Pharmacokinetics of meloxicam in patients with juvenile rheumatoid arthritis

The pharmacokinetics of a meloxicam suspension were studied in 18 children with juvenile rheumatoid arthritis. Children received a single 0.25-mg/kg dose up to a maximum of 15 mg. Pharmacokinetic parameters after the first dose were calculated by noncompartmental methods. Geometric mean (percent coefficient of variation for geometric mean [gCV]) C(max), AUC(0- infinity ), apparent clearance, apparent volume of distribution, and elimination half-life values were 1.24 microg/mL (47% gCV), 25.6 microg x h/mL (81% gCV), 0.17 mL/min/kg (83% gCV), 0.19 L/kg (63% gCV), and 13.4 hours (54% gCV) in the younger group and 1.89 microg/mL (25% gCV), 35.8 microg x h/mL (21% gCV), 0.12 mL/min/kg (23% gCV), 0.13 L/kg (22% gCV), and 12.7 hours (21% gCV) for the older group, respectively. Area under the curve, volume of distribution, and clearance tended to be higher in the younger group, whereas elimination half-lives were similar. A post hoc comparison to pharmacokinetic data in adults revealed no relevant differences. Thus, a common body weight-normalized dose is considered appropriate for children older than 2 years.     

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients

The pharmacokinetics and bioavailability of low-dose methotrexate (MTX) (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received 10 mg/m2 (to the nearest 2.5 mg) of MTX in a single oral dose and a single intravenous (iv) dose one week apart. Serum concentrations for this low-dose regimen were monitored using a radiochemical ligand binding assay. The results indicate the MTX is cleared from the plasma at a rate of 84.6 mL/min/m2. The terminal half-life was approximately 6 h. The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2, respectively. The mean residence time in the body, in the systemic circulation, and in the periphery were estimated to be 4.7, 3.0, and 1.7 h, respectively, with a peripheral single-pass mean transit time of 6.0 h and an intrinsic mean residence time in the periphery of 7.9 h. The mean absorption time was 1.2 h and the oral bioavailability was 0.70. The ratio of synovial fluid concentration to serum concentration 4 and 24 h after a dose was found to be approximately 1.0, indicating that at least within that time range serum and synovial fluid concentrations are approximately equal. Because of conflicting results and insufficient data from previous high-dose pharmacokinetic studies, it is difficult to say whether or not low-dose MTX pharmacokinetics differs from those of high-dose MTX.     

Pharmacokinetics and immunoglobulin response of subcutaneous and intravenous atacicept in patients with systemic lupus erythematosus

Atacicept, a recombinant fusion protein of the TACI receptor and human IgG, is an inhibitor of B-Lymphocyte Stimulator (BLyS) and APRIL, potent stimulators of B cell maturation, proliferation, and survival. Pharmacokinetics (PKs) and biological activity of intravenous (iv) and subcutaneous (sc) atacicept are described here for patients with systemic lupus erythematosus in two randomized, double-blind, placebo-controlled, Phase Ib studies. Study 1: Six cohorts of eight patients received sc atacicept (single dose: 0.3, 1, 3, or 9 mg/kg; four weekly doses: 1 or 3 mg/kg), or placebo (3:1 ratio). Study 2: Four cohorts of six patients received iv atacicept (single dose: 3, 9, or 18 mg/kg; multiple dose: 2 × 9 mg/kg), or matching placebo (5:1 ratio). PK profiles were determined through serum atacicept and atacicept–BLyS complex, and biological activity through IgA, IgG, and IgM levels. PK profiles of atacicept were influenced by saturable binding between atacicept and its ligands, and were consistent and predictable across doses and regimens. Atacicept's biological activity was compatible with its presumed mechanism of action. Bioavailability was ～30–40% following sc or iv administration and similar doses yielded similar biological activity irrespective of administration route. This observation may have a mechanistic foundation and may inform dosing regimen design for future studies. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:524–538, 2010     

Pharmacokinetics of CTLA4Ig fusion protein in healthy volunteers and patients with rheumatoid arthritis

Aim： To evaluate single-dose and multiple-dose pharmacokinetics of cytotoxic T-lymphocyte-associated antigen 4 fusion protein （CTLA4Ig） in healthy volunteers and patients with rheumatoid arthritis （RA）.
Methods： The clinical trials included two phase I open studies： study 1 was an open-label dose-escalation study in 27 healthy volunteers and study 2 was a single-group, open-label study in patients with rheumatoid arthritis. In study 2, 9 patients were arranged to receive 10 mg/kg of CTLA4Ig at 0, 2, 4, 8, 12, and 16 weeks. The concentration-time data obtained by a validated ELISA method were subjected to non-compartmental pharmacokinetic analysis by DAS 2.1 software.
Results： In study 1, serum CTLA4Ig concentrations climbed rapidly to the peak and declined slowly with a t1/2 of 15.1±2.6 d, 14.2±2.3 d, and 11.8±1.2 d after a single infusion of 1, 10, and 20 mg/kg, respectively. Cmax and AUC0-∞,increased proportionally with the dose. In study 2, the steady-state condition for CTLA4Ig following multiple doses of 10 mg/kg appeared to be attained at the fourth dose （d 56）, with peak and trough concentrations of 239.8±45.3 mg/L and 20.5±7.9 mg/L, respectively. After multiple infusions, serum concentrations dropped slowly and the terminal half-life was 12.6±4.7 d.
Conclusion： Intravenous infusion of CTLA4Ig was well tolerated in healthy volunteers and patients with rheumatoid arthritis. CTLA4Ig exhibited linear pharmacokinetics over the dose range of 1 to 20 mg/kg in healthy volunteers. The pharmacokinetics in RA patients appeared to be similar to that in healthy volunteers. No system accumulation appeared upon repeated infusions of 10 mg/kg every 4 weeks.     

Pharmacokinetics and tolerance of slow-release indomethacin tablets in rheumatoid arthritis

Summary The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (t_max 3.7 h and < 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.     

Ocular surface findings in patients with rheumatoid arthritis under methotrexate or biological agent therapy

Purpose: To evaluate the ocular findings in patients with rheumatoid arthritis (RA) treated with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) or MTX with biological agents.

Methods: One hundred and twelve eyes of 56 patients with RA and treated with MTX or MTX with biological agents were included in the study. Patients were divided into two groups using DMARDs only (group 1) and patients using DMARDs and biologic agents together (group 2). In both groups; Schirmer’s II test, tear film break-up time (tBUT), central corneal thickness (CCT), corneal volume (CV), intraocular pressure (IOP) measurement, and anterior segment and fundus examinations of the eye with slit lamp were carried out. Ocular surface disease index (OSDI) score questionnaire were performed.

Results: Thirty-eight patients with a mean age of 53.00?±?8.19 years were in group 1 and 18 patients with a mean age of 51.00?±?9.54 years were in group 2. The mean duration of RA was 6.89?±?7.96 years in group 1 and 5.70?±?9.00 years in group 2. There was a statistically significant difference between two groups with tBUT, CCT, CV, IOP (p < 0.05) and there was no significant difference with age, sex, disease duration, disease activity, and Schirmer’s II test (p > 0.05). The disease duration showed a significant moderate negative correlation with CCT and CV in group 2 (p < 0.05).

Conclusions: Although tBUT values were significantly higher in the combination treatment group, CCT and CV values were significantly lower. Due to the decrease in corneal thickness, IOP was determined to be significantly lower.     

Advances in the therapy of rheumatoid arthritis with biological agents

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune inflammatory disease. The physiology of inflammation has been systemically studied and this has provided specific therapeutic targets for its modulation. The classical treatments of the disease, such as myocrisin and sulphasalazine, are not always effective at controlling the disease. This has necessitated the development of novel agents for treating RA, most of which are biological in nature and are targeted at specific sites of the inflammatory cascades. Advances in molecular biology have heralded the advent of bio-drugs (recombinant proteins) and gene therapy in which specific genes are introduced to locally enhance in vivo gene expression or suppress gene(s) of interest with a view to downregulating inflammation. Some bio-drugs, such as antitumour necrosis factor-α (TNF-α) antibodies and interleukin-1 receptor antagonists (IL-1Ra) have been tested, shown to be effective, and are licensed for clinical use. The clinical effects that have been observed are transient, necessitating repeated treatments and increasing the risk of vaccination effects. Anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor-β (TGF-β) and interferon-β (IFN-β) are undergoing clinical trials. Many of these agents have to be administered parenterally and production costs are very high. Consequently, chemical entities which can be taken orally need to be developed. Since the immune system is very complex with pleiotropic cytokines and redundancy in some of the regulatory networks, it may be necessary to use multiple agents targeting different specific sites of the inflammatory cascade or different agents that could be given at different stages of the disease, in order to induce disease remission and maintain the response to it. Cytokines and other mediators play important physiological roles in the host’s defence systems against infections and malignancy. The chronic inhibition, exogenous administration or constitutive overexpression of some cytokines may therefore lead to the development of side effects. Thus, carefully controlled long-term studies will be required to assess the safety of selective targeting of processes involved in the physiology of inflammation. This review summarises the important developments in the biotherapy of RA.     

Inflammatory and immunological parameters of disease activity in rheumatoid arthritis patients treated with minocycline

The objective of this study was to analyze the anti-inflammatory effect of minocycline in rheumatoid arthritis. Serum samples of 65 RA patients who completed a 26-week randomized double-blind trial of minocycline (100 mg twice a day) versus placebo were studied. In this trial some clinical parameters and in particular the acute phase response decreased significantly in the minocycline-treated group. Serum levels of albumin and interleukin-6 (IL-6) were compared with CRP levels in order to study the acute phase response. Furthermore, rheumatoid factor (RF) and total immunoglobulin isotypes as well as serum levels of soluble interleukin-2 receptor (sIL2-2R) were determined in order to study immunological parameters of the disease. Immunoglobulins and cytokines were measured by ELISA. Serum levels of albumin remained stable, whereas serum CRP levels decreased both in the minocycline- and in the placebo-treated group. Serum levels of IL-6 decreased in the minocycline-treated group only and this decrease was positively correlated with the decrease in CRP levels. Minocycline significantly decreased serum IgM-RF, IgA-RF, total IgM and total IgA levels. In addition the ratio of IgM-RF/total IgM decreased in the minocycline-treated group. No such changes were observed in the placebo-treated group. The anti-inflammatory effect of minocycline in RA patients may be due to the reduction in the synthesis of IL-6 and rheumatoid factor.     

Pain-mood relationships in patients with rheumatoid arthritis

Pain-mood relationships were investigated in 23 patients with long-standing rheumatoid arthritis over a two-week period. Patients completed form B of the Eysenck personality inventory on entry to the study and visual analogue scales for pain, anxiety and sadness daily throughout the study period. Two pain-mood relationships were identified: a synchronous relationship in which pain and mood scores were positively correlated and an asynchronous relationship in which pain and mood scores were uncorrelated. Furthermore, in all patients reporting high pain and showing synchronous relationships, the pain and mood scores were similar in magnitude, while in all patients reporting high pain and showing asynchronous relationships, the pain and mood scores were dissimilar in magnitude. The latter patients remained calm and happy despite severe pain. All patients reporting low pain showed synchronous and close relationships between pain and mood. Extraversion, neuroticism, age, duration and severity of disease were unrelated to pain severity and the pain-mood relationships recorded. The asynchronous pain-mood relationship was attributed to a coping response to severe pain. Patient education combined with physical, psychological and pharmacological treatments might induce such a response in patients unable to cope with chronic pain.     

Tacrolimus: in patients with rheumatoid arthritis

Tacrolimus, a hydrophobic macrolide with immunosuppressant properties, has recently been evaluated as a new treatment for adults with active rheumatoid arthritis. Oral tacrolimus 3mg once daily was significantly more effective than placebo in patients with rheumatoid arthritis (RA) who were refractory or intolerant to disease-modifying antirheumatic drugs (DMARDs), according to results from a 6-month, phase III trial; American College of Rheumatology 20 (ACR20) response rates were 27% and 10%. Tacrolimus 3mg once daily was effective in the same patient group in a 12-month, open-label trial; the ACR20 response rate was 38%. Oral tacrolimus 3 mg once daily was effective in combination with established methotrexate therapy in patients with RA in a 6-month, open-label trial. The ACR20 response rate was 53%. Oral tacrolimus 3 mg once daily was generally well tolerated by patients with active RA refractory or intolerant to previous DMARD treatment or when administered as combination therapy in patients with RA on established methotrexate therapy.     

Pharmacokinetics of dexamethasone in a rat model of rheumatoid arthritis

Dexamethasone (DEX) is often given for the treatment of rheumatoid arthritis and clinical dosing regimens of DEX have often been based empirically. This study tests whether the inflammation processes in a rat model of rheumatoid arthritis alters the clearance and volume of distribution of DEX when compared with healthy controls. Groups of healthy and arthritic male Lewis rats received either a low (0.225 mg/kg) or high (2.25 mg/kg) intramuscular dose of DEX. Arthritis was induced by intradermal injection of type II porcine collagen in incomplete Freund's adjuvant emulsion at the base of the tail. DEX was dosed in the arthritic animals 22 days post arthritis induction. Plasma DEX concentrations were determined by HPLC. Plasma concentration versus time data were analysed by non-compartmental analysis and pharmacokinetic model fitting using the population pharmacokinetic software NONMEM V. A linear bi-exponential pharmacokinetic model with extravascular input described the data for both healthy and arthritic animals. Clearance was the only parameter determined statistically different between both groups (healthy=1.05 l/h/kg, arthritic=1.19 l/h/kg). The steady-state volume of distribution for both groups was 4.85 l/kg. The slight difference in clearance was visibly undetectable and unlikely to produce meaningful changes in DEX disposition in arthritic rats. Copyright (c) 2008 John Wiley & Sons, Ltd.     

类风湿关节炎的生物治疗进展

类风湿关节炎（RA）是常见的系统性自身免疫性疾病,致残率高,严重影响患者健康。随着基因和生物技术的进步,发现多种RA治疗靶点,相关生物制剂的开发是近期研究的热点。本文主要综述近年用于RA治疗的生物药物的研究进展,包括针对细胞因子、免疫细胞和信号转导过程各种酶的药物。     

Salicylate pharmacokinetics in patients with rheumatoid arthritis.

1. The pharmacokinetics of salicylic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2. The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3. Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4. During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5. Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations.     

Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver and adipose tissue, and hepatic ethoxyresorufin O-deethylase (EROD) activity were studied subsequent to a single subcutaneous injection of TCDD. Two types of experiments were performed to study: (a) time-dependent changes following a single injection of 300 ng TCDD/kg body wt (points 1-4), and (b) dose-dependent changes measurable after 7 days following a single injection (points 5-7). 1. Absorption of TCDD following a single subcutaneous injection was about 90% after 3 days and 98% after 5 days. 2. Following a single dose of 300 ng TCDD/kg body wt peak concentrations were: liver (after 3 days): 4.7 +/- 0.9 ng/g wet wt, and adipose tissue (after 7 days): 0.82 +/- 0.07 ng/g wet wt. 3. T1/2 of TCDD in liver was 13.6 days over the total experimental period (from day 10 to 91 of the study), apparently with an initial faster phase: 11.5 days (from day 10 to 49), and a slower period at the end of the experiment: 16.9 days (from day 49 to 91); in adipose tissue the t1/2 was 24.5 days (from day 14 to 91 of the study). 4. Maximum induction of EROD in the liver was observed (14-fold at 300 ng TCDD/kg body wt) 3-7 days following the injection; the activity was decreased to about one third of the maximum 3 weeks after the injection; increase in total cytochrome P-450 at this dose was only about 1.4-fold at the induction maximum. 5. The ratio of the TCDD concentrations in liver and adipose tissue increased considerably between doses of 3 ng TCDD/kg body wt (ratio: about 0.74) and 3000 ng TCDD/kg body wt (ratio: about 7.7). 6. The extent of EROD induction in the liver increased dose dependently. A significant effect was first observed with a dose of 3 ng TCDD/kg body wt (activity about +32% above control activity). The corresponding tissue concentration was about 10 pg TCDD/g liver wet wt. 7. An almost perfect linear relationship exists (when using a double-log plot) between the hepatic TCDD concentration and the EROD activity for tissue concentrations ranging from 40 to 30,000 pg TCDD/g wet wt.     

Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Wistar rats were treated initially with very high single doses of ¹⁴C-2,3,7,8-TCDD (either 75 or 25 g/kg body wt) followed by weekly maintenance doses of 15 and 5 g/kg body wt, respectively. ¹⁴C-radioactivity was measured in various organs over a period of 22 weeks. 1) 75 g TCDD/kg body wt (followed by the maintenance doses) was lethal for all the rats within a period of 9 weeks. While the concentration of ¹⁴C-TCDD equivalents in liver and thymus stayed reasonably constant during this period in the surviving rats, the concentration in adipose tissue and kidneys clearly increased in the same animals. 2) The dose of 25 g TCDD/kg body wt (followed by weekly doses of 5 g/kg body wt) proved to be a just tolerable dose over a period of 22 weeks for our strain of rats. 3) Within the individual variabilities the TCDD concentrations in the investigated organs showed no clear-cut decline, indicating that the animals were exposed to fairly constant levels of TCDD throughout the study. Thus, this dosing regime is suitable for maintaining constant TCDD exposure during long-term studies.Abbreviations TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin     

类风湿性关节炎患者间质性肺疾病的临床概况

目的 了解类风湿性关节炎肺间质病变的发生情况、特征及相关因素分析,以便早期发现类风湿性关节炎的肺部病变.方法 类风湿性关节炎患者45例,免疫比浊法检测类风湿因子、C反应蛋白、免疫球蛋白及补体;间接免疫荧光法和免疫印迹法检测抗核抗体及亚类.血气分析测定氧分压、动脉血二氧化碳分压和肺泡-动脉血氧分压差.肺功能仪测定潮气容积、最大肺活量、用力肺活量、第1秒用力呼气容积、最大呼气中段流量、最大通气量和一氧化碳弥散功能.放射学检查包括胸部正侧位X线片、双手像和肺高分辨率CT扫描.结果 45例类风湿关节患者中,14例存在肺间质病变,其中10例有呼吸道症状.肺功能检测异常主要为弥散功能降低和限制性通气障碍.8例胸部X线片存在异常,14例高分辨率CT发现异常.肺高分辨率CT在发现类风湿性关节炎肺间质病变病变时优于普通胸部X线片.结论 类风湿性关节炎肺间质病变的发生与疾病活动性和严重性相关,肺弥散功能、高分辨率CT在早期发现病变时有诊断意义.     

Monitoring methotrexate therapy in patients with rheumatoid arthritis

OBJECTIVE: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. MATERIAL AND METHODS: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. RESULTS: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-beta-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. CONCLUSION: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug.