A controlled study of stanozolol in primary Raynaud's phenomenon and systemic sclerosis

Transcription

1 Annals ofthe Rheumati Diseases 1991; 50: Rheumati Diseases Centre, University of Manhester, Hope Hospital, Salford, M6 8HD, UK M V Jayson C D Holl A Keegan K llingworth L Taylor Correspondene to: Dr Jayson. Aepted for publiation 12 February 1990 A ontrolled study of stanozolol in primary Raynaud's phenomenon systemi slerosis Malolm V Jayson, Christopher D Holl, Anita Keegan, Karen llingworth, Lesley Taylor Abstrat A double blind, rossover study of fibrinolyti enhanement treatment using stanozolol has been performed in primary Raynaud's phenomenon in systemi slerosis. The outome riteria inluded subjetive evaluation, linial examination, physiologial measurements of peripheral blood flow, fibrinolyti measurements. Nineteen patients entered 11 ompleted the study of primary Raynaud's phenomenon. There was nonsignifiant evidene of improvement in peripheral blood flow. Twenty four patients entered 17 ompleted the study of systemi slerosis. There was marked objetive but not subjetive evidene of improvement in the peripheral miroirulation during the stanozolol treatment period. There was also a nonsignifiant improvement in dermal slerosis. There were improvements in fibrinolyti ativity during the stanozolol treatment period. There was no alteration in fibrinolyti reserve as measured by 1-desamino-8-D-arginine vasopressin stimulation, however. Although adverse events were ommon in both treatment periods, withdrawals predominantly ourred during the period of treatment with stanozolol were prinipally due to anaboli problems. There does not seem to be any indiation for the use of stanozolol in primary Raynaud's phenomenon. Fibrinolyti enhanement with stanozolol does appear useful in treating the mirovasular features of systemi slerosis. Raynaud's phenomenon is a syndrome in whih exposure to old often other stimuli produes transient digital ishaemia with a biphasi or triphasi olour hange ommonly assoiated with numbness paraesthesiae. n primary Raynaud's phenomenon no underlying ause an be found, whereas in seondary Raynaud's phenomenon, onnetive tissue diseases, in partiular, systemi slerosis are important auses. Systemi slerosis is haraterised by progressive vasular obstrution, exessive proliferation of onnetive tissue elements,, espeially, ollagen ishaemi atrophy of the tissues. Patients ommonly have severe Raynaud's phenomenon, often ompliated by digital pitting uleration. The harateristi vasular disease inludes arteriolar intimal proliferation with fibrin deposition assoiated with endothelial damage platelet aggregation adherene. These hanges lead to progressive vasular obstrution. n addition, there is hyperfibrinogenaemia with hypervisosity of the blood,' partiularly at low temperatures at low shear rates2 as ours in peripheral vessels in the hs with defetive fibrinolyti ativity.3 For this reason stimulation of the fibrinolyti system orretion of this fibrinolyti defet may be of therapeuti value in orreting the vasular problems by improving vasular pateny reduing plasma visosity.4 We therefore onduted a double blind, ontrolled trial of stimulating the fibrinolyti system with stanozolol, whih is an anaboli steroid with low virilising potential is known to enhane normalise impaired fibrinolyti ativity. Patients methods PATENTS Nineteen patients with primary Raynaud's phenomenon (17 women, two men; mean age 43-3 (SE 3-3) years; mean duration of disease 109X3 (SE 27 8) months) 24 patients with systemi slerosis (22 women, two men; mean age 50 5 (2 8) years; mean duration of disease 206O0 (32 7) months) entered the study. Patients were not taking drugs whih might influene fibrinolyti ativity, had no evidene of ardia, hepati, renal or other disease known to influene fibrinolysis or whih might ontraindiate the use of stanozolol. Women patients, additionally, were not pregnant, had no risk of pregnany, or were using effetive ontraeptive methods, exluding the pill. There were seven urrent smokers in the group with primary Raynaud's phenomenon seven in the group with systemi slerosis. All gave written informed onsent the study was performed with the approval of the Salford ethial ommittee. Patients with primary Raynaud's phenomenon had bilateral symmetrial Raynaud's phenomenon, with at least two of the three olour hanges in response to old, with no evidene of mehanial or drug indued auses of Raynaud's phenomenon, no linial or laboratory evidene of onnetive tissue disorders, inluding negative tests for antinulear fator, extratable nulear antigen, antientromere antibody. Patients with systemi slerosis satisfied the Amerian Rheumatism Assoiation riteria5 for defmite systemi slerosis also had Raynaud's phenomenon. TREATMENT Treatment was with either stanozolol 5 mg orally twie a day or mathing plaebo tablets

2 42 Javyson, Holl, Keegan, llingworth, Taylor twie a day. Patients were romly alloated to reeive six months treatment with stanozolol or plaebo given in a double blind fashion then rossed over to the alternate regimen for a further period of six months. ASSESSMENTS Assessments were performed one week before entry, on entry to the study, at four, 12, 24 weeks of the first treatment period, again at four, 12, 24 weeks of the seond treatment period. Adverse events were assessed by a stard questionnaire overing all possible problems before entry to the trial at eah assessment. A blood ount, renal liver funtion tests, urine examination were undertaken at eah assessment. On entry patients underwent detailed assessments of the severity duration of disease. To assess progress sequential measurements of linial physiologial variables fibrinolyti hanges were made. Clinial variables A subjetive assessment was obtained by noting the frequeny duration of Raynaud's phenomenon using diary ards. For patients with systemi slerosis a measurement of skin disease was made with a modified Rodnan sleroderma skin sore, grip strengths in both hs, the ability to make a fist measured by the sum of the distanes between the finger tips the transverse palm rease, the intervermilion distane on opening the mouth, the degrees of fixed flexion of the elbows. Physiologial variables Patients attended at the same time eah morning having fasted from the previous midnight. After resting for 30 minutes in a room with ontrolled temperature (20±0-50C) humidity (45±5%) the following measurements of the peripheral irulation were made: (1) Ultrasoni Doppler index of digital artery pateny, in whih the patenies of digital artery segments are reorded by ausultation for arterial flow over the medial lateral sides of eah phalanx. There are six segments for eah figer four for eah thumb so that the maximum total for the two hs is 56. (2) The skin temperature over the finger pulps nail beds using a Heimann medial infrared thermometer. Fibrinolyti measurements A 10 ml venous blood sample was taken without a tourniquet by a 'lean' single venepunture tehnique. The following fibrinolyti measurements were performed: euglobulin lot lysis time (ELT) in an automated lot lysis reorder; fibrin plate lysis area (FPLA); fibrinogen, plasminogen, a2 maroglobulin, a2 antiplasmin. The maximum plasminogen ativator reserve was measured after taking the 10 ml basal blood sample by inserting a butterfly intravenous annula into a suitable arm vein infusing 10 tg of 1-desamino-8-D-arginine vasopressin (DDAVP) diluted in 25 ml sterile saline over 15 minutes. A further 5 ml of blood was then taken by repeat 'lean' venepunture for ELT FPLA measurements. STATSTCAL TECHNQUES The data were analysed to determine whether there were any arry over effets for the inidene duration of Raynaud's attaks the reporting of adverse events between the stanozolol plaebo periods of treatment.6 No signifiant effets were deteted. The subsequent analyses ombined the data from both treatment periods. The hanges ourring within eah treatment period the differenes between the effets of the stanozolol plaebo treatment periods were tested with Student's t test. Results SUBJECTS STUDED AND ADVERSE EVENTS Of the 21 patients with primary Raynaud's phenomenon, 11 ompleted the study reeiving both stanozolol plaebo for a period of six months eah. Two patients were exluded (one through lak of interest, one was too young). Seven patients withdrew during the stanozolol treatment period one while being treated with plaebo. Despite the preautions listed in the entry riteria two had beome pregnant, one while reeiving stanozolol the other during the plaebo period. The trial drug was stopped at 12 seven weeks of pregnany respetively; spontaneous abortions ourred a further five three weeks later. Of the 24 patients with systemi slerosis, 17 ompleted the study seven withdrew, six while reeiving stanozolol one during the plaebo period. An attempt was made to analyse the effets of the weather on the study. This proved extremely diffiult. Study of the data, however, showed that the assessments were similarly distributed in the warmer ooler halves of the year for both stanozolol plaebo treatment periods. Table 1 shows the reasons for withdrawal. Weight gain musle ramps were the most ommon problems during treatment with stanozolol. Adverse events not requiring withdrawal from the study were in general more ommon during the stanozolol period than the plaebo periods (primary Raynaud's phenomenon study 145 events during stanozolol 121 during plaebo treatment; systemi slerosis study 210 during stanozolol 156 during plaebo treatment), but the differenes were not statistially signifiant. One patient died during the trial. She was a 73 year old patient with a four year history of rapidly progressive systemi slerosis. She had severe diffuse utaneous features of the disease also gastrointestinal trat disease. She had been reeiving stanozolol for five months was admitted to hospital with aute liver damage aute renal failure. Two months previously her liver renal funtion tests had been normal, subsequent tests suggested that the

3 Use ofstanozolol in Raynaud'sphenomenon systemi slrosis Table Reasoms for withdrawal Disease Tream Age Sex Reason peid e) Primary Raynaud's 22-4 M Weight gain, diarrhoea, phenomenon myalgia 25-2 Malaise 19-9 Pregnay 54-3 Weight gain, no benefit 67-8 Failure to attend 28-0 Weight gain, amenorrhoea 44-9 F Did not wish to ontinue Plaebo 35-8 F Pregnany Systemi slerosis 70 5 F Diarrhoea vomiting 44-4 F Musle ramps, moving abroad 56-7 F Weight gain, musle ramps, mouth ulers 48-7 F Fluid retention, amenorrhoea, ane 49 4 F Weight gain, musle ramps, headahes, nausea 73-7 F Died Plaebo 46-5 F Disease progression deterioration in renal funtion preeded aute liver failure. She was deeply jaundied on admission. There was evidene of aute liver ell damage an enlarged liver with fluid overload renal failure. Despite dialysis she subsequently developed a large gastrointestinal haemorrhage died. Permission for a neropsy was refused. This ase has been reported to the Committee on Safety of Mediines. PRMARY RAYNAUD'S PHENOMENON STUDY Clinial hanges After 24 weeks' treatment with stanozolol there were non-signifiant redutions in the frequeny (p=0 10) duration (p=0 28) of Raynaud's attaks. n ontrast, with plaebo there were inreases in frequeny (p=0-16) duration Table 2 Primay Raynaud's phenomenon study. Euglobulin lysis time fibrin plate lysis area before after l-desamino-8-d-argjnine vasopressn stnulaton. Values are given as means (SEM) Week Plaebo p Value stanozolol Euglobulin lysis time (mm) Fasting (36 7) (30-1) o.o (29-0) (8 0) p After DDAVP* stimulation (10-2) 77-2 (9 7) (7-2) 44-6 (3 8) p Fibrin plate lysis area (mm2) Fasting (17-0) 93-5 (10-6) (13-7) (12-3) p After DDAVP stimulation (25-1) (21-8) (2917) (18-6) p *DDAVP=ldesamino 8-a e vasopressin. Table 3 Primay Raynauds phenomenon stud. Changes in fibrinogen plasminogen with plaebo stanozolol treatment. Values are given as means (SEM) Week Plaebo Stanozold p Value stanozoko Fibrinogen (g/l) (0-19) 2-74 (0-23) (0-37) 2-17 (0-24) p Pl.asminogen (% mean normal) (6-5) (4-8) o* (4-0) (6 0) p (p=0 27) of attaks. The differenes between the plaebo stanozolol periods were not statistially signifiant. Physiologial hanges There were no signifiant hanges in the Doppler index during either 24 week treatment period. After 24 weeks' treatment with stanozolol there were inreases in the mean finger pulp skin temperature (p=0-18) in the nailbed skin temperature (p=o 16). After 24 weeks' treatment with plaebo there was a redution in mean finger pulp finger temperature (p=007) in the mean nailbed skin temperature (p=0 05). The hanges of the mean finger pulp nailbed skin temperatures were not signifiantly different between the two treatment periods (p= ) after 24 weeks. Fibrinolyti hanges After 24 weeks' stanozolol treatment there were signifiant redutions in the ELT both in the basal measurements (p=0 007) after DDAVP stimulation (p=002). There were non-signifiant inreases after 24 weeks' treatment with plaebo. There were signifiant differenes between the two treatment periods in the basal (p=0 05) post-ddavp (p=002) measurements of ELT (table 2). After 24 weeks' stanozolol treatment there were signifiant inreases in the fasting (p=00009) post-ddavp (p=005) measurements of the FPLA. With plaebo there was a signifiant redution in the fasting FPLA (p=002) a non-signifiant redution (p=0-17) after DDAVP. The differenes in fasting FPLA between the two treatment periods were signifiantly different (p=00009) (table 2). There was a signifiant redution in plasma fibrinogen (p=0 04) after 24 weeks of treatment with stanozolol a non-signifiant inrease after 24 weeks with plaebo. The differenes between treatments were not signifiantly different (p=0 06) (table 3). There was a signifiant inrease in plasminogen (p=0 003) with stanozolol treatment but no signifiant hange with plaebo. The differenes between the two treatments were signifiantly different (p=0 03) (table 3). No signifiant hanges were found in the a2 antiplasmin or a2 maroglobulin onentrations. SYSTEMC SCLEROSS STUDY Clinial hanges There were redutions in the mean frequeny of Raynaud's attaks during both stanozolol (p=045) plaebo (p=0 44) treatment. These hanges did not reah statistial siglnifiane, there were no signifiant differenes between the two treatment periods (p=094). The duration of individual attaks fell after 24 weeks' treatment with stanozolol (p=ot38) inreased after plaebo (p=063). These hanges were not signifiant there were no 43

4 44 Jayson, Holl, Keegan, llinguorth, Taylor signifiant differenes between the two treatment periods (p=044). The sleroderma skin sore remained unhanged during plaebo treatment fell with stanozolol, but the hanges were not signifiant (fig 1). Mean grip strength (fig 2) inreased after treatment with stanozolol (p=0 14) dereased with plaebo (p=0 15). These hanges the differenes between them were not signifiant (p=007). Physiologial hanges There was a signifiant inrease in the ultrasoni Doppler index (fig 3) after 24 weeks' treatment with stanozolol (p=0 006) a signifiant derease with plaebo (p=0 02). The differene between the two treatment periods was signifiant (p=0007). During stanozolol treatment there were signifiant inreases in finger pulp (p=0001) nailbed (p=0001) temperatures, whereas after plaebo there was a non-signifiant derease in finger pulp (p=0-08) a signifiant derease in nailbed (p=004) temperatures. The differenes between stanozolol plaebo periods ai iu 4An i; a E 'C a x CL 2 ' Week Treatment Plaebo p = 0-88 p = 0-37 Figure Systemi slerosis. Mean sleroderma skin sore (SEM) during plaebo stanozolol treatment. 'a EE - & C- x w 150JJJ L Week 0 Treatment T T 4 12 Plaebo p = 0-15 T-- 24 p = p = 0-14 Figue 2 Systemi skrosis. Mean grip strength (SEM) during plaebo stanozolol treatment o L p = * Week Treatment Plaebo p=0-02 p=0006 Figure 3 Systemi slerosis. Mean ultrasont Doppler index (SEM) during plaebo stanozolol treatment. 30 & 28 C- E E 26 & 24 C Week 0 Treatment p = Plaebo p = p = Figure 4 Systemi slerosis. Mean finger pulp temperature (SEM) during plaebo stanozolol treatment. p = Week Treatment Plaebo p=004 p=0-001 Figre 5 Systemi slerosis. Mean nadbed temperatures (SEM) during plaebo stanosolol treatment. were signifiant for nailbed (p=0005) but not finger pulp temperatures (p=009) (figs 4 5). Fibinolyti hanges There was a signifiant redution in the fasting ELT (p=005) non-signifiant redution after DDAVP stimulation (p=009) with 24

5 Use ofstnozolol in Raynaud's phenomeno systemi slerosis 45 Table 4 Systemi slerosis study. Euglobulin lysis time fibrin plate ysis area before after l-desamino-8-d-arginine vasopressin (DDAVP) stimulation. Values are given as means (SEM) Week Plaebo p Value stanozolol Euglobulin lysis time (min) Fasting (43-0) (31-4) (23-6) (24-7) 033 p After DDAVP stimulation (23-3) 97-4 (14-1) (11-8) 60-9 (8 9) 0-83 p Fibrin plate lysis area (mm2) Fasting (14-4) (12-1) (10-8) (15-3) p After DDAVP stimulation (20 6) (21-4) (25 7) (27 2) 092 p Table S Systemi slerosis study. Changes infibrinogen plasminogen with plaebo stanozolol treatment. Values are given as means (SEM) Week Plaebo p Value stanozolol Fibrinogen (g/l) (0-29) 3-02 (0-21) (0 20) 2-46 (0-25) p Plasminogen (% mean normal) (5-8) (4-0) (4-8) (40) p stanozolol treatment, but these did not reah statistial signifiane when ompared with the plaebo data. Similarly, there was a signifiant inrease in the fasting FPLA (p=0 05) nonsignifiant inrease after DDAVP (p=049) with stanozolol (table 4). There was a nonsignifiant fall in fibrinogen during stanozolol treatment an inrease with plaebo. There was a signifiant inrease in plasminogen after 24 weeks' treatment with stanozolol (p=0002) ompared with a non-signifiant derease with plaebo. The two treatment periods were signifiantly different (p=0002) (table 5). There were no signifiant hanges in the a2 antiplasmin a2 maroglobulin onentrations. Disussion Raynaud's phenomenon is a ommon problem. n primary Raynaud's phenomenon no underlying ause an be found on linial examination or investigation. During long term follow up no underlying disorder is deteted in most of these patients. n a small proportion, however, evidene of an underlying onnetive tissue disorder may beome apparent. The mehanisms underlying primary Raynaud's phenomenon are unertain. n partiular there may be abnormal vasular reativity with vasoonstrition ourring on exposure to old. Hypervisosity of the blood has been desribed.' n that study, however, in hoosing their patients with Raynaud's phenomenon the authors apparently did not exlude patients showing immunologial evidene of onnetive tissue disease, possibly their results are due to the inlusion of suh subjets. Studies of plasma fibrinogen of the fibrinolyti system have not shown any abnormality in patients with arefully haraterised primary Raynaud's phenomenon there is no evidene that fibrinolyti abnormalities play any part in the pathogenesis of this disorder.3 n ontrast, in systemi slerosis there is progressive vasular obliteration, with intimal proliferation assoiated with platelet aggregation to the vessel walls endothelial damage. Fibrin deposition in the vessel walls may ontribute towards vasular obstrution.7 Progressive narrowing of the peripheral arterioles leads to a derease in digital artery pressure digital blood flow. n partiular, the ritial losing pressure of the digital blood vessels may derease so that peripheral blood flow beomes more sensitive to other fators, suh as old. There is an inrease of blood visosity.2 This is assoiated with hyperfibrinogenaemia diminished fibrinolyti ativity. n addition, fibrin may be deposited in the perivasular tissues blok diffusion of oxygen. As a result of vasular insuffiieny patients with systemi slerosis ommonly have severe Raynaud's phenomenon frequently ompliated by digital pitting uleration. Defetive fibrinolyti ativity is ommon in systemi slerosis3 may ontribute towards the hyperfibrinogenaemia the persistene of fibrin deposits in vessel walls perivasular tissues. For this reason stimulation of the fibrinolyti system orretion of the defet may be of therapeuti value in improving the vasular problems. The relation between vasular hanges onnetive tissue proliferation in systemi slerosis remains unertain. There is evidene that mirovasular injury ours first.8 f this is so, orretion of the vasular problem might help to ontrol the proliferation of ollagen other onnetive tissue elements in systemi slerosis. is an anaboli steroid with relatively little rogeni ativity. t has been shown to

6 46 Jayson, HoU, Keegan, llinguorh, Taylor enhane impaired fibrinolyti ativity.9 n lipodermatosierosis there is hroni induration fibrosis of the skin subutaneous tissues of the leg after deep venous thrombosis. Fibrin is deposited in the tissues there is a fibrinolyti defet in the blood. Fibrinolyti enhanement with stanozolol is effetive in orreting the defet, reduing the fibrin in the tissues reduing the area of liposlerosis.'0 Clinial improvements by similar mehanisms are suggested in rheumatoid arthritis" in utaneous vasulitis. 12 A previous study of systemi slerosis Raynaud's phenomenon suggested stanozolol is of value.4 This was an unontrolled study, however in whih patients reeived stanozolol for two periods of three months with an intervening period of three months without drug treatment. Raynaud's phenomenon systemi slerosis are extremely diffiult to assess plaebo ontrolled studies are essential to evaluate any form of treatment. Moreover, although the authors state the trial was in patients with both idiopathi sleroderma assoiated Raynaud's phenomenon, they did not define the riteria for either group. All these 20 patients in the trial had severe bilateral disease with trophi hanges symptoms suh as pain reurrent infetion in the finger tips. From review of the paper it seems likely that they all had systemi onnetive tissue disease. We have onduted, therefore, further more detailed studies to determine the linial, physiologial, biohemial effets of stanozolol in patients with primary Raynaud's phenomenon systemi slerosis. Assessment of Raynaud's phenomenon is notoriously diffiult. n partiular, in long term studies subjetive assessments of frequeny severity of Raynaud's attaks are ompliated by hange in season it an be very diffiult to determine the values of any form of treatment without objetive measures of peripheral blood flow after stabilisation at ontrolled temperatures. Patients have more longer attaks in the winter than in the summer it is possible that winter weather plus an effetive agent equates with summer weather plus plaebo so that a real effet might be missed. For these reasons we attah muh greater value to the objetive measurements than to the subjetive reordings of frequeny duration of Raynaud's attaks. n patients with primary Raynaud's phenomenon there were some small non-signifiant trends towards improvement in the peripheral miroirulation during the stanozolol treatment periods ompared with the ontrol treatment periods. t remains possible that some of these patients with primary Raynaud's phenomenon were in the early stages of onnetive tissue disease but without any linial features. Benefit in these subjets might aount for the minor improvements that were seen. n view of the side effets there is no indiation for stanozolol in primary Raynaud's phenomenon. n the patients with systemi slerosis the duration of Raynaud's attaks fell during stanozolol treatment inreased with plaebo, though these differenes were not signifiant. The objetive measures of peripheral blood flow, however, showed signifiant improvements during stanozolol treatment ompared with plaebo. These differenes were marked in terms of digital pateny measured by the ultrasoni Doppler index skin temperatures both of the finger pulps nail beds. These results indiate a marked improvement in the miroirulation during the period of stanozolol treatment. Anedotal evidene suggests that fibrinolyti enhanement is most effetive if given early in the disease. One vessels are totally oluded, perhaps fibrin deposits are stabilised the patient is showing major evidene of peripheral ishaemia possibly with digital gangrene, only limited improvement, if any, may be expeted during treatment with stanozolol. A further trial of fibrinolyti enhanement speifially limited to early systemi slerosis is indiated. We also found a non-signifiant improvement in the sleroderma skin sore, whih is an index of the degree of skin affeted by fibroti hange. The number of patients in this study was small. t remains possible that a larger study of longer duration might show signifiant improvement of skin involvement during treatment with stanozolol. The grip strength inreased during stanozolol treatment dereased during the ontrol periods. f this is a real hange it may reflet the ontrol of the underlying disease. Differenes in grip strength may be due to the anaboli effets of stanozolol on musle strength, however. Defetive fibrinolyti ativity is well reognised in systemi slerosis but not in arefully defined primary Raynaud's phenomenon.3 n this study we found a prolonged ELT redued FPLA in the patients with systemi slerosis ompared with those with primary Raynaud's phenomenon. is known to stimulate fibrinolyti ativity,9 in the urrent studies we found that the treatment period was assoiated with a fall in the ELT, an inrease in the FPLA, a redution in plasma fibrinogen onentrations. Fibrinolyti ativity is determined by the onentrations of tissue plasminogen ativator, whih is derived from the vasular endothelium.'3 This forms the ative fibrin adsorbable omponent of tissue plasminogen ativator,'4 the plasminogen ativator ativity seems to be a balane between the amounts of ativator inhibitor that are present. appears to at, at least in part, by dereasing the onentrations of tissue plasminogen ativator inhibitor.15 Perhaps demonstration of raised onentrations of tissue plasminogen ativator inhibitor may indiate those patients most likely to respond to treatment with stanozolol. Venous olusion leads to enhanement of fibrinolyti ativity is thought to be due to release of tissue plasminogen ativator from the vessel walls.'6 This has been termed the fibrinolyti reserve. The stard test requires venous olusion for 20 minutes presents speial diffiulties in patients with peripheral vasular impairment as in systemi slerosis. l-desamino- 8-D-arginine vasopressin (DDAVP) given by

7 Use ofstanozolol in Raynaud's phenomenon systemi skrosis infusion produes a profound inrease in fibrinolyti ativity. nfusion of 10 1tg DDAVP led to a marked inrease in fibrinolyti ativity in healthy subjets,'7 it has been possible to show a fivefold to sevenfold inrease in fibrinolyti ativity with infusions of 0 4 jig of DDAVP per kg body weight. 8 We found a signifiant redution in response to DDAVP in patients with systemi slerosis ompared with ontrols,'9 suggesting defetive reserve or release of endothelial ell derived plasminogen ativator in systemi slerosis. n the patients with systemi slerosis we found no obvious differenes in the responses DDAVP during stanozolol plaebo treatment periods, though in the patients with primary Raynaud's phenomenon there might have been a greater response to DDAVP in those reeiving stanozolol rather than plaebo. This again suggests that in systemi slerosis stanozolol does not affet vessel wall plasminogen ativator storage or release. t is ompatible with the proposal that stanozolol prinipally stimulates the fibrinolyti system by inhibiting formation of tissue plasminogen ativator inhibitor. Considerably more adverse events were reorded by a questionnaire during both treatment plaebo periods than before the trial. They were somewhat more ommon during stanozolol treatment than with plaebo, but there were no lear differenes in patterns of adverse events. Withdrawals from the trial ourred predominy during treatment with stanozolol were usually due to anaboli effets. One patient died during stanozolol treatment with aute hepatorenal failure. She had rapidly advaning systemi slerosis with viseral manifestations. Aute renal failure is a ommon problem in this sublass of systemi slerosis is the ommonest ause of death. She did develop aute hepatoellular damage, however, though the sequene of liver funtion tests suggests that this followed the deterioration of renal funtion. t is known that stanozolol may raise the levels of liver enzymes suh as aspartate transaminase alanine transaminase.' t remains unertain whether the aute hepatoellular damage in this ase was an adverse effet of stanozolol. n onlusion, ontrolled studies of stanozolol have been performed in primary Raynaud's phenomenon systemi slerosis. n primary Raynaud's phenomenon there was a minimal suggestion of linial improvement but a high proportion of withdrawals, prinipally beause of anaboli effets in a young female population. There does not seem to be any indiation for the use of stanozolol in primary Raynaud's phenomenon. n systemi slerosis there was a signifiant marked improvement in the peripheral miroirulation by objetive but not subjetive measures, a non-signifiant improvement in the sleroderma skin sore. Adverse effets again were ommon. does seem to be useful in treating the mirovasular features of systemi slerosis. We wish to thank Sterling Researh Laboratories for supporting this study. Goyle K B, Dormy F L. Abnormal blood visosity in Raynaud's phenomenon. Lanet 1976; i: MGrath M A, Peek R, Penny R. Blood visosity with redued blood flow in sieroderma. Ann Rheum Dis 1977; 26: Holl C D, Jayson M V. Venous blood fibrinolysis fibrinolyti potential in primary Raynaud's phenomenon systemi slerosis assoiated Raynaud's phenomenon. n: Blak C M, Myers A R, eds. Progressive systemi slerosis. New York: Gower, 1985: Jarrett P E M, Morl M, Browse N L. Treatment of Raynaud's phenomenon by fibrinolyti enhanement. Br Med J 1978; ii: Masi A T, Rodnan G P, Medsger T A, et al. Preliminary riteria for lassifiation of systemi slerosis (sieroderma). Arthritis Rhewn 1980; 23: Hills M, Armitage P. The two-period ross-over linial trial. Br J Clin Pharmaol 1979; 8: Norton W L. 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