AU4266996A - Creation of Inventions and Patents with Artificial Intelligence

AU4266996A – Combined use of diclofenac and tribenoside to treat osteoarthritis
– Google Patents

AU4266996A – Combined use of diclofenac and tribenoside to treat osteoarthritis
– Google Patents
Combined use of diclofenac and tribenoside to treat osteoarthritis

Info

Publication number
AU4266996A

AU4266996A
AU42669/96A
AU4266996A
AU4266996A
AU 4266996 A
AU4266996 A
AU 4266996A
AU 42669/96 A
AU42669/96 A
AU 42669/96A
AU 4266996 A
AU4266996 A
AU 4266996A
AU 4266996 A
AU4266996 A
AU 4266996A
Authority
AU
Australia
Prior art keywords
compound
tribenoside
diclofenac
mice
osteoarthritis
Prior art date
1994-12-16
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.)

Granted

Application number
AU42669/96A
Other versions

AU697425B2
(en

Inventor
Lucille Bitensky
Joseph Chayen
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.)

KS Biomedix Ltd

Original Assignee
KS Biomedix Ltd
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.)
1994-12-16
Filing date
1995-12-18
Publication date
1996-07-03

1995-12-18
Application filed by KS Biomedix Ltd
filed
Critical
KS Biomedix Ltd

1996-07-03
Publication of AU4266996A
publication
Critical
patent/AU4266996A/en

1998-10-08
Application granted
granted
Critical

1998-10-08
Publication of AU697425B2
publication
Critical
patent/AU697425B2/en

2015-12-18
Anticipated expiration
legal-status
Critical

Status
Ceased
legal-status
Critical
Current

Links

Espacenet

Global Dossier

Discuss

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

A61K31/70—Carbohydrates; Sugars; Derivatives thereof

A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P19/00—Drugs for skeletal disorders

A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

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

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Description

COMBINED USE OF DICLOFENAC AND TRIBENOSIDE TO TREAT OSTEOARTHRITIS Field of the Invention
This invention relates to compositions for use in the treatment of osteoarthritis (OA) . Background of the Invention
Many drugs are known for the treatment of osteoarthritis, but in general their effectiveness is low, especially if side-effects are to be avoided. A known drug of this type is diclofenac sodium. In normal articular cartilage (human as well as murine) , monoamine oxidase in chondrocytes can be found located precisely in mitochondria. During the development of the natural disease in mice, these granules become larger and apparently burst, the monoamine oxidase (MAO) activity becomes distributed through the cytoplasm of the chondrocytes and even into the surrounding matrix. This was described by Chambers et al, Int. J. Exp. Path. 73.:115- 123 (1992), who related the MAO activity in the medial as against that in the (normal) lateral cartilage in untreated mice and in those treated with diclofenac.
The presumption from these findings was as follows: when circulating pharmacologically-active amines, such as adrenalin, enter normal chondrocytes they are detoxified by the MAO inside the mitochondria. Such detoxification requires both the close association of the MAO with the coenzyme FAD (flavine adenine dinucleotide) and the close presence of a peroxidase to remove the H202 generated by the MAO activity. When the MAO occurs in the matrix of the cartilage, it is unlikely to be functional, because (i) it may have been disrupted from its coenzyme (FAD) , and (ii) if it were to be operative, it would be generating H20, which would be damaging to the matrix.
When diclofenac sodium was given to mice, there was a marked improvement in the localisation of the MAO in the potentially osteoarthritic cartilage. There was no sign of activity in the general cytoplasm or in the matrix.

It was suggested that the diclofenac molecule might become split to yield monoamines which would be a weak substrate for the relevant enzyme, and act as competitive inhibitors of the MAO activity. However, diclofenac sodium did not stop the development of OA in these mice.
Diclofenac sodium is related to fena ic acid. Derivatives of fenamic acid have been used as anti- inflammatory agents, particularly influencing the cyclooxygenase and/or 5-lipoxygenase systems; see US-A- 5114958.
Summary of the Invention
The present invention is based on the postulate that two influences are involved in the development of OA: a cellular and an extracellular factor. The first is improved by, for example, diclofenac sodium or another compound having the same effect; the second, namely oedema of the matrix, is improved by, for example, tribenoside or another compound having the same effect. Whether or not the postulate is correct, it has been found experimentally that administration of diclofenac resulted in at least 9/10 mice having severe OA, but that a combination of the two drugs has resulted in 7/9 mice having no sign of OA.
A composition according to the present invention comprises compounds that respectively act on the chondrocytes and that reduce the water content of the chondrocyte matrix. These compounds can be given simultaneously or sequentially, for the prevention or treatment of OA. Description of the Invention The two active components used in this invention may be formulated as a mixture or independently, in kit form, for simultaneous, separate or sequential administration to a subject. Each compound may be formulated together with a suitable pharmaceutically-acceptable solid, semi-solid or liquid excipient, for oral, parenteral or topical administration. Depending on the desired route of administration, any of a variety of carriers may be used.

Examples of such materials are known to those skilled in the art, and include powders such as talc, and aqueous carriers. The composition may be formulated, again in known manner, e.g. as a tablet, solution, suspension, ampoule, capsule or other unit dose. For example, 25, 50 and 75 mg tables of diclofenac sodium are already available.
An amount of each active component is given, that is effective for the desired treatment. Each compound may be given in an amount of 1 to 2000 g/day, but this is merely a guide, and in any given case the amount will be chosen, if appropriate by the attending physician, having regard to factors such as the age, health and weight of the patient, and the severity of the complaint under treatment. In general, suitable dosages of the active components can simply be determined.
Compositions of this invention are suitable for use in the treatment of osteoarthritis in humans and in animals, e.g. domesticated and farm animals such as dogs, cats and horses.
Although the invention will be specifically described with relation to the use of diclofenac, other suitable materials include the series of fenamic acid derivatives since all have the relevant nitrogen atom between two benzene rings. Oxicams come into this category, as does piroxicam. Basically any compound which has the general formula Rt-NH-R2 would be a candidate, depending on its toxicity and on how readily R, or R2 could be removed in the body to yield a pseudo-substrate for monoamine oxidase (“pseudo-substrate” is one which can bind to the enzyme but which can be only slowly oxidised by it, or not oxidised at all) . Basically this concept applies to any molecule which either alone or with minimal breakage of the molecule, could yield an aromatic amine which might be a weak substrate for monoamine oxidase.

Similarly, biologues of tribenoside (glyvenol) may be used, e.g. compounds similarly based on a sugar nucleus, with bulky substituents.
The extra-cellular factor was studied by quantitative interference microscopy, as described by Ross, “Phase Contrast and Interference Microscopy for Cell Biologists” Arnold: London, p.36 (1967). This form of microscopy allows the investigator to measure the dry mass, per unit area (Cs) , in selected regions of a section or of a cell. This measurement then allows the assessment of water content (Cw) :
Cw = 100 – 0.75 Cs Such quantitative microscopic interferometric measurements showed that the concentration of dry mass in the affected, medial cartilage of these mice was markedly less than that of the unaffected lateral cartilage (Chambers et al, 1992) . The water content of the latter was very similar to that found in both medial and lateral tibial cartilages of CBA mice which were not prone to osteoarthritis.
Feeding STR/ORT mice with diclofenac sodium has no effect on the dry mass per unit area (and therefore, on the water content) . On the one hand, however, feeding such mice with tribenoside markedly increased the content of dry mass of the medial cartilage, making the dry mass/unit area even of the medial cartilage virtually equivalent to that of the lateral cartilage of these mice, or to the cartilages of CBA mice (Table 1) . On the other hand, such feeding did not improve the localisation of MAO activity. Mice were then fed with diclofenac sodium and tribenoside: both the water content and the MAO activity in the medial cartilage of such mice were “normal”; i.e. equivalent to the activities in the lateral cartilage. The consequences of this treatment, in three separate experiments, were that whereas 9/10 of the STR/ORT mice of this colony, and of this age, had damaged cartilage, only 2/7 that had been treated in this way showed any sign of damage. Results are

shown in Table 1, i.e. the dry mass per μm in the matrix of cartilages of the tibial plateau of STR/ORT mice after various treatments. Three mice were treated with diclofenac (Df) alone, four with tribenoside (Tb) alone, and four with both (Df + Tb) .

duplicate sections covered by meniscus or no lateral in the section

Claims (7)

CLARIS
1. A composition comprising (i) a compound that acts on the chondrocytes and (ii) a compound that reduces the water content of the chondrocyte matrix, as a combined preparation, for simultaneous, separate or sequential use in the treatment of osteoarthritis.

2. A composition comprising a mixture of compounds (i) and (ii) as defined in claim 1, and a physiologically- acceptable carrier, for therapeutic use.

3. A composition according to claim l or claim 2, wherein compound (i) is diclofenac sodium.

4. A composition according to any preceding claim, wherein compound (ii) is tribenoside.

5. A method for the treatment of osteoarthritis in a subject, which comprises administering to said subject an effective amount of each of (i) a compound that acts on the chondrocytes and (ii) a compound that reduces the water content of the chondrocyte matrix.

6. A method according to claim 5, wherein compound (i) is diclofenac sodium.

7. A method according to claim 5, wherein compound (ii) is tribenoside.

AU42669/96A
1994-12-16
1995-12-18
Combined use of diclofenac and tribenoside to treat osteoarthritis

Ceased

AU697425B2
(en)

Applications Claiming Priority (3)

Application Number
Priority Date
Filing Date
Title

GB9425487

1994-12-16

GBGB9425487.7A

GB9425487D0
(en)

1994-12-16
1994-12-16
Osteoarthritis treatment

PCT/GB1995/002955

WO1996018403A1
(en)

1994-12-16
1995-12-18
Combined use of diclofenac and tribenoside to treat osteoarthritis

Publications (2)

Publication Number
Publication Date

AU4266996A
true

AU4266996A
(en)

1996-07-03

AU697425B2

AU697425B2
(en)

1998-10-08

Family
ID=10766094
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

AU42669/96A
Ceased

AU697425B2
(en)

1994-12-16
1995-12-18
Combined use of diclofenac and tribenoside to treat osteoarthritis

Country Status (8)

Country
Link

US
(2)

US6034122A
(en)

EP
(1)

EP0796100A1
(en)

JP
(1)

JPH10510528A
(en)

CN
(1)

CN1088361C
(en)

AU
(1)

AU697425B2
(en)

CA
(1)

CA2207911A1
(en)

GB
(1)

GB9425487D0
(en)

WO
(1)

WO1996018403A1
(en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

GB9425487D0
(en)

1994-12-16
1995-02-15
Res Inst
Osteoarthritis treatment

GB9608133D0
(en)

1996-04-19
1996-06-26
Gemini International Holdings
Diagnostic method and apparatus

US6765000B2
(en)

1999-03-17
2004-07-20
Bonner Jr Ernest L
Treatment for reactive arthritis or bursitis

US7884090B2
(en)

1999-03-17
2011-02-08
Ernest L. Bonner, Jr.
Compositions and methods for the treatment of arthritis

US7691831B2
(en)

1999-03-17
2010-04-06
Ernest L. Bonner, Jr.
Pharmaceutical combination and method for treatment of reactive arthritis or bursitis

US6197776B1
(en)

1999-03-17
2001-03-06
Ernest L. Bonner, Jr.
Method for treatment of reactive arthritis or bursitis

US20050137181A1
(en)

1999-03-17
2005-06-23
Bonner Ernest L.
Method for treatment of reactive arthritis or bursitis

GB0104571D0
(en)

2001-02-23
2001-04-11
Ks Biomedix Holdings Plc
Composition

EP2996704B1
(en)

2013-05-14
2021-01-06
Mars, Incorporated
Joint care composition

GB201414910D0
(en)

2014-05-23
2014-10-08
Mars Inc
Composition

CN112138015B
(en)

2020-10-22
2022-08-05
合肥博思科创医药科技有限公司
Application of tribenoside in treating skin diseases caused by microcirculation disturbance

Family Cites Families (4)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US4464376A
(en)

1982-07-22
1984-08-07
Richardson-Vicks, Inc.
Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same

CH662505A5
(en)

1985-04-30
1987-10-15
Seuref Ag
Pharmaceutical composition for protective action vascular.

US5095037B1
(en)

1989-12-21
1995-12-19
Nissho Kk
Combined anti-inflammatory agent

GB9425487D0
(en)

1994-12-16
1995-02-15
Res Inst
Osteoarthritis treatment

1994

1994-12-16
GB
GBGB9425487.7A
patent/GB9425487D0/en
active
Pending

1995

1995-12-18
CA
CA002207911A
patent/CA2207911A1/en
not_active
Abandoned

1995-12-18
EP
EP95941182A
patent/EP0796100A1/en
not_active
Withdrawn

1995-12-18
AU
AU42669/96A
patent/AU697425B2/en
not_active
Ceased

1995-12-18
WO
PCT/GB1995/002955
patent/WO1996018403A1/en
not_active
Application Discontinuation

1995-12-18
US
US08/849,513
patent/US6034122A/en
not_active
Expired – Fee Related

1995-12-18
CN
CN95196816A
patent/CN1088361C/en
not_active
Expired – Fee Related

1995-12-18
JP
JP8518488A
patent/JPH10510528A/en
active
Pending

2000

2000-01-18
US
US09/484,011
patent/US6369107B1/en
not_active
Expired – Fee Related

Also Published As

Publication number
Publication date

EP0796100A1
(en)

1997-09-24

US6034122A
(en)

2000-03-07

GB9425487D0
(en)

1995-02-15

MX9704409A
(en)

1998-07-31

JPH10510528A
(en)

1998-10-13

CN1170366A
(en)

1998-01-14

CA2207911A1
(en)

1996-06-20

CN1088361C
(en)

2002-07-31

US6369107B1
(en)

2002-04-09

WO1996018403A1
(en)

1996-06-20

AU697425B2
(en)

1998-10-08

Contact information