Safety profile of baricitinib in patients with systemic lupus erythematosus: an integrated analysis.

OBJECTIVES: To assess the safety of the oral Janus kinase inhibitor baricitinib in adult patients with systemic lupus erythematosus (SLE) receiving stable background therapy. Topics of special interest included infections and cardiovascular and thromboembolic events. METHODS: This analysis included integrated safety data from three randomised, placebo-controlled studies (one phase 2 and two phase 3) and one long-term extension study. Data are reported in three data sets: placebo-controlled, extended exposure and all-baricitinib. Outcomes include treatment-emergent adverse events (AEs), AEs of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IRs) were calculated. RESULTS: A total of 1655 patients received baricitinib for up to 3.5 years (median duration 473 days). With baricitinib 4 mg, baricitinib 2 mg and placebo, respectively, 50.8%, 50.7% and 49.0% of patients reported at least one infection and 4.4%, 3.4% and 1.9% of patients had a serious infection. The most common treatment-emergent infections included urinary tract infection, COVID-19, upper respiratory tract infection and nasopharyngitis. Herpes zoster was more common with baricitinib 4 mg (4.7%) vs baricitinib 2 mg (2.7%) and placebo (2.8%). Among baricitinib-4 mg, 2 mg and placebo-treated patients, respectively, 4 (IR=0.9), 1 (IR=0.2) and 0 experienced at least one positively adjudicated major adverse cardiovascular event, and 0, 3 (IR=0.6) and 2 (IR=0.4) reported at least one positively adjudicated venous thromboembolism. CONCLUSIONS: The results of this integrated safety analysis in patients with SLE are not substantially different to the established safety profile of baricitinib. No increased venous thromboembolism was found.

Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial.

BACKGROUND: Juvenile idiopathic arthritis can be refractory to some or all treatment regimens, therefore new medications are needed to treat this population. This trial assessed the efficacy and safety of baricitinib, an oral Janus kinase 1/2-selective inhibitor, versus placebo in patients with juvenile idiopathic arthritis. METHODS: This phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial was conducted in 75 centres in 20 countries. We enrolled patients (aged 2 to <18 years) with polyarticular juvenile idiopathic arthritis (positive or negative for rheumatoid factor), extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or juvenile psoriatic arthritis, and an inadequate response (after ≥12 weeks of treatment) or intolerance to one or more conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The trial consisted of a 2-week safety and pharmacokinetic period, a 12-week open-label lead-in period (10 weeks for the safety and pharmacokinetic subcohort), and an up to 32-week placebo-controlled double-blind withdrawal period. After age-based dosing was established in the safety and pharmacokinetic period, patients received a once-daily 4 mg adult-equivalent dose of baricitinib (tablets or suspension) in the open-label lead-in period. Patients meeting Juvenile Idiopathic Arthritis-American College of Rheumatology (JIA-ACR) 30 criteria (JIA-ACR30 responders) at the end of the open-label lead-in (week 12) were eligible for random assignment (1:1) to receive placebo or continue receiving baricitinib, and remained in the double-blind withdrawal period until disease flare or up to the end of the double-blind withdrawal period (week 44). Patients and any personnel interacting directly with patients or sites were masked to group assignment. The primary endpoint was time to disease flare during the double-blind withdrawal period and was assessed in the intention-to-treat population of all randomly assigned patients. Safety was assessed in all patients who received at least one dose of baricitinib throughout the three trial periods. For adverse events in the double-blind withdrawal period, exposure-adjusted incidence rates were calculated. The trial was registered on ClinicalTrials.gov, NCT03773978, and is completed. FINDINGS: Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled and received at least one dose of baricitinib (152 [69%] girls and 68 [31%] boys; median age 14·0 years [IQR 12·0-16·0]). 219 patients received baricitinib in the open-label lead-in period, of whom 163 (74%) had at least a JIA-ACR30 response at week 12 and were randomly assigned to placebo (n=81) or baricitinib (n=82) in the double-blind withdrawal period. Time to disease flare was significantly shorter with placebo versus baricitinib (hazard ratio 0·241 [95% CI 0·128-0·453], p<0·0001). Median time to flare was 27·14 weeks (95% CI 15·29-not estimable) in the placebo group, and not evaluable for patients in the baricitinib group (<50% had a flare event). Six (3%) of 220 patients had serious adverse events during the safety and pharmacokinetic period or open-label lead-in period. In the double-blind withdrawal period, serious adverse events were reported in four (5%) of 82 patients (incidence rate [IR] 9·7 [95% CI 2·7-24·9] per 100 patient-years at risk) in the baricitinib group and three (4%) of 81 (IR 10·2 [2·1-29·7]) in the placebo group. Treatment-emergent infections were reported during the safety and pharmacokinetic or open-label lead-in period in 55 (25%) of 220 patients, and during the double-blind withdrawal period in 31 (38%) of 82 (IR 102·1 [95% CI 69·3-144·9]) in the baricitinib group and 15 (19%) of 81 (IR 59·0 [33·0-97·3]) in the placebo group. Pulmonary embolism was reported as a serious adverse event in one patient (1%; IR 2·4 [95% CI 0·1-13·3]) in the baricitinib group in the double-blind withdrawal period, which was judged to be related to study treatment. INTERPRETATION: Baricitinib was efficacious with an acceptable safety profile in the treatment of polyarticular juvenile idiopathic arthritis, extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, and juvenile psoriatic arthritis, after inadequate response or intolerance to standard therapy. FUNDING: Eli Lilly and Company under licence from Incyte.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I).

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study. METHODS: In a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on a modified intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT03616912. FINDINGS: 760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (142 [57%]; odds ratio 1·57 [95% CI 1·09 to 2·27]; difference with placebo 10·8 [2·0 to 19·6]; p=0·016), but not baricitinib 2 mg (126 [50%]; 1·14 [0·79 to 1·65]; 3·9 [-4·9 to 12·6]; p=0·47), reached SRI-4 response compared with placebo (116 [46%]). There were no significant differences between the proportions of participants in either baricitinib group reaching any of the major secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. 26 (10%) participants receiving baricitinib 4 mg had serious adverse events, 24 (9%) participants receiving baricitinib 2 mg, and 18 (7%) participants receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: The primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed. FUNDING: Eli Lilly and Company.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II).

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. In this Article, we report the evaluation of efficacy and safety of baricitinib in patients with SLE in a 52-week phase 3 study. METHODS: In this phase 3 double-blind, randomised, placebo-controlled study, SLE-BRAVE-II, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, baricitinib 2 mg, or placebo once daily for 52 weeks. The primary endpoint was the proportion of patients with an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on an intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue. This study is registered with ClinicalTrials.gov, NCT03616964, and is complete. FINDINGS: A total of 775 patients were randomly assigned and received at least one dose of baricitinib 4 mg (n=258), baricitinib 2 mg (n=261), or placebo (n=256). There was no difference in the primary efficacy outcome of the proportion of SRI-4 responders at week 52 between participants who received baricitinib 4mg (121 [47%]; odds ratio 1·07 [95% CI 0·75 to 1·53]; difference with placebo 1·5 [95% CI -7·1 to 10·2]), 2 mg (120 [46%]; 1·05 [0·73 to 1·50]; 0·8 [-7·9 to 9·4]) and placebo (116 [46%]). None of the major secondary endpoints, including glucocorticoid tapering and time to first severe flare, were met. Serious adverse events were observed in 29 (11%) participants in the baricitinib 4 mg group, 35 (13%) in the baricitinib 2 mg group, and 22 (9%) in the placebo group. The safety profile of baricitinib in patients with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: Although phase 2 data suggested baricitinib as a potential treatment for patients with SLE, which was supported in SLE-BRAVE-I, this result was not replicated in SLE-BRAVE-II. No new safety signals were observed. FUNDING: Eli Lilly and Company.

Ixekizumab Demonstrates Consistent Efficacy Versus Adalimumab in Biologic Disease-Modifying Anti-rheumatic Drug-Naïve Psoriatic Arthritis Patients Regardless of Psoriasis Severity: 52-Week Post Hoc Results from SPIRIT-H2H.

INTRODUCTION: Ixekizumab, a selective interleukin-17A antagonist, was compared with adalimumab in the SPIRIT-H2H study (NCT03151551) in patients with psoriatic arthritis (PsA) and concomitant psoriasis. This post hoc analysis reports outcomes to week 52 in patients from SPIRIT-H2H, stratified by baseline psoriasis severity. METHODS: SPIRIT-H2H was a 52-week, multicenter, randomized, open-label, rater-blinded, parallel-group study of biologic disease-modifying antirheumatic drug (DMARD)-naïve patients (N = 566) with PsA and active psoriasis (≥ 3% body surface area involvement). Patients were randomized to ixekizumab or adalimumab (1:1) with stratification by baseline concomitant use of conventional synthetic DMARDs and psoriasis severity (with/without moderate-to-severe psoriasis). Patients received on-label dosing according to psoriasis severity. The primary endpoint was the proportion of patients simultaneously achieving ≥ 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100) at week 24. Secondary endpoints included musculoskeletal, disease activity (defined by composite indices), skin and nail, quality of life and safety outcomes. In this post hoc analysis, primary and secondary endpoints of SPIRIT-H2H were analyzed by baseline psoriasis severity. RESULTS: A greater proportion of patients achieved the combined endpoint of ACR50 + PASI100 and PASI100 with ixekizumab compared with adalimumab at weeks 24 and 52, regardless of baseline psoriasis severity. ACR response rates were similar for ixekizumab and adalimumab across both patient subgroups. For musculoskeletal outcomes, similar efficacy was seen for ixekizumab and adalimumab, but ixekizumab showed greater responses for skin outcomes regardless of psoriasis severity. The safety profiles of ixekizumab and adalimumab were consistent between subgroups. CONCLUSIONS: Regardless of baseline psoriasis severity, ixekizumab demonstrated greater efficacy than adalimumab with respect to simultaneous achievement of ACR50 + PASI100, and showed consistent and sustained efficacy across PsA-related domains. It also demonstrated higher response rates for skin outcomes. These subgroup analyses highlight the efficacy of ixekizumab in patients with PsA irrespective of the severity of concomitant psoriasis.

Measuring treatment effect on psoriatic arthritis-related domains: insights from the SPIRIT-H2H study at weeks 24 and 52.

INTRODUCTION: Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). OBJECTIVE: These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. METHODS: Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. RESULTS: Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. CONCLUSION: High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity. Trial registration NCT03151551 Key Points • Treatment goals for patients with psoriatic arthritis emphasise the importance of improving both musculoskeletal and non-musculoskeletal manifestations of the disease. • A combined endpoint considering both these manifestations, achievement of at least 50% improvement in American College of Rheumatology criteria and 100% improvement in Psoriasis Area Severity Index, was linked with achievement of a number of other endpoints relevant to psoriatic arthritis, including health-related quality of life that are important to patients with psoriatic arthritis. • Patients meeting the combined endpoint were more likely to achieve a disease state of remission, which is the stated aim of treatment for psoriasis.

Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis.

Objectives: To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)-naïve or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Methods: Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same baricitinib dose as at originating study completion. At 52 weeks, DMARD-naïve patients receiving methotrexate (MTX) or combination therapy (baricitinib 4 mg+MTX) were switched to baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to baricitinib 4 mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo were switched to baricitinib 4 mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified Total Sharp Score. Linear extrapolation was used for missing data. Results: Of 2573 randomised patients, 2125 (82.6%) entered the LTE, of whom 1893 (89.1%) entered this analysis. At year 2, progression was significantly lower with initial baricitinib (monotherapy or combination therapy) versus initial MTX in DMARD-naïve patients (proportion with non-progression defined by ≤smallest detectable change (SDC): 87.3% baricitinib 4 mg+MTX; 70.6% MTX; p≤ 0.001). In MTX-IR patients, progression with initial baricitinib was significantly lower than with initial placebo and similar to initial adalimumab (≤SDC: 82.7% baricitinib 4 mg; 83.5% adalimumab; 70.6% placebo; p≤0.001). In csDMARD-IR patients, significant benefit was seen with baricitinib 4 mg (≤SDC: 87.2% vs 73.2% placebo; p≤0.01). Conclusions: Treatment with once-daily baricitinib resulted in low rates of radiographic progression for up to 2 years.

The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib.

Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.

Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the phase 3 RA-BEGIN study.

The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.

[Operation - rehabilitation - employment]. / Mutét - rehabilitáció - munkavállalás.

In this article we would like to bring the attention to the importance of early rehabilitation, coordinated operation of different subdivisions of rehabilitation and the expanding opportunities after medical care through following a 38- year-old female patient's case who was operated 6 years ago with anaplasticus oligodendroglioma. We find it important that the experts working on the field of health care, social services or labour should be aware of the possibilities of rehabilitation of their patients from the capability assessment, through its development until their placement in integrated labour market. It is important, that even during the medical care both the client and their relatives receive proper information.

The Importance of Technical Devices in the Self-care of Upper Limbs Amputees.

The National Institute of Medical Rehabilitation (NIMR) is engaged in the rehabilitation of posttraumatic patients, including also attending traumatic cases with amputated upper limbs. The lack of upper limbs is a great obstacle in essential functioning for the injured, and that is why we give high priority to planning, constructing and individually adopting appliances for aiding everyday life. Special literature gives distinguished attention to operative techniques and the possibilities of prosthetic devices, but no professional articles present any special devices needed for discharging everyday vital functions. The purpose of this lecture is to present the results of our follow-up examination aimed at upper limbs amputees reeducated since 1994 at the NIMR (9 patients). Case studies conclude that the prosthetic care plays a surprisingly small part in the self-sufficiency of the injured. Claims to individual appliances are already more considerable but these cannot be obtained in normal commerce because of unprofitable production in view of users so few in number.

Identical, similar or different? Learning about immunomodulatory function of mesenchymal stem cells isolated from various mouse tissues: bone marrow, spleen, thymus and aorta wall.

Mesenchymal stem or multipotent stromal cells (MSCs) have been implicated in tissue maintenance and repair and regulating immune effector cells through different mechanisms. These functions in mouse were primarily described for bone marrow (BM)-derived MSCs. To learn more about MSCs of different tissue origin, we compared the immunophenotype, differentiation ability to adipocyte and bone and immunomodulatory activity of MSCs isolated from BM, spleen, thymus and aorta wall of 14-day-old C57Bl/6 mice. The established cell lines fulfilled the requirements described for MSCs in terms of morphology, surface marker expression and differentiation potential although they were distinguishable regarding the expression pattern of the MSC markers and ability generating other cell types. Most importantly, a remarkable diversity was shown in the capacity of inhibition of mitogen- and alloantigen-induced T-cell proliferation, since BM- and spleen-derived MSCs were the most powerful aorta-derived MSCs were less effective, whereas thymus-derived mesenchymal cells were unable to block T-cell growth in vitro. Accordingly, BM, spleen and aorta, but not thymus-derived MSCs, in combination with BM hematopoietic cells were equally efficient to prevent streptozotocin-induced diabetes in vivo. These findings suggested that MSCs residing in different organs might stem from common ancestor; however, once populating into a given tissue microenvironment, they acquire specific properties mainly in the term of the immunoregulatory function.

Sensitive LC-MS/MS methods for the quantification of RGH-188 and its active metabolites, desmethyl- and didesmethyl-RGH-188 in human plasma and urine.

Selective and sensitive LC-MS/MS methods have been developed and validated for simultaneous determination of RGH-188, a novel atypical antipsychotic, and its two active metabolites, desmethyl- and didesmethyl-RGH-188 in human plasma and urine. Deuterated analytes, [2H6]-RGH-188, [2H3]-desmethyl-RGH-188 and [2H8]-didesmethyl-RGH-188 were used as internal standards (IS). The compounds were isolated from the alkalized biological matrix using liquid-liquid extraction (LLE) and the extracts were analysed by reversed-phase HPLC with MS/MS detection. The chromatographic run time was 5.0min per injection. The PE Sciex API 365 mass spectrometer was equipped with a TurboIonSpray interface and operated in positive-ion, multiple reaction monitoring (MRM) mode. The mass transitions monitored were m/z 427.3-->382.2, 413.2-->382.2, 399.2-->382.2, 433.3-->382.2, 416.2-->382.2 and 407.3-->390.2 for RGH-188, desmethyl-RGH-188, didesmethyl-RGH-188, [2H6]-RGH-188, [2H3]-desmethyl-RGH-188 and [2H8]-didesmethyl-RGH-188, respectively. The lower limit of quantification (LLOQ) was 0.05 and 0.1ng/ml for RGH-188 and its metabolites, respectively, using 1ml of plasma. LLOQ in 1ml of urine was 0.1ng/ml for all three analytes. The methods were validated for selectivity, linearity, accuracy and precision. The lower limit of quantification, dilution integrity, matrix effect, stability of the analytes in the biological matrix during short- and long-term storage and after three freeze-thaw cycles were also tested. The assays were simple, specific and robust enough to support clinical development of RGH-188.

Long-term persistence of chromosome aberrations in uranium miners.

Chromosome aberration analyses were performed on blood samples from 165 active underground uranium miners between 1981 and 1985. After decommissioning the mine in 1997 chromosome aberration analyses were also included in the medical laboratory investigations of health conditions of 141 subjects between 1998 and 2002 within the framework of a follow-up-study. The numerical data are presented as functions of the exposure categories expressed in working level month up to 600. In the active groups the dicentric level was 7 to 12 times higher than in the unexposed population, the acentrics also higher with more than an order of magnitude, the frequency of total aberrations--including dicentrics, acentrics, rings, deletions, minits and numerical aberrations, i.e. both chromatid and chromosome type of aberrations were also well above the control level. In the group of former uranium miners although there were slight decreases in the dicentrics after 8 to 25 yr, the values were not significantly different from the values of active miners. The frequency of deletions was also maintained in the post-mining period. The frequency of acentrics, however, decreased significantly, but even the lowest values remained 2-3 times higher than the values in the unexposed population.The possibility is suggested that for the long-term persistence of cytogenetic alterations the permanent production and presence of clastogenic factors might be responsible. The comparison of the two datasets suggest a long-term persistence of cytogenetic alterations above the population average values in a large fraction of persons investigated.