.,.2d72

MAYER AND CONNELL: SINTROM

Canad. M. A. J. Feb. 15, 1957, vol. 768. KANOF, A., KRAMER, B. AND CARNES, M.: J. Pediat., 14: 712, 1939. 9. BOWMAN, W. D.: Personal communication, 1953. 10. MARTIN, W. J. et al.: Proc. Staff Meet. Mayo CliGu.. 29: 379, 1954. 11. TAYLOR, W. J.: Personal communication, 1954. 12. GARROD, L. P. AND WATERWORTH, P. M.: Brit. M. J., 2: 61, 1956.

1. It is emphasized that this disease occurs in infants and young children. 2. The danger of hospital infection is noted. 3. The mortality rate was high (44%). 4. The frequency of complications has been shown. 5. The ineffectiveness of most antibiotics has been noted. 6. The value of nasal swabs is noted.My thanks are due to Professor Harry Dr. I. Graham.REFERENCES

RESUMEL'auteur rapporte ici les observations qu'il a ete 'a menme de faire en traitant 27 cas de pneumonie ai staphylocoques chez des enfants dont la majorit, etait agee de 3 mois ou moins. Plusieurs d'entre eux avaient souffert d'infections 'i staphylocoques anterieurement, soit au niveau de la peau ou au niveau du tube digestif. Neuf de ces petits malades montrerent tres peu de signes cliniques 'a l'admission. Des complications surgirent dans 22 cas, et le taux de mortalite s'eleva La 44.4%. La grande majorite des souches de staphylocoques dores obtenues dans ces cas etait resistante 'a la plupart des antibiotes sauf le chloramphenicol et l'erythromycine. Comme dans plusieurs autres hopitaux, on isola des staphylocoques resistants des voies nasales de 84% dui personnel employe au departement de maternite. Ces observations confirment celles contenues dans d'autres articles sur le meme sujet dejLa parLs dans cette revue. M.R.D.

Mledovy

and

65: 439, 1951. 2. KANOF, A. et al.: Pediatrics, 11: 385, 1953. 3. BLOOMER, W. E. et al.: J. Thoracic Sury., 30: 265, 1955. 4. BEAVEN, D. W. AND BURRY, A. F.: Lancet, 2: 211, 1956. 5. RODGERS, D. E. et al.: Ann. New York Acad. Sc., 65: 57, 1956. 6. GUTHRIE, K. J. AND MONTGOMERY, G. L.: Lancet, 2: 752, 1947. 7. MACAULAY, D.: Ai-ch. Dis. Child., 27: 107, 1952.

1. DE PAPE, A. J. AND MCEWEN, D. S.: Catnad. M. A. J.,

THE ANTICOAGULANT EFFECT OF A NEW COUMARIN DERIVATIVE - SINTROM (GEIGY)AND ITS CONTROL BY STANDARDIZED CLOTTING TIME*GEORGE A. MAYER, M.D. and W. FORD CONNELL, M.D., Kingston, Ont.

IN A PREVIOUS PAPER, we demonstrated a consistent relationship between dicoumarol therapy and the clotting time of unmodified whole blood measured by a standardized procedure.1 Clinical observation and statistical analysis of our data showed that this might be a more reliable method of controlling dicoumarol therapy than the Quick one-stage prothrombin test. In this study the daily prescription of dicoumarol was governed largely by prothrombin values - the standardized clotting time being registered only for purposes of our research. We now report the result of anticoagulant therapy in 42 patients, controlled solely by the standardized clotting time. The anticoagulant used in this study was 3 - [a(44 nitrophenyl) -,facetylethyl] - 4 oxycou*From the Departmenit of NIedicine, Queen's University and the Kingston General Hospital. This study was supported by the J. P. Bickell Foundation, Toronto. The heparin was supplied by the Coninaught Medical Research Laboratories, Toronto.

marin (Sintrom) t, a new coumarin derivative synthesized by Stoll and Litvan.2 Considerable information is already available on this drug. Milligram for milligram, it is 25 times as potent as is phenylindandione3 and 40 times as potent as Tromexan.4 After its administration, factor VII and prothrombin are decreased in amount; factor V is unaffected.4 A prothrombin level of 30%o could be attained in from 24 to 72 hours after the first dose.5 Weiner; and his colleagues have recently reported this drug to act somewhat more rapidly than dicoumarol but more slowly than Tromexan. Prothrombin time was shown to return to normal in from 24 to 48 hours after the drug was discontinued. No toxic effects or gastro-intestinal disturbances were reported in either animals or humans when doses were kept in the usual therapeutic range. Early workers'5 recommended a starting dose of 28 mg., 20 to 24 mg. on the second day, and 12 to 20 mg. on the third. Thereafter, prothrombin time was used to regulate dosage. Of the 42 patients we treated, 22 had acute myocardial infarction (15 "poor risk" cases), 12 had acute coronary insufficiency, three pulmonary embolism, four peripheral thrombophlebitis and one cerebral embolism.tSintromn was stupplied by Geigy Pharimiacetiticals l,td., Monit real.

Canad. M. A. J. Feb. 15, 1957, vol. 76

MAYER

AND

CONNELL: SINTRoM 273

METHODS

1. Standardized clotting time (SCT) was measured on unmodified venous blood immediately after withdrawal, following the method of Mayer.7 Readings were expressed in minutes. Normal values were 9.69 + 0.55 minutes. 2. The Quick one-stage prothrombin test8 was performed in the laboratories of the Kingston General Hospital within two hours of blood withdrawal. Each day fresh Difco BactoThromboplastin (dried rabbit brain) was used. The daily normal prothrombin time varied between 13 and 16 seconds. Prothrombin activity in per cent (PTR) was calculated from the dilution curve of pooled normal human plasma. Blood for both tests was taken in the morning. Patients were not always in the fasting state.

Sintrom was started on the first day, with a dose of 20 to 24 mg. On each of the following three days we reduced the dose by 4 mg.-the total dose for the day being given at noon, after food. Thereafter, the dosage of Sintrom was adjusted to maintain SCT readings in our therapeutic range of between 15 and 20 minutes. PTR was registered for purposes of comparison only. All patients received 500 mg. of ascorbic acid daily throughout anticoagulant therapy. Other drugs were administered as was dictated by the clinical course.RESULTS The anticoagulant treatment of these 42 patients was studied for a total of 866 treatment

TABLE I.-STANDARDIZED CLOTTING TIME (SCT) DURING SINTROM THERAPYDaysnMean1

2

3

4

5

6

7

8

9

10

11

12

1s

14

15

16

17

18

19

20

4010.70

3912.41*0.41

4114. 27 *0. 43

40

42

4117.83*0. 64

3817.97 3 .90*0. 63

3618. 695618.1

3317.87 *0.63

2817.03 68

2716.25

2618.07

2217.27 *0.85 23.3

2416.7 *0. 7923.4

1917.52

1817.11 *0. 77 19.2

1916.94 *0.6416.5

1518.00 0. 97 20.7

1218.41 22 23.0

1417.211 14

SD

.

*1.

1. 55 *2.57 *2.8020.719.7

SE .0. 24

C*

.14 5

15.92 16.85 3 3 *0. 58 *0. 58 22.6 23.3

.71

.81 *4.1523.3

*1=3.38*3.60 3.6120.121.2

3.801

*4.60*0.9025.5

4.031

*3.90 *2.06 3.29 2.80*3.72 4.25 4 25*0. 47 11.8

*0. 7323.4

21.7

24.7

*Coefficient of variation in per cent.TABLE II.-PRoTHROMBIN (PTR) ACrivITY (QUICK ONE-STAGE METHOD) DURING SINTROM THERAPYDaysn1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

42 42 41 42 41 31 26 28 26 20 22 39 35 18 18 19 16 Mean 58.00 26.57 18.3 20.43 21.14 21.73 22.76 25.97 31.61 30.73 33.00 30.92 37.1 41.54 35.72 34.55 36.26 32.06 SD *16.7 *13.09 *14.03 *16.1 *16.6 *12.7 *14.0 *15.5 *19.4 *20.3 *17.7 *20.66 *18.8 *16.7 *11.5 *16.2 *16.6 *13.2 SE *2.6 *2.02 *2.16 *2.51 *2.56 *1.98 *2.24 *02.62 *3.48 *3.98 *3.34 *9.05 *1.22 *3.56 *2.71 *3.82 *3.81 *3.3 C* 76.7 78.8 78.5 58.4 61.5 59.7 61.4 66.1 53.6 28.8 49.3 66.8 50.7 40.2 32.2 46.9 45.8 41.2 *Coefficient of variation in per cent.41

*10.891=17.6 *3.336.1

11 30.18

13 39.30

*4.88

41.8

TREATMENT

Anticoagulant therapy was initiated in all cases by the intravenous administration of 100 mg. heparin; this dose was repeated approximately seven-hourly during the daytime thereafter. The usual times of injection were 9 a.m., 4 p.m. and 11 p.m. Blood tests were taken each morning 9 to 10 hours after the bedtime dose and always before the morning dose of heparin. This schedule was maintained until the SCT attained approximately 14 minutes, when the daily heparin dosage was reduced to 100 mg. b.i.d. (injections at 10 a.m. and 10 p.m.). When the SCT reached the 15-16 minute level, heparin was discontinued. In rare instances the effect of heparin was unduly prolonged; this was detected easily by maintained rise of SCT (Fig. 3) and the subsequent doses of heparin' were adjusted or entirely omitted.

days. On 18 of these days heparin only was administered, and for 128 days heparin and Sintrom were given concurrently. For 720 treatment days Sintrom was the only anticoagulant given. Statistical analysis of the SCT readings showed a slow, steady rise of the arithmetic mean (Table I) until the eighth day, when the 18-minute level was attained. The mean remained approximately at this level during the subsequent days. The coefficient of variation was approximately 20% throughout the study. The corresponding mean of the PTh (Table II) showed a very rapid decrease. In from 36 to 48 hours after the first Sintrom dose it was 26%, and on the third day 18%. It remained around this level until the ninth day, when it rose to 30%, and on the 13th day to 37%, varying thereafter from 30 to 40%. The wide variation in individual IPTR readings is shown by the high coefficients of variation.

274 MAYER AND CONNELL: SINTROM

Canad. M. A. J. Feb. 15, 1957, vol. 76

PTR

with adequate SCT prolongations. Later, on the 21st day, 60%--20, _ _ a similar PTR value was asso70 Y0* -ciated with an excessively high 80% -10 SCT value (33 minutes). On the average, 4.3 days 6 4 10 12 14 16 0 2 8 were required to attain an 18 20 DAYS Fig. 1.-Curves of means of SCT and PTR (Quick one-stage method) in SCT of 15 minutes. Individual 42 patients under Sintrom therapy. Note the rapid decrease of PTR and slow cases exhibited marked variacssehbtd'akdvra rise of SCT. tions in the rapidity of- the Correlation coefficients between SCT and PTR onset of adequate SCT levels (Table III). A varied from -0.1 to -0.47. PTR level of 30% was reached on the average The curves of the means J. E. d' 37 Y CORONARY INSUFFICIENCY (Fig. 1) show a lag of SCT as compared with PTR during p;R the first nine days of therapy. 0 Thereafter, they run more or CT mi. 10 % less parallel. We found several cases exhibiting marked PTR 20 % 40 , depression with therapeutic . %. SCT levels (Fig. 2).' In other 40% 30 cases similar SCT readings 50 % were maintained with very 70 % 20 moderate depression of PTR40 %- -30

20 % 40 30% t r

10% SCT min.

PTR

mean

_ -

'~'

_

same patients. A case is illus