540

STREPTOMYCIN REACTIONSRELATION TO EXERCISE

H. R. C. RICHESM.B. Lond., M.R.C.P.

RESIDENT MEDICAL OFFICER, BROMPTON HOSPITALSANATORIUM, FRIMLEY, SURREY

A RELATIVELY large number of patients experienceunpleasant symptoms within a few hours of an intra-muscular injection of streptomycin. In most of them these " reactions " are trivial, but in some they are

extremely unpleasant and may render the patientincapable of work.

Such reactions occur less commonly in patients restingin bed. Therefore the present investigation was under-taken to elucidate the cause of these reactions to strepto-mycin, with special reference to the part that exerciseplays in their aetiology.

Material

91 patients in the Brompton Hospital’ Sanatoriumwho were having, or had had, streptomycin were

questioned about whether streptomycin had affectedthem in any way. Leading questions were deliberatelyavoided as much as possible.The various unpleasant symptoms reported were

tingling paræsthesiæ in and around the mouth, vertigo,ataxia, headaches, lassitude, " muzziness in the head,"a sensation of tightness of the skin around the eyes,and difficulty in visual accommodation.

Of the 91 patients treated with streptomycin 31 (34%)complained of toxic symptoms on the day of injection.The frequency with which the various toxic symptomsoccurred was as follows :

The severity of the reactions was classified into threegrades (see table).The symptoms usually began within 1-3 hours of an

injection of streptomycin, and some or all persisted for1-24 hours.

InvestigationOf the 12 patients with moderate or severe reactions

8 complained that their symptoms were made worse bySEVERITY OF REACTIONS

exercise and relieved, partially or completely, by rest.It was therefore decided to investigate the serum-

streptomycin levels following an intramuscular injectionof streptomycin sulphate in 5 patients, both at restand during exercise.The serum-streptomycin levels at rest and during

exercise were determined on consecutive days for eachpatient. On the first day the patient rested in bed,and samples of venous blood were taken immediatelybefore and 1/2 hour, 11/2 hours, and 3 hours after anintramuscular injection of streptomycin sulphate 1 g. intothe buttock. The same procedure was repeated on the

following day, but with the patient ambulant and takingwalking exercise in the grounds of the Sanatorium.The serum-streptomycin levels were all determined

at the Brompton Hospital laboratory by the diffusionmethod of Mitchison and Spicer (1949).

Results

In all 5 patients the highest blood-streptomycin levelwas found during activity, the peak level occurring11/2 hours after the injection of streptomycin in 4 ofthe 5 patients. In the remaining patient the highestblood-streptomycin level was found 3 hours after theinjection.

3 patients had reactions only when they were active.and the time of onset of these reactions corresponded

Serum-streptomycin levels of 5 patients at rest and,during exercise-after intramuscular injection of streptomycin I g. : continuous line,during exercise ; interrupted line, at rest ; arrows mark onsetof reactions.

closely to the time that the streptomycin was reachingits peak level in the blood. 1 patient had a reactionwhilst resting, but this was less severe than that whichhe had during activity. The remaining patient had nt)reaction during the test.The serum-streptomycin levels of the 5 patients at

rest and during activity are shown in the accompanyingfigure.

Treatment

It is a common practice in sanatoria to give patientstheir injections of streptomycin first thing in the morning.before the start of the day’s activity. But, becauserest after the injection appeared to diminish or preventsubsequent reactions, 5 patients who experienced rear,tions were given their streptomycin at night, shortlvafter retiring to bed. With this regimen, 3 patieiii,obtained complete relief from symptoms and 1 was

considerably improved. The remaining patient (ca.,e’2. see figure) complained that he was not improv ed, becausehe was left with a headache the following morning.

Discussion

I have not been able to find any published report ot

transient, toxic reactions following intramuscular strepto-mycin as described here, nor any reference to theinfluence of exercise on the rate of absorption of intra-muscular streptomycin.

It is perhaps surprising that unpleasant symptomsoccurring as frequently as in this series should not haveattracted more attention. In many cases, of course.

the symptoms are only trivial ; but, even if these arr

ignored, there still remain a significant number (13°of patients in whom the reactions are more seriou-One can only suppose that in the past, when streptomycin was usually given in relatively short courses to

bed-patients, the reactions caused little concern. since.with the patient at rest, the blood-streptomycin lest-

! remains lower and there is less likelihood of reactions

541

With the present-day tendency to give long courses ofstreptomycin to ambulant patients, however, thesereactions become more important, especially if the

patients are to continue streptomycin therapy after

returning home and beginning work.The onset of a reaction appears to coincide fairly

closely with the peak blood-streptomycin level, whichM usually attained 1-11/2 hours after an injection inambulant patients. In this investigation all the reactionsbegan when the serum-streptomycin level had risen

higher than 30 µg. per ml.The effect of exercise on the rate of absorption of a

drug given intramuscularly does not appear to be fullyappreciated, since many papers citing serum-streptomycinlevels do not stipulate whether the patients investigatedwere resting or ambulant (Hunt and Fell 1949, Kornegayet al. 1946, Zini 1950). -

That activity should influence the rate of absorptionis quite logical, since it is well known that the blood-flowthrough a muscle, and the lymph return from it, are

both considerably increased with exercise. It is notunreasonable to suppose, therefore, that an injection ofstreptomycin given into the leg or the buttock will bemore quickly absorbed in an ambulant patient than inone who is resting. This supposition has been confirmedin 4 of the 5 cases so far investigated. The more rapidabsorption of streptomycin during activity and the higherblood-streptomycin levels attained, may be factors inthe aetiology of these reactions.The study of a larger series of cases is being undertakento establish the best method of preventing these

impleasant reactions. Meanwhile the findings in thissmall series strongly suggest that a period of rest followingthe administration of streptomycin may be of benefitto those patients who experience reactions. This can beachieved quite simply by giving the injections in theevening.

SummaryOf 91 patients treated with intramuscular strepto-

mycin 31 (34%) complained of toxic symptoms withina few hours of the injection.These reactions occurred less commonly when patients

were resting.The blood-streptomycin level during exercise is

generally higher than that found during rest.A period of rest following the administration of

streptomycin may be of benefit to those patients whoexperience reactions.I wish to thank the physicians of Brompton Hospital for

permission to investigate their patients ; Dr. J. L. Livingstoneand Dr. A. F. Foster-Carter for the encouragement andadvice they gave me during this investigation ; Dr. J. W.

Clegg for granting me laboratory facilities at the BromptonHospital; and Mr. F. J. Baker and Miss M. A. Swan, of thebacteriology department, Brompton Hospital, for doing allthe technical work.

" If statistics or information about road accidents could, bythemselves, prevent casualties the roads would indeed be safe.If every thousand words written about them could save a lifethere would be few if any fatal accidents during the year.But the casualty rate still mounts. One hundred and eightythousand killed or injured in 1949, two hundred and sixteenthousand in 1951, two hundred and twenty-six thousand in1953. The greater the number of casualties the more doeseach organisation of road users try to impute the blame toothers. Progress will be only slow and halting if individualsand organisations alike see the primary solution of the problemas someone else’s responsibility."-The Price of Road Safety,Planrtirtg, March 10, 1954. Published by P.E.P, 16, QueenAnne’s Gate, London, S.W.I.

REFERENCES

Hunt, A. D. jun., Fell, M. B. (1949) Pediatrics, 4, 163.Kornegay, G. B., Forgacs, J., Henley, T. F. (1946) J. Lab, clin. Med.

31, 523.Mitchison, D. A., Spicer, C. G. (1949) J. gen. Microbiol, 3, 184.Zini, F. (1950) Acta med. scand. 136, 209.

CORTICOTROPHIN ZINC PHOSPHATE

AND HYDROXIDELONG-ACTING AQUEOUS PREPARATIONS

J. D. H. HOMANPh.D. Groningen

J. P. J. NEUTELINGS

G. A. OVERBEEKPh.D. Leiden

C. J. BOOIJ

J. VAN DER VIESFrom the Research Laboratories of N. V. Organon, Oss, HollandVARIOUS attempts have been made to produce prepara-

tions of adrenocorticotrophic hormone (corticotrophin)with increased or prolonged action, so as to obtain moreefficient utilisation of corticotrophin after either intra-muscular or subcutaneous injection. In these preparationscorticotrophin is combined with different and more orless complex substances which delay absorption (Wolfsonet al. 1951, Raben et al. 1952, Fletcher and Williams

1952, Holtermann and Thorsdalen 1953) or are intendedto inhibit enzymatic destruction of the hormone

(Hamburger 1952, Fischer et al. 1953).Since it is known that zinc salts can potentiate or

retard the action of certain protein hormones (Maxwell1934, Rabinowitch et al. 1936, Scott and Fisher 1935,1936), and that zinc inhibits several kinds of protein-splitting enzymes (Bang 1946, Adams and Smith 1951,Green et al. 1952) the influence of zinc salts on theaction of corticotrophin was investigated.The experiments showed that both zinc phosphate and

zinc hydroxide, when precipitated from a solution con-taining corticotrophin at about neutral pH, carry thecorticotrophin activity with them. In this way easilyinjectable suspensions of small particle-size can beobtained. The active material and enzyme-inhibitingzinc compounds are slowly released by solution in tissuefluids after subcutaneous or intramuscular injection of thesuspension.

Experiments were made in which the distribution ofcorticotrophin in preparations containing zinc phosphatewas studied, starting with corticotrophin prepared frompig pituitaries. The activities of these preparations variedbetween 1 and 3 United States Pharmacopeia (U.S.P.)units per mg. Occasionally use was made of furtherpurified corticotrophin preparations obtained by the

oxycellulose method of Astwood et al. (1951). Theresults of one of the experiments are presented in theaccompanying figure, showing the relative amount oftotal protein (curve A) and activity (curve B) left in solu-

tion at variousconcentrations ofzinc phosphate insystems at pH 6containing 20U.S.P. units of

corticotrophin perml. After a sharpinitial drop thecurves flatten out.The zinc-phos-phate precipitateswere obtained bythe addition of tri-sodium phosphateto an acid solution

containing corti-

cotrophin andzinc chloride, fol-lowed by adjust-ment of the pHto 6 with sodium-

hydroxide solu-tion. The proteinwas determined

Amounts of protein (A) and activity (B), in %of original value, present in the liquid phaseof corticotrophin-zinc-phosphate suspensions(each containing 20 U.S.P. units) with differ-ent amounts of zinc at pH 6-0 ; tempera-ture = 25°C ; corticotrophin preparationno. 54/ 55 (2-6 U.S.P. units per mg.)-