Phase 1, placebo-controlled, dose escalation trial of chicory root extract in patients with osteoarthritis of the hip or knee

<p>Abstract</p> <p>Background</p> <p>Extracts of chicory root have anti-inflammatory properties <it>in vitro </it>and in animal models of arthritis. The primary objective of this investigator-initiated, Phase 1, placebo-controlled, double blind, dose-escalating trial was to determine the safety and tolerability of a proprietary bioactive extract of chicory root in patients with osteoarthritis (OA). Secondary objectives were to assess effects on the signs and symptoms of this disorder.</p> <p>Methods</p> <p>Individuals greater than 50 years of age with OA of the hip or knee were eligible for trial entry. A total of 40 patients were enrolled in 3 cohorts and were treated with escalating chicory doses of 600 mg/day, 1200 mg/day and 1800 mg/day for 1 month. The ratio of active treatment to placebo was 5:3 in cohorts 1 and 2 (8 patients) each and 16:8 in cohort 3 (24 patients). Safety evaluations included measurement of vital signs and routine lab tests at baseline and the end of the treatment period. Efficacy evaluations at baseline and final visits included self-assessment questionnaires and measurement of the 25-foot walking time.</p> <p>Results</p> <p>In the highest dose cohort, 18 patients who completed treatment per protocol were analyzed for efficacy. In this group, 13 patients showed at least 20% improvement in the defined response domains of pain, stiffness and global assessment: 9 of 10 (90%) patients randomized to active treatment with chicory and 4 of 8 (50%) patients randomized to placebo (P = 0.06). In general, the treatment was well-tolerated. Only one patient who was treated with the highest dose of chicory had to discontinue treatment due to an adverse event.</p> <p>Conclusions</p> <p>The results of this pilot study suggest that a proprietary bioactive extract of chicory root has a potential role in the management of OA and merits further investigation. Clinicaltrials.gov identifier: NCT 01010919.</p

Hypertension in pregnancy and risk of coronary heart disease and stroke: A prospective study in a large UK cohort.

BACKGROUND: Many studies investigating long-term vascular disease risk associated with hypertensive pregnancies examined risks in relatively young women among whom vascular disease is uncommon. We examined the prospective relation between a history of hypertension during pregnancy and coronary heart disease (CHD) and stroke in middle-aged UK women. METHODS: In 1996-2001, 1.1 million parous women (mean age=56years) without vascular disease at baseline reported their history of hypertension during pregnancy and other factors. They were followed for incident CHD and stroke (hospitalisation or death). Adjusted relative risks (RRs) were calculated using Cox regression. RESULTS: Twenty-six percent (290,008/1.1 million) reported having had a hypertensive pregnancy; 27% (79,163/290,008) of women with hypertensive pregnancy, but only 10% (82,145/815,560) of those without hypertensive pregnancy, reported being treated for hypertension at baseline. Mean follow-up was 11.6years (mean ages at diagnosis/N of events: CHD=65years/N=68,161, ischaemic stroke=67years/N=8365, haemorrhagic stroke=64years/N=5702). Overall, the RRs (95% confidence interval [CI]) of incident disease in women with hypertensive pregnancy versus those without such history were: CHD=1.29 (1.27-1.31), ischaemic stroke=1.29 (1.23-1.35), and haemorrhagic stroke=1.14 (1.07-1.21). However, among women with hypertensive pregnancy who were not taking hypertension treatment at baseline, their RRs (95% CI) were only modestly increased: CHD=1.17 (1.14-1.19), ischaemic stroke=1.18 (1.11-1.25), and haemorrhagic stroke=1.09 (1.02-1.18). CONCLUSION: Hypertension during pregnancy was associated with increased CHD and stroke incidence in middle age, largely because such women also had hypertension in their 50s and 60s, which has a substantially greater effect on vascular disease risk than hypertension during pregnancy without hypertension later in life

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

ETUDE RETROSPECTIVE DES METHODES ANTALGIQUES DANS UNE UNITE DE SOINS PALLIATIFS GERIATRIQUE (ETUDE PRELIMINAIRE SUR UNE PERIODE D'UNE ANNEE)

PARIS13-BU Serge Lebovici (930082101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Ecological or recalled assessments in chronic musculoskeletal pain? A comparative study of prospective and recalled pain assessments in low back pain and lower limb painful osteoarthritis.

OBJECTIVES: The objective of this study was to compare ecological and recalled pain intensity assessments over 29 days in hip and knee osteoarthritis (O) and chronic low back pain (L). PATIENTS AND METHODS: Rheumatologists were asked to enroll patients with O and L, with pain intensity above 40 mm, in a prospective study for 29 days. Pain intensity was assessed with physicians on Days 1 and 29, and ecologically, over the intervening 28-day period, by random phone calls. RESULTS: We carried out correlation analyses for 353 (159 O, 194 L) patients: Overall recalled daily pain was strongly correlated with calculated 3-day mean pain assessments (r=0.96 [O]; 0.93 [L]) and evening pain (r=0.96 [O], 0.90 [L]). Correlations between ecological and recalled measures were stronger for recall over the last 7 days than for recall over the last 28 days in osteoarthritis patients (r=0.78, r=0.63), but were similar for both recall periods in low back pain patients (r=0.70, r=0.72). Correlations between assessments for the last 7 and 28 days were stronger for ecological (r=0.88 [O], 0.91 [L]) than for clinical (r=0.77 [O]; 0.86 [L]) assessments. After adjustment for current pain intensity, correlations remained significant for ecological assessments, but not for clinical assessments. Recalled pain assessments were more accurate when made after 24 hours (r=0.71 [O]; 0.70 [L]) than when made after 48 hours (r=0.63 [O]; 0.61 [L]). CONCLUSIONS: For both low back pain and osteoarthritis, overall daily pain recall is a reliable measurement correlated with daily ecological measurements, whereas a rapid decrease in recall occurs after 48 hours. The most reliable period for pain recall was 7 days, but the results obtained were influenced by current pain

Efficacy of epicardially delivered adipose stroma cell sheets in dilated cardiomyopathy

International audienceFew studies have assessed the effects of cell therapy in non-ischaemic cardiomyopathies which, however, contribute to a large number of cardiac failures. Assuming that such conditions are best suited for a global delivery of cells, we assessed the effects of epicardially delivered adipose tissue-derived stroma cell (ADSC) sheets in a mouse model of dilated cardiomyopathy based on cardiac-specific and tamoxifen-inducible invalidation of serum response factor. Three weeks after tamoxifen administration, the function of the left ventricle (LV) was assessed by echocardiography. Twenty-nine mice were then allocated to control (n 9, non-transgenic), sham (n 10, transgenic non-treated), and treated (n 10, transgenic) groups. In the treated group, 3 10(6) allogeneic ADSCs were cultured for 2 days onto temperature-responsive polymers and the generated sheets were then transplanted over the surface of the heart. In 10 additional mice, the sheet was made of green fluorescent protein (GFP)-labelled ADSCs to track cell fate. Function, engraftment, and fibrosis were blindly assessed after 3 weeks. In the non-treated group, fractional shortening declined compared with baseline, whereas the sheet application resulted in its stabilization. This correlated with a lesser degree of LV remodelling, as LV end-diastolic and end-systolic diameters did not differ from baseline values. Many GFP cells were identified in the epicardial graft and in the myocardium. Treated animals also displayed a reduced expression of the stress-induced atrial natriuretic factor and beta-myosin heavy chain genes. These protective effects were also accompanied by a reduction of myocardial fibrosis. These results strongly suggest the functional relevance of epicardially delivered cell-seeded biomaterials to non-ischaemic heart failure

Long-Term Functional Benefits of Epicardial Patches as Cell Carriers

International audienceBoth enzymatic dissociation of cells prior to needle-based injections and poor vascularization of myocardial infarct areas are two important contributors to cell death and impede the efficacy of cardiac cell therapy. Because these limitations could be overcome by scaffolds ensuring cell cohesiveness and codelivery of angiogenic cells, we used a chronic rat model of myocardial infarction to assess the long-term (6 months) effects of the epicardial delivery of a composite collagen-based patch harboring both cardiomyogenesis-targeted human embryonic SSEA-1(+) (stem cell-derived stage-specific embryonic antigen-1 positive) cardiovascular progenitors and autologous (rat) adipose tissue-derived angiogenesis-targeted stromal cells (n=27). Cell-free patches served as controls (n=28). Serial follow-up echocardiographic measurements of left ventricular ejection fraction (LVEF) showed that the composite patch group yielded a significantly better preservation of left ventricular function that was sustained over time as compared with controls, and this pattern persisted when the assessment was restricted to the subgroup of rats with initial LVEFs below 50%. The composite patch group was also associated with significantly less fibrosis and more vessels in the infarct area. However, although human progenitors expressing cardiac markers were present in the patches before implantation, none of them could be subsequently identified in the grafted tissue. These data confirm the efficacy of epicardial scaffolds as cell carriers for ensuring long-term functional benefits and suggest that these effects are likely related to paracrine effects and call for optimizing cross-talks between codelivered cell populations to achieve the ultimate goal of myocardial regeneration

Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience

International audienceAim This paper describes the multi-step translational approach that has resulted in the generation of clinical-grade human embryonic stem cell-derived cardiac progenitor cells for transplantation in patients with severe ischaemic heart failure. There is now compelling evidence that cells committed to a cardiac lineage are most effective for improving the function of infarcted hearts. This has been confirmed by our pre-clinical studies entailing transplantation of human embryonic stem cell (hESC)-derived cardiac progenitors in rat and non-human primate models of myocardial infarction. These data have paved the way for a translational programme aimed at a phase I clinical trial. Methods and results The main steps of this programme have included (i) the expansion of a clone of pluripotent hESC to generate a master cell bank under good manufacturing practice conditions (GMP); (ii) a growth factor-induced cardiac specification; (iii) the purification of committed cells by immunomagnetic sorting to yield a stage-specific embryonic antigen (SSEA)-1-positive cell population strongly expressing the early cardiac transcription factor Isl-1; (iv) the incorporation of these cells into a fibrin scaffold; (v) a safety assessment focused on the loss of teratoma-forming cells by in vitro (transcriptomics) and in vivo (cell injections in immunodeficient mice) measurements; (vi) an extensive cytogenetic and viral testing; and (vii) the characterization of the final cell product and its release criteria. The data collected throughout this process have led to approval by the French regulatory authorities for a first-in-man clinical trial of transplantation of these SSEA-1(+) progenitors in patients with severely impaired cardiac function. Conclusion Although several facets of this manufacturing process still need to be improved, these data may yet provide a useful platform for the production of hESC-derived cardiac progenitor cells under safe and cost-effective GMP conditions