversity-oriented synthesis of 3-functionalized oxindoles via photochemically induced selective cleavage of C(sp3)-H bonds. A variety of 3-substituted oxindoles with functionalities such as ethers, polyhalogens, benzyl, and formyl groups can be obtained by a rational design. This strategy is characterized by its simple operation and mild conditions, aligning well with the developmental requirements for sustainable chemistry. The gram-scale continuous-flow synthesis and efficient construction of bioactive molecules highlight its practical utility.

10.
Int J Pharm ; 653: 123868, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38309485

RESUMEN

Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.


Asunto(s)
Celulosa , Absorción Gastrointestinal , Humanos , Composición de Medicamentos , Administración Oral , Percepción del Gusto , Estabilidad de Medicamentos
11.
Sci Total Environ ; 922: 171149, 2024 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-38402977

RESUMEN

The coupling relationship between land-use carbon emissions (LCE) and ecological environmental quality (EEQ) is critical for regional sustainable development. Rapid urbanization promotes a notable increase in LCE, which imparts significant stress on EEQ. This study used land use and cover change (LUCC) and Open-Data Inventory for Anthropogenic Carbon dioxide (ODIAC) data from the urban agglomeration in the middle reaches of the Yangtze River (UAMRYR) to evaluate LCE, applied a remote sensing ecological index (RSEI) model to calculate EEQ, and combined gravity and centroid movement trajectory models to analyze the spatiotemporal evolution characteristics of LCE and EEQ. Four-quadrant and coupling degree (CD) models were used to analyze the synergistic relationship and interaction intensity between LCE and EEQ based on three different scales of pixels, counties, and cities. The results show that: (1) LCE and EEQ exhibit clear spatial inequality distribution, and the total amount of LCE increased from 40.16 Mt. in 2000 to 131.99 Mt. in 2020; however, LCE has not yet reached peak carbon emissions. (2) From 2000 to 2020, cities with a strong correlation between LCE and EEQ showed an increasing trend, and the centroid of LCE moved sharply to Jiangxi during 2000-2005 and 2005-2010. (3) High-CD areas were primarily located in quadrant II, and low-CD areas in quadrant IV. The relationship between LCE and EEQ has improved over the past 21 years, and CD has been increasing. (4) The stability of the coupling results between LCE and EEQ was affected by different research scales; the larger the research scale is, the greater the change in the results. This study provides a scientific basis and practical scheme for LCE reduction, ecological environmental management, and regional sustainable development in the UAMRYR.

12.
Int J Soc Psychiatry ; 70(2): 289-297, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37947259

RESUMEN

OBJECTIVE: Many people with mental disorders are cared for by informed caregivers, but they usually have limited care-related training and lack caregiving capacity and support networks. In order to provide professional training and social support for informed caregivers, we designed the Caregivers-to-Caregivers Training Programme (C2C) and performed a pilot study to assess its effect. METHODS: Caregivers of persons with mental disorders who participated in the C2C were asked to participate in a quasi-experimental study to assess their knowledge and skills development, self-care ability, trainer engagement, and training content. A total of 800 participants completed self-designed evaluation questionnaires and two open-ended questions to gather suggestions and feedback. Assessments were carried out at pretest (baseline), post-test, and at 2-month follow-up. Results were analyzed using one-way repeated measures analysis of variance (ANOVA) and pairwise comparison method. RESULTS: At post-test, 667 assessments were considered valid and 515 were deemed valid at 2-month follow-up. One-way repeated-measures ANOVA showed that the main effect of the scores on knowledge and skills development and self-care ability from baseline to 2-month follow-up was significant (p < .001). Results of pairwise comparison method showed that the scores on each item of knowledge and skills development and self-care ability at post-test and at 2-month follow up were higher than those at baseline (p < .001). The scores on items of trainer engagement and training content were all above average (4/5). The open-ended questions resulted in 678 comments indicating that participants gained significant support from other caregivers and healthcare professionals in the alliance and wanted more and continuously updated material. CONCLUSION: This study demonstrated that C2C effectively improved the development of caregivers' knowledge, skills, and their self-care ability. Available social support for caregivers was better than average, including professional support and peer support.


Asunto(s)
Cuidadores , Trastornos Mentales , Humanos , Cuidadores/educación , Proyectos Piloto , Trastornos Mentales/terapia , Personal de Salud , Apoyo Social
13.
J Adv Nurs ; 2023 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-38041587

RESUMEN

AIMS: Fear of cancer recurrence (FCR) is a multifaceted concept influenced by individual characteristics, social support, psychological factors. This study aims to identify distinct FCR profiles among breast cancer patients and explore the associated variables with these patterns. DESIGN: A cross-sectional study was conducted from April 2022 to March 2023. METHODS: A convenience sample of 339 patients completed a questionnaire that assessed general and disease-related data, including the Fear of Progression Questionnaire-Short Form, Social Support Rating Scale, Medical Coping Modes Questionnaire. Statistical analysis involved latent profile analysis (LPA) and multinomial logistic regression. RESULTS: Three latent patterns of FCR were found: the low fear (28.9%), the moderate fear (51.3%), and the high fear (18.0%). The study identified the social support, family monthly income, employment status, utilization of confrontation coping mode and avoidance coping mode, as factors that impacted the FCR. CONCLUSIONS: Social support, family monthly income, employment status, and medical coping modes have been found to impact the FCR among newly diagnosed breast cancer patients. Healthcare professionals should focus on addressing FCR at diagnosis and implement effective interventions, such as promoting social support and encouraging adaptive coping, to alleviate this concern. IMPACT: Urgently addressing the FCR in Chinese breast cancer patients is imperative due to its profound influence on their holistic health. Through advanced LPA, we categorized the FCR progression, highlighting risks. These findings have implications for healthcare strategies, offering new insights to manage the FCR and improve patient well-being. Our study adds a fresh perspective to the factors underlying the FCR in breast cancer patients, contributing to the broader comprehension and management of this complex survivorship issue. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

14.
Org Lett ; 25(46): 8350-8355, 2023 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-37943664

RESUMEN

Herein, we describe a metal-free approach for the cross-coupling of arenes or styryl-thianthrenium salts (TTs) with diarylphosphines via an electron donor-acceptor (EDA) complex. Various tertiary phosphines were obtained with high site selectivity and good functional group tolerance. This method enables straightforward construction of C-P bonds via C-H activation of arenes and allows the late-stage functionalization of natural products or pharmaceutical molecules. Mechanistic studies support the approach involving a photoinduced EDA complex.

15.
Front Cell Dev Biol ; 11: 1282119, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38033870

RESUMEN

Most mammals tolerate exposure to hypobaric hypoxia poorly as it may affect multiple regulatory mechanisms and inhibit cell proliferation, promote apoptosis, limit tissue vascularization, and disrupt the acid-base equilibrium. Here, we quantified the functional state of germ cell development and demonstrated the interaction between the germ and somatic cells via single-cell RNA sequencing (scRNA-seq). The present study elucidated the regulatory effects of hypobaric hypoxia exposure on germ cell formation and sperm differentiation by applying enrichment analysis to genomic regions. Hypobaric hypoxia downregulates the genes controlling granule secretion and organic matter biosynthesis, upregulates tektin 1 (TEKT1) and kinesin family member 2C (KIF2C), and downregulates 60S ribosomal protein 11 (RPL11) and cilia- and flagella-associated protein 206 (CFAP206). Our research indicated that prosaposin-G protein-coupled receptor 37 (PSAP-GPR37) ligands mediate the damage to supporting cells caused by hypobaric hypoxic exposure. The present work revealed that hypoxia injures peritubular myoid (PTM) cells and spermatocytes in the S phase. It also showed that elongating spermatids promote maturation toward the G2 phase and increase their functional reserve for sperm-egg binding. The results of this study provide a theoretical basis for future investigations on prophylactic and therapeutic approaches toward protecting the reproductive system against the harmful effects of hypobaric hypoxic exposure.

16.
Artículo en Inglés | MEDLINE | ID: mdl-37820002

RESUMEN

Niclosamide is usually used for the treatment of parasite infections in animals. However, niclosamide and one of its metabolites 2-chloro-4-nitroaniline are mutagenic substances, and their residues in animal-derived foods are potential risks to consumers. As far as we know, there has been no immunoassay or pseudo immunoassay reported to determine niclosamide and its metabolites in animal-derived foods. In this study, a molecularly imprinted microsphere for niclosamide was first synthesized, and a streptavidin-horseradish peroxidase labelled conjugate was also synthesized. The two reagents were used to develop a pseudo enzyme-linked immunosorbent assay on conventional microplates for the determination of niclosamide and its two metabolites (2-chloro-4-nitroaniline and 5-chlorosalicylic acid) in fish. Because biotinylated horseradish peroxidase was used to amplify the signal, the method sensitivities for the three analytes were increased fivefold to 27.5-fold (limits of detection of 0.004-0.03 ng/mL) in comparison with the use of single horseradish peroxidase labelled conjugate (limits of detection of 0.11-0.16 ng/mL). Their recoveries from the standards fortified blank fish samples were in the range of 70.6-95.5%. This is the first study reporting a molecularly imprinted polymer-based pseudo immunoassay for screening of niclosamide and its metabolites in food sample.


Asunto(s)
Impresión Molecular , Niclosamida , Animales , Microesferas , Ensayo de Inmunoadsorción Enzimática/métodos , Peroxidasa de Rábano Silvestre , Impresión Molecular/métodos
17.
Mol Pharm ; 20(11): 5888-5900, 2023 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-37792707

RESUMEN

Various approaches have been developed to enhance the solubility or dissolution rate for the delivery of poorly water-soluble molecules. In this work, guided by an in silico solubility sensitivity analysis for oral absorption, a comparative assessment of the biopharmaceutical performance of a jet-milled free base, a tosylate salt, and a 50:50 (w/w) amorphous solid dispersion (ASD) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) of a weak base drug candidate, GDC-3280, was conducted. Successful particle size reduction without amorphization or form change was confirmed for the jet-milled free base. The potential of solubility enhancement and desupersaturation risk were identified for tosylate salt and ASD formulation by measurements of tosylate salt solubility product constant (Ksp) and amorphous solubility of GDC-3280. In vitro dissolution testing demonstrated dissolution rate improvement for the jet-milled free base when compared with the unmilled free base and confirmed solubility enhancement followed by desupersaturation for GDC-3280 tosylate salt and ASD formulation. A crystallization inhibitor, hydroxypropyl methylcellulose (HPMC), was found to slow down the desupersaturation of tosylate salt solution, providing general insights for the development of pharmaceutical salts with disproportionation risks. Finally, a pharmacokinetic study in dogs showed that the in vivo exposure increased by 1.7- to 2-fold for the tosylate salt and ASD formulation compared with the jet-milled free base, consistent with the in silico solubility sensitivity analysis for the fraction of drug absorbed. Overall, this work provides insights into the evaluation of multiple formulation approaches for enhancing the biopharmaceutical performance of poorly water-soluble drugs.


Asunto(s)
Productos Biológicos , Animales , Perros , Preparaciones Farmacéuticas/química , Tamaño de la Partícula , Química Farmacéutica , Solubilidad , Agua/química , Liberación de Fármacos
18.
Mol Pharm ; 20(5): 2452-2464, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37010134

RESUMEN

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.


Asunto(s)
Excipientes , Polímeros , Animales , Perros , Disponibilidad Biológica , Solubilidad , Dodecil Sulfato de Sodio/química , Polímeros/química , Comprimidos/química , Excipientes/química , Liberación de Fármacos
19.
Artículo en Inglés | MEDLINE | ID: mdl-37022430

RESUMEN

Real-world face super-resolution (SR) is a highly ill-posed image restoration task. The fully-cycled Cycle-GAN architecture is widely employed to achieve promising performance on face SR, but is prone to produce artifacts upon challenging cases in real-world scenarios, since joint participation in the same degradation branch will impact final performance due to huge domain gap between real-world and synthetic LR ones obtained by generators. To better exploit the powerful generative capability of GAN for real-world face SR, in this paper, we establish two independent degradation branches in the forward and backward cycle-consistent reconstruction processes, respectively, while the two processes share the same restoration branch. Our Semi-Cycled Generative Adversarial Networks (SCGAN) is able to alleviate the adverse effects of the domain gap between the real-world LR face images and the synthetic LR ones, and to achieve accurate and robust face SR performance by the shared restoration branch regularized by both the forward and backward cycle-consistent learning processes. Experiments on two synthetic and two real-world datasets demonstrate that, our SCGAN outperforms the state-of-the-art methods on recovering the face structures/details and quantitative metrics for real-world face SR. The code will be publicly released at https://github.com/HaoHou-98/SCGAN.

20.
Artículo en Inglés | MEDLINE | ID: mdl-36901332

RESUMEN

Foodborne diseases are a critical public health problem worldwide and significantly impact human health, economic losses, and social dynamics. Understanding the dynamic relationship between the detection rate of bacterial foodborne diseases and a variety of meteorological factors is crucial for predicting outbreaks of bacterial foodborne diseases. This study analyzed the spatio-temporal patterns of vibriosis in Zhejiang Province from 2014 to 2018 at regional and weekly scales, investigating the dynamic effects of various meteorological factors. Vibriosis had a significant temporal and spatial pattern of aggregation, and a high incidence period occurred in the summer seasons from June to August. The detection rate of Vibrio parahaemolyticus in foodborne diseases was relatively high in the eastern coastal areas and northwestern Zhejiang Plain. Meteorological factors had lagging effects on the detection rate of V. parahaemolyticus (3 weeks for temperature, 8 weeks for relative humidity, 8 weeks for precipitation, and 2 weeks for sunlight hours), and the lag period varied in different spatial agglomeration regions. Therefore, disease control departments should launch vibriosis prevention and response programs that are two to eight weeks in advance of the current climate characteristics at different spatio-temporal clustering regions.


Asunto(s)
Infecciones Bacterianas , Enfermedades Transmitidas por los Alimentos , Vibriosis , Humanos , Análisis Espacio-Temporal , Clima , Conceptos Meteorológicos , Incidencia , China/epidemiología
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