Publications by authors named "Ashley Brant"

10 Publications

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Recommendations for the content and management of Certificates of Analysis for reference standards from the GCC for bioanalysis.

Bioanalysis 2021 Apr 13;13(8):609-619. Epub 2021 Apr 13.

Worldwide Clinical Trials, Austin, TX, USA.

The 13th Global CRO Council (GCC) closed forum for bioanalysis was held in New Orleans, LA, USA on 5 April 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. While ICH M10 will cover requirements for reference standards, one of the biggest challenges facing the CRO community is the lack of consistency and completeness of Certificates of Analysis for reference standards used in regulated bioanalysis. Similar challenges exist with critical reagents (e.g., capture and detection antibodies) used for assays supporting biologics. The recommendations provided in this publication are the minimum requirements for the content that GCC members believe should be included in Certificates of Analysis for reference standards obtained from commercial vendors, sponsors and compendial suppliers, for use in regulated bioanalytical studies. In addition, recommendations for internal standards, metabolites and critical reagents are discussed.
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http://dx.doi.org/10.4155/bio-2021-0046DOI Listing
April 2021

Medical regimens for abortion at 12 weeks and above: a systematic review and meta-analysis.

Contracept X 2020 20;2:100037. Epub 2020 Aug 20.

The UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), World Health Organization, Department of Reproductive Health and Research, Avenue Appia 20, 1211 Geneva, Switzerland.

Background: Mifepristone and misoprostol are recommended for second-trimester medical abortion, but consensus is unclear on the ideal regimen.

Objectives: The objectives were to systematically review randomized controlled trials (RCTs) investigating efficacy, safety and satisfaction of medical abortion at ≥ 12 weeks' gestation.

Data Sources: We searched PubMed, Popline, Embase, Global Index Medicus, Cochrane Controlled Register of Trials and International Clinical Trials Registry Platform from January 2008 to May 2017.

Study Eligibility Participants And Interventions: We included RCTs on medical abortion at ≥ 12 weeks' gestation using mifepristone and/or misoprostol. We excluded studies with spontaneous abortion, fetal demise and mechanical cervical ripening and those not reporting ongoing pregnancy (OP).

Study Appraisal And Synthesis Methods: After extracting prespecified data and assessing risk of bias in accordance with the Cochrane handbook, we used Revman5 software to combine data and GRADE to assess certainty of evidence.

Results: We included 43 of the 1894 references identified. Combination mifepristone-misoprostol had lower rates of OP [risk ratio (RR) 0.12, 95% confidence interval (CI) 0.04-0.35] vs. misoprostol only. A 24-h interval between mifepristone and misoprostol had lower OP rate at 24 h than simultaneous dosing (RR 3.13, 95% CI 1.23-7.94). Every 3-h dosing had lower OP rate at 48 h (RR 0.39, 95% CI 0.17-0.88).

Limitations: Direct comparisons of buccal misoprostol to sublingual or vaginal routes after mifepristone were limited. Evidence from clinical trials on how to best manage women with prior uterine incisions was lacking.

Conclusion: Our analysis supports the use of mifepristone 200 mg 1 to 2 days before misoprostol 400 mcg vaginally every 3 h at ≥ 12 weeks' gestation.

Implications: Where available, providers should use mifepristone plus misoprostol for second-trimester medical abortion. Vaginal misoprostol appears to be most efficacious with fewest side effects, but sublingual and buccal routes are also acceptable.
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http://dx.doi.org/10.1016/j.conx.2020.100037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484538PMC
August 2020

Integrating HIV Pre-Exposure Prophylaxis into Family Planning Care: A RE-AIM Framework Evaluation.

AIDS Patient Care STDS 2020 06;34(6):259-266

MedStar Washington Hospital Center, Washington, District of Columbia, USA.

We aimed to systematically evaluate the feasibility of integrating HIV prevention services, including pre-exposure prophylaxis (PrEP), into a family planning setting in a high-prevalence community. We used the RE-AIM Framework (Reach, Efficacy, Adoption, Implementation, Maintenance) to evaluate the integration of HIV prevention services into a family planning clinic over 6 months. Before the integration, PrEP was not offered. We implemented a staff training program on HIV PrEP. We determined the proportion of women presenting to the clinic who were screened, eligible for, and initiated PrEP through chart review. We assessed staff comfort with PrEP pre- and post-integration. We compared planned and actual implementation, interviewed staff to determine barriers and facilitators, and tracked systems adaptations. We assessed maintenance of PrEP after the study concluded. There were 640 clinical encounters for 515 patients; the rate of HIV counseling and PrEP screening was 50%. The rate was 10% in month 1 and peaked to 65% in month 3. Nearly all screened patients were eligible for PrEP (98.4%) and 15 patients (6%) initiated PrEP. Staff knowledge and comfort discussing PrEP improved after education. Facilitators included partnering with local experts, continuing education, clinical tools for providers, and patient education materials. Barriers included competing priorities during clinical encounters, limited woman-centered patient education materials, and insurance-related barriers. Embedding HIV prevention services in the family planning setting was feasible in this pilot. The proportion of women screened for PrEP rapidly increased. In this high HIV prevalence community, nearly all screened women were eligible and 6% initiated PrEP.
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http://dx.doi.org/10.1089/apc.2020.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262643PMC
June 2020

11th GCC Closed Forum: cumulative stability; matrix stability; immunogenicity assays; laboratory manuals; biosimilars; chiral methods; hybrid LBA/LCMS assays; fit-for-purpose validation; China Food and Drug Administration bioanalytical method validation.

Bioanalysis 2018 Apr 27;10(7):433-444. Epub 2018 Apr 27.

Worldwide Clinical Trials, Austin, TX, USA.

The 11th Global CRO Council Closed Forum was held in Universal City, CA, USA on 3 April 2017. Representatives from international CRO members offering bioanalytical services were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The second CRO-Pharma Scientific Interchange Meeting was held on 7 April 2017, which included Pharma representatives' sharing perspectives on the topics discussed earlier in the week with the CRO members. The issues discussed at the meetings included cumulative stability evaluations, matrix stability evaluations, the 2016 US FDA Immunogenicity Guidance and recent and unexpected FDA Form 483s on immunogenicity assays, the bioanalytical laboratory's role in writing PK sample collection instructions, biosimilars, CRO perspectives on the use of chiral versus achiral methods, hybrid LBA/LCMS assays, applications of fit-for-purpose validation and, at the Global CRO Council Closed Forum only, the status and trend of current regulated bioanalytical practice in China under CFDA's new BMV policy. Conclusions from discussions of these topics at both meetings are included in this report.
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http://dx.doi.org/10.4155/bio-2018-0014DOI Listing
April 2018

Update on abortion policy.

Curr Opin Obstet Gynecol 2016 12;28(6):517-521

aStanford University School of Medicine, Stanford, California bNational Abortion Federation cWashington Hospital Center, Washington, DC dJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Purpose Of Review: To review the status of antiabortion restrictions enacted over the last 5 years in the United States and their impact on abortion services.

Recent Findings: In recent years, there has been an alarming rise in the number of antiabortion laws enacted across the United States. In total, various states in the union enacted 334 abortion restrictions from 2011 to July 2016, accounting for 30% of all abortion restrictions since the legalization of abortion in 1973. Data confirm, however, that more liberal abortion laws do not increase the number of abortions, but instead greatly decrease the number of abortion-related deaths. Several countries including Romania, South Africa and Nepal have seen dramatic decreases in maternal mortality after liberalization of abortion laws, without an increase in the total number of abortions. In the United States, abortions are incredibly safe with very low rates of complications and a mortality rate of 0.7 per 100 000 women. With increasing abortion restrictions, maternal mortality in the United States can be expected to rise over the coming years, as has been observed in Texas recently.

Summary: Liberalization of abortion laws saves women's lives. The rising number of antiabortion restrictions will ultimately harm women and their families.
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http://dx.doi.org/10.1097/GCO.0000000000000324DOI Listing
December 2016

Carrageenan analysis. Part 3: Quantification in swine plasma.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2014 18;31(10):1673-7. Epub 2014 Sep 18.

a Celtic Colloids Inc ., Topsham , ME , USA.

Development and validation of this method was conducted to support a 28-day piglet feeding study of swine-adapted infant formulations stabilised with carrageenan. The validation was performed in accordance with USFDA Good Laboratory Practice (GLP) Regulations and associated current bioanalytical guidelines. Separation of carrageenan from plasma protein was unsuccessful using saturated sodium chloride due to the extremely strong cross-linking interactions between carrageenan and protein. Poligeenan is the deliberately acid-hydrolysed low molecular weight polygalactan non-food product produced from carrageenan. Poligeenan molecules are nearly identical to carrageenan molecules with respect to molecular structure, the primary difference being molecular weight. These poligeenan molecules have similar molecular weight when compared with the lowest molecular weight fraction of carrageenan called the low molecular-weight tail (LMT). Poligeenan was separated from plasma protein using the salting procedure, this being due to the significantly weaker interaction with protein caused by its shorter molecular chain length. Thus, poligeenan was applied as a chemical analyte surrogate for the LMT of carrageenan solely for the development and validation of the method. This method was used to try to detect the LMT of the carrageenan test material during the 28-day piglet feeding study, and if such was absorbed into the bloodstream. Successful development and validation of the method was achieved using LC-MS/MS coupled with ESI in negative-ion mode. A standard curve of instrument response versus poligeenan concentration was developed using swine plasma spiked with a range of poligeenan concentrations. The lower level of quantification (LLOQ) of poligeenan was 10.0 µg ml⁻¹, and the quantification range was 10.0-100.0 µg ml⁻¹. No animals were fed poligeenan.
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http://dx.doi.org/10.1080/19440049.2014.955538DOI Listing
June 2015

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.

J Lipid Res 2013 Jan 1;54(1):134-51. Epub 2012 Nov 1.

Esperion Therapeutics, Inc., Plymouth, MI, USA.

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation. However, the molecular mechanism(s) mediating these activities remained undefined. Studies described here show that ETC-1002 free acid activates AMP-activated protein kinase in a Ca(2+)/calmodulin-dependent kinase β-independent and liver kinase β 1-dependent manner, without detectable changes in adenylate energy charge. Furthermore, ETC-1002 is shown to rapidly form a CoA thioester in liver, which directly inhibits ATP-citrate lyase. These distinct molecular mechanisms are complementary in their beneficial effects on lipid and carbohydrate metabolism in vitro and in vivo. Consistent with these mechanisms, ETC-1002 treatment reduced circulating proatherogenic lipoproteins, hepatic lipids, and body weight in a hamster model of hyperlipidemia, and it reduced body weight and improved glycemic control in a mouse model of diet-induced obesity. ETC-1002 offers promise as a novel therapeutic approach to improve multiple risk factors associated with metabolic syndrome and benefit patients with cardiovascular disease.
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http://dx.doi.org/10.1194/jlr.M030528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520520PMC
January 2013

Simple PCR assays improve the sensitivity of HIV-1 subtype B drug resistance testing and allow linking of resistance mutations.

PLoS One 2007 Jul 25;2(7):e638. Epub 2007 Jul 25.

Laboratory Branch, Division of HIV/ADS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

Background: The success of antiretroviral therapy is known to be compromised by drug-resistant HIV-1 at frequencies detectable by conventional bulk sequencing. Currently, there is a need to assess the clinical consequences of low-frequency drug resistant variants occurring below the detection limit of conventional genotyping. Sensitive detection of drug-resistant subpopulations, however, requires simple and practical methods for routine testing.

Methodology: We developed highly-sensitive and simple real-time PCR assays for nine key drug resistance mutations and show that these tests overcome substantial sequence heterogeneity in HIV-1 clinical specimens. We specifically used early wildtype virus samples from the pre-antiretroviral drug era to measure background reactivity and were able to define highly-specific screening cut-offs that are up to 67-fold more sensitive than conventional genotyping. We also demonstrate that sequencing the mutation-specific PCR products provided a direct and novel strategy to further detect and link associated resistance mutations, allowing easy identification of multi-drug-resistant variants. Resistance mutation associations revealed in mutation-specific amplicon sequences were verified by clonal sequencing.

Significance: Combined, sensitive real-time PCR testing and mutation-specific amplicon sequencing provides a powerful and simple approach that allows for improved detection and evaluation of HIV-1 drug resistance mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000638PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1919426PMC
July 2007

Development and validation of an LC/MS/MS procedure for the quantification of endogenous myo-inositol concentrations in rat brain tissue homogenates.

Anal Chem 2004 Aug;76(16):4901-8

myo-Inositol is being investigated as a biomarker to monitor disease states involving the central nervous system. We have developed and validated a quantitative method to study endogenous myo-inositol metabolism in rat brain tissue. Tissue samples were homogenized, and their myo-inositol content was determined using spiked calibration curves and mass spectrometry. The assay was validated on an LC/MS/MS platform, and specificity was evaluated using accurate mass measurements. A novel chiral LC/MS/MS method was also developed to resolve myo-inositol from other endogenous inositol epimers and confirm the selectivity of the quantitative procedure. The validated method is selective, convenient, precise (<15% RSD), accurate (<15% RE), and sensitive over a linear range of 0.100-100 microg/mL. This method could potentially be used as an instrument for monitoring pathological conditions related to psychotherapeutics, as well as a tool for screening curative pharmaceuticals for efficacy.
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http://dx.doi.org/10.1021/ac049746wDOI Listing
August 2004

Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis.

Clin Cancer Res 2003 Feb;9(2):853-60

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University Of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA.

Purpose: The purpose of this study was to determine whether expression of migration inhibitory factor (MIF) is increased in non-small cell lung cancer, and whether it correlates with angiogenesis and/or prognosis.

Experimental Design: We measured vessel density, and levels of MIF, angiogenic CXC chemokines, and vascular-endothelial growth factor (VEGF; by ELISA) in tumor and normal lung tissue from 87 patients after resection of lung cancer. We compared vessel density with levels of MIF, VEGF, or angiogenic CXC chemokines in the corresponding tumor homogenate. Disease-free survival was analyzed in a Cox proportional hazards model.

Results: Levels of MIF in lung cancer demonstrated a bimodal distribution, with some having "normal" values (relative to normal lung tissue) and a second cluster with markedly high values. The increased levels of MIF in lung cancer were statistically significant in both paired and unpaired comparisons (P < 0.05). The strongest correlation of vessel density was with the sum of angiogenic CXC chemokines. MIF correlated very strongly with levels of angiogenic CXC chemokines. Tumors in the high MIF group had a strong correlation between MIF level and vessel density. Risk of recurrence was associated with high levels of glutamic acid-leucine-arginine amino acid motif CXC chemokines, MIF, and/or VEGF in a Cox proportional hazards model.

Conclusions: MIF expression in non-small cell lung cancer occurs in a bimodal distribution, and is closely associated with tumor levels of angiogenic CXC chemokines and with vessel density. High levels of tumor-associated CXC chemokines, MIF, or VEGF are associated with risk of recurrence after resection of lung cancer.
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February 2003