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1.
Cancer Chemother Pharmacol ; 91(3): 267-280, 2023 03.
Article in English | MEDLINE | ID: mdl-36914828

ABSTRACT

PURPOSE: Galectin-3, a ß-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants. METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal. RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75-4 h (median) post-dose; mean half-life was 11-16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected. CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052).


Subject(s)
Galectin 3 , Humans , Administration, Oral , Area Under Curve , Dose-Response Relationship, Drug , Double-Blind Method , Galectin 3/antagonists & inhibitors , Healthy Volunteers
2.
Ann Rheum Dis ; 72(9): 1475-80, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-22984171

ABSTRACT

OBJECTIVES: To evaluate the efficacy and safety of an oral phosphodiesterase 4 inhibitor, apremilast, in treatment of ankylosing spondylitis (AS) by monitoring symptoms and signs in a pilot study including exploratory investigation of effects of PDE4 inhibition on blood biomarkers of bone biology. METHODS: In this double-blind, placebo-controlled, single-centre, Phase II study, patients with symptomatic AS with active disease on MRI were randomised to apremilast 30 mg BID or placebo over 12 weeks. Bath Indices were monitored serially. Patients were followed for 4 weeks after stopping medication. Bone biomarkers were assessed at baseline and day 85. RESULTS: 38 subjects were randomised and 36 subjects completed the study. Although the primary end-point (change in BASDAI at week 12) was not met, apremilast was associated with numerically greater improvement from baseline for all clinical assessments compared with placebo with mean change in BASDAI (-1.59±1.48 vs -0.77±1.47), BASFI (-1.74±1.91 vs -0.28±1.61) and BASMI (-0.51±1.02 vs -0.21±0.67); however, differences did not achieve statistical significance. The clinical indices returned to baseline values by 4 weeks after cessation of apremilast. Six apremilast patients (35.3%) vs 3 placebo (15.8%) achieved ASAS20 responses (p=0.25). There were statistically significant decreases in serum RANKL and RANKL:osteoprotegrin ratio and plasma sclerostin but no significant changes in serum DKK-1, bone alkaline phosphatase, TRAP5b, MMP3, osteoprotegrin, or osteocalcin. CONCLUSIONS: Although a small pilot study, these results suggest that apremilast may be effective and well tolerated in AS and modulates biomarkers of bone biology. These data support further research of apremilast in axial inflammation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Phosphodiesterase 4 Inhibitors/therapeutic use , Spondylitis, Ankylosing/drug therapy , Thalidomide/analogs & derivatives , Adaptor Proteins, Signal Transducing , Administration, Oral , Adult , Aged , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Biomarkers/blood , Bone Morphogenetic Proteins/blood , Bone and Bones/drug effects , Bone and Bones/metabolism , Disability Evaluation , Double-Blind Method , Female , Genetic Markers , Health Status , Humans , Male , Middle Aged , Osteoprotegerin/blood , Phosphodiesterase 4 Inhibitors/adverse effects , Pilot Projects , RANK Ligand/blood , Severity of Illness Index , Spondylitis, Ankylosing/blood , Spondylitis, Ankylosing/pathology , Spondylitis, Ankylosing/physiopathology , Thalidomide/adverse effects , Thalidomide/therapeutic use , Treatment Outcome
3.
Arthritis Res Ther ; 14(5): R198, 2012 Sep 12.
Article in English | MEDLINE | ID: mdl-22972032

ABSTRACT

INTRODUCTION: We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA). METHODS: A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15 mg or 7.5 mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP). RESULTS: All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures. CONCLUSIONS: Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00746512.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/drug therapy , Endpoint Determination , Metacarpophalangeal Joint/diagnostic imaging , Prednisone/therapeutic use , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/blood , Biomarkers/blood , C-Reactive Protein/metabolism , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Reproducibility of Results , Sensitivity and Specificity , Treatment Outcome , Ultrasonography
4.
Clin Exp Rheumatol ; 30(2): 254-61, 2012.
Article in English | MEDLINE | ID: mdl-22409880

ABSTRACT

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Enzyme Inhibitors/therapeutic use , Metacarpophalangeal Joint/drug effects , Nitric Oxide Synthase Type II/antagonists & inhibitors , Prednisolone/therapeutic use , Sulfides/therapeutic use , Synovitis/drug therapy , Ultrasonography, Doppler , Adult , Aged , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/enzymology , Disability Evaluation , Double-Blind Method , England , Female , Humans , Male , Metacarpophalangeal Joint/blood supply , Metacarpophalangeal Joint/diagnostic imaging , Metacarpophalangeal Joint/enzymology , Middle Aged , Nitric Oxide Synthase Type II/metabolism , Placebos , Predictive Value of Tests , Serbia , Synovitis/diagnostic imaging , Synovitis/enzymology , Time Factors , Treatment Outcome
6.
Musculoskeletal Care ; 9(4): 222-7, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21972039

ABSTRACT

Disease Activity Score in 28 Joints (DAS28) scoring in rheumatoid arthritis (RA) is now recommended as a basis for clinical decisions about treatment initiation and alteration. The British Society of Rheumatology suggests that most RA patients should have a DAS28 assessment at every clinic visit, to monitor disease activity and the impact of therapy. Establishing an accurate baseline assessment of DAS28, with regular re-evaluation, is considered crucial, so that progress towards a defined target of remission (or low disease activity) can be measured. The Treat-to-Target initiative, launched in March 2010, is now impacting on clinical practice throughout the UK and Europe. One of its key recommendations is that patients should be regularly monitored using validated composite measures of disease activity that include joint assessments. DAS28 is recommended as one of the most useful of these methods but, although it is becoming more widely adopted and training is ongoing, supported by materials produced by the European League Against Rheumatism (EULAR), the variability inherent in the four components of DAS28 means that standardization of practice methods is now an important issue. This short report details some of the pitfalls that can occur when applying DAS28 in clinical practice and suggests some workable solutions to enable departments to set up their own standard operating procedure.


Subject(s)
Arthritis, Rheumatoid/diagnosis , Drug Monitoring/methods , Joints/pathology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/physiopathology , Arthrography/standards , C-Reactive Protein/analysis , Disease Progression , Drug Monitoring/standards , Edema/diagnosis , Female , Health Status , Humans , Joints/physiopathology , Male , Reproducibility of Results , Severity of Illness Index , Sickness Impact Profile
7.
J Rheumatol ; 37(12): 2493-501, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20889600

ABSTRACT

OBJECTIVE: To investigate the stability over 2 weeks of ultrasonographic assessments of synovial thickness and vascularity in all 10 metacarpophalangeal joints of subjects with rheumatoid arthritis (RA) with a range of disease activities as measured by the validated Disease Activity Score-28 joint score (DAS28-ESR). And in subjects with severe disease activity, to compare the sensitivity of these measurements, acute-phase markers, and vascular endothelial growth factor to change in response to 2 weeks of oral prednisolone (7.5 mg daily). METHODS: A group of 38 subjects with RA were enrolled, 13 (mean DAS28 2.1), 14 (mean DAS28 5.2), and 11 (mean DAS28 5.7) meriting oral corticosteroid treatment. Synovial thickness and vascularity were assessed by ultrasonography at 3 timepoints. Images were ranked by semiquantitative scale. Vascularity was also measured by quantitative determination of the power Doppler area (PDA). RESULTS: In the whole RA cohort, baseline indices of synovial thickness and vascularity correlated with DAS28, as did PDA (r = 0.42, p < 0.05). In the RA groups on stable therapy, synovial thickness and vascularity showed little variation over 2 weeks. In the corticosteroid group, PDA had fold changes of -1.9-fold (p < 0.05) after 1 week and -2.2-fold (p < 0.05) after 2 weeks. These were the largest fold changes of all measured variables. CONCLUSION: Ultrasonographic measures can differentiate disease severity in RA correlating closely with DAS28. Quantitative power Doppler signal was significantly reduced within 1 week of oral prednisolone, a rapid kinetic suggesting that PDA may have value as a sensitive early marker of therapeutic response.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Arthritis, Rheumatoid , Metacarpophalangeal Joint/anatomy & histology , Metacarpophalangeal Joint/diagnostic imaging , Synovial Membrane/blood supply , Synovial Membrane/diagnostic imaging , Ultrasonography, Doppler/methods , Adult , Aged , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Humans , Metacarpophalangeal Joint/pathology , Middle Aged , Synovial Membrane/pathology , Treatment Outcome
8.
Clin Rheumatol ; 27(11): 1441-3, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18716729

ABSTRACT

Rheumatoid arthritis (RA) might lead to voice impairment through several mechanisms but its prevalence has been little investigated. RA patients attending a rheumatology outpatient clinic had joint assessments and completed the Voice Handicap Index-10 (VHI-10). A comparator group consisted of patients attending the department with other diseases. Seventy-three patients with RA and 73 comparators were recruited. Four patients with RA (5%) and one comparator (1%) had significantly abnormal VHI-10 scores. RA patients with a Disease Activity Score 28 >3.2, indicating more active disease, had significantly higher VHI-10 scores. A low prevalence of self-reported voice handicap occurs in RA and associates with more active disease.


Subject(s)
Arthritis, Rheumatoid/complications , Voice Disorders/complications , Voice Disorders/epidemiology , Aged , Arthritis, Rheumatoid/epidemiology , Case-Control Studies , Disability Evaluation , Female , Humans , Male , Middle Aged , Prevalence , Severity of Illness Index , United Kingdom/epidemiology
9.
Ann Rheum Dis ; 66(11): 1491-6, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17412740

ABSTRACT

OBJECTIVE: To conduct a cross-sectional review of non-selected consecutive outpatients with rheumatoid arthritis (RA) as part of standard clinical care in 15 countries for an overview of the characteristics of patients with RA. METHODS: The review included current disease activity using data from clinical assessment and a patient self-report questionnaire, which was translated into each language. Data on demographic, disease and treatment-related variables were collected and analysed using descriptive statistics. Variation in disease activity on DAS28 (disease activity score on 28-joint count) within and between countries was graphically analysed. A median regression model was applied to analyse differences in disease activity between countries. RESULTS: Between January 2005 and October 2006, the QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) project included 4363 patients from 48 sites in 15 countries; 78% were female, >90% Caucasian, mean age was 57 years and mean disease duration was 11.5 years. More than 80% of patients had been treated with methotrexate in all but three countries. Overall, patients had an active disease with a median DAS28 of 4.0, with a significant variation between countries (p<0.001). Among 42 sites with >50 patients included, low disease activity of DAS28 50% of patients had high disease activity of DAS28 >5.1. CONCLUSIONS: This international multicentre cross-sectional database provides an overview of clinical status and treatments of patients with RA in standard clinical care in 2005-6 including countries that are infrequently involved in clinical research projects.


Subject(s)
Arthritis, Rheumatoid/diagnosis , International Cooperation , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/epidemiology , Cross-Sectional Studies , Databases, Factual , Drug Administration Schedule , Drug Utilization/statistics & numerical data , Female , Humans , Male , Methotrexate/administration & dosage , Middle Aged , Severity of Illness Index , Sex Distribution
10.
Blood ; 109(10): 4328-35, 2007 May 15.
Article in English | MEDLINE | ID: mdl-17255353

ABSTRACT

The T-cell receptor zeta (TCRzeta) chain is a master sensor and regulator of lymphocyte responses. Loss of TCRzeta expression has been documented in infectious, inflammatory, and malignant diseases, suggesting that it may serve to limit T-cell reactivity and effector responses at sites of tissue damage. These observations prompted us to explore the relationship between TCRzeta expression and effector function in T cells. We report here that TCRzeta(dim) lymphocytes are enriched for antigen-experienced cells refractory to TCR-induced proliferation. Compared to their TCRzeta(bright) counterparts, TCRzeta(dim) cells share characteristics of differentiated effector T cells but use accessory pathways for transducing signals for inflammatory cytokine gene expression and cell contact-dependent pathways to activate monocytes. TCRzeta(dim) T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. Whilst blocking leukocyte trafficking with anti-TNF therapy in vivo is associated with the accumulation of TCRzeta(dim) T cells in peripheral blood, this T-cell subset retains the capacity to migrate in vitro. Taken together, the functional properties of TCRzeta(dim) T cells make them promising cellular targets for the treatment of chronic inflammatory disease.


Subject(s)
Cell Movement/immunology , Inflammation/immunology , Lymphocyte Subsets/metabolism , Membrane Proteins/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/physiology , Adult , Animals , Arthritis, Psoriatic/blood , Arthritis, Psoriatic/immunology , Arthritis, Reactive/blood , Arthritis, Reactive/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , CHO Cells , Cricetinae , Cricetulus , Flow Cytometry , Fluorescence , Humans , Middle Aged , Transfection
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