WO2010096869A1 - Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur - Google Patents

Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur Download PDF

Info

Publication number
WO2010096869A1
WO2010096869A1 PCT/AU2010/000214 AU2010000214W WO2010096869A1 WO 2010096869 A1 WO2010096869 A1 WO 2010096869A1 AU 2010000214 W AU2010000214 W AU 2010000214W WO 2010096869 A1 WO2010096869 A1 WO 2010096869A1
Authority
WO
WIPO (PCT)
Prior art keywords
relaxation
riluzole
heart
contractility
disease
Prior art date
Application number
PCT/AU2010/000214
Other languages
English (en)
Inventor
Steven Michael Weiss
David Albert Saint
Original Assignee
Steven Michael Weiss
David Albert Saint
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
Priority claimed from AU2009900848A external-priority patent/AU2009900848A0/en
Application filed by Steven Michael Weiss, David Albert Saint filed Critical Steven Michael Weiss
Publication of WO2010096869A1 publication Critical patent/WO2010096869A1/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a method for improving contractility or relaxation of the mammalian heart and for combating diseases which cause poor contractility or relaxation as well as diseases resulting from poor contractility or relaxation.
  • the present invention further relates to a method for treating degenerative cardiac diseases, as an adjunct therapy for medical and surgical procedures, and for treating certain psychological, immunological, hormonal, circulatory and environmental events and conditions.
  • the function of the heart in the mammalian body is to pump blood to and from the organs of that body and in so-doing, provide a vehicle for both supplying those organs with the nutrients necessary for their function (including oxygen) as well as for removal of waste products from those organs.
  • diseases of the body affect the capacity of the heart to pump blood efficiently and effectively - that is, they affect the contractility or relaxation of the cells of the heart and of the heart overall.
  • diseases include: ischaemic heart diseases such as angina and myocardial infarction, non-ischaemic heart diseases such as cardiomyopathies including dilated cardiomyopathy and heart failure, and metabolic diseases such as diabetes
  • diseases of the body degenerate as a result of the heart's poor capacity to pump blood efficiently and effectively. Examples of these diseases include: angina, cardiomyopathies including dilated cardiomyopathy, heart failure and diabetic myopathy.
  • kidney failure and orthostatic hypotension.
  • many medical and surgical procedures can temporarily reduce contractility or relaxation. Examples of these include when a patient is anaesthetised or treated with anticancer drugs. Many medical and surgical procedures can also permanently reduce contractility or relaxation. Examples of these include: cardiac ablation therapy and ischaemia and reperfusion (such as coronary bypass procedures).
  • the pumping of blood by the heart is created by a complex contraction and subsequent relaxation motion of the heart.
  • the heart contracts, it squeezes blood from inside its chambers out of the heart and into the circulatory system.
  • the heart squeezes more blood into the circulatory system and hence continues to push the blood further and further around the circulatory system.
  • the heart muscle After each contraction, the heart muscle must relax and refill with blood for the next contraction.
  • the heart has valves within which prevent the ejected blood from returning along the same path to the heart when it relaxes and thus ensure that the pumping of blood continues in one direction only from the heart into the circulatory system.
  • the amount by which the heart contracts in each cycle of contraction and relaxation is called its contractility.
  • An agent which affects the degree of contractility is called an inotrope, and an agent which increases contractility is called a positive inotrope.
  • Another important factor which affects the amount of blood being ejected in each cardiac cycle is the extent by which the heart relaxes during the relaxation phase of the cycle. The more the heart relaxes in each cardiac cycle, the more blood it can accommodate for the next contraction and therefore, the more blood it has available for ejection and the more blood it ejects. This again is generally a good attribute, however there are limits in how far the heart muscle can relax.
  • An agent which affects the degree of relaxation of the heart muscle is called a lusitrope, and an agent which increases relaxation is called a positive lusitrope.
  • the compound riluzole may be an effective positive inotrope agent.
  • a first aspect of the invention provides for a method for increasing the contractility or relaxation of a mammalian heart, comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • a second aspect of the invention provides for a method for the treatment, amelioration or prevention of a disease or condition related to compromised contraction or relaxation of a mammalian heart, comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • a third aspect of the invention provides for a method for the concomitant treatment of a medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart, comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • a fourth aspect of the invention provides for the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for increasing the contractility or relaxation of a mammalian heart.
  • a fifth aspect of the invention provides for the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the treatment, amelioration or prevention of a disease or condition related to compromised contraction or relaxation of a mammalian heart.
  • a sixth aspect of the invention provides for the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the concomitant treatment of a medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart.
  • a seventh aspect of the invention provides for riluzole or a pharmaceutically acceptable salt or derivative thereof for use in increasing the contractility or relaxation of a mammalian heart.
  • An eighth aspect of the invention provides for riluzole or a pharmaceutically acceptable salt or derivative thereof for use in the treatment, amelioration or prevention of a disease or condition related to compromised contraction or relaxation of a mammalian heart.
  • a ninth aspect of the invention provides for riluzole or a pharmaceutically acceptable salt or derivative thereof for use in the concomitant treatment of a medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart.
  • FIG. 1 A section of chart recording of an experiment in which riluzole (8 mg/kg) was administered to a normoxic anaesthetised intact pig intraperitoneally.
  • the chart shows arterial blood pressure plotted against time.
  • the systolic pressure rose from 85 to 120 mmHg
  • the diastolic pressure rose from 50 to 66 mmHg
  • the pulse pressure rose from 35 to 54 mmHg.
  • the increase in systolic pressure arose largely from an increase in contractile force during contraction of the heart and hence suggests a positive inotropic effect of riluzole.
  • FIG. 2 A chart recording from an ischaemic experiment in a non-treated anaesthetised intact pig.
  • the chart shows arterial blood pressure plotted against time.
  • the systolic and diastolic pressures decreased rapidly when the heart was subjected to a coronary artery occlusion (heart attack). This was followed by some degree of spontaneous recovery wherein the diastolic pressure returned to a pressure similar to the pre-occlusion pressure, but the systolic pressure remained lower than the pre-occlusion pressure.
  • Upon clearing the coronary artery occlusion (reperfusion) there was a further recovery in systolic pressure, however this pressure stabilised and remained at a pressure lower than pre-occlusion pressure.
  • FIG. 3 A trace from an ischaemic experiment in an intact pig similar to that shown in Figure 2 except that riluzole was infused intravenously over several minutes after the coronary artery occlusion and before the reperfusion.
  • the trace shows arterial blood pressure plotted against time.
  • systolic pressure decreased rapidly following coronary artery occlusion.
  • the systolic pressure rapidly rose to a pressure higher than the pre-occlusion pressure.
  • systolic pressure again rose rapidly and stabilised at a pressure about 20 mmHg higher than the pre-occlusion pressure.
  • This Figure demonstrates a doubly beneficial positive inotropic effect of riluzole during occlusion, and again during reperfusion, of the coronary artery.
  • Figure 4 Two chart recordings from an ischaemic isolated heart experiment in which hearts were removed from rats and supported in a Langendorff apparatus. Heart rhythm and functionality was maintained by perfusion with Tyrode's solution.
  • Figure 4A shows left ventricular (LV) pressure in a NON-riluzole-treated heart wherein perfusion of the heart through the arteries was stopped which resulted in cessation of the pumping of the heart and a rapid fall in systolic and diastolic pressure until they were both zero.
  • Reperfusion was commenced approximately 30 minutes later causing both systolic and diastolic pressure to rise simultaneously; this rise representing significant contraction of the ventricles with no pumping and being indicative of reperfusion injury (muscle damage).
  • FIG. 5 A graph of the normalised rate of change of maximum left ventricular pressure (dLVPmax/dt) in normoxic isolated perfused rat hearts.
  • dLVPmax/dt is a measure of contractility and in these experiments can be seen to increase by 60% upon administration of 1 ⁇ M riluzole and 72% upon administration of 10 ⁇ M riluzole. Thus, these data show that riluzole is positively inotropic in a dose-dependent manner in normoxic hearts.
  • Figure 6 A graph of the normalised rate of change of maximum left ventricular pressure (dLVPmax/dt) in isolated perfused rat hearts subsequent to myocardial reperfusion following a 30-minute absence of perfusion.
  • FIG. 7 A graph of the normalised rate of change of minimum left ventricular pressure (dLVPmin/dt) in normoxic isolated perfused rat hearts.
  • dLVPmin/dt is a measure of relaxation and in these experiments can be seen to increase by 67% upon administration of 1 ⁇ M riluzole and 74% upon administration of 10 ⁇ M riluzole.
  • riluzole is positively lusitropic in normoxic hearts.
  • FIG. 8 A graph of the normalised rate of change of minimum left ventricular pressure (dLVPmin/dt) in isolated perfused rat hearts subsequent to myocardial reperfusion following a 30-minute absence of perfusion.
  • dLVPmin/dt doubled upon administration of 3 ⁇ M riluzole and upon administration of 10 ⁇ M riluzole.
  • Figure 9 Two graphs of the extent of cell length shortening during contraction of individual rat heart muscle cells during normoxia, after 20 minutes of hypoxia, and during reoxygenation in cells which were non-treated ( Figure 9A) and in cells which were treated ( Figure 9B) with riluzole.
  • the hypoxia reduced the extent of muscle cell contraction by 80% when compared with the contraction during normoxia.
  • reoxygenation reduced the extent of muscle cell contraction by 98%.
  • the hypoxia reduced the extent of muscle cell contraction by only 12% when compared with the contraction during normoxia and actually increased the extent of muscle cell contraction by 55% following reperfusion.
  • Figure 10 A graph of normalised left ventricular pulse pressure in an isolated heart study of four normal (non-hypoxic, non-diseased) rat hearts.
  • the scale along the bottom axis is not linear and represents the times: 10 minutes prior to the administration of 3 ⁇ M riluzole (300), 30 seconds prior to the administration of the riluzole (301), the peak response immediately following administration of the riluzole (302), 10 minutes after riluzole administration (303), 30 seconds prior to riluzole washout (304), the peak drop in systolic pressure immediately following riluzole washout (305), 10 minutes after riluzole washout (306) and 20 minutes after riluzole washout (307).
  • normalised left ventricular systolic pressure increased and continued to increase following riluzole administration
  • normalised left ventricular diastolic pressure decreased and continued to decrease following administration of riluzole.
  • the normalised left ventricular systolic pressure continued to increase, and the normalised left ventricular diastolic pressure continued to decrease, even after the washout of riluzole thus indicating a prolonged effect of riluzole.
  • FIG. 11 A graph of normalised left ventricular pulse pressure in an isolated heart study of four rat hearts before (at times 400) a 30-minute episode of ischaemia and 20 minutes after subsequent reperfusion (at times 401).
  • the white bars at time points 400C and 401C show the left ventricular pressure for the NON-riluzole-treated hearts while the black bars at 400R and 40 IR show the left ventricular pressure for the riluzole-treated hearts.
  • the normalised left ventricular systolic, diastolic and pulse pressures in the NON-riluzole-treated hearts did not return to the pre-ischaemic values and remained severely compromised at 20 minutes after reperfusion.
  • Figure 12 A chart recording similar to that in Figure 1 except that in Figure 12, the chart is of left ventricular pressure from a normoxic isolated rat heart as opposed to peripheral arterial blood pressure from an anaesthetised intact pig as shown in Figure 1.
  • the similarity between Figure 12 and Figure 1 demonstrates that sympathetic drive and peripheral vasodilation and vasoconstriction played no part in the arterial blood pressure responses to riluzole shown in Figure 1, and hence that the results shown in Figure 1 were indeed positively inotropic and positively lusitropic.
  • ' > Fi g ure 13 A chart of dLVP/dt taken from the same example and at the same time as shown in Figure 12.
  • dLVP/dt is the rate of change of left ventricular pressure and directly represents the rate of increase in the force of contraction (by the top of the trace) and the rate of relaxation (by the bottom of the trace) of the heart muscle.
  • contractility rose following and in direct response to the introduction of riluzole into the perfusion solution.
  • the increase in contractility directly represents a positive inotropic effect of riluzole.
  • the rate of relaxation increased (ie, an increase in negative value) following and in direct response to the introduction of riluzole into the perfusion solution.
  • the increase in relaxation directly represents a positive lusitropic effect of riluzole.
  • administering includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means.
  • treatment refers to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever.
  • the term "therapeutically effective amount” includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular agent being administered, the mode of administration, and so forth. Thus, it is not possible to specify an exact “therapeutically effective amount”. However, for any given case, an appropriate “therapeutically effective amount” may be determined by one of ordinary skill in the art using only routine experimentation. In the context of the specification it is to be understood that the term “contractility” means the force of contraction of the heart muscle or the rate of increase of pressure in the heart as result of contraction or the amount or extent of shortening of the heart muscle.
  • the term “relaxation” means the rate at which the force of contraction of the heart muscle decreases or the rate at which the pressure developed by the heart muscle decreases or the rate or extent at which the heart muscle lengthens.
  • ischaemia includes, but is not limited to, a reduction or absence of blood flow, or a reduction or absence of flow of a solution used as a blood substitute.
  • hypooxia includes, but is not limited to, a reduction or absence of the amount of oxygen supplied to a tissue. In principle, “ischaemia” and “hypoxia” can occur independently, however in practice “ischaemia” always includes “hypoxia”.
  • Riluzole (2-amino-6-trifluoromethoxybenzothiazole) which has the following structure: is described as a treatment for amyotrophic lateral sclerosis (ALS) (US 5,527,814), a disease unrelated to myocardial contractility or relaxation.
  • ALS amyotrophic lateral sclerosis
  • Riluzole has also been found to be useful as an anticonvulsant, an anxiolytic and a hypnotic (US 4,370,338), in the treatment of schizophrenia (US 4,882,345), in the treatment of sleep disorders and of depression (US 4,906,649), in the treatment of cerebrovascular disorders and as an anaesthetic (US 4,826,860), in the treatment of spinal, cranial or cranio-spinal traumas (WO94/13288), in the treatment of Parkinson's disease (US 5,674,885), and in the treatment of mitochondrial diseases (US 5,686,475).
  • riluzole has been identified for use in preventing optic nerve degeneration associated with glaucoma (US 6,326,389) and as a persistent sodium channel blocker in rat cortical neurons (Spadoni et ai, Neuroreport, 2002, 13(9): 1167-70). Riluzole has also recently been identified in WO 07/022568 for reducing the incidence of cardiac arrhythmias and the extent of myocardial damage or the consequences thereof, subsequent to hypoxia or a loss, reduction or interruption in coronary blood flow.
  • riluzole treats diseases or conditions which are not neuronal.
  • the function of the heart and the function of the cells in the heart work very differently to the functions of the brain and nervous system and to neurons; heart muscle cells produce the physical motion of contraction and relaxation whereas neurons do not produce any physical motion. Therefore, it was quite surprising to discover that the pharmaceutical compound riluzole for treating neuronal diseases may be effective for treating the contractility or relaxation of cardiac pumping as well as the diseases which cause poor contractility or relaxation and the diseases resulting from poor contractility or relaxation.
  • riluzole which is known from WO 07/022568 to treat certain arrhythmias and myocardial damage, may be effective for treating the contractility or relaxation of cardiac pumping as well as the diseases which cause poor contractility or relaxation and the diseases resulting from poor contractility or relaxation.
  • riluzole treats arrhythmias and myocardial damage arising from hypoxia or a loss, reduction or interruption in coronary blood flow.
  • These actions of riluzole are very different to the actions of positive inotropy and positive lusitropy, since positive inotropy and positive lusitropy occur irrespective of any myocardial hypoxia or loss, reduction or interruption in coronary blood flow.
  • compounds such as digoxin, epinephrine and nitric oxide, hi the converse, myocardial arrhythmias and myocardial damage arising from hypoxia or a loss, reduction or interruption in coronary blood flow occur irrespective of any changes in contractility or relaxation.
  • compounds such as amiodarone, sotalol, aspirin and streptokinase are examples of arrhythmias and myocardial damage arising from hypoxia or a loss, reduction or interruption in coronary blood flow.
  • one aspect of the invention provides for a method for increasing the contractility or relaxation of a mammalian heart, comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • the contractility of the mammalian heart is increased.
  • the relaxation of the mammalian heart is increased.
  • both the contractility and relaxation of the mammalian heart are increased.
  • the present invention relates to a method for increasing contractility of a mammalian heart by systemically or directly administering to the heart a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • Another embodiment the invention relates to a method for increasing relaxation of a mammalian heart by systemically or directly administering to that heart one or more pharmaceutical compositions which include an amount of riluzole sufficient to effect an increase in relaxation.
  • Another aspect of the invention provides for a method for the treatment, amelioration or prevention of a disease or condition related to compromised contraction or relaxation of a mammalian heart, comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • the disease or condition is selected from the group consisting of poor contractility of a mammalian heart, poor relaxation of a mammalian heart, ischaemic heart disease, non-ischaemic heart disease, metabolic disease, diabetes, myocardial disease, kidney failure, heart failure or orthostatic hypotension.
  • the ischaemic heart disease is selected from the group consisting of angina or myocardial infarction.
  • the ischaemic heart disease is angina.
  • the ischaemic heart disease is a myocardial infarction.
  • the non-ischaemic heart disease is cardiomyopathy.
  • the condition is poor contractility or poor relaxation of a mammalian heart.
  • condition is poor contractility of a mammalian heart. In a further embodiment the condition is poor relaxation of a mammalian heart.
  • disease or condition is selected from the group consisting of metabolic disease, diabetes, myocardial disease, kidney failure, heart failure or orthostatic hypotension. In another embodiment the disease or condition is kidney failure, heart failure or orthostatic hypotension. In another embodiment the disease is metabolic disease. In one embodiment the metabolic disease is diabetes.
  • the condition related to compromised contraction or relaxation of the mammalian heart is selected from the group consisting of a psychological, immunological, hormonal, circulatory or environmental condition.
  • the psychological, immunological, hormonal, circulatory or environmental condition is selected from the group consisting of emotional shock, sepsis, circulatory shock, hormonal abnormalities, injury, chemical or toxin exposure, or radiation exposure.
  • the environmental condition is chemical or toxin exposure or radiation exposure.
  • the disease or condition results from compromised contraction or relaxation of the mammalian heart.
  • the disease or condition causes compromised contraction or relaxation of the mammalian heart.
  • the risk of development of a disease is reduced.
  • the rate of development of a disease is reduced.
  • the rate of degradation of the disease is reduced.
  • the disease is myocardial, hi another embodiment the disease is selected from the group consisting of heart failure, kidney failure and orthostatic hypotension.
  • the present invention is directed to a method for treating a disease of the body which affects the capacity of the heart to pump blood efficiently and effectively; such diseases including: ischaemic heart diseases such as angina and myocardial infarction, non-ischaemic heart diseases such as cardiomyopathy and heart failure, and metabolic diseases such as diabetes.
  • ischaemic heart diseases such as angina and myocardial infarction
  • non-ischaemic heart diseases such as cardiomyopathy and heart failure
  • metabolic diseases such as diabetes.
  • the present invention is directed to a method for treating a disease of the body which degenerates as a result of the heart's poor capacity to pump blood efficiently and effectively; such diseases including: angina, cardiomyopathies including dilated cardiomyopathy, heart failure and diabetic myopathy.
  • the present invention is directed to a method for treating a secondary disease which may be produced in the body by the heart's poor ability to pump blood efficiently and effectively; such diseases including: kidney failure and orthostatic hypotension.
  • a further aspect of the invention provides for a method for the concomitant treatment of a medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart, comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • the medical or surgical procedure which produces poor contractility or poor relaxation of the mammalian heart is selected from the group consisting of anesthesia or ablation therapy.
  • the medical or surgical procedure is anesthesia.
  • the medical or surgical procedure is ablation therapy.
  • the present invention is directed to a method for providing concomitant therapy to a medical or surgical procedure which may decrease the heart's ability to pump blood efficiently and effectively; such procedures including: anaesthesia, anti-cancer treatment, ablation therapy and vascular bypass.
  • the present invention is directed to a method for treating a temporary or permanent decrease in the heart's ability to pump blood efficiently and effectively caused by a psychological, immunological, hormonal, circulatory or environmental factor including: emotional shock, sepsis, circulatory shock, hormonal abnormalities, injury, chemical and toxin exposure, and radiation exposure.
  • compositions of riluzole or a pharmaceutically acceptable salt or derivative thereof according to the present invention having positive inotropic or positive lusitropic properties may treat degenerative diseases by breaking or slowing the cycle of degradation which cause poor contractility or relaxation.
  • pharmaceutical compositions of riluzole according to the present invention having positive inotropic or positive lusitropic properties may slow or stop the rate at which diseases of the body develop or degrade from poor contractility or relaxation.
  • the present invention includes one or more pharmaceutical compositions which include the compound riluzole or salts or derivatives thereof, when used to promote positive inotropy in a mammalian heart.
  • the present invention includes one or more pharmaceutical compositions which include the compound riluzole or salts or derivatives thereof, when used to promote positive lusitropy in a mammalian heart.
  • the present invention includes a method for the treatment, amelioration or prevention of poor contractility in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment, amelioration or prevention of poor relaxation in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment, amelioration or prevention of an ischaemic cardiac disease such as angina or myocardial infarction as well as a non-ischaemic heart disease such as cardiomyopathies including dilated cardiomyopathy which produce poor contractility in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment, amelioration or prevention of an ischaemic cardiac disease such as angina and myocardial infarction as well as a non-ischaemic heart disease such as cardiomyopathies including dilated cardiomyopathy which produce poor relaxation in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • an ischaemic cardiac disease such as angina and myocardial infarction
  • a non-ischaemic heart disease such as cardiomyopathies including dilated cardiomyopathy which produce poor relaxation in a mammalian heart
  • the present invention includes a method for the concomitant treatment of a medical or surgical procedure such as anaesthesia or ablation therapy which produce poor contractility in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the concomitant treatment of a medical or surgical procedure such as anaesthesia or ablation therapy which produce poor relaxation in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment of certain psychological, immunological, hormonal, circulatory and environmental conditions such as emotional shock, sepsis, circulatory shock, hormonal abnormalities, injury, chemical and toxin exposure, and radiation exposure which produce poor contractility in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment of certain psychological, immunological, hormonal, circulatory and environmental conditions such as emotional shock, sepsis, circulatory shock, hormonal abnormalities, injury, chemical and toxin exposure, and radiation exposure which produce poor relaxation in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment, amelioration or prevention of diseases which result from poor contractility in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • the present invention includes a method for the treatment, amelioration or prevention of diseases which result from poor relaxation in a mammalian heart, wherein the method involves the step of administering an effective amount of one or more pharmaceutical compositions including the compound riluzole or a salt or derivative thereof.
  • a further aspect of the invention provides for the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for increasing the contractility or relaxation of a mammalian heart.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of increasing myocardial contractility. In another embodiment the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of increasing myocardial relaxation.
  • Another aspect of the invention provides for the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the treatment, amelioration or prevention of a disease or condition related to compromised contraction or relaxation of a mammalian heart.
  • the disease or condition is selected from the group consisting of poor contractility of a mammalian heart, poor relaxation of a mammalian heart, ischaemic heart disease and, non-ischaemic heart disease, metabolic disease, diabetes, myocardial disease, kidney failure, heart failure or orthostatic hypotension.
  • the ischaemic heart disease is selected from the group consisting of angina and myocardial infarction.
  • the ischaemic heart disease is angina.
  • the ischaemic heart disease is a myocardial infarction, hi one embodiment the non-ischaemic heart disease is cardiomyopathy.
  • the condition is poor contractility or poor relaxation of a mammalian heart.
  • condition is poor contractility of a mammalian heart. In a further embodiment the condition is poor relaxation of a mammalian heart.
  • disease or condition is selected from the group consisting of metabolic disease, diabetes, myocardial disease, kidney failure, heart failure or orthostatic hypotension. In another embodiment the disease or condition is kidney failure, heart failure or orthostatic hypotension. In another embodiment the disease is metabolic disease. In one embodiment the metabolic disease is diabetes.
  • condition related to compromised contraction or relaxation of the mammalian heart is selected from the group consisting of a psychological, immunological, hormonal, circulatory and environmental condition.
  • the psychological, immunological, hormonal, circulatory and environmental condition is selected from the group consisting of emotional shock, sepsis, circulatory shock, hormonal abnormalities, injury, chemical or toxin exposure, or radiation exposure.
  • the environmental condition is chemical or toxin exposure or radiation exposure.
  • the disease or condition results from compromised contraction or relaxation of the mammalian heart.
  • the disease or condition causes compromised contraction or relaxation of the mammalian heart.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of reducing the rate of degradation of a myocardial disease which produces poor contractility.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of reducing the rate of degradation of a myocardial disease which produces poor relaxation.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of reducing the rate of development of a disease arising from poor contractility.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of reducing the rate of development of disease arising from poor relaxation.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of providing concomitant therapy to a medical or surgical procedure which may decrease contractility.
  • a further aspect of the invention provides for the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the concomitant treatment of a medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart.
  • the medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart is selected from the group consisting of anaesthesia or ablation therapy.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of providing concomitant therapy to a medical or surgical procedure which may decrease relaxation.
  • the present invention includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of providing therapy to psychological, immunological, hormonal, circulatory and environmental conditions which may decrease contractility.
  • the present invention also includes the use of riluzole or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for the purpose of providing therapy to psychological, immunological, hormonal, circulatory and environmental conditions which may decrease relaxation.
  • One embodiment of the present invention is to increase contractility or increase relaxation of a mammalian heart by the administration of riluzole.
  • a further aspect of the invention provides for riluzole or a pharmaceutically acceptable salt or derivative thereof for use in increasing contractility or relaxation of a mammalian heart.
  • Another aspect of the invention provides for riluzole or a pharmaceutically acceptable salt or derivative thereof for use in the treatment, amelioration or prevention of a disease or condition related to compromised contraction or relaxation of a mammalian heart.
  • a further aspect of the invention provides for riluzole or a pharmaceutically acceptable salt or derivative thereof for use in the concomitant treatment of a medical or surgical procedure which produces poor contractility or poor relaxation of a mammalian heart.
  • one embodiment of the present invention is to slow the rate of degradation of cardiac diseases by the administration of riluzole.
  • a further embodiment of the present invention is to reduce the risk of diseases including heart failure, kidney failure and orthostatic hypotension which may develop as a result of the afore-mentioned cardiac diseases or a decrease in contractility or relaxation.
  • Another embodiment of the present invention is to provide concomitant therapy to medical and surgical procedures including anaesthesia, anti-cancer therapy, vascular bypass and ablation therapy which may decrease contractility or relaxation.
  • a further embodiment of the present invention is to provide treatment for psychological, immunological, hormonal, circulatory and environmental conditions including emotional shock, sepsis, circulatory shock, hormonal abnormalities, injury, chemical and toxin exposure, and radiation exposure which may decrease contractility or relaxation.
  • Additional embodiments of the present invention are to provide a betterment in the quality of life for patients suffering or subject to diseases relating to a level of contractility or relaxation less than their physiological requirements by administering to those patients a pharmaceutical composition which includes riluzole for increasing contractility or increasing relaxation.
  • the quality of life benefits to these patients are: psychological, in terms of the comfort they may gain from the knowledge that their heart is pumping more efficiently; psychological, in terms of the comfort they may gain from the knowledge that the rate of degradation of their cardiac disease may be slowed or stopped by the administration of the composition; psychological, in terms of the comfort they may gain from the knowledge that the likelihood of developing a secondary disease is reduced or eliminated by the administration of the composition; physiological, in terms of the patient's improved capacity to perform physical activities and work by having an improved contractility or relaxation; physiological, in terms of the patient's body systems receiving more blood and nutrients; physiological, in terms of the patient's reduced rate of degradation of their myocardial disease; and physiological, in terms of reduced risk of secondary diseases resulting from poor contractility or relaxation.
  • a further embodiment of the methods of the present invention is the simultaneous reduction or cessation of the rate of degradation of a myocardial disease together with the reduction or cessation of the development of a secondary disease.
  • riluzole administration slows or ceases the progression or degradation of a heart disease.
  • riluzole increases contractility or relaxation and hence treats the diseases causing poor contractility or relaxation while reducing the risk of secondary diseases and at the same time reducing the risk of myocardial arrhythmias and the development of myocardial damage resulting from hypoxia or a loss, reduction or interruption in coronary blood flow.
  • riluzole promotes contractility or relaxation, it enhances the speed and extent of recovery of tissue and of haemodynamic function while also providing cardio-protection and preventing and reducing the incidence and extent of future cardiac or body system diseases.
  • a further embodiment of the invention is the ability of riluzole to improve psychological and physiological quality of life.
  • the above-mentioned mammalian heart is human.
  • riluzole may be administered at doses similar to or lower than those recommended for its primary action.
  • a further embodiment of the present invention is to treat ischaemic cardiac diseases such as angina and myocardial infarction by increasing the contractility or the relaxation of cardiac pumping.
  • a still further embodiment of the methods of the present invention is that riluzole or a pharmaceutically acceptable salt or derivative thereof can be used to concomitantly treat diseases producing and or produced by poor contractility or poor relaxation, as well as heart disease and neuronal conditions, such as stroke.
  • the pharmaceutical compositions treat myocardial disorders in a mammalian heart by enhancing the recovery of tissue or haemodynamic function subsequent to the onset of a heart disease.
  • compositions comprising riluzole treat myocardial disorders in a mammalian heart by conferring cardioprotective properties to protect the heart by inhibiting or reducing the incidence of future cardiac rhythm disorders or by inhibiting or reducing the incidence of future myocardial damage disorders or by reducing the extent of future myocardial damage disorders or by reducing the incidence or extent of future haemodynamic disorders which may arise from a heart disease.
  • Dilated cardiomyopathy is a disease which usually degenerates over time.
  • dilated cardiomyopathy is that the effective myocardial contractility is reduced and hence the effective transport of blood, nutrients and oxygen to tissues around the body is reduced.
  • a further consequence of a reduced effective contractility is that the cardiomyopathy worsens - thus further decreasing the contractility and further worsening io the cardiomyopathy and so-forth.
  • Increasing the contractility in dilated cardiomyopathy patients as per the present invention therefore breaks, or at least slows, the cycle of degradation.
  • one embodiment of the present invention provides for a method for the treatment, amelioration or prevention of cardiomyopathies including dilated
  • cardiomyopathy comprising administering to a mammal in need thereof a therapeutically effective amount of riluzole or a pharmaceutically acceptable salt or derivative thereof.
  • cardiomyopathies including dilated cardiomyopathy are well known to affect the lungs, liver, and other body systems. As such, slowing down or stopping the rate of degradation of a cardiomyopathies including
  • Preparation of the compounds utilised in accordance with the methods of the present invention is based upon the delivery of an effective amount of riluzole to the heart 30 cells. Techniques for such preparation are known to those skilled in the art.
  • riluzole as utilised in accordance with the present invention may include a vehicle, preservatives, buffers, tonicity and pH adjusters, antioxidants and water provided that none of these additives have a deleterious or toxic effect on the heart or indeed on the patient.
  • riluzole when used for the treatment or prevention of organ, tissue or cellular damage or death, riluzole may be administered alone. Alternatively, riluzole may be administered as a pharmaceutical or veterinarial formulation. Riluzole may also be present as suitable salts, including pharmaceutically acceptable salts. Derivatives of riluzole may also be used. Derivatives of riluzole in addition to salts include, but are not limited to, solvates and hydrates of riluzole.
  • salt By pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art and include acid addition and base salts. Hemisalts of acids and bases may also be formed.
  • suitable pharmaceutically acceptable salts may be acid addition salts.
  • suitable pharmaceutically acceptable salts of such compounds may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with riluzole.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, asparate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
  • Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • alkali or alkaline earth metal salts include sodium, lithium potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine and the like.
  • Pharmaceutically acceptable salts of riluzole may be prepared by methods known to those skilled in the art, including:
  • the above reactions (i)-(iii) are typically carried out in solution.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • Riluzole may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when the solvent is wat
  • compositions according to the present invention may be administered to the mammal by any one or more of the routes from the group: orally, sublingually, nasally, intravenously, intracavitorily directly into one or more chambers of the heart, intra-muscularly, intra-myocardially, topically to any surface including the epicardium, endocardium, pericardium, skeletal muscle and skin, intraperitoneally, intrapleurally, intrapericardially, or subcutaneously.
  • compositions according to the present invention may be administered to the mammal via one or more devices from the group: biodegradable implantable drug-eluting devices, non-biodegradable implantable drug-eluting devices, and implantable drug pumps.
  • Administration of riluzole to the heart cells may be achieved by any one or more of the following routes: intravenous administration; intracavitary administration directly into one or more chambers of the heart, oral administration in either a solid or a liquid form or a combination of both a solid and a liquid form; intramuscular administration either in skeletal muscle or directly into the heart muscle; topical administration either through the skin or directly applied onto the heart muscle; intra-pleural administration; intra- pericardial administration; intra-peritoneal administration; or inhalant administration.
  • Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, topical creams or gels or powders, or rectal administration.
  • the formulation or riluzole may be coated with a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the compound.
  • Riluzole may also be administered parenterally or intraperitoneally.
  • Dispersions of riluzole may also be prepared in glycerol, liquid polyethylene glycols, or propylene glycol and mixtures thereof and in oils. Under ordinary conditions of storage and use, pharmaceutical preparations may contain a preservative to prevent the growth of microorganisms.
  • Riluzole compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the composition is stable under the conditions of manufacture and storage and may include a preservative to stabilise the composition against the contaminating action of microorganisms such as bacteria and fungi.
  • riluzole may be administered orally, for example, with an inert diluent or an assimilable edible carrier.
  • Riluzole and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into an individual's diet.
  • riluzole may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • such compositions and preparations may contain at least 1% by weight of active compound.
  • the percentage of riluzole in pharmaceutical compositions and preparations may, of course, be varied and, for example, may conveniently range from about 2% to about 90%, about 5% to about 80%, about 10% to about 75%, about 15% to about 65%; about 20% to about 60%, about 25% to about 50%, about 30% to about 45%, about 35% to about 45%, about 2% to about 20%, about 5% to 20%, about 5% to 15%, or about 5% to 10% of the weight of the dosage unit.
  • the amount of riluzole in therapeutically useful compositions is such that a suitable dosage will be obtained.
  • pharmaceutically acceptable carrier is intended to include solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compound, use thereof in the therapeutic compositions and methods of treatment and prophylaxis is contemplated.
  • Supplementary active compounds may also be incorporated into the compositions according to the present invention. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of riluzole is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the riluzole may be formulated for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • the carrier may be an orally administrable carrier.
  • Another form of a pharmaceutical composition is a dosage form formulated as enterically coated granules, tablets or capsules suitable for oral administration. Also included in the scope of this invention are delayed release formulations, sustained release formulations, modified release formulations, controlled release formulations and repeat-action dosage forms.
  • Riluzole may also be administered in the form of a "prodrug".
  • a prodrug is an inactive form of a compound which is active form of the compound.
  • riluzole may be administered by injection.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by including various anti-bacterial and/or anti-fungal agents. Suitable agents are well known to those skilled in the art and include, for example, parabens, chlorobutanol, phenol, benzyl alcohol, ascorbic acid, thimerosal, and the like. In many cases, it may be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the analogue in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared by incorporating the analogue into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • Tablets, troches, pills, capsules and the like can also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin or a flavouring agent such as peppermint, oil of wintergreen
  • tablets, pills, or capsules can be coated with shellac, sugar or both.
  • a syrup or elixir can contain the analogue, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially nontoxic in the amounts employed.
  • the analogue can be incorporated into sustained-release preparations and formulations.
  • the pharmaceutical composition may further include a suitable buffer to minimise acid hydrolysis.
  • suitable buffer agent agents are well known to those skilled in the art and include, but are not limited to, phosphates, citrates, carbonates and mixtures thereof.
  • Riluzole as utilised in accordance with the present invention would usually be administered as an ongoing therapy or adjunct to other therapy against cardiac pumping inefficiencies including low contractility, poor relaxation, low cardiac output, low ejection and ejection fraction, low systolic blood pressure, high diastolic blood pressure, low pulse pressure, low mean arterial blood pressure, muscle tone degradation, as well as the diseases producing or resulting from these pumping inefficiencies.
  • Riluzole, as utilised in accordance with the present invention could also be administered prophylactically or as an adjunct to other medical or surgical treatments such as in preparation or following certain cardiac, coronary or vascular surgical procedures. Those skilled in the art will recognize that the frequency of administration depends on the precise nature of the active ingredient and its concentration in the formulation.
  • Single or multiple administrations of riluzole may be carried out. Similarly, single or multiple routes of administration may be carried out.
  • One skilled in the art would be able, by routine experimentation, to determine effective, non-toxic dosage levels and routes of administration of riluzole and an administration pattern which would be suitable for treating the diseases or conditions to which riluzole is applicable.
  • an effective dosage per 24 hours may be in the range of about 0.0001 mg to about 1000 mg per kg body weight; suitably, about 0.001 mg to about 750 mg per kg body weight; about 0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mg per kg body weight.
  • an effective dosage per 24 hours may be in the range of about 1.0 mg to about 200 mg per kg body weight; about 1.0 mg to about 100 mg per kg body weight; about 1.0 mg to about 50 mg per kg body weight; about 1.0 mg to about 25 mg per kg body weight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20 mg per kg body weight; about 5.0 mg to about 15 mg per kg body weight, about 0.1 mg to about 20 mg per kg body weight, about 0.1 mg to about 10 mg per kg body weight, about 0.2 mg to about 10 mg per kg body weight, about 0.5 mg to about 10 mg per kg body weight, or about 0.5 mg to about 5 mg per kg body weight.
  • an effective dosage may be up to about 500mg/m 2 .
  • an effective dosage is expected to be in the range of about 5 to about 500mg/m 2 , about 25 to about 350mg/m 2 , about 25 to about 300mg/m 2 , about 25 to about 250mg/m 2 , about 5 to about 150mg/m 2 , about 10 to about lOOmg/m 2 , about 10 to about 50mg/m 2 , about 50 to about 250mg/m 2 , and about 75 to about 150mg/m 2 .
  • the effective dosage may be administered in single or multiple dose regimes per day dependent on factors such as pharmacokinetics of the agent/s in question and the specific indication or intervention.
  • Figure 1 shows a section of chart recording of an experiment in which riluzole (8 mg/kg) was administered to a normoxic anaesthetised intact pig intraperitoneally.
  • the chart shows arterial blood pressure plotted against time.
  • the systolic blood pressure can be seen to be about 85 mmHg at 203 while the diastolic blood pressure can be seen to be about 50 mmHg at 202.
  • the pulse pressure being the difference between the systolic and diastolic blood pressures, is about 35 mmHg (85 - 50 mmHg).
  • both the systolic and diastolic pressures start to rise until the diastolic pressure reaches about 66 mmHg at 204 and the systolic pressure reaches about 120 mmHg at 205 about 400 seconds following riluzole administration. At this point the pulse pressure is about 54 mmHg.
  • riluzole administration increased the systolic pressure from 85 to 120 mmHg, the diastolic pressure from 50 to 66 mmHg, and the pulse pressure from 35 to 54 mmHg.
  • Figure 2 shows a chart recording from an ischaemic experiment in an anaesthetised intact pig. In this experiment, the arterial systolic pressure 224 and the diastolic pressure
  • Figure 3 shows a trace from a similar ischaemic experiment in an anaesthetised intact pig except that riluzole was infused intravenously over several minutes after the coronary artery occlusion and before the reperfusion.
  • systolic pressure 224 in the experiment shown in Figure 2 systolic pressure 244 decreased rapidly following coronary artery occlusion at 241 and stabilised at systolic pressure 246.
  • systolic pressure 246 rapidly rose to a pressure 249 higher than the pre-occlusion systolic pressure 244, and then continued to rise until it attained a pressure 252 about 10 mm Hg wherein it stabilised before cessation of the infusion at 253.
  • systolic pressure 252 again rose rapidly to peak about 13 mm Hg higher again at 251 before stabilising at 254 at a pressure about 20 mmHg higher than the pre-occlusion systolic pressure 244 thus demonstrating a doubly beneficial positive inotropic effect of riluzole during occlusion of the coronary artery and during reperfusion of the coronary artery.
  • Diastolic pressure 243 in Figure 3 is not affected by coronary artery occlusion 241 as seen at 245.
  • diastolic pressure 245 rose to diastolic pressure 248 upon commencement of riluzole infusion at 247 but to a lesser degree than the rise in systolic pressure 249.
  • diastolic pressure 248 continued to rise to 250, the increase in diastolic pressure between 248 and 250 was less than the increase in systolic pressure between 249 and 252 thus, as with Figure 1, showing an increase in pulse pressure and hence a potentially positive lusitropic effect of riluzole.
  • diastolic pressure 250 remained constant following infusion and throughout reperfusion of the coronary artery at 242, thus demonstrating a further increase in pulse pressure and a further potentially positive lusitropic effect of riluzole during reperfusion.
  • Figure 4 shows a chart recording from a different type of ischaemic experiment.
  • hearts were removed from rats and supported in a Langendorff apparatus. Heart rhythm and functionality was maintained by perfusion with Tyrode's solution.
  • Figure 4 A shows left ventricular (LV) pressure 262 in a NON- riluzole-treated heart bounded at its upper edge by systolic pressure 263 and at its lower edge by diastolic pressure 264.
  • LV left ventricular
  • FIG 4B shows the same experiment as Figure 4A except that the heart in this experiment was pre-treated with riluzole. Immediately upon treatment with the positive inotrope riluzole (not shown), contraction of the ventricles increased and produced an increase in systolic pressure 283. As with the experiment in Figure 4A, systolic pressure 283 and diastolic pressure 284 both fell to zero at time 286 following cessation of perfusion of the heart at time 285.
  • Example 3 the changes in blood pressure described in Example 3 were likely to be a direct result of positive inotropy and positive lusitropy. This is further supported by the following Examples which look directly at contractility and relaxation of the heart muscle. These Examples further show that the blood pressure changes in Examples 1 and 2 were due to a positive inotropic and positive lusitropic effect of riluzole.
  • Example 4 In a fourth type of experiment, ventricular contractility was determined by evaluating the rate of change of maximum left ventricular pressure (dLVPmax/dt) in isolated perfused rat hearts. In these experiments, the average increase in dLVPmax/dt, that is, the average increase in contractility, was 60% upon administration of 1 ⁇ M riluzole and 72% upon administration of 10 ⁇ M riluzole. These data are shown in Figure 5. As can be seen by the bar at 701, the average contractility of the isolated hearts prior to the administration of riluzole was normalised to 100%.
  • the average normalised contractility of the isolated hearts was 160% ⁇ 23% (SEM) following administration of 1 ⁇ M riluzole - that is, the contractility following 1 ⁇ M riluzole administration was 1.6 times greater than in the absence of riluzole.
  • the bar at 703 shows that the average normalised contractility following administration of 10 ⁇ M riluzole was 172% ⁇ 10% (SEM) - that is, the contractility following 10 ⁇ M riluzole administration was 1.72 times greater than in the absence of riluzole.
  • the average normalised contractility of the isolated hearts was 208% ⁇ 44% (SEM) following administration of 1 ⁇ M riluzole - that is, the contractility following 1 ⁇ M riluzole administration was twice as great as in the absence of riluzole.
  • the bar at 713 shows that the average normalised contractility following administration of 10 ⁇ M riluzole was 196% ⁇ 17% (SEM) - that is, the contractility following 10 ⁇ M riluzole administration was also twice as greater as in the absence of riluzole.
  • ventricular relaxation was determined by evaluating the rate of change of minimum left ventricular pressure (dLVPmin/dt) in isolated perfused rat hearts.
  • dLVPmin/dt minimum left ventricular pressure
  • the average normalised relaxation of the isolated hearts was 165% ⁇ 23% (SEM) following administration of 1 ⁇ M riluzole - that is, the relaxation following 1 ⁇ M riluzole administration was 1.6 times greater than in the absence of riluzole.
  • the bar at 723 shows that the average normalised relaxation following administration of 10 ⁇ M riluzole was 174% ⁇ 11% (SEM) - that is, the relaxation following 10 ⁇ M riluzole administration was 1.74 times greater than in the absence of riluzole.
  • the average normalised relaxation of the isolated hearts was 201% ⁇ 42% (SEM) following administration of 1 ⁇ M riluzole - that is, the relaxation following 1 ⁇ M riluzole administration was twice as great as in the absence of riluzole.
  • the bar at 733 shows that the average normalised relaxation following administration of 10 ⁇ M riluzole was 195% ⁇ 20% (SEM) - that is, the relaxation following 10 ⁇ M riluzole administration was also twice as great as in the absence of riluzole.
  • Example 8 In an eighth type of experiment as shown in Figure 9, the lengths of individual rat heart muscle cells were measured during normoxic perfusion, during hypoxia, and during re-oxygenation in cells which were non-treated and in cells which were treated with riluzole.
  • the hypoxia reduced the extent of muscle cell contraction by 80% as shown at 102 when compared with the contraction during normoxic perfusion shown at 101.
  • re-oxygenation reduced the extent of muscle cell contraction by 98% as shown at 103 when compared with the contraction during normoxic perfusion as shown at 101.
  • the hypoxia reduced the extent of muscle cell contraction by only 12% as shown at 112 when compared with the contraction during normoxic perfusion as shown at 111. Furthermore, in the riluzole group, re-oxygenation actually increased the extent of muscle cell contraction by 55% as shown at 113 when compared with the contraction during normoxic perfusion as shown at 111.
  • compositions according to the present invention which include riluzole, have positive inotropic or positive lusitropic properties.
  • Figure 10 shows a graph of normalised left ventricular pulse pressure in an isolated heart study of four normal rat hearts.
  • the vertical bars in the graph represent left ventricular pulse pressure wherein the top of each bar refers to systolic left ventricular blood pressure and the bottom of each bar refers to diastolic left ventricular blood pressure.
  • the error bars on the top and bottom of each bar show the standard error of the mean for each bar derived from the variation in pressure between the four animals from which the data was collected.
  • Time point 300 represents the normalised left ventricular pulse pressure 10 minutes prior to the administration of 3 ⁇ M riluzole. At this time the heart had not yet been exposed to riluzole and by normalising the pressure for each animal, the systolic pressure is equal to one.
  • the bar at time 301 represents the normalised left ventricular pulse pressure 30 seconds prior to the administration of riluzole and can be seen to be almost identical to the bar at time 300.
  • the bar at time 302 represents the normalised left ventricular pulse pressure as it peaks immediately following riluzole administration. Here we see that riluzole created a 15% increase in the amplitude of left ventricular systolic pressure.
  • Time points 303, 304, 305, 306 and 307 represent the normalised left ventricular pulse pressures recorded at: 10 minutes after riluzole administration (303), 30 seconds prior to riluzole washout (304), the peak drop in systolic pressure immediately following washout of riluzole (305), 10 minutes after washout of riluzole (306) and 20 minutes after washout of riluzole (307).
  • normalised left ventricular systolic pressure generally continued to increase following riluzole administration and normalised left ventricular diastolic pressure generally continued to decrease following administration of riluzole.
  • the normalised left ventricular systolic pressure continued to increase even after washout of riluzole and the normalised left ventricular diastolic pressure continued to decrease even after the washout of riluzole indicating a prolonged effect of riluzole.
  • an increase in left ventricular systolic pressure is indicative of positive inotropy
  • a decrease in left ventricular diastolic pressure is indicative of positive lusitropy.
  • Figure 11 shows a graph of normalised left ventricular pulse pressure in an isolated heart study of four rat hearts before and after a 30-minute episode of ischaemia.
  • This study shows the positive inotropic and positive lusitropic effects of riluzole in hearts significantly damaged by 30 minutes of global ischaemia and hypoxia produced by stopping the perfusion pump to the hearts.
  • the vertical bars in the graph represent left ventricular pulse pressure wherein the top of each bar refers to systolic left ventricular blood pressure and the bottom of each bar refers to diastolic left ventricular blood pressure.
  • the error bars on the top and bottom of each bar show the standard error of the mean for each bar derived from the variation in pressure between the four animals from which the data was collected.
  • Time points 400C and 400R represent the normalised left ventricular blood pressure 10 minutes prior to the onset of ischaemia.
  • Time points 401C and 40 IR represent the normalised left ventricular blood pressure 20 minutes after reperfusion (re-starting of the perfusion pump).
  • the white bars at time points 400C and 401C show the left ventricular pressure for the NON-riluzole-treated hearts.
  • the black bars at 400R and 40 IR show the left ventricular pressure for the riluzole-treated hearts.
  • the normalised systolic left ventricular blood pressure in the NON-riluzole-treated hearts has not yet returned to the pre-ischaemic normalised value of 1 and therefore remains compromised following the episode of ischaemia.
  • the normalised diastolic left ventricular blood pressure in the NON-riluzole-treated hearts is considerably higher than the pre-ischaemic normalised value of around 0 and therefore remains compromised following the episode of ischaemia.
  • the amplitude of the pulse pressure at 401C remains severely compromised at 20 minutes after reperfusion.
  • the normalised systolic left ventricular blood pressure in the riluzole-treated hearts following the episode of ischaemia has not only returned to the pre-ischaemic normalised value of 1 at 400R, but has exceeded the pre-ischaemic value by 23%.
  • This boost in systolic pressure in an intact animal/human would not only promote recovery of the heart and peripheral organs by the resumption of blood pressure, but would enhance such recovery by the substantial additional pressure developed.
  • the normalised left ventricular pulse pressure in the riluzole-treated hearts following reperfusion is about 10% higher than the pre- ischaemic normalised value at 400R thus further enabling heart and other organ recovery from an episode of ischaemia.
  • riluzole significantly increased systolic, diastolic and pulse pressures at 40 IR following ischaemia as compared with the NON-riluzole-treated hearts at 401 C. Due to the isolation of the heart from sympathetic drive and peripheral vasoconstriction, the increase in left ventricular systolic pressure at 40 IR as compared with 401C demonstrates positive inotropy, and the decrease in left ventricular diastolic pressure at 40 IR as compared with 401C demonstrates positive lusitropy.
  • Figure 12 shows a chart recording similar to that in Figure 1 except that in Figure
  • the chart is of left ventricular pressure from a normoxic isolated rat heart as opposed to peripheral arterial blood pressure from an anaesthetised intact pig as shown in Figure 1.
  • Figure 12 Given the isolation of the heart in Figure 12 from sympathetic drive and peripheral vasodilation and vasoconstriction, the similarity between Figure 12 and Figure 1 demonstrates that sympathetic drive and peripheral vasodilation and vasoconstriction played no part in the arterial blood pressure responses to riluzole shown in Figure 1 , and hence that the results shown in Figure 1 were indeed positively inotropic and positively lusitropic.
  • normoxic left ventricular systolic pressure shown as the top of the trace at 500 rose from an initial value of around 33 mmHg at 501 to a value in excess of 40 mmHg at 502 following and in direct response to the introduction of riluzole into the perfusion solution at 503.
  • the increase in systolic pressure arises from an increase in contractile force during contraction of the heart and hence represents a positive inotropic effect of riluzole.
  • the left ventricular diastolic pressure shown as the bottom of the trace at 510 rose from an initial value of around 6 mmHg at 511 to a value in excess of around 8 mmHg at 512 following and in direct response to the introduction of riluzole into the perfusion solution at 503.
  • Figure 12 shows that the diastolic pressure rose by a much smaller degree than the systolic pressure and as such, indicates a positive lusitropic effect of riluzole simultaneous with the positive inotropic effect.
  • Figure 13 is a chart of dLVP/dt taken from the same example and at the same time as shown in Figure 12.
  • dLVP/dt is the rate of change of left ventricular pressure over time and directly represents the rate of increase in the force of contraction (by the top of the trace) and the rate of relaxation (by the bottom of the trace) of the heart muscle.
  • contractility shown as the top of the dLVP/dt trace at 600, rose from an initial value of around 1300 mmHg/s at 601 to a value of around 1900 mmHg/s at 602 following and in direct response to the introduction of riluzole into the perfusion solution at 603.
  • the increase in contractility directly represents a positive inotropic effect of riluzole.
  • the rate of relaxation shown as the bottom of the dLVP/dt trace at 610, increased (ie, an increase in negative value) from an initial value of around -900 mmHg/s at 611 to a value of around -1200 mmHg/s at 612 following and in direct response to the introduction of riluzole into the perfusion solution at 603.
  • the increase in relaxation directly represents a positive lusitropic effect of riluzole.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode permettant d'améliorer la contractilité ou le relâchement du cœur des mammifères et de combattre des maladies qui provoquent une contractilité ou un relâchement médiocre ainsi que des maladies résultant d'une contractilité ou d'un relâchement médiocre. La présente invention a en outre pour objet une méthode de traitement de maladies cardiaques dégénératives, en tant que thérapie d'appoint pour des procédures médicales et chirurgicales, et de traitement de certains accidents et certaines affections psychologiques, immunologiques, hormonaux/hormonales, circulatoires et environnementaux/environnementales.
PCT/AU2010/000214 2009-02-26 2010-02-24 Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur WO2010096869A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2009900848A AU2009900848A0 (en) 2009-02-26 Positive Inotrope Agent, Positive Lusitrope Agent and Agent for the Treatment of Related Diseases
AU2009900848 2009-02-26

Publications (1)

Publication Number Publication Date
WO2010096869A1 true WO2010096869A1 (fr) 2010-09-02

Family

ID=42664938

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2010/000214 WO2010096869A1 (fr) 2009-02-26 2010-02-24 Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur

Country Status (1)

Country Link
WO (1) WO2010096869A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210008038A1 (en) * 2017-07-31 2021-01-14 Above And Beyond Nb, Llc Formulation of a riluzole solution with beta-cyclodextrins
EP4039247A3 (fr) * 2014-11-21 2022-11-16 Biohaven Pharmaceutical Holding Company Ltd. Formulation sublinguale de riluzole

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037276A1 (fr) * 2003-10-09 2005-04-28 Aventis Pharma S.A. Utilisation du riluzole dans le traitement des tremblements essentiels
WO2007022568A1 (fr) * 2005-08-25 2007-03-01 Steven Michael Weiss Réduction d’un dommage myocardique et de l’incidence d’une arythmie survenant à la suite d’une perte, d’une réduction ou d’une interruption de la circulation coronarienne
WO2007114925A2 (fr) * 2006-04-04 2007-10-11 The Trustees Of Columbia University Of In The City Of New York Canaux à deux p utilisés comme cible thérapeutique pour la protection contre l'ischémie myocardique et comme adjuvant en chirurgie cardiaque

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037276A1 (fr) * 2003-10-09 2005-04-28 Aventis Pharma S.A. Utilisation du riluzole dans le traitement des tremblements essentiels
WO2007022568A1 (fr) * 2005-08-25 2007-03-01 Steven Michael Weiss Réduction d’un dommage myocardique et de l’incidence d’une arythmie survenant à la suite d’une perte, d’une réduction ou d’une interruption de la circulation coronarienne
WO2007114925A2 (fr) * 2006-04-04 2007-10-11 The Trustees Of Columbia University Of In The City Of New York Canaux à deux p utilisés comme cible thérapeutique pour la protection contre l'ischémie myocardique et comme adjuvant en chirurgie cardiaque

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LIPP, A. ET AL.: "Riluzole and Blood Pressure in Multiple System Atrophy.", CLINICAL AUTONOMIC RESEARCH., vol. 13, no. 4, 2003, pages 271 - 274 *
MESTRE, M. ET AL.: "Frequency-Independent Blockade of Cardiac Na+ Channels by Riluzole Comparison with Established Anticonvulsants and Class I Anti-Arrhythmics", FUNDAMENTAL & CLINICAL PHARMACOLOGY., vol. 14, no. 2, 2000, pages 107 - 117 *
SCELSA, S.N ET AL.: "Blood Pressure Elevations in Riluzole-Treated Patients with Amyotrophic Lateral Sclerosis.", EUROPEAN NEUROLOGY., vol. 43, 2000, pages 224 - 227 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4039247A3 (fr) * 2014-11-21 2022-11-16 Biohaven Pharmaceutical Holding Company Ltd. Formulation sublinguale de riluzole
US20210008038A1 (en) * 2017-07-31 2021-01-14 Above And Beyond Nb, Llc Formulation of a riluzole solution with beta-cyclodextrins

Similar Documents

Publication Publication Date Title
US8653123B2 (en) Ester pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for treating retinal diseases
US20210077487A1 (en) Pharmaceutical composition containing hdac6 inhibitor as active ingredient for prevention or treatment of itching
WO2014005080A1 (fr) Oxabicycloheptanes et oxabicycloheptènes pour le traitement d'une lésion de reperfusion
Fujii et al. Effect of postoperative landiolol administration for atrial fibrillation after off pump coronary artery bypass surgery
WO1994003171A1 (fr) Agent de protection cardiaque
US20080161389A1 (en) Method of treating ocular hypertension and intestinal disorders by using dianhydrohexite mononitrate derivatives
US9629817B2 (en) Reducing myocardial damage and the incidence of arrhythmia arising from loss, reduction or interruption in coronary blood flow
TWI464147B (zh) 吲哚氫胺酸和吲哚啉氫胺酸於治療心臟衰竭或神經損傷的用途
US3922340A (en) Pharmaceutical compositions for treating lung diseases
WO2010096869A1 (fr) Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur
RU2345769C2 (ru) Комбинация вориконазола и противогрибкового ингибитора cyp2c19
CA2241856C (fr) Agent pour prophylaxis et traitement s'appliquant aux complications de diabetes
EP3827827A1 (fr) Composition pharmaceutique permettant de prévenir, de soulager ou de traiter l'arthrose contenant un dérivé de rhodanine en tant que principe actif
WO2011003129A1 (fr) Traitement de lésion de cellules, tissus et organes non neuronaux et non myocardiques et de la douleur associée à des inhibiteurs sodiques persistants
WO2020242537A1 (fr) Compositions et méthodes de traitement d'une maladie métabolique
EP1553944B1 (fr) Composition pharmaceutique associant le tenatoprazole et un antagoniste des recepteurs h2 a l histamine
KR101047387B1 (ko) 뇌신경 보호를 위한 병용요법
AU2015200961B2 (en) Treatment of Non-Neuronal and Non-Cardiac Cell, Tissue and Organ Damage and Associated Pain with Persistent Sodium Current Blockers
BE1009851A3 (fr) Composition pharmaceutique pour le traitement des cephalees et son utilisation.
KR20160020411A (ko) 빈맥성부정맥 및 고혈압의 장기 치료에서 란디오롤 하이드로클로라이드의 용도
KR20190093374A (ko) 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경병증 통증의 예방 또는 치료용 약학적 조성물
WO1997038691A1 (fr) Medicament pour neuropathie retinienne
LU85371A1 (fr) Procede de traitement antiarythmique de classe iii
KR101035522B1 (ko) 뇌신경 보호를 위한 병용요법
US20220257542A1 (en) Pharmaceutical composition comprising trimethobenzamide or pharmaceutically acceptable salt thereof as active ingredient for preventing or treating neuropathic pain

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10745728

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10745728

Country of ref document: EP

Kind code of ref document: A1