Doses Of Salicylate Research Articles

Salicylate- and quinine-induced tinnitus and effects of memantine

Conclusion: Memantine, an antiglutamatergic drug, has been proposed as a treatment for tinnitus. Objectives: The purpose of this study was to determine if memantine would prevent salicylate-induced tinnitus. Local field potentials were also recorded from auditory cortex to determine what effect salicylate, memantine, and the combination of both drugs would have on evoked potential amplitudes. Materials and methods: Schedule induced polydipsia-avoidance conditioning was used to identify the doses of salicylate or quinine that reliably induced tinnitus in rats. Rats were trained to lick for water during quiet intervals and avoid licking during sound intervals. Results: Rats injected with saline or a low dose of sodium salicylate or quinine failed to develop tinnitus-like behaviors. However, high doses of salicylate (150–300 mg/kg/day) or quinine (100–150 mg/kg/day) greatly reduced licks-in-quiet, behavior consistent with the presence of tinnitus. Licks-in-quiet increased slightly when memantine (1.5 or 3 mg/kg/day) was co-administered with salicylate; however, the effect was not statistically significant or dose-dependent. These results indicate that memantine does not completely suppress salicylate-induced tinnitus. Cortical auditory evoked potential amplitude increased after salicylate treatment; co-administration of memantine failed to block this salicylate-induced increase.

Antipyretic effect of oral sodium salicylate after an intravenous E. coli LPS injection in broiler chickens

1. A study was set up to investigate the influence of sodium salicylate on fever and acute phase reaction after lipopolysaccharide (LPS) injection in broiler chickens. 2. An acute phase reaction was provoked through the intravenous injection of Escherichia coli LPS. Four oral doses of sodium salicylate were tested. Apart from body temperature, other inflammation indices, such as plasma corticosterone and ceruloplasmin, serum thromboxane B2 and zinc concentrations were monitored. 3. Intravenous LPS induced a fever of about 1°C. A dose-dependent attenuation of the fever response of the chickens in the salicylate treated groups was observed. LPS-injected chickens also showed elevated plasma corticosterone and ceruloplasmin, while serum thromboxane and zinc concentrations decreased. Except for thromboxane B2, no linear relationship with increasing salicylate dose could be shown for the other blood variables. 4. These data confirm that sodium salicylate is an effective antipyretic agent after injection of LPS in chickens, if used at an appropriate dosage. No dose-related change could be found for the other inflammation indices.

Effects of non-steroidal anti-inflammatory drugs on pain-related behaviour in a model of articular pain in the domestic fowl

The optimum doses of carprofen, flunixin, ketoprofen and sodium salicylate for the treatment of inflammatory pain were determined in domestic fowl using the microcrystalline sodium urate model of articular pain. The response criteria were the changes in pain-related behaviour over 60 min commencing 1 h after an intra-articular injection of sodium urate and an intramuscular injection of a range of doses of each of the drugs. The minimum effective doses for carprofen, flunixin and ketoprofen, respectively, were 30, 3 and 12 mg kg −1. The minimum dose for sodium salicylate ranged from 100 to 200 mg kg −1 and did not fully restore normal behaviour.

A novel behavioral paradigm for assessing tinnitus using schedule-induced polydipsia avoidance conditioning (SIP-AC)

A behavioral technique was developed that allowed the onset and recovery of tinnitus to be measured in individual rats treated with different doses of salicylate. Food-restricted rats were self-trained to lick for water during the time between scheduled delivery of food pellets, i.e., schedule-induced polydipsia (SIP). SIP-induced licking was placed under stimulus control by administering foot shock if licks occurred when sound (one of six stimuli, 40 dB SPL) was present; rats were allowed to lick during quiet. After the number of licks-in-quiet (correct response) exceeded 90% of total licks, rats were treated with saline and four different doses of salicylate (50, 100, 150 and 350 mg/kg, intraperitoneally (i.p.); 2 days). Performance was assessed before, during and after treatment. Licks-in-sound remained extremely low with saline and all four salicylate doses indicating that the sounds were audible under all treatment conditions. Licks-in-quiet remained high during the saline control and 50 mg/kg dose of salicylate, behavior consistent with the absence of tinnitus. However, licks-in-quiet showed a statistically significant decline with the 150 and 350 mg/kg dose, behavior consistent with the presence of tinnitus. Licks-in-quiet gradually recovered to baseline level 2–3 days following high-dose salicylate treatments, behavior consistent with the gradual disappearance of tinnitus. The salicylate dose needed to induce tinnitus and the length of recovery are consistent with previous reports, providing support for the method. The ability to obtain sequential estimates of tinnitus-like behavior in an animal after administering a tinnitus-inducing agent could aid in understanding the underlying neural mechanisms and assessing potential treatments.

Expression of c-fos in auditory and non-auditory brain regions of the gerbil after manipulations that induce tinnitus.

Subjective tinnitus is a phantom sound sensation that does not result from acoustic stimulation and is audible to the affected subject only. Tinnitus-like sensations in animals can be evoked by procedures that also cause tinnitus in humans. In gerbils, we investigated brain activation after systemic application of sodium salicylate or exposure to loud noise, both known to be reliable tinnitus-inductors. Brains were screened for neurons containing the c-fos protein. After salicylate injections, auditory cortex was the only auditory area with consistently increased numbers of immunoreactive neurons compared to controls. Exposure to impulse noise led to prolonged c-fos expression in auditory cortex and dorsal cochlear nucleus. After both manipulations c-fos expression was increased in the amygdala, in thalamic midline, and intralaminar areas, in frontal cortex, as well as in hypothalamic and brainstem regions involved in behavioral and physiological defensive reactions. Activation of these non-auditory areas was attributed to acute stress, to aversive-affective components and autonomous reactions associated with the treatments and a resulting tinnitus. The present findings are in accordance with former results that provided evidence for suppressed activation in auditory midbrain but enhanced activation of the auditory cortex after injecting high doses of salicylate. In addition, our present results provide evidence that acute stress coinciding with a disruption of hearing may evoke activation of the auditory cortex. We interpret these results in favor of our model of central tinnitus generation.

A behavioral paradigm to judge acute sodium salicylate-induced sound experience in rats: a new approach for an animal model on tinnitus

Behavioral conditioning studies on rats have been proven to be a valid animal model for the evaluation of acute and chronic phantom auditory experience (tinnitus). We developed an animal model for short-term, acute induced phantom auditory sensations in rats. Rats were trained in a conditioning chamber to actively access a liquid feeder whenever a constant white noise sound was present. During silence, no reward was given. Fulfilling the demands of animal protection laws for maximal avoidance of pain and fear, punitive paradigms were maximally reduced. After 15–17 learning sessions, all animals performed more accesses to the reward feeder during periods of sound than during periods of silence. Tinnitus was induced by the administration of sodium salicylate (350 mg/kg body weight) given 3 h before testing. The feeder access activity of a rat treated with salicylate was significantly increased during periods of silence, indicating a phantom auditory experience. The presumptive auditory experience was estimated to be comparable to a white noise sound of about 30 dB SPL rms. The activity increase was less pronounced for lower doses of sodium salicylate (150 mg/kg body weight) and was not found in animals trained on a dark–light paradigm, as expected. As the learning sessions of the operant conditioning were performed without pharmacological treatment, unintentional drug effects, for example, on learning and motivation of a rat were minimized in this behavioral paradigm. Furthermore, the behavioral changes reported here were shown to be a specific drug effect evoking a phantom auditory experience of a rat and cannot be explained by unspecific drug effects on motor activity, motivation, learning or hearing loss. The conditional paradigm is discussed in the context of its potential as a model for testing drugs that may have a therapeutic value in tinnitus research.

Does The Administered Salicylate Dose Predict IVIG Treatment Failure in Kawasaki Disease?

A sub-group of KD patients fails initial IVIG treatment, develops persistent or recurrent fever and inflammatory signs, and require repeat IVIG or other therapy. Factors contributing to IVIG treatment failure are incompletely understood. We hypothesized that administering lower aspirin doses contributes to initial IVIG treatment failure. Methods: From our database of 394 KD patients treated from 1992-2001, we identified those who received more than one 2gm/kg dose of IVIG. Each was matched with two KD controls by gender, age and illness day at initial IVIG treatment. Data regarding clinical and echocardiographic features, aspirin dosing, and laboratory findings were were assessed and compared for retreated patients and matched controls. Results: 26 patients (6.5%) had been treated with more than one 2gm/kg dose of IVIG, including 20 who were retreated once and six retreated twice. Fifty matched controls were identified. There was no significant difference between patients and matched controls with respect to age, gender, day of illness of initial treatment, and pre-treatment WBC, absolute band count, hemoglobin, albumin, and ESR. Retreated patients had significantly higher pre-preatment absolute neutrophil counts (P=0.008) and total bilirubin levels (P=0.009). No differences in KD presenting clinical features between retreated patients and matched controls, except that peripheral desquamation was noted more often in retreated patients (p=0.043). Although marked differences in aspirin dosing were not observed, a significantly greater proportion of retreated patients than matched controls were initially treated with < 80 mg/kg ASA (35% vs. 12%, respectively [P=0.022] on the first treatment day, 36% vs. 12% on the second treatment day [p=0.020], and 32% vs. 14% on the third treatment day [P=0.086]). Retreated patients had abnormal echocardiograms more foten than mathed controls (p=0.027), mainly reflecting baseline abnormalities. We conclude that lower administered initial doses of ASA may contribulte to IVIG treatment failure and thus to consequent need for retreatment and possibly poorer echocardiographic outcomes.

Differential changes in Fos-immunoreactivity at the auditory brainstem after chronic injections of salicylate in rats

In human, salicylate-induced tinnitus sometimes occurs a few days after its administration, but the chronic effects of salicylate in animal models are not fully known. In this study, we revealed the distribution of active cells in the rat auditory brainstem by staining an activity marker Fos-protein after multiple daily injections of salicylate. Experimental animals were first given five daily doses of sodium salicylate (250 mg/kg, i.p.). On day 6 they were placed inside a sound room for 8 h before sacrifice. Immunohistochemistry showed a significant increase in the number of Fos-positive cells at the inferior colliculus (IC), particularly its central division. At the cochlear nucleus (CN), only a few Fos-stains were found at the dorsal nucleus while no Fos-stain appeared at the ventral nucleus. The scarcity of Fos-stains at the CN reflected more a lack of external sound inputs than an adaptation in Fos-expression. Since Fos-stains in CN could still be induced on day 6 following brief tonal stimulation. Results are consistent with the hypothesis that salicylate-induced tinnitus is a phantom sound perception related to overactivity of cells at the IC.

Interaction of cyclooxygenase-2 inhibitors and salicylate in gastric mucosal damage

The interactions of sodium salicylate and the selective cyclooxygenase-2 inhibitors N-{2-(cyclohexyloxy)-4-nitrophenyl}-methanesulfonamide (NS-398) and 5.5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5II)-furanone (DFU), dexamethasone and the nitric oxide (NO) synthase inhibitor N G-nitro- l-arginine methylester ( l-NAME) were examined in ischaemia–reperfusion damage and adaptive protection in the rat stomach. Ischaemia–reperfusion damage was substantially aggravated by pretreatment with NS-398 (4 mg/kg), DFU (2 mg/kg), dexamethasone (1 mg/kg) or l-NAME (3 and 10 mg/kg). Salicylate (0.01–0.05 mg/kg) reversed the aggravating effect of NS-398, DFU and dexamethasone, while the effect of l-NAME was counteracted by l-arginine (twice 400 mg/kg) but not salicylate (0.05 or 10 mg/kg). Instillation of 20% ethanol prevented mucosal damage induced by 70% ethanol. This adaptive gastroprotection was abolished by pretreatment with NS-398 (1 mg/kg), DFU (0.2 mg/kg) or l-NAME (10 mg/kg). Salicylate (0.01–0.05 mg/kg) reversed the inhibition of protection by NS-398 and DFU, while the effect of l-NAME (10 mg/kg) was antagonized by l-arginine (100 mg/kg) but not salicylate (0.05 mg/kg). The precise mechanism of the functional antagonism between extremely low doses of salicylate and selective cyclooxygenase-2 inhibitors remains to be investigated.

Cocaine and salicylate: documentation of hydroxyl radical formation in hearts and brains of 18-day-old chick embryos and unexpected interactive toxicity.

Multiple low doses of cocaine (COC) may cause intermittent vasoconstriction and reperfusion, leading to elevations in damaging reactive oxygen species, such as hydroxyl free radicals (*OH). Salicylate may offer protection because it reacts with *OH and/or because of its anti-inflammatory actions. To measure *OH concentrations in hearts and brains of chicken embryos exposed to multiple, small doses of COC, and to determine if otherwise non-toxic doses of sodium salicylate (NaSal) protected against the marginal but significant reduction in hatchability caused by a model of "binge" COC exposure. Three experiments were carried out. In the first, 67.5 mg COC/kg egg was administered as five doses of 13.5 mg/kg egg or 0.675 mg/egg every 1.5 h, injected just beneath the shell, on day 18 of development (E18), 1 h after NaSal (25 or 100 mg/kg egg) was injected as a bolus. Hearts and brains taken shortly afterward were analyzed for *OH. In experiment 2, the dose of COC was reduced to 56.5 mg/kg egg so as to achieve a small but significant reduction in hatchability in order to determine if NaSal protected against or enhanced COC's toxicity, manifest as an increase or decrease in hatchability. The doses of NaSal for this experiment were 50, 100 or 200 mg/kg egg, all devoid of effects upon hatchability when injected alone. Experiment 3 was done to confirm the presence of vascular disruptions/hemorrhages observed on COC-exposed embryos while harvesting hearts and brains for chemical analyses and to quantify what appeared to be enhanced COC-related vascular accidents associated with NaSal pretreatment. The dose of NaSal used in experiment 3 was 200 mg/kg egg and COC was injected again at 5x13.5 mg/kg egg. COC increased *OH in hearts and brains of chicken embryos on E18, and non-toxic doses of NaSal (i.e. 100 or 200 mg/kg egg) enhanced COC's toxicity in a dose-related manner. The lowest NaSal dose (50 mg/kg egg) may have offered some protection against the effects of COC, as the reduction in hatchability caused by 56.5 mg COC/kg egg was no longer significant. Vascular disruptions/hemorrhages were associated with and most likely responsible for the interactive toxicity. Our unexpected findings may be of clinical relevance because of the use of aspirin for treatment of misdiagnosed "preeclamptic" COC-abusing pregnant women and its possible use for COC abusers at risk for reduced cerebral blood flow and stroke.

Effects of an oral dose of acetyl salicylate at tail docking on the behaviour of lambs aged three to six weeks

To investigate a practical method of providing analgesia for docking of lambs’ tails, the effectiveness of an oral dose of aspirin (acetyl salicylate) in reducing discomfort behaviour immediately following application of elastrator rings, was evaluated. The study involved a pilot trial and an experiment, both using Romney crossbred lambs aged 3–6 weeks accompanied by their mothers in a group pen, with behaviour recorded on videotape. In the pilot trial, lambs were manually restrained, an elastrator ring was applied, then lambs were given either an oral dose (26 mg/kg) of aspirin dissolved in water (Treatment RA, n=5 lambs) or an oral dose of water (Treatment R, n=4 lambs), and released. RA lambs changed posture between sternal recumbency and standing less frequently than R lambs, significantly so from 10 to 20 min post-treatment (11 times for RA, compared with 28% (S.E.D. 6.6%) for R lambs). In the experiment, 56 lambs were given one of two docking treatments (either RA: application of an elastrator ring plus the same aspirin treatment as in the pilot trial, or R: application of the ring plus water), or one of two control treatments (CA: restraint plus aspirin; or C: restraint plus water). During the hour after treatment, docking was associated with differences in over three quarters of 52 postures and activities used to describe behaviour ( P<0.05), and marked changes over time in the postures/activities affected were observed. Differences were evident within 5 min and some were still apparent at 60 min post-treatment. When postures and activities were designated as ‘normal’ or ‘abnormal’ (typical of docked lambs), over the total hours of observation the mean frequency of abnormal postures was 3.5% for control lambs and 22.6% (S.E.D. 1.64%) for docked lambs, and the mean frequency of abnormal activities was 5.2% for control lambs and 19.3% (S.E.D. 1.40%) for docked lambs. Provision of aspirin to docked lambs was associated with similar levels to those seen in control lambs for two activities but was also associated with increased levels of some activities/postures ( P<0.05). These effects were minor compared with the effects of docking and there was no indication of effective analgesia. Thus, when elastrator tail docking rings were applied, behavioural effects indicative of pain were observed immediately and did not subside fully within 1 h. Despite indications in the pilot trial of an analgesic effect of aspirin, further experimentation did not substantiate this effect.

Salicylate and cocaine: interactive toxicity during chicken mid-embryogenesis

Increased free radical production, due to ischemia and reperfusion, has been postulated as a cause of cocaine’s (COC) developmental toxicity. Salicylate reacts with hydroxyl free radicals ( OH) to form stable, quantifiable reaction products, which can be measured with high-pressure liquid chromatography (HPLC). To determine if chicken embryos’ brains and hearts were exposed to increased OH concentrations after injection of COC, an injection of a nontoxic dose of sodium salicylate (NaSAL, 100 mg/kg egg, or 5 mg/egg), followed by 5 injections of COC (13.5 mg/kg or 0.675 mg/egg, every 1.5 h), was administered to eggs containing embryos on the 12th day of embryogenesis (E12). In addition to finding increased OH concentrations in E12 embryonic hearts and brains, we observed that the developmental toxicity of COC, manifest as vascular disruption (hemorrhage) and lethality, was enhanced by NaSAL injection. These results confirm and extend results of similar experiments performed upon older embryos (E18), and indicate that increased OH concentration in embryonic tissues after COC exposure and toxic interactions of COC and NaSAL can also occur at an earlier stage of development. The results are discussed in light of possible exposure of human fetuses to both COC and salicylates, since COC-abusing pregnant women can be misdiagnosed with pre-eclampsia and aspirin is used to treat this syndrome.

Salicylate induced changes in outer hair cell lateral wall stiffness

Micropipette aspiration was used to study the lateral wall stiffness of isolated guinea pig outer hair cells (OHCs) perfused with a sodium salicylate solution. Salicylate treatment significantly decreased lateral wall stiffness as measured by a stiffness parameter (S) compared to cells perfused with a standard bathing solution (S=0.68±0.26 vs. S=1.09±0.25, P<0.05). The effect was reversible – cells treated with salicylate and then with bathing solution exhibited a lateral wall stiffness similar to control cells (S=1.10±0.40, P=0.94). Salicylate perfusion diminishes electromotile responses in isolated OHCs and physiologic doses of salicylate produce hearing loss and tinnitus in human subjects. The OHC lateral wall, the locus of electromotility, consists of three concentric layers: (1) an outermost plasma membrane, (2) a cytoskeletal network of actin and spectrin called the cortical lattice and (3) an innermost collection of flattened membranes called the subsurface cisternae (SSC). Ultrastructural studies have shown that salicylate treatment dilates and vesiculates the lateral wall subsurface cisternae (SSC) in guinea pig OHCs. In addition, salicylate causes an outward curvature of plasma membranes in human erythrocytes. The reversible, salicylate induced increase in lateral wall compliance may result from a direct action on the SSC and/or the plasma membrane.

Salicylate protects against MPTP-induced impairments in dopaminergic neurotransmission at the striatal and nigral level in mice.

The analgesic and anti-inflammatory drug sodium salicylate was studied for its potential protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. C 57BL/6 mice were treated with a single dose of sodium salicylate (50 mg/kg or 100 mg/kg i.p.) or saline immediately before injection of MPTP (30 mg/kg or 40 mg/kg s.c.) or saline. Analysis of striatal dopamine and metabolites as well as immunostaining for tyrosine hydroxylase of nigral sections was performed 7 days after MPTP treatment. MPTP (30 mg/kg) led to a strong decrease in striatal dopamine levels (1.87+/-0.27 ng/mg) compared to saline-treated controls (15.72+/-0.78 ng/mg), which was significantly attenuated by sodium salicylate 50 mg/kg and 100 mg/kg (5.59+/-0.56 ng/mg and 8.64+/-0.89 ng/mg, respectively). Remarkably, the MPTP-induced loss of tyrosine hydroxylase immunoreactivity in nigral cell bodies was nearly completely prevented by the higher dose of sodium salicylate. Furthermore, salicylate demonstrated radical scavenging effects in an in vitro Fenton system indicated by HPLC determination of the dihydroxylated reaction products of salicylate, namely, 2,3- and 2,5-dihydroxybenzoic acid. The protective effects of salicylate against reversible or irreversible impairments in dopaminergic neurotransmission after MPTP treatment may be related to its radical scavenging properties and other mechanisms which need to be clarified.

Reye's Syndrome and Salicylate Use, by Karen M. Starko, MD, et al,Pediatrics, 1980;66:859–864; andNational Patterns of Aspirin Use and Reye Syndrome Reporting, United States, 1980 to 1985, by Janet B. Arrowsmith et al,Pediatrics, 1987;79:858–863

ABSTRACT OF ORIGINAL ARTICLE (STARKO ET AL). During an outbreak of influenza A, seven patients with Reye's syndrome and 16 ill classmate control subjects were evaluated for characteristics of the patients' prodromal illness and the control subjects' illness and for medication usage. Patients during the prodrome and control subjects had similar rates of sore throat, coyza, cough, headache, and gastrointestinal complaints except for documented fever which occurred significantly more often in patients than in control subjects ( P = .05). While medications which did not contain salicylate were taken as frequently by patients as control subjects, patients took more salicylate-containing medications than did control children ( P < .01). All seven patients took salicylate whereas only eight of 16 control subjects did so ( P < .05) Patients took larger doses of salicylate than did the entire control group ( P < .01). When the eight control subjects who took salicylate were compared with the patients, the patients still tended to take larger doses ( P = .08). Patients with fever took salicylate more frequently than control subjects with fever ( P < .01). In addition, salicylate consumption was correlated with severity of Reye's syndrome ( P < .05). It is postulated that salicylate, operating in a dose-dependent manner, possibly potentiated by fever, represents a primary causative agent of Reye's syndrome . ABSTRACT OF ORIGINAL ARTICLE (ARROWSMITH ET AL). The number of cases of Reye syndrome reported annually to the Centers for Disease Control and Prevention declined markedly between 1980 and 1985. In this article we present pharmaceutical marketing research data that suggest sharp decreases in the use and purchase of children's aspirin between 1980 and 1985. These trends appear to correspond to the decrease in reporting of Reye syndrome cases. Additionally, analysis of physician mentions of aspirin and acetaminophen for treating flu and chickenpox showed statistically significant trends …

Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose

The efficacy of intravenous gamma globulin (IVGG) for treatment of Kawasaki disease (KD) is clearly established. In a metaanalysis, we reviewed U.S. and Japanese multicenter, randomized controlled studies regarding the effect of various doses of IVGG with aspirin administered within the first 7 to 10 days of illness on the prevalence of coronary artery abnormalities in KD. We studied 1629 patients with acute KD from the six reported studies that included blinded echocardiographic assessments. In 868 Japanese patients treated with moderate-dose aspirin (30 to 50 mg/kg per day), the prevalence of coronary abnormalities at the subacute stage (illness day 30) was 26.8% with aspirin alone, 18.1% with total IVGG dose < 1 gm/kg, 17.3% with total IVGG of 1.0 to 1.2 g/kg, and 5.3% with total IVGG of 2 gm/kg; the corresponding prevalence at the convalescent stage of illness (illness day 60) was 17.5%, 13.5%, 9.8%, and 3.5%, respectively. In 761 U.S. patients treated with high-dose aspirin (80 to 120 mg/kg per day), the prevalence of coronary abnormalities at the subacute stage (2 to 3 weeks after enrollment) was 23.0% with aspirin alone, 9.0% with total IVGG of 1.0 gm/kg, 8.6% with total IVGG of 1.6 gm/kg, and 4.6% with total IVGG of 2.0 gm/kg; corresponding prevalence at the convalescent stage (6 to 8 weeks after enrollment) was 17.7%, 9.0%, 6.3%, and 3.8%, respectively. When all data for the 1629 patients were combined, the prevalence at the subacute stage was 25.8% with aspirin alone, 18.1% with IVGG < 1 gm/kg, 15.7% with IVGG of 1 to 1.2 gm/kg, 8.6% with IVGG of 1.6 gm/kg, and 4.8% with IVGG of 2 gm/kg (adjusted R 2 = 0.966, p = 0.0017); corresponding prevalence at the convalescent stage was 17.6%, 13.5%, 9.7%, 6.3%, and 3.8%, respectively (adjusted R 2 = 0.993, p = 0.0602). The prevalence of coronary abnormalities was inversely related to the total dose of IVGG and was independent of the aspirin dose. We conclude that 2 gm/kg IVGG combined with at least 30 to 50 mg/kg per day aspirin provides maximum protection against development of coronary abnormalities after KD. (J Pediatr 1997;131:888-93)

Inhibition of nuclear factor kappa B subunit p65 mRNA accumulation in lipopolysaccharide-stimulated human monocytic cells treated with sodium salicylate.

Lipopolysaccharide is one of the most potent trigger substances for monocytes and macrophages causing secretion of inflammatory mediators such as tumor necrosis factor and interleukin-1. The nature of the nuclear factors involved in regulation of these cytokine genes is still unknown. Nuclear factor kappa B (NF-kappa B; heterodimer of p50 and p65) proteins have been suggested to play an important role in gene transcription of inflammatory mediators when monocytes are stimulated with lipopolysaccharide. Nonsteroidal anti-inflammatory drugs such as salicylates have been used to treat symptoms of inflammation, and a new mechanism of drug action was suggested recently. Salicylates have been shown to inhibit lipopolysaccharide-induced gene transcription via inhibition of NF-kappa B activation by preventing the degradation of NF-kappa B inhibitor "I kappa B", blocking the translocation of NF-kappa B into the nuclear compartment. However, the nature of the subunit involved in this mechanism has not been defined. To examine the mechanisms by which salicylates affect cytokine gene transcription, the amount of active and inactive NF-kappa B and NF-kappa B mRNA, in Porphyromonas gingivalis lipopolysaccharide-stimulated human monocytic cells was assessed. High doses of sodium salicylate suppressed NF-kappa B p65 mRNA accumulation, resulting in suppression of total NF-kappa B, p50 on tissue oligonucleotide had no effects on lipopolysaccharide-induced NF-kappa B activation. The data demonstrate that the p65 subunit of NF-kappa B is inhibited by salicylate treatment and highlight the role of salicylate in the control of gene expression of inflammatory mediators.

Interaction of salicylate and ibuprofen with the carboxylic acid: CoA ligases from bovine liver mitochondria.

Neither salicylate nor ibuprofen was a substrate or inhibitor of the long-chain fatty acid:CoA ligase. In contrast, all three xenobiotic-metabolizing medium-chain fatty acid:CoA ligases (XL-I, XL-II, and XL-III) had activity toward salicylate. The K(m) value for salicylate was similar for all three forms (2 to 3 microM), but XL-II and XL-III had higher activity at Vmax. For ibuprofen, only XL-III catalyzed its activation, and it had a K(m) for ibuprofen of 36 microM. Studies of salicylate inhibition of XL-I, XL-II, and XL-III revealed that it inhibited the benzoate activity of all three forms with K1 values of ca. 2 microM, which is in agreement with the K(m) values obtained with salicylate as substrate. Kinetic analysis revealed that salicylate conjugation by all three forms is characterized by substrate inhibition when salicylate exceeds ca. 20 microM. Substrate inhibition was more extensive with XL-I and XL-III. Previous work on the ligases employed assay concentrations of salicylate in the range of 0.1 to 1.0 mM, which are clearly inhibitory, particularly toward XL-I and XL-III. Thus, activity was not properly measured in previous studies, which accounts for the fact that salicylate conjugation was only found with one form, which is most likely XL-II since it has the highest Vmax activity and shows the least amount of substrate inhibition. Studies with ibuprofen indicated that it inhibited XL-I, XL-II, and XL-III, with KI values being in the range of 75-125 microM. The short-chain ligase was inhibited by both salicylate and ibuprofen with KI values of 93 and 84 microM, respectively. It was concluded that pharmacological doses of salicylate, but not ibuprofen, will affect the metabolism of medium-chain fatty acids and carboxylic acid xenobiotics and that the previously described mitochondrial ibuprofen:CoA ligase activity is attributable to XL-III.

Salicylate‐induced changes in auditory thresholds of adolescent and adult rats

Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level. © 1996 John Wiley & Sons, Inc.

Salicylate-induced changes in auditory thresholds of adolescent and adult rats.

Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level.