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Home , Salicin, Salicylamide

Postgrad Med J: first published as 10.1136/pgmj.28.317.179 on 1 March 1952. Downloaded from I79

SOME NEW IN THE TREATMENT OF RHEUMATIC FEVER By M. J. H. SMITH, M.PHARM., PH.D., F.R.I.C. Department of Chemical Pathology, King's College Hospital Medical School, London

Introduction every 4 to 8 hours. Symptoms such as dizziness, The usefulness of salicylates in rheumatic fever drowsiness and nausea developed in a small pro- is unquestioned, though their undesirable side- portion of the subjects, but in no instance were effects on the gastro-intestinal tract and on the these side-effects serious. The substance differed special senses are a drawback in prolonged therapy. from in producing a depression of Attempts to find allied substances with a greater the central nervous system in laboratory animals safety margin have been made and three com- and a decrease in the prothrombin time in man. pounds, , sodium gentisate and The favourable clinical reports have led to the y-resorcylic acid, have recently been introduced. proposal that a large well-controlled trial should The treatment of rheumatic fever with ACTH be made.6 and cortisone has been the subject of a number of general reviews1' 2 and will not be discussed in the Gentisic Acid (2: 5-dihydroxybenzoic acid) present article. The cost and scarcity of these COOH by copyright. materials have stimulated a search for simpler compounds with a similar physiological action and a cinchoninic acid derivative (HPC) for which an ACTH-like activity is claimed, has been tried \AOH clinically in acute rheumatic fever. It has been HO-- postulated that salicylates themselves exert their therapeutic effects by stimulation of the pituitary Gentisic acid is a normal metabolite of salicylate and adrenal glands. This view that salicylates are in the body, occurring to the extent of 4 to 8 per a sort of chemical ACTH is not borne out by all cent. in urine. The substance was to in- reported http://pmj.bmj.com/ the available experimental evidence and must be hibit hyaluronidase activityin muchsmallerconcen- treated with reserve.3 trations than salicylate.7 The enzymehyaluronidase depolymerises hyaluronic acid which acts as an Salicylamide interfibrillar cement in the tissues, and it has been CONH2 suggested that there is increased hyaluronidase activity inrrheumatic disease.8 These considera- tions led to the introduction of the sodium salt of

/ uOH gentisic acid in the treatment of rheumatic fever. on September 27, 2021 by guest. Protected Favourable results in five cases were reported by Meyer and Ragan9 and supporting clinical %\/ evidence has been provided by American10 and The amide of salicylic acid foims a white French workers.11'12 The general opinion was crystalline powder which is sparingly soluble in that the substance appeared to be as active as water. Its chronic toxicity in animals is less than salicylate in controlling the manifestations of that of .4 Clinical trials of the in cases rheumatic fever and possessed the great advantage of rheumatoid arthritis, rheumatic fever, fibrositis of being virtually non-toxic. A suitable dosage is and osteoarthritis have been carried out. A 2 to 3 gm. at 4-hourly intervals (0.25- and o.5-gm. marked effect was observed in about tablets are available commercially), and no un- half of the 60 patients and a 'moderate' one in toward effects have been noticed with doses up about a quarter.5 Only seven cases of rheumatic to 20 gm. per day. A number of methods for the fever were treated, but the results were considered determination of plasma gentisate concentrations promising. The recommended dosage is 2 gm. are available.TM A point of difference from salicyl- Postgrad Med J: first published as 10.1136/pgmj.28.317.179 on 1 March 1952. Downloaded from I8o POSTGRADUATE MEDICAL JOURNAL March 1952 ates is that no reduction of the plasma alkali 0 reserve occurs in patients receiving gentisate t.-.----~--A m-_~ therapy. The absence of toxicity of gentisate is °\ /0"o a very valuable property and if its effectiveness in rheumatic fever .receives confirmation by large C H trials, then this drug should be an important oral therapy. /Il-O y-Resorcylic acid (2: 6-dihydroxybenzoic acid) COOH %/ If the formation of this type of ring structure, HO-j \-OH which is known as a chelate ring, is responsible 1I for the therapeutic activity of salicylates it was % / reasoned that the formation of a second chelate / ring in the molecule might enhance the activity; Salicylic acid is the only one of the three isomeric y-resorcylic acid can form a double chelate ring monohydroxybenzoic acids to possess any thera- and a trial of its action in rheumatic fever was peutic activity in rheumatic fever. An examina- therefore carried out.14 tion of the properties of salicylic acid and its m- and p-isomers was made to determine if any COOH essential difference in chemical structure existed which paralleled the therapeutic activities. HO- -OH COOH \ / %/ \i-OH y-resorcylic acid by copyright. 1/1 0 Salicylic acid (o-hydroxybenzoic acid) "\ ,/\ COOH H C H \ / ,/ \ \o-1 !1--oII 11 http://pmj.bmj.com/ >I-OH %./ %/ m-hydroxybenzoic acid Resorcylate ion COOH Sodium y-resorcylate in doses of one-tenth the usual therapeutic dose of salicylate had about the same action in rheumatic fever, but the undesir- II able side-effects seemed to be equally potentiated, on September 27, 2021 by guest. Protected though the lethal dose of y-resorcylate in animals % / was less than that of salicylate. The authors admit that, because no proportional reduction in OH the side-effects have been produced by the intro- p-hydroxybenzoic acid duction of the extra hydroxyl group, the substance may have little or no advantage over salicylate in Salicylic acid is a much stronger acid than the practice. other isomers and this has been attributed to the If salicylic acid is taken as the parent compound close proximity of the o-hydroxyl and carboxyl then the marked increase in therapeutic activity groups, the hydrogen of the OH group being due to the introduction of a second chelate ring, shared with the carboxyl group to form an as in y-resorcylic acid, is ofgreat theoretical impor- additional ring. The structure of the salicylate tance. In gentisic acid the extra hydroxyl group ion may be written as follows, the negative charge is situated in position 5 so that a second chelate being equally shared by the two carboxyl oxygens. ring is not possible and its effect seems to be a Postgrad Med J: first published as 10.1136/pgmj.28.317.179 on 1 March 1952. Downloaded from March 1952 SMITH: Some New: Drugs in the Treatment of Rheumatic Fever i8i reduction of the toxicity without affecting the the activity of rheumatic disease necessitates a therapeutic activity. somewhat empirical approach to the problem of developing new methods of treatment. A different H.P.C. (3-hydroxy-2-phenyl cinchoninic acid) reason was responsible for the introduction of each of the four substances discussed. Salicyl- COOH amide is a relatively simple derivative of salicylic /\ /\ acid, investigated in the hope that it would be / %\/-OH more active and less toxic, gentisate was considered promising because of its anti-hyaluronidase II activity, y-resorcylic acid was developed in an attempt to correlate the physico-chemical pro- N perties of salicylic acid with its therapeutic action and HIPC was discovered during a search for During the investigation of a series of cin- simpler compounds with an ACTH-like action. choninic acid derivatives as antidiuretics it was Some of the original hypotheses which led to the found that certain of these compounds caused a trial of these substances may well prove to be stimulation of the adrenal cortex.15 It was sug- untenable, but will have been of value if they gested that one of these substances, HPC, which produce a useful drug. Maclagan introduced showed a minimal toxicity in animal experiments.16 , the from the , in the was worthy of clinical trial in cases likely to benefit treatment of acute rheumatism in i87619 on the from a drug with ACTH-like properties. Ten basis that nature produces the remedy under patients with acute rheumatic fever were given climatic conditions similar to those which give the drug for periods up to 2I days, a dose of io or rise to the disease. This conclusion he derived 20 mg. per kg. body weight was given daily or on from the fact that trees of the Cinchonaceae grew alternate days. A rapid disappearance of the in areas where intermittent fever was joint pains and fever occurred and fol- readily relapses prevalent. by copyright. lowed withdrawal of the drug. Toxic effects were The theory that the chelate ring in salicylic acid few and consisted of nausea, vomiting and is important for therapeutic activity is most attrac- abdominal cramps.17 Four cases of rheumatic tive. The available information is limited, but fever were treated with similar doses of the drug the presence of this structure in salicylic acid, by Rennie, Milne and Sommerville18 who con- gentisic acid and HPC and the enhanced activity cluded that the substance was at least as good as due to two such rings in y-resorcylic acid is very and less toxic. Relapses The reduction of toxic effects when occurred in two suggestive. patients after withdrawal of the a hydroxvl group at position 5 is introduced into drug, the symptoms being relieved in one case the molecule of salicylic acid, as in gentisic acid, by aspirin and in the other by a further course of offers promising possibilities, and the activity and http://pmj.bmj.com/ HPC. The characteristic salicylic acid structure, toxic actions of a compound in which such a carboxyl and phenolic hydroxyl groups in ortho hydroxyl group had been introduced into the positions, is present in HPC and the formation molecule of y-resorcylic acid would be interesting. of a chelate ring is therefore possible. The four compounds which have been discussed are certainly developments in the treatment of General remarks acute rheumatic fever and controlled clinical The of the mechanisms concerned in large obscurity trials are now necessary for their assessment. on September 27, 2021 by guest. Protected REFERENCESJ I. LEADING ARTICLE, (i951), Lancet, ii, I2Io. 12. CAMELIN, A., STIEGER, R., MOREL, M., and TARY, A. 2. SAVAGE, 0. (I95 ), Postgrad. med. Y., 27, 73. (I950), Presse med., 58, 889. 3. MEADE, B. W., and SMITH, M. J. H. (i951), Lancet, ii, 224. I3. MEADE, B. W., and SMITH, M. J. H. (I95), J. clin. Path., Salicylamide 4, 226. 4. HART, E. R. (I947), J. Pharmacol., 89, 205. y-Resorcylic acid 5. LITTER, M., MORENO, A. R., and DONIN, L. (i951), Ibid., Ioi, 119. 14. REID, J., WATSON, R. D., COCHRAN, J. B., and 6. Annotation (I95I), Lancet, ii, 629. SPROULL, D. H. (195I), Brit. med. J., ii, 321. Sodium gentisate H.P.C. 7. MEYER, K., RAGAN, C., and WEINSHELBAUM, H. I5. BLANCHARD, K. C., DEARBORN, E. H., MOREN, T. H., (1948), Fed. Proc., 7, 173. and MARSHALL, E. (I95o), Bull. Johns Hopk. Hosp., 86, 83. 8. MEYER, K., and RAGAN, C. (1948), Mod. Concepts card. I6. MARSHALL, E. K., and DEARBORN, E. H. (I950), Ibid., Dis., 17, 2. 87, 36. 9. MEYER, K., and RAGAN, C. (1948), Science, Io8, 28I. I7. BLANCHARD, K. C., HARVEY, A. M., HOWARD, J. E., Io. SCHAEFER, L. E., RASHKOFF, I. A., and MEGIBOW, KATTUS, A., MARSHALL, E. K., NEWMAN, E. V., R.S. (I950), Circulation, 2, 265. and SUBROD, C. G. (1950), Ibid., 87, 50. I. CAMELIN, A., ACCOYER, P., PELLERAT, J., LAFUMA, I8. RENNIE, J. B,, MILNE, J. A., and SOMMERVILLE, J. J., and COIRAULT, R. (1949), Bull. Soc. med. Hop. Paris, (I951), Brit. med. J., i, 383. 65, 826. 19. MACLAGAN, T. (1876), Lancet, 1, 342.