[go: up one dir, main page]

WO2008001053A1 - Traitement et/ou prévention de la douleur faisant intervenir des polyols de polyéther - Google Patents

Traitement et/ou prévention de la douleur faisant intervenir des polyols de polyéther Download PDF

Info

Publication number
WO2008001053A1
WO2008001053A1 PCT/GB2007/002349 GB2007002349W WO2008001053A1 WO 2008001053 A1 WO2008001053 A1 WO 2008001053A1 GB 2007002349 W GB2007002349 W GB 2007002349W WO 2008001053 A1 WO2008001053 A1 WO 2008001053A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyether polyol
pain
use according
aqueous solution
aqueous
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/GB2007/002349
Other languages
English (en)
Inventor
Gareth Ackland
Alexander V. Gourine
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.)
University College London Hospitals NHS Foundation Trust (UCLH)
Original Assignee
University College London Hospitals NHS Foundation Trust (UCLH)
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 University College London Hospitals NHS Foundation Trust (UCLH) filed Critical University College London Hospitals NHS Foundation Trust (UCLH)
Publication of WO2008001053A1 publication Critical patent/WO2008001053A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to a medicament for the treatment and/or prevention of pain and to the use of such a medicament for the treatment and/or prevention of pain.
  • Pain may be acute or chronic. Acute pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [International Association for the Study of Pain]. Despite the availability of a variety of analgesics for the treatment of acute pain, recent studies demonstrate that about 50-70% of patients still experience moderate to severe pain after surgery [Best Pract Res Clin Anaesthesiol. 2007 ;21(1):3-13]. Acute pain usually resolves but may persist.
  • Chronic pain is defined as a persistent pain that is not amenable to treatments based upon specific remedies, or to the routine methods of pain control such as non-narcotic analgesics [International Association for the Study of Pain]. Diverse diseases and tissue trauma are associated with the development of chronic pain. Conservative estimates suggest that 5-20% of all patients undergoing a variety of elective surgical procedures will develop chronic pain. Chronic pain results in a systemic syndrome characterized by pain, prolonged psychological symptoms and the development of other medical problems, such as pain at other body sites, fatigue and cardiovascular disease. Chronic pain persists over a long period of time and is notoriously resistant to many analgesics and other medical treatments, rendering it as a leading cause of disability in the United States.
  • Neuropathic pain is a complex, chronic pain state that may be accompanied by tissue injury.
  • the nerve fibres themselves may be damaged, dysfunctional or injured. These damaged nerve fibres send incorrect signals to those parts of the brain that control the sensation of pain.
  • Many common diseases such as post-herpetic neuralgia, trigeminal neuralgia, diabetes mellitus, cancer, stroke, and degenerative neurological diseases may produce neuropathic pain.
  • Conventional analgesics fpain- killers such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids (e.g. morphine) are often ineffective.
  • Neuropathic pain accounts for 25-50% of pain clinic visits every year with an estimated prevalence of 4 million sufferers in the US alone (Curr Opin Anaesthesiol. 2005 Oct; 18 (5):548-54).
  • Pro-inflammatory cytokines released by immune cells can induce or facilitate pain. It is thought that pro-inflammatory cytokines contribute as much to the development and maintenance of pain as the initial damage itself. Studies using animal models have shown that up-regulation of chemokines is one of the mechanisms underlying the development and maintenance of chronic pain. Cytokine release results in neuroinflammation, where immune cells infiltrate the site of injury in response to damage to the nervous system. Neuroinflammation occurs in persistent pain states following peripheral and central nervous system injury, through neuroimmune activation involving endothelial cells, microglia and astrocytes. In particular, an excessive release of pro-inflammatory cytokines at the site of nerve injury manifests in behaviour suggestive of neuropathic pain (see e.g. DeLeo et al, The role of neuroinflammation and neuroimmune activation in persistent pain, Pain 90 (2001) 1-6).
  • Pain thresholds are not only lower, but also altered in that minor stimuli are sensed as excessively painful- hyperalgesic neuropathic pain. Furthermore, stimuli that are normally innocuous become painful - allodynic pain.
  • the development of chronic, neuropathic pain after surgery is a particularly undesirable yet common complication. This is exacerbated by the ineffectiveness of many analgesics, which have major side effects that limit both their use and efficacy. For example, the use of the most effective analgesic morphine is often limited by its strong tendency to provoke nausea and vomiting, excessive sedation and depression of breathing.
  • Polyether polyol in particular polyether glycol, and most particularly polyethylene glycol, is a widely used substance for both household and industrial purposes. It possesses some remarkable properties that have been explored in several laboratory-based scenarios, although the mechanisms through which polyethylene glycol acts under different experimental conditions are unclear. Polyethylene glycol improves function in experimental transplant organs (JP Faure et al, American Journal of Transplantation 2004 vol 4; 495-504) reverses experimental spinal cord injury (R Borgens and R Shi, FASEB J. vol 14, 27-35, 2000) and protects against experimentally-induced colonic cancer (DE Corpet et al, Carcinogenesis vol.20 no.5 pp.915-918, 1999).
  • FR-A-2316923 discloses complex solutions comprising a number of components (urethane, ethylene glycol, etc) including high molecular weight (6000) polyethylene glycol in a high concentration (2.5%). There is no evidence given that the beneficial effect of this solution is related to the properties of polyethylene glycol.
  • DE-A-10204696 discloses the use of polyethylene glycol in a nasal spray (comprising several other substances) to treat viral infections causing coughs and sneezes.
  • WO-A-2004/047778 discloses a solution based on a high molecular weight, at least 5,000 daltons, polyethylene glycol given in a very high concentration in an experimental model of microbe-mediated epithelial disorders.
  • polyethylene glycol solution (Pseudomonas aeruginosa) was administered mixed with a polyethylene glycol solution. It is proposed that high molecular weight; high concentration polyethylene glycol prevents contact of pathogens with the epithelial surface. The disclosure has no relevance to the treatment or prevention of pain. Furthermore, polyethylene glycols are known for use as bowel purgatives in common clinical practice.
  • None of these prior disclosures addresses the treatment of acute and chronic pain in an individual, in particular for surgical and medical emergencies, for chronic post-operative pain and in particular, neuropathic pain.
  • the present invention at least partially aims to meet at least one, or more preferably all of those needs.
  • the present invention provides the use of an aqueous solution of at least one polyether polyol for the treatment and/or prevention of pain.
  • the polyol polyether of the any aspect of the present invention can be of any suitable molecular weight for treating and/or preventing pain in a subject, but it is preferred that it has a molecular weight of from 100 to 10,000, preferably 200 to any one of 5,000, 6,000, 7,000 or 8,000, or most preferably, 200 to 4000.
  • the molecular weight may be any one of 200, 400, 600, 800, 1 ,000, 1 ,500, 2,000, 2,500, 3,000, 3,500 or 4,000, and may be a range between any one of these points (i.e. 200 to 1,000).
  • Molecular weight is represented in Daltons (Da).
  • the present invention may employ a "low molecular weight polyethylene glycol", meaning the range of molecular weight of the polyethylene glycols is from 200 to 1000, or alternatively the present invention may employ a "medium molecular weight polyethylene glycol", meaning the range of molecular weights of the polyethylene glycol is from 1000 to 4000.
  • a mixture of such a "low molecular weight polyethylene glycol” and a “medium molecular weight polyethylene glycol” may alternatively be employed.
  • the polyol polyether of any aspect of the present invention can be of any suitable concentration for treating and/or preventing pain in a subject.
  • the concentration of the polyol polyether falls within the range of 0.01 to 1000 mg/ml, more preferably, 0.01 to 500 mg/ml, most preferably 0.01 to 100 mg/ml.
  • the polyether polyol is at a concentration of 0.01 to 10 mg/ml.
  • the polyether polyol can be present in the aqueous solution at a level of 0.01, 0.1 , 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/ml, or a range including 2 or more of these points (i.e. 0.1 to 7 mg/ml).
  • the concentration of the at least one polyether polyol in the aqueous solution is from 1 to 10 mg/ml, more preferably 5 to 10 mg/ml.
  • the final dosage to be administered will depend on the precise mode of administration, but may preferably be such as to provide between 10 mg and 5 g to a typical subject of 70kg. Most preferably it will provide between 35 mg and 3.5g, or between 100 mg and 3g, or between 1g and 2g.
  • the present invention provides the use of an aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing pain.
  • the present invention provides the use of a composition comprising at least one polyether polyol and an aqueous solution for administration to a mammal for the manufacture of a combined preparation for the simultaneous, separate or sequential use as a medicament for treating and/or preventing pain.
  • the present invention provides a composition comprising an aqueous solution of at least one polyether polyol for administration to a mammal as a combined preparation for use as a medicament, in particular for treating and/or preventing pain.
  • the composition or medicament described herein is for administration to a mammal, the medicament or composition comprising at least one polyether polyol in aqueous solution, the at least one polyether polyol consisting of the sole active therapeutic constituent of the composition or medicament, wherein the at least one polyether polyol preferably has a molecular weight of from 200 to 4000 and is dissolved in an aqueous fluid selected from an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids.
  • the concentration of the at least one polyether polyol in the aqueous solution is from 0.01 to 10 mg/ml, more preferably from 1 to 10 mg/ml.
  • the polyether polyol may comprise a single polyether polyol, or may comprise a mixture of at least two polyether polyols.
  • the polyether polyol is preferably a polyether glycol, most preferably polyethylene glycol.
  • the polyethylene glycol preferably has a molecular weight of from 200 to 4000, most preferably 200 to 2000, or 200 to 1000.
  • the invention most preferably has medical use for administration to human beings, although it may also have veterinary use for treating other mammals, such as domestic pets (cats, dogs, etc.), horses, farm animals (cattle, etc.).
  • the aqueous fluid for administration to a human being or a mammal is a medical-grade liquid, such as an aqueous intravenous (e.g. resuscitation) fluid or an aqueous fluid for intrathecal or intraperitoneal therapy which preferably comprises an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids.
  • an aqueous intravenous (e.g. resuscitation) fluid or an aqueous fluid for intrathecal or intraperitoneal therapy which preferably comprises an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids.
  • Preferred aqueous crystalloid solutions include Ringer's lactate solution, compound sodium lactate solution (for example comprisingi sodium 131 mmol/l, potassium 5 mmol/l 1 , calcium 2 mmol/l, chloride 111 mmol/l, lactate 29 mmol/l; pH 6-7; osmolarity 278 m ⁇ smol/l) and normal saline solution (for example 0.9% sodium chloride in water), or mixtures of two or more of these solutions.
  • a most preferred fluid for administration contains sodium lactate.
  • Preferred aqueous colloid suspensions include succinylated gelatine suspended in, for example 0.9% saline solution and starch based colloid preparations (including hydroxyethylated starch) in aqueous suspension.
  • the preferred crystalloid-colloid solutions include one or more aqueous crystalloid solutions in admixture with one or more aqueous colloid suspensions.
  • the at least one polyether polyol is dissolved in the aqueous fluid for administration to a human being in a concentration (with respect to the volume of the initial aqueous fluid) of from 0.01 to 10 mg/ml, more preferably from 1 to 10 mg/ml.
  • the present invention provides a method of treating and/or preventing pain, the method comprising administering to a patient an aqueous solution of at least one polyether polyol.
  • the present invention provides the use of an aqueous solution of at least one polyether polyol as an analgesic.
  • the analgesic is for treating/preventing pain.
  • the medicament solution of the present invention can be administered in any suitable way, but is preferably administered orally, intravenously, intraperitoneal ⁇ or intrathecal ⁇ for central nervous system administration.
  • the administration method is the same as for the conventional administration of an intravenous fluid or administration of intrathecal or intraperitoneal therapy.
  • the administration may be in a single dose, or in plural doses administered over a period of time.
  • the medicament solution or composition of the invention can be administered as a peri- operative fluid, most preferably intravenously.
  • the medicament solution or composition can be administered as a pre-operative fluid and/or intra-operative and/or post-operative fluid, most preferably, intravenously.
  • low molecular weight polyethylene glycol administered in low concentration of from 1-7 mg/ml, inhibits production and/or release of major endogenous pro-inflammatory mediators (cytokines) from immune cells directly implicated in pathophysiology of acute and chronic pain.
  • cytokines major endogenous pro-inflammatory mediators
  • the inventors postulate that the solutions of the present invention may act to reduce/prevent pain by reducing the production and/or release of pro-inflammatory cytokines that are involved with the initiation/development of pain.
  • the solution is thought to act via attenuation of cytokine production/release.
  • the present invention is predicated on the finding by the inventors that there is a marked benefit resulting from the administration of polyether polyol, in particular polyethylene glycol-saline solutions in experimental models of acute inflammation.
  • the therapeutic application of this finding uses widely practiced, accepted means of maintaining/restoring organ function through administration of fluid, for example as a perioperative fluid, but with the additional benefit of anti-inflammatory, thus pain-relieving substance within that fluid.
  • the present invention therefore is based in part on the discovery of a new and unexpected medical use of a known compound, which, according to the experimental data obtained by the present inventors, has profound properties which decrease the production of the pro-inflammatory cytokines, which to the inventors' knowledge was previously unrecognised by those skilled in the art.
  • the polyethylene glycol-saline solution can be administered easily, safely and effectively.
  • polyethylene glycol has previously been recognised as being safe for human use, being used widely in foods and drugs (categorised as a "GRAS" (Generally Recognised as Safe) substance by The United States Food and Drug Administration), there is an immediate clinical opportunity to develop polyethylene glycol-saline solutions as an acute analgesic, and/or to prevent or treat chronic pain.
  • GRAS Generally Recognised as Safe
  • the administration of the polyether polyol-saline solutions may readily be achieved using a standard mode of care (fluid therapy) to deliver, in a resuscitation or peri-operative fluid, the additional pain-relieving benefit of the polyether polyol compounds.
  • the medicament of the present invention may be used for its pain-relieving properties for the treatment of pathophysiological states where there is acute and/or chronic pain.
  • acute pain may result from disease, inflammation, or trauma/injury to tissues.
  • Chronic pain is associated with several medical conditions encompassing: alcoholism; amputation; back, leg, and hip problems; chemotherapy and/or following surgical procedures associated with post-operative pain.
  • the pain may for example cancer (e.g. breast cancer), infection (e.g. otitis media, pelvic inflammatory disease, peptic ulcer disease), autoimmune disease (i.e.
  • systemic lupus erythematosis systemic lupus erythematosis
  • anatomical pathology mechanical back, leg, and hip pain, including sciatica
  • chronic inflammation including hepatitis, pancreatitis, irritable bowel disease, chronic kidney failure, dysplasia, , repetitive strain injury , sickle cell anemia, rheumatoid spondylarthropathies, diabetes mellitus; facial nerve inflammation [Bell's palsy]; AIDS; multiple sclerosis and shingles (herpes zoster virus infection).
  • syndromes or diseases for which treatment of pain may be beneficial include headache, migraine, neuralgia, toothache and appendicitis, as well as toxic shock syndrome and/or thromboembolism, hernia, crizos, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, ischemia, lipedema, malaria, peripheral neuropathy, pinched nerve, ectopic pregnancy, menstruation, diverticulitis, urolithiasis, pyelonephritis, peptic ulcer disease, gastroenteritis, cholecystitis, aortic aneurysm, Osgood-Schlatter disease, cholestasis, and chondritis.
  • composition, method or medicament of the present invention may thus be used to treat any condition, disease, injury, or infection that is associated with pain, particularly those associated with persistent or chronic pain.
  • the present invention may be used to treat any one of those conditions listed above.
  • Figures Figure 1 shows the relationship between body temperature and time, and thus demonstrating inflammatory response, for rats treated with a medicament in accordance with Example 1 of the present invention and in a comparative control sample.
  • Figures 2 (a), (b) and (c) show the relationship between blood plasma levels of the respective cytokines and composition of the injection for rats treated with a medicament in accordance with Example 2 of the present invention and in comparative control samples.
  • Figures 3 (a) and b) show responses to mechanical hyperalgesia in a neuropathic pain model .
  • Animals were treated with saline [vehicle], morphine or PEG and response was demonstrated by force tolerated before paw withdrawal and time to paw withdrawal. Differences shown are between mean differences between paws * p ⁇ 0.05 vs. before drug; #p ⁇ 0.05 vs. before drug.
  • Figure 4 shows changes in mean paw volume vs. baseline (%) in the carrageenan inflammatory pain model - p ⁇ 0.05 vs. vehicle; **p ⁇ 0.01 vs. vehicle treated group.
  • Figure 5(a) shows the similar baseline response of rats to mechanical stimuli, before they receive carrageenan and then treatment [PEG or saline control].
  • Figure 5(b) shows the difference in responses to mechanical stimuli between paws 3 hours after one paw has been been injected with carrageenan resulting in acute inflammatory pain while the other paw serves as a control.
  • the rats received either PEG or saline treatment 3 hours after the injection of the carrageenan, *p ⁇ 0.01 vs. vehicle.
  • Figure 6(a) shows that the release of the inflammatory mediators MIP-1, lnterleukin-6 and PGE2 by human peripheral blood mononuclear cells [which are all centrally implicated in the pathogenesis of acute and chronic pain] is reduced when these immune cells are treated with a medicament in accordance with Example 1 of the present invention, but treated with control [vehicle] solution in a comparative control sample.
  • Figure 6(a) also shows that at the same concentration, higher molecular weight PEG (>4000) was not so efficacious, but MW ⁇ 2000 had a significant anti-inflammatory effect on cytokine production.
  • Figure 6(b) shows that the most efficacious concentration of PEG that reduced prostaglandin E2 production was between 7-10mg/ml. * denotes significant difference (p ⁇ 0.05). Examples
  • An isotonic solution of polyethylene glycol in compound sodium lactate solution in accordance with the present invention was prepared.
  • the solution had a concentration of 6.2 mg/ml of the polyethylene glycol in compound sodium lactate solution, and the polyethylene glycol had an average molecular weight of 200, and is available in commerce from the company Sigma, of Poole, UK (amongst many others).
  • This polyethylene glycol solution is referred to hereinafter in these Examples as PEG 200- saline
  • the results are summarised in Figure 1.
  • the temperature data for each time measurement are presented as mean temperature values ⁇ standard error of the mean value.
  • bacterial endotoxin lipopolysaccharide LPS
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-6 interleukin-6
  • TNF ⁇ tumour necrosis factor- ⁇
  • Plasma IL-1 ⁇ , IL-6 and TNF ⁇ concentrations were measured after a period of 1 hour following injection of the respective solutions (either containing LPS or not).
  • the results are summarised in Figures 2 (a), (b) and (c), which show data presented as means + standard errors of the means. Numbers in parentheses indicate sample sizes.
  • IL-1 ⁇ , IL-6 and TNF ⁇ levels in plasma of rats treated with both polyethylene glycol 200-saline solution and lipopolysaccharide were significantly lower than in plasma of rats injected with saline and lipopolysaccharide (p ⁇ 0.05).
  • This Example shows that administration of a polyethylene glycol-saline solution in accordance with the present invention can substantially reduce the production and/or release of major pro-inflammatory cytokines during systemic inflammation in vivo from immune cells stimulated by bacterial endotoxins, similar to their response evoked by local and/or systemic trauma and injury.
  • the purpose of this example was to evaluate the analgesic activity of PEG in the chronic partial sciatic ligation model for Neuropathic Pain in rats.
  • PBS Phosphate buffered saline
  • PEG 400 was supplied by Sigma.
  • Morphine HCI was supplied by Teva Pharmaceutical Industry as a clear liquid.
  • Catgut suture was supplied by SMI.
  • Clorketam (for anesthesia) was supplied by vetoquinol.
  • Xlyalzine was supplied by Medical Market.
  • Ketamine Sodium (Clorketam) was dissolved in Saline to achieve a concentration of 7 mg/ml 1 .
  • Xylazine HCI was dissolved in Saline to achieve a concentration of 1.5 mg/ml. Both materials were injected IP at a volume of 10 ml/kg.
  • PEG400 was diluted in PBS To achieve the desired concentration of 5mg/ml.
  • the test system employed rats (SD) from Harlan Laboratories, Israel. Young adult males were used having a weight of 200-22Og at the study initiation.
  • Rats [n 10 each group] were administered either vehicle (IV ), PEG (IV) or Morphine (which served as a positive control in this study, IP, 5mg/kg) once 15 minutes before the pain threshold test.
  • This procedure was carried out 3 times: before surgery to determine baseline, 14 days post surgery before drug administration and 15 minutes post drug administration.
  • PEG400 administered once intravenously, reduced neuropathic pain induced in rats substantially [p ⁇ 0.05]. Furthermore, in this model, PEG 400 was as effective as morphine, which served as a positive control in this study. All data are mean (95% confidence intervals).
  • Example 4 The purpose of this example was to demonstrate the analgesic activity of intravenous administration of PEG-400 in the acute carrageenan induced inflammatory pain model
  • PBS Phosphate buffered slaine
  • PEG 400 was supplied by Sigma
  • ⁇ Carrageenan was provided by Sigma as an off-white lyophilized powder.
  • PEG400 was diluted in PBS To achieve the desired concentration of 5mg/ml.
  • a 2% solution of carageenan was prepared 24 hours prior to injection (in distilled water). The solution was stirred and heated during the process to 37 0 C to aid the solution preparation. The final solution was kept at 4 0 C, until half an hour before injection, when it was kept at room temperature
  • the test system employed rats (SD) from Harlan Laboratories, Israel. Groups of young adult males were used having average weights of around 186 to 189 g at the study initiation.
  • 2% Carrageenan was injected into the planar surface of the right hind paw, resulting in inflammation, swelling and pain.
  • the same volume of Saline was administered into the left hind paw. Both paw volumes (right and left) were measured before drug administration on study day 0 and served as baseline.
  • the paws were measured again 3 hours post Carrageenan injection using a plethysmometer Paw volume and response to touch stimuli (mechanical hyperalgesia) were measured before treatment (study day 0) and 3 hours post Carrageenan injection.
  • PEG400 was diluted in phosphate buffered saline to achieve a final concentration of 5mg/ml.
  • the rat was placed in an enclosure positioned an the metal mesh surface and allowed to move freely. A straight metal filament was moved towards the rat paw such as to touch the planar surface and exert an upward force below the threshold of feeling. The force was increased until either the animal removed the paw or a preset force was met. This procedure was carried out before drug administration (to serve as baseline) and 3 hours after Carrageenan injection. The force required for paw withdrawal after Carrageenan injection was compared to the force required for paw withdrawal before Carrageenan injection between treatments.
  • Figures 6(a) and 6(b) show that pre-administration of a polyethylene glycol-saline solution in accordance with the present invention can substantially reduce the production and/or release of major pro-inflammatory cytokines and prostaglandins [PGE2] during systemic inflammation from immune cells stimulated by bacterial endotoxins, which is similar to their response evoked by local and/or systemic trauma and injury.
  • PGE2 major pro-inflammatory cytokines and prostaglandins
  • these Examples in accordance with the invention show that treatment with polyethylene glycol-saline solutions markedly reduces pain in both acute (carragenann) and chronic neuropathic (sciatic ligation) models of pain.
  • Polyethylene glycol-saline inhibits the production and/or release of pro-inflammatory cytokines from immune cells involved in the response to pain. From these data the inventors conclude, without being bound by theory, that the effect of polyethylene glycol-saline infusion in acute and/or chronic pain is due to inhibition of overzealous production and/or release of harmful quantities of pro-inflammatory cytokines.

Landscapes

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

Abstract

L'invention concerne l'utilisation d'une solution aqueuse contenant au moins un polyol de polyéther destinée à traiter et/ou à prévenir une douleur, en particulier une douleur aiguë, chronique ou neuropathique.
PCT/GB2007/002349 2006-06-27 2007-06-25 Traitement et/ou prévention de la douleur faisant intervenir des polyols de polyéther Ceased WO2008001053A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0612749.2A GB0612749D0 (en) 2006-06-27 2006-06-27 Treatment and/or prevention of pain
GB0612749.2 2006-06-27

Publications (1)

Publication Number Publication Date
WO2008001053A1 true WO2008001053A1 (fr) 2008-01-03

Family

ID=36888166

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/002349 Ceased WO2008001053A1 (fr) 2006-06-27 2007-06-25 Traitement et/ou prévention de la douleur faisant intervenir des polyols de polyéther

Country Status (2)

Country Link
GB (1) GB0612749D0 (fr)
WO (1) WO2008001053A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1002531A1 (fr) * 1998-01-12 2000-05-24 Panacea Biotec Limited Composition miscible à l'eau d'anti-inflammatoires non stéroidiens
WO2004002533A1 (fr) * 2002-06-26 2004-01-08 Pharmacia Corporation Formulation de parecoxib liquide stable administree par voie parenterale
WO2006067502A1 (fr) * 2004-12-23 2006-06-29 University College London Hospitals Nhs Foundation Trust Traitement de maladies inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1002531A1 (fr) * 1998-01-12 2000-05-24 Panacea Biotec Limited Composition miscible à l'eau d'anti-inflammatoires non stéroidiens
WO2004002533A1 (fr) * 2002-06-26 2004-01-08 Pharmacia Corporation Formulation de parecoxib liquide stable administree par voie parenterale
WO2006067502A1 (fr) * 2004-12-23 2006-06-29 University College London Hospitals Nhs Foundation Trust Traitement de maladies inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KARLSSON P C ET AL: "Polyethylene glycol reduces inflammation and aberrant crypt foci in carcinogen-initiated rats", CANCER LETTERS, NEW YORK, NY, US, vol. 223, no. 2, 8 June 2005 (2005-06-08), pages 203 - 209, XP004894639, ISSN: 0304-3835 *

Also Published As

Publication number Publication date
GB0612749D0 (en) 2006-08-09

Similar Documents

Publication Publication Date Title
US9872876B2 (en) Pharmaceutical composition for use in the treatment and/or the prevention of osteoarticular diseases
HU220995B1 (hu) TNF-antagonisták alkalmazása megnövekedett interleukin-6 szérumszinttel járó szepszis kezelésére szolgáló gyógyszerkészítmény előállítására
JPH03504121A (ja) 抗ウイルス及び抗菌組成物並びに使用方法
WO2009101210A1 (fr) Composition pharmaceutique destinée à traiter et/ou à prévenir des maladies ostéo-articulaires
JPH0354089B2 (fr)
JP2020527606A (ja) 抗細菌物質およびその組成物、該物質および組成物を用いた医学的および非医学的使用、ならびに該物質および組成物を含む産物
Mirshafiey et al. Alginate and its comonomer mannuronic acid: medical relevance as drugs
JPH10506884A (ja) マクロファージ浸潤に関連する病気あるいは容体、特に脳卒中、心筋梗塞の治療
NZ254135A (en) Inhibition of biosynthesis of tumour necrosis factor (tnf) by administering the dimerised from of lysozyme; formulations containing lysozyme and an antibiotic
WO2008001053A1 (fr) Traitement et/ou prévention de la douleur faisant intervenir des polyols de polyéther
US20080292580A1 (en) Treatment of Inflammatory Diseases
US9554998B1 (en) Composition of analgesic bioadhesive healing microspheres
US20230172878A1 (en) Compositions and methods for treating cytokine storms
KR100601080B1 (ko) (-)-에피갈로카테킨 갈레이트를 유효성분으로 하는류마티스성 관절염 치료제
CN114828838B (zh) 粘膜或皮肤中的炎性病况的治疗
EP1248638B1 (fr) Utilisation de l'enoxaparine pour le traitement de l'ischemie cerebrale
RU2320325C1 (ru) Способ лечения неспецифических маститов у коров
CN116059327A (zh) 一种溶菌酶鼻腔喷雾剂及其制备方法
WO2008001055A1 (fr) Procédé de traitement et/ou de prévention d'une maladie pulmonaire inflammatoire
CN120501857A (zh) 一种适配器水凝胶联合模块化car-t产品及其在类风湿关节炎治疗中的应用
JP4709343B2 (ja) 細胞の酸化窒素の生産を阻害するためのキチン質物質の使用
PL176407B1 (pl) Kompozycja farmaceutyczna zawierająca dimer lizozymu

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07733344

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07733344

Country of ref document: EP

Kind code of ref document: A1