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A Synthetic Anticoagulant: A Polysulfuric Acid Ester of Polyanhydromannuronic Acid (Paritol) Experience with Its Use in Man Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 By C. W. SORENSON, M.D. AND IRVING S. WRIGHT, M.D. The effects of the use of Paritol administered intravenously to 35 individuals are herein reported. This synthetic anticoagulant produces a prolongation of the clotting time similar to that produced by heparin but of longer duration, if appropriate dosage is used. As with heparin, at therapeutic clotting time levels, the prothrombin time is slightly prolonged. Certain untoward effects have been noted and are described. Further studies with Paritol appear justified in order to evaluate its usefulnes3 as a rapidly acting anticoagulant. is concerned with further studies made on the action of Paritol in man. T HE AVAILABILITY of a rapidly acting anticoagulant is extremely important in the treatment of medical and surgical thromboembolic conditions. The most serious handicaps in the use of heparin in this role has been the difficulty of its preparation and the resulting high cost which seriously limit its clinical use. Chemical studiesl-3 on the structure of heparin indicate that it is a polysaccharide esterified with sulfuric acid. Therefore, considerable work4-7 has been done on the synthesis of various polysaccharide sulfuric acid esters having anticoagulant activity. Most of these synthetic compounds have been found to be toxic when administered to animals and thus have no clinical value. Seifter and Begany' reported studies on the pharmacology and toxicology of a polysulfuric acid ester of polyanhydromannuronic acid (Paritol) which suggested its possible clinical use. The anticoagulant activity of this material and its low -toxicity in animals warranted further investigation. A preliminary report relating to its use in man appeared in 1949.9 The present report METHOD Observations have been made on the administration of Paritol* to 35 individuals. Their ages ranged from 20 to 70 years. Thirty-one were males; 4 were females. Four were normal controls; 31 had a variety of disease conditions, including pulmonary infarction, thrombophlebitis, thromboangiitis obliterans, axillary vein thrombosis, carcinoma of the lung, arteriosclerosis obliterans, myocardial infarction, diabetes mellitus, embolus to a peripheral artery from a fibrillating rheumatic heart, and postoperative arterial-venous anastomosis. In 15 patients the drug was used therapeutically because of some thromboembolic disease; in the other 16 it was given to observe its effect. With 2 exceptions, patients were selected who showed no evidence of liver or kidney disease, or allergic or hemorrhagic tendencies. One exception was a patient who had chronic nephritis complicating rheumatic heart disease with a pulmonary infarction. The other had arteriosclerotic heart disease, auricular fibrillation, congestive heart failure, early cirrhosis of the liver, and multiple pulmonary emboli. The effects of the intravenous administration of Paritol were observed for the following: the From the Department of Medicine, The New York Hospital-Cornell University Medical College. This work was conducted under the auspices of the Committee on Anticoagulants of the American Heart Association aided by grants from the Samuel H. Kress Foundation, the Albert and Mary Lasker Foundation, the Lillia Babbitt Hyde Foundation and the Julius W. Hampil Foundation. * Supplied through the courtesy of Wyeth, Inc. 658 Circulation, Volume II, November, 1950. 659 C. W.SORENSON AND I. S. WRIGHT response of the blood pressure, pulse, and respirations; delayed reactions as manifested by temperature rise or allergic manifestations; alterations in the clotting time, the red blood cell count, the white blood cell count, and the sedimentation rate; changes in kidney function as manifested by changes in the urine, the blood urea nitrogen, and the phenolsulfonthalein test; and alterations in liver function as indicated by cephalin flocculation, thymol turbidity, total protein, and bromsulfalein excretion. Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 The anticoagulant action was measured by a modification of the Lee-White procedure. After careful venepuncture and release of the tourniquet, approximately 2 ml. of blood were drawn through the needle. This blood and syringe were discarded, leaving the needle in place. Approximately 5 ml. of blood were then drawn carefully into a silicone coated syringe, with a stop-watch being started at this time. One ml. of blood was immediately placed in each of three dry Pyrex tubes, 10 mm. in diameter. Each tube was tipped gently at one minute intervals and the end point taken as the time when the blood held a vertical surface with the tube in a horizontal position. The three tubes were measured simultaneously and the clotting time reported was the average of the three tubes. By this method the average clotting time of 47 control determinations was 9 minutes, with a range from 6 to 12 minutes. Careful adherence to this technic was maintained; all blood specimens were drawn by the same individual and all the end points were determined by one of two individuals in order to obtain the maximum accuracy possible with this method. Prothrombin times were done by the Link-Shapiro modification of the Quick one-stage method, using dried rabbit lung thromboplastin. The anticoagulant action of Paritol was compared with that of heparin by observations of the clotting time following the intravenous administration of the sodium salt of heparin (Li- quaemin, Roche). The Paritol was obtained as a sterile solution of the water soluble sodium salt which is stable at room temperature. It was given intravenously in 1, 5, and 10 per cent solutions, allowing 5 to 10 minutes for slow administration of the given amount. The 10 per cent solution was found to be the most convenient dilution to use. RESULTS Clotting Times Single Doses. The averages of the results obtained by following the clotting times after single doses of 2 mg. per Kg. and 5 mg. per Kg. of 10 per cent Paritol solutions (Lot Nos. L-81B and 286) are shown in table 1. TABLE 1.-Average Clotting Times Obtained After. Single I.V. Dose Of Paritol (10% Solution) Clotting Time in Minutes Time After Administration of Paritol 2 mg./Kg. 5 mg./Kg. Average-2 curves Average-21 Curves 9 55 38 26 20 16 11 12 8 39 Control 30 min. 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours 14 18 12 TABLE 2.-Average Clotting Times Obtained After Single I.V. Dose of Heparin (10% Solution) Time After Administration of Hepari Control 30 min. 2 hours 4 hours 6 hours Clotting Time in Minutes 0.8 mg/Kg. 1.0 mg./Kg. Average-4 Average-3 Average-3 .- 0.5 mg./Kg. curves curves curves 10 37 13 10 10 47 23 10 10 74 45 14 9 For comparison, the averages of the clotting times obtained after the administration of heparin in single intravenous doses of 0.5, 0.8, and 1.0 mg. per Kg. are shown in table 2. Repeated Doses. Ten patients with thromboembolic conditions have been treated with repeated doses of Paritol for periods over 48 hours. The longest period of therapy has been eight days in each of 2 cases. The total amount of the drug given ranged from 250 mg. in a 48 hour period to 3440 mg. in a 5 day period as shown in table 3. Average clotting times obtained during these periods of the repeated administration of Paritol in amounts of 2 mg., 3 mg., and 5 mg. per Kg. are shown in table 4. C.IC c Ci I m . l cq cq , '- ) oocj c oC _ ___ _- dq - cq LO bC N °o m°5 CD CD Ip ,iCl) _ cq~~~~~cc cq 4 ° I O0 mI CO 1OCe- o '-4 CO °0 t_ 00 0 CmO CO 0 0I 0 0 0 qmIuu0q c O0 OD c c oo t o < oo pp I I) Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 -s - CO ~- , t -{ Cl C- CO _Il 0a -s _I - O' - ~ l' - B~~~~~~~~~~~~~~~~~~~~~~~P P bo o pp w C-CO 0 Q4 bo C CO)-CO t>C10 bo 0 bi) ho_bOh 0 0I o P *C) 4) . n . QOOo a Wy~~C <; C.@0o - - ____ - C) C)C) I. . . . . DCD0C to 0 m- 0 0 nO lt - C)CO - -- ClC - m000000 CDOCl,-440 0 cO C) C) cr cr Cl '- - l 0 000 0 DC c 0 - O O . 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CoC cdCO COIO ~~~~~ CO4|'C 41 O10C- C 10 ~4 QQQ 18 12 12 1z~4 12 1G' 0o Io 1t- 0 1 ~ COO Q0b) u1 CN 660 c- C -I1~~0 C 1H__0 C H t-..I ^H -~~~~~~~~~~- Q 18 S 12 1 ° |N) N o eq mO CV co e N es 0 O 0 0 oc4 _ oo N -e '0 0 00 t-. 0003 CO t- _I X eCOC m OO0o00 _: eq 0 eq - X00 N eq O t CCO eqeq 0O t- CID cc CO + eq O0 0 CO C 0 - 0 '0 4 C '0 It eq ; eq ' u4 cmO C '0 0 _e ee a:t>t tt CD C e C s s t + ' e 0 CD + +~~~~~~~~~ce + CO e 0 0 0 e CO c Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 0~~~~~~~~~ 0 C0 e) CO oo o Co I u sI) aC) e ) eq 00 0 0 t -4 _l 0 |~_N C|O 4 _ _, 0 0 -z '-4-oo-.0 00 0 0 0 0 0 CO 00 '-4 - '-i - 0 C0 0c 0C0 0 000 '4 _ _ _ '0N _ _ _ P- I !q- CO eq 6611 0 _ S -o0U0 - eq l~t _ 0 q '0!4eq 2 !eq'0 Y) 0 CO '0 _J I04 0 ~ )Q)C 0 4 P4 e'0 e 0 0 ~ 0 _1i O OC o-0~ ~'0COCO O - 0 ~ 004 0 0 C ) A ~ 0 -0 & CO 00q| 00 00 CD toC) C C ,C) C) '0 0 0 _ O~~~~~~~~~00 O q~ 00 - 0c H ' . CD CO q 0 0 0o 0'0 0 0 eq COb 'CO 10 - * * ' N est ._ 'i ._ Io U, CO CO . - e ,qjn,IUxgqj, |q N + | 'O *oj:Iq oO I-b -n 0 q~n~ui~cqj~ q 0 t r_ |'cD q CO oO cO 0 I C rm C5 4c]f10 4 .: p 110 ~~ o 1 0~~c 0 1 550 Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 i C) 00 00 e s 0 ~~~~~~~~CO N CO U,~~~~~~~~~~~~~~~- 1) ___q eq o oo .0$ r. z 0 Pt~~. c k z CO CD _ _ cq cq cq 00-koCC~ N CDC c] Z CcD tCYD z 1 s0 occo 0 CO -Q ___ - m_ ~~~ m CO CO -z O+ t to ~.O ~ ~ I ° - 0" I0," .P & I~ - 10 O . 0 . Cd Cd On I ce ee 02~~~~~~ I >o~~~~~~~~~~~~~~~~~~c < o (4~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-. t_ | -I § ||410 CdI 10 10 P-( uz~ ~ 1 10 CO _el -10 4) CO 662 0 ~ ~ ~ - 10 10 _ 0 bl10 C. W. SORENSON AND I. S. WRIGHT Prothrombin Times. The effect of the administration of Paritol on the prothrombin time as determined by the Link-Shapiro modification of the Quick one-stage test is shown in table 5. TABLE 4.-Average Clotting Times Obtained During Maintenance Treatment With Repeated Doses of Paritol I.V. (10% Solution) Clotting Time in Minutes Time After Administration of Paritol 2 mj g./Kg. Aver age-22 3 mg./Kg. Average-7 Cuirves Curves Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 Before any Paritol administered..... Before next dose of Paritol ........... 30 min........ 8 hours...... 10 hours...... 12 hours...... 5 mg./Kg. Average-19 Cut lies 9 8 9 114 t 50 15 13 55 12 69 k 18 15 16 TABLE 5.-Prothrombin Time Determinations after 5 mg./Kg. of Paritol I.V. (10% Solution) Prothrombin Time in Sec. Time After Paritol Clotting Time in Minutes Administration UndilutedPlasma Diluted-12.5% 16 23 22 17 38 47 41 39 100% Control 30 min. 2 hours 4 hours 6 hours 7 57 32 15 14 Plasma 6.-Prothroinbin Time Determinations after Heparin 1 mg./Kg. I.V. (10% Solution) TABLE Time After Tieparter Administration Clotting C Time Clotting Time in Minutes Prothrombin Undiluted100% Plasma Time in Sec. Diluted-12.5% Plasma Control 10 15 37 30 min. 2 hours 74 45 14 10 24 19 16 42 39 39 4 hours 6 hours For comparison, the prothrombin times obtained following the administration of heparin are shown in table 6. The Effect of Paritol on Other Laboratory Deter- minations Table 3 summarizes the laboratory determinations done on the 10 patients given re- 663 peated doses of Paritol for periods over 48 hours. Hemoglobin, Red Blood Cell Count, and White Blood Cell Count. No change in these values has been observed that could be attributed to Paritol. Platelets. No change in the platelets was observed as determined by the estimation of the number of platelets in relation to red blood cells on stained smears. Kidney Function. There was no change noted in the urine with the administration of Paritol. Case 21, a patient with no recognized renal disease prior to administration of the drug, showed a rise in the blood urea nitrogen from 11 mg. to 26 mg. per 100 cc. after receiving 1680 mg. of Paritol over a period of four days. During this same time he was receiving Thiomerin 2 ml. daily. The Paritol was discontinued and the blood urea nitrogen continued to rise to 30 mg. per 100 cc. Three days later, Thiomerin was stopped and the blood urea nitrogen promptly fell to within normal range. The data indicated that the urea retention was due more probably to the action of the Thiomerin than of the Paritol. Case 28, a patient with pulmonary infarction, rheumatic heart disease, congestive heart failure, and chronic nephritis with a consistently elevated blood urea nitrogen of about 30 mg. per 100 cc. was given 380 mg. of Paritol in two days. There was a rise in the blood urea nitrogen to 54 mg. per 100 cc., following which the Paritol was discontinued. The blood urea, nitrogen then fell to the pretreatment level of around 30 mg. per 100 cc. Four hundred eighty mg. of Paritol was then administered during three days and the blood urea nitrogen rose to 60 mg. per 100 cc. After the Paritol was discontinued the blood urea nitrogen gradually returned to the former level (30 mg. per 100 cc.). The Paritol was considered to be responsible for the increased urea retention occurring in the presence of decreased kidney function. There was no evidence that the drug had cause(1 a further permanent decrease in the renal function. Liver Function. One patient (case 23) had arteriosclerotic heart disease, auricular fibrillation, congestive heart failure, multiple 664 A SYNTHETIC ANTICOAGULANT Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 pulmonary infarctions, and evidence of early cirrhosis of the liver. Before Paritol was administered, the cephalin flocculation was elevated to 12 units (normal, below 5) and the thymol turbidity was 6 units (normal, below 5). During the period he received the drug the cephalin flocculation rose to 18 units and the thymol turbidity to 9 units. Twenty-five days after the treatment, the cephalin flocculation was 7 units and the thymol turbidity was 7 units. This patient was extremely ill during the first two weeks of hospitalization and it was impossible to determine with certainty whether the drug was responsible for the evidence of increased liver damage. On a clinical basis, however, the impairment of liver function might well have been due to his serious illness and not to a toxic effect of the drug. No other patients developed any evidence of liver damage following the administration of Paritol. Effect of Paritot on the Blood Pressure, Pulse, and Respirations The pulse, respiratory rate, and blood pressure determinations during and after the administration of Paritol to 13 patients are shown in table 7. The systolic blood pressure of patient 7 decreased 20 mm. Hg during the administration of 350 mg. (6 mg. per Kg.) of the drug without a corresponding decrease in the diastolic pressure (120/75 to 100/70). Two days later his pressure was found to be at the reduced level (100/65). A second dose of 400 mg. (7 mg. per Kg.) of the drug produced no change in the pressure. Patient 9 showed no change in blood pressure with the first administration of 400 mg. (4.2 mg. per Kg.) of Paritol. Two days later he was given 325 mg. (3.5 mg. per Kg.) and with this there was a transient fall in the systolic and diastolic pressures (126/66 to 106/54) associated with flushing of the face and a feeling of fullness in the epigastrium. These minor manifestations disappeared spontaneously within fifteen minutes after the injection was completed. Reactions to Paritol Of the 35 patients to whom Paritol has been given, 3 have shown immediate reactions: one of these was severe, two were mild. The severe reaction occurred in a 40 year old woman (patient 2) with rheumatic heart disease, auricular fibrillation, mitral stenosis, and an embolus to the left popliteal artery. She had received three injections of Paritol in amounts of 125 mg. (2 mg. per Kg.), 185 mg. (3 mg. per Kg.), and 185 mg. on successive days without reaction, although she later stated that with two of these she had felt "uneasy." The fourth dose, administered the next day, was 315 mg. of a 1 per cent solution (5 mg. per Kg.). About five minutes after the completion of the injection the patient developed nausea, vomiting, abdominal cramps, defecation, oppression in the precordial area, pallor, sweating, bradycardia and a fall in the blood pressure to imperceptible levels. These manifestations subsided rapidly following the administration of of 0.3 mg. of epinephrine subcutaneously and within 30 minutes the blood pressure had returned to normal levels and the patient was feeling much improved. It is noteworthy that this patient developed similar, but less severe reactions to the intravenous administration of papaverine and had a somewhat similar reaction to magnesium sulfate used in determining the circulation time. Two patients (cases 7 and 24) developed a reaction following Paritol administration which the authors have not previously encountered with any drug. This consisted of the development within 15 minutes of "pins and needles" sensations in the hands and feet followed by a moderate swelling of the hands, and to a lesser degree of the feet. This was associated with stiffness of the finger joints and inability to close the fingers completely. In one patient this swelling subsided spontaneously in about eight hours. In the second, the administration of 0.3 mg. of epinephrine subcutaneously was followed by a decrease in the symptoms of tingling in the hands and feet and stiffness of the fingers within 20 minutes. The swelling gradually disappeared within about six hours. Neither patient showed any evidence of urticaria elsewhere nor did they develop respiratory signs or symptoms. Neither gave personal or family histories of allergic manifestations. One patient with an acute pulmonary in- TABLE 7.-Blood Pressure, Pulse, and Respiration Changes during Paritol Administration in 13 Cases #3 2mg./Kg. # 4 Smg./Kg. #5 6mg/Kg. Time ls B.P. 110/72 Control Start injection 4 min. 6 min. 8 min. 10 min. End Injection 2 min. 5 min. 10 min. 15 min. 20 min. 116/80 112/78 120/84 118/80 118/80 P R B.P. P R 116/66 120/70 122/74 76 72 76 18 20 20 110/88 120/80 118/84 122/88 50 74 60 58 16 16 20 16 128/74 118/68 88 80 28 22 125/68 80 20 118/68 64 20 118/80 124/80 120/84 118/82 118/86 56 60 64 58 54 16 16 16 16 16 p R B.P. P R B.P. 84 16 130/70 72 20 20 20 16 16 16 80 80 78 78 80 130/75 130/70 132/75 140/80 130/70 68 68 72 80 76 20 16 20 20 20 # 6 8mg/Kg. # 7 6mg/Kg. # 7 7mg./Kg. #8 6mg./Kg. #9 Smg./Kg. Time P R BRP. P R B.P. P R B.P. P R 120/75 120/78 118/74 115/75 100/70 104/68 60 60 60 78 96 92 16 16 16 16 12 16 96/64 100/65 98/65 98/65 98/62 100/68 68 68 64 68 68 68 20 20 20 24 20 20 134/86 150/86 120/80 115/78 132/90 130/90 92 94 96 88 100 96 24 28 20 20 16 20 120/78 126/70 120/76 120/76 122/76 118/68 76 76 80 76 82 80 16 16 16 16 96/68 106/72 104/74 104/72 100/72 68 64 64 64 68 16 16 20 20 16 98/64 98/64 96/62 72 72 72 20 20 20 138/90 100 20 118/70 82 16 130/86 92 20 122/74 84 16 68 20 132/88 92 20 B.P. Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 Control Start Injection 4 min. 6 min. 8 min. 10 min. End Injection 2 min. 5 min. 10 min. 15 min. 20 min. 96/62 #9b 5mg./Kg. # 11 5 mg/Kg. # 10 Smg./Kg. Time B.P. 126/66 Control Start Injection 4 min. 6 min. 8 min. 10 min. End Injection 2 min. 5 min. 10 min. 15 min. 20 min. l~ P 100 # 125 mg./Kg. P R B.P. P R 88 16 150/90 18 18 18 18 18 18 134/100 100 I 24 160/80 160/80 150/100 150/100 92 92 88 92 92 92 134/100 130/94 112 100 24 24 155/78 92 18 132/98 96 24 155/70 150/95 148/100 150/100 B.P. 135/100 R B.P. P R 24 148/72 148/76 68 70 68 68 64 18 16 16 16 68 68 68 16 16 16 68 16 118/64 118/70 106/54 104 16 16 16 106/60 110/70 88 88 20 16 150/100 114/74 118/74 118/74 92 92 16 16 150/100 92 18 126/94 100 I 20 168/78 156/70 88 16 150/100 92 18 128/94 100 142/66 84 100 20 #1'[4 5mg/Kg. # 13 Smg./Kg. Time 16 16 18 # 15 Smg./Kg. B.P. p R B.P. P R 124/70 124/72 130/70 126/70 128/70 126/70 60 60 64 64 64 64 16 16 16 16 16 16 155/80 160/86 165/80 158/78 98 96 104 104 18 18 20 20 156/78 100 20 128/70 124/64 120/68 68 68 68 16 16 16 144/76 104 20 120/66 68 16 150/78 -1 B.P. P R 170/90 180/94 170/90 120 112 120 24 22 24 164/88, 116 24 166/88 120 24 176/90 120 24 210/111 124 24 I- Control Start Injection 4 min. 6 min. 8 min. 10 min. End Injection 2 min. 5 min. 10 min. 15 min. 20 min. 665 100 20 6A SYNTHETIC ANTICOAGULANX1 i66` farction and alcoholism was nauseated on admission. The administration of Paritol appeared to increase the nausea and vomiting. However, after his nausea had subsided, repeated doses of the same amount of Paritol were given without causing any symptoms. In 2 patients, small extravasations of Paritol outside the veins produced a moderate amount of pain, swelling, increased heat, and redness in a localized area which lasted about 24 hours. No slough occurred. Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 DIscussION Paritol is a polysulfuric acid ester of polyanhydromannuronic acid. The structural formula compared with that of heparin is shown in figure 1. Seifter and Begany (8) have reHEPARIN H HH H OH H CH2OH O-SO H -0 °I 0-- H 0 COOH Glucuronic HHSO OH H Glucosomine Acid(v n PARI TOL H COOH H O H OH HSO-O 0 H 0-SO H COOH Mannuronic Acid H OH H3 0 H o H H Mannuronic H Acid n FIG. 1. Formula of hepariii compared with that of Paritol. ported that in animals its toxicity was no greater than that of heparin and much less than that of other synthetic polysaccharide sulfuric acid esters that were tested. The halflethal dose in mice determined as mg. per Kg. were: heparin, 1500-2000; Paritol 1898; cellulose sulfuric ester, 100; and oxycellulose sulfuric ester, 200. They found the anticoagulant activity of Paritol to be about one-seventh that of heparin. Preliminary studies on the action of Paritol9 (formerly known as Heparinoid), demonstrated that it had definite anticoagulant activity when administered intravenously to humans. These preliminary observations with the preparations then available (Lots 137 and 289) indicated that it was about one-thirteenth as active as the sodium salt of heparin (Liquaemin, Roche) in prolonging the clotting times. Extension of the previously reported studies with more recent preparations of Paritol (Lots 286 and L-81-B) indicate that in man the present potency is about one-seventh that of heparin. More important, however, is the fact that prolongation of the clotting time continues for 8 to 12 hours after Paritol administration, while with crystalline heparin the action is demonstrable for only 4 to 5 hours after intravenous administration. It has therefore been possible to treat patients with thromboembolic diseases with intravenous doses of Paritol administered at intervals of 8 to 12 hours and with improvement in their clinical conditions. This represents an advantage over the use of heparin for intermittent intravenous therapy where the dose must be repeated about every 4 hours. The local reactions produced by Paritol when extravasation occurred outside the veins have precluded its use by the intramuscular or subcutaneous route. The data on case 28 appears to demonstrate that in the presence of decreased kidney function and an elevated blood urea nitrogen, Paritol caused further urea retention. Seifter and Begany8 found that in animals about 25 per cent of the administered dose of Paritol is excreted in the urine. The remainder appears to be inactivated in the blood and the inactivated product picked up by the reticuloendothelial system. The manner in which this polysaccharide may interfere with urea excretion in a damaged kidney requires more study. Until further experience is obtained, however, Paritol should be used with caution in the presence of decreased kidney function. The mechanism of the other reactions to Paritol here noted are also at present obscure. The explanation of the severe reaction in case 2 is complicated by the fact that the patient developed reactions to other drugs given intravenously. However, the reaction has some of the toxic manifestations of other of the sul- C. W. SORENSON AND I. S. WRIGHT Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 furic acid esters of polysaccharides. Also in case 9 there was a transient moderate fall in the blood pressure during the administration of Paritol associated with mild flushing of the face. Therefore, the toxicity of Paritol must be evaluated with a larger series of carefully studied patients before its general use can be advocated. Such a study is now in progress by the Committee on Ant icoagulants of the American Heart Association. The swellings limited to the hands and feet of 2 patients (cases 7 and 24) would appear to be vascular in nature. The exact mechanism responsible for these changes which appeared to be limited too the peripheral vessels is obscure. CoN CLUSIoNS 1. The polysulfuric acid ester of polyanhydromannuronic acid (Paritol) produces a significant prolongation of the clotting time when administered intravenously to humans. 2. The duration of anticoagulant effect of Paritol is from two to three times as long as that of heparin. 3. When compared mg. per Kg. with reference to the maximum clotting time obtained the effect of Paritol as presently prepared is approximately one-seventh that of heparin. 4. This may be compensated by administering Paritol in doses sufficient to produce clotting times comparable to those obtained with heparin. 5. Repeated doses of Paritol at 8 to 12 hour intervals have been given for periods up to eight days with evidence of satisfactory maintenance of anticoagulant therapy. 6. Paritol produces a slight prolongation of the prothrombin time similar to that produced by heparin. This is proportional to the effect on the clotting time. CW-0 7. Paritol appeared to cause a further rise in the blood urea nitrogen in a patient with an elevated blood urea nitrogen due to kidney disease. The drug should therefore be used with caution in patients with serious kidney damage. 8. Of 35 patients to whom Paritol has been given, 3 others have developed reactions. One was severe, with generalized symptoms including vascular collapse. Two have had mild reactions characterized by swelling of the hands and feet, which are suggestive of some vascular change in the peripheral vessels. The mechanism of these reactions is not clear. 9. Further studies with Paritol are justified in order to evaluate more completely its usefulness as a rapidly acting anticoagulant for the treatment of thromboembolic diseases. REFERENCES 1 JORPES, E.: The chemistry of heparin. Biochem. J. 29: 1816, 1935. On heparin, its chemical nature and properties. Acta med. Scandinav. 88: 427, 1936. 3~ , AND BERGSTROM, S.: Heparin: A mucoitin polysulfuric acid. J. Biol. Chem. 118: 447, 1937. 4BERGSTROM, S.: Uber Polysaccharidester-schwefelsauren mit Heparinwirkung. Ztschr. Physiol. Chem. 238: 163, 1936. 5 ASTRUP, T., GALSMAR, I. AND VOLKERT, M.: Polysaccharide sulfuric acids as anticoagulants. Acta physiol. Scandinav,. 8: 215, 1944. 6 , AND PIPER, J.: Cellulose sulfuric acids as anticoagulants. Acta physiol. Scandinav. 9: 351, 1945. 7CHARGAFF, E., BANCROFT, F. I., AND STANLEYBROWN, Al.: Studies on the chemistry of blood coagulation. II. On the inhibition of blood clotting by substances of high molecular weight. J. Biol. Chem. 115: 155, 1936. 8 SEIFTER, J., AND BEGANY, A. J.: Studies on the action of a synthetic heparinoid. Am. J. M. Sc. 216:,234, 1948. 9 SORENSON, C. W., SEIFTER, JOSEPH, AND WRIGHT, I. S.: A new synthetic anticoagulant (heparinoid). Preliminary report of its action in humans. Bull. New York Acad. AMed. 25: 448, 1949. 2 A Synthetic Anticoagulant: A Polysulfuric Acid Ester of Polyanhydromannuronic Acid (Paritol): Experience with Its Use in Man C. W. SORENSON and IRVING S. WRIGHT Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017 Circulation. 1950;2:658-667 doi: 10.1161/01.CIR.2.5.658 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1950 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/2/5/658 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. 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