JP2003514014A - Glucose and insulin containing liquid formulations for intravenous infusion - Google Patents

Abstract

  (57) [Summary] Patients, in many clinical situations, receive intravenous fluid in the form of fluids, media, nutrients, minerals, vitamins, antibiotics and other life-saving drugs. This is also a reliable and effective means of giving patients a predictable effect with minimal discomfort. This would be the only remedy that could be implemented on many occasions as a rescue resuscitation procedure to restore a patient from a critical condition to a living condition and back to normal life. Currently available liquids are inadequate in all aspects, except for the water content required by patients. These liquids are actually hypotonic when used in a severe condition, even if they are isotonic. The inventor has found that under such circumstances the patient's desire is barely satisfied by the liquid currently being infused. Thus, the patient is faced with the situation and is disadvantaged in having to recover to normal. With the development of science, the hopes and expectations of patients continue to increase with better outcomes, less cost, less labor and less time working when they are more treatable than before. In addition, resuscitation and life prolongation, which were not possible in the past, are also expected. Much has been achieved in medical science in these directions. As part of the treatment, even today, intravenous infusions consist primarily of water, glucose and electrolytes. As a result, the same route has been used to administer solutions of antibiotics, proteins and lipids, along with many other soluble materials required in certain cases.

Description

Detailed Description of the Invention

In many clinical situations, patients receive intravenous fluids in the form of fluids, media, nutrients, minerals, vitamins, antibiotics and other life-saving medications. This is for the patient
It is also a reliable and effective means of providing predictable effects with minimal discomfort. This would be the only therapeutic modality that could be offered on many occasions as a treatment for emergency resuscitation to restore a patient from a critical condition to a living condition and back to normal life. Currently available liquids are inadequate in all respects except the water content required by the patient. The liquids are actually hypotonic, even if isotonic, when used in a critical state. The present inventor is
I have felt that the liquid that is currently being injected is almost unfilled. Thus, the patient is faced with the situation and is at a disadvantage in having to recover to a normal state.

BACKGROUND OF THE INVENTION With the development of science, the hopes and expectations of patients continue to increase in terms of better outcomes, less cost, less effort and less time spent working than ever before. In addition, resuscitation and life extension, which were impossible in the past, are expected. Much has been achieved in these directions in medical science. As part of therapy, even today, intravenous infusions consist primarily of water, glucose and electrolytes. As a result, the same routes have been used to administer solutions of antibiotics, proteins and lipids, along with many other soluble materials needed in specific cases.

A commonly used solution is a 500 ml package, 5% glucose 2. 0.9% NaCl solution 3. It is in the form of Ringer's lactic acid solution or the like. All of these have been used as the base fluid when the patient required administration of therapeutic fluids and other ingredients. In a special environment: 1. 10% glucose 2. 2. 10% glucose in normal saline (0.9%) 3. 20-25% glucose 4. Dialysis liquid 5. Blood and blood components 6. Low molecular weight dextran 7. Mannitol 8. Bulk antibiotic, and 9. Many other drugs are in use today.

It appears now that energy substrates have provided insufficient and inadequate calories from a limited source of the required calories. Electrolytes,
So are vitamins and other necessary elements. This late recognition of inadequate knowledge of what is needed about the treatment of stress, shock, and critical conditions has led many central institutions to caution to study and assess their effects. And increased labor. Such efforts will lead to more specific and related formulations, and the need to restore homeostasis to normal by restoring tissue perfusion and acid-base balance to normal. Is emphasized. This will allow them to improve their condition, come back to life, and recover normally, as has been emphasized by researchers.

The liquids currently available are: Inability to meet patient caloric needs. These required calories need to come from glucose, amino acids, and lipids.

2. It is unable to meet the electrolytes required by the patient in terms of breed and quantity.

3. The body is unable to use available energy substrates and electrolytes for high levels of catecholamines, along with qualitative and quantitative deficiencies of insulin, and disturbed hormone levels.

All of these effects lead to catabolic states. Their significant effects on the body are well described as the state of auto cannibalism. This needs to be stopped or prevented from occurring or continuing. This places emphasis on injectables that provide the body's requirements for calories, electrolytes, vitamins and other essential ingredients that are possible and can be used to treat, improve, revive and restore normal conditions. Prophylactic treatment of this line of procedure in anticipated situations, such as the main surgical procedure, can significantly minimize the risk of that procedure.

The liquids required are broadly classified for use in a variety of situations. The liquids should be in a 500 ml package for calculation. The following abbreviations are used to indicate liquids and their places of use. G-
gangal, N-non-diabetic, D-diabetic, E-electrolyte, H-heparin, V-vitamin, I-insulin, where K is marked if supplemental potassium was added. PL-Plain / Soluble Bovine Insulin or potentially equivalent human insulin is preferred. Dext-Glucose. 500m regarding content value
I should be taken as a package of A. E-the actual electrolyte that replaces extracellular electrolytes, A. M-The actual electrolyte required in the maintenance solution, as is currently available. The liquid required to treat a patient said to be non-diabetic, as is known to date, is called GN1 which contains the components as mentioned in the abbreviations below.

[0010]

[Table 1] There may / may be higher electrolyte requirements. In such situations,
It is necessary to give a higher dosage in the form of a solution group of GN2-E.

[0011]

[Table 2] Heparin may / may be required and added to the GN1 solution group. These so prepared liquids are referred to as the GN3-H solution group.

[0012]

[Table 3] Vitamin may be required / may be added to the GN1 solution group. These so prepared liquids are referred to as the GN4-V solution group.

[0013]

[Table 4] Heparin may be needed and electrolyte requirements may be higher /
is there. In such situations, it is necessary to provide these doses more in the form of GN5-EH solution groups.

[0014]

[Table 5] There may / may be requirements that require additional electrolytes and vitamins with the GN1 solution. In such situations, it is necessary to provide these dosages in the form of GN6-EV solution groups.

[0015]

[Table 6] There may / may be a requirement that heparin and vitamins be needed along with the GN1 solution. In such situations, it is necessary to provide these doses in the form of GN7-HV solution groups.

[0016]

[Table 7] There may / may be a requirement that higher amounts of electrolytes, heparin and vitamins are needed with the GN1 solution. In such situations, GN8-EH
It is necessary to provide these dosages in the form of V solution groups.

[0017]

[Table 8] There is a clear need for insulin when using GN1 fluids in treating cases of overt diabetes. Therefore, an additional amount of insulin has been added to this solution group called GD9.

[0018]

[Table 9] It is possible / may be that the electrolyte requirements are higher than the solution of GD9. In such situations, it is necessary to provide a higher dosage to provide the 10th solution group designated GD10-E.

[0019]

[Table 10] Heparin may / may be required and added to the solution group of GD9. These so prepared liquids are referred to as the GD11-H solution group.

[0020]

[Table 11] Vitamin may be required / may be added to the GD9 solution group. These liquids so prepared are referred to as the GD12-V solution group.

[0021]

[Table 12] Heparin may be needed and electrolyte requirements may be higher /
is there. In such situations, it is necessary to provide these dosages more in the form of GN13-EH solution groups.

[0022]

[Table 13] The solution of GD9 is supplemented with electrolytes and vitamins to give a GD14-EV solution.

[0023]

[Table 14] A solution of GD9 is supplemented with heparin and vitamins to give a GD15-HV solution.

[0024]

[Table 15] The combination solution of GD9 is supplemented with electrolytes, heparin and vitamins.
These liquids give GD16-EHV solutions.

[0025]

[Table 16] Explanatory Information The table below describes the A. E (actual electrolyte in extracellular replacement) and A. Provide information about M, the actual electrolyte in the maintenance solution, as available. The values shown in the table for each item are 100 m of each liquid as it is used today.
It is the actual content of the components in l.

[0026]

[Table 17] Bicarbonic acid precursor-Osmolarity (AE solution) about 570 Calculated Osmolarity (AM solution) about 400 Electrolyte concentration (meq / L)

[Table 18] Vitamin added per 500 ml of liquid.

[0027]

[Table 19] The fat-soluble vitamins A, D, E have been made water-soluble for use herein.

These improved formulations are able to meet the widely needed requirements under various types of critical clinical conditions, as currently envisioned.

It should be appreciated that these formulations will be able to meet the required requirements. These formulations have room for future better ways to standardize the technique and further improve the formulation. Thus, within the scope of the appended claims to the formulation, additional opportunities may be provided to improve the formulation in order to give even more results. A better broader range of their use in various other conditions is also obtained.

The formulation consists of the following ingredients and the other ingredients mentioned above and in the description.

1. Water: Water is the body's main essential natural component and is also the main vehicle / medium in which the body's circulation is maintained. This allows the essential elements of life and function to be available from the body to the cellular level, from which the organ waste is excreted from the body. Water helps maintain physiological conditions in and around the body that are comfortable to maintain a normal life. The volume of water required by the body varies depending on the level of function, the problems faced and the environment. Therefore, in order to balance the required amount with the discharged amount and to maintain effective circulation, the required liquid volume to be injected is
It needs to be considered in order to calculate.

2. Glucose: A major energy source in all essential energy substrates. Essential for life and life support.

Glucose in the form of 5% as an isotonic solution was the predominant form of intravenous infusion in all forms of conditions in which injection forms a therapeutic as well as emergency resuscitation procedure. Under conditions of stress, shock, and conditions, this isotonic solution is now understood to have a hypotonic solution effect. Liquids of this kind are likely to have great detrimental effects. Normally, this liquid forms the main energy source to be supplemented by the amino acid and the emulsified lipid solution. This can prevent the adverse effects and rebound effects of long-term use of carbohydrates alone, as well as essential amino acids,
And help meet lipid demands. This leads to the accumulation of acidic components, which triggers the catecholamine response, which is an abnormal response that actually occurs occasionally, further affecting the already critical condition. Here, 10%, 15%, and 20% are used to provide high amounts of glucose, along with insulin, electrolytes, vitamins, and heparin to meet high levels of metabolism. This avoids self-eating and is likely to have survival consequences.

3. Na: Sodium chloride forms the important and main electrolyte. This is also referred to as a second pump for maintaining circulation.

Sodium Chloride: 0.9% NaCl is an isotonic solution commonly used by itself or in combination with glucose solution. It is one of the main electrolytes the body needs. It is predominantly an extracellular electrolyte that has an inverse gradient relationship with K ions in response to any efficacious reagent, with a minor presence as an intracellular component.
Intake and excretion need to be balanced.

The body contains large amounts of Na around 5000 meq and requires on average 80-100 meq / day. It is mostly lost in urine. In normal individuals, on the one hand, there is a large store, but on the other hand, there is an excellent mechanism for keeping Na constant by a normally functioning kidney. As a result, when Na is not ingested, the urine loss of Na can be made close to zero. Still, large fluctuations occur with the resulting serious problems. Therefore, Na needs to be properly managed in order to maintain biological homeostasis.

4. Ca: calcium also forms an important cation component of the body, which plays a role in homeostasis, membrane potential, cell junctions and cell function.

Calcium: Calcium forms about 2% of body weight. 99% of them are in the form of bones. Some of them are constantly changing due to their contribution to extracellular components. Calcium is under the influence of simple ion exchange. Paratormons, vitamin D, corticosteroids cause a disturbance in calcium content. Any fluctuations in extracellular components affect biological homeostasis. This, in turn, disrupts cell function. An average Indian diet will contain as little as 0.2 grams of calcium for a daily requirement of 0.5-0.6 grams on average. The requirements are higher for later pregnancy and lactation, thus requiring up to about 1 gram of calcium daily. Intracellular Ca regulates cell metabolism, its function and permeability between connections.

A normally functioning kidney causes 99% of Ca to be reabsorbed from the tubules. Urinary Ca excretion increases with hypercalcemia of any cause, metabolic acidosis and the use of cortisone. Ca is an important component of the cell membrane and competes with Na. Elevated Ca in the blood raises the contraction threshold and low Ca leads to tetany.

Ca also plays a role in blood coagulation, muscle excitation-contraction coupling mechanisms, and insulin secretion mechanisms.

5. K: Potassium is an intracellular electrolyte that mainly plays an important role in cell membrane potential and cell function.

Potassium chloride: KCl solutions are available for intravenous use and require significant dilution for use. Normally, there are approximately 3500 meq of potassium in the body, 98% of which is intracellular and less than 2% is in the extracellular compartment. A small portion of this potassium
It plays a major role in the function of smooth muscle, skeletal muscle and myocardium. As a result, any fluctuations that occur in that level can certainly cause significant problems.

75% of that potassium is found in skeletal muscle. Usually, on average, the body is about 50 daily
Requires 80 meq potassium. The main route of loss is through the normally functioning kidney. The minimum amount lost by urine can be 20 meq even when potassium is not ingested.

With respect to high amounts of potassium in the intracellular compartment, any injury to the organs has been linked to elevated extracellular potassium. It depends to some extent on the levels of sodium, other hormones and diuretics. The migration / transport of potassium is associated with metabolism. Normal plasma levels may result in intracellular potassium deficiency.
In such situations, careful evaluation is required, rather than mere observation.

6. Other electrolytes: A. E (extracellular electrolyte replacement component solution) and A. M (electrolyte maintenance replacement component solution) is also essential for the function of the body and needs to be maintained in balance.

[0046]   All of these have been used in clinical applications.

7. Insulin: Insulin is an essential hormone required in the process of carbohydrate, protein and lipid metabolism. It is involved in almost every organ in the body. It is now well accepted that there is a qualitative and quantitative deficiency of insulin in clinical situations that require intravenous infusion.

8. Heparin: This is a naturally occurring substance that does not appreciably occur in the blood and prevents coagulation. Heparin plays an important role in the case of trauma caused by any reason.

Clotting is essentially a series of enzymatic reactions involving numerous plasma proteins. Many of these are only present in trace amounts. Within the intact and healthy circulatory system, these enzymes
For the most part, in its inactive form, a series of autocatalytic enzymatic reactions are initiated when blood flows from a moist surface. This is a more complex process and results, interpretations and opinions are confusing.

Heparin acts at multiple sites, along with a chain reaction when added as a therapeutic agent. Its likely first effect is to prevent the development of thromboplastin activity. Heparin acts immediately on the clotting system. Heparin is a naturally occurring sulfonated polysaccharide that has a strong anticoagulant effect. It is rapidly inactivated and removed from the circulation. It is difficult to maintain therapeutic levels in the blood while avoiding the danger of bloodshed. It is used here to prevent the initial thromboembolic event from starting.

In the present situation, medical science is not as accurate as mathematics and will not be so forever. Life sciences are overly complex, adding to every effort to understand, evaluate, or treat, including the need for time, money, risk, and invasive methods.

9. Vitamins: Fat-soluble and water-soluble vitamins are organic compounds, carbohydrates,
It is formed as a cofactor or component for enzymes involved in lipid and protein metabolism.

Most vitamins come from nutritional sources. It is synthesized in the body only to a very small extent.

[0054]   The vitamin B group acts as an essential coenzyme required in the middle stage of metabolism.

A dietary vitamin needs to be converted to its coenzyme form in order to be useful. It should also be noted that these vitamins are interdependent on their metabolism and use. In the absence of a source or in a highly metabolic environment, there is an opportunity to use drugs that affect the metabolism of vitamins to provide these required vitamins in the form of intravenous administration.

These vitamins are classified as fat-soluble vitamins A, D, E and K and stored in the body.

The water-soluble vitamins B and C are not stored and any excess is excreted in the urine. Those vitamins are not toxic and tend not to interact with the drug.

Vitamin deficiency, which is likely to occur during parenteral full nutrition, is addressed by providing:

Vitamin A: Approximately 10,000 to 20,000 I.V. in water-soluble manufactured form. U. Daily dose of will be essential to maintain epithelial cell integrity, glucocorticoids, cholesterol, and upper respiratory epithelial synthesis for body growth.

Vitamin B ₁ : Mainly involved in carbohydrate metabolism. High dose IV / IM administration may cause anaphylactic shock and interfere with the action of other B vitamins.

B ₃ : Nicotinic acid is required for protein metabolism required for respiration.

B ₆ : Indirectly affects the metabolism of carbohydrates and directly affects catecholamines, gamma aminobutyric acid and the like.

B ₇ : Involved in basic biological reaction.

B ₁₂ : Necessary for maintaining the function of nervous system and conduction mechanism.

C: Associated with cellular respiration / oxidation-reduction reactions and collagen formation, cartilage intracellular matrix development, wound healing, carbohydrate metabolism.

Vitamin D: Promotes inter-vitamin metabolism between vitamins and maintains Ca homeostasis. It is extremely important in acute conditions such as the circulation of insulin and the coupling mechanism of excitatory contraction mechanism of muscle. These have some relevance to normal organ function and essential hypertension in diabetic patients.

E: Alpha-tocopherol acetate is said to be essential for maintaining the integrity and stability of the normal structure and function of biological membranes, nervous system, and is mostly used empirically. . Also known as an antioxidant.

Choline chloride, which is similar to the B vitamins, is synthesized in the human body. As a structural component of tissues, it plays an important role in the metabolic reaction of living organisms. Choline chloride is
It is a precursor to acetylcholine and several hormones. Its biogenesis is universal in nature. Helps to give amino acids in protein synthesis.

Choline chloride prevents fat infiltration of the liver. Thickening agent. Average estimated consumption is about daily
Seems like 500 to 900 mg.

DL-methionine: Sulfur containing amino acids and non-separable food ingredients. Methionine has a lipotropic effect and is considered as a useful adjunct in the treatment of liver disease. It enhances the synthesis of glutathione required for detoxification of paracetamol's toxic metabolites. The average required amount is about 200 to 500 mg.

Inositol: Occurs in almost all plant and animal cells. This suggests that inositol is an essential cellular component. Inositol has been found to be a component of the amylase enzyme system. Inositol is to some extent synthesized by the gut microbiota. It has a weak lipotropic activity that prevents fatty liver. Inositol may be beneficial in diabetic neuropathy.

Stress, trauma, shock, critical condition, sepsis, surgery increase the rate of metabolic catabolism. This increased catabolic rate is a self-defeating response to the diseases mentioned above.
This is also called self-eating, which requires everyone's attention to prevent its outbreak.

Developments in medical science appear to have largely been based on the efforts of interested individuals. At the level of government and at their own level, there has been no systematic developmental effort to study life sciences, as it is less prioritized. Therefore, compared to defense, industry, etc., the allocation of funds to this field is very poor. In such an environment, it is difficult to determine the value. The treatment methods currently employed are largely based on an individual's knowledge and the ability to assess the situation in which they are dealing, thus increasing the range of differences and resulting outcomes.

In view of the experience of experimental surgery in the treatment of clinically ill patients, life-threatening trauma patients and the performance of open heart surgery, the concept adopted by the inventor and the comparatively good results as a result of the study And decided to investigate for more information. The inventor wishes a senior colleague (with pretty good results)
I continued to try the concept in situations where I could not expect, and came to the conviction that this approach offered a good opportunity in such situations. Now that more information is available, the opportunity to use the inventor's concept has greatly expanded, and the results have proven its worth to carry out. All of the different approaches in different clinical situations require considerable variation with the continuing basic concept being a key element.

Feeling that stress, trauma, critical state of shock, surgical infection disrupt the neurohormonal response, alter hormone catecholamine levels, homeostatic status, alter defense mechanisms and metabolic levels. ing. All needs should be addressed to provide the appropriate physiological response to restore normal conditions.
This approach needs to be well-balanced, gradual, predictable and modest in order to have a nearly natural and normal life without the need for life-prolonging treatment.

1) I feel that all individuals are potentially diabetic or hypertensive, and that quite a few now confirm that they are more prone under stress and similar conditions.

2) Under stress and a critical condition, metabolism becomes active, leading to self-eating, which is the worst condition leading to a multi-organ dysfunction syndrome.

These fluids are used in the following as prophylactic measures to minimize such occurrences: 1) stress-primary hypertensive angina, 2) shock, a) multiple trauma, b) Perforated peritonitis, c) Pancreatitis, d) Large surgical method, e) Large vascular surgery, Thrombus intimal resection, Anatomy of the inferior vena cava in the mesenteric vein in the case of portal hypertension, 3) Liver cirrhosis, 4) Scorpion bites 5) Bacterial resistant infection-septic shock, 6) The following conditions a) Coronary artery disease, b) Myocardial infarction, c) After cardiovascular surgery, 7) Adult respiratory distress syndrome / multi-organ function Disorder syndrome, 8) Treatment of cancer, 9) Polycystic kidney disease, 10) Alzheimer's disease and many other clinical conditions associated with critical illness 11) These fluids are likely to be HIV and Australian antigen virus infected rabies , And in situations like tetanus The Rukoto, to nearly normal levels, by restoring the cell and organ environment, give better results, to assist the defense mechanism of the body will have a beneficial effect on cell membranes.

Claims 1 to 4 claim that these liquids are effective in treating the abovementioned conditions.

The formulations described above have been proven to be effective from the outset, immediately after formulation and use. If formulation stability issues arise, they should be in a combination (separate) package suitable for mixing just prior to use.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/19 A61K 31/198 31/198 31/355 31/355 31/375 31/375 31/4415 31 / 4415 31/465 31/465 31/51 31/51 31/525 31/525 31/593 31/593 31/7004 31/7004 31/714 31/714 31/727 31/727 33/04 33/04 33/06 33/06 33/14 33/14 33/42 33/42 A61P 1/16 A61P 1/16 3/02 3/02 101 101 3/10 3/10 7/02 7/02 9/10 9 / 10 17/02 17/02 25/00 25/00 25/28 25/28 31/04 171 31/04 171 35/00 35/00 39/02 39/02 A61K 37/26 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG) , CI, CM, GA, GN, GW, ML, MR NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL , TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, Z (72) Inventor Gangal, Madumati H. India Karnataka 580 021 Fubry Hoshua Peaby Road and Third Cross F Term (reference) 4C076 AA12 BB13 CC21 CC22 FF11 4C084 AA02 AA03 BA44 DB34 MA02 MA17 MA66 NA05 ZC211 BA09A4A0C BC19 BC42 BC83 DA39 EA01 EA27 HA02 HA04 HA17 HA19 MA03 MA04 MA17 MA66 NA05 ZC21 ZC22 ZC75 4C206 AA01 AA02 CA05 DA02 DA07 GA05 GA23 JA57 MA03 MA04 MA37 MA86 NA05 ZC21 ZC22

Claims (4)

[Claims] 1. A liquid formulation containing glucose and insulin for intravenous infusion therapy, which has a synergistic interaction. 2. About 500 ml of water as a main medium,   10 to 20% glucose,   0.32 to 0.40 IU of insulin per gram of glucose,   0 to 4.5 g of sodium chloride (NaCl),   0.6875 to 1.375 g of calcium gluconate,   0 to 1.5 g potassium chloride (KCl),   0 to 3.2 g of sodium acetate,   0-375 mg sodium citrate,   0 to 260 mg calcium chloride,   0 to 155 mg magnesium chloride,   0 to 105 mg sodium metabisulfite, and   0 to 0.65 g dipotassium hydrogen phosphate, A formulation according to claim 1, characterized in that it contains: 3. 0 to 4000 IU vitamin A, 0 to 50 mg thiamine hydrochloride, 0 to 6 mg pyridoxine hydrochloride, 0 to 6 mg sodium riboflavin phosphate, 0 to 50 mg nicotinamide, 0 to 10 mg D-pantothenol , 0 to 15 mg vitamin B ₁₂ , 0 to 200 mg ascorbic acid, 0 to 300 IU cholecalciferol, 0 to 2 mg alpha tocopherol acetate, 0 to 5 mg choline chloride, 0 to 5 mg DL-methionine, and 0 to A formulation according to claim 1 or 2, characterized in that it contains 3 mg of inositol. 4. A formulation according to any one of claims 1 to 3, characterized in that it contains 0 to 1000 IU of heparin.