STREPTOMYCIN REACTIONS

540

STREPTOMYCIN REACTIONS RELATION TO EXERCISE

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

following day, but with the patient ambulant and taking walking exercise in the grounds of the Sanatorium. The serum-streptomycin levels were all determined at the Brompton Hospital laboratory by the diffusion method of Mitchison and Spicer (1949). Results

RESIDENT MEDICAL

OFFICER, BROMPTON HOSPITAL SANATORIUM, FRIMLEY, SURREY

A RELATIVELY large number of patients experience unpleasant symptoms within a few hours of an intramuscular injection of streptomycin. In most of them these " reactions " are trivial, but in some they are extremely unpleasant and may render the patient incapable of work. Such reactions occur less commonly in patients resting in bed. Therefore the present investigation was undertaken to elucidate the cause of these reactions to streptomycin, with special reference to the part that exercise plays in their aetiology.

In all 5 patients the highest blood-streptomycin level was found during activity, the peak level occurring 11/2 hours after the injection of streptomycin in 4 of the 5 patients. In the remaining patient the highest blood-streptomycin level was found 3 hours after the

injection. 3 patients had and the time of

reactions only when they were active. onset of these reactions corresponded

Material

patients in the Brompton Hospital’ Sanatorium having, or had had, streptomycin were questioned about whether streptomycin had affected them in any way. Leading questions were deliberately avoided as much as possible. The various unpleasant symptoms reported were tingling paræsthesiæ in and around the mouth, vertigo, 91

who

were

ataxia, headaches, lassitude, " muzziness in the head," 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 symptoms occurred was as follows :

a

The severity of the reactions was classified into three grades (see table). The symptoms usually began within 1-3 hours of an injection of streptomycin, and some or all persisted for 1-24 hours.

Investigation 8

Of the 12 patients with moderate or severe reactions complained that their symptoms were made worse by SEVERITY OF REACTIONS

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 onset of reactions.

Serum-streptomycin

closely to the time that the streptomycin was reaching its peak level in the blood. 1 patient had a reaction whilst resting, but this was less severe than that which he 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 accompanying figure. Treatment

It is a common practice in sanatoria to give patients their injections of streptomycin first thing in the morning. before the start of the day’s activity. But, because rest after the injection appeared to diminish or prevent subsequent reactions, 5 patients who experienced rear, tions were given their streptomycin at night, shortlv after 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, because he was left with a headache the following morning. Discussion

exercise and relieved, partially or completely, by rest. It was therefore decided to investigate the serumstreptomycin levels following an intramuscular injection of streptomycin sulphate in 5 patients, both at rest and during exercise. The serum-streptomycin levels at rest and during exercise were determined on consecutive days for each patient. On the first day the patient rested in bed, and samples of venous blood were taken immediately before and 1/2 hour, 11/2 hours, and 3 hours after an intramuscular injection of streptomycin sulphate 1 g. into the buttock. The same procedure was repeated on the!

I have not been able to find any published reportot transient, toxic reactions following intramuscular streptomycin as described here, nor any reference to the influence of exercise on the rate of absorption of intramuscular streptomycin. It is perhaps surprising that unpleasant symptoms occurring as frequently as in this series should not have attracted 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 seriouOne can only suppose that in the past, when strepto mycin was usually given in relatively short courses to bed-patients, the reactions caused little concern. since. with the patient at rest, the blood-streptomycin lestremains lower and there is less likelihood of reactions

541 With the present-day tendency to give long courses of streptomycin to ambulant patients, however, these reactions 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, which M usually attained 1-11/2 hours after an injection in ambulant patients. In this investigation all the reactions began 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 fully appreciated, since many papers citing serum-streptomycin levels do not stipulate whether the patients investigated were resting or ambulant (Hunt and Fell 1949, Kornegay

et al. 1946, Zini 1950).

-

activity should influence the rate of absorption quite logical, since it is well known that the blood-flow through a muscle, and the lymph return from it, are It is not both considerably increased with exercise. unreasonable to suppose, therefore, that an injection of streptomycin given into the leg or the buttock will be more quickly absorbed in an ambulant patient than in one who is resting. This supposition has been confirmed in 4 of the 5 cases so far investigated. The more rapid absorption of streptomycin during activity and the higher blood-streptomycin levels attained, may be factors in the aetiology of these reactions. The study of a larger series of cases is being undertaken to establish the best method of preventing these impleasant reactions. Meanwhile the findings in this small series strongly suggest that a period of rest following the administration of streptomycin may be of benefit to those patients who experience reactions. This can be achieved quite simply by giving the injections in the evening. That

is

Summary Of 91

patients treated with intramuscular streptomycin 31 (34%) complained of toxic symptoms within a 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 who experience reactions. I wish to thank the

physicians

of

Brompton Hospital for J. L. Livingstone

CORTICOTROPHIN ZINC PHOSPHATE AND HYDROXIDE LONG-ACTING AQUEOUS PREPARATIONS

J. D. H. HOMAN Ph.D. Groningen J. P. J. NEUTELINGS J. VAN

DER

From the Research Laboratories

of N.

Experiments were made in which the distribution of corticotrophin in preparations containing zinc phosphate was studied, starting with corticotrophin prepared from pig pituitaries. The activities of these preparations varied between 1 and 3 United States Pharmacopeia (U.S.P.) units per mg. Occasionally use was made of further purified corticotrophin preparations obtained by the oxycellulose method of Astwood et al. (1951). The results of one of the experiments are presented in the accompanying figure, showing the relative amount of total protein (curve A) and activity (curve B) left in solution at various concentrations of zinc

phosphate in systems at pH 6 20 U.S.P. units of corticotrophin per ml. After a sharp initial drop the curves flatten out. The zinc-phos-

containing

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

Hunt, A.

31, 523.

3, 184.

phate precipitates were obtained by

If statistics or information about road accidents could, by themselves, prevent casualties the roads would indeed be safe. "

If every thousand words written about them could save a life there would be few if any fatal accidents during the year. But the casualty rate still mounts. One hundred and eighty thousand killed or injured in 1949, two hundred and sixteen thousand in 1951, two hundred and twenty-six thousand in 1953. The greater the number of casualties the more does each organisation of road users try to impute the blame to others. Progress will be only slow and halting if individuals and organisations alike see the primary solution of the problem as someone else’s responsibility."-The Price of Road Safety, Planrtirtg, March 10, 1954. Published by P.E.P, 16, Queen Anne’s Gate, London, S.W.I.

C. J. BOOIJ VIES V. Organon, Oss, Holland

suspension.

and Dr. A. F. Foster-Carter for the encouragement and advice they gave me during this investigation ; Dr. J. W. Clegg for granting me laboratory facilities at the Brompton Hospital; and Mr. F. J. Baker and Miss M. A. Swan, of the bacteriology department, Brompton Hospital, for doing all the technical work.

C. G. (1949) J. gen. Microbiol, scand. 136, 209.

Ph.D. Leiden

VARIOUS attempts have been made to produce preparations of adrenocorticotrophic hormone (corticotrophin) with increased or prolonged action, so as to obtain more efficient utilisation of corticotrophin after either intramuscular or subcutaneous injection. In these preparations corticotrophin is combined with different and more or less complex substances which delay absorption (Wolfson et al. 1951, Raben et al. 1952, Fletcher and Williams 1952, Holtermann and Thorsdalen 1953) or are intended to 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 (Maxwell 1934, Rabinowitch et al. 1936, Scott and Fisher 1935, 1936), and that zinc inhibits several kinds of proteinsplitting enzymes (Bang 1946, Adams and Smith 1951, Green et al. 1952) the influence of zinc salts on the action of corticotrophin was investigated. The experiments showed that both zinc phosphate and zinc hydroxide, when precipitated from a solution containing corticotrophin at about neutral pH, carry the corticotrophin activity with them. In this way easily injectable suspensions of small particle-size can be obtained. The active material and enzyme-inhibiting zinc compounds are slowly released by solution in tissue fluids after subcutaneous or intramuscular injection of the

permission to investigate their patients ; Dr.

Mitchison, D. A., Spicer, Zini, F. (1950) Acta med.

G. A. OVERBEEK

the addition of trisodium phosphate to an acid solution containing corti-

cotrophin

and

zinc chloride, followed in and by adjustAmounts of protein (A) % activity (B), of original value, present in the liquid phase ment of the pH of corticotrophin-zinc-phosphate suspensions to 6 with sodium(each containing 20 U.S.P. units) with differ- hydroxide soluent amounts of zinc at pH 6-0 ; temperation. The protein ture 25°C ; corticotrophin preparation was determined no. 54/ 55 (2-6 U.S.P. units per mg.)=