25 results found
Howard LSGE, He J, Watson GMJ, et al., 2021, Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials., Ann Am Thorac Soc
RATIONALE: Iron deficiency, in the absence of anaemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin levels. The safety and benefit of parenteral iron replacement in this patient population is unclear. OBJECTIVES: To evaluate the safety and efficacy of parenteral iron replacement in pulmonary arterial hypertension. METHODS: In two randomised, double blind, placebo-controlled 12 week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject®) 1000 mg (or 15 mg/kg if weight < 66.7Kg) or saline as placebo and 17 patients in China received iron dextran (Cosmofer®) 20 mg iron/kg body weight or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by: a serum ferritin < 37 µg/l or iron < 10.3 µmol/l or transferrin saturations < 16.4%. RESULTS: Both iron treatments were well tolerated and improved iron status. Analysed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6 minute walk test) or cardio-pulmonary haemodynamics, as assessed by right heart catheterisation, cardiac magnetic resonance or plasma NT-proBNP, at 12 weeks. CONCLUSION: Iron repletion by administration of a slow release iron preparation as a single infusion to PAH patients with iron deficiency without overt anaemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).
Owen DRJ, Fan J, Campioli E, et al., 2017, TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis, Biochemical Journal, Vol: 474, Pages: 3985-3999, ISSN: 1470-8728
The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
Abbara A, Clarke SA, Islam R, et al., 2017, A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of OHSS: a phase 2 randomized controlled trial, Human Reproduction, Vol: 32, Pages: 1915-1924, ISSN: 1460-2350
STUDY QUESTIONCan increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)?SUMMARY ANSWERA second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS.WHAT IS KNOWN ALREADYKisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS.STUDY DESIGN, SIZE, DURATIONPhase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L).Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK.Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%.Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence.MAIN RESULTS AND THE ROLE OF CHANCEA second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspepti
Prague JK, Roberts RE, Comninos AC, et al., 2017, Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial, Lancet, Vol: 389, Pages: 1809-1820, ISSN: 1474-547X
BackgroundHot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes.MethodsThis phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40–62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185.Findings68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99&nda
Lyasere OU, Brown EA, Johansson L, et al., 2016, Quality of Life and Physical Function in Older Patients on Dialysis: A Comparison of Assisted Peritoneal Dialysis with Hemodialysis, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 11, Pages: 423-430, ISSN: 1555-9041
Rizzuto I, Stavraka C, Chatterjee J, et al., 2015, Risk of Ovarian Cancer Relapse Score A Prognostic Algorithm to Predict Relapse Following Treatment for Advanced Ovarian Cancer, International Journal of Gynecological Cancer, Vol: 25, Pages: 416-422, ISSN: 1525-1438
Objective: The aim of this study was to construct a prognostic index that predicts risk ofrelapse in women who have completed first-line treatment for ovarian cancer (OC).Methods: A database of OC cases from 2000 to 2010 was interrogated for InternationalFederation of Gynecology and Obstetrics stage, grade and histological subtype of cancer,preoperative and posttreatment CA-125 level, presence or absence of residual disease aftercytoreductive surgery and on postchemotherapy computed tomography scan, and time toprogression and death. The strongest predictors of relapse were included into an algorithm,the Risk of Ovarian Cancer Relapse (ROVAR) score.Results: Three hundred fifty-four cases of OC were analyzed to generate the ROVARscore. Factors selected were preoperative serum CA-125, International Federation ofGynecology and Obstetrics stage and grade of cancer, and presence of residual disease atposttreatment computed tomography scan. In the validation data set, the ROVAR score had asensitivity and specificity of 94% and 61%, respectively. The concordance index for thevalidation data set was 0.91 (95% confidence interval, 0.85-0.96). The score allows patientstratification into low (G0.33), intermediate (0.34Y0.67), and high (90.67) probability ofrelapse.Conclusions: The ROVAR score stratifies patients according to their risk of relapsefollowing first-line treatment for OC. This can broadly facilitate the appropriate tailoring ofposttreatment care and support.
Libri V, Yandim C, Athanasopoulos S, et al., 2014, Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study, The Lancet, Vol: 384, Pages: 504-513, ISSN: 0140-6736
BackgroundFriedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia.MethodsIn this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2–8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809.FindingsNicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5–6 g resulted in a sustained and significant (p<0&m
Libri V, Gibbs JSR, Pinato DJ, et al., 2014, Capsaicin 8% patch for Treprostinil SC infusion site pain in Pulmonary Hypertension Patients., British Journal of Anaesthesia, Vol: 112, Pages: 337-347
Barnes GD, Alam S, Carter G, et al., 2013, Sustained Cardiovascular Actions of APJ Agonism During Renin-Angiotensin System Activation and in Patients with Heart Failure., Circulation:Heart Failure, Vol: 6, Pages: 482-491
Rhodes CJ, Wharton J, Boon RA, et al., 2013, Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension., American Journal of Respiratory and Critical Care Medicine, Vol: 187, Pages: 294-302
MicroRNAs (miRNAs or miRs) are implicated in the pathogenesis of various cardiovascular diseases, including pulmonary arterial hypertension (PAH).
HUSON LW, 2012, Phase I Oncology Trials Incorporating Patient Choice of Dose, British Journal of Cancer, Vol: 107, Pages: 1022-1024
WORTHAM NC, AHAMED E, NICHOL SM, et al., 2009, The DEAD-box protein p72 regulates ERα-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ERα-positive breast cancer, Oncogene, Vol: 28, Pages: 4053-4064, ISSN: 1476-5594
The DEAD-box RNA helicases p68 (DDX5) and p72 (DDX17) have been shown to act as transcriptional co-activators for a diverse range of transcription factors, including oestrogen receptor-α (ERα). Here, we show that, although both proteins interact with and co-activate ERα in reporter gene assays, small interfering RNA-mediated knockdown of p72, but not p68, results in a significant inhibition of oestrogen-dependent transcription of endogenous ERα-responsive genes and oestrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ERα-positive primary breast cancers for p68 and p72 indicate that p72 expression is associated with an increased period of relapse-free and overall survival (P=0.006 and 0.016, respectively), as well as being inversely associated with Her2 expression (P=0.008). Conversely, p68 shows no association with relapse-free period, or overall survival, but it is associated with an increased expression of Her2 (P=0.001), AIB-1 (P<0.001) and higher tumour grade (P=0.044). Our data thus highlight a crucial role for p72 in ERα co-activation and oestrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ERα activity in breast cancer.
HUSON LW, KINNERSLEY N, 2009, Bayesian Fitting of a Logistic Dose-Response Curve with Numerically-Derived Priors., Pharmaceutical Statistics, Vol: 4, Pages: 279-286
HUSON LW, CHUNG JC, SALGO M, 2007, Missing Data Imputation in Two Phase III Trials Treating HIV Infection., Journal of Biopharmaceutical Statistics, Pages: 159-172
HUSON LW, CHUNG JC, SALGO M, 2006, Multiple Polyexponentials and Quasipolynomials as Empirical Nonlinear Regression Models: a case study with HIV viral load data., Journal of Biopharmaceutical Statistics, Vol: 16, Pages: 165-179
LAZZARIN A, CLOTET B, COOPER D, et al., 2003, Efficacy of enfuvirtide in patients infected with drug-resistant HIV1 in Europe and Australia., New England Journal of Medicine, Vol: 22, Pages: 2186-2195
WELLIVER R, MONTO S, CAREWICZ O, et al., 2001, Effectiveness of Oseltamivir in Preventing Influenza in Household Contacts., Journal of The American Medical Association, Vol: 6, Pages: 748-754
HAYDEN F, ATMAR R, SCHILLING M, et al., 1999, Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza., New England Journal of Medicine, Vol: 18, Pages: 1336-1343
WINTON F, CORN T, HUSON LW, et al., 1989, Effects of Light upon Mood and Melatonin in Patients with Seasonal Affective Disorder., Psychological Medicine, Pages: 585-590
JUHLIN LJ, GIBSON JR, HARVEY SJ, et al., 1987, Acrivastine vs Clemastine in the Treatment of Chronic Idiopathic Urticaria., International Journal of Dermatology., Vol: 26, Pages: 653-654
HUSON LW, 1984, Definition and Properties of a Coefficient of Sensitivity for Mathematical Models., Ecological Modelling., Vol: 21, Pages: 149-159
HUSON LW, 1983, A Rapid Approximate Method of Estimating the Median of a Dose-Tolerance Distribution., Tropical Pest Management, Vol: 2, Pages: 183-185
HUSON LW, 1982, A Graphical Aid to Multivariate Sensitivity Analysis., Ecological Modelling, Vol: 16, Pages: 91-98
FAWCETT SC, BUNYAN PJ, HUSON LW, et al., 1981, Excretion of Radioactivity Following Intraperitoneal Administration of C-DDT, C-DDD, C-DDE and C-DDMU to the Rat and Japanese Quail., Bulletin of Environmental Contamination and Toxicology, Vol: 27, Pages: 386-392
HUSON LW, 1980, Statistical Analysis of Comparative Field Trials of Acute Rodenticides., Journal of Hygiene (Cambridge), Vol: 84, Pages: 341-346
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