The Relative Potencies of Some Substituted Salicylic Acids as Metabolic Stimulants in the Intact Rat

Andrews, Muriel M.

doi:10.1111/j.1476-5381.1958.tb00232.x

Cited by 6 publications

(9 citation statements)

References 12 publications

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“…In rats they are less toxic than salicylate (33). Since they also lack the calorigenic effects of salicylate (21,22), they appeared to be ideal agents for use in assessing the effects on peripheral T4 metabolism of inhibiting the binding of T4 by TBPA.7 The studies that were therefore carried out have provided what is apparently the first strong evidence that TBPA plays a significant role in regulating the peripheral metabolism of T4 in man.…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…Supported in part by research grant Am-00267-10 from the National Institute of Arthritis and Metabolic Diseases, Bethesda, Md. hypermetabolism (19, 20), again the changes in T4 metabolism that these agents induce cannot necessarily be ascribed to an inhibition of T4-binding by TBPA.Previous reports have indicated that certain congeners -of salicylate do not uncouple oxidative phosphorylations in vitro (19) or stimulate oxygen consumption in vivo (21,22). We therefore made a search among these compounds for inhibitors of T4 binding by TBPA in order to study their effects on T4-metabolism in man.…”

mentioning

confidence: 99%

“…Previous reports have indicated that certain congeners -of salicylate do not uncouple oxidative phosphorylations in vitro (19) or stimulate oxygen consumption in vivo (21,22). We therefore made a search among these compounds for inhibitors of T4 binding by TBPA in order to study their effects on T4-metabolism in man.…”

mentioning

confidence: 99%

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The Effects of Noncalorigenic Congeners of Salicylate on the Peripheral Metabolism of Thyroxine*

Woeber¹,

Ingbar²

1964

J. Clin. Invest.

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Various experiments have indicated the presence in whole human serum of three major thyroxine (T4)-binding 1 proteins: T4-binding globulin (TBG), T4-binding prealbumin (TBPA), and albumin (1, 2). It is well established that, in vitro, TBG and TBPA are the major T4-binding proteins, whereas albumin is a relatively weak secondary carrier (3-5). These proteins interact with the hormone in a reversible binding equilibrium in which the majority of the hormone is bound but a measurable proportion is unbound or free. Free T4 has been suggested as the metabolically active component available to the cells in vivo for degradation, excretion, and initiation of hormonal action, with the bound hormone acting as a metabolically inert reservoir (3-5).The role of TBG in the transport and peripheral metabolism of T4 in man is well accepted. This acceptance is based on studies demonstrating a consistent relationship between changes in the T4-binding activity of TBG, as assessed by electrophoresis in vitro and changes in the concentration and fractional turnover of T4 in vivo (6-8). From these observations, the conclusion has been drawn that TBG regulates the peripheral metabolism of T4 by limiting the concentration of unbound hormone.The existence of TBPA as a normal constituent of human serum has been satisfactorily demonstrated by several techniques, and earlier doubts concerning its function in binding T4 at physiological pH have been dispelled (5, 9, 10). The role, if any, of -TBPA in regulating the peripheral metabolism of T4 in vivo has remained uncertain.* Submitted for publication December 9, 1963; accepted January 8, 1964. Supported in part by research grant Am-00267-10 from the National Institute of Arthritis and Metabolic Diseases, Bethesda, Md. hypermetabolism (19, 20), again the changes in T4 metabolism that these agents induce cannot necessarily be ascribed to an inhibition of T4-binding by TBPA.Previous reports have indicated that certain congeners -of salicylate do not uncouple oxidative phosphorylations in vitro (19) or stimulate oxygen consumption in vivo (21,22). We therefore made a search among these compounds for inhibitors of T4 binding by TBPA in order to study their effects on T4-metabolism in man. Methods and MaterialsIn vitro studiesThe effect of benzoic acid and a number of its hydroxy-, dihydroxy-, and amino-substituted derivatives 2 on the binding of T4 in normal serum was assessed by electrophoretic and dialysis techniques.

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Section: In Vivo Studiesmentioning

confidence: 99%

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confidence: 99%

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The Effects of Noncalorigenic Congeners of Salicylate on the Peripheral Metabolism of Thyroxine*

Woeber¹,

Ingbar²

1964

J. Clin. Invest.

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“…The calorigenic action of salicylate is not relevant to the present findings, because no sex difference in this effect was found in the rat by Andrews (1958), and because neither benzoate nor gentisate possesses this property (Meade, 1954;Andrews, 1958). Furthermore, 2:4-dinitrophenol, which is a powerful metabolic stimulant, had no effect on rat liver glutathione concentration.…”

Section: Discussionmentioning

confidence: 53%

“…In contrast, salicylate is excreted rather slowly in the rat, with a half-time of plasma concentration of 10 hr (Andrews, 1958).…”

Section: Discussionmentioning

confidence: 99%

Salicylate and Liver Glutathione

Sproull¹

1961

British Journal of Pharmacology and Chemotherapy

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The effects of sodium salicylate, benzoate, gentisate, m-and p-hydroxybenzoates, antipyrine, and 2: 4-dinitrophenol on the reduced glutathione concentration of rat liver were determined. An increase in concentration in the male, but not in the female, rats was found after salicylate, benzoate and gentisate; after antipyrine, a comparable increase occurred in the females only. There is a relation, in these compounds, between capacity to increase the concentration of reduced glutathione in the rat liver in one sex and therapeutic activity in rheumatic fever.In continuation of a search for pharmacological actions of salicylate which are correlated with its therapeutic properties, the effect of salicylate on the reduced glutathione concentration of liver was examined. A two-fold increase in the reduced glutathione concentration of rat liver after administration of sodium salicylate has been reported by Lutwak-Mann (1942). The present results do not confirm this finding: a moderate increase in the reduced glutathione concentration of rat liver was induced by salicylate, but in the male sex only.An attempt has been made to evaluate this finding, by comparing the activity of salicylate on rat liver glutathione with that of a variety of other compounds. In addition to salicylate, the following were studied: other antirheumatic drugs of the same series (benzoate and gentisate), and of a different series (antipyrine); m-and p-hydroxybenzoates, which are therapeutically inert isomers of salicylate, and 2:4-dinitrophenol, which, like salicylate, is a peripheral metabolic stimulant.In the first experiments, an interval between administration of the drug and termination of the experiment was arbitrarily selected as adequate and convenient for salicylate. This interval was unlikely to be suitable for the rapidly excreted compounds such as benzoate. Rather than find the optimal interval for each compound, a second series of observations was made, in which two doses were given of each of the compounds which in single doses of 200 mg/ 100 g body weight were tolerated without noticeable effect. Salicylate was included for comparative purposes.A relation was then found, within the present group of compounds, between therapeutic activity in rheumatic fever and capacity to increase rat liver glutathione concentration in one sex.

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The permeability to plasma proteins of the peritoneal blood vessels of the mouse, and the effect of substances that alter permeability

Northover

1963

J. Pathol.

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PERITONms is associated with the accumulation of plasma protein in the peritoneal cavity, and a study is being made of the significance of this protein in the defence against bacterial infection. The accumulation of plasma protein in the peritoneal cavity can be measured by a method involving labelling the circulating plasma protein with Evans blue: this method for studying the permeability of the peritoneal vascular bed has the advantage that it can be used for investigating conditions ranging from approximate normality to severe inflammation, the mechanism of inflammation and the mode of action of antiinflammatory compounds. h4ATERUI.s AND m o mA n i d . Adult mice weighing 25-30 g. were used in these experiments as they gave more consistent respoases than smaller animals; the results quoted were obtained with male mice, but female mice were equally suitable. The animals were fed on a cube diet and allowed drinking water ad libitum, except that for 12 hr prior to the test food was withheld, and during the test both food and water were withheld.Procehre. The mice were arranged in groups of 12; unless otherwise stated in the text, the procedure was as follows. Each mouse received 4 ml. of 0.9 per cent. sodium chloride solution at 38°C. intraperitoneally through a hebore needle inserted in the ventral abdominal surface, and within the next 30 sec. 0-2 ml. of a 0-5 per cent. solution of Evans blue in saline via a lateral tail vein. After 1 hr the peritoneal fluid was withdrawn from each animal through a widebore needle and centrifuged at once, and the optical extinction of the Supernatant was measured in a Klett Summerson model 800-3 photophotometer using a green filter and a saline blank. In earlier experiments the optical extinction was measured with a Beckman model DU spectrophotometer at 615 mp against a saline blank, but subsequent experience showed that equally reliable results were obtained with photophotometry, so the latter was employed for most of this work.Culculation of the results. The mean optical extinction for each group was calculated, together with the standard deviation of the mean, and the mean expressed as a percentage of the value obtained with the control group. This is referred to as the mean per cent. optical extinction. Where a compound was tested for antiinflammatory activity it was administered in a range of doses or concentrations and a graph plotted of the mean per cent. optical extinction against the dose or concentration. From this graph the dose or concentration corresponding to a mean per cent. optical extinction of 50 per cent. m a y be found, and this is termed the ED50 dose or concentration.Substances that reduce the dye accumulation due to intraperitoneal injection of suline are said to show inhibitory activity. h PATH. BAcT.--voL. 85 (1963) 361 362 B. J. NORTHOVER Substances used. Saline is 0.9 per cent. sodium chloride in freshly distilled water. The Tyrode solution contained NaClO.8 per cent., KCl 0.02 per cent., CaCl2 0.02 per cent., Mfl2 0.01 per cent., NaHCO3 0.1 per cent...

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The Relative Potencies of Some Substituted Salicylic Acids as Metabolic Stimulants in the Intact Rat

Cited by 6 publications

References 12 publications

The Effects of Noncalorigenic Congeners of Salicylate on the Peripheral Metabolism of Thyroxine*

The Effects of Noncalorigenic Congeners of Salicylate on the Peripheral Metabolism of Thyroxine*

Salicylate and Liver Glutathione

The permeability to plasma proteins of the peritoneal blood vessels of the mouse, and the effect of substances that alter permeability

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