EP0726780A1 - Treatment for rheumatoid arthritis - Google Patents

Treatment for rheumatoid arthritis

Info

Publication number
EP0726780A1
EP0726780A1 EP95900514A EP95900514A EP0726780A1 EP 0726780 A1 EP0726780 A1 EP 0726780A1 EP 95900514 A EP95900514 A EP 95900514A EP 95900514 A EP95900514 A EP 95900514A EP 0726780 A1 EP0726780 A1 EP 0726780A1
Authority
EP
European Patent Office
Prior art keywords
crf
administering
patient
inflammatory
arthritis
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.)
Withdrawn
Application number
EP95900514A
Other languages
German (de)
English (en)
French (fr)
Inventor
Irwin A. Braude
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neurobiological Technologies Inc
Original Assignee
Neurobiological Technologies 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 Neurobiological Technologies Inc filed Critical Neurobiological Technologies Inc
Publication of EP0726780A1 publication Critical patent/EP0726780A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2228—Corticotropin releasing factor [CRF] (Urotensin)
    • 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]

Definitions

  • This invention generally relates to a method of treating a patient suffering from a chronic inflam ⁇ matory arthritides, and more particularly to the use of corticotropin-releasing factor or its analogs in reducing swelling during episodic acute responses of chronic inflammatory conditions.
  • rheumatoid arthritis is the cause of an estimated about 33,000 deaths in the United States each year. As yet, there is no cure for the disease, and the cause is uncertain. Rheumatoid arthritis sufferers periodically experience flare-ups, or episodic acute responses, of from a week up to a month of duration.
  • Sauvagine is a 40 amino acid peptide and has been reported to have biological activity in lowering blood pressure in mammals and stimulating the secretion of
  • Por ⁇ cine CRF shares a common amino acid sequence (residues 1-39) with rat/human CRF and differs from these only in position 40 and 41.
  • Residue 40 can be either dsparagine or isoleucine and residue 41 is phenylalanine-amide.
  • U.S. Patent 4,801,612 inventor Wei, issued January 31, 1989, discloses the use of inhibiting an inflammatory response (acute) in the skin or mucosal membranes of a patient by administering Corticotropin- Releasing Factor, or its analogs
  • U.S. Patent 5,137,871, issued August 11, 1992, inventor Wei describes the use of CRF (or a salt or analog thereof) in treating a patient for injury to or disease of the brain, nervous system, or musculature in which edema is a factor.
  • corticotropin-releasing factor to patients suffering from one of the chronic inflammatory arthritides, such as rheumatoid arthritis, reduces episodic acute inflammatory responses to the disease.
  • Doses of CRF in accordance with the invention give anti-inflammatory results in a dose responsive manner even in well-established disease.
  • practice of the invention provides a therapeutic treatment for these unremitting diseases that are refractory to current therapies.
  • Figure " is a perspective view illustrating the paws of two mycobacterium induced arthritis- susceptible male Lewis "LEW/N" rats where paw 10 is a control and paw 12 has been injected with Mycobacterium to induce arthritis;
  • Figure 2 graphically illustrates foot pad swelling (with one unit equivalent to 0.001 inches) in an animal model of arthritis-susceptible rats as a function of time for control animals and animals treated in accordance with the invention at two different doses (50 and 100 ⁇ g CRF; injected subcutaneously, per kg of body weight) , with the foot pad swelling measurement being made of mycobacterium injected paws (left hind) ;
  • Figure 3 is similar to Fig. 2, but illustrates measurements of the paws opposite to the injected paws in the transverse plane (right hind) ;
  • Figure 4 graphically illustrates the plot of arthritis scores as a function of time for the right hind paw of Fig. 3;
  • Figure 5 is similar to Fig. 4, but is of the other pair of paws (left and right front) ;
  • Figure 6 including panels A-E, is similar to Fig. 2 but plots the larger dose (100 ⁇ g/kg body weight) administered subcutaneously in the mycobacterium injected foot pad (left hind) in accordance with the invention beginning at times delayed up to 40 days after induction of disease;
  • Figure 7 including panels A-E, is similar to Fig. 6 but is of the opposite foot pad in the traverse plane (right hind) ; and Figure 8 graphically illustrates plots of arthritis scores in a manner similar to that of Fig. 4, but in the format similar to that of Fig. 6.
  • CRF CRF-related peptides known to the art.
  • Therapeutic formations of CRF may be prepared for storage by mixing CRF having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers, in the form of lyophilized cake or aqueous solutions.
  • Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed when administered, and include buffers such as phosphate, citrate, and other organic acids; anti- oxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins.
  • Other components can include glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt- forming counterions such as sodium; and/or" nonionic surfactants such as Tween, Pluronics, or PEG.
  • glycine glutamine, asparagine, arginine, or lysine
  • monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins
  • chelating agents such as EDTA
  • sugar alcohols such as mannitol or sorbitol
  • salt- forming counterions such as sodium
  • nonionic surfactants such as Tween, Pluronics, or PEG.
  • Administration may be by any mode of admini ⁇ stration known in the art, including, but not limited to, intra-articular, intravenous, intrathecal, subcu ⁇ taneous, injection, intranasal, oral, or via an implanted device.
  • Suitable implants include, for example, gel foam, wax, or microparticle-based implants.
  • Topical administration preferably includes agents or apparatus to facilitate skin delivery, such as solubilizing agents or directed delivery systems as are known and being developed in the rapidly emerging technologies of skin delivery systems.
  • Therapeutically effective doses of CRF or its analogs in practicing this invention preferably are at least about 0.01 ⁇ g/kg in humans.
  • For systemic administration e.g. subcutaneous and intravenous
  • more preferred doses are in the range of about 0.1 to about 50 ⁇ g/kg, and most preferred about 1 to about 30 ⁇ g/kg.
  • For local administration e.g. intra-articular
  • the preferred dose is in a range of about 1 to about 100 ⁇ g/kg.
  • Administration of CRF doses may be infused slowly, such as subcutaneously or intradermally, or may be injected directly into an afflicted body part.
  • Patients treated will be under the care of a health care professional, such as a physician, who may herself administer the therapeutic composition including
  • CRF may prescribe such for the patient's self administration (such as, for example, preloaded syringes) .
  • Systemic forms of administration are particularly preferred due to the frequent multiple sites of episodic situations, or flares.
  • treatments in accordance with the invention, as further illustrated hereinafter, are shown efficacious, when treatment is stopped then efficacy also ceases.
  • the therapeutic method of this invention may be r combined with other pharmaceuticals and other therapeutic approaches to the disease being treated.
  • CRF CRF in accordance with this invention
  • side effects e.g. Cushing's Syndrome
  • practice of this invention is primarily contemplated for treating acute, episodic flares, and CRF administration can be undertaken up to forty days after an episodic acute inflammation occurs.
  • the peptides are generally water soluble as typically synthesized, they may be admini ⁇ stered in the form of pharmaceutically acceptable non-toxic salts, such as acid addition salts.
  • Illustra ⁇ tive acid addition salts are hydrochloride, hydrobro- mide, sulfate, sulphate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate, or the like.
  • CRF may be administered in any pharmacologically acceptable carrier, depending upon the desired mode of administration it may be formulated along with liquid carrier into liposomes, microcapsules, polymers, or wax-based and controlled release prepara ⁇ tions, or be formulated into tablet, pill, or capsule forms.
  • a method for treating a patient in accordance with this invention involves patients suffering from one of the chronic inflammatory arthritides.
  • chronic inflammatory arthritides are meant to include rheumatoid arthritis, Reiters Syndrome, ankylosing spondylitis, psoriatic arthritis, and inflammatory bowel disease.
  • Treatments are particularly useful for episodic acute inflammations and provide anti-inflammatory results in a dose responsive manner.
  • time administered e.g. up to about forty days after an episodic acute inflammation
  • practice of the invention reduces inflammation even in well established disease; however, when treatment is discontinued, then the inflammatory symptoms have been found to reoccur.
  • the present invention is most likely a treatment rather than a cure.
  • CRF Five days after induction of the disease in the rats, CRF was administered subcutaneously twice a day at either a dose per administration of 50 ⁇ g/kg or 100 ⁇ g/kg. The twice a day administrations were continued for a period of 20 days. By approximately 16 days post-induction, the CRF treated animals have comparatively little swelling or inflammation.
  • the amount of swelling was determined by the use of calipers in measuring the thickness of left hind (injected) paw. This measurement served as a determination for the degree of "primary,” or acute, inflammation. Subsequently (usually about an additional 10-12 days) the right hind paw also swells and becomes inflamed. This represents a chronic inflammatory response.
  • Fig. 2 the primarily inflamed left hind paw swelling data (measured through day 32) is shown for control rats, for rats receiving twice a day administrations of CRF at 50 ⁇ g/kg body weight, and for rats receiving twice a day administrations of CRF at 100 ⁇ g/kg body weight.
  • the vertical axis is measured in units where one unit is equivalent to 0.001 inches.
  • administrations of CRF in accordance with the invention gave anti-inflammatory results and in a dose responsive manner.
  • the three graphs of Fig. 2 all begin five days after the left hind paw was challenged with Mycobacterium. With twice a day injection of 50 ⁇ g/kg CRF, there was reduced swelling relative to control. Results were even of greater significance with administrations of 100 ⁇ g/kg.
  • FIG. 3 data similar to that of Fig. 2 are represented, but the degree of foot pad swelling being measured is that of the right hind paw and thus represents a chronic inflammatory response.
  • Administration of CRF at doses of either 50 ⁇ g/kg or 100 ⁇ g/kg were begun five days after challenge, as with Fig. 2, but the right hind paw has a swelling on-set later than does the left hind paw illustrated by the Fig. 2 data.
  • the right hind paw also experiences less swelling than the left hind paw.
  • the right hind paw is not itself directly challenged as is the left hind paw.
  • Fig. 4 the animals as in Fig. 3 were also assessed for the extent of arthritis by using a s ring system in which "0" indicated no arthritis and "4" represented severe arthritis.
  • the arthritis scores were made by evaluating a combination of factors including the percent involvement of the foot pads plus the overall symptoms of the disease (which include swelling, redness, and disfigurement) .
  • the Fig. 4 data shows that both doses of CRF (50 ⁇ g/kg and 100 ⁇ g/kg) are active in reducing the arthritis scores, although the 100 ⁇ g/kg dose appears to show a greater effect.
  • the right hind paw of the animals were used for the Fig. 4 scoring.
  • Fig. 5 conducted similarly to the just described Fig. 4, the two front paws were evaluated. That is, Figs 4 and 5 both represent chronic, rather than acute, situations. However, the front paws used for the Fig. 5 data experienced an on-set of swelling and other symptoms even more delayed and less pronounced than for the right hind paws of Fig. 4. As is seen particularly with the Fig. 5 data, administrations of CRF in accordance with this invention are very effective in t eating for the clinical manifestations of chronic inflammatory arthritis.
  • Panel A plots the foot pad thickness for the control rats and for rats who received treatment beginning on day 5 after induction of the disease (indicated by the open arrow) and ending on day 20 (indicated by the filled in, or closed, arrow) .
  • footpad thickness was considerably reduced with respect to the control, and the thickness reductions continued until treatment was discontinued, at which time swelling began and continued until by about day 60 there was substantially no difference between the previously treated footpad and the control (never treated) footpad.
  • panel B illustrates data for the control and test rats with treatment beginning on day 10 and ending on day 30, panel C with treatment beginning on day 15 and ending on day 35, panel D with treatment beginning on day 25 and ending on day 45, and panel E with treatment beginning on day 40 and ending on day 60.
  • FIG. 7 the data illustrated by panels A-E are similar to those described for Fig. 6, but the foot pad swelling was measured in the animals' right hind foot pad. That is, as with Fig. 3, since the degree of foot pad swelling being measured is that of the right hind paw (where the left hind paw is the site of mycobacterium injections and may represent acute flares) , the right hind paw may represent chronic inflammatory responses.
  • these data demonstrate that administering CRF in accordance with the invention profoundly reduces swelling, even in established disease, for chronic inflammatory conditions. r In experiments similar to Figs. 6 and 7, but where the animals were assessed for the extent of arthritis by using a scoring system such as is described for Fig.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP95900514A 1993-11-02 1994-11-02 Treatment for rheumatoid arthritis Withdrawn EP0726780A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14652093A 1993-11-02 1993-11-02
US146520 1993-11-02
PCT/US1994/012621 WO1995012416A1 (en) 1993-11-02 1994-11-02 Treatment for rheumatoid arthritis

Publications (1)

Publication Number Publication Date
EP0726780A1 true EP0726780A1 (en) 1996-08-21

Family

ID=22517765

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95900514A Withdrawn EP0726780A1 (en) 1993-11-02 1994-11-02 Treatment for rheumatoid arthritis

Country Status (10)

Country Link
EP (1) EP0726780A1 (cs)
JP (1) JPH09504792A (cs)
AU (1) AU8131694A (cs)
CA (1) CA2175457A1 (cs)
CZ (1) CZ122696A3 (cs)
HU (1) HUT74275A (cs)
LT (1) LT96079A (cs)
NO (1) NO961747L (cs)
PL (1) PL314191A1 (cs)
WO (1) WO1995012416A1 (cs)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9017029B2 (en) 2011-05-06 2015-04-28 Rolls-Royce Deutschland Ltd & Co Kg Gas-turbine balancing device

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6060288A (en) * 1994-08-03 2000-05-09 Mosaic Technologies Method for performing amplification of nucleic acid on supports
US5780431A (en) * 1996-09-20 1998-07-14 Neurobiological Technologies, Inc. Pharmaceutical formulations of corticotropin releasing factor having improved stability in liquid form
JP2002503954A (ja) 1997-04-01 2002-02-05 グラクソ、グループ、リミテッド 核酸増幅法
AR031640A1 (es) 2000-12-08 2003-09-24 Applied Research Systems Amplificacion isotermica de acidos nucleicos en un soporte solido
EP1565436B1 (en) * 2002-11-27 2012-04-25 Incyte Corporation 3-aminopyrrolidine derivatives as modulators of chemokine receptors
WO2008093098A2 (en) 2007-02-02 2008-08-07 Illumina Cambridge Limited Methods for indexing samples and sequencing multiple nucleotide templates
WO2010038042A1 (en) 2008-10-02 2010-04-08 Illumina Cambridge Ltd. Nucleic acid sample enrichment for sequencing applications
US8182994B2 (en) 2009-09-15 2012-05-22 Illumina Cambridge Limited Centroid markers for image analysis of high denisty clusters in complex polynucleotide sequencing
CN115137809A (zh) * 2021-03-31 2022-10-04 张菁 含有促肾上腺皮质激素及其衍生物的药物及其用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006330A (en) * 1988-11-30 1991-04-09 The United States Of America As Represented By The Of The Department Of Health And Human Services Evaluative means for detecting inflammatory reactivity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9512416A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9017029B2 (en) 2011-05-06 2015-04-28 Rolls-Royce Deutschland Ltd & Co Kg Gas-turbine balancing device

Also Published As

Publication number Publication date
LT96079A (en) 1996-10-25
WO1995012416A1 (en) 1995-05-11
PL314191A1 (en) 1996-09-02
AU8131694A (en) 1995-05-23
HUT74275A (en) 1996-11-28
NO961747L (no) 1996-07-02
JPH09504792A (ja) 1997-05-13
HU9601149D0 (en) 1996-06-28
NO961747D0 (no) 1996-04-30
CA2175457A1 (en) 1995-05-11
CZ122696A3 (en) 1996-12-11

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