Serum Salicylate Levels Research Articles

Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis.

AbstractSalicylates were administered to 6 patients with juvenile rheumatoid arthritis in doses sufficient to produce a serum salicylate level in excess of 25 mg/100 ml. All 6 patients developed elevations of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase. In addition, 4 patients had other evidence of hepatic dysfunction. Abnormalities were dose‐related and were reversible upon lowering the salicylate dose. Liver biopsies performed in 2 patients revealed a mononuclear cell infiltrate of portal triads in both and scattered single cell necrosis in the parenchyma in 1 case.

Effect of intravenous salicylates on the gastric mucosal barrier in man.

A high incidence of gastric ulceration is reported in patients with rheumatoid arthritis and in addicts taking large doses of aspirin. In rheumatoid arthritis a serum salicylate level of 15 mg% is considered to be therapeutic. We studied gastric mucosal permeability to ions in 9 healthy subjects given 3 g aspirin intravenously over 2 hours (mean serum salicylate, 17 mg%). Atropine was injected intravenously to reduce acid secretion which masks H+ loss. H+ and Na+ fluxes during aspirin infusion were not significantly different from those during intravenous saline infusion. Thus, high blood levels of salicylates did not impair the gastric mucosal barrier. Intragastric salicylic acid following intravenous aspirin infusion increased gastric mucosal permeability to H+ and Na+ ions. Under the conditions of these studies the effect was more marked in males. Gastric absorption of salicylic acid was similar in males and females, and the amount absorbed was unaffected by the presence of high blood levels of salicylates. Absorption of salicylic acid was significantly greater in the first period of salicylic acid instillation (mean, 28%) than in the second (mean, 21%) and third (mean, 16%) periods. Percentage absorption of undissociated salicylic acid was at least three times greater than that of H+ ions.

Estimating severity of Darvon® ingestions

When Darvon Compound or other drug mixtures containing salicylate are ingested, determine serum salicylate levels to obtain a rapid, approximate assessment of the degree of propoxyphene intoxication.

Salicylate-induced increases in free triiodothyronine in human serum. Evidence of inhibition of triiodothyronine binding to thyroxine-binding globulin and thyroxine-binding prealbumin.

Addition of sodium salicylate to human serum at concentrations often obtained during aspirin therapy causes 100-200% increases in free triiodothyronine (T(3)) and free thyroxine (T(4)) as estimated by ultrafiltration. The increase in free T(3) was unexpected since previous data had suggested that salicylate inhibits binding of T(4) only to thyroxine-binding prealbumin (TBPA) and that T(3) is not bound to this protein. Using ultrafiltration techniques, we demonstrated binding of T(3) to TBPA. The affinity constant for T(3)-TBPA binding appears to be slightly greater than that for albumin-T(3) binding. While salicylate inhibits the binding of T(3) (and T(4)) to TBPA, it can be predicted that little change will be observed in the free T(3) (or free T(4)) without inhibition of thyroid hormone binding to thyroxine-binding globulin (TBG). Using a competitive-binding protein displacement technique, it has been shown that sodium salicylate, like diphenylhydantoin (DPH), inhibits the binding of T(3) and T(4) to TBG. The magnitude of the increase in free T(3) and free T(4) induced by salicylates suggests that interference with TBG binding is its major effect. Aspirin was administered orally to two normal subjects in quantities sufficient to obtain serum salicylate levels of 20-25 mg/100 ml. This resulted in a decrease of 20-30% in total serum T(3) and T(4) levels. This decrease in T(4) levels is similar in magnitude to that previously observed in subjects receiving DPH. Unlike what has been observed with DPH treatment, therapeutic salicylate levels are associated with increases of 50-75% in the unbound fraction of both T(3) and T(4) which persist throughout an 8-10 day treatment period.

Studies on Enteric-Coated Aspirin-Vitamin C Tablets

Enteric-coated tablets of aspirin-vitamin C, produced by nine Japanese makers, were examined in a disintegration test, for serum salicylate level after one oral administration and after repeated oral administration for six days.The analgesic effects of the drugs and adverse reactions to the drugs were investigated in the patients and compared with the patients' salicylate levels.As a result of these studies, which entailed administration of aspirin-vitamin C 6 T (as aspirin 1.5 g) three times a day, no significant difference could be found, between the analgesic effects of these drugs and the effect of a placebo. However, a clear difference between the drugs and the placebo was found in the adverse reactions to the drugs, at a level of significance of 5%.As for serum salicylate levels during repeated oral administration for six days, it was observed that the serum salicylate level during administration of entericcoated tablets tended to be slightly lower than that during administration of the same quantity of aspirin powder. There was no relationship between the serum salicylate level and the patients' evaluation of analgesic effects or adverse reactions.

Letter To The Editor

Doctors Pross, Bradford, and Krueger comment on these two letters as follows: We appreciate the comments of Dr. Shaw and Dr. Mortimer. The question of a relationship between salicylates and Reye's syndrome has been raised by various authors.1-3 Utian reported 14 patients with this syndrome in which "several" had received aspirin, but serum salicylate levels were never more than "mild to moderately elevated." Norman,3 in describing 21 cases measured salicylate levels in 10 patients and all were below 25 mg/100 ml.

Serum Salicylate Levels in Blood Donors

Salicylate levels were determined in serum from 240 volunteer blood donors who had denied recent drug exposure. Twenty-seven serum samples had levels ranging from 1.6 to 13.6 mg/100 ml, indicating exposure to salicylate preparations, which presumably were not considered by donors to be drugs. The observed elevated salicylate levels might affect adversely an extremely hypersensitive blood or plasma recipient. Salicylate ingestion might also suppress fever in donors.

A simple method of estimating plasma salicylate levels.

A rapid, reliable, and simple method of estimating serum salicylate levels is described which makes this estimation available not only to units managing patients suffering from salicylate self-poisoning but also to departments using salicylates for medication and needing an easy method of checking the serum levels.

The Influence of Acetyl-Salicylic Acid on Growth and Some Respiratory Enzymes in Broiler Chicks.

The enzyme, succinic dehydrogenase, was observed to be significantly inhibited by salicylate in in vitro studies(l). A serum salicylate level of 137 mg/100 ml had no effect on hexokinase, cytochrome oxidase or DPNH-cytochrome c reductase(2). In vitro studies with rat liver mitochondria indicated that malate and isocitric dehydrogenase activities were inhibited by salicylate(3,4). An additional study has demonstrated that acetyl salicylic acid fed at levels of 0.005-0.08% of the diet failed to produce a significant difference in growth rate or feed conversion in 3 chick studies(5).New Hampshire X Delaware chicks were fed 0.3, 0.6 and 0.9% acetyl-salicylic acid (ASA) in addition to the basal diet (Table I). Each dietary treatment was replicated 5 times, and each replicate employed in the experiment consisted of 4 males and 4 females. All chicks were reared for 4 weeks in electrically-heated chick batteries with raised wire floors, and feed and tap water were supplied ad libitum. Feed and body weights were d...

In vivo Drug Release Rate from Hard Gelatin Capsules

Serum salicylate levels were utilized to evaluate the relative release rate of aspirin from a commercial aspirin tablet and from a hard gelatin capsule. Although a few subjects obtained rapid release from the capsules, the majority had an appreciable delay relative to tablets. The population distribution of levels is markedly different between capsules and tablets at the times studied. The median delay for significant levels is approximately 15 min. Serum salicylate levels were utilized to evaluate the relative release rate of aspirin from a commercial aspirin tablet and from a hard gelatin capsule. Although a few subjects obtained rapid release from the capsules, the majority had an appreciable delay relative to tablets. The population distribution of levels is markedly different between capsules and tablets at the times studied. The median delay for significant levels is approximately 15 min.

STUDIES OF DELAYED-ACTION MEDICATION. IV. SALICYLATES.

Single 1.0 Gm. doses of aspirin were administered as uncoated tablets and as two different enteric‐coated preparations. Enteric coating of aspirin considerably delayed absorption, significant serum levels of salicylate usually not appearing until 6 hours or more. In contrast, absorption from uncoated aspirin tablets was rapid, significant serum salicylate levels being obtained by the first hour and maintained for the next 3 hours, followed by a slow fall. Absorption from the enteric‐coated sodium salicylate preparation studied resembled that from uncoated aspirin, though delayed by about 4 hours. A study of serum salicylate levels during and following four 1.0 Gm. doses of aspirin or sodium salicylate at 4 hour intervals confirmed the considerable delay in obtaining adequate serum levels from the enteric‐coated aspirin preparations. The most consistent daily curve of serum levels was obtained follOWing administration of uncoated tablets. A new tableted preparation of aspirin combined with retarding agents was found to delay absorption of the drug by about one hour without any loss in physiologic availability. If such a preparation should produce less gastric distress on further clinical trial, it might be the preferred preparation where gastric irritation is a problem. Until this is established, aspirin in dissolved form might be the best alternative if uncoated tablets cannot be tolerated because of gastric distress. Enteric‐coated aspirin should not be used in any case where an immediate analgesic or antipyretic effect is desired because of their erratic and often greatly delayed absorption.

Aspirin Formulation and Absorption Rate I: Criteria for Serum Measurements with Human Panels

Replication of serum salicylate level distribution in a human panel is obtained by rigorous adherence to properly selected protocols. The panel must be sufficiently large to represent all types of absorption variability after aspirin ingestion. The inherent variability of the human group can be measured. Thus, it is possible to calculate panel sizes required to provide the sensitivity, in terms of least significant differences, needed to evaluate factors of aspirin absorption. With the panels studied, random crossover testing offers no advantage over sequential testing. During the initial absorption period, serum salicylate levels existing at the time of ingestion, whether small artifacts or real and appreciable levels, may be treated as deductible blanks for the study of aspirin absorption.

Aspirin Formulation and Absorption Rate II: Influence on Serum Levels of Tablets, Antacids, and Solutions

Serum salicylate levels were measured for seven aspirin preparations alone and with a mixture of dihydroxyaluminum glycinate and magnesium carbonate. A twofold increase in serum levels at 10 and 20 minutes after ingestion was observed with the mixture present. With the aspirin preparations, the salicylate serum levels clearly reflected the technology of the aspirin granulation preparation. An optimum level of antacid for rapid absorption was found. A study of the salicylate levels resulting with time from ingestion of solutions and tablets showed that more rapid absorption was accompanied by earlier and higher serum levels.

ALKALINE DIURESIS IN TREATMENT OF ASPIRIN POISONING.

The rate at which salicylates are removed from the body is augmented by making the urine alkaline (Morris and Graham, 1931). MacPherson, Milne, and Evans (1955) have shown that the production of an alkaline polyuria ensures a rapid removal of salicylate and suggest this as a method of treatment in patients with salicylate intoxication. Such a method has been widely used in children poisoned with salicylates, the serum salicylate level undergoing a 50% reduction in two to five hours without untoward side-effects. These results compare favourably with those obtained with exchange transfusion and haemodialysis (Oliver and Dyer, 1960 ; Whitten, Kesaree, and Goodwin, 1961).

Salicylate absorption patterns: a comparison between rectal and oral administration.

Serum salicylate levels of 40 subjects who had received 0.65 gm. of aspirin both orally (aspirin tablets) and rectally (cacao-butter-aspirin suppositories) were compared at 0, 10, 20, 40, 60, 120, 180, and 240 min. At all times, the oral route provided significantly higher blood salicylate levels (p=<0.001) than the rectal route.

SALICYLATE INTOXICATION

Studies on 38 children and adults who ingested large amounts of salicylate revealed a poor correlation of salicylate level in serum with clinical severity of salicylate intoxication. Serial measurements of serum salicylate levels in dogs and in 17 previously well patients revealed that the disappearance of salicylate from circulation is a first-order reaction in the post-absorptive period. It is possible, therefore, to calculate the half-life of circulating salicylate. In the present study the mean salicylate half-life in 17 patients was 20 hours. It is possible to eliminate the variable of time since ingestion by utilizing the rate of removal (half-life) of salicylate to extrapolate from the observed salicylate level at any time following ingestion to a theoretical zero-time salicylate concentration (So). There was found to be an excellent correlation of So with the clinical severity of salicylate intoxication. A nomogram that eliminates the necessity for calculating So is presented. Calculation of So or use of the nomogram provide better means than were previously available for predicting the severity of salicylate intoxication on the basis of measurements of blood salicylate. Particularly noteworthy was the fact that four patients who died despite intensive conventional treatments had So values which greatly exceeded those found in patients who recovered. This observation suggests that an So of greater than 160 is essentially incompatible with life and that measures for rapidly reducing salicylate levels, such as hemodialysis or exchange transfusion, should be instituted. The data are not sufficient to permit conclusions to be drawn concerning the influence of various factors on salicylate removal and toxicity. However, the use of So and salicylate half-life should facilitate such studies.

On differences between some effects of salicylate and 2 : 4-dinitrophenol

The human RBC treated in vitro for 2 hr with 3 × 10 −3M salicylate or 5 × 10 −3 M 2:4-dinitropheno), lose in average 11–22 (salicylate), 13–44 (DNP) mEq./l. cell potassium and take up 2.01 (salicylate), 2.89 (DNP) mEq./l. sodium and 40.8 (salicylate), 34.6 (DNP) mi/l. cell water. 2-Nitrophenol, 3-nitrophenol, and 2:4:6-trinitrophenol have no similar effects. In the RBC of normal persons in whom during acute experiment the serum salicylate level rose to 30–48 mg% similar changes occurred. On the contrary, DNP given (a) to humans in doses which induce a metabolic increase similar to that produced by salicylate. and (b) in higher doses (30 mg/kg) to rats. did not influence the electrolyte and water content of RBC. High salicylate doses induce a water, potassium and sodium diuresis in the rat, but DNP exerts no similar action. DNP shows no considerable effect in rat's hind-paw oedema-test, whilst salicylate inhibits the oedema. These differences may be explained by their divergent energetic effects in the organism. Although both substances have striking influence on metabolism and uncouple oxidative phosphorylation. DNP increases oxygen consumption parallel with the dose, whilst this effect ofsalicylale is limited. Therefore, unlike DNP, salicylate seems to induce a considerable energy deficiency state of the cells.

THE EFFECT OF SODIUM BICARBONATE ON THE SERUM SALICYLATE LEVEL

During a study of massive salicylate therapy in rheumatic fever, a patient who was taking a constant daily amount of sodium salicylate by mouth and was maintaining a fairly constant serum salicylate level asked for sodium bicarbonate to relieve his "gastric discomfort." When this was given it was noted that the serum salicylate level fell decidedly, although the patient continued to receive the same dose of sodium salicylate. Since it is claimed that plasma salicylate levels of at least 350 micrograms per cubic centimeter are importantin the treatment of rheumatic fever¹and since it is customary to give equal amounts of sodium salicylate and bicarbonate during salicylate therapy, it was thought of importance to investigate the influence of sodium bicarbonate on the serum salicylate level. <h3>METHOD</h3> Daily determinations of blood salicylate levels were made according to the method recently described by Brodie, Udenfriend and Coburn,²with