WO2003000246A1

WO2003000246A1 - The use of rhein and derivatives thereof in pain treatment

Info

Publication number: WO2003000246A1
Application number: PCT/GB2002/002887
Authority: WO
Inventors: Robin Mark Bannister; Alan Rothaul
Original assignee: Arakis Ltd.
Priority date: 2001-06-25
Filing date: 2002-06-24
Publication date: 2003-01-03

Abstract

The use of a compound selected from rhein and derivatives thereof, for the manufacture of a medicament for use in pain therapy.

Description

THE USE OF RHEIN AND DERIVATIVES THEREOF IN PAIN TREATMENT

Field of the Invention

This invention relates to the use of anthroquinones in pain treatment. Background of the Invention Pathological pain represents an important area of medical need. Whilst a considerable number of analgesic agents are in current medical use, a significant proportion of patients are not adequately treated. This situation is a particular issue for neuropathic pain where few effective medicines are available. Pain has classically been regarded as mediated by the neuronal system and as such the mediators of pain have been regarded as solely neuroexcitatory substances. Recent studies indicate that in chronic pain conditions there is activation of non-neuronal glial cells in the vicinity of the neurons. Activation of these cells results in the release of a range of cytokines that are thought to enhance the activation of pain-transmitting neurons. The result is the maintenance of pain and/or the production of hyperalgesia, allodynia or spontaneous pain.

A great number of diseases involve tissue remodelling as a key component of their etiology. For example, all inflammatory disease involves an element of tissue remodelling. Minimally, this is involved in allowing the movement of proinflammatory cells to the disease tissue. In other diseases, remodelling plays a greater role, for example in both rheumatoid and osteoarthritis where cartilage and bone destruction are fundamental features of the disease. In other diseases, the promotion of new vessel growth, a remodelling process, is key to the development of the disease, e.g. solid organ tumours. In many circumstances, these diseases are associated with significant pain (e.g. arthritic conditions, cancer, endometriosis, trophic ulceration of the skin). Summary of the Invention

According to the invention, diacerein and related compounds have hitherto undescribed benefits for the treatment of pathological pain states. In conditions of pain, diacerein reduces sensitivity to pain. This is the first time that this activity of diacerein has been observed. Further, diacerein and related compounds have hitherto undescribed benefits for the treatment of conditions involving pain and tissue remodelling. In conditions involving tissue remodelling and pain, they can reduce the signs of pain associated with this condition. Description of Preferred Embodiments

Compounds that can be used in the invention are anthroquinone derivatives of the formula

wherein R, = R₂ = H and R₃ = OH (rhein) or R, = R₂ = Ac and R₃ = OH (diacerein), as well as monoacetylrhein, or a prodrug of any of these active components. Such prodrugs include esters, amides and salts, e.g. acyl derivatives at R., and R₂, and ester and amide derivatives at R₃. Compounds of this type, and their preparation, are described in, inter alia, US-A-6057461 and EP-A-0570091 , the contents of which are incorporated herein by reference.

Diacerein and its active metabolite rhein reduce production of both IL-1 and nitric oxide. This suggests why diacerein and rhein may be effective in pain management. The activity of diacerein and rhein in combination with other analgesic and anti-inflammatory agents has additional benefit for pain treatment. For use, the active agent is typically formulated, e.g. with a conventional diluent or carrier, in a medicament adapted to be delivered by the oral, intravenous, rectal, vaginal, topical to skin, inhalation or intraarticular route. Oral delivery is preferred. Such formulations and suitable dosages are known to those skilled in the art, and will be chosen according to the usual considerations such as the potency of the drug, the severity of the condition and the route of administration. Suitable compositions for oral use include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups and elixirs. Suitable additives include sweetening agents, flavouring agents, colouring agents and preserving agents. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, e.g. inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated, to form osmotic therapeutic tablets for controlled release. Hard gelatin capsules may include an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; soft gelatin capsules may include water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

The present invention is illustrated by the following Studies. Study 1

Diacerein was tested in the sciatic ligature model of neuropathic pain, often referred to as the Bennett and Xie model (after the original authors of the technique; see Pain, 33, 87-107, 1988). The model involves chronic constriction injury of the common sciatic nerve in rats. This is associated with hyperalgesia, allodynia (the sensation of pain induced by non-painful stimuli) and spontaneous pain. This is regarded as a standard model of neuropathic pain.

This particular study included a morphine-dosed group, to indicate the integrity of the study (the dose of morphine used is far greater than that which would be typically given to patients). The study parameters were as follows: N = 10 per group

Diacerein: 1 , 10 and 50 mg/kg po, uid day 1 -day 9 (day 0 is day of surgery) and 60 mins prior to test (day 10) Positive Control: morphine 128 mg/kg (vehicle dosed on other occasions to maintain blind) Measurement of response to thermal (latency to withdrawal) and tactile (force for withdrawal) stimuli Comparison of operated vs non-operated paw For diacerein, the force inducing paw withdrawal was c. 80 g in the contralateral paw and c. 20 g in the ipsilateral paw. The latency to paw withdrawal following thermal stimulus was c. 35 sec for the contralateral paw and c. 10 sec for the ipsilateral paw.

The force inducing paw withdrawal was c. 20 g for vehicle and c. 36 g for morphine. The approximate respective values for 1 , 10 and 50 mg/kg diacerein were 23, 28 and 19 g.

The latency to withdrawal following thermal stimulus was c. 11 sec for vehicle and c. 43 sec for morphine. The approximate respective values for 1 , 10 and 50 mg/kg diacerein were 13, 13 and 17 sec. Study 2

This experiment had the same design as Study 1 , but diacerein was dosed twice daily at oral doses of 50, 100 & 150 mg/kg. As comparator in this experiment, the neuropathic pain treatment agent gabapentin was dosed at 100 mg/kg orally 60 mins prior to testing (morphine and vehicle were dosed on other occasions to maintain blind).

The force inducing withdrawal of the ipsilateral paw was 14.5 sec. for vehicle-treated animals, 42.3 sec. for morphine and 32.5 sec. for gabapentin. The values for diacerein were 14.3, 11.2 and 22.5 sec. for 50, 100 and 150 mg/kg, respectively.

Claims

1. The use of a compound selected from rhein and derivatives thereof, for the manufacture of a medicament for use in pain therapy.

2. Use according to claim 1 , in which the medicament is adapted to be delivered by the oral route.

3. Use according to claim 1 or claim 2, wherein the compound is rhein, monoacetylrhein or diacerein.

4. Use according to claim 3, wherein the compound is diacerein.

5. Use according to any preceding claim, wherein the pain is associated with a disease involving tissue remodelling.

6. Use according to any preceding claim, wherein the pain is neuropathic pain.

7. Use according to any preceding claim, in combination with at least one other agent selected from a non-steroidal anti-inflammatory drug, a narcotic analgesic, a local anaesthetic, an NMDA antagonist, a neuroleptic, an anti- convulsant, an anti-spasmodic, an anti-depressant and a muscle relaxant.