593

(approximately + 16%) represents abnormal thyroidenlargement or that the mean thyroid size is greater by16% in Nithsdale children.

Geographical variations, both national and local, in

goitre incidence in children and adults in the British Isleshave been a regular feature of previous careful surveys(Stocks 1928, Erskine 1933, O’Shea 1946, Murray et al.1948, Hughes et al. 1959, Trotter et al. 1962, Kilpatricket al. 1963) and the higher prevalences have almost

invariably been found in rural areas where other thyroidabnormalities may have a persistently high incidence.Wilkes’ (1966) survey in Derbyshire emphasises this.More than 100 years ago Mitchell (1862) described

goitre in the Nithsdale Valley and the condition seemedto be common enough to merit the term " Nith neck ".Local physicians still refer to this term in describingthyroid enlargement in this area (Laurie and Drainer1967). Other small geographical pockets of endemic

goitre in Scotland have been described in the last century(Sloan 1883, McKenzie 1899, Ogilvy 1911, McKay1914-17).The aetiology of the goitres found in the present study

is not known. In a detailed study of 172 pairs of twins,aged from 12 to 70 years (mean, 21-7 years) from theGlasgow area, the aetiological importance of genetic pre-disposition, autoimmunity, and iodine deficiency as causesof simple goitre were evaluated. None of these factorswere found adequately to correlate with the presence ofgoitre (McGirr 1966, Greig et al. 1967). The only positiveconclusion derived from this study was that goitre in youngpeople is related to a non-genetic female endocrineinfluence. Our results are consistent with this conclusion,goitre being positively related to the age range 11-15 yearsand to the female sex, in Glasgow and Dumfries where theprevalence of goitre was relatively low.The selectively greater prevalence of goitre in pubertal

females than in pubertal males is likely to be relevant tothe persistence of goitre in adulthood, in which the

female/male ratio is high. Whether during and after

puberty the female endocrine influence is progoitrogenicor the male endocrine influence antigoitrogenic has,however, yet to be determined. The difference is so

striking as to make it unlikely that differences in thyroid-hormone requirements and in iodine requirements alonewould account for it.The higher prevalence of goitre in Nithsdale is not

associated with a difference in prevalence among femalesand males up to the age of 15 years. This, together withthe possibility that goitre has been more prevalent in thisarea for more than 100 years notwithstanding populationmigration, suggests that an extrinsic factor is mainlyresponsible for the thyroid enlargements in this rural area.The lack of a preponderance of goitre in the Nithsdalefemale children may favour the hypothesis that anyintrinsic goitrogenic endocrine influence present inadolescence has been preceded by and relegated to asubsidiary role because of the life-long effects of anextrinsic or environmental factor.

Comparative studies are now being made to determinewhether this excess of goitre prevalence in Nithsdale isdue to correctable factors such as iodine-deficiency state(Crooks et al. 1964, Wayne et al. 1964), or of goitrogenicsubstances in the flora, milk, and water of the region(Clements 1960, Peltola 1960, Kilpatrick and Wilson1964).We thark Dr. T. S. Wilson, principal medical officer, School

Health Service, Glasgow, Dr. S. K. Drainer, medical officer of health,

County of Dumfries, and the staffs of all the schools for their generoushelp and cooperation; Dr. J. Laurie, senior physician, Dumfries andGalloway Royal Infirmary for his interest and advice. W. R. G. is inreceipt of a grant from the Wellcome Trust and E. M. McG. a grant,A.M. 05444 End., from the U.S. Public Health Service.

Requests for reprints should be addressed to W. R. G., UniversityDepartment of Medicine, Royal Infirmary, Glasgow C.4.

REFERENCES

Annual report of National Food Survey Committee (1966). Domestic FoodConsumption and Expenditure for 1964-1966. H.M. Stationery Office.

Clements, F. W. (1960) Br. med. Bull. 16, 133.Crooks, J., Aboul-Khair, S. A., Youngson, A. (1964) Scott. med. J. 9, 433.Erskine, F. M. (1933) J. State Med. 41, 672.Greig, W. R., Boyle, J. A., Duncan, A., Nicol, J., Gray, M. J. B., Buchanan,

W. W., McGirr, E. M. (1967) Q. Jl Med. (in the press).Harden, R. McG., Alexander, W. D., Harrison, M. T. (1964) Br. med. J.

i, 1419.Hughes, D. E., Rodgers, K., Wilson, D. C. (1959) ibid. i, 280.Kilpatrick, R., Milne, J. S., Rushbrooke, M., Wilson, E. S. B., Wilson, G. M.

(1963) ibid. i, 29.— Wilson, G. M. (1964) in The Thyroid Gland (edited by R. Pitt-

Rivers and W. R. Trotter); vol. II, p. 88. London.Laurie, J., Drainer, S. K. (1967) Personal communication.McGirr, E. M. (1966) in Symposium on Advanced Medicine (edited by

J. R. Trounce); p. 253. London.McKay, N. (1914-17) Caled. med. J. 10, 71.McKenzie, D. (1899) Glasg. med. J. 1, 15.Mitchell, A. (1862) Br. for. med. chir. Rev. 29, 502.Murray, M. M., Ryle, J. A., Simpson, B. W., Wilson, D. C. (1948) Med.

Res. Coun. Memo. no. 18.Ogilvy, S. G. (1911) Thesis, University of Glasgow.O’Shea, E. M. (1946) Irish J. med. Sci. 251, 749.Peltola, P. (1960) Acta endocr., Copenh. 34, 121.Sloan, A. T. (1883) Edinb. med. J. 29, 30.Spence, A. W. (1952) Br. med. J. ii, 529.Stocks, P. (1928) Q. Jl Med. 21, 223.Taylor, S. (1953) J. clin. Endocr. 13, 11, 232.

— (1960) Br. med. Bull. 16, 102.Trotter, W. R. (1962) Diseases of the Thyroid. Oxford.

— Cochrane, A. L., Benjamin, I. T., Miall, W. E., Exley, D. (1962)Br. J. prev. soc. Med. 16, 16.

Wayne, E. J., Koutras, D. A., Alexander, W. D. (1964) Clinical Aspects ofIodine Metabolism. Oxford.

Wilkes, E. (1966) Lancet, ii, 959.Wilson, G. M. (1963) in The Thyroid and its Diseases (edited by A. S.

Mason); p. 64. London.

EFFECTS OF OCTANOIC ACID ON SERUM-LEVELS OF FREE FATTY ACIDS, INSULIN,

AND GLUCOSE IN PATIENTS WITH

CIRRHOSIS AND IN HEALTHY VOLUNTEERS

WILLEM G. LINSCHEERM.D. Leyden

ASSISTANT PROFESSOR OF MEDICINE

DENNIS SLONEM.D. W’srand

SENIOR INSTRUCTOR IN MEDICINE

THOMAS C. CHALMERSM.D. Columbia

PROFESSOR OF MEDICINE

TUFTS UNIVERSITY SCHOOL OF MEDICINE,BOSTON, MASSACHUSETTS, U.S.A.

From the Divisions of Gastroenterology and Clinical Pharmacologyof the Medical Service of the Lemuel Shattuck Hospital, Depart-ment of Public Health, Commonwealth of Massachusetts, and

Tufts University School of Medicine, Boston, Massachusetts

Summary The effects of intraduodenal infusions of

glucose and octanoic acid on the serum-levels of glucose, free fatty acids (F.F.A.), and insulin havebeen determined in four healthy volunteers and in fivepatients with cirrhosis. Serum-insulin levels rose in both

groups during glucose infusions but the rise was signifi-cantly greater when octanoic acid was added. This effectdid not seem to be mediated by the serum-glucose becausethe addition of octanoic acid did not affect this level.Serum-F.F.A. levels fell in both groups but the inclusionof octanoic acid had no effect on the rate of fall of serum-F.F.A.

594

Introduction

IMPAIRED glucose tolerance with elevated fatty-acidlevels has been described in patients with obesity (Karamet al. 1965), maturity-onset diabetes (Laurell 1956,Bierman et al. 1957, Randle et al. 1963), acromegaly(Karam et al. 1965), and cirrhosis (Reinberg and Lipson1950, Dole 1956, Stormont et al. 1961). Randle et al.

(1963) suggested that the elevated serum-free-fatty-acid(F.F.A.) levels common to all of these diseases may con-tribute in part to the reduction in glucose toleranceobserved. Furthermore, glucose tolerance has been shownto be impaired in healthy individuals when serum-F.F.A.has been raised by a high fat intake followed by intra-venous heparin (Schalch and Kipnis 1965). We haveinvestigated hepatic glucose production as a factor in

regulating glucose tolerance in the presence of a F.F.A.flux. A rapid increase of fatty acids in the portal circula-tion was obtained by adding a medium-chain fatty acid(M.C.F.A.) to a duodenal infusion of glucose. M.C.F.A.S

were used because they are transported from the gut bythe portal venous system (Kiyasu et al. 1952, Playoust andIsselbacher 1964, Greenberger et al. 1966), in contrast tolong-chain fatty acids which are absorbed via the

lymphatics. Thus the enteral administration of M.C.F.A.gives rise to the portal perfusion of the liver with thesefatty acids and results in acute quantitative as well asqualitative changes of the fatty acids in the portalcirculation.

Volunteers, Patients, and MethodsVolunteers and PatientsFour healthy male volunteers, aged between 20 and 35,

without any family history of diabetes mellitus were used ascontrols. Diabetes mellitus was excluded by performing an oralglucose tolerance test (100 g.).

Five patients with moderately severe cirrhosis of the liverwere investigated. None had a clinical history of diabetes or ofglycosuria (table i). We included patients with cirrhosis

TABLE I-CLINICAL DATA ON THE PATIENTS WITH CIRRHOSIS

because we had found significantly higher serum-octanoic-acidlevels after intraduodenally infused octanoic acid in such

patients than in non-cirrhotic patients (Linscheer, Patterson,Moore, Clermont, Robins, and Chalmers 1966).Experimental DesignTwo glucose infusions were performed in all subjects.

Octanoic acid was added to one of the two infusions in randomorder. Serum glucose, insulin, octanoic acid, and total F.F.A.were determined before, during, and after the infusion pro-cedure. Octanoic acid alone was infused in two cirrhotic

patients.Technique of Duodenal InfusionA one-lumen tube (diameter 6 mm.) was passed into the

proximal duodenum and positioned under fluoroscopic control.After the tube was properly situated, a test solution wasinfused for 60 minutes at a constant rate of 6 ml. per minute

by means of a Holter infusion pump. The order of the infusion

Fig. 1-Regression lines (x on y and y on x) for the ratio of octanoic-acid concentration (0-60 tg. per mi.) to 20 (g. nonanoic acid per ml.and the ratio of the peak heights on the gas/liquid chromatogram.x=0’0874+0’8724y; y= -0’0613+ 1.1135x.

was randomly selected and was performed on different days.At the end of the 60-minute infusion period the tube wasremoved. Blood-samples for the determination of serum-total-F.F.A., octanoic acid, glucose, and insulin were drawn before,at 10-minute intervals during the 60-minute infusion period,and during the first 2 hours after the removal of the tube

(15-minute intervals during the first hour and 30-minuteintervals during the second hour).Infusate

Both test solutions contained glucose (138-9 mg. per ml.),sodium-taurocholate (20 mg. per ml.), and sodium chloride(8-5 mg. per ml.) in water; one solution also contained octanoicacid (10 mg. per ml.).Analysis of Serum-total-F.F.A.The Dole method was used when no M.C.F.A.S were present

(glucose infusion without octanoic acid). A modification of theDole method in combination with quantitative gas/liquidchromatography was used when octanoic acid was also presentin serum.

Serum (1 ml.) was extracted by 5 ml. isopropanol/heptane/N sulphuric-acid, 4/10/1 (v/v). The heptane layer was thenseparated by the addition of water (2 ml.) and heptane (3 ml.).The upper phase (3 ml.) was titrated with 0-015 N sodium-hydroxide solution as described by Dole. The long-chainF.F.A. fraction of the serum was completely extracted by thisprocedure but only a partial extraction (58%) was obtained foroctanoic acid. In the absence of octanoic acid a single standard,palmitic acid was used to express the long-chain F.F.A.. in

tieq. per litre. The serum-F.F.A. is then the product of thenominal value and the ratio of titration equivalents of unknownand palmitic-acid standards. This calculation is invalid ifoctanoic acid is also present in serum since this acid is

incompletely extracted by this method.The serum-octanoic-acid fraction was measured by quan-

titative gas/liquid chromatography. The octanoic aciddetermined by this method is expressed in Eq. per litre andconverted into Eq. sodium hydroxide per litre, using theoctanoic-acid standard. This is then subtracted from the totalamount of sodium hydroxide used for the simultaneous titrationof octanoic acid and long-chain F.F.A. extracted from serum(1 ml.). The difference is the long-chain F.F.A. fraction andcan be expressed as Eq. per litre using palmitic acid as astandard. Thus the long-chain F.F.A. and octanoic-acid serumfractions are known, and the sum of the two fractions will givea value for the total serum-F.F.A.

595

Determination of Serum-octanoic-acid by Quantitative Gas/liquidChromatographyAs an internal standard, nonanoic acid (20 g.) dissolved in

acetone (0-04 ml.) was added to each ml. of serum. The serum(1 ml.) was extracted by the Dole procedure (see above). Theinternal standard allows for correction for incomplete extractionof octanoic acid by the Dole method. After separation of theheptane layer the upper phase (3 ml.) was divided into threeportions each. Each portion was evaporated to dryness at 0°Cin vacuo by lyophilisation. The dry fatty-acid samples weredissolved in carbon disulphide and a fraction (0-5-1-0 (jd.) wasused for injection into the gas chromatograph. Octanoic acidin serum was calculated by using the ratios of peak heights(C8/C9) and the ratios of C8 and C9 (C8/C9) in serum (fig. 1).Since C9 in serum is constant (20 g. per ml.), concentrationof C8 can be calculated from the equation:

y== 0-0613 +1-1135x

_ .g. C8/ml. serum and peak height C8y fg. C9/ml. serum

and peak height C9Standard conditions were vaporiser temperature 260°C, columntemperature 180°C, detector temperature 230°C, nitrogenpressure 20 lb. per sq. in. Peaks were identified by retention-time and standards.

Insulin MeasurementsSerum-insulin was measured by an immunoassay method

(Soeldner and Slone 1965). To test a possible effect of octanoicacid on serum-insulin determinations, octanoic acid (20-200 tieq. per litre) was added to pooled serum, containing44 i.u. of insulin. No detectable effect of octanoic acid on theinsulin measurements was observed.

Glucose Measurements

True serum-glucose was measured by the glucose-oxidasetechnique (Washko and Rice 1961).Statistical Analysis

Since octanoic acid has a high absorption-rate and ismetabolised immediately (Schwabe et al. 1964), a statisticalanalysis was performed on the glucose and insulin dataobtained during the infusion period (0-60 minutes). Theserum-F.F.A. levels decreased after 10 minutes and the

regression lines were calculated for the period between 10 and80 minutes. Regression lines representing the correlationbetween serum glucose, insulin, and total F.F.A. concentrationsand time were expressed by the formula y=a+bx (r>0-9 inall instances). The effect of octanoic acid was measured bydetermining differences between the slopes of the regressionlines and the standard error of the differences.

ResultsSerum-glucose Response

In all four volunteers a rise of approximately twice thefasting levels of glucose occurred during the duodenalinfusion. A return to preinfusion levels of serum-glucosewas reached 45 minutes after the tube had been removed.The addition of octanoic acid to the infusate did notresult in significant differences in glucose levels (fig. 2,table 11).

In four of the five cirrhotic patients, serum-glucose rosewithin 10 minutes of starting the infusion. Serum-

glucose levels were still elevated 45 minutes after dis-continuation of the infusion in all five patients. Theaddition of octanoic acid to the infusion did not change theserum-glucose concentrations (fig. 2).Serum-insulin Response

All four volunteers had fasting serum-insulin levelsbetween 2 and 24 i.u. per ml. A rise in insulin levelsconcomitant with glucose changes occurred in all cases.In no instance did the serum-insulin exceed 150 l.u. perml. (fig. 2). A return to fasting levels of insulin occurred45 minutes after removal of the duodenal tube in all cases.This corresponded to the return of normal glucose levels.

The addition of octanoic acid to a second infusion ofglucose resulted in significantly higher insulin levels

(p < 0’01).Two of the five cirrhotic patients had elevated fasting

serum-insulin levels. A rise in serum-insulin occurred inall patients. The maximum rise for each patient did notexceed 160 jjn.u. per ml. Addition of octanoic acid to theinfusion resulted in peak levels greater than 160 l.u. perml. in four of the five patients studied. As in the volun-teers, the insulin levels were significantly higher (p < 0-01)

Fig. 2-Changes in serum levels of insulin, glucose, and free fattyacids in controls and in cirrhotic patients receiving glucose withnv without notslnoic acid.

596

TABLE II&mdash;CHANGES IN SERUM GLUCOSE, INSULIN, TOTAL F.F.A., AND OCTANOIC ACID FROM FASTING LEVELS DURING INTRADUODENALINFUSION OF GLUCOSE (A) AND GLUCOSE AND OCTANOIC ACID (B)

when octanoic acid was demonstrable in the systemiccirculation. As observed with glucose alone, a delayedreturn of insulin to preinfusion levels was noted (table 11,fig. 2).Serum-total-F.F.A.

Serum-total-F.F.A. levels fell in all volunteers during theglucose infusion (fig. 2, table 11). The lowest level wasreached between 15 and 30 minutes after the glucoseinfusion had stopped and when serum-glucose was

receding from the maximal levels reached. 2 hours after

ending the infusion the serum-total-F.F.A. had reboundedto fasting levels in all cases. The inclusion of octanoicacid had no significant effect on the rate of fall of theserum-F.F.A. (P < 0-5).A fall in serum-total-F.F.A. level occurred in all cirrhotic

patients during the glucose infusion. The lowest level wasreached between 60 and 90 minutes after the terminationof the glucose infusion. The addition of octanoic acid tothe glucose infusion did not result in a significant differ-ence (0-10> p > 0-05) (fig. 2, table 11).Serum-octanoic-acid ResponseNo measurable levels of octanoic acid were detectable

in the four volunteers during the glucose infusion. Whenoctanoic acid was added to the glucose infusion allvolunteers showed measurable levels of octanoic acidwithin 10 minutes of the beginning of the infusion. Amaximum concentration was observed within 30 minutesand a return to fasting levels occurred within 45 to

60 minutes after discontinuation of the infusion procedure.In all five cirrhotic patients no measurable levels of

octanoic acid were detected during the glucose infusionalone. Addition of octanoic acid to the infusate resultedin detectable amounts of octanoic acid in the serum within10 minutes of beginning the infusion. After discontinua-tion of the infusion, a return of fasting levels of octanoicacid was delayed as compared to the volunteers.

Octanoic Acid Infused Alone by Intraduodenal TubeTwo patients with cirrhosis were investigated. No

change in glucose or insulin concentration was detectedthroughout the infusion. Serum-octanoic-acid levels wereobserved which were identical with those of cirrhotics

given an infusion containing octanoic acid plus glucose.Discussion

The addition of small amounts of octanoic acid tointraduodenal infusions of glucose (50 mg.) resulted inelevated levels of serum-immunoreactive-insulin as com-

pared with intraduodenal glucose infusions alone. Thiswas true of both healthy volunteers and patients withcirrhosis of the liver. This effect is probably not

accounted for by a rise in serum-glucose, since no sig-nificant difference in glucose concentrations was observed.It is of interest to note that the serum-insulin rose onlyduring the period of octanoic-acid absorption and it isconceivable that a causal relationship exists.The finding that the serum-glucose levels remained

unchanged during the paired infusion experimentssuggests that octanoic acid did not alter the hepaticproduction of glucose.Although the slopes of the regression lines of the

fatty-acid levels were not significantly different, the

fatty-acid levels were probably higher during the octanoic-acid infusion (fig. 2). These slight differences in F.F.A.levels may have been responsible for the observed increaseof serum-insulin concentrations, although in the experi-ments described by Schalch and Kipnis (1965), the glucosetolerance and plasma-insulin levels were affected only bydrastic increases in serum-F.F.A.

If the elevation of serum-insulin is not accounted forby the slight rise of F.F.A. during the octanoic-acidinfusion, it is.possible that octanoic acid exerted a directstimulatory effect upon the pancreas, or alternativelystimulated the release of an unknown factor in the bowel

597

wall which then affected the release of pancreatic insulin.It is interesting that Horino et al. (1966) have observed arise in serum-insulin in sheep in response to the intra-venous infusion of short-chain fatty acids. This rise alsooccurred in the presence of unchanged serum-glucose levels.

It has been suggested that the formation of serum-ketoacids, after the administration of the M.C.F.A.s, areresponsible for the stimulation of insulin secretion

(T’Yangkul et al. 1965). We did not measure serum-ketoacids.The cirrhotic patients showed significantly higher levels

of serum-glucose, insulin, and F.F.A., but the two groupswere not age-matched and as glucose tolerance decreasesin the older age-groups no conclusions are drawn(Streeten et al. 1965).We thank Nel de Groot, Brigita Krastins, and Janny Brussee for

performance of the laboratory determinations; Anne Long andMargaret Wilcox and the nursing staff for taking care of the patientson the metabolic ward; and Rasma Klints and Dr. Hugo Muenchfor their assistance in the statistical analysis. This investigation wassupported by contract no. DA-49-193-MD-2707 between TuftsUniversity and the Office of the Surgeon General, Department of theArmy, Washington, D.C., by research-grant nos. AM-03729,AM-07417, and HE-5616 of the U.S. Public Health Service.

Requests for reprints should be addressed to D. S., Divisionof Clinical Pharmacology, Lemuel Shattuck Hospital, Boston,Massachusetts 02130, U.S.A.

REFERENCES

Bierman, E. L., Dole, V. P., Roberts, T. N. (1957) Diabetes, 6, 475.Dole, V. P. (1956) J. clin. Invest. 35, 150.Greenberger, N. J., Rodgers, J. B., Isselbacher, K. J. (1966) ibid. 45, 217.Horino, M., Machlin, L. J., Hertelendy, F. A., Kipnis, D. M. (1966)

Unpublished.Karam, J. H., Grodsky, G. M., Pavlatos, F. C., Forsham, P. H. (1965)

Lancet, i, 286.Kiyasu, J. Y., Bloom, B., Chaikoff, I. L. (1952) J. biol. Chem. 199, 415.Laurell, S. (1956) Scand. J. clin. Lab. Invest. 8, 81.Linscheer, W. G., Patterson, J. F., Moore, E. W., Clermont, R. J., Robins,

S. J., Chalmers, T. C. (1966) J. clin. Invest. 45, 1317.Playoust, M. R., Isselbacher, K. J. (1964) J. clin. Invest. 43, 878.Randle, P. J., Garland, P. B., Hales, C. N., Newsholme, E. A. (1963)

Lancet, i, 785.Reinberg, M. H., Lipson, M. (1950) Ann. intern. Med. 33, 1195.Schalch, D. S., Kipnis, D. M. (1965) J. clin. Invest. 44, 2010.Schwabe, A D., Bennett, L. R., Bowman, L. P. (1964) J. appl. Physiol.

19, 335.Soeldner, J. J., Slone, D. (1965) Diabetes, 14, 771.Stormont, J. M., Mackie, J. E., Davidson, C. S. (1961) Proc. Soc. exp. Biol.

Med. 106, 642.Streeten, D. H. P., Phil, D., Gerstein, M. M., Marmor, B. M., Doisy, R. J.

(1965) Diabetes, 14, 579.T’Yangkul, P., Hashim, S. A., Van Itallie, Th. B. (1965) ibid. p. 448.Washko, M. E., Rice, E. M. (1961) Clin. Chem. 7, 542.

THERAPEUTIC HAZARDS OF

PHENYLBUTAZONE AND OXYPHENBUTAZONEIN POLYMYALGIA RHEUMATICA

BENGT WADMANM.D. UppsalaPHYSICIAN

IVAR WERNERM.D. Uppsala

ASSOCIATE PROFESSOR

DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF UPPSALA, SWEDEN

POLYMYALGIA RHEUMATICA and temporal arteritis areaccepted nowadays as different manifestations of a dis-seminated arteritis. In most cases of temporal arteritis thediagnosis is obvious at the first examination of the patient.In patients with primarily myalgic symptoms, however,the diagnosis is often obscure for a long time, and theselection of patients for treatment with corticosteroids-the only available treatment that can protect againstocular complications-is difficult. Visual loss is uncom-mon in myalgic patients, initially free from headache but,according to Olhagen (1963) and Balmforth (1964), thiscan happen. Thus, the observation of extracranial

arteritis in myalgic patients must be of definite clinicalimportance; patients with suspected polymyalgia rheu-matica should be instructed to report immediately to theirdoctor if they have thickening or pain in the distributionof the temporal artery. We have seen polymyalgic dis-orders develop into typical temporal arteritis in four

patients undergoing therapy with phenylbutazone or

oxyphenbutazone. One patient had partial loss of visionin one eye. Though all four patients were completelyrelieved of their myalgic pains by these drugs, theircontinued use, by masking progression of the disease,creates a hazard.

The PatientsCase 1A woman, aged 57 years, with no history of earlier rheumatic

disease, had headache and muscular pains in her calves for ashort while in 1962. In January, 1963, the pain in her calveswas so bad that she could not get out of her bed. She felt verytired and her temperature was slightly raised. The erythrocyte-sedimentation rate (E.S.R.) was 47 mm. in the first hour

(Westergren); plasma-fibrinogen 0-8 g. per 100 ml. Oxyphen-butazone was given in a dose of 600 mg. a day for 2 days andthen reduced to 300 mg. a day. During the week of treatment,the patient had no muscular pains; her temperature was stillraised, however, and her E.S.R. was almost doubled to 91 mm.A temporal-artery biopsy specimen on microscopy was

suggestive of arteritis. Prednisone was given instead of

oxyphenbutazone, and within a few days the temperature andE.S.R. returned to normal.

Case 2A man, aged 70 years, was admitted to another hospital in

January, 1965, on account of bitemporal headache and fever;his E.S.R., was 100 mm. in the first hour. After 3 days onphenylbutazone 600 mg. a day his temperature was normal andhe was completely relieved of his pains. 4 days after he leftthe hospital he was still free of pain when he noticed a defect ofthe visual field of his left eye. He returned to the hospitalwhere now a bilateral thickening of his temporal arteries couldbe detected. Ophthalmoscopy revealed oedema of his left opticdisc. The E.S.R. was 129 mm. The patient was sent to ourclinic where biopsy of a temporal artery established thediagnosis of arteritis. The E.S.R. decreased rapidly with

prednisolone therapy, but the visual-field defect was irre-versible. In August, 1965, the treatment was interrupted bymistake; this was rapidly followed by a return of headache,fever, and raised E.S.R. The symptoms again rapidly subsidedon reinstitution of steroid therapy.Case 3A woman, aged 68 years, was taken ill in August, 1965, with

severe pains in the back of her neck, both knee-joints, and leftshoulder. She also felt very tired and had lost 12 kg. of weight.The E.s.R. was 80 mm. in the first hour. Her temporal arterieswere examined several times without any abnormal findings.All pain disappeared after treatment with oxyphenbutazone300 mg. a day, subsequently reduced to 100-200 mg. a daywithout a return of the pain. In October-8 weeks after the

therapy was started-we felt circumscribed thickening inrelation to the branches of the temporal arteries. Micro-scopically, there was a typical giant-cell arteritis. The E.S.R. atthe time of biopsy was 44 mm. The thickening disappearedwith prednisone therapy, and the general condition of thepatient improved rapidly.Case 4A woman, aged 75 years, was in hospital in July, 1965, on

account of hasmatemesis, probably due to epistaxis. The E.S.R.was 80 mm. in the first hour; this induced a thorough search formalignancy without positive findings. Within a week of her

leaving the hospital, she was almost totally immobilised bydiffuse myalgic pains over all her extremities and trunk,including the back of her neck. The E.S.R. was 115 mm. Bothtemporal arteries were normal on palpation. Oxyphenbutazonewas given in a dose of 600 mg. a day, reduced after a few days

L3