- Freeze-dried plasma stability under prehospital field conditions. [Journal Article]Transfusion 2019T
- CONCLUSIONS: Our data show minimal decreases in clotting factors in FDP after storage under field conditions, when compared to laboratory normal ranges. Along with the many advantages of FDP, this supports its use at the point of injury under battlefield conditions, despite uncontrolled storage environments. Under controlled storage conditions at 4°C, shelf life could possibly be extended, although further study is required.
- Optimization of Cancer Treatment in the Frequency Domain. [Journal Article]AAPS J 2019; 21(6):106AJ
- Thorough exploration of alternative dosing frequencies is often not performed in conventional pharmacometrics approaches. Quantitative systems pharmacology (QSP) can provide novel insights into optimal dosing regimen and drug behaviors which could add a new dimension to the design of novel treatments. However, methods for such an approach are currently lacking. Recently, we illustrated the utilit…
Thorough exploration of alternative dosing frequencies is often not performed in conventional pharmacometrics approaches. Quantitative systems pharmacology (QSP) can provide novel insights into optimal dosing regimen and drug behaviors which could add a new dimension to the design of novel treatments. However, methods for such an approach are currently lacking. Recently, we illustrated the utility of frequency-domain response analysis (FdRA), an analytical method used in control engineering, using several generic pharmacokinetic-pharmacodynamic case studies. While FdRA is not applicable to models harboring ever increasing variables such as those describing tumor growth, studying such models in the frequency domain provides valuable insight into optimal dosing frequencies. Through the analysis of three distinct tumor growth models (cell cycle-specific, metronomic, and acquired resistance), we demonstrate the application of a simulation-based analysis in the frequency domain to optimize cancer treatments. We study the response of tumor growth to dosing frequencies while simultaneously examining treatment safety, and found for all three models that above a certain dosing frequency, tumor size is insensitive to an increase in dosing frequency, e.g., for the cell cycle-specific model, one dose per 3 days, and an hourly dose yield the same reduction of tumor size to 3% of the initial size after 1 year of treatment. Additionally, we explore the effect of drug elimination rate changes on the tumor growth response. In summary, we show that the frequency-domain view of three models of tumor growth dynamics can help in optimizing drug dosing regimen to improve treatment success.
- Relationship between Circadian Variation in Ictus of Aneurysmal Subarachnoid Hemorrhage and Physical Activity. [Journal Article]J Korean Neurosurg Soc 2019; 62(5):519-525JK
- CONCLUSIONS: This study reaffirmed that aSAH occurs in a bimodal pattern, especially showing the highest prevalence in the morning. Although aSAH could be related to daily activity, there were no significant changes in diurnal variations affected by the degree of physical exertion.
- Method to Predict Glass Vial Fogging in Lyophilized Drug Products. [Journal Article]J Pharm Sci 2019JP
- Glass fogging is a phenomenon occurring in lyophilized drug products and can be described as a thin product layer deposited on the inner surface of the glass container, in the area not covered by the lyo cake itself. It is often considered a cosmetic defect; however, the loss of container closure integrity is a potential consequence of the fogging's expansion to the vial neck region, making this …
Glass fogging is a phenomenon occurring in lyophilized drug products and can be described as a thin product layer deposited on the inner surface of the glass container, in the area not covered by the lyo cake itself. It is often considered a cosmetic defect; however, the loss of container closure integrity is a potential consequence of the fogging's expansion to the vial neck region, making this a potential critical defect. Thus, a method for predicting the extent of vial fogging before the actual freeze-drying is of particular interest for the pharmaceutical industry. For that reason, we evaluated a simple method ("simulated fogging") applicable to drug product formulations in a specific container closure system. Two different vial types with different surface hydrophilicity were tested using 3 model protein formulations, comparing the simulated fogging test and the degree of fogging after actual lyophilization. The simulated fogging method could predict fogging and showed a correlation to fogging in lyophilized drug product glass vials. We observed that all formulations showed fogging in the hydrophilic vials. By contrast, hydrophobic vials prevented fogging, however, interestingly with remaining defects of so-called droplet formation. Other than extent of fogging, no additional differences of lyophilized cake properties or other product quality attributes were observed between products using the different glass vial types tested.
- Assessment of interstitial lung disease among black rheumatoid arthritis patients. [Journal Article]Clin Rheumatol 2019CR
- CONCLUSIONS: Our study indicates RA-ILD among Blacks is predominantly a disease of elderly females with higher rates of GERD and CVD risk factors. Further studies are needed to identify the pathogenetic differences accounting for the gender distribution of RA-ILD among Black and White populations. Key Points • First study to assess ILD among predominantly Black RA patients. • The prevalence of RA-associated ILD was 6.36%, affecting mostly women in their sixth decade with seropositive disease. • COPD was the most common airway disease among non-RA-ILD Black population. • GERD was found in approximately one-third of patients with RA-associated ILD versus one-fifth of those RA patients without any lung disease.
- Optimised lyophilisation-based method for different biomolecule single-extractions from the same rat brain sample: Suitability for RNA and protein expression analyses after ischemic stroke. [Journal Article]J Neurosci Methods 2019; 327:108402JN
- CONCLUSIONS: The lyophilisation-based method for different biomolecule single-extractions from tissue powder aliquots, representing the same rat brain sample, is sample saving, contributes to the reduction principle in animal research, and allows coordinated analysis for accurate correlations between the transcriptome and proteome in stroke and other neuroscience research.
- Roux-en-Y gastric bypass is a safe and effective option that improves major Co-Morbidities associated with obesity in an older, veteran population. [Journal Article]Am J Surg 2019; 218(4):684-688AJ
- CONCLUSIONS: RYGB offers sustained, long-term weight loss with significant resolution of major comorbidities in older veterans, with acceptably low morbidity and mortality.
- Half-life extension and non-human primate pharmacokinetic safety studies of i-body AD-114 targeting human CXCR4. [Journal Article]MAbs 2019; 11(7):1331-1340MABS
- Single domain antibodies that combine antigen specificity with high tissue penetration are an attractive alternative to conventional antibodies. However, rapid clearance from the bloodstream owing to their small size can be a limitation of therapeutic single domain antibodies. Here, we describe and evaluate the conjugation of a single domain i-body, AD-114, which targets CXCR4, to a panel of half…
Single domain antibodies that combine antigen specificity with high tissue penetration are an attractive alternative to conventional antibodies. However, rapid clearance from the bloodstream owing to their small size can be a limitation of therapeutic single domain antibodies. Here, we describe and evaluate the conjugation of a single domain i-body, AD-114, which targets CXCR4, to a panel of half-life extension technologies including a human serum albumin-binding peptide, linear and branched PEG, and PASylation (PA600). The conjugates were assessed in murine, rat and cynomolgus monkey pharmacokinetic studies and showed that the branched PEG was most effective at extending circulating half-life in mice; however, manufacturing limitations of PEGylated test material precluded scale-up and assessment in larger animals. PA600, by comparison, was amenable to scale-up and afforded considerable half-life improvements in mice, rats and cynomolgus monkeys. In mice, the circulating half-life of AD-114 was extended from 0.18 h to 7.77 h following conjugation to PA600, and in cynomolgus monkeys, the circulating half-life of AD-114-PA600 was 24.27 h. AD-114-PA600 was well tolerated in cynomolgus monkeys at dose rates up to 100 mg/kg with no mortalities or drug-related clinical signs.
- Genetic variants and cognitive functions in patients with brain tumors. [Journal Article]Neuro Oncol 2019; 21(10):1297-1309NO
- CONCLUSIONS: This novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.
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- Confounders in Adenoma Detection at Initial Screening Colonoscopy: A Factor in the Assessment of Racial Disparities as a Risk for Colon Cancer. [Journal Article]J Cancer Ther 2019; 10(4):269-289JC
- CONCLUSIONS: In this sample, there was no association between race and adenoma detection. While this may be due to a lower prevalence of risk factors for adenomas in this sample, our findings were confounded by a lower detection rate by consultant gastroenterologists at one institution. The study allowed us to rectify the problem and characterize patients for future trials.