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Harvey B.H.,North West University South Africa | Shahid M.,MSD
Pharmacology Biochemistry and Behavior | Year: 2012

Anxiety disorders are amongst the most common and disabling of psychiatric illnesses and have severe health and socio-economic implications. Despite the availability of a number of treatment options there is still a strong medical need for novel and improved pharmacological approaches in treating these disorders. New developments at the forefront of preclinical research have begun to identify the therapeutic potential of molecular entities integral to the biological response to adversity, particularly molecules and processes that may pre-determine vulnerability or resilience, and those that may act to switch off or "unlearn" a response to an aversive event. The glutamate system is an interesting target in this respect, especially given the impact anxiety disorders have on neuroplasticity, cognition and affective function. These areas of research demonstrate expanding and improved evidence-based options for treating disorders where stress in various guises plays an important etiological role. The current review will discuss how these pathways are involved in fear circuitry of the brain and compare the strength of therapeutic rationale as well as progress towards pharmacological validation of the glutamate pathway towards the treatment of anxiety disorders, with a particular focus on metabotropic and ionotropic glutamate receptors. Specific reference to their anxiolytic actions and efficacy in translational disease models of posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder and phobia will be made. In addition, the availability of ligands necessary to assist clinical proof of concept studies will be discussed. © 2011 Elsevier Inc. All rights reserved.

Kraft W.K.,Thomas Jefferson University | Chang P.S.,Thomas Jefferson University | Van Iersel M.L.P.S.,MSD | Waskin H.,Merck And Co. | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a >10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87-1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Griesinger G.,University of Lübeck | Mannaerts B.,MSD | Andersen C.Y.,Copenhagen University | Witjes H.,MSD | And 2 more authors.
Fertility and Sterility | Year: 2013

Objective To compare the impact of elevated P during the late follicular phase on the chance of pregnancy in low, normal, and high responders. Design Retrospective combined analysis from six clinical trials. Setting IVF centers. Patient(s) Women up to 39 years of age with a regular menstrual cycle and an indication for ovarian stimulation before IVF/intracytoplasmic sperm injection. Intervention(s) Ovarian stimulation with recombinant (r) FSH in a GnRH antagonist protocol. Main Outcome Measure(s) Ongoing pregnancy rates (OPRs) assessed with the use of univariate and multivariate analyses according to serum P levels ≤1.5 ng/mL versus >1.5 ng/mL on the day of hCG administration and compared among low (1-5 oocytes), normal (6-18 oocytes), and high (>18 oocytes) responders. Result(s) A total of 157/1,866 women (8.4%; 95% confidence interval [CI] 7.2%-9.8%) had elevated P. Incidence of elevated P increased from 4.5% in low responders to 19.0% in high responders. Overall, OPRs were significantly lower in women with elevated P. Per started cycle, the >1.5 to ≤1.5 ng/mL adjusted odds ratio was 0.55 (95% CI 0.37-0.81). OPRs were not impaired in high responders with P elevation and were significantly higher compared with normal responders with P elevation. Conclusion(s) The incidence of elevated P increases with ovarian response, and elevated P at a threshold of 1.5 ng/mL is independently associated with a decreased chance of pregnancy in low to normal responders, but not in high responders, when using an rFSH/GnRH antagonist protocol. © 2013 American Society for Reproductive Medicine, Published by Elsevier Inc.

Harker W.R.R.,University of Bath | Carswell E.L.,MSD | Carbery D.R.,University of Bath
Organic and Biomolecular Chemistry | Year: 2012

α-Alkyl β-amino esters are available in high diastereoselectivity through a silicon-free Claisen enolate [3,3]-sigmatropic rearrangement of enamide esters. Optimisation studies have probed the crucial role of the initial enolisation and the nature of the enamide N-centre. The demonstration of chirality transfer and the formation of β-proline systems, is also presented. © 2012 The Royal Society of Chemistry.

Harker W.R.R.,University of Bath | Carswell E.L.,MSD | Carbery D.R.,University of Bath
Organic Letters | Year: 2010

The E/Z-selectivity in the formation of silylketene acetals derived from phenylacetate esters, mediated by LiHMDS, has been studied by in situ NMR techniques. The formation is seen to be highly E-selective with use of the newly developed protocol. Isolated aryl-substituted silylketene acetals are now attainable with high levels of E-geometrical purity in excellent yield. © 2010 American Chemical Society.

Fatemi H.M.,Universitair Ziekenhuis Brussel | Doody K.,Center for Assisted Reproduction | Griesinger G.,University of Lübeck | Witjes H.,MSD | Mannaerts B.,MSD
Human Reproduction | Year: 2013

Study Question Is the ovarian response to controlled ovarian stimulation (COS) related to the ongoing pregnancy rate when taking into account the main covariates affecting the probabilities of pregnancy following fresh embryo transfer? Summary Answer In patients treated with corifollitropin alfa or daily recombinant FSH (rFSH) in a GnRH-antagonist protocol, a high ovarian response did not compromise ongoing pregnancy rates and increased cumulative pregnancy rates following fresh and frozen-thawed embryo transfer.WHAT IS KNOWN AND WHAT THIS PAPER ADDSA strong association between the number of oocytes and pregnancy rates has been described but this is the first comprehensive analysis assessing important confounders that might affect pregnancy rates. Study Design In a large, prospective, double-blind, randomized trial (Engage; n = 1506), patients were treated with either a single dose of 150 μg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH-antagonist (ganirelix) protocol. In this retrospective analysis, patients were categorized into five groups according to the number of oocytes retrieved (0-5, 6-9, 10-13, 14-18 and >18 oocytes). The number of good-quality embryos obtained and transferred, as well as the ongoing pregnancy rates, live birth rates and cumulative ongoing pregnancy rates per started cycle by group were evaluated. Univariate analysis was performed to identify factors that predict the chance of ongoing pregnancy. Logistic regression analysis on the dependent variables ongoing pregnancy and cumulative ongoing pregnancy, respectively, including oocyte category as an independent factor in the model, was performed by treatment group (corifollitropin alfa and rFSH) and overall. The likelihood of ongoing pregnancy and cumulative ongoing pregnancy was then evaluated taking into account ovarian response as well as other identified significant predictors of success.PARTICIPANTS AND SETTINGIn total, 1506 patients had been randomized in a ratio of 1:1 to either of the treatment groups. Patients were aged ≤36 years and had a body weight >60 kg. Main Results and the Role of Chance The ongoing pregnancy rates per started cycle increased in the corifollitropin alfa and rFSH groups from 31.9 and 31.3%, respectively, in the lowest response group (0-5 oocytes) to 41.9 and 43.4% in the highest response group (>18 oocytes) with a significant linear trend (P = 0.04). The cumulative pregnancy rates taking frozen-thawed embryo transfers into account increased from 33.0 and 31.3% to 60.8 and 55.9% in the corifollitropin alfa and rFSH groups, respectively. Univariate logistic regression analyses of ongoing pregnancy showed significant effects for the following factors: embryo transfer (double or single, P < 0.01), region of treatment (North America or Europe, P < 0.01), progesterone level on the day of hCG (>1.5 or ≤1.5 ng/ml, P < 0.01), start day of the stimulation (cycle day 2 or 3, P = 0.02) and age (P = 0.04). Logistic regression analysis of ongoing pregnancy using 10-13 oocytes as the reference category, per treatment group and overall revealed estimated odds ratios (OR) close to 1.0 versus the reference, without statistically significant differences with and without adjustment for significant predictive factors affecting pregnancy rates. Unadjusted OR for cumulative pregnancy reflected significantly lower odds of pregnancy for the lowest response group and significantly higher odds of pregnancy for the highest response group in comparison with the reference. When adjusted for the predictive factors, the cumulative ongoing pregnancy OR (95% confidence interval) of the highest response group versus the reference group was 1.87 (1.34-2.59) when the data of both treatment groups were pooled.BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTIONThe number of covariates included in the final model was limited to five major factors and not all other potentially significant predictive factors were available for evaluation.GENERALIZABILITY TO OTHER POPULATIONSThis analysis is limited to IVF patients with a regular menstrual cycle up to 36 years of age and a body weight >60 and ≤90 kg treated with a GnRH-antagonist protocol and cannot be extrapolated to other patient populations or treatment regimens. Study Funding/Competing Interest (S)Financial support for this study was provided by Merck, Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc, Whitehouse Station, NJ, USA. Medical writing and editorial assistance was provided by P. Milner, PhD, of PAREXEL, UK. This assistance was funded by Merck, Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ. Author conflicts of interest are as follows: H.F. has received honorarium for expert meeting with MSD, lectures for various companies; K.D. has received consultancy fees for Ferring and TEVA Pharmaceutical, payment for lectures and speaker bureaus for Ferring and Watson Pharmaceutical; G.G. has received honoraria as speaker, and served as advisory board member for Ferring, Merck Serono, MSD and IBSA. He has received travel grants from Merck Serono, MSD and grants from Ferring and Merck Serono; H.W. and B.M. are employees of MSD. Trial Registration Numberntc00696800. © 2012 The Author.

Laurent-Ledru V.,MSD | Thomson A.,Sanofi S.A. | Monsonego J.,Women Against Cervical Cancer
Vaccine | Year: 2011

The vaccinology landscape has changed, with national authorities now being increasingly accountable to new stakeholders such as health insurers, regional regulatory bodies, the media, and civil society. Here, we discuss how civil society organisations (CSOs), such as patient and women's groups, have become important drivers in the introduction and sustainability of new vaccination programs. This shift in public implication in vaccine policy has been well illustrated in the recent introduction of human papillomavirus (HPV) vaccination in Europe. Patient and women's groups which were traditionally focused on advocacy of treatments have also become advocates for prevention with the advent of HPV vaccination. Civil society advocacy at the European level supported key resolutions and white papers which in turn informed national recommendations on cervical cancer vaccination. CSOs were also active at the national level, supporting national policy makers. These organisations may bring innovative and effective new approaches to communication on vaccination benefits, using public events, celebrities and various social media. Working with experts, CSOs can also be an important bridge from the science to the lay public. This may provide a vital counterbalance to media hype and antivaccination groups, although CSOs may also be active and vocal opponents of immunization. The successful implementation and sustainability of future vaccination programs against infections such as HIV will be dependent upon the active participation of civil society to inform, to reassure and to maintain public trust. © 2010 Elsevier Ltd.

Vroling B.,Radboud University Nijmegen | Sanders M.,MSD | Baakman C.,Radboud University Nijmegen | Borrmann A.,Radboud University Nijmegen | And 5 more authors.
Nucleic Acids Research | Year: 2011

The GPCRDB is a Molecular Class-Specific Information System (MCSIS) that collects, combines, validates and disseminates large amounts of heterogeneous data on G proteincoupled receptors (GPCRs). The GPCRDB contains experimental data on sequences, ligand-binding constants, mutations and oligomers, as well as many different types of computationally derived data such as multiple sequence alignments and homology models. The GPCRDB provides access to the data via a number of different access methods. It offers visualization and analysis tools, and a number of query systems. The data is updated automatically on a monthly basis. The GPCRDB can be found online at http://www.gpcr .org/7tm/. © The Author(s) 2010.

Broekmans F.J.,University Utrecht | Verweij P.J.M.,MSD | Eijkemans M.J.C.,University Utrecht | Mannaerts B.M.J.L.,MSD | Witjes H.,MSD
Human Reproduction | Year: 2014

study question: Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol? summaryanswer: Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH. what is known already: Predictors of ovarian response have been identified in GnRH agonist protocols.With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles. study design, size, duration: A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial. participants/materials, setting, methods: Infertilewomen with an indication forCOSprior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis. main results and the role of chance: In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive valueswere 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were lowovarian responders. The slope of the calibration linewas 0.81 and 1.35 for high and lowovarian responses, respectively, both not statistically different from 1.0. In summary,commonprognostic factors for high and low ovarian responses were female age,AFCand basal serum FSHand LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH. limitations, reasons for caution: Anti-Müllerian hormone was not included in the prediction modelling. wider implications of the findings: The findings will help with the identification of patients at risk of a too high or too lowovarian response and individualization of COS treatment. © The Author 2014.

Kerr W.J.,University of Strathclyde | Morrison A.J.,MSD | Pazicky M.,University of Strathclyde | Weber T.,University of Strathclyde
Organic Letters | Year: 2012

Bismesitylmagnesium has been shown to successfully mediate the Shapiro reaction. A range of tosylhydrazones has been subjected to the developed system, which furnishes exceptionally high incorporation of the introduced electrophiles and good yields of the functionalized styrenes. At conveniently accessible temperatures and with a comparably small excess of base reagent, this protocol offers an efficient alternative to the lithium-mediated process. Importantly, 1.05 equiv of Weinreb amides are sufficient to obtain aryl enones in good yields. © 2012 American Chemical Society.

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