WO1989006137A1 - Therapie orale de reduction de la bilirubine - Google Patents

Therapie orale de reduction de la bilirubine Download PDF

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Publication number
WO1989006137A1
WO1989006137A1 PCT/US1988/004711 US8804711W WO8906137A1 WO 1989006137 A1 WO1989006137 A1 WO 1989006137A1 US 8804711 W US8804711 W US 8804711W WO 8906137 A1 WO8906137 A1 WO 8906137A1
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WO
WIPO (PCT)
Prior art keywords
bilirubin
deactivator
mammal
conjugated
agarose
Prior art date
Application number
PCT/US1988/004711
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English (en)
Inventor
Paul J. Soltys
Claudy J. P. Mullon
Robert S. Langer
Original Assignee
Massachusetts Institute Of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Massachusetts Institute Of Technology filed Critical Massachusetts Institute Of Technology
Publication of WO1989006137A1 publication Critical patent/WO1989006137A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y103/00—Oxidoreductases acting on the CH-CH group of donors (1.3)
    • C12Y103/03—Oxidoreductases acting on the CH-CH group of donors (1.3) with oxygen as acceptor (1.3.3)
    • C12Y103/03005—Bilirubin oxidase (1.3.3.5)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y204/00—Glycosyltransferases (2.4)
    • C12Y204/01—Hexosyltransferases (2.4.1)
    • C12Y204/01017—Glucuronosyltransferase (2.4.1.17)

Definitions

  • This invention relates to the general field of controlling excessive levels of bilirubin.
  • bilirubin In the human body, bilirubin is produced by the breakdown of cyclic tetrapyrroles, particularly hemoglobin. Excessive bilirubin concentrations, manifest as jaundice, can cause irreversible damage to the central nervous system.
  • conjugated bilirubin bilirubin-glucuronic acid conjugate
  • conjugated bilirubin bilirubin-glucuronic acid conjugate
  • Bacterial flora reduce conjugated bilirubin, which is then excreted in the stool.
  • Excessive bilirubin is common in infants for a number of reasons including a high rate of hemolysis,. immaturity of liver function necessary to form conjugated bilirubin, obstruction of the bilary system, and the absence of intestinal flora to reduce bilirubin conjugate. In the absence of intestinal flora and their reducing enzymes, conjugated bilirubin may be deconjugated, and the resulting unconjugated bilirubin may be reabsorbed by the intestine, increasing serum bilirubin concentrations.
  • Bilirubin deactivators useful in the invention include those which specifically adsorb bilirubin and are excreted (i.e., they undergo surface physical interaction with bilirubin, thereby physically removing it from liquid-phase reactions) .
  • bilirubin conversion enzymes i.e., enzymes that operate on the unconjugated bilirubin substrate to yield products that are physiologically compatible in that they are not reabsorbed, or, if reabsorbed, they are nontoxic in the blood stream.
  • the bilirubin deactivator is preferably introduced in the intestinal tract or lumen (specifically the area adjacent the bile duct) by oral administration in a stabilized form.
  • the deactivator is carried by an inert carrier such as a solid support resistant to intestinal degradation.
  • the method is particularly effective for mammals (e.g., - --. -
  • the method is simple and noninvasive, requiring only the oral ingestion of, e.g., microbeads.
  • the method can be combined with other methods, such as phototherapy, and may increase the effectiveness of such treatments, particularly treatments such as phototherapy whose effectiveness is undercut by enhanced biliary secretion of unconjugated bilirubin.
  • Other features and advantages of the invention will be apparent from the following description of a preferred embodiment thereof and from the claims .
  • Fig. 1 is a graph depicting the results of experiments described below. Conversion Enzymes
  • the preferred bilirubin conversion enzymes are those which tolerate the intestinal environment, and which convert unconjugated bilirubin to relatively harmless products.
  • bilirubin oxidase catalyzes the oxidation of bilirubin with 0,, initially producing biliverdin, which then may be oxidized further.
  • Such bilirubin oxidation products apparently are not teratogenic, cytotoxic, or mutagenic. See Levin et al ⁇ , cited above.
  • Bilirubin oxidase is obtained from Myrothecium verricaria and can be purified from this organism as described by Murao et al. , Aqric. Biol. Chem., 46:2031 (1982) and Tanaka et al. , Aqric. Biol. Chem. 46:2499 (1982). See also, Broderson et al. Eur. J. Biochem. . 10:468 (1969), and Eiichi et al» , French 2,576,909 and JP appl'n. 85/20625. Bilirubin Adsorbents
  • Suitable bilirubin-specific adsorbents include activated carbon, cellulose that has been coated with serum albumin or Y-protein (ligandin), which is known to be useful to study bilirubin uptake in hepatocytes.
  • Albumin-coated cellulose is described in the following references: Sideman et al. , Proc. Int' 1. Sympos. on Art. Liver Support, 103 (1981); Sideman et al. , Am. Soc. Art. Intern. Orq. J. 4:164 (1981); Plotz et al. , J. Clin. Invest.
  • Y-protein can be obtained as described by Litwack et al. Nature 234 : 66 (1977), or Arias, J ⁇ Clin. Invest. 51 . : 677 (1972).
  • the inert carrier is preferably a polymeric bead that is stable to passage through the mammalian intestinal tract and physiologically inert.
  • the beads should be small enough for easy oral administration to neonates.
  • the carrier also preferably enhances the enzyme's resistance to functional denaturation over that of its soluble form, and reduces losses of activity from denaturing conditions in the stomach and intestine.
  • Suitable beads include agarose beads, for example, Sepharose 4B-CL beads (Pharmacia), which mammals cannot degrade.
  • the bilirubin conversion enzyme can be immobilized on the carrier by various known techniques, e.g., the cyanogen bromide and tresyl chloride activation procedure described by Kohn et al . , Biochem. Biophys. Res. Com. 107:878 (1982) and Nilsson and Mosbach, Biochem. 3iophys. Res. Com. 102:449 (1981), respectively.
  • the following specific example is provided to illustrate the invention, and does not limit its scope.
  • Example Bilirubin oxidase purchased from Kodak Bio-Products, was immobilized on tresyl chloride activated agarose beads as cited above. Bilirubin oxidase activity was measured, in vitro, using a human serum albu in-bilirubin mixture with a molar ratio of 0.7. Under conditions encountered in the stomach (37°C, pH 3.0, for one hour), the enzymatic activity was substantially retained (90% retention).
  • Bilirubin oxidase immobilized to agarose prepared as described above, was administered orally to Gunn rats (350g) (Blue Spruce Vendors) as follows. Each day, the rats received 15 grams of regular chow (Whitmer et al. , Semin. Liver Pis. 3:42 (1983)). Enzyme-agarose conjugate in a freeze-dried form was mixed thoroughly with the chow for three days. After day three, the rats were fed the same amount of chow without the enzyme-agarose supplement. Control rats were fed each day with either 15 grams of chow or 15 grams of chow and agarose without the enzyme-agarose conjugate.
  • Plasma bilirubin concentrations were measured daily using the assay described by Jendrassik and Grof, Biochem. Z. 297:81 (1938) and were normalized with respect to the initial plasma bilirubin concentrations (Co) from day 0. By day 3, test rats receiving enzyme had C/Co values close to 0.5. When enzyme administration was discontinued, plasma bilirubin levels in test rats were slow to recover to original levels. Control rats experienced steady plasma bilirubin levels after an intial decrease as shown by Fig. 1.
  • test dosage was 2.0 mg. bilirubin immobilized to 0.2 g agarose; the control agarose dosage was 0.2 g.
  • test dosage was 4.0 mg. bilirubin immobilized to 0.4 g agarose; and the control agarose dosage was 0.4 g.
  • the test dosage was 0.l mg enzyme immobilized to 10 mg dry agarose. The results are shown in Fig. 1.
  • enzyme immobilized to agarose was heat denatured (incubated at 45°C for 68 hours) prior to its addition to the feed chow. After denaturation, in vitro assays revealed no enzymatic activity of the enzyme-agarose conjugate. Values of C/Co for the test animals were 0.53 and 0.69; for six control animals the values averaged 0.93.
  • Nonenzymatic bilirubin deactivators can be used, e.g., bilirubin specific adsorbents that are excreted and thereby remove unconjugated bilirubin from the intestinal tract.
  • Suitable adsorbents include: activated carbon, agarose, and cellulose supports coated with serum albumin or Y-protein (ligandin). Serum albumin and Y-protein serve as natural carriers by binding bilirubin in the bloodstream and in the liver, respectively.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

On peut réduire le taux de bilirubine dans le sérum de mammifères en administrant au tube intestinal du mammifère une substance (un ''désactivateur'' de la bilirubine) qui transforme la bilirubine non conjuguée en produits non toxiques physiologiquement compatibles, réduisant ainsi la réabsorption de la bilirubine non conjuguée dans la circulation entéro-hépatique. Des désactivateurs utiles de la bilirubine comprennent des substances qui adsorbent spécifiquement la bilirubine puis sont excrétées, et des ''enzymes de conversion de la bilirubine'', c'est-à-dire des enzymes qui agissent sur la bilirubine non conjuguée de façon à obtenir des produits physiologiquement compatibles en ce sens qu'ils ne sont pas réabsorbés ou lorsqu'ils sont réabsorbés, ne sont pas toxiques dans le courant sanguin.
PCT/US1988/004711 1988-01-11 1988-12-30 Therapie orale de reduction de la bilirubine WO1989006137A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14212988A 1988-01-11 1988-01-11
US142,129 1988-01-11

Publications (1)

Publication Number Publication Date
WO1989006137A1 true WO1989006137A1 (fr) 1989-07-13

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GR (1) GR890100007A (fr)
WO (1) WO1989006137A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001008679A1 (fr) * 1999-07-30 2001-02-08 Hendrik Jan Verkade Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US992254A (en) * 1910-12-12 1911-05-16 Hubert Rieck Method of producing a medicinal composition.
US4363801A (en) * 1981-02-09 1982-12-14 The Texas A&M University System Method for treating hyperbilirubinemia
US4701411A (en) * 1983-09-01 1987-10-20 Eastman Kodak Company Bilirubin-specific enzyme preparation, assay compositions, analytical elements and methods using same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3239236A1 (de) * 1982-02-18 1983-09-01 Amano Pharma Co Ltd Verfahren zur quantitativen bestimmung von physiologischen komponenten in biologischen fluessigkeiten oder gasen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US992254A (en) * 1910-12-12 1911-05-16 Hubert Rieck Method of producing a medicinal composition.
US4363801A (en) * 1981-02-09 1982-12-14 The Texas A&M University System Method for treating hyperbilirubinemia
US4701411A (en) * 1983-09-01 1987-10-20 Eastman Kodak Company Bilirubin-specific enzyme preparation, assay compositions, analytical elements and methods using same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LAVIN et al., "Enzymatic Removal of Bilirubin from Blood: A Potential Treatment for Neonatal Jaundice", SCIENCE, Volume 230, issued 01 November 1985, See the entire document. *
ODELL et al., "Enteral Administration of Agar as an Effective Adjunct to Phototherapy of Neonatal Hyperbilirubinemia", PEDIATRIC RESEARCH, Volume 17, No. 10, issued 1983, pages 810-814, see the summary. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001008679A1 (fr) * 1999-07-30 2001-02-08 Hendrik Jan Verkade Procede pour augmenter l'excretion des substances hydrophobes endogenes autres que les sterols en augmentant l'excretion fecale des matieres grasses

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GR890100007A (el) 1994-03-31

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