Antiphlogistic action of phenylbutazone in normal and adrenalectomized rats of different ages relation to the 5-hydroxytryptamine blood concentration.

The authors have attempted to demonstrate the effect of bilateral adrenalectomy on carrageenin-induced oedema and on the antiphlogistic action of phenylbutazone in relation to the changes of blood 5-hydroxtryptamine (5-HT) in rats of different ages (21 days, 42 days, 3 months and 18 months old). It was found that the influence of adrenalectomy on the antiphlogistic action of phenylbutazone and on the blood 5-HT concentration is related to the age of rats. The lowest antiphlogistic action of phenylbutazone was found in 21-day-old rats and highest in the 18-month-old ones. In adrenalectomized 21- and 42-day-old rats the antiphlogistic action is decreased and fully suppressed in rats 3 and 18 months old. Adrenalectomy does not influenced basal values of blood 5-HT concentration. Blood 5-HT in adrenalectomized rats with inflammationadrenalectomized rats 42 days and 3 months old with inflammation after injection of phenylbutazone an increase of 5-HT was observed, but in 18-month-old animals in which antiphlogistic action is highest a decrease of 5-HT was observed.     

Alcohol-drug interaction in rat embryogenesis: the effect of separate and combined action of sodium salicylate and ethanol

A combined administration of sodium salicylate and ethanol to female rats in threshold embryotoxic doses on the 9th, 10th, 12th and 13th days of pregnancy results in a sharp increase of embryolethal and teratogenic effects. The embryotoxic effect of sodium salicylate and ethanol at their combined injection exceeds the summational embryotoxic effect at the separate action of the preparations. The spectrum of malformations after their combined effect does not differ from that induced with sodium salicylate.     

Endotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity

The reversible airway hyper-reactivity (AHR) of asthma is modeled by sensitizing and challenging mice with aerosolized ovalbumin. However, the C57BL/6 murine strain does not display the large increase in circulating IgG and IgE antibodies found in human atopy and asthma. We found that commercial ovalbumin was contaminated with lipopolysaccharide (LPS) in amounts sufficient to fully activate endothelial cells in an in vitro assay of the first step of inflammation. Desensitization of TLR4 by LPS pretreatment suppressed the inflammatory effect of ovalbumin. The presence of LPS was occult, because it does not require serum presentation and, like the LPS of Salmonella minnesota, was not suppressed by polymyxin B. Purified ovalbumin did not activate endothelial cells in vitro; however, endotoxin-free ovalbumin was far more effective than commercial material in stimulating IgE production and respiratory dysfunction in a C57BL/6 murine model of AHR. Moreover, endotoxin-free ovalbumin induced lung inflammation with alveolar enlargement and destruction in a histologic pattern that differed from the changes caused by commercial, endotoxin-contaminated ovalbumin. Reconstitution of purified ovalbumin with S. minnesota LPS decreased lung inflammation, decreased changes in lung function, and suppressed anti-ovalbumin antibody production. We conclude endotoxin contaminates ovalbumin preparations and that endotoxin co-administration with the ovalbumin antigen creates a state of tolerance in a murine model of AHR. Co-exposure to endotoxin and antigen occurs in humans through organic dusts, so murine models of AHR may reflect the clinical situation, but models based on commercial ovalbumin do not accurately reflect the effect of protein antigen alone on animal physiology.     

Diuresis or urinary alkalinisation for salicylate poisoning?

Forty-four adults with aspirin poisoning were treated with oral fluids only, standard forced alkaline diuresis, forced diuresis alone, or sodium bicarbonate (alkali) alone. Alkali alone was at least as effective and possibly more effective than forced alkaline diuresis in enhancing salicylate removal. Unlike the diuresis regimens it did not cause fluid retention or biochemical disturbances. The renal excretion of salicylate depends much more on urine pH than flow rate, and forced diuresis alone had little useful effect. In overdosage aspirin causes sodium and fluid retention and may impair renal function. Attempts to force a diuresis are potentially hazardous and the spurious fall in plasma salicylate concentration caused by haemodilution gives a false impression of efficacy. Further studies are required to determine the optimum treatment for salicylate poisoning.     

Membrane protein phosphorylation during stomatocyte-echinocyte transformation of human erythrocytes

The normal, discoid shape of red blood cells represents an equilibrium between two opposing factors, i.e., stomatocytic and echinocytic transformations. Most stomatocytic agents were found to be inhibitors of calmodulin, a regulator of the phosphorylation of membrane proteins. We determined whether red cell shape transformations could be caused by changes in phosphorylation of membrane proteins, specifically the cAMP-dependent phosphorylation of ankyrin and band 4.1. Red blood cells were incubated with 32P and 100 microM chlorpromazine (stomatocytic transformation) or 30 mM sodium salicylate (echinocytic transformation) for various time intervals. Ghost membrane proteins were examined by polyacrylamide gel electrophoresis and autoradiography. Spectrin (beta-chain), ankyrin, band 3, band 4.1 and 4.9 were phosphorylated. No change was found in the degree and pattern of phosphorylation after stomatocytic transformation. Salicylate caused a reversible inhibition of transmembranous phosphate transport in both directions. The results indicate that the stomatocytic transformation induced by chlorpromazine and the echinocytic transformation induced by salicylate do not involve a change in phosphorylation, but that the echinocytic transformation induced by salicylate is associated with an inhibition of transmembranous transport of phosphate. Studies with salicylate suggest that the phosphorylation sites of band 3 are found mainly on the endofacial side of the membrane.     

Molecular dynamics simulations of salicylate effects on the micro- and mesoscopic properties of a dipalmitoylphosphatidylcholine bilayer

Salicylate, an amphiphilic molecule and a popular member of the nonsteroidal anti-inflammatory drug family, is known to affect hearing through reduction of the electromechanical coupling in the outer hair cells of the ear. This reduction of electromotility by salicylate has been widely studied, but the molecular mechanism of the phenomenon is still unknown. In this study, we investigated one aspect of salicylate's action, namely the perturbation of electrical and mechanical membrane properties by salicylate in the absence of cytoskeletal or membrane-bound motor proteins such as prestin. In particular, we simulated the interaction of salicylate with a dipalmitoylphosphatidylcholine (DPPC) bilayer via atomically detailed molecular dynamics simulations to observe the effect of salicylate on the microscopic and mesoscopic properties of the bilayer. The results demonstrate that salicylate interacts with the bilayer by associating at the water-DPPC interface in a nearly perpendicular orientation and penetrating more deeply into the bilayer than either sodium or chloride. This association has several affects on the membrane properties. First, binding of salicylate to the membrane displaces chloride from the bilayer-water interface. Second, salicylate influences the electrostatic potential and dielectric properties of the bilayer, with significant changes at the water-lipid bilayer interface. Third, salicylate association results in structural changes, including decreased headgroup area per lipid and increased lipid tail order. However, salicylate does not significantly alter the mechanical properties of the DPPC bilayer; bulk compressibility, area compressibility, and bending modulus were only perturbed by small, statistically insignificant amounts by the presence of salicylate. The observations from these simulations are in qualitative agreement with experimental data and support the conclusion that salicylate influences the electrical but not the mechanical properties of DPPC membranes.     

Effect of aurothioglucose on some allergic and non-allergic skin reactions in animals.

The antiphlogistic effect of aurothioglucose was examined in reversed passive Arthus reaction, delayed-type hypersensitivity and carrageenan oedema. A close association existed between the antiphlogistic effect of aurothioglucose and the pathogenetic role of polymorphonuclear leukocytes. In reversed passive Arthus reaction and in carrageenan oedema the drug decreased the inflammation considerably, whereas in delayed hypersensitivity, where the leukocytes play a less important part, it exerted only a mitigating effect.     

Inhibition by salicylates of urea synthesis by isolated rat hepatocytes and citrulline synthesis by isolated rat mitochondria: an effect independent of uncoupling

1. Acetylsalicylate and salicylate inhibited urea synthesis by isolated rat hepatocytes and citrulline synthesis by isolated rat mitochondria. The effects were dose-dependent and occurred at drug concentrations seen in salicylate induced hepatoxicity. 2. Although ATP concentration was decreased in the hepatocytes the effect of the salicylates on citrulline synthesis remained after treatment with oligomycin and carbonyl cyanide m-chlorophenyl hydrazone. This suggests that the effect is independent of uncoupling of oxidative phosphorylation. 3. This in vitro inhibition of urea synthesis by salicylates is similar to that produced by valproate and endogenous organic acids, which are also associated with hyperammonaemic clinical toxicity, and is a possible mechanism for the action of salicylates in the hyperammonaemia of Reye's syndrome.     

Pharmacokinetics of Repeated Sodium Salicylate Administration to Laying Hens: Evidence for Time Dependent Increase in Drug Elimination from Plasma and Eggs

Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs) to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus) salicylate (SA) may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS) to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1^st, 7^th and 14^th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT), minimal plasma concentration (C_min, C_16h) and elimination half-life (T_1/2el) of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (Cl_B) increased. Layers administered with the higher dose showed a decrease only in the T_1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment.     

Salicylate-induced teratogenesis in the ferret

A single subcutaneous injection of 400 mg/kg sodium salicylate produced a high resorption rate on day 13 (91%) and on day 18 (66%) of gestation. Malformations were seen in the surviving fetuses. Pregnant ferrets injected with 250 mg/kg salicylate produced a lower resorption rate of between 31% and 43%. Malformations were seen in the surviving fetuses of animals injected with lower doses of sodium salicylate both at 13 and 18 days of gestation.Salicylate-induced teratogenicity at 400 mg/kg was compared with that produced in a closed colony of Wistar rats. The concentration of salicylate in whole blood (and serum) was determined after a single injection of 125 mg/kg or 400 mg/kg sodium salicylate. Although salicylate concentration in the blood in both species showed remarkable similarity at the doses tested and the times of sampling, the results indicated that the drug was far more embryo-toxic in ferrets than in rats. The inter-order variation in the embryotoxicity of sodium salicylate is such that it would be unwise to ignore its possible teratogenic activity in man.     

Effects of salicylate on insulin and glucagon secretion by the isolated and perfused rat pancreas

The effects of sodium salicylate, a prostaglandin synthesis inhibitor, on glucose-induced secretion of insulin and glucagon by the isolated perfused rat pancreas have been studied. Sodium salicylate inhibited both basal (2.8 mM glucose) and stimulated (16.7 mM glucose) insulin release in a dose dependent manner (1, 5 and 10 mM). This inhibition is not interpretable in terms of a simple inhibition of cyclooxygenase by sodium salicylate. Basal glucagon release was not changed by 1 mM sodium salicylate but the latter partially blocked its inhibition by 16.7 mM glucose. Higher doses of sodium salicylate (5 and 10 mM) inhibited basal glucagon secretion without affecting its response to 16.7 mM glucose. These findings suggest a predominant stimulatory action of endogenous prostaglandins on glucagon release.     

Salicylate-promoted permeation of cefoxitin, insulin and phenylalanine across red cell membrane. Possible mechanism

Uptake of sodium cefoxitin, D-phenylalanine and insulin into human red blood cells was significantly enhanced by the presence of salicylate and 5-methoxysalicylate in the medium. The mechanism of adjuvant action appeared to depend on an affinity between the adjuvant and the protein fraction in the erythrocyte membrane. The inhibitory effect of DIDS and phlorizin on the salicylate-enhanced uptake of these compounds strongly suggests that the ability of salicylate to permeate the membrane may be essential for it to act as an adjuvant.     

Effects of sodium salicylate on epithelial cells of the rectal mucosa of the rat: A light and electron microscopic study

Using a ligation method, rat rectal epithelium was exposed to 2% sodium salicylate, and light and electron microscopic methods were used to assay for: 1) permeability of the epithelium to a marker dye, trypan blue, and 2) damage expressed in terms of disruption of the epithelial surface. Rectal mucosa was exposed to salicylate at pH 4.8, 7.0, and 9.0, and the effects of pretreatment with phlorizin were also studied. Results indicated that 2% sodium salicylate does very little damage to rectal epithelial cells at pH 7.0 while enhancing their permiability to trypan blue, an effect that is reversed upon washing out the sodium salicylate. The major cellular change induced by salicylate was a reduction in the length or distribution of glycocalyx filaments on microvilli of epithelial cells. It was also noted that pretreatment with phlorizin counteracted some of the effects of salicylate treatment.     

A model-based system to determine the relative value of different variables in a diagnostic system using Bayes theorem

A model system is described which simulates the presenting features of cases of vaginal discharge. This system was used to examine the effects of removing individual clinical features on the overall efficiency of diagnosis by Bayes theorem. The diagnostic efficiency was significantly reduced by elimination of inflammation, of a frothy discharge, or of a curdy discharge. Elimination of more than one significant factor further reduced the number of correct diagnoses, but elimination of more than one non-significant factor made no obvious difference. The most significant clinical feature was presence of inflammation; elimination of this feature had a substantial effect on the diagnosis of gardnerella, viral, gonorrhoea and foreign body. Elimination of two of the variables (bloodstaining and odour) which did not influence overall diagnostic efficiency nevertheless had a substantial effect on the diagnosis of neoplasms and foreign bodies. It is proposed that a simulation of this type is of potential practical value in determining a minimum subset of clinical features for diagnostic systems involving Bayes theorem.     

Calpain 1在水杨酸钠诱导耳鸣大鼠的下丘脑神经元中的表达及对听力的影响

为了考察Calpain 1在水杨酸钠诱导耳鸣大鼠的下丘脑神经元中的表达及对听力的影响,本研究通过腹腔注射水杨酸钠建立耳鸣大鼠模型,并腹腔注射钙蛋白酶抑制剂ALLN来处理大鼠。听性脑干反应(ABR)测试显示,水杨酸钠可显著升高大鼠的的听力阈值和Ⅰ、Ⅲ和Ⅴ波潜伏期、Ⅰ~Ⅴ和Ⅲ~Ⅴ波间潜伏期,而钙蛋白酶抑制剂可明显抑制这种变化。免疫组化、RT-PCR和Western blotting检测结果均显示,水杨酸钠可明显上调大鼠下丘组织中Calpain 1的表达,而钙蛋白酶抑制剂可显著抑制Calpain 1的上调。此外,钙蛋白酶抑制剂可显著抑制水杨酸钠诱导的大鼠下丘组织中NMDA受体亚型NR2A的上调。水杨酸钠上调了大鼠耳蜗核组织中炎症因子TNF-α、IL-1β和IL-6的表达,而钙蛋白酶抑制剂可显著抑制炎症因子的表达。本研究提示,水杨酸钠可损伤大鼠的听觉功能,上调Calpain 1、NMDA受体和促炎细胞因子的表达。钙蛋白酶抑制剂可显著改善大鼠的听觉功能,其机制与抑制Calpain 1、NMDA受体和促炎细胞因子的表达有关。     

Effect of Anti-inflammatory Drug Therapy on Clearance of 133Xe from Knee Joints of Patients with Rheumatoid Arthritis

The degree of joint inflammation in 13 patients with rheumatoid arthritis, as measured by clinical indices, was reduced by both sodium salicylate and indomethacin. The clearance rate of ¹³³Xe was reduced by indomethacin alone, and showed no correlation with the clinical features.