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EP1117396A1 - Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses - Google Patents

Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses

Info

Publication number
EP1117396A1
EP1117396A1 EP99937113A EP99937113A EP1117396A1 EP 1117396 A1 EP1117396 A1 EP 1117396A1 EP 99937113 A EP99937113 A EP 99937113A EP 99937113 A EP99937113 A EP 99937113A EP 1117396 A1 EP1117396 A1 EP 1117396A1
Authority
EP
European Patent Office
Prior art keywords
compound
excretion
fat
accumulation
faeces
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99937113A
Other languages
German (de)
English (en)
Inventor
Hendrik Jan Verkade
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Individual
Original Assignee
Individual
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Filing date
Publication date
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Publication of EP1117396A1 publication Critical patent/EP1117396A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/739—Lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention concerns a method to increase the excretion of non-sterol endogenous hydrophobic substances or metabolic derivatives thereof by increasing excretion via the faeces of the hydrophobic substance or metabolic derivative thereof. Also the invention concerns a method for prevention or treatment of conditions associated with the accumulation of non-sterol endogenous hydrophobic substances or metabolic derivatives thereof.
  • Bilirubin is bilirubin. Under physiological conditions, bilirubin undergoes two conjugation reactions with glucuronic acid, derived from UDP- glucoronide, which results in the formation of bilirubin diglucuronide. Bilirubin diglucuronide is significantly more water-soluble than the parent compound, unconjugated bilirubin (UCB), and can be readily excreted via the bile into the faeces. The two conjugation reactions are catalysed by the hepatic enzyme uridine diphosphoglucuronosyl transferase (h-UDPGTbil, EC 2.4.1.17).
  • CN Crigler Najjar's disease
  • CN type II Crigler Najjar's disease
  • Increased serum levels of UCB are also found during the neonatal period, especially in preterms, during increased rates of haemoglobin degradation (for example sickle cell crisis, anaemic crisis in G6PD-def ⁇ cient individual, ABO-antagonism or other forms of immune or non-immune hemolysis), or during impaired hepatic conjugation efficiency (for example viral infections, metabolic diseases, and others)(for review, see Chowdhury et al., Hereditary jaundice and disorders of bilirubin metabolism.
  • haemoglobin degradation for example sickle cell crisis, anaemic crisis in G6PD-def ⁇ cient individual, ABO-antagonism or other forms of immune or non-immune hemolysis
  • impaired hepatic conjugation efficiency for example viral infections, metabolic diseases, and others
  • the configurational isomers can spontaneously revert to the normal configuration and be absorbed from the intestinal lumen. These features of the configurational isomers obviously decrease the efficacy of phototherapy.
  • Crigler-Najjar's disease patients in particular type I
  • neonates with unconjugated hyperbilirubinemia are generally admitted to hospitals for phototherapeutic treatment.
  • phototherapy fails to lead to clinically acceptable serum concentrations of UCB, patients may need to undergo one or more exchange transfusions, which comprises a high-risk therapy with considerable morbidity and even mortality.
  • Protoporphyrin is a hydrophobic intermediate in the biosynthesis of heme. Heme is an iron-containing, prosthetic group in many proteins, which function in for example oxygen en electron transport, H 2 0 generation and degeneration, and nitric oxide synthesis. Catalysed by the enzyme ferrochelatase (EC 4.99.1.1), PP is converted into heme through the addition of a Fe 2+ -atom.
  • heme synthesise heme the major site is the bone marrow, where approximately 85% of the body's heme is produced for the formation of hemoglobin.
  • the second major site of heme synthesis in mammalians is the liver (see for review Kappas et al., The Porphyrias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, Inc. 1995:2103-2159).
  • EPP erythropoietic protoporphyria
  • EPP is an autosomal dominant, inherited disease, which is characterised by a strongly reduced activity of the ferrochelatase enzyme.
  • PP accumulation particularly in erythrocytes, liver and faeces increased PP concentrations are found (Romslo et al., Arch Dermatol 1982;118:668-671, Beukeveld et al., Clin Chem 1987;33:2164-2170).
  • the clinical consequences of increased concentrations of PP in the body can be exemplified by the symptoms of EPP.
  • EPP patients At young age, EPP patients have a cutaneous photosensitivity in light-exposed areas.
  • the mechanism of the photosensitivity involves the generation of free oxygen radicals from accumulated PP in the skin, under influence of light (wavelength 400-410 nm).
  • the reactive oxygen radicals damage primarily the mitochondria and cellular membranes, leading to severely discomforting skin lesions (burn-like lesions, itching, oedema, scarring).
  • the disposal from the body of PP involves biliary secretion and subsequent loss via the stools. It is not known whether the highly hydrophobic parent molecule PP can be reabsorbed by the intestinal mucosa and undergoes enterohepatic cycling. Strong, indirect support for this possibility can be derived from the observed beneficial effects of cholestyramine on PP accumulation in EPP.
  • the present invention is directed at a novel mechanism of intestinal capture of non-sterol endogenous hydrophobic compounds, specifically the induction of increased fat excretion via the faeces (steatorrhoea).
  • hydrophobic compounds By increasing the lipophilic phase, or amount of fat, in the intestinal lumen, as disclosed according to the invention, hydrophobic compounds will dissolve or diffuse into the generated apolar phase.
  • the apolar, lipophilic phase persists throughout the digestive tract and will drag hydrophobic compounds along the intestinal tract, which eventually will be excreted.
  • the hydrophobic phase is virtually impermeable for polar detergents, such as bile salts. It can be expected that the absorption of fat-soluble compounds such as fat soluble vitamins, such as vitamin A, vitamin D, vitamin E, and vitamin K, will also be inhibited. To compensate for this, an increased dietary intake, either in natural or in water-soluble form, may be warranted.
  • the induction of increased faecal fat excretion by any means increases the disposal of endogenous hydrophobic substances such as UCB and PP from the body, at least under conditions of their previous accumulation.
  • the present invention provides a method to prevent or treat conditions such as neonatal jaundice, haemolytic jaundice and erythropoietic protoporphyria.
  • the plasma cholesterol concentration is related to the intestinal absorption of cholesterol, derived either from the diet or from the bile.
  • decreasing the intestinal (re)absorption of cholesterol is associated with an improved plasma lipid and lipoprotein profile (Jandacek, Int J Obes 1984;8 Suppl:13- 21, Jandacek et al., Metabolism 1990;39:848-852, US 3,954,976, US 4,005,195, US 4,005,196).
  • sucrose polyesters to detoxify humans and lower animals after accidental or chronic ingestion of lipophilic toxins such as insecticides (for example, DDT, Kepone), herbicides (for example, PCP) or industrial chemicals (for example, polychlorinated biphenyls (PCB's), polybrominated biphenols (PBB's)) has also been patented (US 4,241 ,054).
  • insecticides for example, DDT, Kepone
  • PCP herbicides
  • industrial chemicals for example, polychlorinated biphenyls (PCB's), polybrominated biphenols (PBB's)
  • the present invention however is directed at the general approach to increase the disposal from the body of non-sterol endogenous hydrophobic compounds, such as UCB and PP, namely by inducing/increasing the faecal excretion of a hydrophobic (lipophilic) phase, through whatever mechanism.
  • the previous disclosures are directed at elimination of a different category of compounds to the invention, using different means.
  • the previous disclosures have been available in the prior art for a long time and nevertheless the skilled person in the field of for instance hyperbilirubinemia or protoporphyria have been occupied with totally different concepts of treatment.
  • Dietary fat consists for 92-96% of triacylglycerols, which have to be hydrolysed by lipolytic enzymes before they can be absorbed. Interference with the lipolysis can be obtained by inhibition of the lipase enzymes, operational in the gut lumen, for example by orlistat (Hochuli et al., J Antibiot (Tokyo) 1987;40:1086-1091 , Weibel et al, J Antibiot (Tokyo) 1987;40:1081-1085) or functionally and/or structurally related compounds (Yoshinari et al., J Antibiot (Tokyo) 1994;47:1376- 1384) (see also for example US.
  • orlistat Hochuli et al., J Antibiot (Tokyo) 1987;40:1086-1091 , Weibel et al, J Antibiot (Tokyo) 1987;40:1081-1085
  • functionally and/or structurally related compounds Yoshin
  • Carrier-mediated uptake mechanisms for lipids have been hypothesised and partially identified at the level of the brush border membrane of the small intestinal mucosa (Compassi et al., Biochemistry 1995;34:16473-16482, Schoeller et al, Clin Invest Med 1995;18:380-388, Fitscher et al., Proc Soc Exp Biol Med 1996;212:15-23, Schulthess et al., J Lipid Res 1996;37:2405-2419, Boffelli et al., Biochemistry 1997;36:10784-10792).
  • Candidate proteins involved in these processes have been indicated and it is reasonable to assume that specific inhibitors of this (these) carrier system(s) would inhibit the absorption of lumenal lipids, leading to increased faecal fat excretion.
  • An example of this phenomenon can be derived from the studies by Stremmel et al. (J Clin Invest 1985;75:1068-1076), in which the translocation of a fatty acid across brush border membrane vesicles could be inhibited by the incubation with a specific antibody.
  • chylomicron assembly and/or basolateral chylomicron secretion: After lipids have entered the small intestinal mucosal cell, they are reassembled into chylomicrons, either with (monoacylglycerols, fatty acids, lysophospholipids, unesterified sterols) or without (fraction of unesterified sterols, phospholipids) prior to reacylation.
  • the intracellular events in fat absorption and chylomicron assembly are only partially understood (see for review Tso P. Intestinal lipid absorption. In: Johnson LR, ed. Physiology of the gastrointestinal tract.
  • Non-absorbable hydrophobic compounds include for example (poly)esters of fatty acids and sugars or alcohols.
  • Administration of olestra one particular type of sucrose polyester, has been demonstrated to decrease intestinal absorption and decrease body disposal of the hydrophobic sterol cholesterol in hypercholesterolemic man (Mellies et al., Am J Clin Nutr 1983;37:339-346, Jandacek et al., Metabolism 1990;39:848-852) or of hydrophobic environmental pollutants in gerbils (Jandacek et al., Drug Metab Rev 1982;13:695-714, Mutter et al., Toxicol Appl Pharmacol 1988;92:428-435).
  • the specific use of sucrose polyesters to detoxify humans and lower animals after accidental or chronic ingestion of toxic lipophilic materials has also been patented (US 4,241,054).
  • the present invention is also directed at pharmaceutical compositions comprising the compound to be administered as active compound in an effective amount according to any of the abovementioned strategies for prevention or treatment of conditions associated with the accumulation of non-sterol endogenous hydrophobic substances or metabolic derivatives thereof together with a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are directed at the prevention or treatment of conditions that are associated with the accumulation of unconjugated bilirubin or protoporphyrin, such as neonatal jaundice, haemolytic jaundice or erythropoietic protoporphyria.
  • the present invention is also directed at the use of any compound being the compound to be administered as active compound according to any of the abovementioned strategies for the manufacture of a pharmaceutical composition for prevention or treatment of conditions associated with the accumulation of non-sterol endogenous hydrophobic substances or metabolic derivatives thereof, such as the accumulation of unconjugated bilirubin or protoporphyrin, possibly leading to, for example, neonatal jaundice, haemolytic jaundice or erythropoietic protoporphyria.
  • the active compound according to the invention has to be delivered in the intestinal lumen in a therapeutically effective amount.
  • the form of admistration of the active compound or pharmaceutical composition containing the active compound according to the invention can be any suitable form known to one of ordinary skill in the art for administering a therapeutically active agent to the intestinal lumen, e.g. oral, enteral or rectal adminstration. Selection of the dosage is to be made by anyone of ordinary skill in the art of medicine, giving consideration to age, sex, size, fat mass/lean body mass ratio and the condition the recipient is suffering or to be prevented from suffering.
  • mice Male Gunn rats (body weight 300-350 g) were fed a high-fat (16 wt%) chow diet for 2 weeks.
  • Major long-chain fatty acid composition of the diet palmitic acid, 31.9%; stearic acid, 5.2%; oleic acid, 32.7%; linoleic acid 30.2%; Hope Farms, Woerden, The Netherlands).
  • Blood samples were collected obtained in EDTA-containing cups by tail bleeding at day 6, and plasma was obtained by centrifugation (10 min, 2000 rp, 4 °C) and stored under light-protected conditions until analysis (within hours after sampling). Bilirubin concentration in plasma was determined by automated analysis, based on the diazo method (Novros et al., Clin Chim Acta 25:1891-9; 1979). The results are depicted in Fig. 1. A significant decrease of the plasma concentration of unconjugated bilirubin as a result of an orlistat containing diet was observed.
  • mice Male Gunn rats (body weight 300-350 g) were fed a high-fat (16 wt%) chow diet for 2 weeks.
  • Major long-chain fatty acid composition of the diet palmitic acid, 31.9%; stearic acid, 5.2%; oleic acid, 32.7%; linoleic acid 30.2%; Hope Farms, Woerden, The Netherlands).
  • Faeces production was compared with plasma bilirubin concentrations at day 6 (see Fig. 1) in individual animals. The results are represented in Fig.2.
  • Fig.2 Inverse relation of the plasma concentration of unconjugated bilirubin and the amount of faeces production in Gunn rats on orlistat-containing diets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à un procédé servant à augmenter l'excrétion des substances hydrophobes endogènes autres que les stérols ou des dérivés métaboliques de cette substance, en augmentant l'excrétion fécale de ces substances hydrophobes ou des dérivés métaboliques de celles-ci, ce procédé se caractérisant en ce que l'excrétion fécale des matières grasses est accrue. Le but de cette invention est de prévenir ou de traiter les états associés à l'accumulation de substances hydrophobes endogènes autres que les stérols ou de dérivés métaboliques de ces substances, ces substances étant la bilirubine ou la protoporphyrine non conjuguée. Plus particulièrement, la lipstatine, l'orlistat, la tétrahydrolipstatine, les acides gras de polyol tels que l'olestra et les doses non habituelles de matières grasses diététiques sont utilisées pour traiter l'ictère physiologique du nouveau-né, l'ictère hémolytique et la protoporphyrie érythropoiétique.
EP99937113A 1999-07-30 1999-07-30 Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses Withdrawn EP1117396A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/NL1999/000492 WO2001008679A1 (fr) 1999-07-30 1999-07-30 Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses

Publications (1)

Publication Number Publication Date
EP1117396A1 true EP1117396A1 (fr) 2001-07-25

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ID=19866607

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EP99937113A Withdrawn EP1117396A1 (fr) 1999-07-30 1999-07-30 Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses

Country Status (5)

Country Link
EP (1) EP1117396A1 (fr)
JP (1) JP2003505504A (fr)
AU (1) AU5200299A (fr)
CA (1) CA2345753A1 (fr)
WO (1) WO2001008679A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1216625A1 (fr) * 2000-12-21 2002-06-26 The Procter & Gamble Company Utilisation d'un lipide non-digestible, non-absorbable pour le traitement de l'hyperbilirubinémie
ES2399721T5 (es) 2004-03-05 2016-05-25 Univ Pennsylvania Métodos para tratar trastornos o enfermedades asociados a la hiperlipidemia e hipercolesterolemia minimizando los efectos adversos
WO2013070856A1 (fr) * 2011-11-09 2013-05-16 Denovo Inc. Produit alimentaire décontaminant de toxine et procédé de traitement de troubles du tractus gastro-intestinal
CA3186856A1 (fr) 2020-07-29 2022-02-03 Ruth NALLEN Lomitapide destine a etre utilise dans des methodes de traitement de l'hyperlipidemie et de l'hypercholesterolemie chez des patients pediatriques

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4363801A (en) * 1981-02-09 1982-12-14 The Texas A&M University System Method for treating hyperbilirubinemia
AU570143B2 (en) * 1985-01-14 1988-03-03 Rockefeller University, The Method of increasing heme excretion from a mammal using tin protoporphyrin
WO1989006137A1 (fr) * 1988-01-11 1989-07-13 Massachusetts Institute Of Technology Therapie orale de reduction de la bilirubine
US5665775A (en) * 1995-07-28 1997-09-09 Arab Pharmaceutical Manufacturing Co., Ltd. Different way of management of neonatal hyperbilirubinemia
JPH10330265A (ja) * 1997-06-02 1998-12-15 Lederle Japan Ltd 肝疾患治療剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0108679A1 *

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JP2003505504A (ja) 2003-02-12
AU5200299A (en) 2001-02-19
WO2001008679A1 (fr) 2001-02-08
CA2345753A1 (fr) 2001-02-08

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