SOMMAIBE Le Sulfinpyrazone (Anturan)

Canad. Med. Ass. J. 818 SMYTHE AND OTHERS: PLATELET ECONOMY April 10, 1965, vol. 92

SOMMAIBE Le sulfinpyrazone (Anturan), administr6 .i doses th6rapeutiques pendant une p&iode de plusieurs semaines, a entrain6 une survie prolong6e des plaquettes et un ralentisse- ment du roulement biologique, tout en n'affectant gu.re Ia coagulation du sang. Les modifications portant sur la survie des plaquettes et leurs roulement biologique provenaient d'une diminution de l'adh6rence des plaquettes. Ii est done possible de r6aliser une 6conomie sensible des plaquettes chez l'homme sans, pour autant, toucher .i Ia coagulation sanguine. Canad. Med. Ass. J. April 10, 1965, vol. 92 SMYTHE AND OTHERS: PLATELET ECONOMY 819

TABLE 1.-CoAGUlATIoN TESTS Mean (harmonic) Mean (geometric) Mean plasma dotting time prothrombin time thromboplastin Mean platelet (minutes) (seconds) time (seconds) adhesive index No No No No Subject** Age Diagnosis therapy Suif. therapy Suif. therapy Suif. therapy Suif. Si.60 M.I. 10.4 7.6 - - 12.5 12.4 1.10 1.05 An.59 R.A. 9.7 6.0 14.0 12.3 11.4 11.9 0.96 1.25 Ma.50 Gout ------So.60 S.gout - - 15.0 15.0 14.1 13.3 1.28 1.32 Mi.65 Myel. ------1.12 Na.54 M.I. 9.0 9.1 14.5 13.3 11.3 12.6 1.89 1.24 Sh.41 M.I. 12.0 8.1 14.0 15.0 10.1 11.4 1.31 0.96 Ha.23 Normal 9.1 11.7 13.0 13.0 11.5 16.3 1.32 1.48 liar.62 S.gout - - - 18.1 - - - 1.23 She.69 Gout 10.7 12.7 15.0 14.9 10.9 14.0 1.26 0.87 Bu.41 Phieb. 10.5 12.6 13.2 13.8 10.2 12.1 1.47 1.25 By.57 Gout 10.6 12.6 15.4 14.4 12.1 12.0 1.48 1.45 Cl.35 Gout 15.4 9.9 14.5 15.8 12.0 10.1 1.09 1.16 Cia.42 Gout 7.0 11.8 14.7 13.6 12.0 12.5 1.20 1.09 Ca.51 Gout 6.7 8.5 13.7 14.8 11.8 13.2 1.69 1.14 Hu.38 Gout 9.8 12.0 14.0 14.7 11.4 11.3 1.18 1.08 Co.51 Gout 8.7 12.8 14.9 14.3 11.8 9.0 1.42 1.24 Mar.57 MI. 10.7 7.4 14.6 14.3 10.9 15.6 1.23 1.02 Da.71 M.I. 9.2 11.2 14.5 13.0 17.1 12.0 1.08 1.06 Ro.36 Normal 12.5 10.5 14.3 13.4 13.4 10.2 1.12 1.14 Ja.45 Normal 9.9 10.5 13.5 13.3 11.5 11.1 1.51 1.32 Meanof means.9.76 10.15 14.30 14.22 11.58 12.07 1.325 1.184 Significance of differences between means* t 0.421 t 0.283 t 0.968 t 1.949 Subjects 1 - 17 p <0.7 p <0.8 p <0.4 p <0.1 All subjects t 0.170 t 1.013 t 0.371 t 2.309 p <1.0 P <0.4 p <0.8 p <0.05 M.I. = myocardial infarct; R.A. = rheumatoid arthritis; S. gout = secondary gout; Myel. = myeloproliferative disease; Phieb. = phlebitis. *Based on paired difference analysis. **Subjects Mar, Da, Ro and Ja received therapy for only four weeks or less.

Cohen'2 using radioactive di-isopropyl fluorophos- the period of treatment (Table II). The four sub- phate (DFP32). Platelet turnover values were cal- jects who did not show an effect (Mar, Da, Ro culated on the basis of the average platelet count and Ja) had been given the drug for only a period during the period of the study, using a formula of four weeks or less prior to the study. One of recorded elsewhere.'1 these subjects (Mar) was studied again after being on the drug for four months. At that time Statiatical Canuiderations his platelet half-life value was 4.65 days, which is considerably longer than the pre-treatment value. The statistical considerations involved in the Platelet survival in the 17 subjects receiving the evaluation of data of this type have been described drug for a period longer than five weeks was over elsewhere." 10, . . Since the same subjects were 40% longer than that seen in the pre-treatment studied during a "treatment" period and a "no period. Platelet turnover showed a similar trend. treatment" period, the analysis of the data was All but two of the subjects receiving the drug for by paired differences. a period of five weeks or longer showed a reduction in platelet turnover. The average reduction (based RESULTS on the exponential model) produced in these 17 There was no difference in the clotting time for subjects by sulfinpyrazone therapy was over 40%. the subjects during the "no treatment" and "treatment" periods (Table I). Similarly, neither the DIsCUsSION plasma thromboplastin time nor the prothrombin These studies show that sulfinpyrazone, which has time showed any consistent trend. Twelve of 18 a uricosuric effect, also has a considerable influence subjects showed lower platelet adhesiveness during on platelet economy. The change in platelet survi- the "treatment" period than during the "no treat- val is striking and the effect on platelet turnover ment" period and there was a significant difference greater than that which has been observed with between the means (Table I). There was a signffi- most other manipulative procedures.3' 14,15 Since, in cant reduction in the mean platelet count during their usual therapeutic doses, drugs commonly used the period of therapy. All but four of the 21 sub- to treat thrombosis, such as bishydroxycoumarin and jects showed a longer platelet survival time during heparin, do not exert so great an effect, the question 820 SMYTHE AND onmiis: PLATELET Canad. Med. Ass. 3. ECONOMY April 10, 1965, vol. 92

TABLE 11.-PLATELET SURVIVAL AND TURNOVER Mean Platelet survival (days) Platelet turnover (No./c.mm./day) platelet count (No./c.mm.) Exponential Gaussian Exponential Gaussian No No No No No Subject therapy Suif. therapy Suif. therapy Suif. therapy Sulf. therapy Suif. Si.218,000 320,000 3.655 5.034 10.877 13.192 41,340 44,060 20,040 24,260 An.280,000 256,000 2.809 4.137 10.695 11.629 69,090 42,890 26,180 22,010 Ma.220,000 178,000 2.978 3.424 10.153 11.038 51,210 36,030 21,670 16,130 So.118,000 96,000 3.610 4.881 10.899 12.899 22,660 13,630 10,830 7,450 Mi.750,000 622,000 3.736 4.339 10.703 11.803 139,150 99,360 70,070 52,700 Na.260,000 245,000 3.038 5.997 10.335 13.774 59,320 28,320 25,160 17,790 Sh.220,000 178,000 2.840 4.787 10.523 13.110 53,690 25,770 20,910 13,580 Ha.372,000 144,000 3.734 4.035 11.189 12.081 69,050 24,740 33,250 11,920 Har.220,000 155,000 6.745 8.285 14.183 19.088 22610 12970 15510 8120 She.173,000 124,000 3.366 4.047 10.838 11.590 35:620 21,240. 15,960 10,700 Bu.470,000 309,000 2.708 5.611 10.389 14.340 120,300 38,170 45,240 21,550 By.233,000 232,000 3.510 3.744 11.300 11.283 46,010 42,950 20,620 20,560 Cl.224,000 247,000 2.008 4.831 9.680 12.970 77,320 35,440 23,140 19,040 Cia.214,000 182,000 2.476 2.927 9.933 11.461 59,910 43,100 21,540 15,880 Ca.182,000 122,000 2.517 3.953 9.385 11.835 50,120 21,390 19,390 10,310 Ru.180,000 170,000 2.230 7.150 9.886 15.420 55,950 16,480 18,210 11,020 Co.246,000 212,000 2.766 4.120 10.402 11.650 61,650 35,670 23,650 18,200 Mar. 308,000 244,000 4.133 3.127 12.095 10.625 51,650 54,090 25,470 22,960 Da.207,000 233,000 4.013 3.785 11.698 11.286 35,750 42,670 17,700 20,650 Ro.204,000 206,000 3.059 2.767 10.453 10.150 46,220 51,600 19,520 20,300 Ja.366,000 304,000 3.536 3.461 11.008 11.060 71,750 60,880 33,250 27,490 Mean or mean of means. 269,800 223,100 3.308 4.497 10.792 12.489 59,065 37,688 25,110 18,696 Significance of differences between means* t 2.607 t 5.206 t 5.862 t 5.498 t 4.459 Subjects 1-17 p <0.02 p <0.001 p <0.001 p <0.001 p <0.001 All subjects.. t 2.823 t 3.979 t 4.316 t 4.606 t 4.192 p <0.02 p <0.001 p <0.001 p <0.001 p <0.001 *Based on paired difference analysis. must be raised whether sulfinpyrazone might not modify such factors as kidney function. As the be a more effective drug in the treatment of vascu- changes in platelet economy seem to occur con- lar disease in which platelet thrombosis is involved. siderably later than the fall in the serum uric acid, There is some evidence that this may be so.6' 7 the changes in platelet survival could be related to Furthermore, these observations indicate that it the reduction in the serum concentration of uric may well be possible to employ drugs which affect acid. However, since we have been able to repro- the platelet rather than coagulation, in the manage- duce this effect of sulfinpyrazone on platelet survi- ment of thrombosis. val in the rabbit,'7 which does not have significant The lack of a demonstrable effect of suffinpyra- amounts of circulating uric acid, it seems likely zone on coagulation in this study may mean that that this effect on platelet economy is due to some the effect on platelet economy is mediated through other mechanism. Furthermore, it must not be sup- some other mechanism. Compounds of this type posed that the effect of sulfinpyrazone on platelet have been reported to act on cell membranes.16 economy is the drug's sole effect on the formed Since there is evidence to suggest that the primary elements of the blood. There may conceivably be factor determining the fate of the platelet in the an effect on red cell and white cell turnover also. circulation is its reaction with the endothelium It is apparent from these studies that the action or other tissues in the vessel wall,3 it might be of drugs like the pyrazole compounds on body expected that compounds which influence the metabolism is complex. There are several interest- platelet membrane could prolong platelet survival. ing relationships between their effects on uric acid The evidence from the present study is compati- metabolism and gout and their effects on blood ble with this hypothesis. platelets or the vessel wall. Thus they may possibly The relationship, if any, of the changes in plate- influence thrombosis itself. Further study will be let economy to changes in uric acid metabolism is necessary to define this relationship. not clear, since it is unlikely that they would influence the serum uric acid levels by a factor of SUMMARY more than perhaps 5% to 10%. However, it is Sulfinpyrazone (Anturan) administered in thera- possible that the action of this compound on cell peutic doses over a period of several weeks produced membranes (such as the endothelium and platelets) prolongation of platelet survival and reduced platelet may influence vessel wall permeability and thereby turnover but with little change in blood coagulation. Canad. Med. Ass. J. REVIEW ARTICLE: DEPRESSIVE SYNDROME 821 April 10, 1965, voL 92

REFERENCES 10. MURPHY, E. A. AND MUSTARD, J. F.: Circ. lIes., 8: 1187, 1960. 1. MUSTARD, J. F. et al.: Canad. Med. Ass. J., 89: 1207, 1963. 11. Idem: Circulation, 25: 114, 1962. 2. CROOKSTON, J. H., MURPHY, E. A. AND MUSTARD, J. F.: 12. LEEKSMA, C. H. AND COHEN, J. A.: J. Clin. Invest., 35: Unpublished observations. 964, 1956. 3. MUSTARD, J. F. et al.: Thromb. Diath. Haemorrh., Suppi. Med. J., 1: 13: 245. 1964. 13. MUSTARD, J. F. AND MURPHY, E. A.: Brit. 4. BURNS, J. J. et al.: Nature (London), 182: 1162, 1958. 1651, 1962. 5. BURNs, J. 3. et al.: Ann. N.Y. Acad. Sci., 86: 253, 1960. 14. MURPHY, E. A. AND MUSTARD, J. F.: Lancet, 2: 960, 1961. 6. BOURDE, C. et al.: Th6rapte, 17: 1375, 1962. 15. MUSTARD, J. F. AND MURPHY, E. A.: Blood, 22: 1, 1963. 7. MONTIGEL, 0.: .1. Ass. Physicians India, 11: 257, 1963. 16. RECHENBERG, H. K.: Butazolidin. Phenylbutazon, 2nd ed., 8. BizzozERo, G.: Virchow Arch. Path. Anat., 90: 261, 1882. Georg Thieme Verlag, Stuttgart, 1961. 9. POOLE, J. C. F. AND FRENCH, 3. E.: 3. Atheroscier. Res., 17. MUSTARD, J. F., SMYTHE, H. A. AND ROWSELL, H. C.: 1: 251, 1961. Unpublished obserYations.

TICLX, The Pharmacotherapy of the Depressive Syndrome H. E. LEHMANN, M.D.,* Montreal

ABSTRACT SOMMAIRE Three therapeutic modalities have proved Trois formes de traitement ont fait leurs effective in the treatment of depressive preuves, comme traitement psychiatrique syndromes: electroconvulsive therapy (ECT), de syndrome d6pressif: l'6lectrochoc (E C), pharmacotherapy and psychotherapy. ECT la pharmacoth6rapie et la psychoth&apie. gives the most reliable and most rapid re- Des trois, c'est l'6lectrochoc, qui donne les sults but may be contraindicated in certain r6sultats les plus st.krs et les plus rapides. cases. Psychotherapy is limited in its ap- Mais ce mode de traitement peut .tre plication to the reactive aspects of a de- contre-indiqu6 en certains cas. La psycho- pression. Pharmacotherapy is currently the th6rapie voit son application limit6e aux most widely applied treatment of depres- aspects r6actifs de Ia d6pression. C'est la sion. Two classes of drugs are available pharmacoth6rapie qui est aujourd'hui le which are effective in about 60% of de- mode de traitement le plus largement em- pressed patients: the monoamine oxidase ploy6 dans la d6pression et elle fait l'objet inhibitors and tricyclic compounds. Their du pr6sent article. On peut classer en deux mechanism of action is probably related to cat6gories les m6dicaments qui agissent the regulation of the biogenic amine chez pr.s de 60% des d6prim6s: les inhibi- balance in the brain. The distinction be- teurs de la mono-amine oxydase et les tween antipsychotic and antidepressant compos6s tricycliques. Leur mode d'action drugs is not as sharp as was formerly est probablement 1i6 .i la r.guIation de assumed. Maintenance pharmacotherapy l.6quilibre des amines biog.nes du cerveau. has been shown to have prophylactic value La distinction actueliement 6tablie entre in preventing relapses. les m6dicaments antipsychotiques et anti- d6presseurs n'est plus aussi nette qu'on la croyait auparavant. Une m6dication d'entretien s'est r6v616e comme un hon H ISTORICALLY three phases can be distin- moyen prophylactique d'6viter les rechutes. EU. gmshed in the development of the psychiatric treatment of depression: 1. The phase of ineffective somatic treatment and of psychotherapy. enjoyed a short-lived popularity and hormones were 2. The phase of convulsive therapy and lobotomy. tried for the treatment of involutional depressions. 3. The phase of pharmacotherapy. Hematoporphyrin2 and other photosensitizing During the first phase, which lasted until the agents were credited with therapeutic effects, as middle thirties of this century, a great variety of were a variety of other substances, such as dinitrile treatment methods were tried in the management of succinate3 and nicotinic acid.4 The variety of depressive states. For many years tincture of opium physical procedures employed ranged from the was the treatment of choice.' The amphetamines artificial induction of anoxia5 to x-ray irradiation.6 None of these treatments had a reliable therapeutic *clinical Director, Verdun Protestant Hospital. and Associate action, although each seemed to help, at times, in Professor of Psychiatry, McGill University. Montreal, Que. individual patients.