This review describes essential aspects about application of HP-β-CD as excipient in pharmaceutical formulation, including physico-chemical properties of HP-β-CD, supply chain, regulatory, patent ...landscape, marketed drugs with HP-β-CD, analytics and analytical challenges, stability and control strategies, and safety concerns. It also provides an overview of different studies, and outcomes thereof, regarding formulation development for IgGs and Ig-based molecules in liquid and solid (lyophilized) dosage forms with HP-β-CD. The review specifically highlights the challenges for formulation manufacturing of IgG and Ig-based therapeutics with HP-β-CD and identifies areas for future work in pharmaceutical and formulation development.
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The main challenge to develop HCF for IgG and Ig-based therapeutics is to achieve essential solubility, viscosity and stability of these molecules in order to maintain product quality and meet regulatory requirement during manufacturing, production, storage, shipment and administration processes. The commonly used and FDA approved excipients for IgG and Ig –based therapeutics may no longer fulfil the challenge of HCF development for these molecules to certain extent, especially for some complex Ig-based platforms. 2-Hydroxypropyl beta-cyclodextrin (HP-β-CD) is one of the promising excipients applied recently for HCF development of IgG and Ig-based therapeutics although it has been used for formulation of small synthesized chemical drugs for more than thirty years.
This review describes essential aspects about application of HP-β-CD as excipient in pharmaceutical formulation, including physico-chemical properties of HP-β-CD, supply chain, regulatory, patent landscape, marketed drugs with HP-β-CD, analytics and analytical challenges, stability and control strategies, and safety concerns. It also provides an overview of different studies, and outcomes thereof, regarding formulation development for IgGs and Ig-based molecules in liquid and solid (lyophilized) dosage forms with HP-β-CD. The review specifically highlights the challenges for formulation manufacturing of IgG and Ig-based therapeutics with HP-β-CD and identifies areas for future work in pharmaceutical and formulation development.
To present the 3-year experience of using venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure in a single centre in Hong Kong.
Case series.
A 19-bed Intensive ...Care Unit of a tertiary hospital in Hong Kong.
All patients who were managed with venovenous extracorporeal membrane oxygenation from 1 July 2010 to 30 June 2013 in the Intensive Care Unit.
Overall, 31 patients (mean age, 42.2 years, standard deviation, 14.1 years; 21 males) received venovenous extracorporeal membrane oxygenation for the treatment of severe respiratory failure. Of these, 90.3% (28 patients) presented with pneumonia as the cause of the respiratory failure, and 22 of them had identifiable causes. A total of nine (29.0%) patients were diagnosed to have H1N1 infection. The median Murray score was 3.5 (interquartile range, 3.0-3.5); the median duration of venovenous extracorporeal membrane oxygenation support was 5.0 (2.8-8.6) days; and the median duration of mechanical ventilator support was 18.2 (7.8-27.9) days. The overall intensive care unit mortality was 19.4% (n=6). The overall in-hospital mortality and the 28-day mortality were both 22.6% (n=7). Among the 22 patients who had identifiable infective causes, those suffering from viral infection had lower intensive care unit and hospital mortality than those who had bacterial infection (8.3% vs 20.0%). All the H1N1 patients survived. Complications related to extracorporeal membrane oxygenation included severe bleeding (n=2; 6.5%) and mechanical complications of the circuits (n=3; 9.7%).
Venovenous extracorporeal membrane oxygenation is an effective adjunctive therapy and can be used as a life-saving procedure for carefully selected patients with severe acute respiratory distress syndrome when the limits of standard therapy have been reached.
We conducted a retrospective cohort study to determine the 3-year reincarceration rate of all HIV-infected inmates (n = 1917) released from the Texas prison system between January 2004 and March ...2006. We also analyzed postrelease changes in HIV clinical status in the subgroup of inmates who were subsequently reincarcerated and had either CD4 lymphocyte counts (n = 119) or plasma HIV RNA levels (n = 122) recorded in their electronic medical record at both release and reincarceration. Multivariable analyses were performed to assess predictors of reincarceration and clinical changes in HIV status. Only 20% of all HIV-infected inmates were reincarcerated within 3 years of release. Female inmates (hazard ratio HR 0.63; 95% confidence interval CI, 0.47, 0.84) and inmates taking antiretroviral therapy at the time of release (HR 0.31; 95% CI, 0.25, 0.39) were at decreased risk of reincarceration. African Americans (HR 1.58; 95% CI, 1.22, 2.05), inmates with a major psychiatric disorder (HR 1.82; 95% CI, 1.41, 2.34), and inmates released on parole (HR 2.86; 95% CI, 2.31, 3.55) were at increased risk of reincarceration. A subgroup of reincarcerated inmates had a mean decrease in CD4 cell count of 79.4 lymphocytes per microliter (p < 0.0003) and a mean increase in viral load of 1.5 log(10) copies per milliliter (p < 0.0001) in the period between release and reincarceration. Our findings, although substantially limited by selection bias, highlight the importance of developing discharge planning programs to improve linkage to community-based HIV care and reduce recidivism among released HIV-infected inmates.
Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number ...of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.
Peripheral blood microRNAs (miRNA) have been identified as potential biomarkers for Alzheimer's disease (AD). Study results have generally been inconsistent and limited by sample heterogeneity. The ...aim of this study is to establish candidate blood miRNA biomarkers for AD by comparing differences in miRNA expression between participants with brain amyloid imaging-defined AD and normal cognition.
Blood RNA was extracted from a subset of participants from the Australian Imaging Biomarkers Lifestyle Study of Ageing cohort (AIBL) with brain amyloid imaging results. MiRNA profiling was performed using small RNA sequencing on 71 participants, comprising 40 AD with high brain amyloid burden on imaging (amyloid positive) and 31 cognitively normal controls with low brain amyloid burden (amyloid negative). Cross-sectional comparisons were made between groups to examine differential miRNA expression levels using Fisher's exact tests. Replication of results was undertaken using a publicly available dataset of blood miRNA data of AD and controls. In silico analysis of downstream messenger RNA targets of candidate miRNAs was performed to elucidate potential biological function.
After quality control, 816 miRNAs were available for analysis. There were 71 significantly differentially expressed miRNAs between the AD and control groups (p < 0.05). Two of these miRNAs, miR-146b-5p and miR-15b-5p, were also significant in the replication cohort. Pathways analysis showed these miRNAs to be involved in innate immune system and regulation of the cell cycle, respectively, both of which have relevance to AD pathogenesis.
Blood miR-146b-5p and miR15b-5p showed consistent differential expression in AD compared to controls. Further replication and translational studies in strictly phenotyped cohorts are needed to establish their role as biomarkers for AD to have clinical utility.
Interruption of antiretroviral therapy (ART) during the first weeks after release from prison may increase risk for adverse clinical outcomes, transmission of human immunodeficiency virus (HIV), and ...drug-resistant HIV reservoirs in the community. The extent to which HIV-infected inmates experience ART interruption following release from prison is unknown.
To determine the proportion of inmates who filled an ART prescription within 60 days after release from prison and to examine predictors of this outcome.
Retrospective cohort study of all 2115 HIV-infected inmates released from the Texas Department of Criminal Justice prison system between January 2004 and December 2007 and who were receiving ART before release.
Proportion of inmates who filled an ART prescription within 10, 30, and 60 days of release from prison.
Among the entire study cohort (N = 2115), an initial prescription for ART was filled by 115 (5.4%) inmates within 10 days of release (95% confidence interval CI, 4.5%-6.5%), by 375 (17.7%) within 30 days (95% CI, 16.2%-19.4%), and by 634 (30.0%) within 60 days (95% CI, 28.1%-32.0%). In a multivariate analysis of predictors (including sex, age, race/ethnicity, viral load, duration of ART, year of discharge, duration of incarceration, parole, and AIDS Drug Assistance Program application assistance), Hispanic and African American inmates were less likely to fill a prescription within 10 days (adjusted estimated risk ratio RR, 0.4 95% CI, 0.2-0.8 and 0.4 95% CI, 0.3-0.7, respectively) and 30 days (adjusted estimated RR, 0.7 95% CI, 0.5-0.9 and 0.7 95% CI, 0.5-0.9). Inmates with an undetectable viral load were more likely to fill a prescription within 10 days (adjusted estimated RR, 1.8 95% CI, 1.2-2.7), 30 days (1.5 95% CI, 1.2-1.8), and 60 days (1.3 95% CI, 1.1-1.5). Inmates released on parole were more likely to fill a prescription within 30 days (adjusted estimated RR, 1.3 95% CI, 1.1-1.6) and 60 days (1.5 95% CI, 1.4-1.7). Inmates who received assistance completing a Texas AIDS Drug Assistance Program application were more likely to fill a prescription within 10 days (adjusted estimated RR, 3.1 95% CI, 2.0-4.9), 30 days (1.8 95% CI, 1.4-2.2), and 60 days (1.3 95% CI, 1.1-1.4).
Only a small percentage of Texas prison inmates receiving ART while incarcerated filled an initial ART prescription within 60 days of their release.
To document the time course of perceived stress among women through the period of a natural disaster, to determine the effect of sleep quality on this time course, and to identify risk factors that ...predict higher levels of perceived stress.
Longitudinal study from 2006-2012.
Community-based family planning clinics in southeast Texas.
There were 296 women aged 18-31 y who experienced Hurricane Ike, September 2008.
Cohen Perceived Stress Scale (PSS) was administered every 2 mo from 6 mo before to 12 mo after Hurricane Ike. Sleep quality was assessed 1 mo after Hurricane Ike using the Pittsburg Sleep Quality Index (PSQI). Good sleep was defined as a PSQI summary score < 5, and poor sleep as a score ≥ 5. Hurricane Ike stressors (e.g., property damage, subjective stressors) and pre-Ike lifetime major life events and emotional health (e.g., emotional dysregulation, self-control) were also assessed.
Over the entire period of 18 mo (6 mo before and 12 mo after the hurricane), perceived stress was significantly higher among poor sleepers compared to good sleepers, and only good sleepers showed a significant decrease in perceived stress after Hurricane Ike. In addition, a higher level of perceived stress was positively associated with greater Ike damage among poor sleepers, whereas this correlation was not observed among good sleepers. In the final multivariate longitudinal model, Ike-related subjective stressors as well as baseline major life events and emotional dysregulation among poor sleepers predicted higher levels of perceived stress over time; among good sleepers, additional factors such as lower levels of self-control and having a history of a psychiatric disorder also predicted higher levels of perceived stress.
Sleep quality after Hurricane Ike, an intense natural disaster producing substantial damage, impacted changes in perceived stress over time. Our findings suggest the possibility that providing victims of disasters with effective interventions to improve sleep quality could help to reduce their perceived stress over time.
The acquisition of reliable kinetic parameters for the characterization of biomolecular interactions is an important component of the drug discovery and development process. While several benchmark ...studies have explored the variability of kinetic rate constants obtained from multiple laboratories and biosensors, a direct comparison of these instruments' performance has not been undertaken, and systematic factors contributing to data variability from these systems have not been discussed. To address these questions, a panel of ten high-affinity monoclonal antibodies was simultaneously evaluated for their binding kinetics against the same antigen on four biosensor platforms: GE Healthcare's Biacore T100, Bio-Rad's ProteOn XPR36, ForteBio's Octet RED384, and Wasatch Microfluidics's IBIS MX96. We compared the strengths and weaknesses of these systems and found that despite certain inherent systematic limitations in instrumentation, the rank orders of both the association and dissociation rate constants were highly correlated between these instruments. Our results also revealed a trade-off between data reliability and sample throughput. Biacore T100, followed by ProteOn XPR36, exhibited excellent data quality and consistency, whereas Octet RED384 and IBIS MX96 demonstrated high flexibility and throughput with compromises in data accuracy and reproducibility. Our results support the need for a “fit-for-purpose” approach in instrument selection for biosensor studies.
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