Clinical pharmacology of aminocaproic and tranexamic acids

Transcription

1 J Clin Pathol, 33, Suppl (Roy Coll Path), 14, Clinial pharmaology of aminoaproi and tranexami aids INGA MARIE NILSSON From the Coagulation Laboratory, University of Lund, Allmdnna Sjukhuset, Malmo, Sweden In a systemati searh for a substane with antifibrinolyti properties Okamoto and his group in Japan found that several merapto- and aminoarboni aids were ative. Of these substanes epsilon-aminoaproi aid (EACA) had the strongest antifibrinolyti effet.1 2 The Japanese workers desribed it as a plasmin inhibitor in vitro and useful in inhibiting proteolyti enzymes in vivo. They gave EACA in a dose of 1-2 g a day by mouth or intravenously to over 1 patients and observed no toxi effets. Their investigation did not inlude any metaboli studies. EACA has sine been widely used and its mode of ation and pharmaokinetis intensively studied. In a ontinued searh for more potent antifibrinolyti omponents p-aminomethyl ylohexane,arboxyli aid (AMCHA) was found to be more potent than EACA.3 This ompound ontains two stereoisomers. Independently Melander et al.4 and Okamoto et al.5 found that only the trans-form was antifibrinolytially ative. The antifibrinolytially ative form was alled tranexami aid (AMCA). It is 6-1 times stronger than EACA and is now used more widely. Its pharmaokinetis have been the subjet of several studies. This paper surveys the pharmaology and toxiology of EACA and AMCA. Pharmaokinetis AMINOCAPROIC ACID (EACA) The absorption, distribution, and exretion of EACA given intravenously and by mouth have been studied in man.6-8 High-voltage eletrophoresis and plasma amino-aid hromatography with ion exhange resin loaded paper were used for assaying EACA in plasma, serum, urine, and tissues.7-9 The blood was assayed for fibrinolyti ativity by measuring the plasma euglobulin lot lysis time and/or the ativity of plasma and of resuspended euglobulin preipitate on unheated and heated fibrin plates. The urokinase ativity of urine was assayed by a lot lysis method or by a fibrin plate tehnique in whih the results are expressed in 41 arbitrary urokinase units by referene to a standard urokinase preparation.' 11 Intravenous administration of 1 g EACA or 1 mg EACA/kg bodyweight produes an initial serum onentration of about 15 mg/1 ml whih falls to 3 5 mg/1 ml within 3-4 hours (Fig. 1). The biologial half life was alulated to be about 77 minutes. Andersson et al.8 found that about 7 % of the dose given intravenously was exreted in the urine within 24 hours (Fig. 2). MNiol et al.7 found 8-1I% of the given dose in the urine within 4-6 hours. The EACA is thus onentrated E 8-9 a, a, C w 1 mg EACA/ kg Intravenous o-o By mouth v Time after administration ( hours) Fig. 1 Conentration ofeaca (mg/l ml) in serum after a dose of 1 mg/kg bodyweight intravenously or by mouth. J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.

2 42-36 EA CA intravenous 32 Average reovery 284 n 2 d 16 & hours: 71 / after injetion EACA by mouth Average reovery -24hours 64' / O after ingestion Fig. 2 Urinary reovery of EACA in four men volunteers after reeiving 1 mg/kg bodyweight intravenously or by mouth. many times during exretion, urinary levels being 5 to 1 times those found in plasma. MNiol et al.7 measured the renal learane rates ofeaca in healthy volunteers at a time when their plasma EACA onentrations were stable (that is, they had reeived repeated doses of EACA). Simultaneously endogeneous reatinine learane rates were also measured. EACA learanes when the plasma onentrations were in the range of 14 to 19 mg/1 ml varied from 65 to 92 % of the reatinine learane. These findings indiated that the kidney handled EACA primarily by filtration. EACA given by mouth is rapidly absorbed, almost entirely from the gastrointestinal trat. After 1 mg/kg bodyweight by mouth the peak plasma onentration of EACA was 3 mg/1 ml two to three hours after ingestion (Fig. 1). At four hours it was 16 mg/1 ml ompared with 3 9 mg/1 ml four hours after intravenous injetion. After six hours the onentration was similar to that found after intravenous administration. Renal exretion differed from that found after intravenous injetion (Fig. 2). Only 1% of the dose had been exreted within one hour, and 25% within three hours. The 24-hour urinary reovery after the oral administration was 64%. The figure given by MNiol et al.7 is somewhat higher-namely, 78 %. EACA enters human red ells and various tissues.7 8 It appears to move in and out of the ells aording to the extraellular onentration. It is quite lear that the major portion of EACA is not metabolised in vivo. Sine not all of the EACA was reovered in the urine a small portion may be atively metabolised. In-vitro experiments and linial experiene indiate that a plasma EACA onentration of at least about 13 mg/1 ml is required to ontrol systemi fibrinolyti ativity Sine EACA is Nilsson rapidly exreted in the urine it must be given intravenously at short intervals to maintain a therapeuti level. Nilsson et al.6 12 reommended a dose of -1 g/kg bodyweight every 3-4 hours. MNiol et al.7 reommended an initial loading dose of 1 g followed by a ontinuous intravenous infusion of 1 g/hour to keep a steady plasma onentration of about 13 mg/1 ml. With these doses it has also been possible to inhibit the fibrinolyti ativity indued by infusion of streptokinase. A therapeuti onentration an also be maintained by giving -1 g/kg bodyweight every 4-6 hours.6 12 To inhibit the urokinase ativity in the urine EACA has to be present in the urine in a onentration of about.1 mol/l-that is, 1 times higher than that needed to inhibit systemi fibrinolysis in plasma. But sine the drug is greatly onentrated during exretion, the urinary onentrations being 5 to 1 times those in plasma, effetive onentrations of urinary EACA an be ahieved by giving smaller doses, whih have only a slight systemi effet. Thus a dose of 3 g EACA three times a day is suffiient to inhibit the loal fibrinolyti ativity in the urinary trat.'2 TRANEXAMIC ACID (AMCA) Andersson et al.8 13 first studied the absorption, distribution, and exretion of AMCA given intravenously and by mouth in man. They measured the aid in serum with a biologial method as well as with high-voltage paper eletrophoresis. AMCA in urine was measured by high-voltage paper eletrophoresis. After intravenous administration of 1 mg AMCA/kg bodyweight the serum onentration was 18, 1, and 5 Htg/ml after 1, 3, and 5 hours, respetively (Fig. 3). The biologial half life was alulated to be about 8 hours. About 3% was reovered in the urine during the first hour, 55 % during the first three hours, and about 9% within 24 hours (Fig. 4). After AMCA 1 mg/kg bodyweight by mouth the maximum serum onentration was only about 2,tg/ml after three hours. After 1 mg/kg by mouth a plasma onentration of 4,ug/ml was reahed within four hours (Fig. 3). Thus AMCA is not absorbed from the gastrointestinal trat so effetively as EACA. About 4% of an oral dose of 1-15 mg/kg was reovered in the urine within 24 hours (Fig. 4). Similar results have been reported by Kaller.14 More reently Eriksson et al.15 have investigated the pharmaokinetis of AMCA. Two healthy volunteers reeived 1 g AMCA intravenously. The onentration of AMCA in plasma and urine was measured by a method using high-voltage eletrophoresis. The plasma onentration urve (Fig. 5) showed three monoexponential deays. The first was J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.

3 Clinial pharmaology of aminoaproi and tranexami aids 1 I \ I \ I \ 1 mg/ kg AMCA intravenous *.-a lomg/kg AMCA by mouth - 1mg/kg AMCA by mouth o---o u Time after administration (hours) Fig. 3 Conentration of AMCA (,ug/ml) in serum after various doses intravenously or by mouth. A MCA 1 mg/ kg int ravenous A M CA 1-15 mg/ kg by mouth 3 Average reovery Average reovery 1:6 O-24h:91'/. -24h: 39/ 25 (mean of 1men) 1 meanof11 men) N 2-15 N 1N o Fig. 4 Urinary reovery of AMCA in 1 men volunteers after a single intravenous injetion of 1 mg/kg bodyweight and in 11 men after a single dose by mouth of 1-15 mg/kg. 31 C * ECP EVn.Q CT i t-) Ea, 6- O r E 1 O 8 E 2-6- A 4X g Fig. 5 Left. Plasma onentration of AMCA (,ug/ml) after single intravenous dose of 1 g. Right. Calulated amounts of AMCA after single intravenous dose of 1 g. A. Amount in entral ompartment. B. Amount in tissue ompartment. C. Amount exreted in urine. ( ) Urinary exretion, experimental points. (From Eriksson et al.'5 by permission of the Editor, European Journal of Clinial Pharmaology.) a very rapid one, the seond had a half life of hours, and the third a half life of 9-18 hours. About half of the dose was reovered unhanged in the urine during the first 3-4 hours, 9-95% within 24 hours, and % within hours.16 Fig. 5 also shows the alulated amounts of AMCA in the entral and tissue ompartments at various times and the amounts eliminated. The elimination half life was about one-fourth of the disposition half life.15 This was owing to the distribution of AMCA in the tissue ompartment, whih makes it partly unavailable for elimination. The unorreted plasma learane rate was ml/min, whih, orreted for an average plasma protein binding of 15 %, approximately equalled the glomerular filtration. This indiates that AMCA is eliminated by glomerular filtration and that neither tubular exretion nor absorption takes plae. Impairment of renal funtion prolongs the biologial half life of AMCA. Thus in patients with serum reatinine onentrations of > 5,umol/l (5-6 mg/1 ml) the half life was 24 to 48 hours.'7 Vessman and Str6mberg18 have developed a rapid gas hromatographi method for measuring AMCA in small biologial samples. The lower limit of detetion is 4 pg/ml. They studied the plasma onentration of AMCA after giving 5 g and 2- g by mouth. Peak onentrations of about 5 and 15,ug/ml, respetively, were noted within 2-4 hours. After 12 hours the onentration was less than 1,ug/ml. Like EACA, AMCA is widely distributed throughout the extraellular and intraellular ompartments. AMCA 1 g given 4-hourly intravenously to patients with subarahnoid haemorrhage enters the erebrospinal fluid at a onentration of about 2-5 jug/ml.19 Ahlberg et al.2 gave 1 mg AMCA/kg bodyweight to patients before knee joint operations. They found that AMCA rapidly diffused into the joint fluid and synovial membranes and reahed the same onentration in the joint fluid as in the serum. The biologial half life in the joint fluid was about 3 hours. Bramsen2' has investigated the aqueous humour onentration of AMCA after oral administration of the drug. On a dose of 25 mg AMCA/kg bodyweight three times a day the onentration within three hours was 1-6,ug/ml ompared with a serum onentration of 15,tg/ml. The AMCA disappeared slowly from the aqueous humour. Given by mouth or intravenously AMCA diffuses into semen and inhibits its normally high fibrinolyti ativity. AMCA has no effet on the motility of spermatozoa.22 AMCA passes transplaentally to the fetus.23 After intravenous injetion of 1 mg/kg bodyweight the onentration in the fetal serum may be anything between 4 and J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.

4 44,ug/ml. Tranexami aid an be found in the milk of latating women given AMCA (Eriksson, personal ommuniation), but the onentration is very low and is about 1/1 of that in the maternal plasma. AMCA and EACA are distributed among various tissues. The tissues ontain plasminogen ativators, whih the antifibrinolyti drugs inhibit Normal tissue ativators most probably do not indue but rather sustain bleeding, sine they dissolve the small lots sealing opened vessels and essential for the first stage of wound healing. In treating loal fibrinolysis due to the ation of tissue ativators it is important to know whih onentrations of the drugs are required and also how long the fibrinolyti inhibitor persists in different tissues. Andersson et al.8 studied the fibrinolyti ativity of various tissue extrats obtained at operation in the presene of inreasing onentrations of AMCA and EACA. A 98-1O% redution of the tissue ativator ativity required the presene of AMCA in a onentration of about 1,ug/ml. The orresponding onentration for EACA was 1 jug/ml. An 8% inhibition required 1,ug/ml of EACA or 1 Hg/ml of AMCA. Judging from linial experiene an 8% inhibition is suffiient to suppress the ativity. Andersson et al.8 measured the fibrinolyti ativity and the onentration of AMCA and EACA in serum and in piees of human tissue (olon, kidneys, prostate) obtained at operation. The fibrinolyti ativity of homogenates of the tissues was measured on unheated fibrin plates and the onentration of AMCA and EACA with highvoltage eletrophoresis. AMCA was given hours before the operation in four doses of about 1-2 mg/kg bodyweight eah. The orresponding dose of EACA was 1 mg/kg. The last dose was given at various intervals before operation. The results showed that the antifibrinolytially ative onentration of AMCA (1,tg/ml) persisted longer in the tissues examined than did the orresponding onentration of EACA (1,ug/ml). AMCA thus has not only a higher fibrinolyti ativity than EACA but it also persists longer in the tissues. After repeated intravenous or oral doses of AMCA (1 mg/kg intravenously 4-5 times a day or 2 mg/kg by mouth 3-4 times a day) an adequate antifibrinolyti ativity in tissues an be maintained for up to 17 hours without any further dose. Risberg26 found a retention of AMCA in the lung tissue in rats. Judging from in-vitro experiments and linial experiene ontrol of systemi fibrinolysis requires a plasma AMCA onentration of about 1-15,ug/ml. Sine the drug is rapidly exreted in the urine it must, like EACA, be given intravenously at Nilsson short intervals to maintain a therapeuti level. Andersson et al.8 13 reommended a dose of 1 mg/kg bodyweight every 3-4 hours. AMCA is not so readily absorbed as EACA and therefore when given by mouth is only three times as ative as EACA. An oral dose of about 3-4 mg/kg bodyweight every 4-5 hours should be optimal in treating onditions with generalised fibrinolysis. For inhibiting tissue ativators-that is, in the treatment of onditions assoiated with loal fibrinolysis- AMCA has been reommended in a dose of about 2 mg/kg 3-4 times a day. Inhibition of urokinase ativity in the urine requires an AMCA onentration of about 2,ug/ml. After AMCA by mouth in a dose of 1 mg/kg bodyweight the fibrinolyti ativity of the urine is muh redued (Fig. 6). A dose of 1-2 g two to three times a day is suffiient to inhibit the urokinase ativity in the urine ' 6-4, 4-4X a ol 1 op I. 12 2A 48 Fig. 6 Fibrinolyti ativity of urine after AMCA 1 mg/kg bodyweight by mouth. Toxiology Both EACA and AMCA are of low aute toxiity.4 No fetal abnormalities have been found in teratogeni studies in rats, rabbits, and mie given AMCA in doses of up to 5,ug/kg a day. Retinal hanges have been reported in dogs after reeiving AMCA by mouth over a period of one year in doses approximately seven times higher than the maximum reommended daily dose for man. No suh hanges were seen in dogs given for a year three and a half times the maximal oral dose per kg bodyweight reommended for man, in rats given seven times the maximal human dose for 22 months, or monkeys that had been given 18 times the maximal intravenous dose for 14 days.28 Neither were any retinal hanges seen in patients treated with AMCA for months or years (Pandolfi, personal ommuniation). In patients to be treated ontinuously for several weeks, however, visual auity, olour pereption, the oular fundi, and fields of vision should be reviewed. J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.

5 Clinial pharmaology of aminoaproi and tranexami aids Adenoma and adenoarinoma of the liver have been reported in rats after 22 months' oral treatment with about 27 times the maximum dose of AMCA/kg bodyweight reommended for man, but not after 12 months' treatment. No suh tumours have been seen in rats given six times the maximum daily dose per kg bodyweight reommended for human beings.28 Carroll and Tie29 found that doses of 3 to 14 g of EACA/kg given intravenously to nephretomised dogs produed hyperpotassaemia. They believed that EACA is taken up by musle ells and thereby inreases the esape of intraellular K+. Musle pain with inreases in the serum enzymes, reatinine phosphokinase, and aldolase have been reported in linial investigations of EACA in patients with hereditary angioneuroti oedema.3 In one ase Korsan-Bengtsen et al.31 found Zenker's hyaline degeneration in musle ells in a musle biopsy speimen. Wysenbeek et al.32 have reently reported a patient who developed an aute delirious state after EACA administration. No residual psyhiatri or neurologial symptoms were observed. The side effet was thought to be related to the antifibrinolyti effet of the drug sine a similar reation has been reported with another antifibrinolyti drug, Trasylol, whih ats ompletely differently to EACA. EACA given to dogs and female rats in large doses has resulted in a 5 % redution of fertility but this was reversible.33 EACA and AMCA, though less often, may ause nausea, diarrhoea, nasal stuffiness, and onjuntival suffusion. Oasionally EACA produes orthostati symptoms; AMCA does so only rarely. A fall in blood pressure has been reported in a few ases after administration of AMCA An important question is whether treatment with EACA or AMCA predisposes to thrombosis and intravasular oagulation. There are isolated reports of arterial or venous thrombosis assoiated with EACA therapy, but in eah ase a disease known to predispose to thrombosis has also been present.1' 36 Furthermore, Rydin and Lundberg37 have reported two patients reeiving AMCA to ontrol menorrhagia and Davies and Howell38 one patient treated with AMCA for hereditary angio-oedema who developed intraranial arterial thrombosis. Detailed studies using phlebography39 or 1251-fibrinogen uptake4 have shown no hange in the inidene of venous thrombosis attributable to treatment with EACA after prostatetomy. In a double-blind multientre study of 515 patients untreated or treated with EACA the mortality due to pulmonary embolism and myoardial infartion was largely similar in both groups.41 Hedlund42 reported the inidene of thrombosis as deteted by the 1251 fibrinogen uptake test in 21 prostatetomy patients, 1 of whom had taken 1 g AMCA three times a day and 11 a plaebo. There was no statistially signifiant differene in the inidene of thrombosis between the two groups. In tissue ultures of human veins the ativator ontent is unaffeted by ulture in media ontaining AMCA (1 mg/ml).43 On the other hand, there is no doubt that EACA and AMCA an perpetuate existing fibrin deposits.4445 Saldeen46 found that antifibrinolyti therapy auses persistent fibrin deposits in the lung. Conlusion EACA and AMCA are potent antifibrinolyti drugs. AMCA is 7-1 times more potent than EACA by in-vitro and in-vivo assay. The pharmakokinetis of the drugs are now known and rational dose regimens for treating systemi and loal fibrinolysis have been worked out. The drugs have no serious side effets. There is no evidene that they predispose to thrombosis but they may perpetuate existing fibrin deposits. The following dosages are reommended for various bleeding onditions. Systemi fibrinolysis This relatively rare linial ondition requires EACA 1 mg/kg intravenously at about 3 hourly intervals. After the first injetion EACA an be given by mouth. AMCA 1 mg/kg intravenously 3-4 hourly will give an adequate inhibitory plasma onentration. After an initial intravenous dose about 3-5 mg/kg by mouth may be given 3-4 hourly. Loal fibrinolyti bleedings For inhibiting tissue ativators EACA 1 mg/kg intravenously or by mouth should by given three to four times a day. Owing to its sustained tissue ativity AMCA 1-2 mg/kg may be given by mouth three to four times daily. Haematuria Urokinase ativity in urine has been effetively inhibited by EACA 5 mg/kg 8 hourly intravenously or by mouth. Judging from urinary exretion studies, AMCA 1 mg/kg intravenously or 2 mg/kg by mouth two to three times a day gives satisfatory results. This investigation was supported by grants from the Swedish Medial Researh Counil (B8-19X-87-16C). Referenes 1 Okamoto S. Ref. to British Patent Speifiation 1957; 77, J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.

6 46 2 Okamoto S, et al. A suppressing effet of E-amino-naproi aid on the bleeding of dogs, produed with the ativation of plasmin in the irulatory blood. Keio J Med 1959;8: Okamoto S, Okamoto U. Amino-methyl-ylohexanearboxyli aid: AMCHA. A new potent inhibitor of the fibrinolysis. Keio J Med 1962;11 : Melander B, Glinieki G, Granstrand B, Hanshoff G. The antifibrinolytially ative isomer of AMCHA. Abstrats of the Xth International Congress of Haematology, Stokholm, Aug 3-Sept :G68. Okamoto S, et al. Behaviour of tissue ativators and the ation of a series of potent inhibitors on fibrinolysis. Abstrats of the Xth International Congress of Haematology, Stokholm, Aug 3-Sept : G65. 6 Nilsson IM, Sjoerdsma A, Waldenstrom J. Antifibrinolyti ativity and metabolism of e-aminoaproi aid in man. Lanet 196;1: MNiol GP, Flether AP, Alkjaersig N, Sherry S. The absorption, distribution, and exretion of E-aminoaproi aid following oral or intravenous administration to man. J Lab Clin Med 1962;59: Andersson L, Nilsson IM, Collen S, Granstrand B, Melander B. Role of urokinase and tissue ativator in sustaining bleeding and the management thereof with EACA and AMCA. Ann NY Aad Si 1968; 146: Sjoerdsma A, Hansson A. Determination of -aminoaproi aid in urine by means of high-voltage paper eletrophoresis. Ata Chem Sand 1969;13: MNiol GP, Flether AP, Alkjaersig N, Sherry S. The use of epsilon aminoaproi aid, a potent inhibitor of fibrinolyti ativity, in the management of postoperative hematuria. J Urol 1961 ;86: Andersson L. Fibrinolyti states in prostati disease and their treatment with epsilon-aminoaproi aid. Ata Chir Sand 1963;126: Nilsson IM, Andersson L, Bjorkman SE. Epsilonaminoaproi aid (E-ACA) as a therapeuti agent. Based on 5 years' linial experiene. Ata Med Sand (Suppi) 1966; Andersson L, Nilsson IM, Nilehn J-E, Hedner U, Granstrand B, Melander B. Experimental and linial studies on AMCA, the antifibrinolytially ative isomer of p-aminomethyl ylohexane arboxyli aid. Sand J Haematol 1965 ;2: Kaller H. Enterale Resorption, Verteilung und Elimination von 4-Aminomethylylohexanarbonsaure (AMCHA) und 6-Aminoapronsaure (ACS) beim Menshen. Naunyn Shmiederbergs Arh Pharmaol 1967;256: Eriksson, Kjellman H, Pilbrant A, Shannong M. Pharmakokinetis of tranexami aid after intravenous administration to normal volunteers. Eur J Clin Pharmaol 1974 ;7: Kjellman H. Comments by the manufaturer of yklokapron. In: Verstraete M, ed. Haemostati drugs. A ritial appraisal. The Hague, Martinus Nijhoff Medial Division, 1977: Andersson L, Eriksson, Hedlund PO, Kjellman H, Lindqvist B. Speial onsiderations with regard to Nilsson the dosage of tranexami aid in patients with hroni renal diseases. Urol Res 1978;6: Vessman J, Stromberg S. Determination of tranexami aid in biologial material by eletron apture gas hromatography after diret derivatization in an aqueous medium. Anal Chem 1977;49: Tovi D, Nilsson IM, Thulin C-A. Fibrinolysis and subarahnoid haemorrhage. Inhibitory effets of tranexami aid. A linial study. Ata Neurol Sand 1972 ;48 : Ahlberg A, Eriksson, Kjellman H. Diffusion of tranexami aid to the joint. Ata Orthop Sand 1976; 47: Bramsen T. Effet of tranexami aid on horoidal melanoma. Ata Ophthalmol 1978;56: Liedholm P, Astedt B, Kullander S. Passage of tranexami aid (AMCA) to semen in man and its effet on the fibrinolyti ativity and on migration of spermatozoa. Fertil Steril 1973 ;24: Kullander S, Nilsson IM. Human plaental transfer of an antifibrinolyti agent (AMCA). Ata Obstet Gyne Sand 197;49: Nilsson IM. Loal fibrinolysis as a mehanism for haemorrhage. Thromb Diathes Haemorrh 1975;34: Thorsen S. Influene of fibrin on the effet of 6-aminohexanoi aid on fibrinolysis aused by tissue plasminogen ativator or urokinase. In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC, eds. Progress in hemialfibrinolysis and thrombolysis, vol 3. New York: Raven, 1978 : Risberg B. Effet of tranexami aid on pulmonary tissue fibrinolysis in the rat. Mirovas Res 1976;11: Andersson L, Nilsson IM. AMCA (aminomethyl ylohexane arboxyli aid, Cyklo-kapron) a potent haemostati agent in urinary trat bleeding. Sand J Urol Nephrol 1969;3: Kjellman H. Syntheti antifibrinolytis. In: Nilsson IM, ed. Haemorrhagi and Thromboti Diseases. London: John Wiley, 1974: Carroll HJ, Tie D. The effets of epsilon-aminoaproi aid upon potassium metabolism in the dog. Metabolism 1966;15: Frank MM, Sergent JS, Kane MA, Alling DW. Epsilon aminoaproi aid therapy of hereditary angioneuroti edema. NEnglJMed 1972;286: Korsan-Bengtsen K, Ysander K, Blohme G, Tibblin E. Extensive musle nerosis after long-term treatment with aminoaproi aid (EACA) in a ase of hereditary periodi edema. Ata Med Sand 1969;185: Wysenbeek AJ, Sella A, Blum I, Yeshurun D. Aute delirious state after e-amino aproi aid administration. Clin Toxiol 1979;14: Eneroth G, Grant CA. Epsilon aminoaproi aid and redution in fertility of male rats. Ata Pharm Sue 1966;3: Vermylen J, Verhaegen-Delerq ML, Verstraete M, Fierens F. A double-blind study of the effet of tranexami aid in essential menorrhagia. Thromb Diathes Haemorrh 1968;2: J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.

7 Clinial pharmaology of aminoaproi and tranexami aids 35Hedlund PO. Antifibrinolyti therapy with yklokapron in onnetion with prostatetomy. Sand J Urol Nephrol 1969;3: Naeye RL. Thromboti disorders with inreased levels of antiplasmin and antiplasminogen. N Engl J Med 1961 ;265: Rydin E, Lundberg PO. Tranexami aid and intraranial thrombosis. Lanet 1976;2: Davies D, Howell DA. Tranexami aid and arterial thrombosis. Lanet 1977;1: Beker J, Borgstrom S. Inidene of thrombosis assoiated with epsilon-aminoaproi aid administration and with ombined epsilon-aminoaproi aid and subutaneous heparin therapy. Ata Chir Sand 1968 ;134: Gordon-Smith IC, Hikman JA, El Masri SH. The effet of the fibrinolyti inhibitor epsilon-aminoaproi aid on the inidene of deep-vein thrombosis after prostatetomy. Br J Surg 1972;59: Vinniombe J, Shuttleworth KED. Aminoaproi aid in the ontrol of haemorrhage after prostatetomy: a ontrolled trial. Lanet 1966;1: Hedlund PO. Postoperative venous thrombosis in benign prostati disease. A study of 316 patients, using the 1251-fibrinogen uptake test. Sand J Urol Nephrol (Suppl) 1975 ; Astedt B, Pandolfi M, Nilsson IM. Quantitation of fibrinolyti agents released in tissue ulture. Experientia 1971 ;27: Stark SN, White JG, Langer L, Jr, Krivit W. Epsilonaminoaproi aid therapy as a ause of intrarenal obstrution in haematuria of haemophilias. Sand J Haematol 1965;2: Gobbi F. Use and misuse of aminoaproi aid. Lanet 1967;2: Saldeen T. Quantitative determination of intravasular oagulation in the lungs of experimental animals. Sand J Haematol 1969;6: J Clin Pathol: first published as /jp.s on 1 January 198. Downloaded from on 4 July 218 by guest. Proteted by opyright.