Binding affinity of ibuprofen in human tissues]

In vitro binding of ibuprofen (CAS 15687-27-1) to various human tissues was studied to explain differences in tissue concentration after local application of ibuprofen cream. Radioactive ibuprofen, was incubated with human skin, subcutaneous tissue, muscle, tendon, joint capsule for 2 h at 37 degrees C. Tissue specimens were washed and radioactivity was measured by a liquid scintillation counter. The results show specific binding of ibuprofen to the various tissues of different degrees. Despite of interindividual differences muscle tissues showed the highest, tendons the lowest concentrations of ibuprofen. These findings may explain the in vivo results, where higher concentrations of ibuprofen were found in muscle tissue compared with subcutaneous tissue.     

Effect of some antirheumatics on connective tissue components.

The effects of a number of classical and modern antirheumatics on the biosynthesis of glycosaminoglycans and collagen were studied comparatively. The experimental results indicate that the antirheumatics deeply affect the metabolism of the main components of connective tissue. With regard to the methods used for testing, it may be stated that phenylbutazone, flufenamic acid, ibuprofen, mefenamic acid and trimetazone belong to the most effective of the entire series of antirheumatics tested.     

结缔组织生长因子siRNA抑制高糖诱导的大鼠系膜细胞合成结缔组织生长因子及Ⅰ型胶原的表达

目的研究针对结缔组织生长因子（CTGF）的小于涉RNA（siRNA）对高糖诱导大鼠系膜细胞（RMC）合成CTGF及Ⅰ型胶原（collagentypeⅠ）的抑制作用。方法设计并合成针对CTGF的siRNA。以含有不同浓度葡萄糖（5、10、15、20、25mmol／L）的培养基培养RMC。将CTGFsiRNA转染至高糖（25mmol／L）环境刺激的RMC中,以RT—PCR和western blot检测siRNA对RMC合成CTGF及Ⅰ型胶原的影响。结果随着培养液中葡萄糖浓度的不断升高（最高浓度为25mmol／L）,RMC合成CTGF及I型胶原明显增加,转染针对CTGF的siRNA后,CTGF及Ⅰ型胶原的合成较对照组明显减弱,与正常葡萄糖浓度组水平相当。结论针对CTGF的siRNA能明显抑制高糖诱导的RMC合成CTGF及Ⅰ型胶原。     

Binding of chlorpromazine and imipramine to red cells, albumin, lipoproteins and other blood components.

The binding of model drugs to human blood and individual blood components has been determined by equilibrium dialysis and expressed in terms of classes of binding sites, association constants and binding capacities. Chlorpromazine and imipramine are bound to three major components: membranes of red cells, albumin, and lipoproteins. The affinity and capacity of lipoprotein binding is at least as high as that of albumin and is equally distributed on HDL, LDL, VLDL, and on the chylomicrons. White blood cells and platelets are of minor importance in terms of binding capacity. No binding was detected with gamma-globulins or alpha- or beta-globulins other than lipoproteins. In contrast, salicylic acid was not bound to red cells or lipoproteins.     

Binding of diazoxide and other benzothiadiazines to human albumin

The binding of seven benzothiadiazines to human albumin was studied by equilibrium dialysis. All these 1,2,4-benzothiadiazine-1,1-dioxide analogs are highly bound to human albumin. The unsubstituted benzothiadiazine nucleus is bound less than the substituted analogs. Addition of a chlorine at C-6 and C-7 markedly increases binding, but further addition of methyl or sulfamyl groups results in some reduction of binding. Binding studies on benzothiadiazines do not demonstrated independent binding sites on albumin. Binding of drugs to albumin can be evaluated by fitting a logistic function to the experimental points with a least squares method. This empirical, objective technique allows examination of the nature of the bonds between drug and protein. Diazoxide, the 7-chloro-3-methyl analog, was used for detailed investigations into the mechanism of protein binding of the benzothiadizines. The effects of pH, temperature, ionic strength, cations and deuterium on the binding of diazoxide to human albumin indicate that the drug is bound mainly by hydrophobic interaction and to a lesser extent by hydrogen bonding. Difference spectroscopy studies show a shift in the electron distribution of diazoxide with binding.     

Effect of tolfenamic acid on the metabolism of the main connective tissue components in rats

Tolfenamic acid (Clotam) has been used in the therapy of rheumatic diseases for some years. Regarding its chemical structure it belongs to the group of fenamates. The effect of tolfenamic acid on the synthesis of collagen and proteoglycans in granulation tissue, skin or cartilage of rat weanlings was tested and compared with the action of mefenamic acid. According to the results obtained, tolfenamic acid is a potent inhibitor of collagen as well as proteoglycan syntheses. The concentrations of the constituents of proteoglycans, i.e. protein core, link protein as well as glycosaminoglycans were decreased in the tissue after treatment with tolfenamic acid. In comparison with mefenamic acid, if the same doses were used (50 mg and 100 mg/kg of body weight/day in in vivo experiments and 10 mg/g wet tissue in in vitro experiments), tolfenamic acid exhibits more distinct inhibitory effect. A general inhibitory effect of tolfenamic acid on proteosynthesis is suggested.     

Paraquat increases connective tissue growth factor and collagen expression via angiotensin signaling pathway in human lung fibroblasts

Survivors of paraquat poisoning are left with pulmonary fibrosis which results in a restrictive type of long-term pulmonary dysfunction. Connective tissue growth factor (CTGF) is a key growth factor that initiates tissue repair and underlies the development of lung fibrosis. Angiotensin (ANG) II may induce CTGF expression in the heart and kidney and plays an important role in the pathogenesis of lung fibrosis. The biological effects of ANG II are mediated by ANG II type 1 receptor (AT1R) and AT2R. The aims of this study were to investigate the effects of paraquat on ANG II, ANG II receptors, CTGF, and collagen expressions and to assess the role of ANG II receptors in paraquat-induced collagen synthesis in human lung fibroblasts (MRC-5). MRC-5 cells were incubated with various concentrations of paraquat with or without the ANG II receptor antagonist, saralasin. Paraquat increased ANG II production and AT1R mRNA and protein expression and decreased AT2R mRNA expression. Furthermore, paraquat treatment increased CTGF and collagen mRNA and protein expression in a dose-dependent manner and saralasin inhibited these effects. These results indicate that paraquat increases CTGF and collagen expression by activating angiotensin signaling pathway in human lung fibroblasts.     

Changes in connective tissue components in ulcer tissue during the healing process of acetic acid ulcer in rats.

In order to elucidate the role of connective tissue components on the repair of ulcerated regions, quantitative changes in chemical components in ulcer tissue during the healing process were investigated in acetic acid-induced ulcer in rats. The ulcer index showed a peak on the 5th day after the operation, declined rapidly and maintained a slight level the 15th to the 60th days, without a complete recovery. In ulcer tissue, sialic acid and hexosamine remarkably increased in the early stages of healing, showing a peak on the 5th day. The patterns of time course of changes in both components ran almost parallel with those in the ulcer index. Uronic acid maintained slightly higher levels than normal levels the 5th to the 60th days. Hydroxyproline continued to increase with the time course from the 25th day. When acid mucopolysaccharides in ulcer tissue were isolated into various fractions, there were increases in hyaluronic acid on the 5th day, in chondroitin sulfate A and chondroitin sulfate C on the 30th day and chondroitin sulfate B on the 60th day, respectively. Significance of changes in these components in the healing process is discussed.     

Treatment approach to connective tissue disease-associated interstitial lung disease

Interstitial lung disease (ILD) is a common manifestation in connective tissue diseases (CTD), such as rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory myositis (IM). ILD is associated with significant morbidity and mortality in nearly all CTD highlighting the critical need for effective treatment strategies in this patient population. In this review, we will summarize the approach to treatment when there is concern for CTD-ILD and highlight recent advancements in therapeutics within various forms of CTD-ILD.     

A double-blind comparison of ibuprofen, placebo and ibuprofen with meptazinol in soft tissue rheumatism

The administration of ibuprofen potentiates and prolongs the analgesic effect of meptazinol when the two drugs are given simultaneously to mice. A double-blind three-way crossover study of placebo, ibuprofen (1600 mg/day) and ibuprofen (1600 mg/day) plus meptazinol (400 mg/day) was carried out in 45 patients with soft tissue rheumatism to see if the same potentiation could be demonstrated in man. Treatment order was randomized and each regimen was given for 2 weeks preceded by 1 week on paracetamol alone. Assessments were made, on entry and after each treatment period, of pain parameters using visual analogue or verbal rating scales. Patients' overall impression and final preference showed both active treatments to be better than placebo and demonstrated a slight preference for the combination.     

Binding of neomycin and calcium to phospholipids and other anionic compounds

In order to assess the potential importance of different cellular binding sites for the adverse effects of aminoglycosides (i.e. oto- and nephrotoxicity) the binding of neomycin and calcium to phospholipids and other anionic cell constituents was assayed in vitro. Phospholipids demonstrated binding affinities that strongly favored neomycin (Km, 10 to 100 microM) over calcium (Km, 300 to 1,120 microM). Both neomycin and calcium showed strongest binding to lipids with monoester phosphate groups: phosphatidic acid, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate. The lipids bound 0.2 to 0.4 molecules of neomycin and 0.5 to 1 molecule of calcium, respectively, per lipid. Anionic non-lipid compounds such as melanin, gangliosides or chondroitin sulfate were ineffective competitors of neomycin binding to lipids. The results emphasize the importance of phospholipids as cellular binding sites for aminoglycosides. Furthermore, if one considers extra- and intracellular calcium and neomycin concentrations, the relative affinity of lipids for these two compounds suggests an explanation for both the reversible and the essentially irreversible toxic effects of the aminoglycosides.     

Cholinergic anti-inflammatory pathway and connective tissue diseases

Inflammopharmacology - Connective tissue diseases (CTDs) consist of an extensive range of heterogeneous medical conditions, which are caused by immune-mediated chronic inflammation and influences...