HEPARIN FOR ORAL USE: PRELIMINARY STUDIES ORVILLE HORWITZ and (by invitation) W. T. M. JOHNSON, JOHN J. SAYEN, BROOKE ROBERTS, and ARTHUR F. WHEREAT PHILADELPHIA
It is probably advisable to begin with a brief history of heparin, which was discovered by Jay McLean, a medical student, in the laboratory of William E. Howell, at Johns Hopkins in 1916 (1). My own introduction to heparin was in the laboratory of Dr. Maxwell Wintrobe at Johns Hopkins. Dr. Wintrobe used heparin to keep blood from clotting in the small vials which he distributed to students to examine microscopically for purposes of cell analysis. Dr. Wintrobe mentioned at the time that heparin has no clinical use but that it did stop blood from clotting and was an interesting substance. The first established clinical use of heparin was in the treatment of venous thrombosis and the prevention of pulmonary embolus (2). It was also used to prevent clotting in intravenous tubing. It was next found to be of definite benefit in the immediate treatment of severe coronary heart disease, including unstable angina (3). Sayen, Singer, Peirce and Horwitz reported at the 1982 Association meeting that the use of heparin in dosages of 15,000 to 20,000 units daily, during the acute stage of severe coronary heart disease, followed by long term dosage (0-15,000 units daily), not only reduces mortality and morbidity significantly, but also places these patients in the same statistical group as those who had never before suffered severe coronary heart disease (4). Before, and since that time, the efficacy of heparin for the long term treatment of coronary artery disease has been well established (5, 6, 7, 8). The unfortunate fact is that most patients with coronary artery disease refuse long-term heparin therapy because of the discomfort and nuisance of daily self-injections (5). See Table 1. We believe that if heparin could be administered by mouth, as is coumadin, both doctors and patients would welcome this health-saving medication. Before proceeding further, it is well to look at certain features of the heparin molecule. See Figure 1. Heparin is heterogenous both in molecular weight and chemical structure, and has been fractionated by Rosenberg (9) and others into an anticoagulant fraction (20-30%) and a nonFrom the Department of Medicine (Cardiovascular Section) and the Department of Pharmacology, University of Pennsylvania, Philadelphia, PA. Supported by the Foundation for Vascular-Hypertension Research, University of Pennsylvania, Philadelphia, PA. For reprints, write: Orville Horwitz, M.D., 2 Private Way, Strafford, PA 19087. 94
95
HEPARIN FOR ORAL USE
A.
B.
C.
D.
TABLE 1 Indications and Contra-indications for Herapin Therapy Reasons for usage in general 1. Deep venous thrombosis with or without pulmonary embolus: invariably 2. Severe coronary heart disease: almost invariably 3. Other arterial diseases including cerebrovascular disease: when warranted. Reasons for usage on long term basis Same as above (1) if condition does not clear up rapidly or (2) if it recurs frequently. Legitimate reasons for not giving heparin in above circumstances: 1. Platelet destructive syndromes which are rare 2. Certain hemorrhagic and/or potentially hemorrhagic conditions particularly with higher dosages. Questionable and much more frequent reasons for not giving heparin: 1. Ignorance of available data 2. Unwillingness to accept documented clinical data because of fear of complications which are rare when heparin is properly administered 3. Unwillingness to convince patient or residents of the genuine need for the drug. 4. Lack of knowledge that coumadin derivatives (rat poison) are usually more dangerous than heparin. 5. Unwillingness to take the time to train patients to self-administer. 6. Because patient would prefer oral preparation.
'Coso-
C0~csq
COO'
NH 0
ON
H
Itcosoi
M'coso;
O~~~~~?s NSO,
0
OSO;
0. H
NSO'
OSO'
H
NSX
C",NO~
FIG. 1. A section of the heparin molecule.
anticoagulant fraction. Since structure and function are related, it may be that the different heparin structures account for the many different actions of heparin as given in Table 2. We made two studies of heparin taken orally. In the second study, we used subcutaneous heparin as a control. We attempted to answer the questions: (a) Does heparin get into the blood after oral ingestion, (b) How long does it last, (c) What effect does it have on lipid metabolism and (d) What are the comparative effects of heparin given orally and heparin given subcutaneously? METHODS We used a total of 17 volunteer subjects in normal health, aged 20-75 years. In our 1991 study of 7 subjects, 6 were men. In our 1992 study of 10 subjects, 7 were women.
ORVILLE HORWITZ
96
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
TABLE 2 Anticoagulation and Other Actions of Heparin Anticoagulation: Prevention and treatment of venous and/or coronary thrombi "Clearing" of plasma. Relief of post-fatty meal angina Anti-inflammatory, anti-allergic, anti-trauma effects Reduction of platelet adhesiveness post-operatively Hypoaldosteronism induced by medium dosage Preservation or restoration of vascular wall negativity Antithrombotic properties further defined: Accelerates antithrombin heparin cofactor (AT III) action. Reduced blood viscosity in postoperative and CHD patients Affinity for vascular endothelium 100 fold that of plasma. Pool behavior better filling via s.c. than i.v. injections Inhibition of proliferation of vascular smooth muscle after injury in rats Prostacyclin-mediated increase of coronary flow in CHD patients, inhibited by aspirin Antithrombotic effects of medium dosages reassessed: fully equivalent to OAC in rabbit model; As effective vs. recurrent phlebitis without bleeding Low molecular weight heparin production of greater anti-Xa effectiveness, less antithrombin effect Reduction of anti-tPa activity, release of plasminogen activator in endothelial cells Reduction of incidence of post-operative phlebitis Stimulation of angiogenesis in tumors Alters cholesterol metabolism by increasing HDL to LDL ratio and retards development of atherosclerosis
Subjects signed Informed Consent forms and were asked routine health questions. The heparin used was Heparin, sodium, injection, USP; 20,000 units per cc. Heparin given orally (40,000 units) was placed on a small piece of bread (7 gm) and swallowed, followed by a small amount of water. 5,000 units of heparin was injected into the abdominal wall in the subcutaneous study. In the 1992 study, heparin was given to subjects orally on Day One, followed by subcutaneous heparin on Day Five. Fasting blood was drawn before heparin and, for oral heparin, after 15, 30, 45, and 60 minutes. We followed the findings of Jaques (10) that heparin taken orally disappears from the blood within a few minutes. This is why we selected times up to 45 and 60 minutes for blood collection. In 1992, blood was drawn before heparin and after 15, 30, and 45 minutes. After subcutaneous heparin, blood was drawn at 1, 2, and 3 hours. Blood drawings and analyses for Activated Partial Thromboplastin Time (APTT) clotting time, platelet counts, and analyses for Lipids (Cholesterol (CHOL), Triglycerides (TRIG), and HDL and LDL lipoproteins) were performed by the Pepper Laboratory of the Hospital of the University of Pennsylvania.
HEPARIN FOR ORAL USE
97
RESULTS Our results are shown in Figures 2 and 3. These graphs show that: 1. Heparin given orally (40,000 units), increased APTT clotting time only slightly. This was true for both the 1991 and 1992 studies. 5,000 Units of subcutaneous heparin gave a much larger APTT increase. 2. The largest change caused by oral heparin was a marked decrease in Triglycerides (TRIG). This was found in both oral studies and is a manifestation of the well-known action of heparin in "clearing plasma". A large decrease in TRIG also occurred after subcutaneous heparin.
FIG. 2. Oral Heparin study, 1991. Mean percent changes (+SEM) in APTT clotting time and lipids in seven healthy subjects after oral ingestion of 40,000 units, USP Heparin.
98
ORVILLE HORWITZ
_II
ORAL (40,000.
UNITS) E S C (5,000. UNITS)
FIG. 3. Oral vs. Subcutaneous Heparin study, 1992. A comparison of the effects of 40,000 units of heparin given orally (N = 10, day one), with 5,000 units of heparin given subcutaneously (N = 8, day five). Mean percent changes (+SEM) in APTT clotting time and lipids.
3. The other major lipids, Cholesterol, HDL and LDL lipoproteins, also showed transient changes after heparin, but in opposite directions, depending upon the route of heparin administration. Oral heparin caused small decreases in CHOL, HDL and LDL; subcutaneous heparin caused small increases in these lipids. The effective times differed: oral changes occurred within 45-60 minutes, the subcutaneous heparin changes within 3 hours.
DISCUSSION AND CONCLUSIONS It seems reasonable to conclude that many of the beneficial actions of heparin are derived from effects other than anticoagulation. See Figure 4. The profound effects of heparin on lipid metabolism have been known since the report of Graham, et al in 1951 (11). Oral heparin, with little anticoagulant effect, may still cause actions such as: a. Clearing Triglycerides from plasma. b. The reduction of platelet adhesiveness. This effect is the opposite of heparin-induced thrombocytopenia, which is a result of platelet
HEPARIN FOR ORAL USE
99
FIG. 4. What happens when heparin enters a blood vessel. Heparin first goes to the wall, endothelium. The remainder is in the plasma. Plasma Heparin increases APTT: anticoagulant effect. Wall heparin releases lipoprotein lipase lowering triglycerides: antilipemic effect.
aggregation, a seldom serious complication of heparin therapy, except when it leads to thrombosis (12). c. Reduced blood viscosity. d. Concentration on the vascular endothelium. See Figure 5. e. Inhibition of smooth muscle proliferation. f. Release of plasminogen activator. g. Alteration of lipid metabolism. See again Figures 2 and 3. These established actions of heparin have important therapeutic benefits. It seems clear that heparin given orally has a much lower anticoagulant effect, hence lower hemorrhagic potential, compared to subcutaneous heparin. This finding on oral heparin is similar to the finding that the low molecular weight heparins (LMWH) have lower anticoagulant effects, while retaining the antithrombotic actions of standard heparin (13). There has been a new and promising development of an oral heparin described by Milstein and Baughman (14). They found a way to encapsulate heparin in "proteinoid" microspheres. This product gave large anticoagulant effects in animal studies. Figure 6 shows their results on a dog and Figure 7 shows their results on five primates. At present, they are testing encapsulated low molecular weight heparin on human subjects in the United Kingdom.
100
ORVILLE HORWITZ
A
B
FIG. 5. A. High dose heparin: on endothelium and in plasma. B. low dose heparin offers little risk of hemorrhage: heparin concentrates on the endothelium; little remains in the plasma to cause bleeding. A. G. Shulman, 1991.
FIG. 6. The effect of microencapsulated heparin given orally to a dog (2 MG/KG). S. J. Milstein, et al. Emisphere Technologies, Inc.
It has been established that long-term heparin therapy reduces acute mortality in high risk coronary heart disease (CHD) and reduces both morbidity and mortality on a long term basis (15, 16). In fact, such long term heparin therapy, given to patients who have suffered severe CHD, converts them into the same group, statistically, as those who have never suffered from CHD (4, 17). Small amounts of heparin get into the blood when taken orally in large amounts, 40,000 units. The change in APTT is small, an increase of a
101
HEPARIN FOR ORAL USE A ro 0%
OE1
OC3
K1
IK4
ULt
APTT (SECONDS) VS. TIME (HOURS) FIG. 7. The effect of microencapsulated heparin given orally to five primates (2 MG/ KG): APTT measured at: Baseline, 30, 60 and 90 minutes. S. J. Milstein, et al. Emisphere Technologies, Inc.
few percent over the baseline; the decrease in Triglycerides after oral heparin is several times larger. The decrease in TRIG after oral heparin may be the best way to establish the presence of heparin in the blood after oral ingestion. The changes in APTT and TRIG are both larger from 5,000 units of heparin, given subcutaneously, than from 40,000 units taken orally. The effects of heparin taken orally differ from those of heparin taken subcutaneously, in the magnitudes of the APTT increases, the TRIG decreases, and in the effects on Cholesterol, HDL, and LDL lipoprotein metabolism. Oral ingestion caused initial decreases in these lipids, that return to baseline within 45-60 minutes. Subcutaneous administration of heparin to the same subjects caused initial increases in Chol, HDL, and LDL that return to baseline in approximately 3 hours. In this study, oral heparin lasted up to 60 minutes, subcutaneous heparin lasted approximately 3 hours. Changes in platelet counts were small and transient. There were no adverse health effects suffered by any of the 17 subjects in the two studies. We believe that short-term or acute use of heparin will and should remain exactly the same: Heparin by injection, intravenous or subcutaneous, for surgery, acute heart attack, and venous thrombosis.
102
ORVILLE HORWITZ
For long term heparin therapy in the treatment of chronic, occlusive diseases of the arteries and veins, we believe that heparin taken orally may become the therapy of choice. REFERENCES 1. McLean J. The Thromboplastic Action of Cephalin. AM J Physiol 1916; 41: 250. 2. Sasahara AA, Sonnenblick EH, Lesch M. Pulmonary Emboli. New York: Grune and Stratton; 1974. 3. Telford AM, Wilson C. Trial of Heparin vs. Atenolol in the prevention of MI in intermediate coronary syndrome. Lancet 1981; 1: 1225. 4. Sayen JJ, Singer RB, Peirce G, et al. Unstable Angina, Myocardial Infarction, Heparin and Death. Trans Amer Clin and Clim Association 1982; 94: 141. 5. Horwitz 0, Sayen JJ, Roberts B, et al. Specific Actions of Heparin and Reasons for Usage and Non-Usage by Clinicians. Annals NYAS 1989; 556: 450. 6. Engelberg H. Heparin and the Prevention of Atherosclerosis. New York: Wiley-Liss; 1990. 7. Shulman AG. Heparin and Atherosclerosis. Biomed and Pharmacother 1990; 44: 303. 8. Sayen JJ, Singer RB, Peirce G, et al. Long-Term Flexible Dose Heparin in Coronary Heart Disease. Annals NYAS 1989; 556: 476. 9. Rosenberg RD. Biologic Actions of Heparin. Seminars in Hematology 1977; 14: 427. 10. Jaques LB, Heibert LM, Wice SM. Evidence from endothelium of Gastric Absorption of Heparin and of Dextran Sulfates 8000. J Lab and Clin Med 1991; 117: 122. 11. Graham DM, Lyon TP, Gofman JW, et al. Blood Lipids and Human Atherosclerosis: The Influence of Heparin on Lipoprotein Metabolism. Circulation 1951; 4: 666. 12. Godal HC. Heparin Induced Thrombocytopenia. In Heparin. Chemical and Biological Properties, Clinical Indications. Eds. DA Lane, U Lindahl. 1989 CRC Press, Boca Raton, Fla. 13. Holmer E. Low Molecular Weight Heparin. Ibid. 14. Milstein SJ, Baughman R. Personal Communications, Emisphere Technologies, Inc., 15 Skyline Drive, Hawthorne, NY 10532. 15. Theroux P, Waters D, Lam J, et al. Unstable Angina After Discontinuation of Heparin. N Engl J Med 1992; 327: 141. 16. Freedman MD. Pharmacodynamics, Clinical Indications, and Adverse Effects of Heparin. J Clin Pharmacol 1992; 32: 584. 17. Singer RB, Gajewski J. Patterns in Mortality by Age and Time Elapsed. Praeger, New York, 1990.
DISCUSSION Schreiner, Georgetown: Dr. Horwitz, how have you excluded by giving oral heparin as a local intestinal effect rather than something as a result of absorption because I don't think there's any good information on how heparin is absorbed? Horwitz: There is no question about it that something happens to it when it gets into the gut, but also there's also no question about the fact that some of it through this method does get into the bloodstream as witnessed by the drop in the triglycerides. Gray, Stanford: I want to congratulate you on your communicative skills as charming and I wish some of us could loosen up like you up there on the podium. I have been trying and I'm getting better, but I can't match you. It's wonderful. I work on intestinal assimilation of various things. I think you're correct. Anything in very small micromole or microgram quantities may be absorbed. What I'm worried about
HEPARIN FOR ORAL USE
103
in the studies, for which you have a great deal of very interesting information, is this: the bar graphs show a 10% change. Do you have some sort of control in terms of just simply giving people awful tasting things or things in capsules to see if this small change would occur just from that? Does aspirin do things like this, since everyone seems to be gobbling at least half an aspirin these days? Would it have these sorts of changes immediately after ingestion, as you say, that you show here when you take fairly large doses of oral heparin? The lowering of the various lipids and things that you show might have an ameliorative effect, helpful effect, over the long haul for everyone of us, who is worried about vascular disease. So you want to thin the blood with the heparin. These small changes that you showed, do you have some sort of control with a control capsule to show if something like that could happen just with a control? Would aspirin do something? Horwitz: We do not have that yet. Actually, we expected to get that kind of heparin that I showed you that the man who is first in our program put together. The Federal Drug Administration wouldn't let us give it until we had given it, which made it sort of tough. We had to send it over to England to get it done. And when we sent it over to England, the English, instead of using regular heparin, used low molecular weight heparin. So, we're not sure that they're going to get any results at all, but we're waiting to see what they get. Gardner, Galveston: Pete, what about the osteoporosis that was commented on when people took chronic heparin therapy for postmyocardial protection? That use was described back in the 60's and 70's. You have no evidence at this dosage of subcutaneous heparin that you saw any skeletal changes. Is that correct? Horwitz: In the long-term, the heparin that we have given, we have about 400 patients now, and I think that there have been two cases of osteoporosis that occurred. Gardner: Were all these men? Horwitz: There were men and women.
It is probably advisable to begin with a brief history of heparin, which was discovered by Jay McLean, a medical student, in the laboratory of William E. Howell, at Johns Hopkins in 1916 (1). My own introduction to heparin was in the laboratory of Dr. Maxwell Wintrobe at Johns Hopkins. Dr. Wintrobe used heparin to keep blood from clotting in the small vials which he distributed to students to examine microscopically for purposes of cell analysis. Dr. Wintrobe mentioned at the time that heparin has no clinical use but that it did stop blood from clotting and was an interesting substance. The first established clinical use of heparin was in the treatment of venous thrombosis and the prevention of pulmonary embolus (2). It was also used to prevent clotting in intravenous tubing. It was next found to be of definite benefit in the immediate treatment of severe coronary heart disease, including unstable angina (3). Sayen, Singer, Peirce and Horwitz reported at the 1982 Association meeting that the use of heparin in dosages of 15,000 to 20,000 units daily, during the acute stage of severe coronary heart disease, followed by long term dosage (0-15,000 units daily), not only reduces mortality and morbidity significantly, but also places these patients in the same statistical group as those who had never before suffered severe coronary heart disease (4). Before, and since that time, the efficacy of heparin for the long term treatment of coronary artery disease has been well established (5, 6, 7, 8). The unfortunate fact is that most patients with coronary artery disease refuse long-term heparin therapy because of the discomfort and nuisance of daily self-injections (5). See Table 1. We believe that if heparin could be administered by mouth, as is coumadin, both doctors and patients would welcome this health-saving medication. Before proceeding further, it is well to look at certain features of the heparin molecule. See Figure 1. Heparin is heterogenous both in molecular weight and chemical structure, and has been fractionated by Rosenberg (9) and others into an anticoagulant fraction (20-30%) and a nonFrom the Department of Medicine (Cardiovascular Section) and the Department of Pharmacology, University of Pennsylvania, Philadelphia, PA. Supported by the Foundation for Vascular-Hypertension Research, University of Pennsylvania, Philadelphia, PA. For reprints, write: Orville Horwitz, M.D., 2 Private Way, Strafford, PA 19087. 94
95
HEPARIN FOR ORAL USE
A.
B.
C.
D.
TABLE 1 Indications and Contra-indications for Herapin Therapy Reasons for usage in general 1. Deep venous thrombosis with or without pulmonary embolus: invariably 2. Severe coronary heart disease: almost invariably 3. Other arterial diseases including cerebrovascular disease: when warranted. Reasons for usage on long term basis Same as above (1) if condition does not clear up rapidly or (2) if it recurs frequently. Legitimate reasons for not giving heparin in above circumstances: 1. Platelet destructive syndromes which are rare 2. Certain hemorrhagic and/or potentially hemorrhagic conditions particularly with higher dosages. Questionable and much more frequent reasons for not giving heparin: 1. Ignorance of available data 2. Unwillingness to accept documented clinical data because of fear of complications which are rare when heparin is properly administered 3. Unwillingness to convince patient or residents of the genuine need for the drug. 4. Lack of knowledge that coumadin derivatives (rat poison) are usually more dangerous than heparin. 5. Unwillingness to take the time to train patients to self-administer. 6. Because patient would prefer oral preparation.
'Coso-
C0~csq
COO'
NH 0
ON
H
Itcosoi
M'coso;
O~~~~~?s NSO,
0
OSO;
0. H
NSO'
OSO'
H
NSX
C",NO~
FIG. 1. A section of the heparin molecule.
anticoagulant fraction. Since structure and function are related, it may be that the different heparin structures account for the many different actions of heparin as given in Table 2. We made two studies of heparin taken orally. In the second study, we used subcutaneous heparin as a control. We attempted to answer the questions: (a) Does heparin get into the blood after oral ingestion, (b) How long does it last, (c) What effect does it have on lipid metabolism and (d) What are the comparative effects of heparin given orally and heparin given subcutaneously? METHODS We used a total of 17 volunteer subjects in normal health, aged 20-75 years. In our 1991 study of 7 subjects, 6 were men. In our 1992 study of 10 subjects, 7 were women.
ORVILLE HORWITZ
96
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
TABLE 2 Anticoagulation and Other Actions of Heparin Anticoagulation: Prevention and treatment of venous and/or coronary thrombi "Clearing" of plasma. Relief of post-fatty meal angina Anti-inflammatory, anti-allergic, anti-trauma effects Reduction of platelet adhesiveness post-operatively Hypoaldosteronism induced by medium dosage Preservation or restoration of vascular wall negativity Antithrombotic properties further defined: Accelerates antithrombin heparin cofactor (AT III) action. Reduced blood viscosity in postoperative and CHD patients Affinity for vascular endothelium 100 fold that of plasma. Pool behavior better filling via s.c. than i.v. injections Inhibition of proliferation of vascular smooth muscle after injury in rats Prostacyclin-mediated increase of coronary flow in CHD patients, inhibited by aspirin Antithrombotic effects of medium dosages reassessed: fully equivalent to OAC in rabbit model; As effective vs. recurrent phlebitis without bleeding Low molecular weight heparin production of greater anti-Xa effectiveness, less antithrombin effect Reduction of anti-tPa activity, release of plasminogen activator in endothelial cells Reduction of incidence of post-operative phlebitis Stimulation of angiogenesis in tumors Alters cholesterol metabolism by increasing HDL to LDL ratio and retards development of atherosclerosis
Subjects signed Informed Consent forms and were asked routine health questions. The heparin used was Heparin, sodium, injection, USP; 20,000 units per cc. Heparin given orally (40,000 units) was placed on a small piece of bread (7 gm) and swallowed, followed by a small amount of water. 5,000 units of heparin was injected into the abdominal wall in the subcutaneous study. In the 1992 study, heparin was given to subjects orally on Day One, followed by subcutaneous heparin on Day Five. Fasting blood was drawn before heparin and, for oral heparin, after 15, 30, 45, and 60 minutes. We followed the findings of Jaques (10) that heparin taken orally disappears from the blood within a few minutes. This is why we selected times up to 45 and 60 minutes for blood collection. In 1992, blood was drawn before heparin and after 15, 30, and 45 minutes. After subcutaneous heparin, blood was drawn at 1, 2, and 3 hours. Blood drawings and analyses for Activated Partial Thromboplastin Time (APTT) clotting time, platelet counts, and analyses for Lipids (Cholesterol (CHOL), Triglycerides (TRIG), and HDL and LDL lipoproteins) were performed by the Pepper Laboratory of the Hospital of the University of Pennsylvania.
HEPARIN FOR ORAL USE
97
RESULTS Our results are shown in Figures 2 and 3. These graphs show that: 1. Heparin given orally (40,000 units), increased APTT clotting time only slightly. This was true for both the 1991 and 1992 studies. 5,000 Units of subcutaneous heparin gave a much larger APTT increase. 2. The largest change caused by oral heparin was a marked decrease in Triglycerides (TRIG). This was found in both oral studies and is a manifestation of the well-known action of heparin in "clearing plasma". A large decrease in TRIG also occurred after subcutaneous heparin.
FIG. 2. Oral Heparin study, 1991. Mean percent changes (+SEM) in APTT clotting time and lipids in seven healthy subjects after oral ingestion of 40,000 units, USP Heparin.
98
ORVILLE HORWITZ
_II
ORAL (40,000.
UNITS) E S C (5,000. UNITS)
FIG. 3. Oral vs. Subcutaneous Heparin study, 1992. A comparison of the effects of 40,000 units of heparin given orally (N = 10, day one), with 5,000 units of heparin given subcutaneously (N = 8, day five). Mean percent changes (+SEM) in APTT clotting time and lipids.
3. The other major lipids, Cholesterol, HDL and LDL lipoproteins, also showed transient changes after heparin, but in opposite directions, depending upon the route of heparin administration. Oral heparin caused small decreases in CHOL, HDL and LDL; subcutaneous heparin caused small increases in these lipids. The effective times differed: oral changes occurred within 45-60 minutes, the subcutaneous heparin changes within 3 hours.
DISCUSSION AND CONCLUSIONS It seems reasonable to conclude that many of the beneficial actions of heparin are derived from effects other than anticoagulation. See Figure 4. The profound effects of heparin on lipid metabolism have been known since the report of Graham, et al in 1951 (11). Oral heparin, with little anticoagulant effect, may still cause actions such as: a. Clearing Triglycerides from plasma. b. The reduction of platelet adhesiveness. This effect is the opposite of heparin-induced thrombocytopenia, which is a result of platelet
HEPARIN FOR ORAL USE
99
FIG. 4. What happens when heparin enters a blood vessel. Heparin first goes to the wall, endothelium. The remainder is in the plasma. Plasma Heparin increases APTT: anticoagulant effect. Wall heparin releases lipoprotein lipase lowering triglycerides: antilipemic effect.
aggregation, a seldom serious complication of heparin therapy, except when it leads to thrombosis (12). c. Reduced blood viscosity. d. Concentration on the vascular endothelium. See Figure 5. e. Inhibition of smooth muscle proliferation. f. Release of plasminogen activator. g. Alteration of lipid metabolism. See again Figures 2 and 3. These established actions of heparin have important therapeutic benefits. It seems clear that heparin given orally has a much lower anticoagulant effect, hence lower hemorrhagic potential, compared to subcutaneous heparin. This finding on oral heparin is similar to the finding that the low molecular weight heparins (LMWH) have lower anticoagulant effects, while retaining the antithrombotic actions of standard heparin (13). There has been a new and promising development of an oral heparin described by Milstein and Baughman (14). They found a way to encapsulate heparin in "proteinoid" microspheres. This product gave large anticoagulant effects in animal studies. Figure 6 shows their results on a dog and Figure 7 shows their results on five primates. At present, they are testing encapsulated low molecular weight heparin on human subjects in the United Kingdom.
100
ORVILLE HORWITZ
A
B
FIG. 5. A. High dose heparin: on endothelium and in plasma. B. low dose heparin offers little risk of hemorrhage: heparin concentrates on the endothelium; little remains in the plasma to cause bleeding. A. G. Shulman, 1991.
FIG. 6. The effect of microencapsulated heparin given orally to a dog (2 MG/KG). S. J. Milstein, et al. Emisphere Technologies, Inc.
It has been established that long-term heparin therapy reduces acute mortality in high risk coronary heart disease (CHD) and reduces both morbidity and mortality on a long term basis (15, 16). In fact, such long term heparin therapy, given to patients who have suffered severe CHD, converts them into the same group, statistically, as those who have never suffered from CHD (4, 17). Small amounts of heparin get into the blood when taken orally in large amounts, 40,000 units. The change in APTT is small, an increase of a
101
HEPARIN FOR ORAL USE A ro 0%
OE1
OC3
K1
IK4
ULt
APTT (SECONDS) VS. TIME (HOURS) FIG. 7. The effect of microencapsulated heparin given orally to five primates (2 MG/ KG): APTT measured at: Baseline, 30, 60 and 90 minutes. S. J. Milstein, et al. Emisphere Technologies, Inc.
few percent over the baseline; the decrease in Triglycerides after oral heparin is several times larger. The decrease in TRIG after oral heparin may be the best way to establish the presence of heparin in the blood after oral ingestion. The changes in APTT and TRIG are both larger from 5,000 units of heparin, given subcutaneously, than from 40,000 units taken orally. The effects of heparin taken orally differ from those of heparin taken subcutaneously, in the magnitudes of the APTT increases, the TRIG decreases, and in the effects on Cholesterol, HDL, and LDL lipoprotein metabolism. Oral ingestion caused initial decreases in these lipids, that return to baseline within 45-60 minutes. Subcutaneous administration of heparin to the same subjects caused initial increases in Chol, HDL, and LDL that return to baseline in approximately 3 hours. In this study, oral heparin lasted up to 60 minutes, subcutaneous heparin lasted approximately 3 hours. Changes in platelet counts were small and transient. There were no adverse health effects suffered by any of the 17 subjects in the two studies. We believe that short-term or acute use of heparin will and should remain exactly the same: Heparin by injection, intravenous or subcutaneous, for surgery, acute heart attack, and venous thrombosis.
102
ORVILLE HORWITZ
For long term heparin therapy in the treatment of chronic, occlusive diseases of the arteries and veins, we believe that heparin taken orally may become the therapy of choice. REFERENCES 1. McLean J. The Thromboplastic Action of Cephalin. AM J Physiol 1916; 41: 250. 2. Sasahara AA, Sonnenblick EH, Lesch M. Pulmonary Emboli. New York: Grune and Stratton; 1974. 3. Telford AM, Wilson C. Trial of Heparin vs. Atenolol in the prevention of MI in intermediate coronary syndrome. Lancet 1981; 1: 1225. 4. Sayen JJ, Singer RB, Peirce G, et al. Unstable Angina, Myocardial Infarction, Heparin and Death. Trans Amer Clin and Clim Association 1982; 94: 141. 5. Horwitz 0, Sayen JJ, Roberts B, et al. Specific Actions of Heparin and Reasons for Usage and Non-Usage by Clinicians. Annals NYAS 1989; 556: 450. 6. Engelberg H. Heparin and the Prevention of Atherosclerosis. New York: Wiley-Liss; 1990. 7. Shulman AG. Heparin and Atherosclerosis. Biomed and Pharmacother 1990; 44: 303. 8. Sayen JJ, Singer RB, Peirce G, et al. Long-Term Flexible Dose Heparin in Coronary Heart Disease. Annals NYAS 1989; 556: 476. 9. Rosenberg RD. Biologic Actions of Heparin. Seminars in Hematology 1977; 14: 427. 10. Jaques LB, Heibert LM, Wice SM. Evidence from endothelium of Gastric Absorption of Heparin and of Dextran Sulfates 8000. J Lab and Clin Med 1991; 117: 122. 11. Graham DM, Lyon TP, Gofman JW, et al. Blood Lipids and Human Atherosclerosis: The Influence of Heparin on Lipoprotein Metabolism. Circulation 1951; 4: 666. 12. Godal HC. Heparin Induced Thrombocytopenia. In Heparin. Chemical and Biological Properties, Clinical Indications. Eds. DA Lane, U Lindahl. 1989 CRC Press, Boca Raton, Fla. 13. Holmer E. Low Molecular Weight Heparin. Ibid. 14. Milstein SJ, Baughman R. Personal Communications, Emisphere Technologies, Inc., 15 Skyline Drive, Hawthorne, NY 10532. 15. Theroux P, Waters D, Lam J, et al. Unstable Angina After Discontinuation of Heparin. N Engl J Med 1992; 327: 141. 16. Freedman MD. Pharmacodynamics, Clinical Indications, and Adverse Effects of Heparin. J Clin Pharmacol 1992; 32: 584. 17. Singer RB, Gajewski J. Patterns in Mortality by Age and Time Elapsed. Praeger, New York, 1990.
DISCUSSION Schreiner, Georgetown: Dr. Horwitz, how have you excluded by giving oral heparin as a local intestinal effect rather than something as a result of absorption because I don't think there's any good information on how heparin is absorbed? Horwitz: There is no question about it that something happens to it when it gets into the gut, but also there's also no question about the fact that some of it through this method does get into the bloodstream as witnessed by the drop in the triglycerides. Gray, Stanford: I want to congratulate you on your communicative skills as charming and I wish some of us could loosen up like you up there on the podium. I have been trying and I'm getting better, but I can't match you. It's wonderful. I work on intestinal assimilation of various things. I think you're correct. Anything in very small micromole or microgram quantities may be absorbed. What I'm worried about
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in the studies, for which you have a great deal of very interesting information, is this: the bar graphs show a 10% change. Do you have some sort of control in terms of just simply giving people awful tasting things or things in capsules to see if this small change would occur just from that? Does aspirin do things like this, since everyone seems to be gobbling at least half an aspirin these days? Would it have these sorts of changes immediately after ingestion, as you say, that you show here when you take fairly large doses of oral heparin? The lowering of the various lipids and things that you show might have an ameliorative effect, helpful effect, over the long haul for everyone of us, who is worried about vascular disease. So you want to thin the blood with the heparin. These small changes that you showed, do you have some sort of control with a control capsule to show if something like that could happen just with a control? Would aspirin do something? Horwitz: We do not have that yet. Actually, we expected to get that kind of heparin that I showed you that the man who is first in our program put together. The Federal Drug Administration wouldn't let us give it until we had given it, which made it sort of tough. We had to send it over to England to get it done. And when we sent it over to England, the English, instead of using regular heparin, used low molecular weight heparin. So, we're not sure that they're going to get any results at all, but we're waiting to see what they get. Gardner, Galveston: Pete, what about the osteoporosis that was commented on when people took chronic heparin therapy for postmyocardial protection? That use was described back in the 60's and 70's. You have no evidence at this dosage of subcutaneous heparin that you saw any skeletal changes. Is that correct? Horwitz: In the long-term, the heparin that we have given, we have about 400 patients now, and I think that there have been two cases of osteoporosis that occurred. Gardner: Were all these men? Horwitz: There were men and women.
