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WO2002080892A1 - Utilisation d'un inhibiteur du facteur de necrose de tumeurs destine au traitement de troubles associes au coup du lapin - Google Patents

Utilisation d'un inhibiteur du facteur de necrose de tumeurs destine au traitement de troubles associes au coup du lapin Download PDF

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Publication number
WO2002080892A1
WO2002080892A1 PCT/SE2002/000672 SE0200672W WO02080892A1 WO 2002080892 A1 WO2002080892 A1 WO 2002080892A1 SE 0200672 W SE0200672 W SE 0200672W WO 02080892 A1 WO02080892 A1 WO 02080892A1
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WO
WIPO (PCT)
Prior art keywords
tnf
tnf inhibitor
use according
inhibitor
specific
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.)
Ceased
Application number
PCT/SE2002/000672
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English (en)
Inventor
Kjell Olmarker
Björn Rydevik
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A+ Science AB
Original Assignee
A+ Science Invest AB
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Filing date
Publication date
Application filed by A+ Science Invest AB filed Critical A+ Science Invest AB
Publication of WO2002080892A1 publication Critical patent/WO2002080892A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to substances, pharmaceutical compositions and methods for treatment of whiplash associated disorders (WAD).
  • WAD whiplash associated disorders
  • Whiplash injuries can be quite complex and may include a variety of related problems, such as joint dysfunction, faulty movement patterns, chronic pain and cognitive and higher center dysfunction.
  • Joint dysfunction This occurs when one of the joints in the spine or limbs loses its normal joint play (resiliency and shock absorption). It is detected through motion palpation, a procedure in which the doctor gently moves the joint in different directions and assesses its joint play.
  • joint dysfunction When a joint develops dysfunction, its normal range of movement may be affected and it can become painful.
  • joint dysfunction can lead to a muscle imbalance and muscle pain and a vicious cycle.
  • the loss of joint play can cause abnormal signals to the nervous system (there are an abundance of nerve receptors in the joint).
  • the muscles related to that joint can subsequently become tense or, conversely, underactive.
  • the resulting muscle imbalance can place increased stress on the joint, aggra- vating the j oint dysfunction that already exists .
  • Trigger points are areas of congestion within the muscle where sensitizing compounds accumulate. These sensitizing compounds can irritate the nerve endings within the muscle and produce pain. This pain can occur in the muscle itself or can be referred pain (perceived in other areas of the body). Muscle related mechanisms may also give rise to abnormal signaling to the nervous system. This event can subsequently cause disruption of the ability of the nervous system to properly regulate muscles in other parts of the body, leading to the development of faulty movement patterns.
  • faulty movement patterns cause increased strain in the muscles and joints, leading to pain. They can involve the neck itself or can arise from dysfunction in other areas of the body such as the foot or pelvis. Instability is also considered part of faulty movement patterns.
  • passive instability the ligaments of the neck are loosened
  • dynamic instability the nervous system disruption causes a disturbance in the body's natural muscular response to common, everyday forces. As a result of instability, even mild, innocuous activities can become painful.
  • whiplash associated disorder is due to or related to local stimulation and/or irritation of nerve fibers and receptors located in the spine and within the spinal canal, rather than to nerve injury per se.
  • WAD whiplash associated disorder
  • the inventors have found that this stimulation and/or irritation is due to leakage of discderived substances, or nucleus pulposus material, from the intervertebral disc out into the epidural space of the spinal canal.
  • disc-derived substances will sensitize and irritate the local nerves and nerve-receptors within the spinal canal, primarily at the surface of the annulus fibrosus and the posterior longitudinal ligament. The leakage is the result of trauma.
  • WAD whiplash associated disorder
  • the invention thus relates to the use of a TNF inhibitor for the production of a pharmaceutical composition for treatment of whiplash associated dis- order (WAD).
  • WAD whiplash associated dis- order
  • the invention also relates to a method for treatment of whiplash associated disorder (WAD), wherein a TNF blocking agent or a TNF antagonist that is capable of reducing the effective amount of endogenous biologically active TNF, e.g. by reducing the amount of TNF produced, or by preventing the bind- ing of TNF to its cell surface receptor, TNFR, is administered to a patient.
  • WAD whiplash associated disorder
  • TNF tumor necrosis factor
  • TNF- ⁇ tumor necrosis factor
  • TNF blocking agent TNF blocking substance
  • TNF inhibitor TNF inhibitor
  • patient relates to any human or non- human mammal in need of treatment according to the invention, i.e. a human or non-human mammal suffering from whiplash associated disorder (WAD).
  • WAD whiplash associated disorder
  • treatment used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition.
  • the treatment may either be per- formed in an acute or in a chronic way.
  • TNF blocking substances there are several different types of TNF blocking substances and pharmacological preparations that may be used according to the invention: ⁇ Specific TNF blocking substances, such as
  • Monoclonal antibodies e.g. infiiximab, CDP-571 (HumicadeTM), D2E7, and CDP-870;
  • Soluble cytokine receptors e.g. etanercept, lenercept, pegylated TNF- receptor type I, TBP-1
  • Non-specific TNF blocking substances such as:
  • MMP inhibitors i.e. matrix metalloproteinase inhibitors, or TACE- inhibitors, i.e. TNF Alpha Converting Enzyme-inhibitors
  • Tetracyclines for example Doxycycline, Lymecycline, Oxitetracy- cline, Tetracycline, Minocycline and synthetic tetracycline deriva- tives, such as CMT, i.e. Chemically Modified Tetracyclines;
  • TIMP-1 TIMP-1
  • TIMP-2 adTIMP-1 (adenoviral delivery of TIMP-1)
  • adTIMP-2 adenoviral delivery of TIMP-2
  • nonglucocorticoid 21-aminosteroids such asU-74389G (16- desmethyl tirilazad) and U-74500
  • HP-228 thers such as: - Lactoferrin, and peptides derived from lactoferrin such as those disclosed in WO 00/01730
  • the substance or pharmaceutical composition according to the invention is administered once or repeatedly until a sustained improvement of the pa- tient's condition is observed.
  • the substance or pharmaceutical composition according to the invention is administered in a therapeutically effective amount, i.e. an amount that will lead to the desired therapeutical effect and thus lead to an improvement of the patient's condition.
  • composition according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preservatives etc., which are well known to persons skilled in the art.
  • the pharmaceutical composition is formulated as a sustained-release preparation.
  • the sub- stance according to the invention may then, for example, be encapsulated in a slowly-dissolving biocompatible polymer.
  • the substances or pharmaceutical compositions according to the invention may be administered in any efficacious way normally used to administer TNF inhibitors.
  • the substances or pharmaceutical compositions according to the invention may for example be injected via intra-articular, intravenous (i.v.), intramuscular (i.m.), intraperitoneal (i.p.), intrathecal (i.t), epidural, intracere- broventricular (i.c.v.) or subcutaneous (s.c.) routes by bolus injections or by continuous infusion. They may also be administered orally (per os), e.g. in the form of oral preparations, such as pills, syrups, or lozenges. Furthermore, they may be administered by inhalation. They may also be administered intrana- saily. Moreover, they may be administered transepidermally, e.g. in the form of topical preparations such as lotions, gels, sprays, ointments or patches. Finally, they may also be administered by genetical engineering.
  • substances according to the invention may be used either simultaneously or separately.
  • the substances according to the invention may also be administered in combination with other drags or compounds, provided that these other drugs or compounds do not eliminate the effects desired according to the present invention, i.e. the effect on TNF.
  • the invention also provides a diagnostic preparation and a method for diagnosis. According to this method the diagnostic preparation or a substance according to the invention is administered to a patient suspected of suffering from low back pain. An improvement of the patient's condition is an indication of that the patient has whiplash associated disorder.
  • a total of 15 Sprague Dawley rats were anaesthetized and a facetectomy of the left L4-5 facet-joint was performed.
  • the L4-5 in- tervertebral disc was incised using a 0.4 mm diameter injection needle.
  • the analyses comprised a macro-anatomic assessment regarding degree of fibrosis at the operation site, inflammation at the site of operations, healing of the disc incision, height of the scar formed at the surface of the disc incision (disc herniation tissue) from the disc surface, and consistency of this tissue. In selected cases the disc hernia was processed for light microscopic analysis.
  • F fibrosis
  • I inflammation
  • H healing of disk incision
  • Disc h height of formed disc hernia
  • Disc c consistency of formed disc hernia.
  • nucleus pulposus from intervertebral discs from pigs used for other purposes were harvested.
  • the nucleus pulposus was mixed with barium sul- phate powder (Mixobar® High Density, Astra Tech, M ⁇ lndal, Sweden) and a soluble iodine-contrast medium (Urograf ⁇ n®, Schering AG, Berlin, Germany).
  • Great care was taken to preserve the physical properties of the nucleus pulposus.
  • nucleus pulposus did not form a bulge or nodule that compressed the nerve tissue of the spinal canal. Instead, the nucleus pulposus was evenly spread in the spinal canal and did not compress the either the nerve root or the thecal sac.
  • Ketalar ketamine 50mg/ml; Parke-Davis, Morris Plains, New Jersey
  • an intravenous inj ection 20 mg/kg body weight of Hypnodil (methomidate chloride 50 mg/ml; AB Leo, Helsingborg, Sweden)
  • Stresnil azaperon 2 mg/ml; Janssen Pharmaceutica, Beerse, Belgium
  • Anesthesia was maintained by additional intravenous injections of 2 mg/kg body weight of Hypnodil and 0.05 mg/kg body weight of Stresnil.
  • the antero-ventral aspect of the disc between the 4 th and 5 th lumbar vertebrae was exposed.
  • the annulus fibrosus was incised using a scalpel.
  • the wound was closed and one week later the pig was reanaesthetized and killed by an overdose of potassium chloride.
  • the 4 l and 5 th lumbar vertebrae including the incised disc were removed en bloc.
  • Macroscopic examination revealed that the disc had healed with a fi- brotic scar.
  • the scar was dense and mainly comprised collagen and various cell-types at microscopic examination.
  • the cells were mainly f ⁇ broblasts, but there were also inflammatory cells and cartilage-like cells in the newly formed scar.
  • WAD Woodlash Associated Disorders

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'un inhibiteur du facteur de nécrose de tumeurs (TNF) pour la production d'une composition pharmaceutique destinée au traitement de troubles associés au coup du lapin. L'invention concerne également un procédé de traitement de troubles associés au coup du lapin.
PCT/SE2002/000672 2001-04-06 2002-04-05 Utilisation d'un inhibiteur du facteur de necrose de tumeurs destine au traitement de troubles associes au coup du lapin Ceased WO2002080892A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0101257A SE0101257D0 (sv) 2001-04-06 2001-04-06 Treatment of whiplash associated disorder
SE0101257-4 2001-04-06

Publications (1)

Publication Number Publication Date
WO2002080892A1 true WO2002080892A1 (fr) 2002-10-17

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ID=20283724

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2002/000672 Ceased WO2002080892A1 (fr) 2001-04-06 2002-04-05 Utilisation d'un inhibiteur du facteur de necrose de tumeurs destine au traitement de troubles associes au coup du lapin

Country Status (2)

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SE (1) SE0101257D0 (fr)
WO (1) WO2002080892A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227515B2 (en) * 2003-01-17 2012-07-24 Italfarmaco S.P.A. Use of hydroxamic acid derivatives for the preparation of anti-tumour medicaments

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6015557A (en) * 1999-02-24 2000-01-18 Tobinick; Edward L. Tumor necrosis factor antagonists for the treatment of neurological disorders
WO2000018409A1 (fr) * 1998-09-25 2000-04-06 A+ Science Invest Ab Utilisation de certains medicaments pour traiter les lesions des racines nerveuses
US6177077B1 (en) * 1999-02-24 2001-01-23 Edward L. Tobinick TNT inhibitors for the treatment of neurological disorders
US20010016195A1 (en) * 1999-02-24 2001-08-23 Tobinick Edward L. Cytokine antagonists for the treatment of localized disorders
WO2001062272A2 (fr) * 2000-02-25 2001-08-30 Immunex Corporation Recepteur soluble du facteur de necrose tumorale utilise dans le traitement de certaines affections medicales
US20010026801A1 (en) * 1999-02-24 2001-10-04 Tobinick Edward L. Cytokine antagonists for the treatment of localized disorders

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018409A1 (fr) * 1998-09-25 2000-04-06 A+ Science Invest Ab Utilisation de certains medicaments pour traiter les lesions des racines nerveuses
US20010027175A1 (en) * 1998-09-25 2001-10-04 Kjell Olmarker Use of certain drugs for treating nerve root injury
US6015557A (en) * 1999-02-24 2000-01-18 Tobinick; Edward L. Tumor necrosis factor antagonists for the treatment of neurological disorders
US6177077B1 (en) * 1999-02-24 2001-01-23 Edward L. Tobinick TNT inhibitors for the treatment of neurological disorders
US20010016195A1 (en) * 1999-02-24 2001-08-23 Tobinick Edward L. Cytokine antagonists for the treatment of localized disorders
US20010026801A1 (en) * 1999-02-24 2001-10-04 Tobinick Edward L. Cytokine antagonists for the treatment of localized disorders
WO2001062272A2 (fr) * 2000-02-25 2001-08-30 Immunex Corporation Recepteur soluble du facteur de necrose tumorale utilise dans le traitement de certaines affections medicales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [online] JONSSON HALLDOR JR. ET AL.: "Findings and outcome in whiplash-type neck distortions", Database accession no. PREV199598088077 *
SPINE, vol. 19, no. 24, 1994, pages 2733 - 2743 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227515B2 (en) * 2003-01-17 2012-07-24 Italfarmaco S.P.A. Use of hydroxamic acid derivatives for the preparation of anti-tumour medicaments

Also Published As

Publication number Publication date
SE0101257D0 (sv) 2001-04-06

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