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The Effect of 3-Methyl Salicylic (0-Cresotinic) Acid on Plasma

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The Effect of 3-Methyl Salicylic (0-Cresotinic) Acid on Plasma Diabetologia 7, 94--101 (1971) by Springer-Verlag 1971 The Effect of 3-Methyl Salicylic (0-Cresotinie) Acid on Plasma Insulin and Glucose Tolerance in Diabetic and Non-Diabetic Subjects D.E. HYAMS, A.N. HowAI~D, I.E. EVANS and S.H.H. DAVlSO~ Department of Geriatric Medicine, Chesterton Hospital, Cambridge; Department of Investigative Medicine, University of Cambridge ; West Suffolk Hospital, Bury St. Edmunds; University Department of Biochemistry and Addenbrooke's Hospital, Cambridge, Great Britain Received: April 6, 1970, accepted: October 24, 1970 Summary. Oral administration of 3-methyl salicylic prdvisible des taux plasmatiques de FFA k jeun. -- A acid (3MS) to diabetic and non-diabetic patients in cause des effets secondaires, le 31VIS n'a pas ~tg jugd modest doses (0.9--1.8 g/day) over several months pro- valable en rant qu'agent thdrapeutique. Les rgsultats duced a significant increase in plasma insulin levels, one cependant, sent d'intdr6t acaddmique, car c'est la pre- hour after a glucose load. In 2 diabetic subjects, acute miere d~monstration d'une glgvation de l'insuline plasmati- doses had a similar effect. -- Improvement in glucose que apr~s administration orMe d'un salicylate. tolerance after chronic administration of 3MS to diabetic patients was inconsistent, and could not be conclusively Wirleung der 3-Methyl-Salieyl (O-Kresotin) Sdure auf related to the action of the drug. Although acute doses of das Plasmainsulin und die Glucosetoleranz bei Diabetil~ern 31~{S caused a fall in plasma FFA after 3--6h, chronic and Nichtdiabetilcern treatment gave no predictable change in fasting plasma Die orale Zufuhr yon 3-iYiethyl-Salieyls~iure (31VLS) in FFA levels. -- Because of side effects, 3MS was not con- relativ niedrigen Dosen (0.9--1.8 g/Tag) an Diabetiker sidered suitable for introduction as a therapeutic agent. und stoffwechselgesunde Patienten fiber mehrere Mona- The results, however, are of academic interest since it is te ffihrte zu einem signifikanten Ansticg der Plasmain- the first demonstration of increased plasma insulin after sulinspiegel eine Stunde nach Glucosebelastung. Bei 2 Dia- an oral salicylate. betikern riefen akute Gaben einen ~hnliehen Effekt her- vet. -- Die Besserung der Glucosetoleranz nach chroni- Effet de l'aeide 3-m~thyl salicylique (O-crdsotinique) sur seher 3 MS Verabreiehung an Diabetiker war nur vorfiber- l'insuline plasmatique et la tolerance au glucose chez des gehend und konnte nicht init Sicherheit auf das 1Viedika- sujets diabdtiques et non-diabdtiques ment zurfickgeffihrt werden. Obwohl es 3--6 Std nach R~sumg. L'administration orale d'acide 3-mdthyl akuten Gaben yon 31V~S zu einem Abfall der FFS-Konzen- salieylique (3MS) k des sujets diab6tiques et non-dia- trationen im Plasma kam, 15ste die chronisehe Zufuhr kei- b6tiques, ~ faibles doses (0.9--1.8 g/jour) pendant ne vorhersagbaren Ver~nderungen.der FFS-Spiegel im plusieurs mois produisait une augmentation signifieative Nfichtern-Plasma aus. -- Wegen selner Nebenwirkungen des taux d'insuline plasmatique, une heure apr~s une erscheint uns die 3i~S zur Einffihrung in die Therapie charge ell glucose. Chez 2 sujets diabdtiques, des doses nicht als geeignet. Die Ergebnisse sind aber yon akademi- aigu~s avaient un effct semblable. -- Une am6lioration de schem Interesse, da mit ihnen zum ersten lVial ein Anstieg la tol6ranee au glucose, apr~s administration chronique de der Plasmainsulinspiegel naeh oraler Salicylatzufuhr nach- 3MS ~ des patients diabdtiques, n'a pas dtg ddcelde et n'a gewiesen werden konnte. pas pu ~tre relide ~ Faction de la drogue de fa~on con- eluante. Bien que des doses aigu~s de 31ViS provoquassent Key-words: 3-methyl salicylic acid, o-eresotlnie acid, une chute des FFA plasmatiques au bout de 3--6 hs, hydroxytoluie acid, plasma insulin, glucose tolerance, le traitement chronique ne causait pas de modification diabetes, plasma free fatty acids. The beneficial effect of salicylate in diabetes mel- Effective treatment of elderly diabetic patients by litus has been known for nearly a century. Large doses small doses of aspirin has been reported by Anderson of sodium salicylate (up to 16 g/day) reduced the and Thompson (1963) but this work is unconfirmed, glyeosuria and the symptoms in diabetic patients and the consensus of opinion is that a m~nimum of (Ebstein, 1876; Barrels, 1878; Williamson, 1901). Such about 5 g aspirin per day is the dose required to large doses produced marked toxic effects, and severe provide useful control of hyperglycaemia and glycos- diabetic acidosis and coma were not improved, so that ~ria. Reid and Lightbody (1959) found that toxic this treatment failed to become popular. effects were still troublesome at these dose levels, and From time to time, however, interest has been re- emphasised the need for control of the treatment by awakened in the possible value of salicylate therapy in plasma salicylate levels. diabetes mellitus. Lowering of blood sugar in diabetic Lightbody and Reid (1960) examined various patients given salicylate in smaller doses (5--8 g/day) salieylate compounds for their possible value in dia- was reported by Reid et al. (1957), Reid and Lightbody betes mellitus, and among these were acetyl-o-cresotinie (1959) and ttecht and Goldner (1959). Reid and his acid and sodium 3-methyl salicylate (orthocresotinate). colleagues showed that moderate ketonuria as well as These compounds had the advantage that, whilst their glyeosuria could be eliminated by aspirin therapy. hypoglyeaemie effect was similar to that of aspirin, D.E. Hyams et al. : The Effect of 3-Methyi Salicylic (0-Cresotinlc) Acid 95 they did not cause tinnitus or deafness. At a dosage of 50 g glucose tolerance test performed, starting 2 h after 5 g or more per day, other side-effects were still a a single dose of 900 mg 3MS orally. Preliminary tests on problem, and were attributed to the high serum o- fasting normal subjects had shown a maximum depres- cresotinate levels. Once again, therefore, this treatment sion of plasma FFA between 2 and 4 h after a dose of failed to gain acceptance. 900 mg 3MS, over the period of maximal plasma sali- The present paper is concerned with a new study of cylate levels (Fig. 2). 4 of the subjects were also tested 3-methyl salicylic (o-cresotinic) acid in diabetic and using a placebo (of low carbohydrate content) in place non-diabetic subjects. During the course of a study of of 3MS. At least one week elapsed between the two the effect of this salicylate compound on plasma chol- tests. 1 patient had normal initial glucose tolerance; esterol and free fatty acids (FFA) (Howard et al., the others were all abnormal, 4 being frankly diabetic. 1971), it occurred to us that the drug might have a significant effect on carbohydrate metabolism in doses smaller than those previously used. The half-life of 3MS in man is 19--22 h (Cummings 0 and Martin, 1965) and is not dose dependent. The half- lives of aspirin and sodium salicylate are of this order only when very large doses are given; with low doses, the half-life of aspirin or sodium salicylate is only 3--4 h (Cummings and Martin, 1964). It therefore oc 50 _ seemed that low or modest doses of 3MS might produce u significant effects on carbohydrate and lipid metab- olism without toxic side-effects. Our preliminary stud- ---- placebo ies on subjects with raised blood lipids showed that 3-MS small doses of 3MS (0.9 g/day) were well-tolerated and 100 I i I I I // 1 I ] 2 3 4 5 ]] h 12 a single dose produced a fall in plasma FFA lasting Each point represents the mean of 6values +-5.E.M. several hours (Nature, 1967; Howard etal., 1968). In view of current thought on the aetiology of diabetes mellitus and the relationship between glucose and FFA metabolism (Randle et al., 1963; Hales, 1966) it was decided to study the effect of 3MS in diabetic subjects. If improved glucose tolerance could beachievedwithout toxic side-effects, a further useful oral anti-diabetic agent would be available. v" { I l I I I 0 2 4 6 8 I0 h 12 Materials and Methods Fig. 2. Effect of a single dose of 31~IS (900 rag) on plasma salicylate and plasma FFA levels in fasting man 3.methyl salicylic acid, (ortho-cresotinic acid) has the formula shown in Fig. 1. Its approved name is hydroxytoluic acid. For convenience and to keep this Tests performed: On each blood specimen, blood paper in line with our other communications concern- glucose, plasma insulin and free fatty acid levels were ing this drug (Nature, 1967; Howard et al., 1968; determined. Blood glucose was determined by the Howard et al., 1971) we shall henceforth refer to it as glucose oxidase method using the Technicon auto- 3-methyl salicylic acid or 3MS. analyzer modified from Hill and Kessler (1961), plasma insulin by the immunoassaymethod (Hales and gandle, COOK 1963) and plasma FFA by the method of Dole (1956), after the heptane phase extracts had been washed with 2--3 ml 0.1% ferric nitrate in 0.04% nitric acid in order to avoid the interference of salieylates in the Fig. 1.3-methyl salicylic acid titration. Design of study. The study was performed in two b) Effect of single dose of 3MS on plasma insulin in parts. non-diabetic subjects I) "Acute" effect of 3MS on glucose tolerance and Two small studies were performed by taking serial plasma insulin blood samples at various times after administration of a single dose of 900 mg 3MS to fasting non-diabetic a) Glucose tolerance and plasma insulin. subjects. In the first study, there were 9 subjects given 5 patients attending the Department of Geriatric 3MS, and comparisons were made with 4 subjects given Medicine, Chesterton Hospital, Cambridge, had a 2 ~ h placebo (of low carbohydrate content) and 2 given 96 D.E.
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