Publications by authors named "Christopher McGuigan"

141 Publications

Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer.

Bioorg Med Chem Lett 2021 Mar 26;36:127817. Epub 2021 Jan 26.

School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, Wales, United Kingdom.

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC = 9.09 - 31.11 µM compared to the positive controls: bicalutamide (IC = 45.20 -51.61 µM) and enzalutamide (IC = 11.47 - 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15-30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.
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http://dx.doi.org/10.1016/j.bmcl.2021.127817DOI Listing
March 2021

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS.

Neurol Clin Pract 2020 Dec;10(6):510-519

Department of Neurology (AC), Inselspital, Bern University Hospital, University of Bern, Switzerland; Division of Neuroimmunology and Neurovirology (JR), University of Utah, Salt Lake City, UT; Brain Institute (JR), University of Utah, Salt Lake City, UT; Department of Neurology (JR), University of Utah, Salt Lake City, UT; Rocky Mountain Multiple Sclerosis Center at the University of Colorado (EA), Aurora, CO; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (AB-O), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Children's Hospital of Philadelphia (AB-O), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Central Clinical School (HB), Monash University, VIC, Australia; Mellen Center for Multiple Sclerosis Treatment and Research (RJF), Cleveland Clinic, OH; Department of Neurology (RG), St. Josef-Hospital, Ruhr University Bochum, Germany; South Shore Neurologic Association PC (MG), Patchogue, NY; Eastern Health MS Service (JH), Box Hill, VIC, Australia; Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital (TS), University of Melbourne, Parkville, VIC, Australia; Department of Neurology and Neurotherapeutics (KW), University of Texas Southwestern Medical Center, Multiple Sclerosis and Neuroimmunology Imaging Program, Clinical Center for Multiple Sclerosis, Dallas, TX; Department of Neuroscience (DF, PS), Neurology Unit, Azienda Ospedaliera Universitaria, Modena, Italy; Liverpool Hospital (SH), NSW, Australia; Department of Medicine (TK), CORe Unit, University of Melbourne, VIC, Australia; Department of Neurology (TK), Royal Melbourne Hospital, VIC, Australia; School of Medicine and Public Health (JL-S), University Newcastle, NSW, Australia; Department of Neurology (JL-S), John Hunter Hospital, Hunter New England Health, Newcastle, NSW, Australia; Department of Neurology (C. McGuigan), St. Vincent's University Hospital and University College, Dublin, Ireland; Envision Pharma Group (KS), Fairfield, CT; and Biogen (CC, SF, FW, C. Miller), Cambridge, MA.

Background: Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF.

Methods: Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation.

Results: The majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC ≥0.8 × 10/L was 2-4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC ≥0.91 × 10/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for ≥3 years, lymphocyte reconstitution to ≥0.91 × 10/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting <6 months.

Conclusions: The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2-4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.
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http://dx.doi.org/10.1212/CPJ.0000000000000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837440PMC
December 2020

Synthesis and Biological Evaluation of Bicalutamide Analogues for the Potential Treatment of Prostate Cancer.

Molecules 2020 Dec 24;26(1). Epub 2020 Dec 24.

School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, UK.

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of 15 bicalutamide analogues (sulfide, deshydroxy, sulfone, and -acetylated) were prepared and their antiproliferative activity evaluated against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). Bicalutamide and enzalutamide were used as positive controls. Seven of these compounds displayed remarkable enhancement in anticancer activity across the four PC cell lines. The deshydroxy analogue () was the most active compound with IC = 6.59-10.86 µM. Molecular modeling offers a plausible explanation of the higher activity of the sulfide analogues compared to their sulfone counterparts.
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http://dx.doi.org/10.3390/molecules26010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795644PMC
December 2020

Pharmacovigilance during treatment of multiple sclerosis: early recognition of CNS complications.

J Neurol Neurosurg Psychiatry 2021 Feb 23;92(2):177-188. Epub 2020 Nov 23.

Department of Radiology & Nuclear Medicine, MS Center Amsterdam, Neuroscience Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.

An increasing number of highly effective disease-modifying therapies for people with multiple sclerosis (MS) have recently gained marketing approval. While the beneficial effects of these drugs in terms of clinical and imaging outcome measures is welcomed, these therapeutics are associated with substance-specific or group-specific adverse events that include severe and fatal complications. These adverse events comprise both infectious and non-infectious complications that can occur within, or outside of the central nervous system (CNS). Awareness and risk assessment strategies thus require interdisciplinary management, and robust clinical and paraclinical surveillance strategies. In this review, we discuss the current role of MRI in safety monitoring during pharmacovigilance of patients treated with (selective) immune suppressive therapies for MS. MRI, particularly brain MRI, has a pivotal role in the early diagnosis of CNS complications that potentially are severely debilitating and may even be lethal. Early recognition of such CNS complications may improve functional outcome and survival, and thus knowledge on MRI features of treatment-associated complications is of paramount importance to MS clinicians, but also of relevance to general neurologists and radiologists.
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http://dx.doi.org/10.1136/jnnp-2020-324534DOI Listing
February 2021

Multiscale entropy derived complexity index analysis demonstrates significant mediolateral sway in persons with multiple sclerosis compared to healthy controls.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5176-5179

Clinical assessment of Multiple Sclerosis relies heavily on the Expanded Disability Status Scale, a non-linear rating system based on physician assessment of disease progression and walking ability. This inherently makes this method both subjective and limited in repeatability. This study developed a technically derived outcome measure of posture to compare a cohort of Multiple Sclerosis and Control subjects during an Eyes-Open and Eyes-closed task. Analysing traditional sway parameters and a multiscale entropy derived complexity index of posturography showed a significant difference in medio-lateral sway between groups during the Eyes-Open condition. This technically derived outcome measure may be of clinical benefit in the longitudinal assessment of the functional impact of balance in MS cohorts and assist in the evaluation of pharmaceutical and rehabilitation interventions.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175672DOI Listing
July 2020

Update: Atypical presentation of a midgut neuroendocrine tumor originally diagnosed as eosinophilic fasciitis.

Neurology 2020 10 10;95(15):695-697. Epub 2020 Sep 10.

From the Department of Rheumatology (L.A.S., A.A.G., O.F.), St Vincent's University Hospital, Elm Park, Dublin, Ireland; Department of Pathology (N.S.), St Vincent's University Hospital, Elm Park, Dublin, Ireland; Department of Endocrinology (D.O.S.); and Department of Neurology (C.M., M.H.), St Vincent's University Hospital, Elm Park, Dublin, Ireland.

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http://dx.doi.org/10.1212/WNL.0000000000010715DOI Listing
October 2020

Impact of obstructive sleep apnoea on cognitive function in multiple sclerosis: A longitudinal study.

J Sleep Res 2020 Aug 13:e13159. Epub 2020 Aug 13.

Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.

Cognitive impairment (CI) and fatigue are common in people with multiple sclerosis (MS), with well-known profound effects on quality of life. Sleep disorders, including obstructive sleep apnoea (OSA), are also common in MS patients. The presence of CI has previously been shown to strongly correlate with OSA diagnosed using polysomnography in MS. Treatment of OSA has not previously been investigated as a potential modality to improve cognition in MS patients. Therefore, we sought to investigate the potential effects of OSA treatment on both cognitive function and fatigue in MS patients. Twenty-three participants with MS reporting significant fatigue were enrolled. CI was assessed by the Brief International Cognitive Assessment in MS and the 3-second Paced Auditory Serial Addition Test. All participants underwent overnight polysomnography to assess for possible OSA. Cognitive and fatigue measures were repeated in those subsequently treated for OSA and in a comparative untreated sample. Seven participants (30%) had a diagnosis of OSA based on an apnoea-hypopnea index greater than 5 per hour, with no correlation between the presence of CI and OSA. Verbal learning at follow-up assessment was seen to improve significantly in those treated for OSA, compared with those who were not treated for a sleep disorder. This small study demonstrates the potential for OSA treatment to improve verbal learning in people with MS, larger studies are indicated to further investigate the potential for cognitive and fatigue improvement in people with MS through treatment of comorbid OSA.
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http://dx.doi.org/10.1111/jsr.13159DOI Listing
August 2020

Drug repurposing: phosphate prodrugs of anticancer and antiviral FDA-approved nucleosides as novel antimicrobials.

J Antimicrob Chemother 2020 10;75(10):2864-2878

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.

Objectives: Following a drug repurposing approach, we aimed to investigate and compare the antibacterial and antibiofilm activities of different classes of phosphate prodrugs (HepDirect, cycloSal, SATE and mix SATE) of antiviral and anticancer FDA-approved nucleoside drugs [zidovudine (AZT), floxouridine (FUDR) and gemcitabine (GEM)] against a variety of pathogenic Gram-positive and -negative bacteria.

Methods: Ten prodrugs were synthesized and screened for antibacterial activity against seven Gram-negative and two Gram-positive isolates fully susceptible to traditional antibiotics, alongside six Gram-negative and five Gram-positive isolates with resistance mechanisms. Their ability to prevent and eradicate biofilms of different bacterial pathogens in relation to planktonic growth inhibition was also evaluated, together with their effect on proliferation, viability and apoptosis of different eukaryotic cells.

Results: The prodrugs showed decreased antibacterial activity compared with the parent nucleosides. cycloSal-GEM-monophosphate (MP) prodrugs 20a and 20b were the most active agents against Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and retained their activity against antibiotic-resistant isolates. cycloSal-FUDR-MP 21a partially retained good activity against the Gram-positive bacteria E. faecalis, Enterococcus faecium and S. aureus. Most of the prodrugs tested displayed very potent preventive antibiofilm specific activity, but not curative. In terms of cytotoxicity, AZT prodrugs did not affect apoptosis or cell viability at the highest concentration tested, and only weak effects on apoptosis and/or cell viability were observed for GEM and FUDR prodrugs.

Conclusions: Among the different prodrug approaches, the cycloSal prodrugs appeared the most effective. In particular, cycloSal (17a) and mix SATE (26) AZT prodrugs combine the lowest cytotoxicity with high and broad antibacterial and antibiofilm activity against Gram-negative bacteria.
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http://dx.doi.org/10.1093/jac/dkaa268DOI Listing
October 2020

Alemtuzumab-related thyroid disease in people with multiple sclerosis is associated with age and brainstem phenotype at disease onset.

Mult Scler J Exp Transl Clin 2020 Apr-Jun;6(2):2055217320933928. Epub 2020 Jun 18.

Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.

Background: Autoimmune thyroid disease (AITD) occurs in 40%-50% of alemtuzumab-treated persons with multiple sclerosis (pwMS), most of whom will develop Graves' Disease (GD).

Objective: To explore contributory factors for alemtuzumab-related AITD in pwMS.

Methods: A retrospective patient chart review was performed.

Results: Sixteen out of 52 (30.8%) pwMS developed AITD. GD occurred in 56.3% ( = 9), the majority ( = 7, 77.8%) symptomatic. All but one (85.7%) pwMS with symptomatic GD developed atypical, large and rapid fluctuations in thyroid hormone levels unexplained by effect of anti-thyroid medication alone. All symptomatic GD cases were age ≤32 years when starting alemtuzumab (ɸ = 0.60,  = 0.03). PwMS who started alemtuzumab at a younger age developed thyroid disease earlier ( = 0.51,  = 0.04). PwMS with clinical and radiological evidence of brainstem involvement at onset of multiple sclerosis were 11 times more likely to develop symptomatic GD compared with those with other phenotypes ( < 0.01).

Conclusion: Alemtuzumab-induced reconstitution GD may result from early and increased cross-reactivity between antigens common to the brainstem and thyroid, or presence of shared Human Leukocyte Antigen (HLA) alleles that determine brainstem and thyroid involvement. We suggest cautious use of alemtuzumab in younger (≤32 years) pwMS with early brainstem involvement, especially those actively planning pregnancy, where alternative therapies are readily available.
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http://dx.doi.org/10.1177/2055217320933928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307483PMC
June 2020

Moyamoya disease and moyamoya syndrome in Ireland: patient demographics, mode of presentation and outcomes of EC-IC bypass surgery.

Ir J Med Sci 2021 Feb 19;190(1):335-344. Epub 2020 Jun 19.

National Neurosurgical Centre, Beaumont Hospital, Dublin, Ireland.

Background: There are no previously published reports regarding the epidemiology and characteristics of moyamoya disease or syndrome in Ireland.

Aims: To examine patient demographics, mode of presentation and the outcomes of extracranial-intracranial bypass surgery in the treatment of moyamoya disease and syndrome in Ireland.

Methods: All patients with moyamoya disease and syndrome referred to the National Neurosurgical Centre during January 2012-January 2019 were identified through a prospective database. Demographics, clinical presentation, radiological findings, surgical procedures, postoperative complications and any strokes during follow-up were recorded.

Results: Twenty-one patients were identified. Sixteen underwent surgery. Median age at diagnosis was 19 years. Fifteen were female. Mode of presentation was ischaemic stroke in nine, haemodynamic TIAs in eight, haemorrhage in three and incidental in one. Sixteen patients had Moyamoya disease, whereas five patients had moyamoya syndrome. Surgery was performed on 19 hemispheres in 16 patients. The surgical procedures consisted of ten direct (STA-MCA) bypasses, five indirect bypasses and four multiple burr holes. Postoperative complications included ischaemic stroke in one patient and subdural haematoma in one patient. The median follow-up period in the surgical group was 52 months; there was one new stroke during this period. Two patients required further revascularisation following recurrent TIAs. One patient died during follow-up secondary to tumour progression associated with neurofibromatosis type 1.

Conclusions: Moyamoya is rare but occurs in Caucasians in Ireland. It most commonly presents with ischaemic symptoms. Surgical intervention in the form of direct and indirect bypass is an effective treatment in the majority of cases.
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http://dx.doi.org/10.1007/s11845-020-02280-wDOI Listing
February 2021

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.

Lancet Neurol 2020 04 18;19(4):307-316. Epub 2020 Mar 18.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address:

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.

Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.

Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.

Interpretation: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding: National Health and Medical Research Council Australia and MS Society UK.
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http://dx.doi.org/10.1016/S1474-4422(20)30067-3DOI Listing
April 2020

Radiosynthesis of [F]-Labelled Pro-Nucleotides (ProTides).

Molecules 2020 Feb 6;25(3). Epub 2020 Feb 6.

School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK.

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3'- and 2'-fluorinated ProTides following different radiosynthetic approaches. The 3'-[F]FLT ProTide was obtained via a late stage [F]fluorination in radiochemical yields (RCY) of 15-30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2'-[F]FIAU ProTide was obtained via an early stage [F]fluorination approach with an RCY of 1-5% ( = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/mol (total synthesis time of 240 min).
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http://dx.doi.org/10.3390/molecules25030704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037993PMC
February 2020

Interventions for preventing falls in people with multiple sclerosis.

Cochrane Database Syst Rev 2019 11 28;11:CD012475. Epub 2019 Nov 28.

University of Limerick, Department of Clinical Therapies, Faculty of Education and Health Sciences, Castletroy, Limerick, Ireland.

Background: Multiple sclerosis (MS) is one of the most prevalent diseases of the central nervous system with recent prevalence estimates indicating that MS directly affects 2.3 million people worldwide. Fall rates of 56% have been reported among people with MS in a recent meta-analysis. Clinical guidelines do not outline an evidence-based approach to falls interventions in MS. There is a need for synthesised information regarding the effectiveness of falls prevention interventions in MS.

Objectives: The aim of this review was to evaluate the effectiveness of interventions designed to reduce falls in people with MS. Specific objectives included comparing: (1) falls prevention interventions to controls and; (2) different types of falls prevention interventions.

Search Methods: We searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group, Cochrane Central Register of Controlled Trials (2018 Issue 9); MEDLINE (PubMed) (1966 to 12 September 2018); Embase (EMBASE.com) (1974 to 12 September 2018); Cumulative Index to Nursing and Allied Health Literature (EBSCOhost) (1981 to 12 September 2018); Latin American and Caribbean Health Science Information Database (Bireme) (1982 to 12 September 2018); ClinicalTrials.gov; and World Health Organization International Clinical Trials Registry Platform; PsycINFO (1806 to 12 September 2018; and Physiotherapy Evidence Database (1999 to 12 September 2018).

Selection Criteria: We selected randomised controlled trials or quasi-randomised trials of interventions to reduce falls in people with MS. We included trials that examined falls prevention interventions compared to controls or different types of falls prevention interventions. Primary outcomes included: falls rate, risk of falling, number of falls per person and adverse events.

Data Collection And Analysis: Two review authors screened studies for selection, assessed risk of bias and extracted data. We used a rate ratio (RaR) and 95% confidence interval to compare falls rate between groups. For risk of falling, we used a risk ratio (RR) and 95% CI based on the number of fallers in each group.

Main Results: A total of 839 people with MS (12 to 177 individuals) were randomised in the 13 included trials. The mean age of the participants was 52 years (36 to 62 years). The percentage of women participants ranged from 59% to 85%. Studies included people with all types of MS. Most trials compared an exercise intervention with no intervention or different types of falls prevention interventions. We included two comparisons: (1) Falls prevention intervention versus control and (2) Falls prevention intervention versus another falls prevention intervention. The most common interventions tested were exercise as a single intervention, education as a single intervention, functional electrical stimulation and exercise plus education. The risk of bias of the included studies mixed, with nine studies demonstrating high risk of bias related to one or more aspects of their methodology. The evidence was uncertain regarding the effects of exercise versus control on falls rate (RaR of 0.68; 95% CI 0.43 to 1.06; very low-quality evidence), number of fallers (RR of 0.85; 95% CI 0.51 to 1.43; low-quality evidence) and adverse events (RR of 1.25; 95% CI 0.26 to 6.03; low-quality evidence). Data were not available on quality of life outcomes comparing exercise to control. The majority of other comparisons between falls interventions and controls demonstrated no evidence of effect in favour of either group for all primary outcomes. For the comparison of different falls prevention interventions, the heterogeneity of intervention types across studies prohibited the pooling of data. In relation to secondary outcomes, there was evidence of an effect in favour of exercise interventions compared to controls for balance function with a SMD of 0.50 (95% CI 0.09 to 0.92), self-reported mobility with a SMD of 16.30 (95% CI 9.34 to 23.26) and objective mobility with a SMD of 0.28 (95% CI 0.07 to 0.50). Secondary outcomes were not assessed under the GRADE criteria and results must be interpreted with caution.

Authors' Conclusions: The evidence regarding the effects of interventions for preventing falls in MS is sparse and uncertain. The evidence base demonstrates mixed risk of bias, with very low to low certainty of the evidence. There is some evidence in favour of exercise interventions for the improvement of balance function and mobility. However, this must be interpreted with caution as these secondary outcomes were not assessed under the GRADE criteria and as the results represent data from a small number of studies. Robust RCTs examining the effectiveness of multifactorial falls interventions on falls outcomes are needed.
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http://dx.doi.org/10.1002/14651858.CD012475.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953359PMC
November 2019

Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity.

Bioorg Med Chem Lett 2019 12 23;29(24):126721. Epub 2019 Oct 23.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.

Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge. Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC = 30 nM, HIV-1) and (IC = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both P and F NMR is presented.
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http://dx.doi.org/10.1016/j.bmcl.2019.126721DOI Listing
December 2019

Rash developing after cessation of Daclizumab for relapsing remitting MS; a case series.

Mult Scler Relat Disord 2019 Oct 5;35:239-240. Epub 2019 Aug 5.

St Vincent's University Hospital, Dublin, Ireland. Electronic address:

Daclizumab, a monoclonal antibody directed against CD25, a subunit of the high-affinity IL-2 receptor, was licensed as a disease modifying therapy (DMT) for relapsing remitting multiple sclerosis in 2017. Interference with IL-2 signalling is hypothesised to modulate T cell function. For example it results in a preferential shift of innate lymphoid cell (ILC) into CD56 natural killer cells and a decrease in regulatory T Cells. We present three patients who developed urticarial papulovesicular rashes at a median of 3 months after discontinuation of Daclizumab. We propose an unexpected T cell mediated immune reaction as the cause.
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http://dx.doi.org/10.1016/j.msard.2019.08.008DOI Listing
October 2019

A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF) and pentafluoroethyl (CF) substituents: Improved antiproliferative agents against prostate cancer.

Eur J Med Chem 2019 Oct 3;180:1-14. Epub 2019 Jul 3.

School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edwards VII Avenue, CF10 3NB, Cardiff, Wales, UK.

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.001DOI Listing
October 2019

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

JAMA 2019 01;321(2):175-187

Institute for Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales.

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

Design, Setting, And Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.

Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

Main Outcome And Measure: Conversion to objectively defined secondary progressive MS.

Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).

Conclusions And Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.
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http://dx.doi.org/10.1001/jama.2018.20588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439772PMC
January 2019

Symmetrical Diamidates as a Class of Phosphate Prodrugs to Deliver the 5'-Monophosphate Forms of Anticancer Nucleoside Analogues.

ChemMedChem 2018 11;13(21):2305-2316

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.

The application of phosphorodiamidate technology to pyrimidine and purine nucleosides with anticancer activity to potentially overcome the resistance mechanisms associated with parent nucleosides is reported. Sixteen symmetrical phosphorodiamidates were prepared from the natural amino acids l-alanine and glycine. All the compounds were evaluated for their cytotoxic activity against a wide panel of solid and leukaemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate-type prodrugs.
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http://dx.doi.org/10.1002/cmdc.201800504DOI Listing
November 2018

IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism.

J Immunol 2018 10 24;201(7):2070-2081. Epub 2018 Aug 24.

Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland;

IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C). IRAK1-deficient human microglial cells showed higher basal levels of STAT1 and STAT2 compared with control cells. Blocking the kinase activity of TBK1/IKKε in IRAK1 knockdown human microglial cells reduced the high basal levels of STAT1/2, uncovering a TBK1/IKKε kinase-dependent mechanism controlling basal levels of STAT1/2. Stimulating IRAK1 knockdown human microglial cells with IFN-β led to increased IL-27p28 expression compared with control cells. In IRAK1-deficient murine macrophages, increased IL-27 levels were detected by ELISA following IFN-β stimulation compared with control macrophages together with increased nuclear levels of p-STAT1, IRF1, and IRF9. Treatment of wild-type and IRAK1-deficient murine macrophages with fludarabine similarly reduced TLR3/4-induced IL-27 cytokine levels. To our knowledge, this work represents the first report placing IRAK1 in the IFNAR pathway and identifies IRAK1 as an important regulator of STAT1, controlling IL-27 production downstream of TLR3/4 and IFNAR signaling pathways.
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http://dx.doi.org/10.4049/jimmunol.1701373DOI Listing
October 2018

Platelet Releasate Proteome Profiling Reveals a Core Set of Proteins with Low Variance between Healthy Adults.

Proteomics 2018 08 15;18(15):e1800219. Epub 2018 Jul 15.

SPHERE research group, Conway Institute, University College Dublin, Dublin 4, Ireland.

Upon activation, platelets release a powerful cocktail of soluble and vesicular signals, collectively termed the "platelet releasate" (PR). Although several studies have used qualitative/quantitative proteomic approaches to characterize PR; with debated content and significant inter-individual variability reported, confident, and reliable insights have been hindered. Using label-free quantitative (LFQ)-proteomics analysis, a reproducible, quantifiable investigation of the 1U mL thrombin-induced PR from 32 healthy adults was conducted. MS proteomics data are available via ProteomeXchange, identifier PXD009310. Of the 894 proteins identified, 277 proteins were quantified across all donors and form a "core" PR. Bioinformatics and further LFQ-proteomic analysis revealed that the majority (84%) of "core" PR proteins overlapped with the protein composition of human platelet-derived exosomes. Vesicles in the exosomal-size range were confirmed in healthy-human PR and reduced numbers of similar-sized vesicles were observed in the PR of a mouse model of gray platelet syndrome, known to be deficient in platelet alpha-granules. Lastly, the variability of proteins in the PR was assessed, and reproducible secretion levels were found across all 32 healthy donors. Taken together, the PR contains valuable soluble and vesicular cargo and has low-population variance among healthy adults, rendering it a potentially useful platform for diagnostic fingerprinting of platelet-related disease.
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http://dx.doi.org/10.1002/pmic.201800219DOI Listing
August 2018

New versus old: Implications of evolving diagnostic criteria for relapsing-remitting multiple sclerosis.

Mult Scler 2019 05 12;25(6):867-870. Epub 2018 Apr 12.

Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland/School of Medicine & Medical Science, University College Dublin, Dublin, Ireland.

The International Panel on Diagnosis of Multiple Sclerosis (MS) recently revised the 2010 McDonald criteria and made recommendations for revision, allowing for the earliest possible, accurate diagnosis of MS. For relapsing-remitting MS, positive, unmatched cerebrospinal fluid oligoclonal bands may substitute for dissemination in time. Symptomatic lesions, including brainstem and spinal cord, may demonstrate dissemination in space or in time if enhancing (with the exception of the optic nerve). Cortical and juxtacortical lesions are equivalent. In this retrospective analysis, we applied revised criteria to 250 patients previously diagnosed with relapsing-remitting MS according to 2010 criteria and assessed for change in diagnostic times. There was a significant improvement in time to diagnosis between 2010 and 2017 groups ( p < 0.01). Median time to diagnosis according to McDonald 2010 was 7.4 months, compared with 2.3 months for McDonald 2017. Use of cerebrospinal fluid results most frequently resulted in a reduction in time to diagnosis. Symptomatic gadolinium-enhancing lesions led to earliest diagnostic times.
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http://dx.doi.org/10.1177/1352458518770088DOI Listing
May 2019

Societal costs of multiple sclerosis in Ireland.

J Med Econ 2018 May 7;21(5):425-437. Epub 2018 Feb 7.

a University College Dublin , Dublin , Ireland.

Aims: This paper evaluates the impact of multiple sclerosis (MS) in Ireland, and estimates the associated direct, indirect, and intangible costs to society based on a large nationally representative sample.

Materials And Methods: A questionnaire was developed to capture the demographics, disease characteristics, healthcare use, informal care, employment, and wellbeing. Referencing international studies, standardized survey instruments were included (e.g. CSRI, MFIS-5, EQ-5D) or adapted (EDSS) for inclusion in an online survey platform. Recruitment was directed at people with MS via the MS Society mailing list and social media platforms, as well as in traditional media. The economic costing was primarily conducted using a 'bottom-up' methodology, and national estimates were achieved using 'prevalence-based' extrapolation.

Results: A total of 594 people completed the survey in full. The sample had geographic, disease, and demographic characteristics indicating good representativeness. At an individual level, average societal cost was estimated at €47,683; the average annual costs for those with mild, moderate, and severe MS were calculated as €34,942, €57,857, and €100,554, respectively. For a total Irish MS population of 9,000, the total societal costs of MS amounted to €429m. Direct costs accounted for just 30% of the total societal costs, indirect costs amounted to 50% of the total, and intangible or QoL costs represented 20%. The societal cost associated with a relapse in the sample is estimated as €2,438.

Limitations And Conclusions: The findings highlight that up to 70% of the total costs associated with MS are not routinely counted. These "hidden" costs are higher in Ireland than the rest of Europe, due in part to significantly lower levels of workforce participation, a higher likelihood of permanent workforce withdrawal, and higher levels of informal care needs. The relationship between disease progression and costs emphasize the societal importance of managing and slowing the progression of the illness.
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http://dx.doi.org/10.1080/13696998.2018.1427100DOI Listing
May 2018

Thrombin generation correlates with disease duration in multiple sclerosis (MS): Novel insights into the MS-associated prothrombotic state.

Mult Scler J Exp Transl Clin 2017 Oct-Dec;3(4):2055217317747624. Epub 2017 Dec 26.

University College Dublin, Ireland.

Background: Thrombin is well recognised for its role in the coagulation cascade but it also plays a role in inflammation, with enhanced thrombin generation observed in several inflammatory disorders. Although patients with multiple sclerosis (MS) have a higher incidence of thrombotic disease, thrombin generation has not been studied to date.

Objectives: The aim of this study was to characterise calibrated automated thrombography parameters in patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) in comparison to healthy controls (HCs).

Methods: Calibrated automated thrombography was performed on platelet poor plasma from 15 patients with RRMS, 15 with PPMS and 19 HCs.

Results: We found that patients with RRMS generate thrombin at a significantly faster rate than the less inflammatory subtype, PPMS or HCs. In addition, the speed of thrombin generation was significantly correlated with time from clinical diagnosis in both subtypes. However, in RRMS the rate of thrombin generation was increased with increased time from clinical diagnosis, while in PPMS the rate of thrombin generation decreased with increased time from clinical diagnosis.

Conclusions: These data likely reflect the differential active proinflammatory states in each MS subtype and provide novel mechanistic insights into the clinically relevant prothrombotic state observed in these patients.
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http://dx.doi.org/10.1177/2055217317747624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753921PMC
December 2017

Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides.

Bioorg Med Chem 2018 02 2;26(3):551-565. Epub 2017 Dec 2.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.

A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.
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http://dx.doi.org/10.1016/j.bmc.2017.11.037DOI Listing
February 2018

MRI and multiple sclerosis--the evolving role of MRI in the diagnosis and management of MS: the radiologist's perspective.

Ir J Med Sci 2018 Aug 25;187(3):781-787. Epub 2017 Nov 25.

Department of Radiology, St. Vincent's University Hospital, Elm Park, Nutley Lane, Dublin 4, D04 T6F4, Ireland.

Magnetic resonance imaging (MRI) plays an integral role in the management of multiple sclerosis (MS), from both diagnostic and therapeutic perspectives. This 2-part review aims to detail the evolving and expanding role of MRI for both radiologists and neurologists. In this article, we discuss the diagnostic criteria for MS relevant to radiologists, as well as its varying imaging manifestations. The role of MRI in therapeutic modification and complications are discussed.
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http://dx.doi.org/10.1007/s11845-017-1714-9DOI Listing
August 2018

A Protocol for Improved Precision and Increased Confidence in Nanoparticle Tracking Analysis Concentration Measurements between 50 and 120 nm in Biological Fluids.

Front Cardiovasc Med 2017 3;4:68. Epub 2017 Nov 3.

SPHERE Research Group, UCD Conway Institute, University College Dublin (UCD), Dublin, Ireland.

Nanoparticle tracking analysis (NTA) can be used to quantitate extracellular vesicles (EVs) in biological samples and is widely considered a useful diagnostic tool to detect disease. However, accurately profiling EVs can be challenging due to their small size and heterogeneity. Here, we aimed to provide a protocol to facilitate high-precision particle quantitation by NTA in plasma, the supernatant of activated purified platelets [the platelet releasate (PR)] and in serum, to increase confidence in NTA particle enumeration. The overall variance and the precision of NTA measurements were quantified by root mean square error and relative standard error. Using a bootstrapping approach, we found that increasing video replicates from 5 s × 60 s to 25 s × 60 s captures led to a reduction in overall variance and a reproducible increase in the precision of NTA particle-concentration quantitation for all three biofluids. We then validated our approach in an extended cohort of 32 healthy donors. Our results indicate that for vesicles sized between 50 and 120 nm, the precision of routine NTA measurements in serum, plasma, and PR can be significantly improved by increasing the number of video replicates captured. Our protocol provides a common platform to statistical compare particle size distribution profiles in the exosomal-vesicle size range across a variety of biofluids and in both healthy donor and patient groups.
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http://dx.doi.org/10.3389/fcvm.2017.00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675884PMC
November 2017

Effects of Intravenous Cold Saline on Hyperthermic Athletes Representative of Large Football Players and Small Endurance Runners.

Clin J Sport Med 2018 11;28(6):493-499

Department of Sports Medicine, West Chester University, West Chester, Pennsylvania.

Objective: To evaluate the cooling effects of intravenous (IV) cold normal (0.9%) saline on hyperthermic athletes.

Design: Randomized crossover study design.

Setting: Controlled research laboratory.

Participants: Twelve male participants who were representative of a collegiate cross-country (6) and American football (6) population.

Interventions: Participants underwent body composition analysis using a BodPod. They were placed in an environmentally controlled chamber and brought to a Tc of 39.5°C with dynamic exercise. When temperatures were reached, they were treated with either 2 L of cold saline (CS) (4°C) or intravenous room temperature (22°C) saline (RS) over a ∼30-minute period. Tre was measured with a rectal temperature probe every minute during the treatment period.

Main Outcome Measures: Total ΔTre (ending Tre - starting Tre) and cooling rate (total change in Tre/time) were measured for each condition, and body composition variables calculated included body surface area (BSA), BSA-to-mass ratio (BSA/mass), lean body mass, and body fat percentage (%BF) (P < 0.05).

Results: Statistically significant differences were found in the total ΔTre and cooling rate between the CS and RS trials. The cooling rate for the CS trials was significantly correlated to mass, BSA, BSA/mass, and %BF.

Conclusions: In hyperthermic athletes, core temperature was reduced more effectively using chilled saline during IV infusion. Body composition had a significant impact on overall cooling revealing that the smaller and leaner participants cooled at a greater rate. When indicated, CS infusion could be considered for cooling hyperthermic individuals when other methods are not available.
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http://dx.doi.org/10.1097/JSM.0000000000000505DOI Listing
November 2018

Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides.

J Med Chem 2017 09 19;60(18):7876-7896. Epub 2017 Sep 19.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff, CF10 3NB, U.K.

Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731253PMC
September 2017

Immediate thrombocytopenia at time of alemtuzumab infusion for multiple sclerosis - Not always self-limiting, fully reversible or predictable.

Mult Scler 2018 04 29;24(4):552-553. Epub 2017 Jun 29.

Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1177/1352458517719151DOI Listing
April 2018

Synthetic Approaches for the Preparation of Phosphoramidate Prodrugs of 2'-Deoxypseudoisocytidine.

ChemistryOpen 2017 06 5;6(3):424-436. Epub 2017 May 5.

School of Pharmacy and Pharmaceutical Sciences Cardiff University King Edward VII Avenue Cardiff CF10 3NB UK).

A synthetic procedure for the preparation of phosphoramidate prodrugs of -nucleosides is reported. Different phosphorochloridates were reacted with 3'--protected -acetyl-2'-deoxypseudoisocytidine or 3'--protected 2'-deoxypseudoisocytidine, followed by acidic hydrolysis of the protecting group. In the presence of the -acetyl moiety, the enolisable keto group of the nucleobase was able to react (like the 5'-OH) with the phosphorochloridates to give bisphosphorylated derivatives. Epimerisation (β to α) occurred if the amino group of the nucleobase was unprotected. These side reactions demonstrate the peculiar behaviour of -nucleosides compared to their nucleoside analogues. It was demonstrated that the first enzymatic activation step for this new class of prodrugs can be mediated by carboxypeptidase and that it follows the same pathway and rate reported for ProTides of more conventional nucleoside analogues. These new phosphoramidate derivatives deserve further investigation for their therapeutic potential as anti-cancer agents.
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http://dx.doi.org/10.1002/open.201700019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474688PMC
June 2017