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991.
Aaron B. Krueger Judith Hadley Philip P. Cheney Natalia Markova John F. Carpenter Amber Haynes Fradkin 《Journal of pharmaceutical sciences》2019,108(5):1675-1685
Characterizing and quantifying subvisible particles in protein drug products is critical to ensuring product quality. A variety of analytical methods are used to detect and make meaningful measurements of subvisible particles. Resonant mass measurement (RMM) is a novel technology that characterizes the subvisible particle content of samples on a particle-by-particle basis. The technology presents great promise in the study of therapeutic protein products. As an emerging tool in the biopharmaceutical field, the best practices and limitations of RMM for protein products have not been well established. One key challenge of particle analysis is producing robust and reliable data, with high precision and accuracy, for particle characterization. In this study, we develop a set of possible best practices for RMM using a model protein system. We test the effects of these practices on the repeatability and reproducibility of particle measurements. Additionally, we present the data collected under a rigorously controlled set of operating conditions at 3 collaborating sites as well as a summary of the resulting optimal practices. In employing these practices, we successfully obtained improved relative standard deviation values and achieved high reproducibility and repeatability in both sizing and concentration measurement results over a broad range of sample volumes. 相似文献
992.
Priya N.O. Kasimbeg Fook Chiong Cheong David B. Ruffner Jaroslaw M. Blusewicz Laura A. Philips 《Journal of pharmaceutical sciences》2019,108(1):155-161
Characterizing protein aggregates in the presence of silicone oil is a long standing challenge for the pharmaceutical industry. Silicone oil is often used as a lubricant in devices that deliver and store therapeutic protein products and has been linked to protein aggregation, which can compromise a drug’s effectiveness or cause autoimmune responses in patients. Most traditional technologies cannot quantitatively distinguish protein aggregates and silicone oil in their native formulations for sizes less than 5 μm. We use holographic video microscopy to study protein aggregation to demonstrate its capability to quantitatively distinguish protein aggregates and silicone oil in the presence of varying amounts of the surfactants SDS and polysorbate 80 in the size range of 0.5-10 μm without the need for dilution or special sample preparation. We show that SDS denatures proteins and stabilizes silicone oil. We also show that polysorbate 80 may limit protein aggregate formation if it is added to an IgG solution before introducing silicone oil. 相似文献
993.
Jakob W. Buecheler Matthias Winzer Christian Weber Henning Gieseler 《Journal of pharmaceutical sciences》2019,108(3):1236-1245
Oxidation of biopharmaceutics represents a major degradation pathway, which may impact bioactivity, serum half-life, and colloidal stability. This study focused on the quantification of oxidation and its effects on structure and colloidal stability for a model antibody and its lysine (ADC-L) and cysteine (ADC-C) conjugates. The effects of oxidation were evaluated by a forced degradation study using H2O2 and a shelf-life simulation, which used degrading polysorbate 80 as source for reactive oxygen species. Differential scanning fluorimetry revealed decreasing transition temperatures of the CH2 domain with rising oxidation, resulting in a loss of colloidal stability as assessed by size-exclusion high pressure liquid chromatography. The conjugation technique influences structural changes of the monoclonal antibody (mAb) and subsequently alters the impact of oxidation. ADC-C was most effected by oxidation as the CH2 domain showed the biggest destabilization on conjugation compared to the mAb and ADC-L. Quantification of Fc methionine oxidation by analytical protein A chromatography revealed 4-fold higher oxidation after 8 weeks for the ADC-C compared to the mAb. Payload degradation was observed independently of the conjugation technique used or if free in solution by ultraviolet-visible. In addition, adding antioxidants can be a suitable approach to prevent oxidation and achieve baseline stabilization of the proteins. 相似文献
994.
Masato Kiyoshi Hiroko Shibata Akira Harazono Tetsuo Torisu Takahiro Maruno Michiko Akimaru Yuuka Asano Mai Hirokawa Keisuke Ikemoto Yukari Itakura Takafumi Iwura Aya Kikitsu Takashi Kumagai Naoki Mori Hiroaki Murase Hirotaka Nishimura Atsushi Oda Taiichiro Ogawa Akiko Ishii-Watabe 《Journal of pharmaceutical sciences》2019,108(2):832-841
The evaluation of subvisible particles, including protein aggregates, in therapeutic protein products has been of great interest for both pharmaceutical manufacturers and regulatory agencies. To date, the flow imaging (FI) method has emerged as a powerful tool instead of light obscuration (LO) due to the fact that (1) protein aggregates contain highly transparent particles and thereby escape detection by LO and (2) FI provides detailed morphological characteristics of subvisible particles. However, the FI method has not yet been standardized nor listed in any compendium. In an attempt to assess the applicability of the standardization of the FI method, we conducted a collaborative study using FI and LO instruments in a Japanese biopharmaceutical consortium. Three types of subvisible particle preparations were shared across 12 laboratories and analyzed for their sizes and counts. The results were compared between the methods (FI and LO), inter-laboratories, and inter-instruments (Micro Flow Imaging and FlowCam). We clarified the marked difference between the detectability of FI and LO when counting highly transparent protein aggregates in the preparations. Although FlowCam provided a relatively higher number of particles compared with MFI, consistent results were obtained using the instrument from the same manufacturer in all 3 samples. 相似文献
995.
《Transfusion and apheresis science》2023,62(3):103620
BackgroundA splenectomy can reduce transfusion requirements in patients with thalassemia. However, the role of a splenectomy remains controversial because its efficacy has not yet been fully determined and there are concerns over potential complications. The purpose of this study was to assess the efficacy, potential changes in hematologic parameters, and any complications associated with splenectomy.MethodsMedical records of 50 patients with transfusion-dependent thalassemia (TDT) who had undergone a splenectomy, along with those of 20 control subjects with intact spleens, were retrospectively reviewed.ResultsThe primary outcomes indicate the efficacy of a splenectomy in reducing red cell transfusions. Fifty TDT post-splenectomy patients were included in this study, of which 28 (56%) were female. The median age of all patients was 20.5 (18–28 years of age). Twenty-seven patients (54%) transformed from TDT to non-transfusion-dependent thalassemia (NTDT) after the splenectomy; 100% with Hb H disease, 58.3% with beta-thalassemia/Hb E disease, and 23.5% with homozygous beta-thalassemia. According to multivariable logistic regression analysis, Hb H disease (adjusted OR 55.23, 95% CI 1.35–22.8.10) and receiving a splenectomy at > ten years of age (adjusted OR 25.36, 95% CI 1.62–396.47) were associated with higher responses. The prevalence of pulmonary hypertension and thromboembolic events were similar between the splenectomy patients and non-splenectomy patients.ConclusionSplenectomy reduced transfusion requirements in TDT patients. The predictive factors as a response to a splenectomy included Hb H disease amongthose receiving a splenectomy at > ten years of age. 相似文献
996.
997.
998.
Michael D. Aleo Colleen M. Doshna Daniel Baltrukonis Jay H. Fortner Cynthia A. Drupa Kimberly A. Navetta Carol A. Fritz David M. Potter Maria E. Verdugo William P. Beierschmitt 《Journal of applied toxicology : JAT》2019,39(9):1348-1361
CJ‐12,918, a 5‐lipoxygenase (5‐LO) inhibitor, caused cataracts during a 1‐month safety assessment studies in rats whereas the structurally similar ZD‐2138 was without effect. For CJ‐12,918 analogs, blocking different sites of metabolic liability reduced (CJ‐13,454) and eliminated (CJ‐13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD‐2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanism‐based screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ‐12,918 inhibited lens cholesterol biosynthesis (LCB). A 2‐day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5‐LO inhibitors. Thereafter, this 2‐day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl‐CoA desaturase‐1 inhibitors/D4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH‐6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1 month. 相似文献
999.
Daniel H. Fine Gary C. Armitage Robert J. Genco Ann L. Griffen Scott R. Diehl 《Journal of the American Dental Association (1939)》2019,150(11):922-931
BackgroundLocalized aggressive periodontitis (LAgP) occurs in 2% of African-American adolescents but only 0.15% of white adolescents. First molars and incisors are affected by rapid onset and progression.MethodsThis nonsystematic critical review evaluated published data for LAgP and chronic periodontitis (CP), focusing on potential differences in epidemiology, microbiology, immunology, genetics, and response to therapy.ResultsLAgP differs from CP by localization to incisors and first molars, early onset and rapid progression in adolescents and young adults, and a 10-fold higher prevalence in populations of African or Middle Eastern origin, often with strong familial aggregation. The bacterium Aggregatibacter actinomycetemcomitans and hyperresponsive neutrophils are frequently observed. Antibiotic and nonsurgical therapies are highly effective.ConclusionsLAgP differs in many ways from the far more common CP that affects older adults. The substantial evidence of dissimilarities summarized in this review strongly supports the classification of LAgP as a distinct form of periodontitis.Practical ImplicationsClassifying LAgP as a distinct subcategory of periodontitis will encourage future research and does not conflict with the newly proposed “staging and grading” system. The silent onset and rapid progression of LAgP make early diagnosis and frequent follow-up with patients essential for effective treatment. 相似文献
1000.
Heparin-induced thrombocytopenia (HIT) is a rare, potentially life-threatening condition secondary to unfractionated heparin or low molecular weight heparin exposure. This immune-mediated drug reaction manifests as thrombocytopenia with a paradoxical hypercoagulable state that can result in life-threatening thrombosis. It is imperative to ensure cessation of heparin-based products as soon as HIT is identified. Traditional treatment options include argatroban, bivalirudin, fondaparinux, and danaparoid with a transition to warfarin upon platelet recovery. These anticoagulants are notwithstanding limitations including parenteral administration and routine laboratory monitoring leading to prolonged hospitalizations, emphasizing the need for new therapies. Direct oral anticoagulants (DOACs) have been increasingly investigated for the management of HIT and may overcome the aforementioned challenges of current therapies. The objective of this narrative review is to summarize the current HIT guidelines, discuss limitations to contemporary treatment options, provide insight into the emerging evidence for the DOACs rivaroxaban, apixaban, and dabigatran, and conclude with a clinical summary for their use in this setting. The PubMed, Google Scholar, and MEDLINE databases were searched for peer-reviewed literature from January 1, 2012, to June 31, 2018. Twenty-seven articles met inclusion criteria for review: 1 prospective trial, 5 retrospective cohort studies, and 21 case reports totaling 104 patients treated with a DOAC for HIT. The DOACs prevented new and recurrent thrombosis in 98% (n=102) of cases, and bleeding complications occurred in 3% (n=3). While current literature remains limited, it is suggestive of a potential role of DOACs for HIT, which has led to their integration into the 2018 American Society Hematology Guidelines with a conditional recommendation. 相似文献