Publications by authors named "William Hurst"

34 Publications

Structured benefit-risk evaluation for medicinal products: review of quantitative benefit-risk assessment findings in the literature.

Ther Adv Drug Saf 2020 8;11:2042098620976951. Epub 2020 Dec 8.

Global Epidemiology & Benefit-Risk Evaluation, Sanofi, Chilly-Mazarin, France.

A favorable benefit-risk profile remains an essential requirement for marketing authorization of medicinal drugs and devices. Furthermore, prior subjective, implicit and inconsistent ad hoc benefit-risk assessment methods have rightly evolved towards more systematic, explicit or "structured" approaches. Contemporary structured benefit-risk evaluation aims at providing an objective assessment of the benefit-risk profile of medicinal products and a higher transparency for decision making purposes. The use of a descriptive framework should be the preferred starting point for a structured benefit-risk assessment. In support of more precise assessments, quantitative and semi-quantitative methodologies have been developed and utilized to complement descriptive or qualitative frameworks in order to facilitate the structured evaluation of the benefit-risk profile of medicinal products. In addition, quantitative structured benefit-risk analysis allows integration of patient preference data. Collecting patient perspectives throughout the medical product development process has become increasingly important and key to the regulatory decision-making process. Both industry and regulatory authorities increasingly rely on descriptive structured benefit-risk evaluation and frameworks in drug, vaccine and device evaluation and comparison. Although varied qualitative methods are more commonplace, quantitative approaches have recently been emphasized. However, it is unclear how frequently these quantitative frameworks have been used by pharmaceutical companies to support submission dossiers for drug approvals or to respond to the health authorities' requests. The objective of this study has been to identify and review, for the first time, currently available, published, structured, quantitative benefit-risk evaluations which may have informed health care professionals and/or payor as well as contributed to decision making purposes in the regulatory setting for drug, vaccine and/or device approval.

Plain Language Summary: The review of the benefits and the risks associated with a medicinal product is called benefit-risk assessment. One of the conditions for a medicinal product to receive marketing authorization is to demonstrate a positive benefit-risk balance in which the benefits outweigh the risks. In order to enhance the transparency and consistency in the assessment of benefit-risk balance, frameworks and quantitative methods have been developed for decision making purposes and regulatory approvals of medicinal products. This article considers published quantitative benefit-risk evaluations which may have informed health care professionals and/or payor as well as contributed to decision making purposes in the regulatory setting for drug, vaccine and/or device approval.
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http://dx.doi.org/10.1177/2042098620976951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727082PMC
December 2020

Isolation of 1-(3',4'-Dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol from Grape Seed Extract and Evaluation of its Antioxidant and Antispasmodic Potential.

Molecules 2019 Jul 4;24(13). Epub 2019 Jul 4.

Planta Analytica LLC, New Milford, CT 06776, USA.

HPLC profiling of phenolics in grape seed extracts revealed a prominent peak of an unknown substance with concentrations up to 5.3%. Spectroscopic data allowed the identification of the compound as 1-(3',4'-dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol. is known to be produced from catechin and epicatechin through anaerobic bacteria from human, as well as the rat, intestines. It was hypothesized that the marc remaining after expression of juice from grapes became infested during storage, resulting in the production of . Because compound is infrequently found in nature and has never been found in grape seeds, its presence may be considered a marker of an unwanted anaerobic bacterial process occurring during production. The antioxidant potential of was determined by DPPH, ABTS, and FRAP (ferric reducing antioxidant power) assays and compared to the potential of the following compounds: phloroglucine, pyrogallol, gallic acid, catechin, and epicatechin. Furthermore, it was established that significantly reduced guinea pig ileum contraction induced by histamine.
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http://dx.doi.org/10.3390/molecules24132466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651082PMC
July 2019

Impact of lixisenatide dose range on clinical outcomes with fixed-ratio combination iGlarLixi in patients with type 2 diabetes.

Curr Med Res Opin 2019 04 6;35(4):689-695. Epub 2018 Dec 6.

d Abington Family Medicine , Jenkintown , PA , USA.

Objective: To evaluate the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen (5-20 µg), alone or in fixed-ratio combination with insulin glargine (iGlar; iGlarLixi).

Methods: Data from three clinical studies were analyzed to assess lixisenatide efficacy and safety: a phase 2a trial assessing gastric emptying effects (ACT6011); a phase 2b dose-ranging trial (DRI6012); and a randomized controlled phase 3 trial comparing iGlarLixi with its components of iGlar and lixisenatide (LixiLan-O). Efficacy metrics included glycated hemoglobin A (A1C), post-prandial glucose (PPG) values following a standardized breakfast, fasting plasma glucose (FPG), and weight change. Occurrence of gastrointestinal adverse events was also assessed.

Results: ACT6011: lixisenatide doses from 5-20 μg once daily (QD) suppressed PPG; maximal reductions in mean PPG area under the curve were achieved with doses ≥12.5 µg QD, but doses as low as 5 μg achieved 44% of maximal reduction. DRI6012: lixisenatide doses 5-20 μg QD resulted in significant, dose-dependent decreases in A1C, percentage of patients achieving A1C <7.0%, and 2-h PPG levels; doses of 20 μg achieved complete suppression of PPG. LixiLan-O: iGlarLixi decreased 2-h PPG across the entire dose range. Lixisenatide dose was unrelated to reductions in FPG with iGlarLixi. Similar reductions in A1C were seen with iGlarLixi across all lixisenatide doses.

Conclusions: This analysis demonstrates the clinical benefit of lixisenatide alone or in the formulation of iGlarLixi over the entire dose range of lixisenatide contained in iGlarLixi (5-20 µg), supporting the selection of the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen.
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http://dx.doi.org/10.1080/03007995.2018.1541316DOI Listing
April 2019

Fifteen-year longitudinal follow-up of a patient with severe early-onset Charcot-Marie-Tooth disease type 2A.

Muscle Nerve 2018 05 26;57(5):E126-E128. Epub 2018 Jan 26.

Department of Neurology, Johns Hopkins University School of Medicine, John G. Rangos Building, 855 North Wolfe Street, Suite 227 Baltimore, Maryland, 21205, USA.

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http://dx.doi.org/10.1002/mus.26047DOI Listing
May 2018

Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A.

ACS Chem Neurosci 2018 02 7;9(2):358-368. Epub 2017 Nov 7.

Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School , Charlestown, Massachusetts 02129, United States.

Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [C]CH-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [I]Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs.
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http://dx.doi.org/10.1021/acschemneuro.7b00357DOI Listing
February 2018

Effects of the Adulteration Technique on the Near-Infrared Detection of Melamine in Milk Powder.

J Agric Food Chem 2017 Jul 6;65(28):5799-5809. Epub 2017 Jul 6.

United States Pharmacopeial Convention , 12601 Twinbrook Parkway, Rockville, Maryland 20852-1790, United States.

The United States Pharmacopeial Convention has led an international collaborative project to develop a toolbox of screening methods and reference standards for the detection of milk powder adulteration. During the development of adulterated milk powder reference standards, blending methods used to combine melamine and milk had unanticipated strong effects on the near-infrared (NIR) spectrum of melamine. The prominent absorbance band at 1468 nm of melamine was retained when it was dry-blended with skim milk powder but disappeared in wet-blended mixtures, where spray-dried milk powder samples were prepared from solution. Analyses using polarized light microscopy, Raman spectroscopy, dielectric relaxation spectroscopy, X-ray diffraction, and mass spectrometry indicated that wet blending promoted reversible and early Maillard reactions with lactose that are responsible for differences in melamine NIR spectra between wet- and dry-blended samples. Targeted detection estimates based solely on dry-blended reference standards are likely to overestimate NIR detection capabilities in wet-blended samples as a result of previously overlooked matrix effects arising from changes in melamine hydrogen-bonding status, covalent complexation with lactose, and the lower but more homogeneous melamine local concentration distribution produced in wet-blended samples. Techniques used to incorporate potential adulterants can determine the suitability of milk reference standards for use with rapid detection methods.
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http://dx.doi.org/10.1021/acs.jafc.7b02083DOI Listing
July 2017

Reducing Antibiotic Exposure in Suspected Neonatal Sepsis.

Clin Pediatr (Phila) 2018 Jan 3;57(1):76-81. Epub 2017 Feb 3.

4 Royal Infirmary of Edinburgh, Scotland, UK.

Prolonged antibiotic therapy is associated with antimicrobial resistance and increased mortality in preterm infants. We evaluated the impact of an automatic stop order (ASO) and C-reactive protein (CRP) on the duration of antibiotics and level of intervention in infants screened for early-onset sepsis who had negative cultures. We introduced an ASO for low-risk infants, then, consequently, for all infants treated for suspected sepsis. We subsequently introduced a single CRP measurement at 36 hours. Between 2011 and 2014, 4 time periods were studied, at baseline and after each intervention. The proportion of infants receiving ≤48 hours of antibiotics increased from 19% to 72.5% ( P < .0001), whereas that of infants receiving avoidable doses (>48 hours and <5 days) fell from 50% to 0.8% ( P < .0001). The use of an ASO decreased the proportion receiving avoidable doses from 26/92 (28.3%) to 9/293 (3.1%); P < .0001. There was a reduction in lumbar punctures performed, from 35% to 20%; P = .015.
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http://dx.doi.org/10.1177/0009922816689673DOI Listing
January 2018

Influence of Degree-of-Polymerization and Linkage on the Quantification of Proanthocyanidins using 4-Dimethylaminocinnamaldehyde (DMAC) Assay.

J Agric Food Chem 2016 Mar 9;64(11):2190-9. Epub 2016 Mar 9.

Department of Plant Biology and Pathology, Rutgers University , New Brunswick, New Jersey 08901, United States.

Proanthocyanidins (PACs) are naturally occurring flavonoids possessing health beneficial bioactivities. Their quantification often utilizes the 4-dimethylaminocinnamaldehyde (DMAC) spectrophotometric assay with the assumption that molar absorption coefficients (MACs) are similar across the various PAC species. To assess the validity of this assumption, individual PAC monomers and oligomers were examined for their absorbance response with DMAC. Our results have shown that PAC dimers and trimers with interflavan linkage variations exhibited differential absorbance response. Absence of A-type linkage between the terminal and second units in PAC molecule not only impacts absorbance intensity at 640 nm but also elicits a prominent secondary 440 nm absorbance peak. Cranberry (A-type) and cocoa (B-type) oligomeric PACs exhibited differential absorbance (MACs) relationship with degree-of-polymerization. Thus, PAC structural variations have considerable impact on the resulting MAC. The use of DMAC assay in PAC quantification, especially in comparing across specific oligomers and compositions, should not assume MACs are similar.
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http://dx.doi.org/10.1021/acs.jafc.5b05408DOI Listing
March 2016

Chocolate as medicine.

Authors:
William Hurst

J Agric Food Chem 2015 Nov;63(45):9899-900

The Hershey Company, Hershey, Pennsylvania 17033, United States.

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http://dx.doi.org/10.1021/acs.jafc.5b04057DOI Listing
November 2015

Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy.

Bioorg Med Chem 2015 Feb 23;23(3):429-38. Epub 2014 Dec 23.

Sanofi R&D, 1, Avenue Pierre Brossolette, Chilly-Mazarin 91385, France.

Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 μM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.
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http://dx.doi.org/10.1016/j.bmc.2014.12.036DOI Listing
February 2015

Cocoa extracts reduce oligomerization of amyloid-β: implications for cognitive improvement in Alzheimer's disease.

J Alzheimers Dis 2014 ;41(2):643-50

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.

Background: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by pathological aggregates of amyloid peptide-β (Aβ) and tau protein. Currently available therapies mediate AD symptoms without modifying disease progression. Polyphenol-rich diets are reported to reduce the risk for AD.

Objective: In the present study, we investigated the AD disease-modifying effects of cocoa, a rich source of flavanols, which are a class of polyphenols. We hypothesized that cocoa extracts interfere with amyloid-β oligomerization to prevent synaptic deficits.

Methods: We tested the effects of three different cocoa extracts, viz. Natural, Dutched, and Lavado extracts, on Aβ42 and Aβ40 oligomerization, using photo-induced cross-linking of unmodified proteins technique. To assess the effects of cocoa extracts on synaptic function, we measured long term potentiation in mouse brain hippocampal slices exposed to oligomeric Aβ.

Results: Our results indicate that cocoa extracts are effective in preventing the oligomerization of Aβ, with Lavado extract being most effective. Lavado extract, but not Dutched extract, was effective in restoring the long term potentiation response reduced by oligomeric Aβ.

Conclusion: Our findings indicate that cocoa extracts have multiple disease-modifying properties in AD and present a promising route of therapeutic and/or preventative initiatives.
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http://dx.doi.org/10.3233/JAD-132231DOI Listing
February 2015

Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)phenyl] amide as histamine H(3) receptor antagonist for the treatment of depression.

Bioorg Med Chem Lett 2013 Dec 3;23(23):6269-73. Epub 2013 Oct 3.

LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA. Electronic address:

Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.081DOI Listing
December 2013

Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders.

Bioorg Med Chem Lett 2013 Nov 8;23(22):6141-5. Epub 2013 Sep 8.

LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA. Electronic address:

Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.006DOI Listing
November 2013

Synthesis, characterization, and biological assessment of the four stereoisomers of the H(3) receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide.

Bioorg Med Chem Lett 2013 Jul 30;23(14):4044-7. Epub 2013 May 30.

LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave., Waltham, MA 02451, USA.

This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.
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http://dx.doi.org/10.1016/j.bmcl.2013.05.068DOI Listing
July 2013

Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept.

J Pharm Sci 2013 Aug 31;102(8):2572-88. Epub 2013 May 31.

Pharmaceutical Development, Baxter Healthcare Corporation, Round Lake, Illinois 60048, USA.

During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of -1°C to -6°C, much higher than the range of -10°C to -14°C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343-357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose).
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http://dx.doi.org/10.1002/jps.23610DOI Listing
August 2013

Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II).

Bioorg Med Chem Lett 2013 Jun 28;23(11):3421-6. Epub 2013 Mar 28.

LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA.

A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.
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http://dx.doi.org/10.1016/j.bmcl.2013.03.081DOI Listing
June 2013

Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).

Bioorg Med Chem Lett 2013 Jun 29;23(11):3416-20. Epub 2013 Mar 29.

LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA.

A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
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http://dx.doi.org/10.1016/j.bmcl.2013.03.080DOI Listing
June 2013

Inhibition of key digestive enzymes by cocoa extracts and procyanidins.

J Agric Food Chem 2011 May 26;59(10):5305-11. Epub 2011 Apr 26.

Department of Food Science, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.

This study determined the in vitro inhibitory effects of cocoa extracts and procyanidins against pancreatic α-amylase (PA), pancreatic lipase (PL), and secreted phospholipase A(2) (PLA(2)) and characterized the kinetics of such inhibition. Lavado, regular, and Dutch-processed cocoa extracts as well as cocoa procyanidins (degree of polymerization (DP) = 2-10) were examined. Cocoa extracts and procyanidins dose-dependently inhibited PA, PL, and PLA(2). Lavado cocoa extract was the most potent inhibitor (IC(50) = 8.5-47 μg/mL). An inverse correlation between log IC(50) and DP (R(2) > 0.93) was observed. Kinetic analysis suggested that regular cocoa extract, the pentamer, and decamer inhibited PL activity in a mixed mode. The pentamer and decamer noncompetitively inhibited PLA(2) activity, whereas regular cocoa extract inhibited PLA(2) competitively. This study demonstrates that cocoa polyphenols can inhibit digestive enzymes in vitro and may, in conjunction with a low-calorie diet, play a role in body weight management.
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http://dx.doi.org/10.1021/jf200180nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113527PMC
May 2011

Determination of total procyanidins in selected chocolate and confectionery products using DMAC.

J AOAC Int 2010 Jan-Feb;93(1):89-96

Hershey Center for Health and Nutrition, The Hershey Co., 1025 Reese Ave, Hershey, PA 17033, USA.

A simple, specific, high-throughput colorimetric method based on the reaction of 4-dimethylaminocinnamaldehyde (DMAC) with flavan-3-ols was developed to determine total procyanidins in selected cacao-based products. Extracts of defatted samples were dispensed into a 96-well plate and reacted with DMAC. The absorbance of the reaction products was measured at 640 nm and compared to commercially available procyanidin B2 as a standard. The use of the 96-well plates and a plate reader dramatically improved sample throughput. A standard protocol was established and used for further studies. The calibration was found to be linear from 1-100 ppm. The DMAC reagent reacted relatively specifically to (-)-epicatechin, (+)-catechin, epigallocatechin, gallocatechin, the gallates of catechin, epicatechin, gallocatechin, and epigallocatechin, oligomeric procyanidins of cocoa up to n=4, and A-type procyanidins. Little or no reaction occurred with cyanidins and representative compounds of phenolic acids, flavones, flavanones, flavonols, anthocyanidins, isoflavones, and stilbenes. Sample precision studies were carried out on 10 different test materials over several weeks, and yielded RSD values of 4.0 to 9.5%. The method was ring-tested in three laboratories using blinded test materials including cocoa beans, cocoa powder, chocolate liquor, dark chocolate, and milk chocolate. There was excellent agreement of the results between laboratories.
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May 2010

Characterization of primary standards for use in the HPLC analysis of the procyanidin content of cocoa and chocolate containing products.

Molecules 2009 Oct 15;14(10):4136-46. Epub 2009 Oct 15.

The Hershey Center of Health and Nutrition, The Hershey Company, 1025 Reese Avenue, Hershey, PA 17033, USA.

This report describes the characterization of a series of commercially available procyanidin standards ranging from dimers DP = 2 to decamers DP = 10 for the determination of procyanidins from cocoa and chocolate. Using a combination of HPLC with fluorescence detection and MALDI-TOF mass spectrometry, the purity of each standard was determined and these data were used to determine relative response factors. These response factors were compared with other response factors obtained from published methods. Data comparing the procyanidin analysis of a commercially available US dark chocolate calculated using each of the calibration methods indicates divergent results and demonstrate that previous methods may significantly underreport the procyanidins in cocoa-containing products. These results have far reaching implications because the previous calibration methods have been used to develop data for a variety of scientific reports, including food databases and clinical studies.
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http://dx.doi.org/10.3390/molecules14104136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255096PMC
October 2009

Use of the systems approach to determine the fate of Escherichia coli O157:H7 on fresh lettuce and spinach.

J Food Prot 2009 Jul;72(7):1560-8

Department of Food Science and Technology, University of Georgia, Athens, Georgia 30602, USA.

Lettuce and spinach inoculated with Escherichia coli O157:H7 were processed and handled in ways that might occur in commercial situations, including variations in holding times before and after product cooling, transportation conditions and temperatures, wash treatments, and product storage temperatures and times. Populations of background microflora and E. coli O157:H7 were enumerated after each step in the system. Data analysis was done to predict response variables with a combination of independent categorical variables. Field temperature, time before cooling, and wash treatment significantly affected E. coli O157:H7 populations on both products. The lowest populations of E. coli O157:H7 were encountered when precool time was minimal, lettuce was washed with chlorine, and storage temperature was 4 degrees C. For lettuce, field and transportation temperature were not important once the storage period started, whereas after 2 days E. coli O157:H7 populations on packaged baby spinach were not affected by field temperature. On chopped iceberg lettuce and whole leaf spinach that was packaged and stored at 4 degrees C, E. coli O157:H7 contamination could still be detected after typical handling practices, although populations decreased from initial levels in many cases by at least 1.5 log units. In abusive cases, where populations increased, the product quality quickly deteriorated. Although E. coli O157:H7 levels decreased on products handled and stored under recommended conditions, survivors persisted. This study highlights practices that may or may not affect the populations of E. coli O157:H7 on the final product.
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http://dx.doi.org/10.4315/0362-028x-72.7.1560DOI Listing
July 2009

Impact of alkalization on the antioxidant and flavanol content of commercial cocoa powders.

J Agric Food Chem 2008 Sep 19;56(18):8527-33. Epub 2008 Aug 19.

Hershey Center for Health and Nutrition, The Hershey Company, 1025 Reese Avenue, Hershey, Pennsylvania 17033, USA.

Cocoa is a food ingredient that is important for the contribution of flavor to foods but is also associated with potential health benefits. The chemistry thought to be responsible for its cardiovascular health benefits is the flavanol (flavan-3-ol) antioxidants. Evidence from the literature indicates that natural cocoas are high in flavanols, but when the cocoa is processed with alkali, also known as Dutch processing or Dutching, the flavanols are substantially reduced. This paper provides a survey of the physical and chemical composition of representative natural cocoas and lightly, medium, and heavily alkalized cocoas. As part of the survey, both brown/black and red/brown alkali-processed cocoas were measured. Natural cocoa powders have an extractable pH of 5.3-5.8. Alkalized cocoa powders were grouped into lightly treated (pH 6.50-7.20), medium-treated (pH 7.21-7.60), and heavily treated (pH 7.61 and higher). The natural, nonalkalized powders had the highest ORAC and total polyphenols and flavanols (including procyanidins). These chemical measurements showed a linear decrease as the extractable pH of the cocoa powder increased. Likewise, the flavanol monomers, oligomers, and polymers all showed a linear decrease with increasing pH of the final cocoa powder. When brown/black cocoa powders were compared to red cocoa powders, similar decreases in flavanols were observed with increased alkalization. The average total flavanol contents were 34.6 +/- 6.8 mg/g for the natural cocoas, 13.8 +/- 7.3 mg/g for the lightly processed cocoas, 7.8 +/- 4.0 mg/g for the medium processed cocoas, and 3.9 +/- 1.8 mg/g for the heavily processed cocoa powders. The observed linear and predictable impact of alkalization on flavanol content is discussed with respect to other reports in the literature as well as what implications it may have on diet and food manufacturing.
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http://dx.doi.org/10.1021/jf801670pDOI Listing
September 2008

Washing practices on the microflora on Georgia-grown cantaloupes.

J Food Prot 2008 Jan;71(1):46-51

Department of Food Science and Technology, University of Georgia, Athens, Georgia 30602, USA.

In recent years, several foodborne illness outbreaks have been associated with the consumption of cantaloupe. Cantaloupes can be contaminated with pathogens anywhere from the field to the packing line. In the United States, cantaloupes are handled and packed differently in each state. Georgia-grown cantaloupes are brought to sheds, washed, and packed, whereas California-grown cantaloupes are field packed. In this study, the microbiological status of cantaloupes produced by four Georgia growers that use various washing and packing practices was assessed to determine the influence of these different practices. The facilities were visited four times during the harvest season. Aerobic bacteria, Escherichia coli, and coliforms on these Georgia-grown cantaloupes were enumerated in transport trailers, after washing, and after packing. Samples also were analyzed for the presence of Salmonella and E. coli O157:H7. In sheds 1 and 4, a chlorinated dump tank was used to wash melons. In sheds 2 and 3, heated water with chlorine was used in the dump tanks. Although there was a significant reduction (P < 0.05) in the populations of the aerobic bacteria and E. coli between the transport trailer and the dump tank for sheds 1 and 4, the reduction was less than 0.5 log CFU/cm2. The temperatures of the water in the dump tanks at sheds 2 and 3 were not high enough to effectively reduce the microbial populations evaluated. Populations on the melons increased slightly (< 0.5 log CFU/cm2) after the melons were removed from the dump tank, suggesting possible contamination after washing.
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http://dx.doi.org/10.4315/0362-028x-71.1.46DOI Listing
January 2008

To protect and preserve. Can switching costs help the physician shortage?

Mark Health Serv 2007 ;27(2):22-5

Drury University, Breech School of Business, Springfield, MO, USA.

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December 2007

Lateral and posterior dynamic bending of the mid-shaft femur: fracture risk curves for the adult population.

Stapp Car Crash J 2004 Nov;48:27-51

Virginia Tech - Wake Forest, Center for Injury Biomechanics.

The purpose of this study was to develop injury risk functions for dynamic bending of the human femur in the lateral-to-medial and posterior-to-anterior loading directions. A total of 45 experiments were performed on human cadaver femurs using a dynamic three-point drop test setup. An impactor of 9.8 kg was dropped from 2.2 m for an impact velocity of 5 m/s. Five-axis load cells measured the impactor and support loads, while an in situ strain gage measured the failure strain and subsequent strain rate. All 45 tests resulted in mid-shaft femur fractures with comminuted wedge and oblique fractures as the most common fracture patterns. In the lateral-to-medial bending tests the reaction loads were 4180 +/- 764 N, and the impactor loads were 4780 +/- 792 N. In the posterior-to-anterior bending tests the reaction loads were 3780 +/- 930 N, and the impactor loads were 4310 +/- 1040 N. The difference between the sum of the reaction forces and the applied load is due to inertial effects. The reaction loads were used to estimate the mid-shaft bending moments at failure since there was insufficient data to include the inertial effects in the calculations. The resulting moments are conservative estimates (lower bounds) of the mid-shaft bending moments at failure and are appropriate for use in the assessment of knee restraints and pedestrian impacts with ATD measurements. Regression analysis was used to identify significant parameters, and parametric survival analysis was used to estimate risk functions. Femur cross-sectional area, area moment of inertia (I), maximum distance to the neutral axis (c), I/c, occupant gender, and occupant mass are shown to be significant predictors of fracture tolerance, while no significant difference is shown for loading direction, bone mineral density, leg aspect and age. Risk functions are presented for femur cross-sectional area and I/c as they offer the highest correlation to peak bending moment. The risk function that utilizes the most highly correlated (R2 = 0.82) and significant (p = 0.0001) variable, cross-sectional area, predicts a 50 percent risk of femur fracture of 240 Nm, 395 Nm, and 562 Nm for equivalent cross-sectional area of the 5(th) percentile female, 50(th) percentile male, and 95(th) percentile male respectively.
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November 2004

Predicting zygoma fractures from baseball impact.

Biomed Sci Instrum 2006 ;42:142-7

Virginia Tech - Wake Forest Center for Injury Biomechanics, USA.

The purpose of this study is to develop injury risk functions that predict zygoma fracture based on baseball type and impact velocity. Zygoma fracture strength data from published experiments were mapped with the force exerted by a baseball on the orbit as a function of ball velocity. Using a normal distribution, zygoma fracture risk functions were developed. Experimental evaluation of these risk functions was performed using six human cadaver tests and two baseballs of different stiffness values. High speed video measured the baseball impact velocity. Post test analysis of the cadaver skulls was performed using CT imaging including three-dimensional reconstruction as well as autopsy. The developed injury risk functions accurately identify the risk of zygoma fracture as a result of baseball impact. The experimental results validated the zygoma risk functions at the lower and upper levels. The injuries observed in the post test analysis included fractures of the zygomatic arch, frontal process and the maxilla, zygoma suture, with combinations of these creating comminuted, tripod fractures of the zygoma. Tests with a softer baseball did result in injury but these had fewer resulting zygoma bone fragments and occurred at velocities 50% higher than the major league ball.
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July 2006

Endotoxin removal using a synthetic adsorbent of crystalline calcium silicate hydrate.

Biotechnol Prog 2005 Jul-Aug;21(4):1220-5

World Minerals Inc., 2500 Miguelito Road, Lompoc, CA 93436, USA.

A synthetic adsorbent of crystalline calcium silicate hydrate, the product LRA by Advanced Minerals Corp., has been studied for endotoxin removal from aqueous solutions. This adsorbent removes endotoxin effectively, and the removal is greatly enhanced by the presence of an electrolyte such as NaCl, Tris-HCl, or Na2HPO4. It has an endotoxin removal capacity as high as 6 million endotoxin units (EU) per gram. Its endotoxin removal kinetics is fast, and for instance, over 99.9% endotoxin in a 5000 EU/mL solution was removed by mixing for 2 min at an adsorbent usage of 10 g/L. Using the chromatographic column method to treat a 5000 EU/mL solution, an endotoxin log-reduction factor of 6.2 was achieved with a single pass. This adsorbent also demonstrated significantly better performance when compared to many commonly used endotoxin removal agents, such as ActiClean Etox Endotoxin Removal Resin, Affi-Prep Polymyxin Support, Detroxi-Gel Endotoxin Removing Gel, Q Sepharose Fast Flow Media, and Sigma Endotoxin Removal Solution. Furthermore, it demonstrated a high selective removal of endotoxin from a solution of lambda DNA. This adsorbent provides opportunities for developing disposable, scaleable, and cost-effective methods for endotoxin reduction in many biotechnological and pharmaceutical processes.
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http://dx.doi.org/10.1021/bp0500359DOI Listing
January 2006

An electrokinetic study on a synthetic adsorbent of crystalline calcium silicate hydrate and its mechanism of endotoxin removal.

Colloids Surf B Biointerfaces 2005 Aug;44(2-3):110-6

World Minerals Inc., 2500 Miguelito Road, Lompoc, CA 93436, USA.

A synthetic, disposable adsorbent of crystalline calcium silicate hydrate, LRA product by Advanced Minerals Corp., has been found highly effective for endotoxin removal from aqueous solutions. Endotoxin removal by this adsorbent is greatly enhanced by the addition of an electrolyte, such as NaCl or Tris-HCl. The electrophoretic method has been used to study the mechanism of endotoxin adsorption. In many cases, adding the electrolyte increases the magnitude of negative zeta potential of the adsorbent in water, while endotoxin adsorption reduces the magnitude. It is hypothesized that ion-exchange between monovalent cations from the aqueous phase and Ca2+ ions near the surface of the adsorbent shift zeta potential of the adsorbent to the more negative direction. It is further hypothesized that endotoxins form cationic species through binding between its phosphate groups and Ca2+ ions dissolved from the adsorbent. The adsorption of endotoxins in the form of cationic species is enhanced by the increased negative zeta potential of the adsorbent when an electrolyte is added.
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http://dx.doi.org/10.1016/j.colsurfb.2005.06.005DOI Listing
August 2005

Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation.

Mol Cell Biol 2005 Apr;25(7):2795-807

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation. Supporting this idea, CKIepsilon inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKIepsilon inhibition also slows the degradation of PER2 in cells. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock.
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http://dx.doi.org/10.1128/MCB.25.7.2795-2807.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1061645PMC
April 2005

Spring-mediated cranial reshaping for craniosynostosis.

J Craniofac Surg 2004 Sep;15(5):810-6; discussion 817-8

Department of Plastic and Reconstructive Surgery, Wake Forest University Medical School, Winston-Salem, North Carolina 27157, USA.

The evolution of modern craniofacial surgery has come full circle from the early strip craniectomies to the complete calvarial remodeling and now back to attempts at minimally invasive surgical interventions. The goal of the craniofacial surgeon has always been the correction of form and function with minimization of associated morbidity and mortality. Particularly problematic has been the ability to maintain the anatomical correction beyond the result seen on the operating room table secondary to changes with growth. The ability to improve the clinical result in a growing and developing child has been the impetus for dynamic treatment modalities. Dr Claes Lauritzen's pioneering work in this area has been particularly successful using internal springs to correct craniofacial deformities. The purpose of this study is to assess this treatment modality clinically in terms of safety and efficacy and to develop a methodology for the spring formation that would be easily reproducible. This is an institutional review board-approved prospective study of 15 children (11 male, 4 female) with non-syndromic sagittal suture synostosis. All patients were treated with a sagittal strip craniectomy and placement of 2 omega-shaped stainless steel springs at a mean age of 3.9 months. Patients were followed clinically and with cephalograms; after reossification of the intervening bone, the springs were removed at a mean age of 8.2 months. The mean force applied at initial placement of the springs was 6.9 N, and the mean spring deflection at formation was 6.87 cm. All patients completed the study protocol without any significant morbidity or any mortality. Perioperative variables, including blood loss, transfusion rate, operative time, intensive care unit stay, hospital stay, and hospital charges, were all significantly less (P < 0.05) in this study group compared with children with the same diagnosis treated with cranial vault reshaping during the same period. Furthermore, the preoperative mean cephalic index of 64.3 corrected to 77.6 after surgery and was maintained over time. Spring-mediated cranial reshaping is efficacious and safe for the treatment of sagittal synostosis. Long-term study of cranial development and clinical morphology are ongoing to validate further the effectiveness of this treatment modality.
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http://dx.doi.org/10.1097/00001665-200409000-00021DOI Listing
September 2004
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