A comparison of the effect of timegadine, levamisole, and D-penicillamine on human neutrophil metabolism of endogenous arachidonic acid and chemotaxis

The effect of timegadine, a novel experimental antirheumatic drug, on human neutrophil (PMN) 5-lipoxygenase activity and leukotriene B4 (LTB4) chemotaxis was compared with that of two second-line antiinflammatory drugs, D-penicillamine and levamisole. 1-14C-Arachidonic acid (AA) was incorporated into the purified cells until steady state conditions were obtained. After preincubation with serial dilutions of the three drugs, AA release and metabolism was stimulated with calcium ionophore A23187. The radioactive eicosanoids released were extracted and separated by thin-layer chromatography, followed by autoradiography and quantitative laser densitometry. Chemotaxis of PMNs towards LTB4 was measured in a modified Boyden chamber. Timegadine showed dose-dependent inhibition of both the 5-lipoxygenase pathway (IC50 3.4 x 10(-5) M), and of chemotaxis (IC50 3 x 10(-4) M). Inhibition of the release of AA from phospholipids, however, occurred only at therapeutically irrelevant doses (millimolar concentrations). Levamisole and D-penicillamine did not inhibit any of the cell functions investigated. Inhibition of both neutrophil motility and cellular synthesis of pro-inflammatory eicosanoids, may thus contribute to the clinical effects of timegadine in rheumatoid arthritis.     

Neutrophil functional and arachidonic acid metabolic correlates and clinical disease activity in pirazolac-treated rheumatoid arthritis patients

Neutrophils from 20 medication-free rheumatoid arthritis patients were chemotactically hyporesponsive to 2 x 10(-8) M formyl-methionyl-leucyl-phenylalanine (f-MLP) as compared to 20 normal controls. They were relatively high producers of 5-hydroxyeicosatetraenoic acid (5-HETE) and low producers of leukotriene C4 (LTC4). Neutrophils from 10 patients treated with pirazolac (4-(4-chlorophenyl)-1-(4-fluorophenyl)-5-pyrazole acetic acid) showed increased chemotactic responsiveness concomitantly with normalization of 5-HETE and LTC4 production and a decrease in the clinical parameters of disease activity. Clinically attainable (30-60 micrograms/ml) in-vitro doses of pirazolac further depressed the chemotactic responsiveness of normal neutrophils treated with 10(-5)M f-MLP. Effects on endothelial gating of migrating neutrophil populations may explain this apparent contradiction between in-vivo and in-vitro actions of pirazolac on neutrophil chemotaxis.     

Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis

Leflunomide is a new disease modifying antirheumatic drug (DMARD) that inhibits lymphocyte proliferation by blocking dihydroorotate dehydrogenase (DHODH), the enzyme critical for the production of pyrimidine necessary for DNA synthesis. Through this mode of action, leflunomide inhibits the lymphocyte proliferation associated with the clonal expansion of T cells in rheumatoid arthritis (RA). In clinical trials, leflunomide was superior to placebo and comparable to sulfasalazine and methotrexate for improving both the signs and symptoms of RA. Leflunomide was also superior to placebo and sulfasalazine and comparable to methotrexate in overall improvement of physical function. Leflunomide was equivalent to methotrexate and sulfasalazine in retarding disease progression measured radiographically. Due to its unique mode of action in the treatment of RA, leflunomide shows value in combination therapy with methotrexate for patients refractory to methotrexate alone. The most common adverse reactions associated with leflunomide therapy include gastrointestinal symptoms, allergic reactions, reversible alopecia and elevated liver enzymes. Adverse events were generally mild to moderate, and resolved without complication. The results of phase II and phase III clinical trials indicate that leflunomide is a safe and efficacious drug for the treatment of RA.     

来氟米特与美洛昔康治疗类风湿性关节炎的效果与安全性研究

目的 比较来氟米特片与美洛昔康片治疗类风湿性关节炎的临床效果及安全性.方法 按就诊顺序随机将2013年1～12月在本院第一门诊部(东武社区卫生服务站)治疗的100例类风湿性关节炎患者分为治疗组(50例)和对照组(50例).治疗组口服来氟米特,对照组口服美洛昔康治疗.观察两组患者的临床疗效和不良反应.结果 治疗组总有效率为80.％％,对照组总有效率为70.0％,治疗组临床疗效显著优于对照组(P＜0.05).治疗后,两组临床症状指标均显著改善,与治疗前比较,差异有统计学意义(P＜0.05);且治疗组临床症状指标改善程度大于对照组(P＜0.05).治疗后,两组的类风湿因子(RF)、红细胞沉降率(ESR)及C-反应蛋白(CRP)含量明显下降(P＜0.05);治疗组RF、ESR及CRP含量下降程度显著大于对照组,差异有统计学意义(P＜0.05).治疗组不良反应率为26.0％,对照组不良反应发生率为25.0％,两组不良反应发生率差异无统计学意义(P＞0.05).结论 来氟米特治疗类风湿性关节炎疗效优于美洛昔康,两者不良反应发生率相似,但临床症状特点不同.     

Effects of dilazep on arachidonic acid metabolism by neutrophils and platelet/neutrophil interactions

The effect of dilazep (tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanolbis(3,4, 5-trimethoxy-benzoate)dihydrochloride monohydrate, Comelian), a coronary and cerebral vasodilator and an anti-platelet agent, on endogenous and exogenous arachidonic acid (AA) metabolism by human neutrophils and platelet/neutrophil interactions was studied in vitro. Neutrophils preincubated with dilazep (up to 300 mumol/l) were incubated with the Ca ionophore A23187 in the absence or presence of AA. Platelet/neutrophil mixtures preincubated with dilazep (up to 100 mumol/l) were incubated with thrombin plus N-formylmethionylleucylphenylalanine (FMLP), FMLP plus AA, and platelet-activating factor (PAF) plus AA. AA metabolites including leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE) and 5S,12S-dihydroxyeicosatetraenoic acid (5S,12S-DiHETE) were analyzed and quantitated by reversed-phase high-performance liquid chromatography. The formation of LTB4 and 5-HETE from endogenous AA by neutrophils was inhibited by dilazep, whereas their production from exogenous AA was enhanced. LTB4 synthesis from endogenous AA by platelet/neutrophil interactions was inhibited by dilazep, while 5S,12S-DiHETE production was increased. The production of 5-lipoxygenase metabolites from exogenous AA by these interactions was increased by this drug. Thus, dilazep inhibits endogenous AA metabolism by neutrophils and by platelet/neutrophil interactions, whereas it stimulates exogenous AA metabolism by these blood cells and their interactions.     

美洛昔康治疗类风湿关节炎和骨关节炎的临床研究

目的观察选择性环氧酶(COX)-2抑制剂美洛昔康对类风湿关节炎(RA)和骨关节炎(OA)的疗效和安全性,并与布洛芬比较.方法选取RA患者139例和膝OA患者116例.布洛芬缓释胶囊治疗RA和OA的剂量均为600mg·d     

Evaluation of the therapeutic potential of ketoprofen in rheumatoid arthritis

Summary

A single-blind, non-crossover trial of ketoprofen in 2 dose schedules, compared with ibuprofen, has been carried out in 135 patients with rheumatoid arthritis. The results are also compared with those obtained for prednisone, aspirin, indomethacin and paracetamol in 2 previous studies using the same method.

The trial method employed showed ketoprofen to be significantly more effective than placebo in terms of patient satisfaction rating, but less effective than prednisone. In terms of pain relief, ketoprofen appeared to be more effective than placebo, although the differences did not reach significant levels. The trial, however failed to demonstrate significant differences either between ketoprofen, ibuprofen, aspirin, indomethacin and paracetamol, or between ketoprofen at 2 widely separate dose levels.     

Effects of pirazolac on arachidonic acid metabolism in the human synovial system

Six patients suffering from rheumatoid arthritis with massive knee joint effusions were treated with single daily doses of 600 mg pirazolac, a novel non-steroidal anti-inflammatory drug, for 3 days. Before the first dose, 3 hours after the second and the third dose, specimens of plasma and synovial fluid were drawn simultaneously. Plasma and synovial fluid concentrations of pirazolac, as determined by HPLC, amounted to 47.9 micrograms/ml and 19.8 micrograms/ml (Day 2) and 55.5 micrograms/ml and 18.7 micrograms/ml (Day 3), respectively. The samples were analyzed for PGE2, LTB4, LTC4 and LTD4 applying various extraction procedures and subsequent radioimmunoassays. PGE2 levels decreased during treatment from 928 pg/ml to 443 pg/ml after the third dose of pirazolac. LTB4 levels were slightly but insignificantly augmented. LTC4 and LTD4 concentrations were below the detection limit prior to and after administration of the drug.     

秦川通痹片治疗风湿性关节炎的疗效研究

目的评价秦川通痹片的临床用药安全性及治疗风湿性关节炎(寒湿痹阻型)症状的疗效。方法采用随机分组、阳性药物对照,双盲双模拟临床试验设计方法,对72例风湿性关节炎(寒湿痹阻型)患者进行临床试验观察。结果秦川通痹片治疗组ITT病例35例,总有效率为88.57%;腰息痛胶囊对照组ITT病例34例,总有效率为79.41%。2组临床疗效比较,差异无统计学意义。结论秦川通痹片治疗风湿性关节炎疗效显著,安全,无明显不良反应。     

Differential effects of fexofenadine on arachidonic acid metabolism in cultured human monocytes

The relief of nasal congestion with the antihistamine fexofenadine in seasonal allergic rhinitis is thought to be due to its additional anti-inflammatory properties. The objective of this study was to evaluate the in vitro effects of fexofenadine on stimulated arachidonic acid metabolism. Human monocytes, isolated from blood and donated by 5 healthy volunteers, were either incubated for 20 h with 10 microg/ml lipopolysaccharide, with and without fexofenadine (10(-8)-10(-3) mol/l, n = 8-19), or were incubated for 20 h, with and without fexofenadine, and then stimulated with 0.5 mg/ml zymosan for 2 h. Leukotriene B4 (LTB4), LTC4, LTD4 and LTE4, prostaglandin E2 (PGE2) and F2alpha (PGF2alpha) production was determined by enzyme immunoassay. Zymosan-stimulated production of LTC4, LTD4 and LTE4 was significantly inhibited by clinically relevant concentrations of fexofenadine HCl: 10(-7) mol/l (22% inhibition vs. control, p = 0.008) and 10(-6) mol/l (24% inhibition vs. control, p = 0.020). Higher concentrations of fexofenadine (10(-4) and 10(-3) mol/l) inhibited LTB(4) generation. Lipopolysaccharide-stimulated production of PGE2 was significantly inhibited by fexofenadine HCl 10(-6) mol/l (26% inhibition, p = 0.035) and 10(-5) mol/l (40% inhibition, p = 0.001). Higher concentrations of fexofenadine HCl (10(-4) and 10(-3) mol/l) significantly inhibited PGF2alpha production by 50% (p = 0.026) and 63% (p = 0.001), respectively. Fexofenadine, at both clinically relevant and higher concentrations, inhibits LTC4, LTD4, LTE4 and PGE2 in cultured human monocytes. These additional anti-inflammatory properties may underlie the relief of nasal congestion observed in clinical studies.     

Clinical evaluation of niflumic acid (Squibb) in rheumatoid arthritis

Summary

The effect of 750?mg. of niflumic acid per day administered orally was studied in 15 patients with active rheumatoid arthritis in a double-blind cross-over trial. The patients were followed over a 2-week period with 3 assessments of joint pain and tenderness, duration and severity of morning stiffness, digital joint circumference, grip strength and radioactive pertechnetate (99m Tc) knee and wrist joint uptakes.

The results show that niflumic acid was more effective in relieving pain than placebo. Anti-inflammatory effects could not be demonstrated.     

Actions of gallic esters on the arachidonic acid metabolism of human polymorphonuclear leukocytes

Gallic esters with a varying chain length of its alcohol moiety produced strong inhibition of the conversion of [1-14C]-arachidonic acid to 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE) by isolated human polymorphonuclear leukocytes. Octyl gallate and decyl gallate were the most powerful inhibitors with a concentration of half-inhibition of about 1 mumol . 1-1. Additionally these compounds caused however at 10 mumol . 1-1 a complete inhibition of the incorporation of arachidonic acid in triacylglycerols and phospholipids which is assumed to be a consequence of the damage to the energy metabolism of the cells. In contrast, the other gallic esters enhance the incorporation of arachidonic acid in the ester lipids in addition to moderate inhibition of the 5-lipoxygenase pathway.     

Effect of inhibitors of arachidonic acid metabolism on α-aminoisobutyric acid transport in human lymphocytes

The role of arachidonic acid metabolism (or metabolites) in the modulation of α-aminoisobutyric acid transport in resting and concanavalin A-stimulated human peripheral blood lymphocytes was evaluated using previously characterized inhibitors of arachidonic acid metabolism. Nordihydroguairetic acid (a nonselective antioxidant), 5,8,11,14-eicosatetraynoic acid (an inhibitor of lipoxygenase and cyclooxygenase activities), indomethacin and acetylsalicylic acid (selective cyclooxygenase inhibitors), and 1-benzylimidazole, Ro-22-3581 and Ro-22-3582 (thromboxane synthetase inhibitors) proved to be potent inhibitors of amino acid transport activity in normal resting and lectin-activated lymphocytes at concentrations known to decrease thromboxane A₂ production. The rank order of effectiveness of these various inhibitors compared favorably with their relative potencies as inhibitors of thromboxane B₂ synthesis under the same conditions, as determined by radioimmunoassay. Inhibitory effects noted were not due to overt cytotoxicity and seemed to involve changes primarily in the V_max and not the K_m of the transport process. Drug-induced alterations in the magnitude of concanavalin A binding were not observed. These results suggest that the activity of amino acid transport systems can be influenced by certain arachidonic acid metabolites, probably thromboxanes, in both stimulated and unstimulated lymphocytes. In addition, these findings may provide a partial explanation for the observation that inhibitors of thromboxane formation prevent lymphocyte mitogenesis [J. P. Kelly, M. C. Johnson and C. W. Parker, J. Immun.122, 1563 (1979)].     

Open study on the efficacy and safety of long-term use of SURGAM-SR (sustained-release form of tiaprofenic acid) in rheumatoid arthritis patients

Objective To study the effectiveness and safety of the long-term use of Surgam-SR (tiaprofenic acid sustained-release) in patients with rheumatoid arthritis. Design Open label multicentre study that immediately followed a 6-week double-blind study (previously reported). The last assessment of the double-blind study was taken as baseline in the open study. After baseline all patients were treated with Surgam-SR 600 mg daily for 6 months. Patients treated with Surgam-SR during the preceding 6-week double-blind study and continued on the same regimen in the open label study were named the Surgam-SR group. Patients treated with standard tiaprofenic acid (Surgam), during the 6-week study were referred to as the Surgam group. Patients Fifty patients with rheumatoid arthritis by the American Rheumatism Association definition were entered into the open label study. All patients were assessed at tertiary care rheumatology clinics in Canada. Main outcome measures Patients were assessed at baseline, 3 months, and 6 months for pain score, duration of morning stiffness, number of tender joints, and evaluation of benefit by physician and by patient. Safety and tolerance of treatment were evaluated by number of adverse events and by laboratory measurements completed at baseline, 3 months and 6 months. Results Visual analogue pain scale was significantly improved in the Surgam-SR groups at 6 months (p <0.05, ANOVA for repeated measures). The overall adjectival pain score was significantly better in the Surgam-SR group when compared with the Surgam group at 6 months (p<0.01). A similar trend was observed for the other variables but was not statistically significant. Two gastrointestinal adverse events - pyrosis and epigastric burning - were identified. One patient with headache and one with elevated liver enzymes were withdrawn from the study. Abnormal laboratory values were found in 14/50 patients. Four with elevated liver enzymes were deemed clinically significant. Conclusions The efficacy of Surgam-SR remained stable throughout the 6-month study. The tolerance of long-term use of Surgam-SR is clinically acceptable.     

A comparative study of the long-term efficacy of flurbiprofen and indomethacin in the treatment of rheumatoid arthritis,with special reference to iron metabolism

Summary

Preliminary results are reported for the first 23 rheumatoid arthritis patients entered in a long-term, double-blind trial to compare the efficacy of flurbiprofen and indomethacin. It was planned that, unless withdrawn, patients from matched pairs received either flurbiprofen (150?mg to 300?mg daily) or indomethacin (75?mg to 150?mg daily) over a minimum period of 6 months, dosage being adjusted to suit exacerbations and remission of disease. In addition to clinical assessments of severity of pain, duration and severity of morning stiffness, joint size and joint score, routine laboratory measurements were carried out, including estimates of serum iron and total iron binding capacity, rheumatoid factor and immunoglobulin levels. This interim report gives the statistical analysis of results from the 17 patients completing from 2 to 4 months of treatment and shows that both drugs were equally effective in controlling disease activity. Withdrawals due to side-effects or exacerbations of disease were similar for both drugs.     

Diethyldithiocarbamate (ditiocarb sodium) effect on arachidonic acid metabolism in human mononuclear cells. Glutathione peroxidase-like activity.

Diethyldithiocarbamate (DTC), a thiol delivery agent, has been shown to significantly reduce the frequency of primary opportunistic infections in HIV-infected patients. This therapeutic effect has been related to the capacity of DTC to reverse the deleterious effects of the oxidative stress occurring in HIV infection. The influence of DTC on the oxygenated metabolism of arachidonic acid (AA) was investigated in mitogen-stimulated human peripheral blood mononuclear cells (PBMC). Upon incubation with PBMC previously labelled with [3H]AA, Concanavalin A (Con A) markedly increased cyclooxygenase and lipoxygenase activities, within 30 min, as judged by thromboxane B2 (TxB2) and hydroxyeicosatetraenoic acid (HETE) production. Con A activation of [3H]AA platelets also increased 12-HETE production but did not induce any TxB2 synthesis. Micromolar concentrations of DTC, added simultaneously with the mitogen, significantly enhanced the synthesis of HETEs above the Con A-induced level while TxB2-induced synthesis was inhibited but only at DTC concentrations higher than 50 microM. In the presence of nordihydroguaiaretic acid, a lipoxygenase inhibitor, which inhibited the Con A-induced synthesis of HETEs by 78%, DTC no longer stimulated HETE production above the Con A-induced level. Reverse phase HPLC analysis showed that Con A increased the PBMC production of 5-, 12- and 15-HETEs. In the presence of 5 microM DTC, 5-HETE production was entirely suppressed whereas the 15-HETE level was markedly enhanced, 12-HETE production by the contaminating platelets remained unchanged. In vitro experiments indicated that DTC alone did not significantly influence 15-hydroperoxyeicosatetraenoic (15-HPETE) production by the soybean 15-lipoxygenase but, in the presence of added reduced glutathione, DTC markedly reduced 15-HPETE into 15-HETE. In addition, DTC was able to substitute for cellular extract in the glutathione peroxidase (GPx) assay system. Taken together, these results indicate that DTC, through its "GPx-like" activity is able to modify the lipoxygenase cascade. Its ability to selectively reduce 15-HPETE known to stimulate immunosuppressive T-cells might help to explain its positive regulatory effect upon the immune system.     

阿贝西普的药理作用与临床研究

阿贝西普是一种选择性共刺激调节剂，用于缓解病情抗风湿药疗效不佳的中至重度活动性类风湿性关节炎（RA）的成年患者，以改善RA的症状和体征，减缓骨结构的损伤进程，提高患者的机体功能。现对其药理作用、药动学、临床研究及不良反应进行综述。