WO1994028906A1 - Traitement de l'hyperbilirubinemie neonatale en utilisant de la metalloporphyrine - Google Patents

Traitement de l'hyperbilirubinemie neonatale en utilisant de la metalloporphyrine Download PDF

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Publication number
WO1994028906A1
WO1994028906A1 PCT/US1994/006514 US9406514W WO9428906A1 WO 1994028906 A1 WO1994028906 A1 WO 1994028906A1 US 9406514 W US9406514 W US 9406514W WO 9428906 A1 WO9428906 A1 WO 9428906A1
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WO
WIPO (PCT)
Prior art keywords
treatment
metalloporphyrin
bilirubin
neonatal
infants
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Application number
PCT/US1994/006514
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English (en)
Inventor
Attallah Kappas
George Drummond
Original Assignee
The Rockefeller University
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.)
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Publication date
Application filed by The Rockefeller University filed Critical The Rockefeller University
Priority to AU71035/94A priority Critical patent/AU7103594A/en
Publication of WO1994028906A1 publication Critical patent/WO1994028906A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Definitions

  • This invention is concerned with the treatment of hyperbilirubinemia in neonatal humans by parental administration of a metalloporphyrin which is a heme oxygenase inhibitor.
  • Hyperbilirubinemia is a common affliction of both full term and premature human neonates. It is characterized by an elevated concentration of plasma bilirubin [BR] . A level of about 7 to 20 mg/dL plasma within 36 hours post partum is not uncommon. It appears to result from the rapid degradation of heme resulting from increased heme oxygenase activity before the necessary, normal mechanisms of bilirubin deposition are sufficiently matured thereby causing increased bilirubin levels. Normally, the levels of bilirubin decrease spontaneously after about 96 hours of life by which time the hepatic mechanism for bilirubin disposal is functioning. However, during the period of high [BR] serious and lasting toxic effects may develop.
  • the compounds of the patents have been shown to function by inhibiting the activity of heme oxygenase, the rate controlling enzyme in the degradation of heme to bilirubin. They are, therefore, heme oxygenase inhibitors.
  • a metalloporphyrin which is a heme oxygenase inhibitor can completely replace phototherapy with neonates exposed to the danger of bilirubin toxicity by administration of the selected metalloporphyrin under selected conditions at a selected dosage level and that the compound can act as a potent, direct therapeutic substitute for light treatment in jaundiced newborns.
  • Such compounds include porphyrin chelates of, for example, tin, zinc, manganese cobalt and other metals.
  • a method has now been discovered for treating hyperbilirubinemia without the need of phototherapy in neonatal infants in need of such treatment both full term and premature.
  • the method comprises administration of a selected metalloporphyrin under defined conditions with respect to time of administration and dosage levels.
  • the method is applicable to all infants including both premature and full term. It comprises parenteral administration of from about 1 to 25 umol/Kg body weight preferably, 4 to 8 umol/kg body weight of the selected heme oxygenase inhibitor to patients requiring treatment because of rising bilirubin levels.
  • the exact dosage level will vary with the selected metalloporphyrin, but the above ranges are generally applicable.
  • the preferred method of administration is parenteral administration, suitably by intramuscular or intravenous administration.
  • the useful heme oxygenase inhibitors of this invention such as those identified above are known compounds prepared by known methods. Most of them are readily synthesized or are available commercially.
  • the preferred therapeutic agent is SnMP.
  • the process of this invention is applicable to neonates at risk of a high [BR] as evidenced by a bilirubin level of about 7 mg/dL, and rising, at an age of 36 hours. Neonates with a bilirubin level below this level at 36 hours are generally not at risk, even if the level is rising.
  • Another very important advantage of the process of this invention, in addition to the replacement of phototherapy, is the rapid decrease in bilirubin concentration. Two important consequences of the rapid decrease are that the time of hospital stay is substantially decreased resulting in major economic savings, and the length of time the neonate is exposed to potentially toxic concentrations of bilirubin is also decreased. This has physiological consequences which may improve the quality of life throughout the life span of the neonate. Lastly, there is no need to separate the infant from the mother as is presently the case with phototherapy.
  • the practice of this invention requires that the blood [Br] of the neonate be monitored as is current procedure from shortly after birth and for a period of 24 to 36 hours to determine if there is danger of the development of toxic plasma levels of blood.
  • the standard test for determining bilirubin concentration is described by Jendrassik et al. Biochem Z. (1938) 297:81-89.
  • the values in the table are all average values.
  • the average length of time (Interval) required for the infants who were enrolled in the study and who received phototherapy to reach the level of bilirubin to exit the study was 64.4 hours.
  • the average length of time to exit the study which was required for the infants who did recieve the SnMP was approximately one-half of that time period, i.e. only 32.8 hours.
  • none of the 22 SnMP treated infants received phototherapy.
  • the therapeutic agents of the invention will normally be employed in buffered, isotonic, aqueous solutions at pH 7 to 8.
  • the usual pharmaceutical carriers are isotonic aqueous sodium chloride or glucose solutions buffered, for example, with a phosphate buffer.
  • compositions can also be provided in lyolphilized powder form to be reconstituted with water to the clinical dosage.
  • the selected metalloporphyrin can be taken up in 0.1 molar phosphate or other pharmaceutically acceptable buffer containing sufficient saline or other solute to form isotonic solutions and freeze dried to form a powder.
  • the powder can be reconstituted with distilled water or saline solution to provide solutions containing 0.1 to 12.5 umol/ml therapeutic agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de traitement de l'hyperbilirubinémie néonatale chez les être humains sans thérapie légère en administrant un inhibiteur de heme oxygénase tel que la mésoporphyrine d'étain à un niveau de dosage sélectionné chez le nourrisson avec une concentration de plasma bilirubine augmentant qui, 36 heures après l'accouchement, est d'environ 7 mg/dL.
PCT/US1994/006514 1993-06-14 1994-06-10 Traitement de l'hyperbilirubinemie neonatale en utilisant de la metalloporphyrine WO1994028906A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU71035/94A AU7103594A (en) 1993-06-14 1994-06-10 Treatment of neonatal hyperbilirubin with metalloporphyrin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7657993A 1993-06-14 1993-06-14
US08/076,579 1993-06-14

Publications (1)

Publication Number Publication Date
WO1994028906A1 true WO1994028906A1 (fr) 1994-12-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/006514 WO1994028906A1 (fr) 1993-06-14 1994-06-10 Traitement de l'hyperbilirubinemie neonatale en utilisant de la metalloporphyrine

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AU (1) AU7103594A (fr)
WO (1) WO1994028906A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008045378A2 (fr) * 2006-10-04 2008-04-17 Infacare Pharmaceutical Corporation Traitement d'hyperbilirubinémie infantile en utilisant des faibles dosages de stannsoporfine
US7960371B2 (en) 2006-10-04 2011-06-14 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
US8178664B2 (en) 2002-06-04 2012-05-15 Infacare Pharmaceutical Corporation Preparation of metal mesoporphyrin compounds
US8735574B2 (en) 2011-03-30 2014-05-27 Infacare Pharmaceutical Corporation Methods for synthesizing metal mesoporphyrins
US11878029B2 (en) 2014-09-29 2024-01-23 Fred Hutchinson Cancer Center Compositions, kits, and methods to induce acquired cytoresistance using stress protein inducers

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4657902A (en) * 1985-03-25 1987-04-14 The Rockefeller University Therapeutic use of tin mesoporphyrin
US4684637A (en) * 1981-07-15 1987-08-04 The Rockefeller University Method of decreasing rate of heme metabolism

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684637A (en) * 1981-07-15 1987-08-04 The Rockefeller University Method of decreasing rate of heme metabolism
US4657902A (en) * 1985-03-25 1987-04-14 The Rockefeller University Therapeutic use of tin mesoporphyrin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PEDIATRICS, Volume 81, issued April 1988, KAPPAS et al., "Sn-Protoporphyrin Use in the Management of Hyperbilirubinemia in Term Newborns with Direct Coombs-Positive Abo Incompatibility", pages 485 to 497. *
PEDIATRICS, Volume 84, issued October 1989, RUBALTELLI et al., "Tni-Protoporphyrin in the Management of Children with Crigler-Najjar Disease", pages 728-731. *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8178664B2 (en) 2002-06-04 2012-05-15 Infacare Pharmaceutical Corporation Preparation of metal mesoporphyrin compounds
EP2992886A1 (fr) 2006-10-04 2016-03-09 InfaCare Pharmaceutical Corporation Préparation à grande échelle haute pureté de stannsoporfine
US10273255B2 (en) 2006-10-04 2019-04-30 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
WO2008045378A2 (fr) * 2006-10-04 2008-04-17 Infacare Pharmaceutical Corporation Traitement d'hyperbilirubinémie infantile en utilisant des faibles dosages de stannsoporfine
WO2008045378A3 (fr) * 2006-10-04 2008-06-05 Infacare Pharmaceutical Corp Traitement d'hyperbilirubinémie infantile en utilisant des faibles dosages de stannsoporfine
US8530458B2 (en) 2006-10-04 2013-09-10 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
US7960371B2 (en) 2006-10-04 2011-06-14 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
US8835416B2 (en) 2006-10-04 2014-09-16 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
US9107927B2 (en) 2006-10-04 2015-08-18 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
EP2384756A2 (fr) 2006-10-04 2011-11-09 InfaCare Pharmaceutical Corporation Préparation à grande échelle de stannsoporfine de grande pureté
US11078220B2 (en) 2006-10-04 2021-08-03 Mallinckrodt Hospital Products IP Limited High-purity large-scale preparation of stannsoporfin
US10662209B2 (en) 2006-10-04 2020-05-26 Mallinckrodt Hospital Products IP Limited High-purity large-scale preparation of stannsoporfin
US9517239B2 (en) 2006-10-04 2016-12-13 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
US9902745B2 (en) 2006-10-04 2018-02-27 Infacare Pharmaceutical Corporation High-purity large-scale preparation of stannsoporfin
US8735574B2 (en) 2011-03-30 2014-05-27 Infacare Pharmaceutical Corporation Methods for synthesizing metal mesoporphyrins
US10533024B2 (en) 2011-03-30 2020-01-14 Mallinckrodt Hosptial Products Ip Limited Methods for synthesizing metal mesoporphyrins
US9688705B2 (en) 2011-03-30 2017-06-27 Infacare Pharmaceutical Corporation Methods for synthesizing metal mesoporphyrins
US9181285B2 (en) 2011-03-30 2015-11-10 Infacare Pharmaceutical Corporation Methods for synthesizing metal mesoporphyrins
US12083145B2 (en) 2014-09-29 2024-09-10 Fred Hutchinson Cancer Research Center Compositions, kits, and methods to induce acquired cytoresistance using stress protein inducers
US11878029B2 (en) 2014-09-29 2024-01-23 Fred Hutchinson Cancer Center Compositions, kits, and methods to induce acquired cytoresistance using stress protein inducers

Also Published As

Publication number Publication date
AU7103594A (en) 1995-01-03

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