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51.
AndrewJ. Stott Michel C. Maillard Vahri Beaumont David Allcock Omar Aziz Alexander H. Borchers Wesley Blackaby Perla Breccia Gillian Creighton-Gutteridge Alan F. Haughan Rebecca E. Jarvis Christopher A. Luckhurst Kim L. Matthews George McAllister Scott Pollack Elizabeth Saville-Stones Amanda J. Van de Poël Huw D. Vater Julie Vann Rachel Williams Dawn Yates Ignacio Muoz-Sanjun Celia Dominguez 《ACS medicinal chemistry letters》2021,12(3):380
Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC50, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease. 相似文献
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Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy 总被引:3,自引:0,他引:3
Kwok S Selby PL McElduff P Laing I Mackness B Mackness MI Prais H Morgan J Yates AP Durrington PN Sci FM 《Clinical endocrinology》2004,61(6):760-767
OBJECTIVE: Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. DESIGN AND MEASUREMENTS: Thirty-four women were treated with conjugated equine oestrogens (CEE) 0.625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 microg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. RESULTS: The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P < 0.01) and fibrinogen (P < 0.001). CEE raised serum triglyceride (P < 0.001) and CRP (P < 0.01) concentrations, which reverted towards pre-oestrogen levels with progestogens. Progestogens significantly reduced high density lipoprotein (HDL) cholesterol (P < 0.05). NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP. CONCLUSION: Preconceptions that more androgenic progestogens necessarily have more unfavourable effects on cardiovascular risk factors may require revision. 相似文献
55.
Alison M. Dines David M. Wood Miguel Galicia Christopher M. Yates Fridtjof Heyerdahl Knut Erik Hovda Isabelle Giraudon Roumen Sedefov Paul I. Dargan Euro-DEN Research Group 《Journal of medical toxicology》2015,11(4):415-421
Cannabis is the most commonly used illicit drug in Europe, and is generally regarded
as having low acute toxicity. We present the findings of the first 6 months of data collection from
the Euro-DEN project on presentations related to cannabis use to further understand the acute
toxicity related to the use of cannabis. Data was extracted on clinical features, treatment and
outcome from the Euro-DEN minimum dataset for all cases of acute recreational drug toxicity reported
1st October 2013 to 31st March 2014 for all cannabis-related presentations. Of 2198 presentations
reported by 14 of the 16 Euro-DEN centres, 356 (16.2 %) involved cannabis either alone or together
with other drugs/alcohol. There were 36 that involved lone use of cannabis (1.6 % of all
presentations). Of the 35 non-fatal lone cannabis presentations, the most commonly reported features
were neuro-behavioural (agitation/aggression 8 (22.9 %), psychosis 7 (20.0 %), anxiety 7 (20.0 %))
and vomiting 6 (17.1 %). Most patients (25, 71.4 %) received no treatment and 30 (85.7 %) were
discharged/self-discharged from the ED. There was one fatality amongst these lone-cannabis cases: an
18-year-old male collapsed with an asystolic cardiac arrest whilst smoking cannabis and suffered
hypoxic brain injury related to prolonged cardiac arrest. THC was detected in a urine sample taken
at ED arrival; no other drugs were detected. Lone acute cannabis toxicity was typically associated
with neuro-behavioural symptoms and vomiting. Although uncommon, severe toxicity including
cardiovascular toxicity and death may be under-recognised, and it is important that Emergency
Physicians are aware of this. 相似文献
56.
Saskia PJ Verkleij Pim AJ Luijsterburg Sten P Willemsen Bart W Koes Arthur M Bohnen Sita MA Bierma-Zeinstra 《The British journal of general practice》2015,65(637):e530-e537
Background
The effectiveness of diclofenac versus paracetamol in primary care patients with pain caused by knee osteoarthritis is unclear.Aim
To assess the effectiveness of diclofenac compared with paracetamol over a period of 2, 4, and 12 weeks in patients with knee osteoarthritis.Design and setting
Randomised controlled trial in general practice.Method
There were 104 patients included in the study, they were aged ≥45 years consulting their GP with knee pain caused by knee osteoarthritis. Patients were randomly allocated to diclofenac (n = 52) or paracetamol (n = 52) for at least 2 weeks. Primary outcomes were daily knee pain severity, and knee pain and function measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS).Results
Over a period of 2- and 4-weeks follow-up, no significant difference in daily knee pain was found between the patient groups: estimated differences of 0.5 (95% CI = −0.2 to 1.3) and −0.2 (95% CI = −1.0 to 0.7), respectively. Over the 12-weeks follow-up, no significant differences were found between both groups for KOOS pain: estimated difference of −2.8 (95% CI = −10.7 to 5.1) and KOOS function of −2.7 (−10.6 to 5.0).Conclusion
Over a period of 2- and 4-weeks follow-up no significant difference in daily measured knee pain severity was found between primary care patients with knee osteoarthritis taking paracetamol or diclofenac. Also, over a period of 12-weeks follow-up no significant differences were found regarding KOOS pain and KOOS function between both groups. Patients more frequently reported minor adverse events after taking diclofenac (64%) than paracetamol (46%). 相似文献57.
Gabriele C. DeLuca Richard L. Yates Harry Beale Sarah A. Morrow 《Brain pathology (Zurich, Switzerland)》2015,25(1):79-98
Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS) that has only recent gained considerable attention. Clinical neuropsychological studies have made apparent the multifaceted nature of cognitive troubles often encountered in MS and continue to broaden our understanding of its complexity. Radiographic studies have started to decipher the neuroanatomic substrate of MS‐related cognitive impairment and have shed light onto its pathogenesis. Where radiographic studies have been limited by inadequate resolution or non‐specificity, pathological studies have come to the fore. This review aims to provide an overview of the nature of cognitive impairment typically seen in MS and to explore the literature on imaging and pathological studies relevant to its evolution. In particular, the relative contributions of gray (ie, cerebral cortex, hippocampus, thalamus and basal ganglia) and white matter to MS‐related cognitive impairment will be discussed and the importance of interconnectivity between structures highlighted. The pressing need for longitudinal studies combining standardized neuropsychometric, paraclinical and radiographic outcomes obtained during life with post‐mortem tissue analysis after death is presented. 相似文献
58.
A J Yates G E Gutierrez I R Garrett J J Mencel G W Nuss A B Schreiber G R Mundy 《Endocrinology》1990,126(6):2845-2849
A new analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT; RG-12851; here termed CTR), which lacks the ring structure of native calcitonin, was tested for biological activity in several in vitro and in vivo assay systems. The analog (CTR) and salmon calcitonin (sCT) stimulated kidney cell adenylate cyclase activity and inhibited bone resorption in organ cultures of fetal rat long bones with similar potencies and efficacies. Furthermore, CTR and sCT, at similar doses, induced comparable hypocalcemic responses in mice following sc injection or infusions. However, unlike sCT, CTR did not induce anorexia and weight loss in rats following sc injection. These data suggest that the ring structure of sCT may be important for the anorexigenic effect but is not required for effect on bone resorption or calcium homeostasis. Clinical studies appear warranted as, potentially, CTR might induce fewer side effects than does sCT. 相似文献
59.
Ly Thuy Nguyen Kimberly Alexander Patsy Yates 《Journal of pain and symptom management》2018,55(6):1459-1472
Objectives
To assess the feasibility of conducting a trial of a psychoeducational intervention involving the provision of tailored information and coaching to improve management of a cancer-related symptom cluster (fatigue, pain, and sleep disturbance) and reduce symptom cluster impacts on patient health outcomes in the Vietnamese context and to undertake a preliminary evaluation of the intervention.Methods
A parallel-group single-blind pilot quasi-experimental trial was conducted with 102 cancer patients in one Vietnamese hospital. The intervention group received one face-to-face session and two phone sessions delivered by a nurse one week apart, and the comparison group received usual care. Patient outcomes were measured at baseline before the chemotherapy cycle and immediately preceding the next chemotherapy cycle. Separate linear mixed models were used to evaluate the impact of the intervention on total symptom cluster severity, symptom scores, functional status, depressive symptoms, and health-related quality of life.Results
The study design was feasible with a recruitment rate of 22.6% and attrition rate of 9.8%. Compared to the control group, the intervention group showed a significant reduction in symptom cluster severity, fatigue severity, fatigue interference, sleep disturbance, depression, and anxiety. Significant differences were not observed for pain severity, pain interference, functional status, and health-related quality of life. The intervention was acceptable to the study population, with a high attendance rate of 78% and adherence rate of 95.7%.Conclusion
On the basis of the present study findings, future randomized controlled trials are needed to test the effectiveness of a symptom cluster psychoeducational intervention in Vietnam. 相似文献60.