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WO2000053013A1 - Inhibition de la pkc afin de traiter les insuffisances de permeabilite - Google Patents

Inhibition de la pkc afin de traiter les insuffisances de permeabilite

Info

Publication number
WO2000053013A1
WO2000053013A1 PCT/US2000/006405 US0006405W WO0053013A1 WO 2000053013 A1 WO2000053013 A1 WO 2000053013A1 US 0006405 W US0006405 W US 0006405W WO 0053013 A1 WO0053013 A1 WO 0053013A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
pkc
dialysis fluid
subject
peritoneal dialysis
Prior art date
Application number
PCT/US2000/006405
Other languages
English (en)
Other versions
WO2000053013A8 (fr
Inventor
George Liang King
Original Assignee
Joslin Diabetes Center, Inc.
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 Joslin Diabetes Center, Inc. filed Critical Joslin Diabetes Center, Inc.
Priority to AU36252/00A priority Critical patent/AU3625200A/en
Publication of WO2000053013A1 publication Critical patent/WO2000053013A1/fr
Publication of WO2000053013A8 publication Critical patent/WO2000053013A8/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Definitions

  • the invention relates to peritoneal dialysis fluids, and methods of making and using them. More particularly, it relates to the methods for preventing and treating complications due to peritoneal dialysis.
  • Peritoneal dialysis can be used to treat patients having chronic renal failure.
  • peritoneal dialysis fluid is introduced into the peritoneal cavity of a subject.
  • the fluid generally has a high glucose level, often in the 100 M range.
  • Introduction of this relatively high molarity fluid into the peritoneum causes the osmotic extraction of toxins, for example, urea creatinine, and other substances normally removed by the kidney, from the blood. It can also reduce the level of fluid in the patient.
  • the invention is based, in part, on the discovery that the use of peritoneal dialysis fluid, especially prolonged use, can result in decreasing permeability between the peritoneal dialysis fluid and the blood compartment, that high levels of glucose are involved in changes in the cells lining the peritoneum, that the high glucose levels activate PKC, and that the inhibition of PKC can prevent this chronic complication.
  • the invention can treat an undesirable decrease in the efficiency of exchange between the peritoneal dialysis fluid and the vascular compartment.
  • the invention features, a method of treating a subject. The method includes: introducing peritoneal dialysis fluid into the peritoneum of the subject; and inhibiting a PKC in the subject, 5 thereby treating said subject.
  • an inhibitor of PKC is included in the peritoneal dialysis fluid.
  • the inhibitor is preferably a specific inhibitor of PKC.
  • the inhibitor can be an inhibitor of a PKC ⁇ , e.g., ⁇ l or ⁇ 2, ⁇ , ⁇ , or other isoform.
  • the inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC ⁇ i o inhibitor LY333531, which is described in Ishi et al. ( 1996) Science 272 : 728-731 , hereby incorporated by reference.
  • LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nanometers.
  • the concentration of glucose in the peritoneal dialysis fluid is 200nM.
  • Peritoneal dialysis fluid of the invention is particularly useful for subjects who are already peritoneal dialysis patients.
  • the subject has been a peritoneal dialysis patient for at least 2, 4, 6, 12, or 24 months, e.g., the subject has been administered peritoneal dialysis fluid, either one with or without a PKC inhibitor, periodically for at least 2, 4, 6, 12, or 24 months, or it has been at least 20 2, 4, 6, 12, or 24 months since the subjects first peritoneal dialysis administration.
  • Peritoneal dialysis fluid of the invention can be administered to patients who have already developed permeability disjunction.
  • peritoneal dialysis fluid of the invention is useful for subjects who have not yet had peritoneal dialysis.
  • Peritoneal dialysis fluid of the 25 invention can be administered to patients who have not yet developed permeability disjunction.
  • the invention features, a method of treating a subject.
  • the method includes: introducing peritoneal dialysis fluid and an inhibitor of a PKC into the subject, thereby treating the subject.
  • the peritoneal dialysis fluid and PKC inhibitor are co -administered to the subject; the peritoneal dialysis fluid and PKC inhibitor are introduced separately into the subject; the peritoneal dialysis fluid and PKC inhibitor are combined prior to introduction into the subject and administered together.
  • an inhibitor of PKC is included in the peritoneal dialysis fluid.
  • the inhibitor is preferably a specific inhibitor of PKC.
  • the inhibitor can be an inhibitor of a PKC ⁇ , e.g., ⁇ l or ⁇ 2, ⁇ , ⁇ , or other isoform, or combinations thereof.
  • the inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC ⁇ inhibitor LY333531.
  • LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nanometers.
  • the concentration of glucose in the peritoneal dialysis fluid is 200nM.
  • the subject is administered a second, third, fourth, or fifth, infusion of peritoneal dialysis fluid.
  • Peritoneal dialysis fluid of the invention is particularly useful for subjects who are already peritoneal dialysis patients.
  • the subject has been a peritoneal dialysis patient for at least 2, 4, 6, 12, or 24 months, e.g., the subject has been administered peritoneal dialysis fluid, either one with or without a PKC inhibitor, periodically for at least 2, 4, 6, 12, or 24 months, or it has been at least 2, 4, 6, 12, or 24 months since the subjects first peritoneal dialysis administration.
  • Peritoneal dialysis fluid of the invention can be administered to patients which have already developed permeability disjunction.
  • peritoneal dialysis fluid of the invention is useful for subjects who have not yet had peritoneal dialysis.
  • Peritoneal dialysis fluid of the invention can be administered to patients which have not yet developed permeability disjunction.
  • the subject is at risk for renal failure, for example, the subject is a patient in end-stage renal failure.
  • the invention features, a peritoneal dialysis fluid which includes an inhibitor of a PKC.
  • the peritoneal dialysis fluid is one described herein.
  • an inhibitor of PKC is included in the peritoneal dialysis fluid.
  • the inhibitor is preferably a specific inhibitor of PKC.
  • the inhibitor can be an inhibitor of a PKC ⁇ , e.g., ⁇ l or ⁇ 2, ⁇ , ⁇ , or other isoform, or combinations thereof.
  • the inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC ⁇ inhibitor LY333531.
  • LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nM.
  • the concentration of glucose in the peritoneal dialysis fluid is 200nM.
  • the invention features, a method of making an improved peritoneal dialysis fluid.
  • the method includes, providing a peritoneal dialysis fluid and adding to that fluid an inhibitor of a PKC, for example an inhibitor described herein, for example LY333531.
  • an inhibitor of PKC is included in the peritoneal dialysis fluid.
  • the inhibitor is preferably a specific inhibitor of PKC.
  • the inhibitor can be an inhibitor of a PKC ⁇ , e.g., ⁇ l or ⁇ 2, ⁇ , ⁇ , or other isoform, or combinations thereof.
  • the inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC ⁇ inhibitor LY333531.
  • LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nM.
  • the concentration of glucose in the peritoneal dialysis fluid is 200nM.
  • Subject can refer to a human subject, or a non-human animal, for example, a horse, cow, goat, pig, sheep or other veterinary, food or fiber producing animal, in need of dialysis.
  • the subject can be an individual at risk for (e.g., the individual can have or be predisposed to have) end-stage renal disease, from any cause.
  • Figure 1 shows PKC activity of primary human mesothelial cells at various glucose levels (i.e., low glucose, 60 mM or 150 mM glucose). The PKC activity was determined in the presence or absence or PMA, an activator of PKC.
  • Figure 2 shows the effect of treatment with vitamin E on PKC activity of human primary mesothelial cells.
  • the mesothelial cells were exposed to low or high (150 mM) levels of glucose in the presence or absence of PMA, an activator of PKC, and the presence or absence of vitamin E, a PKC inhibitor.
  • Figure 3 shows PKC activity of primary human mesothelial cells cultured in low glucose concentrations, high glucose concentrations (i.e., 60 M or 150 mM), or mannitol.
  • the PKC activity was determined in the presence or absence or PMA, an activator of PKC.
  • Figure 4 shows DAG activity of transformed mesothelial cells at low glucose levels (5.5 mM) and high glucose levels (60 mM).
  • Peritoneal dialysis for chronic renal failure is used by some patients with renal failure.
  • the fluid for peritoneal dialysis uses glucose at 400-mM range. While not wishing to be bound by theory, it appears that at this concentration level, glucose causes complications which can lead to decreasing permeability between the peritoneal dialysis fluid and the blood compartment. The elevation of high glucose causes changes in the cells lining the peritoneum.
  • the invention is based, in part on, PKC activation, which is believed to cause this chronic decrease in the exchange between the peritoneal fluid and a vascular compartment.
  • PKC activation induced by hyperglycemia either in the peritoneal fluid or in the blood causes cells to behave abnormally.
  • the inhibition of PKC ⁇ isoform by the inhibitor LY333531 can prevent many of the vascular changes induced by glucose levels up to 20-3 OmM.
  • the higher concentration of glucose as used in peritoneal dialysis will also increase PCK activation.
  • Inhibition of PKC activation using a PKC ⁇ , e.g., ⁇ l or ⁇ 2, ⁇ , ⁇ , or other isoform, or combinations thereof, inhibitor will prevent the thickening and the decrease in exchange between peritoneal and vascular compartments, which will improve the efficiency of peritoneal dialysis for chronic renal failure.

Landscapes

  • 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)
  • External Artificial Organs (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne une méthode permettant de traiter un patient présentant une disjonction de perméabilité. Cette méthode consiste à administrer au fluide de dialyse péritonéale un inhibiteur de PKC (protéinekinase C), notamment la PKC β, puis à administrer ce fluide de dialyse à un patient souffrant d'insuffisance rénale. L'invention concerne également un fluide de dialyse péritonéale amélioré ainsi que des méthodes de fabrication de ce.
PCT/US2000/006405 1999-03-12 2000-03-10 Inhibition de la pkc afin de traiter les insuffisances de permeabilite WO2000053013A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36252/00A AU3625200A (en) 1999-03-12 2000-03-10 Inhibition of pkc to treat permeability failure

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12404399P 1999-03-12 1999-03-12
US60/124,043 1999-03-12

Publications (2)

Publication Number Publication Date
WO2000053013A1 true WO2000053013A1 (fr) 2000-09-14
WO2000053013A8 WO2000053013A8 (fr) 2001-04-05

Family

ID=22412423

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/006405 WO2000053013A1 (fr) 1999-03-12 2000-03-10 Inhibition de la pkc afin de traiter les insuffisances de permeabilite

Country Status (2)

Country Link
AU (1) AU3625200A (fr)
WO (1) WO2000053013A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736564A (en) * 1994-06-20 1998-04-07 Smithkline Beecham Corporation Endothelin receptor antagonists
US5929106A (en) * 1997-10-27 1999-07-27 Smithkline Beecham Corporation Endothelin receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736564A (en) * 1994-06-20 1998-04-07 Smithkline Beecham Corporation Endothelin receptor antagonists
US5929106A (en) * 1997-10-27 1999-07-27 Smithkline Beecham Corporation Endothelin receptor antagonists

Also Published As

Publication number Publication date
WO2000053013A8 (fr) 2001-04-05
AU3625200A (en) 2000-09-28

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