Objective. To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA). Methods. Patients with active RA who had discontinued all DMARDs for at least 2 weeks ...and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids. Results. 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67±19 μmol/l (0.76±0.22 mg/dl) at baseline to 75±26 μmol/l (0.85±0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had ≥30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a ≥30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints. Conclusion. This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.
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We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa ...multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
Chromosomal abnormalities which are prevalent in human lymphoid tumours are believed to be involved in tumour pathogenesis and their formation may be the result of erroneous activity by the V‐D‐J ...recombinase. Frequently, recombinase accessibility is provided by prior transcription of the chromosomal regions involved. However, this may not always be so and in those cases DNA structural features must be involved. Here we examine the breakpoints of three different tumour‐specific translocations in the proximity of which we can detect no transcription; two of the translocations involve regions of chromosome 11, (t11;14 p13;q11 and t11;14 q13;q32), and the third is a newly described translocation, t7;10 q35;q24, involving the T cell receptor beta‐gene on chromosome 7. In each case, a purine‐‐pyrimidine tract (potential Z‐DNA) occurs near the translocation breakpoints. Four independent tumours with translocation t11;14 p13;q11 reveal a 2 kb breakpoint cluster region at 11p13 with an adjacent potential Z‐DNA region of 62 bp in length; the analogous purine‐‐pyrimidine tract at 10q24 is 32 bp long. The purine‐‐pyrimidine tract at the 11q13 chromosome breakpoint, however, is very large as it covers approximately 800 bp. The position, surrounding sequence and potential Z‐DNA tract of the human 11p13 TALLber is conserved in rodents. These results suggest that the purine‐‐pyrimidine tracts, presumably in the Z‐DNA form, can influence chromatin structure giving access for recombinase‐mediated translocations. Such putative alterations of chromatin organization are supported by the observation of DNase I hypersensitive sites near to translocation breakpoints on 10q24 and 11p13.
We describe a region of human chromosome 8q24 involved in variant Burkitt's lymphoma translocations, and where an interstitial deletion occurs in an HTLV‐I+ ATL and three c‐myc amplicons terminate. ...The deletion in the ATL DNA begins within 1.3 kb of the cloned Burkitt's lymphoma translocation breakpoint and ends within 700 bases of the cloned human equivalent of the rat retroviral insertion site, mis‐1. In addition, three c‐myc amplicons terminate in this region and the end of one of these (the colon carcinoma COL0320) maps within 12 kb of the distal end of the ATL deletion. This region is probably approximately 300 kb downstream of c‐myc and the consistent occurrence of abnormalities in this region implies involvement in tumour aetiology in several different cell types.
Cytogenetic abnormalities involving chromosome 14 band q32 are consistently observed in human T-cell tumors. Patients with ataxia-telangiectasia (AT) are especially prone to development of these ...tumors, which frequently carry either inversion inv(14)(q11;q32) or translocation t(14;14) (q11;q32) chromosomes. We have previously shown that the cytogenetic breakpoints of one t(14;14)(q11;q32) chromosome and two inv(14)(q11;q32) chromosomes in T-cell tumors from AT and non-AT patients join the T-cell receptor α chain locus, at chromosome band 14q11, with a region(s) at 14q32 centromeric of the immunoglobulin heavy chain variable region (VH) gene IGHV. We now show that these two inv(14) breakpoints are linked by 2.1 kb of germ-line 14q32 DNA and that the three breakpoints define, by in situ hybridization analysis, a single locus at chromosome band 14q32.1 located about 15-20 million base pairs on the centromeric side of the IGH locus. Sequence analysis of the 14q32.1 breakpoint regions indicates that abnormal recombination does not universally result from mistaken V-D-J joining (D = diversity region; J = joining region). Therefore, we invoke a tumor selection model to describe the role of the 14q32.1 locus in tumor development.
T‐cell tumours are frequently found to carry an inversion of chromosome 14 (inv(14)) (q11;q32) or more rarely a chromosome 14 translocation t(14;14) with the same cytogenetic breakpoints (q11;q32). ...We have examined the molecular junctions of an inv(14) and a translocation t(14;14) using T‐cell receptor (TCR) alpha joining (J) region probes. Both of these chromosomal abnormalities have breakpoints within the TCR J alpha locus at 14q11 and both have breakpoints which are proximal (i.e. on the centromeric side) to the immunoglobulin heavy chain JH region at 14q32. The cloned segments corresponding to the junctions at 14q32 are not associated with obvious immunoglobulin‐like sequences. This contrasts to the previously described inv(14) in the cell line SUP‐T1 and places a potential cluster of chromosome 14 breakpoints downstream of the Ig JH locus. The possible role of the varying breakpoints in the development of these tumours is discussed.
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