WO1997038696A1 - Bisphosphonates utilises comme agents anti-inflammatoires - Google Patents

Bisphosphonates utilises comme agents anti-inflammatoires Download PDF

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Publication number
WO1997038696A1
WO1997038696A1 PCT/GB1997/001037 GB9701037W WO9738696A1 WO 1997038696 A1 WO1997038696 A1 WO 1997038696A1 GB 9701037 W GB9701037 W GB 9701037W WO 9738696 A1 WO9738696 A1 WO 9738696A1
Authority
WO
WIPO (PCT)
Prior art keywords
bisphosphonate
ibandronate
inflammatory
treatment
preparation
Prior art date
Application number
PCT/GB1997/001037
Other languages
English (en)
Inventor
Anthony Robert Lyons
Sharon Patricia Mary Crouch
David James Phipps
Andrew Wilcock
Original Assignee
The University Of Nottingham
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 The University Of Nottingham filed Critical The University Of Nottingham
Priority to AU25186/97A priority Critical patent/AU2518697A/en
Publication of WO1997038696A1 publication Critical patent/WO1997038696A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid

Definitions

  • the present invention relates to bisphosphonates as anti-inflammatory agents, and particularly but not exclusively to ibandronate as an anti- inflammatory agent.
  • cytokines Interleukins, Tumour Necrosis Factor
  • the invenuon also provides the use of a bisphosphonate for the preparation of an anti-inflammatory agent for the treatment of disorders.
  • ibandronate for the preparation of an agent for the treatment of chronic immune system activation disorders.
  • the bisphosphonate is used in vitro, and preferably comprises ibandronate.
  • a still further aspect of the present invention provides for the use of bisphosphonates, in particular ibandronate to inhibit pro-mflammatory cytokine production and/or activity.
  • Fig. 1 the effect of ibandronate on TNF secretion (No LPS);
  • Fig. 3 the effect of ibandronate on IL-8 production : lOpg/ml LPS;
  • Fig. 4 the effect of ibandronate on IL-8 secretion (No LPS).
  • IL-1 Interleukin 1
  • IL-lra Intereukin -1 receptor antagonist
  • TNF Tumour Necrosis Factor
  • sTNFRI soluble TNF receptor inhibitor
  • IL-8 lnterleukin-8
  • Ibandronate was seen to inhibit the spontaneous production of TNF however in the presence of LPS there was only significant inhibition after 48 hours of culture which is at the limit for cell viability in this cutlure technique. (Figs. 1 and 2). Ibandronate inhibited IL-8 secretion in a concentration dependent fashion in the presence or absence of LPS. (Figs. 3 and 4). No effect was shown upon the secretion of soluble TNF receptor inhibitor (sTNFRI).
  • sTNFRI soluble TNF receptor inhibitor
  • Ibandronate may act as an anti-inflammatory agent through its inhibitory effects upon IL-8. This may prevent recruitment and activation of inflammatory cells.
  • IL-8 is a potent stimulator of angioneogenesis (new blood vessel formation) at tumour sites and this may be effective in controlling metastatic seeding or growth. No change in the response of the cells was noted when they were first stimulated with LPS. This would suggest that responses to infective processes may be unimpaired and inhibition of the cytokine response would not render subjects immunodefficient.
  • Ibandronate therefore appears to specifically target the TNF and Interleukin-8 pathway to inhibit the production of these pro-inflammatory cytokines, and since cytokines are fundamental to inflammation thereby obviate or mitigate chronic immune system activation inflammation. This not only provides for alleviation of symptoms of many chronic immune system activation disorders, such as cancer, MS and AIDS, but may also provide a basis for keeping such diseases in check or providing a complete cure. Ibandronate can also be used to treat other inflammatory diseases such as rheumatoid arthritis, and also to prevent metastases of cancer.
  • ibandronate has minimal side effects, the only known side effect consisting solely of morning fever.
  • the use of ibandronate in accordance with the present invention will not be associated with the adverse reactions associated with the conventional use of immune suppressants.
  • ibandronate as an anti-inflammatory agent, and for the preparation of an agent for the treatment of chronic immune system activation disease, via the modulation of the activity and cytokine production of immune cells, including lymphocytes and macrophages offers many advantages over known drugs. Since activated macrophages, lymphocytes and pro-inflammatory cytokines are involved in the pathogenesis and generation of symptom burden in disease of chronic immune system activation, ibandronate provides effective treatment for these diseases and their symptoms.

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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

L'invention a pour objet l'utilisation d'un bisphosphonate, et en particulier d'ibandronate (connu auparavant sous la désignation BM21.0955), servant à la préparation d'un agent de traitement de maladies d'activation chronique du système immunitaire et à la préparation d'un agent anti-inflammatoire pour le traitement de troubles inflammatoires.
PCT/GB1997/001037 1996-04-17 1997-04-15 Bisphosphonates utilises comme agents anti-inflammatoires WO1997038696A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25186/97A AU2518697A (en) 1996-04-17 1997-04-15 Bisphosphonates as anti-inflammatory agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9607945.4 1996-04-17
GBGB9607945.4A GB9607945D0 (en) 1996-04-17 1996-04-17 Bisphosponates as Anti-inflammatory agents

Publications (1)

Publication Number Publication Date
WO1997038696A1 true WO1997038696A1 (fr) 1997-10-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/001037 WO1997038696A1 (fr) 1996-04-17 1997-04-15 Bisphosphonates utilises comme agents anti-inflammatoires

Country Status (3)

Country Link
AU (1) AU2518697A (fr)
GB (2) GB9607945D0 (fr)
WO (1) WO1997038696A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR200101841T2 (tr) * 1998-12-23 2001-12-21 Jomaa Pharmaka Gmbh Enfeksiyonlardan korunmak ve enfeksiyon tedavisi için bifosfonatların kullanılmaları
DE60235085D1 (de) 2001-07-16 2010-03-04 Univ Paris Xiii Herstellungsverfahren von derivate von bisphosphonaten

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003451A1 (fr) * 1990-08-21 1992-03-05 The Upjohn Company Derives d'acide bisphosphonique utilises comme agents anti-arthritiques
WO1994009017A1 (fr) * 1992-10-09 1994-04-28 The Upjohn Company Esters de biphosphonate de pyrimidine et acides (alcoxymethylphosphonyl)alkyle phosphoniques utilises comme anti-inflammatoires
WO1996023505A1 (fr) * 1995-01-30 1996-08-08 Olli Pekka Teronen Inhibition de la degradation des composants proteiniques de la matrice des tissus conjonctifs, chez les mammiferes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2813121A1 (de) * 1977-03-29 1978-10-12 Procter & Gamble Verwendung von dichlormethan-diphosphonatverbindungen bei der bekaempfung von collagen-erkrankungen und zur wundheilung
US4634691A (en) * 1980-10-07 1987-01-06 The Procter & Gamble Company Method for inhibiting tumor metastasis
DE3623397A1 (de) * 1986-07-11 1988-01-14 Boehringer Mannheim Gmbh Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003451A1 (fr) * 1990-08-21 1992-03-05 The Upjohn Company Derives d'acide bisphosphonique utilises comme agents anti-arthritiques
US5412141A (en) * 1990-08-21 1995-05-02 The Upjohn Company Bisphosphonic acid derivatives as anti-arthritic agents
WO1994009017A1 (fr) * 1992-10-09 1994-04-28 The Upjohn Company Esters de biphosphonate de pyrimidine et acides (alcoxymethylphosphonyl)alkyle phosphoniques utilises comme anti-inflammatoires
WO1996023505A1 (fr) * 1995-01-30 1996-08-08 Olli Pekka Teronen Inhibition de la degradation des composants proteiniques de la matrice des tissus conjonctifs, chez les mammiferes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"bm21.0955", DRUGS OF THE FUTURE, vol. 20, no. 1, 1995, pages 71 - 72, XP000676639 *
FLEISCH: "bisphosphonates", DRUGS, vol. 42, no. 6, 1991, pages 919 - 944, XP000676675 *
ORR ET AL.: "tumor-bone interactions in skeletal metastasis", CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, vol. 312, 1995, pages 19 - 33, XP000676626 *
SANTY ET AL.: "IL-6 and TNF alpha levels after bisphosphonates treatment...", BONE, vol. 18, no. 2, February 1996 (1996-02-01), pages 133 - 139, XP000676631 *

Also Published As

Publication number Publication date
GB2312165A (en) 1997-10-22
AU2518697A (en) 1997-11-07
GB9707570D0 (en) 1997-06-04
GB9607945D0 (en) 1996-06-19

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