EP0969848A1 - Utilisation de diadenosine polyphosphates pour reduire la pression sanguine - Google Patents

Utilisation de diadenosine polyphosphates pour reduire la pression sanguine

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Publication number
EP0969848A1
EP0969848A1 EP98901777A EP98901777A EP0969848A1 EP 0969848 A1 EP0969848 A1 EP 0969848A1 EP 98901777 A EP98901777 A EP 98901777A EP 98901777 A EP98901777 A EP 98901777A EP 0969848 A1 EP0969848 A1 EP 0969848A1
Authority
EP
European Patent Office
Prior art keywords
adenylated
dinucleotide
diadenosine
composition
blood pressure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98901777A
Other languages
German (de)
English (en)
Inventor
Richard H. Hilderman
M. Michael Swindle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clemson University
Original Assignee
Clemson University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Clemson University filed Critical Clemson University
Publication of EP0969848A1 publication Critical patent/EP0969848A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

Definitions

  • the present invention is based on a provisional application, filed January 13, 1997 and having U.S. Serial No. 60/035,819.
  • the present invention generally relates to a composition and process for reducing blood pressure. More particularly, the process of the present invention is directed to administering a therapeutic agent to a patient for reducing arterial blood pressure during hypertensive emergencies, during surgery to reduce bleeding, and for the treatment of acute congestive heart failure.
  • Blood pressure refers to the force exerted by the blood against the walls of the blood vessels. Blood pressure is created by the rhythmic contraction of the heart in combination with peristaltic waves of contraction in the walls of some blood vessels. In common medical usage, blood pressure refers specifically to the pressure of the blood in the arteries, measured in millimeters of mercury (mmHg) .
  • mmHg millimeters of mercury
  • Blood pressure varies from one individual to another and in the same person from time to time. Blood pressure is at its highest during contraction of the heart, which is referred to as systolic pressure. Blood pressure is at its lowest, on the other hand, during relaxation of the heart muscle, which is referred to as the diastolic pressure. At normal levels, systolic pressure in a human male is typically about 120 mm Hg, while diastolic pressure is typically about 80 mm Hg.
  • Blood pressure in humans should be routinely checked and carefully monitored for abnormalities. Pressures at levels higher or lower than normal pose serious health risks.
  • high blood pressure which is also referred to as hypertension
  • High blood pressure is one of the principal causes of atherosclerosis, heart disease, and kidney disease.
  • High blood pressure is caused by the constriction or narrowing of the arteries. When the arteries are constricted, the heart must pump more forcefully in order to move the blood into the capillaries.
  • hypertensive emergencies steps should be taken immediately to reduce the pressures before any permanent damage occurs to the heart or any internal organs.
  • Sodium nitroprusside is a rapid- acting vasodilator, active on both arteries and veins.
  • a vasodilator refers to an agent that causes blood vessel dilation, thus reducing blood pressure.
  • sodium nitroprusside relaxes the vascular smooth muscle that surrounds peripheral arteries and veins.
  • Sodium nitroprusside is more active on veins than on arteries. Dilation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular pressure and pulmonary capillary wedge pressure. Dilation of the arteries, on the other hand, reduces vascular resistance, systolic arterial pressure and mean arterial pressure.
  • Sodium nitroprusside is particularly well adapted for use during hypertensive emergencies because, once injected into the blood stream, the drug has a quick hypotensive effect, typically reducing blood pressure within a minute or two after infusion. Further, sodium nitroprusside dissipates rapidly after infusion is discontinued. Besides being used during hypertensive emergencies, sodium nitroprusside is also used to reduce blood loss during and after major surgical procedures. Sodium nitroprusside is also used for the treatment of acute congestive heart failure. Unfortunately, the use of sodium nitroprusside does have its disadvantages and drawbacks. For instance, once injected into the body, sodium nitroprusside reacts with hemoglobin producing cyanide as a side product, which is toxic and poisonous to humans.
  • Cyanide when present in sufficient concentrations, can prevent the blood from delivering oxygen to various parts of the body, leading to metabolic acidosis, oxygen depletion, confusion, and death. Consequently, sodium nitroprusside can only be administered to patients within a small range of dosages, can only be administered for short periods of time, should not be administered repeatedly, and cannot be used on patients particularly susceptible to cyanide.
  • Another disadvantage to using sodium nitroprusside is that the tissues of the body have a tendency to absorb the drug during use. Later, after infusion has discontinued, the drug is released by the tissues, causing a hypotensive state when not desired. This effect is referred to as a rebound phenomenon.
  • sodium nitroprusside is a labile and very unstable compound.
  • sodium nitroprusside degrades when exposed to light and cannot be stored for long periods of time.
  • sodium nitroprusside must be handled very carefully prior to and during use.
  • the present invention recognizes and addresses the above noted drawbacks and deficiencies of the prior art. Accordingly, it is an object of the present invention to provide a therapeutic agent for reducing blood pressure. It is another object of the present invention to provide a composition and process for reducing blood pressure during hypertensive emergencies.
  • Another object of the present invention is to provide a composition containing an adenylated dinucleotide for decreasing blood pressure.
  • Still another object of the present invention is to provide a composition and process for reducing blood pressure with improved safety.
  • Another object of the present invention is to provide a composition for reducing blood pressure that is naturally occurring.
  • Another object of the present invention is to provide a composition for reducing blood pressure that is stable and can be stored for extended periods of time.
  • Another object of the present invention is to provide a composition for reducing blood pressure that can be used during hypertensive emergencies, and during and after surgical procedures to reduce bleeding.
  • a further object of the present invention is to provide a lead compound for use in the development of novel therapeutic agents for reducing blood pressure and treating hypertension emergencies.
  • a process for reducing blood pressure comprising the step of administering to a patient a composition containing an adenylated dinucleotide.
  • the adenylated dinucleotide is administered to the patient in a pharmaceutically effective dosage sufficient to reduce the blood pressure of the patient.
  • the composition of the present invention is preferably administered to the patient intravenously, but it is believed that the composition can also be administered via other routes, i.e., subcutaneously and intramuscularly.
  • the composition can contain a liquid carrier, such as saline, plasma, or dextrose.
  • the adenylated dinucleotide is an ⁇ , ⁇ -adenine dinucleotide, such as diadenosine triphosphate, diadenosine tetraphosphate, diadenosine pentaphosphate, or diadenosine hexaphosphate.
  • the composition can contain a single adenylate dinucleotide or a mixture of different adenylated dinucleotides.
  • the adenylated dinucleotide is administered at a dosage level of from about 50 micrograms per kilogram body weight per minute to about 700 micrograms per kilogram body weight per minute, and more particularly between about 100 micrograms per kilogram body weight per minute to about 500 micrograms per kilogram body weight per minute. Because adenylated dinucleotides have been discovered to work very rapidly at reducing blood pressure and because recovery time after administration of the drug has ceased is also very rapid, the composition of the present invention is particularly well suited for use during hypertensive emergencies. The drug is also well adapted for use during and after cardiovascular surgery to reduce bleeding, and for use in treating acute congestive heart failure.
  • Figure 1 is a graphical representation of the results obtained in Example 1
  • Figure 2 is a graphical representation of the results obtained in Example 1
  • Figure 3 is a graphical representation of the results obtained in Example 1.
  • Figure 4 is a graphical representation of the results obtained in Example 4.
  • Figure 5 is a graphical representation of the results obtained in Example 4.
  • FIG. 6 is a graphical representation of the results obtained in Example 4.
  • Repeat use of reference characters in the present specification and drawings is intended to represent same or analogous features or elements of the invention.
  • Detailed Description of the Preferred Embodiments It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention, which broader aspects are embodied in the exemplary constructions.
  • the present invention is directed to a composition and process for reducing blood pressure.
  • the process is directed to administering to a patient a composition containing an adenylated dinucleotide, which has been found to be a hypotensive agent rapidly and significantly reducing the mean arterial pressure in the body.
  • the composition is particularly well suited for use during hypertensive emergencies, during and after cardiovascular surgery in order to reduce bleeding, and for treating acute congestive heart failure.
  • adenylated dinucleotides according to the present invention cause dilation of the arteries. This hypotensive effect occurs very rapidly, typically within ten seconds of administration.
  • mean arterial pressure is reduced and cardiac output is increased without significant effects on heart rate, right ventricular pressure, blood gas levels, or electrocardiogram morphology.
  • the effects of the drug typically disappear within five minutes after infusion is ceased.
  • Adenylated dinucleotides which were discovered in the 1950 *s, are naturally occurring molecules found in bacteria, yeast and animals, including humans. Specifically, adenylated dinucleotides are found in a diverse number of biological tissues including platelets, hepatocytes, adrenal chromaffin cells, and the central nervous system. The particular adenylated dinucleotides found well suited for use in the process of the present invention are referred to as the , ⁇ -adenine dinucleotides, which are also referred to as bis (5-adenosyl)polyphosphates.
  • adenylated dinucleotides of the present invention consist of two adenosine moieties linked via their 5 position by a chain of two or more phosphates.
  • individual adenylated dinucleotides will be abbreviated as follows:
  • Ap 3 A diadenosine triphosphate
  • Ap 4 A diadenosine tetraphosphate
  • Ap 5 A diadenosine pentaphosphate
  • Ap 6 A diadenosine hexaphosphate
  • Ap 4 A is incorporated into the composition of the present invention.
  • adenylated dinucleotides can be easily synthesized.
  • adenylated dinucleotides are commercially available from Sigma Chemical Company in St. Louis, Missouri. In pure form, adenylated dinucleotides generally are available as a powder.
  • adenylated dinucleotides can be used as a lead compound to create analog compounds for use in the process of the present invention.
  • Analog compounds possess similar biological functions, but differ in their chemical structure. Such compounds may be created by substituting different functional groups, such as methyl, acetyl, amino or hydroxyl groups, for those already present on the parent compound. Additional functional groups may also be added to the parent adenylated dinucleotide. The resulting compounds may exhibit more desirable therapeutic properties, or be more pharmacologically active, than the parent molecule. Standard texts such as "PRINCIPLES OF MEDICINAL CHEMISTRY,” William O. Foye, Thomas L. Lemke, and David A. Williams, editors, 4th Ed., 1995, may be consulted to produce such compounds, without undue experimentation.
  • an adenylated dinucleotide When administered to a patient according to the process of the present invention, an adenylated dinucleotide is combined with a carrier and injected into the arterial system.
  • a carrier examples include saline, plasma or dextrose.
  • any suitable carrier may be used that allows the drug to be administered intravenously without any adverse effects.
  • Treatment with adenylated dinucleotides can be administered in dosages and by techniques well known to those skilled in the medical or veterinary arts, taking into consideration such factors as the age, sex, weight, species and condition of the particular patient and the route of administration.
  • the route of administration can be percutaneous, via mucosal administration (e.g., oral, nasal, anal, vaginal), or via a parenteral route (intradermal, intramuscular, subcutaneous, intravenous or intraperitoneal) .
  • Specific adenylated dineucleotides can be administered alone, or can be coadministered or sequentially administered with other treatments or therapies.
  • Forms of administration may include suspensions, syrups or elixirs, and preparations for parenteral, subcutaneous, intradermal, intramuscular or intravenous administration (e.g., injectable administration) , such as sterile suspensions or emulsions.
  • Adenylated dineucleotides may be administered in admixture with a suitable carrier, diluent or excipient such as sterile water, physiological saline, glucose, or the like.
  • the compositions can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard pharmaceutical texts, such as "REMINGTON'S
  • the effective dosage and route of administration are determined by the therapeutic range and nature of the compound, and by known factors, such as the age, weight, and condition of the host as well as LD 50 and other screening procedures which are known.
  • a solution containing an adenylated dinucleotide When injected intravenously into the blood stream, a solution containing an adenylated dinucleotide only takes a few seconds to be distributed throughout the body.
  • the dosage level that is administered to a particular individual will vary depending upon a number of factors. For instance, the dosage level will depend on the age and size of the patient, the patient's condition, the reason for administering the drug, and the amount of reduction in blood pressure that is desired. For most applications, it is believed that a dosage level between about 50 micrograms ( ⁇ g) per kilogram (kg) of body weight per minute to about 700 ⁇ g per kg body weight per minute will be adequate regardless of the application.
  • the dosage level will be between 100 ⁇ g per kg body weight per minute to about 500 ⁇ g per kg body weight per minute.
  • the composition of the present invention containing an adenylated dinucleotide is administered to a patient until the hypertensive emergency is ceased or until the desired effect has been obtained.
  • adenylated dinucleotides administered in accordance with the present invention induce a rapid dose dependent depression of the mean arterial pressure without significant effects on vein dilation, right ventricular pressure or heart rate. Once the drug is injected, reduction in blood pressure can occur within ten seconds, reaching a maximum effect within three minutes.
  • Adenylated dinucleotides have also been found to increase cardiac output by relaxing the heart muscle, thereby increasing the volume of the heart chamber.
  • adenylated dinucleotides have the above described effect on the circulatory system, without significantly affecting any other hemodynamic factors.
  • the mechanism by which adenylated dinucleotides reduce blood pressure according to the present invention remains unknown.
  • AP 4 A has been shown to modulate a number of biological processes including blood vessel tone. This action of AP 4 A may be due to activation of a second message system, since evidence has shown that extracellular AP 4 A initiates a redistribution of intracellular calcium, an ubiquitous second messenger.
  • NOS Nitric Oxide Sythase
  • eNOS vascular endothelium
  • NO relaxes blood vessels by diffusing across the endothelial cell membranes and binding to iron in the heme of vascular smooth muscle guanylate cyclase, thereby activating the enzyme to generate cGMP. It is the action of cGMP, believed to occur through several mechanisms, which elicits smooth muscle relaxation.
  • Adenylated dinucleotides are particularly well suited for use during hypertensive emergencies and during and after cardiovascular surgery to reduce bleeding. Adenylated dinucleotides are naturally occurring, are non-toxic, and can be administered in broad ranges. The drug does not undergo a rebound phenomenon and is completely stable and storable.
  • EXAMPLE 1 The following tests were performed in order to demonstrate that an adenylated dinucleotide (Ap 4 A) rapidly and significantly reduces the mean arterial pressure and is rapidly degraded once administration is discontinued.
  • Ap 4 A adenylated dinucleotide
  • swine Two domestic swine, weighing 13 to 18 kilograms were pre-anesthetized with ketamine, given intramuscularly, and placed under general anesthesia. Swine were selected for this experiment because they share many similarities with humans in cardiovascular function and morphology.
  • the swine were ventilated at 17 to 20 cm H 2 0, 12 to 16 breaths per minute, and 10 to 15 ml/kg tidal volume. Blood gases were stabilized at a ph of 7.36 to 7.42, pC0 2 of 44.1 to 47.3, p0 2 of 112 to 118 at 36.4 to 37.1°C body temperature.
  • infusion of a solution containing Ap 4 A dissolved in physiologic saline using an IMED infusion pump was initiated for 3 minutes at each of the following rates: 100 ⁇ g/kg/min, 150 ⁇ g/kg/min, 200 ⁇ g/kg/min, 250 ⁇ g/kg/min, 300 ⁇ g/kg/min, 350 ⁇ g/kg/min, and 700 ⁇ g/kg/min.
  • Figures 1, 2 and 3 graphically represent the results obtained during the test. As shown in Figure 1, in both animals, the mean arterial pressure (MAP) was depressed in a dose dependent fashion without significant effects on right ventricular (RV) pressure. Specifically, Figure 1 illustrates the relative percent of baseline values for each dose at the end of the three minute infusion.
  • MAP mean arterial pressure
  • RV right ventricular
  • Figure 2 shows the percent change in mean arterial pressure (MAP) for each dosage level, during each three minute infusion. As shown, once infusion was started, the adenylated dinucleotide began reducing blood pressure within ten seconds and reached maximum effect after three minutes.
  • Figure 3 illustrates the change in mean arterial pressure (MAP) after infusion of the adenylated dinucleotide at 700 ⁇ g/kg/min was discontinued. As shown, recovery time to baseline was approximately two minutes. In fact, it was observed that for all dosages, the recovery time was two minutes or less.
  • MAP mean arterial pressure
  • Example 2 Two additional swine were anesthetized and prepared as described in Example 1. In this Example, however, more extensive monitoring was performed on the animals. Specifically, a Swan- Ganz catheter was placed in the right ventricle via venesection of the right femoral vein. The carotid artery catheter was also advanced into the left ventricle. In addition to the measurements made in Example 1, cardiac output was determined using the thermodilution method with a CO computer. Using fluoroscopy, the Swan-Ganz catheter was passed into a small branch of the pulmonary artery and, by using standard balloon inflation and pullback techniques, the following pressure measurements were made: pulmonary capillary wedge, pulmonary artery, right ventricle, right atrium, and inferior venacave.
  • the solution was injected such that Ap 4 A was administered at a rate of 200 ⁇ g/kg/min for fifteen minutes and, following the infusion, for fifteen minutes at a rate of 700 ⁇ g/kg/min.
  • pressure values were measured at baseline, half way through the infusion for each rate, at the end of the infusion, and following a return to baseline values five minutes after stopping the infusion. The results obtained in this Example were similar to Example 1.
  • EXAMPLE 3 A 20 kg male Yucatan miniature pig was used in an acute experiment to develop a model of acute renal hypertension and to test the effects of an adenylated dinucleotide on the condition.
  • the pig was anesthetized as described in Example 1 and catheters were placed in the internal jugular vein and carotid artery to monitor peripheral blood pressure.
  • An ear vein was used to administer a 0.9 percent sodium chloride solution at a rate of 20 ml/kg/hour following an IV bolus.
  • the external jugular vein was cannulated for the administration of the compound.
  • the kidneys of the pig were surgically approached through a mid-line celiotomy.
  • a left nephrectomy was performed, reducing the mean renal blood pressure in the right kidney from 45 mmHg to 11 mmHg using a suture ligature, while monitoring the pressure via a needle attached to a transducer line in the distal segment of the artery.
  • the systemic mean arterial pressure rose from 63 mmHg to 83 mmHg over the course of an hour.
  • Apparent catecholamine induced compensation raised the mean arterial pressure to 74 mmHg a minute later. This rise was rapidly followed by a steady state mean arterial pressure of 68 mmHg. After five minutes, the dosage rate was changed to 700 ⁇ g/kg/min, which resulted in a mean arterial pressure decrease to 55 mmHg. The pressure remained in a steady state for the five minute duration of the infusion. Except for the time during which the heart attempted to compensate in the initial stages of the infusion, the heart rate was not significantly different from the baseline. The mean arterial pressure rose to 82 mmHg within one minute of stopping the infusion.
  • This Example particularly demonstrates how an adenylated dinucleotide administered according to the process of the present invention can be used for treating hypertensive emergencies, such as renal hypertensive emergencies.
  • NO nitrous oxide
  • the sensor probe was inserted vertically into the petri dish containing BAEC, so that the tip of the probe was dipped about 1 mm into the solution.
  • the dishes were not capped and all measurements were performed at room temperature.
  • the data was collected for 60 min. (5 samples/sec) and analyzed using the DUO 18 2 Channel, 18-Bit Data Recording System.
  • the total nmoles of NO were determined after 60 min. of incubation by integration of the curve. Signal to background ratio was 475 (+/-50) . Basal levels of NO varied from 0.3 to 0.4 nmoles/min/10 6 cells, and were zeroed out prior to starting the experiments with the addition of AP 4 A. Various concentrations of AP 4 A, ranging from 0.5 to 2.5 ⁇ M, were added to the cells, and the amount of NO released was measured.
  • Figure 4 graphically represents the results obtained during the test. As shown in Figure 4, NO was released in a linear fashion with an AP 4 A concentration ranging from 0.5 to 2.5 ⁇ M. NO release reached a maximum of 0.84 nmole/min/10 6 cells with a AP 4 A concentration of 3.75 ⁇ M.
  • L-arginine (L-Arg) the biosynthetic precursor of eNOS, and L-NMA and L-NNA, competitive inhibitors of eNOS
  • BAEC were grown in 35 mm gelatin-coated petri dishes, as described above. Cells were incubated for 60 minutes at 37°C with varying concentrations of L-NMA or L-NNA, prior to the addition of 6 uM AP 4 A. Additional cultures were incubated for 60 minutes at 37°C with 100 ⁇ M L-NNA and varying concentrations of L-Arg, prior to the addition of 6 ⁇ M AP 4 A. NO release was recorded and analyzed as described above.
  • both L-NMA and L-NNA analogs inhibit the release of NO in a dose dependent fashion. Approximately 50% of NO released is inhibited at 10 and 22 ⁇ M by L-NMA and L-NNA, respectively.
  • the ability of L-Arg to overcome the inhibitory effect of L-NNA is demonstrated in Figure 6, where variable amounts of L-Arg and a fixed amount of L-NNA were incubated with BAEC for 60 minutes at 37°C, prior to inducing NO synthesis with AP 4 A.
  • L-Arg as expected, effectively reverses the L-NNA inhibition of NO release.

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  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
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  • Medicinal Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

La présente invention concerne un procédé de réduction de la pression sanguine. Ledit procédé consiste à administrer un ou plusieurs dinucléotides adénylés à un patient. Des exemples particuliers de dinucléotides adénylés pouvant être utilisés dans ledit procédé sont le diadénosine triphosphate, le diadénosine tétraphosphate, le diadénosine pentaphosphate et le diadénosine hexaphosphate. La composition de la présente invention réduisant la pression sanguine, elle peut être utilisée pour traiter un patient dans les urgences hypertensives, pour réduire les hémorragies et pour traiter les insuffisances cardiaques globales aiguës.
EP98901777A 1997-01-13 1998-01-13 Utilisation de diadenosine polyphosphates pour reduire la pression sanguine Withdrawn EP0969848A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US3581997P 1997-01-13 1997-01-13
US35819P 1997-01-13
PCT/US1998/000546 WO1998030222A1 (fr) 1997-01-13 1998-01-13 Utilisation de diadenosine polyphosphates pour reduire la pression sanguine

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EP0969848A1 true EP0969848A1 (fr) 2000-01-12

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AU (1) AU5821898A (fr)
CA (1) CA2277479A1 (fr)
WO (1) WO1998030222A1 (fr)

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JPH05286861A (ja) * 1992-04-06 1993-11-02 Fujirebio Inc 低血圧維持剤

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AU5821898A (en) 1998-08-03
WO1998030222A1 (fr) 1998-07-16

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