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WO2001015705A1 - Utilisation de fructose-1,6-diphosphate comme medicament inotrope pour le pontage cardiopulmonaire - Google Patents

Utilisation de fructose-1,6-diphosphate comme medicament inotrope pour le pontage cardiopulmonaire Download PDF

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Publication number
WO2001015705A1
WO2001015705A1 PCT/US1999/019432 US9919432W WO0115705A1 WO 2001015705 A1 WO2001015705 A1 WO 2001015705A1 US 9919432 W US9919432 W US 9919432W WO 0115705 A1 WO0115705 A1 WO 0115705A1
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Prior art keywords
fructose
patient
diphosphate
fdp
surgery
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PCT/US1999/019432
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English (en)
Inventor
Paul J. Marangos
Angel K. Markov
Anthony W. Fox
David Royston
Bernhard Riedel
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Cypros Pharmaceutical Corporation
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Priority to PCT/US1999/019432 priority Critical patent/WO2001015705A1/fr
Priority to AU56919/99A priority patent/AU5691999A/en
Publication of WO2001015705A1 publication Critical patent/WO2001015705A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This invention relates to inotrope drugs, which can increase the strength of a heartbeat.
  • inotrope drugs are often used after cardiac surgery, if a patient's heart is struggling to regain adequate strength after the patient has been taken off of a cardiopulmonary bypass machine.
  • CPB cardiopulmonary bypass
  • bypass involves circulatory bypass of the heart and the lungs, during certain types of surgery.
  • CPB is most commonly used in the following types of surgery: (1) surgery to repair occluded (blocked or clogged) coronary arteries which cannot be adequately reopened by less invasive techniques such as balloon angioplasty; this type of surgery is often referred to as “coronary artery bypass grafting” (CABG) surgery; (2) repair (which includes replacement) of heart valves; (3) surgery to correct cardiac arrhythmias; (4) surgery to remove heart muscle tissue to increase contact between a ventricular wall and oxygenated blood; (5) heart transplant surgery; (6) lung transplant surgery; and, (7) surgery to correct a congenital heart disease.
  • CABG coronary artery bypass grafting
  • LVAD left ventricular assist
  • inotropes drugs
  • cardiac surgery Various drugs (generally referred to as “inotropes” or “cardiotonic” agents) are also widely used to stimulate the heart muscle and increase the strength of a heartbeat, after cardiac surgery.
  • the most widely used inotrope drugs include digitalis glycosides (also called digoxins), various inotropic catecholamines, including epinephrin and norepinephrine (also called adrenaline and noradrenaline), dopamine, and dobutamine, and a drug called amrinone lactate.
  • inotrope drugs suffer from various risks, limitations, and adverse side effects, and they are not administered unless it becomes apparent in a specific patient that such drugs are needed to deal with a medical crisis. In general, they all interact directly with neuronal and/or hormonal receptors (primarily beta receptors, on heart cells), triggering various types of artificially- stimulated excitation of the activated cells and tissue. Therefore, such inotrope drugs alter and disrupt the desirable homeostatic balances and equilibria that a heart tries to maintain. In particular, all previously known inotrope drugs have an undesirable and potentially dangerous side effect: they increase the rate of the heartbeat (the number of beats per minute).
  • a better inotropic drug would increase the strength of the heartbeat (as measured by indices such as volume of blood output per heartbeat stroke), without increasing the heartbeat rate (i.e. , without causing the heart to beat faster.
  • a second undesired and dangerous aspect of previously known inotrope drugs is that their useful effects diminish fairly quickly over time; within about 3 days, the efficacy of any of these drugs drops to about half of what it was when treatment commenced.
  • This drop of efficacy involves a form of drug tolerance that is usually known as "tachyphylaxis". It is especially dangerous, because all beta receptor agonists (which includes nearly all of the inotropic catecholamines) share this property. In other words, if dopamine is used as an initial inotrope, during the first days when someone's heart is not beating adequately after CPB surgery, then it will not help the patient to switch to some other catecholamine or other beta agonist when the dopamine efficacy drops off.
  • inotrope drugs are heart stimulants, pure and simple. Accordingly, giving a weakened patient an inotrope drug, after cardiac surgery, is comparable to giving a stimulant such as amphetamine (commonly called "speed") to someone who has become exhausted due to overexertion and lack of adequate food.
  • the stimulant may offer a quick fix, and it may help the person deal with a specific short-lived demand or deadline. However, after the stimulant wears off, the person will be even more exhausted, depleted, and on the verge of total collapse.
  • Stimulants which increase the heartbeat rate can actually induce (precipitate) hypoxia and ischemia, in tissue that is already starved for oxygen; using stimulant drugs to force the heart to beat faster, shortly after bypass surgery, in some respects is comparable to forcing a person to run sprints, shortly after that person has suffered a near-drowning accident.
  • a heart cannot go to sleep so it can rest, recover, and regain strength. It must continue beating actively, even when the patient is resting or sleeping. Accordingly, it is difficult and dangerous to subject a heart to the type of "double- tired" exhaustion that results from using stimulant drugs to drive the heart harder and faster while it is trying to recover from a severe ordeal such as cardiac surgery.
  • FDP the inotropic drug discussed below
  • FDP works by an entirely different mechanism. Instead of triggering abnormally high activity in heart muscle by stimulating hormonal or neuronal receptors, it provides a completely safe and healthy form of nutrition for the heart muscle.
  • providing FDP to a struggling heart is like giving a good, nutritious, healthy meal (rather than dangerous hunger-suppressing amphetamines) to a starving person.
  • a good, nutritious, and healthy meal can help a starving man regain his strength and restore a safe and stable balance, after he has suffered through a severe ordeal. That is the goal, and the result, of this invention.
  • FDP does not increase the heartbeat rate to abnormally high levels. The tests done to date indicate that FDP has no statistically significant effects on heartbeat rate. Instead, it merely strengthens the heart, so that the "hemodynamic performance" of the heart during each heartbeat is improved, as indicated by the various measures described below.
  • LV refers to the left ventricle
  • mm Hg is a pressure value, expressed as millimeters of a mercury column.
  • the main indices of interest are:
  • CO - cardiac output expressed as liters of blood pumped per minute.
  • CI - cardiac index expressed as liters of blood pumped per minute, divided by the body surface area of the patient, in square meters.
  • SVI - stroke volume index expressed as milliliters of blood pumped per heartbeat, divided by the body surface area of the patient, in square meters.
  • LVSP - left ventricular systolic pressure expressed in mm Hg. This is a peak pressure generated during contraction of the left ventricle.
  • LVSWI - left ventricular stroke work index expressed as grams-meters, divided by the body surface area of the patient in square meters.
  • LVEDP - left ventricular end diastolic pressure expressed as mm Hg.
  • MAP - mean aortic pressure indicates the pressure that contraction of the left ventricle is able to generate, averaged over an entire heartbeat.
  • FDP Fructose- 1,6-diphosphate
  • fructose diphosphate which contains phosphate groups bonded to the #1 and #6 carbon atoms of the fructose molecule, is the only isomer of interest herein.
  • Other isomers such as fructose-2,6-diphosphate exist in nature, but they are not relevant; they do not participate in glycolysis, and they are excluded from any references herein to FDP or fructose diphosphate.
  • FDP might potentially be useful as a medical treatment for medical crises such as strokes, cardiac arrest, heart attack, suffocation, loss of blood due to injury, shooting, or stabbing, etc.
  • Such articles include Markov et al 1980, 1986, and 1987, Brunswick et al 1982, Marchionni et al 1985, Farias et al 1986, Grandi et al 1988, Zhang et al 1988, Lazzarino et al 1989 and 1992, Janz et al 1991, Hassinen et al 1991 , Cargnoni et al 1992, and Munger et al 1994.
  • Relevant US patents include US 4,546,095 (Markov 1985), 4,703,040 (Markov 1987), and 4,757,052 (Markov 1988).
  • FDP is a diphosphate with a strong negative charge; accordingly, it is generally assumed by doctors and researchers that its highly-charged nature will prevent it from entering cells in substantial quantities. Since energy metabolism and glycolysis occur inside cells, it is generally assumed that FDP will not get to the relevant site in sufficient quantities to do any substantial good.
  • FDP has a very short half-life in the blood, and will effectively disappear from the blood within a few minutes after injection or infusion.
  • the other commercially available FDP formulation is a lyophilized preparation that is manufactured in Italy by a company called Biochemica Foscama. To the best of the Applicant's knowledge and belief, it is manufactured by steps that including the following: (1) pouring a large batch of an aqueous mixture of FDP into a large, flat tray; (2) freezing the mixture and subjecting it to a vacuum, to remove the water, thereby creating a large solidified cake; (3) grinding or milling the large cake into small particles; (4) loading the ground-up particles into small vials; and, (5) sealing the vials.
  • This process is not well suited for creating a sterile preparation for injection into humans; a process that uses large machinery to handle and manipulate a large cake, pass it through a device which grinds it up into small particles, pass the particles through various routing and funnelling devices in order to load those particles into small vials, and then seal the vials, creates numerous risks which seriously jeopardize the sterility of the resulting final product.
  • non-sterile FDP is loaded into a sealed vial, it cannot be subsequently treated by a "terminal sterilization" process such as autoclaving or ionizing radiation. Those types of terminal (post-sealing) sterilization treatments would seriously degrade the chemical quality of the FDP in the sealed vials.
  • one object of the subject invention is to provide a better cardiac inotrope for patients who are being prepared for, or who are recovering from, surgery that uses cardiopulmonary bypass.
  • This improved and desired inotrope should strengthen and help stabilize the heartbeat, but it should not increase the heartbeat rate, and it should not have any other undesired side effects.
  • Another object of the subject invention is to disclose that FDP performs as a safe and effective cardiac inotrope drug, for people who are being prepared for surgery which will require cardiopulmonary bypass.
  • Another object of the subject invention is to disclose that FDP can be used as a safe and effective cardiac inotrope drug, when administered to people who have recently had surgery which required cardiopulmonary bypass.
  • Another object of the subject invention is to disclose that when FDP is used as a cardiac inotrope drug before and/or after surgery involving cardiopulmonary bypass, it provides a virtually ideal combination of desired activities coupled with an apparently complete absence of any undesired side effects.
  • Yet another object of this invention is to disclose that when FDP is administered in a preferred manner and at proper inotropic dosages to a patient who is being prepared for surgery involving cardiopulmonary bypass, it also serves to reduce the risk that the patient will suffer from an atrial fibrillation event, after the surgery has been completed.
  • fructose- 1 ,6-diphosphate can be used, safely and effectively as an inotropic drug in humans who undergo surgery involving cardiopulmonary bypass.
  • FDP fructose- 1 ,6-diphosphate
  • inotropic drugs such as dobutamine, epinephrin, or amrinone lactate
  • FDP also can be administered, after cardiopulmonary bypass surgery has been completed, in combination with another inotropic drug that increases the heartbeat rate.
  • FDP can reduce the dosage of the other inotropic drug that is required to achieve the necessary effects.
  • FDP can minimize unwanted and potentially dangerous stress on a struggling heart.
  • FDP has no known adverse effects when used as an inotropic drug in patients who are undergoing or who have completed cardiopulmonary bypass surgery.
  • FDP can also reduce the risk that a patient will suffer from an atrial fibrillation event. Accordingly, FDP can be administered safely in inotropic but non-acidotic dosages, as a preventive measure, among any and all patients who are being prepared for, or emerging from, cardiopulmonary bypass surgery.
  • certain methods are disclosed herein, including the method of preparing a medicament for use in (i) providing inotropic support for, or (ii) reducing inotropic drug requirements among, patients who require surgery using cardiopulmonary bypass.
  • This method of preparing a medicament for such use comprises the addition of fructose- 1,6-diphosphate or a pharmacologically acceptable salt thereof to a liquid formulation suitable for intravenous injection into such patients.
  • FIGURE 1 shows that FDP caused a significant increase in the "left ventricular stroke work index” (LVSWI), compared to a placebo, in patients who underwent cardiopulmonary bypass surgery. It also shows that FDP helped reduce unwanted increases in "pulmonary artery wedge pressures" (PAWP values) after bypass surgery, compared to a placebo.
  • LVSWI left ventricular stroke work index
  • FIGURE 2 shows that FDP caused a significant reduction in CK levels in circulating blood plasma (measured on the first and second post-operative days), compared to a placebo treatment, in patients who underwent cardiopulmonary bypass surgery.
  • FIGURE 3 shows that FDP significantly helped patients regain a more normal leftside heart function, as measured by reduced elevations of pulmonary artery wedge pressure on the first post-operative day.
  • FIGURE 4 is a graph which shows how the biochemical benefits of FDP (measured by CK levels in blood plasma), correlate with the mechanical and hemodynamic benefits of FDP (measured by reduced abnormalities in pressure values). This correlation is statistically significant, and it confirms that FDP provides both biochemical and hemodynamic benefits when administered before circulatory bypass begins.
  • FIGURE 5 is a bar graph showing that, in the Stage 1 and Stage 3 tests, FDP treatment significantly reduced the amount of dopamine (a potentially dangerous inotropic drug) that had to be used to stimulate the hearts of CABG patients after surgery.
  • dopamine a potentially dangerous inotropic drug
  • FIGURE 6 is a bar graph showing that, in the Stage 1 and Stage 3 tests, FDP treatment significantly reduced the amount of glyceryl trinitrate (GTN, a vasodilator drug) that had to be used to stabilize CABG patients after surgery.
  • FIGURE 7 shows the occurrence rate for atrial fibrillation for the different stages of tests involving varying dosages of FDP.
  • FDP treatment reduced the number of patients who suffered atrial fibrillation.
  • FDP was administered at dosages that were found to cause lactic acidosis, and occurrence rates for atrial fibrillation increased.
  • FDP can be used as a safe and effective inotropic drug to strengthen the heartbeats of patients who are being prepared for, or who have recently been through, cardiopulmonary bypass (CPB) surgery.
  • CPB cardiopulmonary bypass
  • FDP can increase the strength of the heartbeat, as measured by indices such as cardiac output (CO; liters/ minute), cardiac index (CI; liters/minute/m 2 ), stroke volume index (SVI; ml/beat/m 2 ), and left ventricular stroke work index (LVSWI; gm-m/m 2 ).
  • FDP treatment before and after CPB surgery can accomplish these highly desirable results without increasing the patient's heartbeat rate (HR; beats/ minute).
  • HR heartbeat rate
  • the ability to increase the heart's beating strength without also increasing heartbeat rate is a very valuable inotropic property of FDP, since increasing the heartbeat rate in a heart which has been badly stressed by major surgery can impose severe and potentially lethal stress and hypoxia on a heart that is struggling hard to recover from an ordeal.
  • the cardiac index also increased, from 2.50 L/min/m 2 (pretreatment) to 2.81 (post-treatment).
  • the LV stroke work index (LVSWI) values increased from 31.7 gm-m/m 2 (pretreatment) to 40.3 (posttreatment) .
  • Pulmonary pressure and resistance declined, and systemic vascular resistance decreased, by virtue of increased cardiac output and unchanged arterial pressure.
  • FDP treatment actually reduced the heartbeat rates in all treatment groups, presumably due to the various regulatory mechanisms that govern heartbeat. If the body is provided with an improved flow of blood due to increased heartbeat strength, the tissues of the body will not send out the various nerve impulses which indicate oxygen deficits, and which cause the heartbeat rate to increase in response to the deficits.
  • FDP In patients with normal baseline LVEDP (defined as having LVEDP values of less than 12 mm Hg; actual mean value was 5.06+0.27), FDP also decreased heart rate and systemic and pulmonary resistance, while LVEDP, mean aortic pressures, and pulmonary pressures were not significantly altered. FDP moderately increased cardiac output, stroke volume index, and LVSWI.
  • FDP can be administered safely to virtually anyone who is being prepared for or who is emerging from CPB surgery, and it will not lead to any significant undesired or disruptive side effects, so long as it is administered at dosages that do not cause or aggravate lactic acidosis;
  • FDP can be administered safely at the earliest onset of any symptoms of cardiac distress following CPB surgery, to minimize the overall stress and strain that a heart must struggle with after CPB surgery; and
  • FDP can even be administered safely as a preventive measure to all patients who are emerging or recovering from CPB surgery, to reduce the risk that such patients will suffer from cardiac deficits and irregularities that would require treatment by strong and potentially harsh and dangerous drugs.
  • Examples 1-3 The detailed procedures used to gather these data are provided in Examples 1-3. These specific tests involved administration of FDP before cardiac catheterization procedures, which were being used to diagnose a number of patients who were suffe ⁇ ng from coronary artery disease. During these clinical trials, the surgeon and anesthesiologist in charge of the tests clearly observed the strong inotropic effects of FDP. However, because of the cellular and biochemical mechanisms involved, it is believed and anticipated that the same types of beneficial inotropic eftects (i.e. , increasing heartbeat strength and cardiac output without increasing heartbeat rate) will also occur if FDP is injected or infused into a patient after cardiopulmonary bypass surgery.
  • beneficial inotropic eftects i.e. , increasing heartbeat strength and cardiac output without increasing heartbeat rate
  • injection or infusion with FDP appears to be highly advisable and may offer either (1) an effective alternative to inotropic catecholamine treatment, or (2) a means to reduce the dosage of (and ameliorate the increase in heartbeat rate caused by) an inotropic catecholamine.
  • Example 12 coronary artery disease an additional set of data is provided in Example 4, obtained du ⁇ ng testing of FDP on patients who underwent open-chest surgery that involved cardiopulmonary bypass. As described in more detail in Example 4, these patients received coronary artery bypass grafting (CABG) Because ot the initial design of the surgical tests, which were planned and designed before it was recognized that FDP would indeed function as an inotrope, these tests involved intusion ot FDP into the patients prior to the commencement ot bypass (usually du ⁇ ng a 30-m ⁇ nute period prior to commencement of bypass) The resulting data clearly indicate that FDP does indeed have inotropic properties in CPB surgery patients, and these data strongly support the conclusion that it can be used as an inotrope for such patients, by injecting or infusing it into such patients after CPB surgery has been completed.
  • CABG coronary artery bypass grafting
  • the baseline value for left ventricular stroke work index was 27 0 + 3.09 (i.e. , this value was measured on such patients after the start of surgery, but before bypass began).
  • the LVSWI values were measured again, 24 hours after surgery had been completed to correct the inadequate supply of blood to the heart muscle, the LVSWI values had increased to 28.9 ⁇ 2 68 Accordingly, the increment (on average) was 1 9
  • the baseline values for LVSWI were 28.9 ⁇ 2.91; this baseline value was not significantly different from the baseline average for the control patients, when LVSWI was measured again, 24 hours after surgery WAS completed, the LVSWI values in these FDP-treated patients increased to 35.75 ⁇ 2.92
  • the increment between baseline values and post-surgical values was, on average, 6.85 in the FDP-treated patients.
  • This increase in stroke work index was 3.6 times higher than the average increase in control patients who did not receive FDP
  • the difference between the two groups was statistically significant at a confidence level of well over 95 % .
  • FDP also helped to reduce unwanted elevations in "pulmonary artery wedge pressures" (PAWP) after bypass surgery, compared to a placebo.
  • PAWP pulmonary artery wedge pressures
  • A-fib Atrial fibrillation
  • A-fib if A-fib occurs, it is a serious and potentially very dangerous event, for a number of reasons which include: (1) it disrupts and interferes with proper blood flow and transport through the heart, thereby impeding the ability of an already-weakened heart to adequately supply the body with blood; (2) the much-too-frequent and badly uncoordinated electrical impulses that can be emitted by affected atrial tissue can trigger and provoke irregularities in adjacent ventricular tissue, leading to potentially serious vent ⁇ cular pumping problems such as bradycardia, tachycardia, and arrhythmias; and, (3) because an atrial chamber is not contracting properly, it poses a serious risk of blood stasis inside the affected atrial chamber, in which a small quantity of blood can becomes trapped and stationary in a pocket or recess inside the atrial chamber If blood stasis occurs as a result of A-fib, the stationary pocket of blood may form a major blood clot, which poses a major threat of becoming dislodged and travelling to the lungs or
  • anti-coagulant drugs create their own problems and adverse side effects; among other things, they can delay and retard the ability of the body to repair itself from the cutting and suturing required by surgery.
  • a single episode of A-fib following CPB surgery usually extends the length of the hospital stay for that patient by at least 3 days, and quite often up to 5 days longer than normal, and requires higher levels of monitoring and medical attention while the patient remains in the hospital Because of the high costs of this type of intensified care in a hospital, a single episode of atrial fibrillation following CPB surgery usually increases the cost of a patient's hospital stay by at least $10,000, on average
  • Atrial fibrillation is a very important factor (also called an "end point" for purposes of statistical analysis) for evaluating the safety and efficacy of any potential drug that might be useful for treating patients who undergo surgery that requires cardiopulmonary bypass
  • Atrial fibrillation deserves attention herein, because it has been discovered, through clinical tnals on humans, that the rates and risks of A-fib after CPB surgery reveal an apparently major dividing line between two totally different things
  • certain methods of using FDP before and during CPB surgery have been shown to be safe, effective, and highly beneficial in substantially reducing the risk of atrial fibrillation after surgery
  • other unsafe methods of using FDP in CPB surgery can have the opposite effect, and can induce unwanted levels of lactic acidosis, which in turn apparently substantially increases the occurrence rate for atrial fibrillation after CPB surgery
  • the invention disclosed herein relates to a method for intravenously injecting FDP into patients in a dosage and a manner (involving factors such as the timing of injections, and the possible co-administration of one or more additional active agents along with the FDP, to counteract a specific danger posed by the FDP) which does not cause lactic acidosis, and which reduces the risks and occurrence rates of atrial fibrillation following CPB surgery
  • FDP can be lyophilized in a pure and chemically stable form which contains a surprisingly high residual moisture content, in the range of about 12 to about 16% residual water, by weight.
  • most lyophilized products contain less than about 2% residual water.
  • Such lyophihzation can be carried out in a completely sterile manufacturing process, which provides pure, sterile, stable FDP in a powder or cake form, in a sealed vial containing up to about 5 grams of FDP.
  • the powder or cake is stable for months or even years when stored at room temperature, and it is ideally suited to reconstitution for injection, using water or any other injectable aqueous solution, such as a dextrose solution, Ringer's lactate, etc Accordingly, since FDP itself in an aqueous solution is relatively unstable and will spontaneously hydrolyze and lose one or both of its phosphate groups to form inactive and useless byproducts, the use of such "partially lyophilized" preparations of FDP is regarded as the best mode of carrying out this invention
  • Any suitable (i.e. , pharmacologically acceptable) salt of FDP can be used, such as a sodium salt, or divalent salts such as calcium or magnesium salts, or mixtures thereof.
  • potassium salts should not be administered intravenously, since an abrupt infusion of potassium might interfere with cardiac functioning
  • the amount of sodium contained in the sodium salt of FDP will not have any adverse effects on the large majority of people who are likely to need it
  • the patient can be treated with a diuretic drug to increase the elimination of sodium in urine or feces
  • Preferred dosages for intravenous infusion of FDP prior to commencement of bypass will generally be in the range of at least about 100 mg/kg (i.e. , milligrams of FDP per kilogram of patient body weight), preferably infused over a span of about 15 minutes or
  • Preferred infusion rates will typically be in the range of about 0.5 to about 5 mg/kg/minute
  • Preferred dosages for bolus injection or intravenous infusion of FDP after bypass has been completed and terminated will generally be in the range of about 75 to about 400 mg/kg.
  • EXAMPLE 1 EFFECTS OF FDP IN PATIENTS WITH ELEVATED LVEDP
  • the study group described in both Examples 1 and 2 comprised 47 men and women who underwent diagnostic cardiac catheterization at the University of Mississippi Medical Center, in Jackson, Mississippi Most patients were known or suspected to have coronary artery disease (CAD). Prior to catheterization, the study was explained to the patients, and they were assured that it would require no longer than 30 minutes, plus the time required to complete the diagnostic procedure Those who volunteered to participate gave informed consent, and the study protocol was approved by the Institutional Review Board.
  • CAD coronary artery disease
  • Hemodynamic measurements included heart rate (HR, beats/ min), mean and phasic systemic arterial pulmonary arterial pressure, LV peak systolic pressure, and end diastolic and mean pressures (all pressures in mm Hg).
  • the cardiac output (CO, L/min) was determined by either thermodilution or the Fick method. From the above measured parameters, systemic and total pulmonary resistance (SVR and TPVR, dynes sec 3 ), stroke volume (SV, ml/beat), stroke volume index (SVI, ml/beat/m 2 ), and LV stroke work index (LVSWI, gm.m.m 2 ) were calculated according to the methods described in Grossman et al 1991 .
  • FDP FDP at 75 mg/kg significantly increased the respiratory quotient (RQ) and calories derived from carbohydrates, indicating increased glycolytic activity.
  • baseline demographic and angiographic characteristics were similar between the groups with elevated LVEDP, and normal LVEDP.
  • three patients with elevated LVEDP three patients had no angiographic evidence of CAD, although two of them had previous myocardial infarction (MI), and one was in heart failure.
  • MI myocardial infarction
  • one was in heart failure In the subset with LVSWI values less than 30 g-m/m 2 , six patients had previous MI, five had triple- vessel disease, two had two-vessel disease, and one had mitral regurgitation.
  • FDP infusion generally produced similar but less pronounced hemodynamic changes, compared to the effects in the group with LV dysfunction; however, FDP did not alter the LVEDP and MPAP values in the patients with normal beginning LVEDP values.
  • HR P ⁇ 0.001
  • HR P ⁇ 0.001
  • SVI SVI
  • LVSWI P ⁇ 0.002
  • PVR P ⁇ 0.004
  • EXAMPLE 3 EFFECTS OF FDP IN PATIENTS WITH ELEVATED LVEDP COMBINED WITH LOW LVSWI
  • LVSWI left ventricular stroke work index
  • her LVEDP declined from 22 to 14 mm Hg, and her CI increased.
  • EXAMPLE 4 EFFECTS OF FDP IN CABG PATIENTS WHO UNDERWENT CARDIOPULMONARY BYPASS SURGERY All surgical and testing procedures described in this example were carried out at the
  • anesthesia was maintained with a combination of agents that sustained unconsciousness, paralysis, and immobility; this required the use of a mechanical ventilator before cardiac bypass began and after it ended.
  • Patients were monitored with various instruments either situated externally (e.g. , to analyze exhaled gases), upon the surface of their body (e.g. , a stethoscope and EKG recording electrodes), or within their body, through a normal orifice (such as a temperature probe placed in the esophagus) or by insertion through the skin (e.g., pressure recording catheters were passed through an incision in the groin or neck, and advanced into the chambers of the heart or a pulmonary artery).
  • instruments either situated externally (e.g. , to analyze exhaled gases), upon the surface of their body (e.g. , a stethoscope and EKG recording electrodes), or within their body, through a normal orifice (such as a temperature probe placed in the esophagus) or by insertion through
  • the chest was opened by longitudinal incision over and through the sternal bone.
  • the chest wall was spread open and held apart with a chest retractor (also called an "alligator” in England).
  • a matched saline placebo was injected into patients in the control population.
  • the anesthesiologist(s) working on any specific patient were unaware whether they had infused that patient with FDP or a placebo.
  • the bypass machine was prepared by filling the pumping chamber with either blood or an oxygenated solution compatible with blood; this process is known as pump priming.
  • the aorta was clamped, punctured, and received the effluent hose from the bypass machine.
  • Additional cannulas were inserted into the coronary arteries and the coronary (venous) sinus, to allow independent perfusion of the heart muscle with cold "cardioplegia" solution containing high concentrations of potassium, to cause the heart to stop beating during surgery. In most cases, additional hoses from the bypass machine were inserted into one or more pulmonary embolism
  • the saphenous vein segment or mammary artery end was sutured into place on the surface of the heart, to create a new coronary artery passageway which circumvented and bypassed an obstructed native coronary artery
  • the heartbeat was restarted, usually with the aid of electric shock, which was often needed more than once due to the tendency ot hearts to fib ⁇ llate as they are rewarmed and restarted after surgery
  • the hoses from the bypass machine were slowly clamped off, to test whether the patient's heart could regain adequate blood pumping pressure, and to allow continuing inspection tor leakage from the sutured artery grafts If all was well, the bypass hoses were removed from the aorta and right side of the heart, and their entry punctures were sutured shut
  • the basin formed by the pencardial membrane was again inspected for leakage, and plastic drainage tubes were inserted into the pencardial space and secured in position with dissolving sutures, these tubes passed through the skin at a location
  • Post-operative monitoring included EKG recording, CK enzyme concentrations in circulating blood, and measurements of heart function through invasive pressure momtonng catheters and echocardiography When FDP-pretreated patient populations were compared to untreated control populations, these measurements clearly demonstrated that injection of FDP, before cardiopulmonary bypass began, resulted in both (1) substantial reductions of heart cell
  • FDP treatment using the Stage 1 or Stage 3 dosages significantly reduced the average number of days that FDP-treated patients had to remain in an intensive care unit, after their surgery, before they could be transferred to ordinary hospital rooms.

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Abstract

La présente invention concerne le fructose-1,6-diphosphate (FDP), pouvant être utilisé de manière sure et efficace comme médicament inotrope chez des patients nécessitant des interventions chirurgicales cardiaques ou autres, y compris le pontage cardiopulmonaire. Comme un composé de phosphate-sucre haute énergie avec des effets inotropes, le FDP peut accroître la force de pompage d'un coeur qui lutte, sans accroître le rythme des battements du coeur. Chez certains patients, ceci peut éliminer le besoin de dobutamine, d'épinéphrine, ou de médicaments inotropes hostiles analogues présentant des effets indésirables potentiellement dangereux. Chez d'autres patients, le FDP peut être administré en combinaison avec un autre médicament inotrope, de manière à réduire la dose nécessaire des autres inotropes. Lorsqu'il est administré avant l'intervention à des doses ne provoquant pas l'acidose lactique, le FDP permet également de réduire le risque qu'un patient souffre de fibrillation auriculaire post-opératoire. En doses adéquates, le fructose-1,6-diphosphate (FDP) ne présente aucun effet indésirable connu chez les patients nécessitant un pontage cardiopulmonaire. Ainsi, il peut être administré comme mesure de prévention à tout ces patients. Les patients ne nécessitant pas de support inotrope ne sont pas affectés négativement, alors que d'autres patients nécessitant de ce support peuvent en tirer un bénéfice maximum, si le FDP est injecté avant le début du pontage, ainsi que tout de suite après l'intervention, ou lors des premiers symptômes de la déficience des battements de coeur.
PCT/US1999/019432 1999-08-30 1999-08-30 Utilisation de fructose-1,6-diphosphate comme medicament inotrope pour le pontage cardiopulmonaire WO2001015705A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US1999/019432 WO2001015705A1 (fr) 1999-08-30 1999-08-30 Utilisation de fructose-1,6-diphosphate comme medicament inotrope pour le pontage cardiopulmonaire
AU56919/99A AU5691999A (en) 1999-08-30 1999-08-30 Use of fructose-1,6-diphosphate as an inotrope drug for cardiopulmonary bypass surgery

Applications Claiming Priority (1)

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PCT/US1999/019432 WO2001015705A1 (fr) 1999-08-30 1999-08-30 Utilisation de fructose-1,6-diphosphate comme medicament inotrope pour le pontage cardiopulmonaire

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Cited By (3)

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EP1734821A2 (fr) * 2004-04-14 2006-12-27 UAB Research Foundation Activateurs de la biosynthese de l'hexosamine en tant qu'inhibiteurs de lesion induite par l'ischemie ou le choc hemorragique
US7379783B2 (en) 2004-05-06 2008-05-27 Smp Logic Systems Llc Manufacturing execution system for validation, quality and risk assessment and monitoring of pharmaceutical manufacturing processes
US7392107B2 (en) 2004-05-06 2008-06-24 Smp Logic Systems Llc Methods of integrating computer products with pharmaceutical manufacturing hardware systems

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US4530902A (en) * 1979-01-16 1985-07-23 Biomedica Foscama Industria Chimico Farmaceutica S.P.A. Method for producing fructose-1,6-diphosphoric acid
US5434255A (en) * 1992-03-27 1995-07-18 Unitika Ltd. Process for purifying fructose 1,6-diphosphate
US5731291A (en) * 1996-05-08 1998-03-24 Cypros Pharmaceutical Corp. Partially lyophilized fructose-1,6-diphosphate (FDP) for injection into humans

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4530902A (en) * 1979-01-16 1985-07-23 Biomedica Foscama Industria Chimico Farmaceutica S.P.A. Method for producing fructose-1,6-diphosphoric acid
US5434255A (en) * 1992-03-27 1995-07-18 Unitika Ltd. Process for purifying fructose 1,6-diphosphate
US5731291A (en) * 1996-05-08 1998-03-24 Cypros Pharmaceutical Corp. Partially lyophilized fructose-1,6-diphosphate (FDP) for injection into humans

Cited By (17)

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EP1734821A2 (fr) * 2004-04-14 2006-12-27 UAB Research Foundation Activateurs de la biosynthese de l'hexosamine en tant qu'inhibiteurs de lesion induite par l'ischemie ou le choc hemorragique
EP1734821A4 (fr) * 2004-04-14 2011-07-06 Uab Research Foundation Activateurs de la biosynthese de l'hexosamine en tant qu'inhibiteurs de lesion induite par l'ischemie ou le choc hemorragique
US7428442B2 (en) 2004-05-06 2008-09-23 Smp Logic Systems Methods of performing path analysis on pharmaceutical manufacturing systems
USRE43527E1 (en) 2004-05-06 2012-07-17 Smp Logic Systems Llc Methods, systems, and software program for validation and monitoring of pharmaceutical manufacturing processes
US7379784B2 (en) 2004-05-06 2008-05-27 Smp Logic Systems Llc Manufacturing execution system for validation, quality and risk assessment and monitoring of pharmaceutical manufacturing processes
US7471991B2 (en) 2004-05-06 2008-12-30 Smp Logic Systems Llc Methods, systems, and software program for validation and monitoring of pharmaceutical manufacturing processes
US7509185B2 (en) 2004-05-06 2009-03-24 Smp Logic Systems L.L.C. Methods, systems, and software program for validation and monitoring of pharmaceutical manufacturing processes
US7799273B2 (en) 2004-05-06 2010-09-21 Smp Logic Systems Llc Manufacturing execution system for validation, quality and risk assessment and monitoring of pharmaceutical manufacturing processes
US7379783B2 (en) 2004-05-06 2008-05-27 Smp Logic Systems Llc Manufacturing execution system for validation, quality and risk assessment and monitoring of pharmaceutical manufacturing processes
US7392107B2 (en) 2004-05-06 2008-06-24 Smp Logic Systems Llc Methods of integrating computer products with pharmaceutical manufacturing hardware systems
US8491839B2 (en) 2004-05-06 2013-07-23 SMP Logic Systems, LLC Manufacturing execution systems (MES)
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