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WO2005079767A2 - Moyen de modulation des effets de substances de type opioide - Google Patents

Moyen de modulation des effets de substances de type opioide Download PDF

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Publication number
WO2005079767A2
WO2005079767A2 PCT/EP2005/000102 EP2005000102W WO2005079767A2 WO 2005079767 A2 WO2005079767 A2 WO 2005079767A2 EP 2005000102 W EP2005000102 W EP 2005000102W WO 2005079767 A2 WO2005079767 A2 WO 2005079767A2
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opioid receptor
opioid
antagonist
phe
seq
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WO2005079767A3 (fr
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Thomas Weber
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Universitaetsklinikum Muenster
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Universitaetsklinikum Muenster
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to the use of an opioid receptor antagonist for the preparation of a pharmaceutical composition for treating or preventing heart failure in a human subject or multi-organ dysfunction syndrome in a subject.
  • the invention also relates to a method for treating a human subject suffering from heart failure or multi-organ dysfunction syndrome comprising the step of administering to said subject an opioid receptor antagonist in a thera-plastically effective dosage.
  • Heart failure is a major world wide public health problem. Heart failure is primarily a disease of the elderly. Heart failure is the most common Medicare diagnosis-related group (DRG), and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis.
  • DRG Medicare diagnosis-related group
  • the ACC and the AHA first published guidelines for the evaluation and management of HF in 1995. Since that time, a great deal of progress has been made in development of both pharmacological and nonpharmacological approaches to treatment for this common, costly, disabling, and generally fatal disorder.
  • Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability ofthe ventricle to fill with or eject blood.
  • HF HF-related hypertension
  • fluid retention which may lead to pulmonary congestion and peripheral edema.
  • Both abnormalities can impair the functional capacity and quality of life of affected individuals, but they do not necessarily dominate the clinical picture at the same time.
  • Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema and report few symptoms of dyspnea or fatigue.
  • Heart failure is preferred over the older term “congestive heart failure.”
  • the clinical syndrome of HF may result from disorders of the pericardium, myocardium, endocardium, or great vessels, but the majority of patients with HF have symptoms due to an impairment of left ventricular function.
  • Heart failure may be associated with a wide spectrum of left ventricular functional abnormalities, which may range from the predominantly diastolic dysfunction of a normal-sized chamber with normal emptying but impaired filling to the predominantly systolic dysfunction of a markedly dilated chamber with reduced wall motion but preserved filling. In many patients, abnormalities of systolic and diastolic dysfunction coexist.
  • patients with predominant systolic dysfunction are depressed left ventricular ejection fraction (generally less than 40%); in contrast, patients with predominant diastolic dysfunction typically have an impairment of 1 or more indices of ventricular filling. Patients with predominant diastolic dysfunction have a different natural history and require different treatment strategies than patients with predominant systolic dysfunction. Coronary artery disease is the cause of HF in about two thirds of patients with left ventricular systolic dysfunction.
  • HF nonischemic cardiomyopathy
  • an identifiable cause e.g., hypertension, thyroid disease, valvular disease, alcohol use, or myocarditis
  • idiopathic dilated cardiomyopathy e.g., idiopathic dilated cardiomyopathy.
  • HF is not equivalent to cardiomyopathy or to left ventricular dysfunction; these latter terms describe possible structural reasons for the development of HF. Instead, HF is a clinical syndrome that is characterized by specific symptoms (dyspnea and fatigue) and signs (fluid retention). There is no diagnostic test for HF, because it is largely a clinical diagnosis that is based on a careful history and physical examination.
  • HF chronic HF
  • many studies have indicated that there is a poor relation between cardiac performance and the symptoms produced by the disease. Patients with a very low ejection fraction are frequently asymptomatic, whereas patients with preserved left ventricular systolic function may have severe disability.
  • the apparent discordance between the severity of systolic dysfunction and the degree of functional impairment is not well understood but may be explained in part by alterations in ventricular distensibility, valvular regurgitation, pericardial restraint, and right ventricular function.
  • many noncardiac factors may contribute importantly to exercise intolerance.
  • cardiac remodeling The principal manifestation of such progression is a change in the geometry of the left ventricle such that the chamber dilates, hypertrophies, and becomes more spherical — a process referred to as cardiac remodeling.
  • This change in chamber size not only increases the hemodynamic stresses on the walls of the failing heart and depresses its mechanical performance but also increases the magnitude of regurgitant flow through the mitral valve. These effects, in turn, serve to sustain and exacerbate the remodeling process.
  • Cardiac remodeling generally precedes the development of symptoms (occasionally by months or even years), continues after the appearance of symptoms, and contributes importantly to worsening of symptoms despite treatment. What factors can accelerate the process of left ventricular remodeling?
  • Stage A Patients at high risk of developing HF because of the presence of conditions which are strongly associated with the development of HF. Such patients have no identified structural or functional abnormalities ofthe pericardium, myocardium, or cardiac valves and have never shown signs or symptoms of HF. (Examples; Systemic hypertension; coronary artery disease; diabetes mellitus; history of cardiotoxic drug or alcohol abuse; personal history of rheumatic fever; family history of cardiomyopathy)
  • Stage B Patients who have developed structural heart disease that is strongly associated with the development of HF but who have never shown signs or symptoms of HF. (Examples; Left ventricular hypertrophy or fibrosis; left ventricular dilatation or hypocontractility; asymptomatic valvular heart disease; previous myocardial infarction)
  • Stage C Patients who have current or prior symptoms of HF associated with underlying structural heart systolic disease. (Examples; Dyspnea or fatigue due to left ventricular dysfunction; asymptomatic patients who are undergoing treatment for prior symptoms of HF.
  • Stage D Patients with advanced structural heart disease and marked symptoms of HF at rest despite maximal medical therapy and who require specialized interventions. (Examples; Patients who are frequently hospitalized for HF and cannot be safely discharged from the hospital; patients in the hospital awaiting heart transplantation; patients at home receiving continuous intravenous support for symptom relief or being supported with a mechanical circulatory assist device; patients in a hospice setting for the management of HF.
  • This staging system recognizes that HF, like coronary artery disease, has established risk factors and structural prerequisites; that the evolution of HF has asymptomatic and symptomatic phases; and that specific treatments targeted at each stage can reduce the morbidity and mortality of HF.
  • patients with left ventricular dysfunction or HF present to the physician in 1 of 3 ways:
  • ADHF in-hospital mortality rate
  • ADHF Alzheimer's disease
  • pulmonary edema is related to a marked increase in systemic vascular resistance superimposed on insufficient systolic and diastolic myocardial functional reserve.
  • ADHF Alzheimer's disease
  • This more physiologic approach to ADHF has been shown to relieve symptoms more rapidly and reduce patient morbidity, and thus has the potential to help control rising health care costs by reducing admissions, length of stay, and rehospitalization.
  • Treatment strategies are using Intravenous Loop Diuretics, Inotropic Agents, Intravenous Vasodilators, and Morphine sulfate.
  • morphine has been a commonly used medication for treating ADHF in the emergency medicine setting. Morphine exerts effects that may be favorable in patients with ADHF. It reduces preload and to a lesser extent afterload (systemic vascular resistance) and heart rate.
  • the technical problem underlying the present invention is to provide means and methods for treating or preventing more efficiently heart failure and multi-organ dysfunction syndrome, which often accompanies said heart failure.
  • the solution to said technical problem is provided by the embodiments characterized in the claims.
  • the present invention relates to the use of an opioid receptor antagonist for the preparation of a pharmaceutical composition for treating or preventing heart failure in a human subject.
  • opioid receptor antagonist relates to compounds which are capable to block or even reverse the biological responses induced by the opioid receptor activity.
  • the opioid receptor is activated by the opioid like substances of the body.
  • opioid like substances and the term “opioids” are used interchangeable throughout the text.
  • These opioid like substances are peptides which are capable of binding to the opioid receptors, e.g., the endorphins, endomorphins, enkephalines, dynorphins, and deltorphins, as well as nociceptine, ⁇ -casomorphin-5, morphiceptin, and dermorphin.
  • the opioid like substances suppress pain and block tachycardia, hypertension, hyperthermia, mydriasis, hyperventilation, anxiety, coughing, dysuria, and urgent need to empty the bowels in emergency situation for the body.
  • the activation ofthe opioid receptors can also be measured in vitro. Suitable assays are well known in the art and are described in detail by Dhawan et al. (Dhawan 1996, Pharmacol Rev 48: 567-592).
  • a screening method for determining an opioid receptor antagonist preferably, comprises the following steps: (a) contacting cells known to comprise a given opioid receptor, preferably mammalian cells, with an opioid known to activate the said receptor and a potential opioid receptor antagonist, and (b) determining the response of said cells upon administration ofthe potential opioid receptor antagonist whereby an antagonist prevents the biological response induced by the opioid.
  • Preferred responses to be determined are described by Dhawan (loc. cit.) or other responses referred to above.
  • the mammalian cells are more preferably cells of the nervous system, such as neurons, dendritic cells, or precursors thereof.
  • suitable mammalian cells may be obtained by genetically engineering cell lines, such as COS-7 cells or Neuro2a cells, with a vector allowing expression of the opioid receptor (Zaki 1996, Annu. Rev. Pharmacol. Toxicol. 36:379-401; Arvidsson 1995, J. Neuroscience 15: 3328-3341; Kieffer 1995, Cell Mol Neuro- biol 15: 615-635; Pan 2003, Methods Mol Med.84:3-16. Pan 2003, Methods Mol Med. 84:17-28).
  • an opioid receptor antagonist can be determined by an assay comprising the steps of (a) contacting an opioid receptor, an opioid known to bind to said receptor and a potential opioid receptor antagonist and (b) determining competition between the opioid and said antagonist for receptor binding.
  • Opioid receptor antagonists may be selected of a diversity of compounds consisting of different types of chemical entities.
  • a first group of compounds interfere with binding of opioid like substances to their respective receptors.
  • Such compounds comprise chemical entities which are capable of interacting with the ligand binding sites of the receptor but which do not activate the receptor.
  • Such compounds may be peptides, peptide analogues, peptidomimetics, PNAs, nucleic acids, small organic molecules or antibodies exhibiting said properties.
  • Peptid antagonist may be obtained by modifying the well known opioid peptide agonists by 2',6'-Dimethyl substitution of the Tyr(l) residue of the opioid agonist peptides and deletion of the positively charged N- terminal amino group or its replacement with a methyl group.
  • This has been recently shown to represent a general structural modification to convert opioid peptide agonists into antagonists.
  • This conversion requires the syntheses of opioid peptide analogues containing either 3- (2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4- hydroxyphenyl)propanoic acid [(2S)-Mdp] in place of Tyr(l).
  • delta-, kappa- and mu-selective opioid peptide agonist peptides can successfully be converted into corresponding delta-, kappa- and m ⁇ -selective antagonists, whereby receptor selectivity is maintained or even improved.
  • two (2S)-Mdp(l)-analogues of the delta-selective cyclic enkephalin analogue H-Tyr-c[D-Pen-Gly-Phe(pF)-Pen]-Phe-OH are potent and selective delta antagonists.
  • kappa antagonists derived from dynorphin A including the highly potent and selective kappa-antagonist [(2S)- Mdp(l)]Dyn A(1-11)-NH(2) (dynantin) and the enzymatically stable octapeptide analogue [(2S)-Mdp(l),MeArg(7),D-Leu(8)]Dyn A(l-8)-NH(2).
  • the (2S)-Mdp(l)-analogues of dynorphin B and alpha-neoendorphin are also kappa antagonists.
  • the Dhp(l)-analogues of the m ⁇ -selective cyclic enkephalin analogue H-Tyr-c[N(epsilon), N(beta)-carbonyl-D- Lys(2),Dap(5)]enkephalinamide and of endomorphin-2 are known to be moderately potent m ⁇ opioid antagonists (Schiller 2003, Life Sci. 73: 691-698). Specific peptide antagonist may be also obtained by way of molecular modelling. Appropriate computer programs can be used for the identification of interactive sites of a putative antagonist and the polypeptides of the invention by computer assistant searches for complementary structural motifs (Fassina 1994, Immunomethods 5:114-120).
  • Antibodies which are suitable as opioid receptor antagonists must specifically recognize an epitope of the receptor which allows upon binding of the antibody to block the binding of the opioid like substance which is the ligand of said receptor.
  • the epitope-antibody complex may alternatively induce changes of the conformation ofthe receptor whereby the receptor is unable to bind its ligand in the induced conformation.
  • Antibodies against such epitopes ofthe receptor can be prepared by well known methods using a (natural or synthetic) fragment comprising the said epitope derived from the receptor as an antigen.
  • Monoclonal antibodies can be prepared, for example, by the techniques as originally described in K ⁇ hler and Milstein 1975, Nature 256:495, and Galfre 1981, Meth. Enzymol.
  • said antibody is a monoclonal antibody, a polyclonal antibody, a single chain antibody, human or humanized antibody, primatized, chimerized or fragment thereof that specifically binds the epitope of the opioid receptor.
  • Such fragments include bispecific antibody, synthetic antibody, antibody fragment, such as Fab, Fv or scFv fragments etc., or a chemically modified derivative of any of these.
  • antibodies or fragments thereof to the aforementioned polypeptides can be obtained by using methods which are described, e.g., in Harlow and Lane 1988, Antibodies, A Laboratory Manual, CSH Press, Cold Spring Harbor. These antibodies can be used, for example, for the immunoprecipitation and immunolocaliza- tion ofthe variant polypeptides ofthe invention as well as for the monitoring ofthe presence of said variant polypeptides, for example, in recombinant organisms, and for the identification of compounds interacting with the proteins according to the invention.
  • surface plasmon resonance as employed in the BIAcore system can be used to increase the efficiency of phage antibodies which bind to an epitope of the protein of the invention (Schier 1996, Human Antibodies Hybridomas 7:97-105; Malmborg 1995, J. Immunol. Methods 183:7-13). Small organic molecules may be obtained by a screening method as referred to above.
  • compounds to be screened are those disclosed in Williams 2001, Physiol Rev 81: 299-343; Boehm 2002, Pharmacol Rev, 54: 43-99; Mogil 2001, Pharmacol Rev 53: 381-415, Bryant 1997, Biol Chem 378: 107-114; Temussi 1994, Biochem Biophys Res Commun 198: 933-939; and Zaki loc. cit. More preferably, the compounds are dike- topiperazines as disclosed in Bryant, loc. cit., or peptide derivatives comprising tetrahydro-3- isoquinoline carboxylic acid as disclosed in Temussi, loc. cit.. A second group of compounds interfere with the expression or translation of the opioid receptors.
  • Such group comprises, e.g., RNAi molecules, antisense RNA, interfereing oligonucleotides or triple helix forming agents.
  • Methods how to generate such molecules are well known in the art and are described in detail below.
  • the structure for such molecules can be easily designed based on the sequence information available for the opioid receptors referred to in detail below.
  • the opioid receptor antagonist ofthe use of the present invention exerts its effects in the central nervous sytem.
  • a preferred opioid receptor antagonist for treating heart failure must pass the blood brain barrier or must be a P-gylcoprotein (P-gp) substrate to exhibit its effects on the central nervous system.
  • P-gp P-gylcoprotein
  • compositions as used herein comprises the opioid receptor antagonists ofthe present invention and optionally one or more pharmaceutically acceptable carrier.
  • the substances of the present invention may be formulated as pharmaceutically acceptable salts. Acceptable salts comprise acetate, methylester, HC1, sulfate, chloride and the like.
  • the pharmaceutical compositions can be conveniently administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the substances may be administered in conventional dosage forms prepared by combining the drugs with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well- known variables.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, either a solid or a liquid.
  • Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary of liquid carriers are phosphate buffered saline solution, syrup, oil such as peanut oil and olive oil, water, emulsions, various types of wetting agents, sterile solutions and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • the substance according to the present invention can be administered in various manners to achieve the desired effect.
  • Said substance can be administered either alone or in the formulated as pharmaceutical preparations to the subject being treated either orally, topically, parenterally or by inhalation.
  • the substance can be administered in combination with other substances either in a common pharmaceutical composition or as separated pharmaceutical compositions.
  • the diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solutions, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nonthera-plastic, nonimmunogenic stabilizers and the like.
  • a therapeutically effective dose refers to that amount of the substance according to the invention which ameliorate the symptoms or condition.
  • Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50%) of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • the dosage regimen will be determined by the attending physician and other clinical factors; preferably in accordance with any one of the above described methods. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Progress can be monitored by periodic assessment.
  • a typical dose can be, for example, in the range of 1 to 1000 ⁇ g; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors.
  • the regimen as a regular administration of the pharmaceutical composition should be in the range of 1 ⁇ g to 10 mg units per day. If the regimen is a continuous infusion, it should also be in the range of 1 ⁇ g to 10 mg units per kilogram of body weight per minute, respectively. Progress can be monitored by periodic assessment. However, depending on the subject and the mode of administration, the quantity of substance administration may vary over a wide range to provide from about 0.01 mg per kg body mass to about 10 mg per kg body mass, usually.
  • the pharmaceutical compositions and formulations referred to herein are administered at least once in accordance with the use of the present invention.
  • compositions and formulations may be administered more than one time, for example from one to four times daily up to a non-limited number of days.
  • Specific formulations of the substance according to the invention are prepared in a manner well known in the pharmaceutical art and usually comprise at least one active substance referred to herein above in admixture or otherwise associated with a pharmaceutically acceptable carrier or diluent thereof.
  • the active substance(s) will usually be mixed with a carrier or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other suitable containers or vehicles.
  • a carrier may be solid, semisolid, gel-based or liquid material which serves as a vehicle, excipient or medium for the active ingredients.
  • Said suitable carriers comprise those mentioned above and others well known in the art, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the formulations can be adopted to the mode of administration comprising the forms of tablets, capsules, suppositories, solutions, suspensions or the like.
  • the dosing recommendations will be indicated in product labeling by allowing the prescriber to anticipate dose adjustments depending on the considered patient group, with information that avoids prescribing the wrong drug to the wrong patients at the wrong dose.
  • treating means that the degree of severity ofthe symptoms accompanied by a disease is reduced, i.e. amelioration, or the symptoms are even absent by a significant number of subjects treated as described herein.
  • a significant difference can be determined by standard statistical methods, such as Student's t-test, chi 2 -test or the U-test according to Mann and Whitney.
  • the term "preventing” as used herein means that symptoms accompanied by a disease do not or less often appear in subjects which have been subjected to the use of the invention while they will appear with a statistically higher frequency in subjects which have not been subjected to the use ofthe invention.
  • a significant difference can be determined by standard statistical methods as described above.
  • heart failure as used in accordance with the present invention is well known in the art. Symptoms and clinical parameters have been described above. Specifically, the heart failure referred to in the context of the present invention is a disorder accompanied by structural damages of the myocardium, in particular on the level of the heart muscle cells. The term “heart failure” is clearly distinguishable for the skilled practitioner from a similar phenomenon, the myocardial stunning. The latter one is a reperfussion disorder (Bolli 1999, Physiological Rev 79: 609-635). Preferably, the heart failure is terminal heart failure accompanied by multi-organ dysfunction syndrome or is heart failure resulting from sepsis. Most preferably, the terminal heart failure is caused by Chagas disease.
  • the patient to be treated suffering from heart failure is free of pain or has been treated with a selective ⁇ (mil) agonist, preferably ⁇ -FNA, M-CAM, CTAP, CTOP, or Cyprodime.
  • a selective ⁇ (mil) agonist preferably ⁇ -FNA, M-CAM, CTAP, CTOP, or Cyprodime.
  • opioid receptor antagonists such as Naloxone or Naltrexone are suitable drugs to efficiently treat or prevent heart failure and diseases conditions accompanied therewith, such as multi-organ dysfunction syndrome.
  • opioid receptor antagonists such as Naloxone or Naltrexone are suitable drugs to efficiently treat or prevent heart failure and diseases conditions accompanied therewith, such as multi-organ dysfunction syndrome.
  • opioid receptor antagonists such as Naloxone or Naltrexone are suitable drugs to efficiently treat or prevent heart failure and diseases conditions accompanied therewith, such as multi-organ dysfunction syndrome.
  • opioid receptor antagonists i.e. opioid receptor agonists such as the opioids.
  • administration of opioid receptor antagonists was thought to be contraindicative for such patients in the prior art (Crit Care Med 31: 1250-1256; Barr, Complications in Anesthesia, John L, Atlee, M.D., W.B. Saunders Com- pany, ISBN 0-7216-7161-6, Chapter 30, Reversal Agents: 114-116; Information onNaloxone by CuraMED Pharma GmbH 1999,
  • an opioid receptor antagonist for the preparation of a pharmaceutical composition for treating or preventing multi-organ dysfunction syndrome in a subject, most preferably a human subject.
  • subject as used in the sense of the present invention comprises animals and humans.
  • Animals in accordance with the invention are, preferably, mammals, most preferably dogs, cats or horses.
  • multi-organ dysfunction syndrome refers to a disease condition in which the function of various organs of the body is impaired.
  • the condition may comprise failures of the kidney, the liver, the gastrointestinal system, the nervous system, the cardiovascular system including the heart, the immune system, and the endocrine organs.
  • the disease condition as referred to in accordance with the invention is preferably accompanied by the following disorders: (a) dysfunction of the unspecific immune system particular of the macrophages, and activation of the blood clotting cascade, the complement system and the kalikrein-kinin system, (b) failure ofthe cardio-vascular system, endothelial dysfunction, tissue ischemia, (c) impaired mucosal barrier function in the gut accompanied with invasion of bacteria or bacterial products into the lymphatic or blood circulation, (d) impaired cellular functions including signal transduction and stress gene expression. Further details are summarized in Rensing 2001, Anaesthesist 50: 819-841. Moreover, the term "multi-organ dysfunction syndrome” also includes sepsis -associated organ dysfunction. Sepsis and sepsis-associated syndrome are discussed in detail in Mitchell loc. cit.
  • opioid receptor antagonist can effectively ameliorate, treat, and prevent the disease condition.
  • Patients suffering from multi-organ dysfunction syndrome are usually also in need of pain blocking medicaments such as opioids. Therefore, administering a opioid receptor antagonist which infers with opioid signalling, is also, in principle, contraindicative for such patients.
  • said multi-organ dysfunction syndrome comprises paralytic ileus and/or kidney failure.
  • said opioid antagonist is capable of binding to at least one opioid receptor having an amino acid sequence encoded by a polynucleotide selected from the group consisting of:
  • a polynucleotide comprising the nucleic acid sequence as shown in SEQ ID NO:l ( ⁇ (delta)), SEQ ID NO:3 ( ⁇ (kappa)), SEQ ID NO:5, 7, 9, 11, or 13 ( ⁇ (sigma)) or encoding the ⁇ (epsilon) opioid receptor;
  • a polynucleotide which has a nucleic acid sequence being at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleic acid sequence ofthe polynucleotide of (a) or (b), whereby the opioid antagonist does not bind to the ⁇ (m ⁇ ) opioid receptor (SEQ ID NO: 9).
  • the term "capable of binding to at least one opioid receptor” encompasses selective antagonists which solely bind to any one of the aforementioned opioid receptors and antagonists which bind to more than one of those receptors with different affinities.
  • an antagonist is capable of binding capable of binding to a receptor can be determined by standard techniques including those discussed in context with screening methods for antagonists above.
  • the binding affinity for the opioid antagonist should be high enough to prevent receptor activation by the opioid ligands of the receptor in order to prevent activation when the receptor is exposed to both substances.
  • Such binding affinities are preferably in the range of K; 1-lOOOnM, more preferably, 1-lOOnM, and most preferably 1-1 OnM.
  • the binding of the antagonist to the receptor(s) shall be selective in that the antagonist must not bind to the ⁇ (m ⁇ ) opioid receptor (SEQ ID NO: 9) in a way as described before.
  • Selectivity of binding is preferably 10 times, more preferably 100 times, most preferably 1000 times calculated as ratio of Ki value of the antagonist for the ⁇ (delta), ⁇ (kappa), ⁇ (sigma) or ⁇ (epsilon) opioid receptor to the K; value of the antagonist for the ⁇ (m ⁇ ) opioid receptor.
  • Suitable assays for determing antagonist binding and for measuring the affinity of an antagonist are disclosed in Williams 2001, Physiol Rev 81: 299-343; Boehm 2002 Pharmacol Rev, 54: 43-99; Mogil 2001 Pharmacol Rev 53: 381-415 and references referred to therein.
  • polynucleotide relates to polynucleotides encoding a opioid receptor as specified above.
  • the structure of polynucleotides encoding the opioid receptors is known in the art and shown, e.g., in SEQ ID NO:l ( ⁇ (delta) receptor), SEQ ID NO:3 ( ⁇ (kappa) receptor), SEQ ID NO:5, 7, 9, 11, or 13 ( ⁇ (sigmal-5) receptors).
  • polypeptides of the invention are those encoding the opioid receptors having an amino acid sequence as shown in SEQ ID NO:2 ( ⁇ (delta) receptor), SEQ ID NO:4 ( ⁇ (kappa) receptor), SEQ ID NO:6, 8, 10, 12 or 14 ( ⁇ (sigmal-5) receptor).
  • the invention further encompasses polynucleotides which are capable to hybridize under stringent conditions to the polynucleotides having the aforementioned nucleic acid sequences or encoding polypetides having the aforementioned amino acid sequences.
  • stringent conditions are hybridization in 300mM sodiumhydrogenphos- phate/dihydrogenphosphate, pH 6.8, 20% SDS, ImM EDTA for one hour at 68°C followed by three to five washing steps in 5mM sodiumhydrogenphosphate/dihydrogenphosphate, pH 6.8, 0.1% SDS, ImM EDTA for 30 minutes each step at 68°C.
  • Said polynucleotides are most preferably at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%o, at least 98% or at least 99%) identical to the polynucleotides having the aforementioned nucleic acid sequences or encoding polypetides having the aforementioned amino acid sequences.
  • Also encompassed by the polynucleotides referred to in connection with the present invention are biologically active fragments of the polynucleotides specified before. Said fragments may be obtained by deletion of one or more nucleotides of the respective nucleic acid sequences. The fragments can be generated by standard techniques well known to the person skilled in the art.
  • fragments may be obtained as the result of naturally occurring alternative splicing of the opioid receptor mRNAs.
  • the fragments referred to in accordance with the invention must comprise the binding or interaction sites for the opioid receptor antagonists. This interaction sites are known in the art or can be determined by standard techniques (Bryant loc. cit; Zaki loc. Cit).
  • BMY 14802 a-(4 ⁇ Fluorophenyl)-4-(5- fluoro-2-pyrimidinyl)- 1 - piperazinebutanol hydro' chloride
  • IPAG l-(4-Iodophenyl> 3-(2- adamantyl)guanidine
  • the opioid antagonist of the embodiment describe before is BNTX: (E)-7-Benzylidenenaltrexone, DALCE: [D-Ala2,Leu5,Cys6]-Enkephalin, Naltriben, 5 '-NTH: Naltrindole 5'-isothiocyanate, TIPP( ⁇ ): H-Tyr-Tic ⁇ -[CH2NH]Phe-Phe-OH, Naltrindole, ICI- 174,864: N,N-Diallyl-Tyr-Aib-Aib-Phe-Leu, TIPP: H-Tyr-Tic-Phe-Phe-OH specific for the ⁇ (delta) opioid receptor or Nor-BNI: nor-Binaltorphimine, GNTI: 5'-Guanidinylnaltrindole, U-50488H specific for the ⁇ (kappa) opioid receptor, or 3-(4-chlorobenzyl)-8-[l l l
  • said opioid antagonist is Naloxone, Naltrexone, ⁇ - Chlornaltrexamine, Diprenorphine, ⁇ -Chlornaltrexamine, Methocinnamox, D-Phe-Cys-Tyr- D-Trp-Arg-Thr-Pen-Thr-NH 2 , D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH 2 , C prodime, SMS-201995, or CTP.
  • said opioid antagonist is a polynucleotide capable of interacting specifically with a polynucleotide as defined in any one of (a) to (c) referred to above and is selected from the group consisting of: RNAi molecules, antisense RNA molecules, oligonucleotides, and triple helix forming agents.
  • RNAi molecules RNAi molecules
  • antisense RNA molecules RNA molecules
  • oligonucleotides oligonucleotides
  • triple helix forming agents triple helix forming agents.
  • the term "of interacting specifically with a polynucleotide” means that the polynucleotide interacts via hybridization, i.e. base pairing, to a polynucleotide having the complementary sequence thereto. A complete base pair match is preferred.
  • RNAi molecules refers to small interfering RNA molecules.
  • Double-stranded RNA-mediated interference is a simple and rapid method of silencing gene expression in a range of organisms. The silencing of a gene is a consequence of degradation of RNA into short RNAs that activate ribonucleases to target homologous mRNA. The resulting phe- notypes either are identical to those of genetic null mutants or resemble an allelic series of mutants. Extensive genetic and biochemical analysis revealed a two-step mechanism of RNAi-induced gene silencing.
  • the first step involves degradation of dsRNA into small inter- fering RNAs (siRNAs), 21 to 25 nucleotides long, by an RNase Ill-like activity.
  • siRNAs join an RNase complex, RISC (RNA-induced silencing complex), which acts on the cognate mRNA and degrades it.
  • RNase complex RISC (RNA-induced silencing complex)
  • RISC RNA-induced silencing complex
  • RNAi is being considered as an important tool not only for functional genomics, but also for gene-specific therapeutic activities that target the rnRNAs of disease-related genes (Agrawal 2003, Microbiol Mol Biol Rev. 67:657-85).
  • the specificity is also achieved by selecting a fragment resembling a nucleic acid fragment of the polynucleotide encoding an opioid receptor.
  • RNAi molecules act as specific antagonists of opioid receptors.
  • the term "antisense RNA molecules” refers to RNA which has the reverse complementary sequence to the messenger RNA encoding the opioid receptors referred to in accordance with the present invention. Accordingly, such an antisense RNA shall be capable of forming a double stranded RNA molecule with the messenger RNA via hybridization. The double stranded RNA molecule including the messenger RNA will be subsequently degraded in a cell. Thus, no opioid receptor proteins are produced.
  • an antisense RNA which is reverse complementary merely to a fragment ofthe full length messenger RNA.
  • a fragment comprises at least 50, at least 100, at least 200, at least 500 or at least 1000 contiguous nucleotides of the opioid receptor sequence in length.
  • antisense RNA can be manufactured.
  • a polynucleotide encoding an opioid receptor could be introduced in a plasmid in reverse orientation with respect to a promoter element present in said plasmid. The promoter induces expression of an antisense RNA instead of the normal messenger RNA.
  • Such a plasmid can be used for in vitro or in vivo transcription of RNA.
  • oligonucleotides encompasses oligonucleotides which are complementary to a fragment ofthe nucleic acid sequence encoding the opioid receptors referred to in accordance with the present invention and chemically modified derivatives thereof.
  • the oligonucleotides comprise at least 10, at least 15, at least 20 or at least 25 contiguous nucleic acids of the opioid receptor sequence in length.
  • Chemical modifications for oligonucleotides are well known in the art. Upon administration ofthe oligonucleotide to the messenger RNA, a complex is formed which will be subsequently degraded in a cell. These modifications may increase the degradation of the complex of oligonucleotide and messenger RNA which forms upon administration ofthe oligonucleotide to the messenger RNA.
  • triple helix forming agents refers to oligonucleotides and polynucleotides which are capable of interacting with a DNA double strand resulting in formation of a triple helix.
  • specificity can be achieved by using a triple helix forming polynucleotide which has a nucleic acid sequence complementary or identical to the target opioid receptor sequence specified above.
  • Specific gene expression involves the binding of natural ligands to the DNA base pairs.
  • oligonucleotides can bind with a high specificity of recognition to the major groove of double helical DNA by forming Hoogsteen type bonds with purine bases ofthe Watson-Crick base pairs, resulting in triple helix formation.
  • potential target sequences were originally restricted to polypurine-polypyrimidine sequences, considerable efforts were devoted to the extension of the repertoire by rational conception of appropriate derivatives. Efficient tools based on triple helices were developed for various biochemical applications such as the development of highly specific artificial nucleases.
  • the opioid receptor antagonist referred in accordance with the present invention may be administered in combination with one or more opioid agonists as long as theses agonists have positive myocardial influences. Accordingly, in a further embodiment any one of the aforementioned ⁇ (kappa) opioid receptor antagonists may be administered in combination with an agonist, preferably, a ⁇ (delta) opioid receptor agonist.
  • said agonist is selected from the group consisting of: [DPDPE: [D-Pen2,5]-Enkephalin, (-)-TAN-67: (-)-2- Methyl-4a ⁇ -(3-hydroxyphenyl)-l,2,3,4,4a,5,12,12a ⁇ -octahydroquinolino[2,3,3-g]isoqui- noline, [D-Ala2,Glu4]-Deltrophin, DSLET: [D-Ser2,Leu5,Thr6]-Enkephalin, BW373U86: ( ⁇ )-(l[S*]2 ⁇ ,5 ⁇ )-4-([2,5-Dimethyl-4-(2- ⁇ ropenyl)-l-piperazinyl][3-hydroxyphenyl]methyl)- N,N-diethylbenzamide], and SNC80: (+)-4-[( ⁇ R)- ⁇ -((2S,5R)-4-allyl-2,5-dimethyl-l- pipe
  • the invention relates to a method for treating a human subject suffering from heart failure comprising the step of inhibiting opioid receptor signalling by administering to said subject an opioid receptor antagonist in a therapeutically effective dosage.
  • the invention encompasses a method for treating a subject suffering from multi- organ dysfunction syndrome comprising the step of inhibiting opioid receptor signalling by administering to said subject an opioid receptor antagonist in a therapeutically effective dosage.
  • said multi-organ dysfunction syndrome comprises paralytic ileus and/or kidney failure.
  • the opioid receptor antagonist is administered in combination with an opioid receptor agonist having positive myocardial influence, preferably a ⁇ (delta) opioid receptor agonist as specified above.
  • the figure shows a schematic drawing of an opioid receptor.

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Abstract

L'invention concerne l'utilisation d'un antagoniste de récepteur d'opiacé pour la préparation d'une composition pharmaceutique destinée à traiter ou à prévenir une insuffisance cardiaque, chez un patient humain, ou un syndrome dysfonctionnel multi-organe chez un patient. L'invention concerne également une méthode pour traiter un patient humain souffrant d'une insuffisance cardiaque ou d'un syndrome de dysfonctionnement multi-organe comprenant l'étape consistant à administrer à un patient, un antagoniste de récepteur d'opiacé, selon un dosage thérapeutiquement efficace.
PCT/EP2005/000102 2004-02-19 2005-01-07 Moyen de modulation des effets de substances de type opioide Ceased WO2005079767A2 (fr)

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US9592239B2 (en) 2014-09-12 2017-03-14 Demerx, Inc. Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake
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Publication number Priority date Publication date Assignee Title
US9561233B2 (en) 2014-03-13 2017-02-07 Demerx, Inc. Use of ibogaine for the treatment of pain
US9592239B2 (en) 2014-09-12 2017-03-14 Demerx, Inc. Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake
US11077118B2 (en) 2014-09-12 2021-08-03 Demerx, Inc. Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake
WO2017141104A3 (fr) * 2016-02-18 2017-11-02 Immune Therapeutics, Inc. Procédé d'induction d'une réponse immunitaire prolongée

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