WO2005070433A1 - Utilisation de la pentoxifylline pour la prevention ou le traitement des ulceres - Google Patents
Utilisation de la pentoxifylline pour la prevention ou le traitement des ulceres Download PDFInfo
- Publication number
- WO2005070433A1 WO2005070433A1 PCT/GB2005/000217 GB2005000217W WO2005070433A1 WO 2005070433 A1 WO2005070433 A1 WO 2005070433A1 GB 2005000217 W GB2005000217 W GB 2005000217W WO 2005070433 A1 WO2005070433 A1 WO 2005070433A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ulcer
- treatment
- pentoxifylline
- use according
- wound
- Prior art date
Links
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960001476 pentoxifylline Drugs 0.000 title claims abstract description 43
- 208000025865 Ulcer Diseases 0.000 title claims abstract description 31
- 231100000397 ulcer Toxicity 0.000 title claims abstract description 31
- 238000011282 treatment Methods 0.000 title claims abstract description 29
- 230000002265 prevention Effects 0.000 title claims abstract description 4
- 206010052428 Wound Diseases 0.000 claims abstract description 16
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 16
- 230000000699 topical effect Effects 0.000 claims abstract description 14
- 230000001684 chronic effect Effects 0.000 claims abstract description 8
- 230000001154 acute effect Effects 0.000 claims abstract description 4
- 208000000558 Varicose Ulcer Diseases 0.000 claims description 11
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
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- 238000002560 therapeutic procedure Methods 0.000 claims description 7
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- 206010056340 Diabetic ulcer Diseases 0.000 claims description 5
- 229960000278 theophylline Drugs 0.000 claims description 5
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 4
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 claims description 4
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- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
- 206010011985 Decubitus ulcer Diseases 0.000 claims description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- 229960003556 aminophylline Drugs 0.000 claims description 2
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960001948 caffeine Drugs 0.000 claims description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims description 2
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- 230000009286 beneficial effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000006071 cream Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010072170 Skin wound Diseases 0.000 description 3
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 200000000007 Arterial disease Diseases 0.000 description 2
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- 239000000499 gel Substances 0.000 description 2
- 230000001435 haemodynamic effect Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229940080024 pentoxifylline 400 mg Drugs 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
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- 206010022562 Intermittent claudication Diseases 0.000 description 1
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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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Definitions
- This invention relates to new therapeutic uses of pentoxifylline, a known compound.
- Venous ulcers, diabetic ulcers, arterial ulcers and decubitus ulcers are chronic skin ulcers. Most leg ulcers are venous, occurring mostly in the ankle area. They are usually secondary to damaged valves in the veins, which results in an inability of the venous pressure to fall as is normal when walking. This is called sustained venous hypertension. Diabetic ulcers occur almost exclusively on the foot. They are either secondary to large vessel atherosclerosis or to diabetic neuropathy and loss of feeling. Neuropathic diabetic ulcers occur on pressure areas of the foot and toes and can be thought of as pressure ulcers, while the atherosclerotic type can be considered ischemic ulcers. Arterial ulcers are secondary to large vessel atherosclerosis.
- Decubitus ulcers also known as pressure ulcers
- Decubitus ulcers are an area of localized necrosis that results from soft tissue being compressed between bone and skin, caused by exerting pressure on an area of the body for extended periods, typically longer than 3 hours. Decubitus ulcers are most commonly seen in the elderly and are usually the result of long hospital stays, most typically following hip fracture. In the US, it is conservatively estimated that 400,000 to 600,000 patients suffer from venous ulcers each year. Similar data have been reported from Europe. Elastic compression therapy is regarded as the ⁇ gold standard' treatment for venous uiceration.
- Pentoxifylline i.e. 3,7-dimethyl-1-(5-oxohexyl)-xanthine
- Pentoxifylline is a methylxanthine derivative with a complex and poorly understood pharmacology. It is believed to improve the flow properties of blood by decreasing its viscosity and/or increasing the deformability of red blood cells. This is believed to underlie the efficacy of the drug in the treatment of intermittent claudication and supposes a systemic action of the drug.
- the usual dose is one 400 mg tablet (Trental) given 3 times per day with meals.
- pentoxifylline has been given orally at doses up to 800 mg three times per day (see Falanga et al 1999, Wound Repair Regen, 7(4):208-213).
- This study used a prospective, randomized, double-blind, parallel group placebo controlled design in a multicenter outpatient setting. Patients with one or more venous ulcer were enrolled, with all patients receiving standardized compression bandaging for treatment for their ulcers. Patients were also randomized to receive either pentoxifylline 400 mg, pentoxifylline 800 mg (two 400 mg tablets), or placebo tablets three times a day for up to 24 weeks. The main outcome measure was time to complete healing of all leg ulcers, using life table analysis. The study was completed as planned in 131 patients.
- patients were excluded from the study if they had a recent myocardial infarction, major hemorrhage or lumbar sympathectomy, or had conditions or were taking medications that could interfere with the study.
- patients were randomly assigned to receive 400 mg of pentoxifylline three times per day or an identical placebo. Patients were followed until the ulcer healed or 24 weeks of treatment had been completed.
- the 101 patients taking pentoxifylline were similar to the 99 patients receiving placebo in all major respects.
- ulcers healed in 65 (64 percent) of the patients receiving pentoxifylline compared with 52 (53 percent) of the patients receiving placebo. This difference did not achieve statistical significance.
- 14 percent of the ulcers in each group healed.
- systemic administration of pentoxifylline to achieve optimal healing rates is subject to poor tolerability.
- Gastrointestinal side-effects associated with oral pentoxifylline include nausea, indigestion and diarrhoea.
- Other side-effects can include chest pain, arrhythmia, hypertension, dyspnea, edema, hypotension, angina, tachycardia, dizziness/lightheadedness, headache, drowsiness/sleepiness, tremor, agitation, anxiety, confusion, insomnia and restlessness.
- Patients with renal disease are at risk of toxicity.
- Pentoxifylline is not safe for people with recent bleeding problems, particularly stroke caused by sudden bleeding, or retinal bleeding.
- Patients on warfarin should have more frequent monitoring of prothrombin times.
- Concomitant administration of pentoxifylline (Trental) and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals.
- Small decreases in blood pressure have been observed in some patients treated with pentoxifylline (Trental); periodic sysyemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy.
- This invention relates to the topical use of pentoxifylline, for the treatment of chronic venous ulcers, chronic diabetic ulcers, chronic arterial ulcers and chronic decubitus ulcers (pressure sores), other chronic wounds and also acute wounds.
- pentoxifylline has pharmacological activity in improving cutaneous blood flow in the lower extremities, when given by the topical route. This effect would be beneficial in the treatment of lower extremity ulcers.
- Pentoxifylline administered topically is also of benefit in treating ulcers on other parts of the body, and in treating other chronic and acute wounds involving skin. The activity of pentoxifylline by the topical route in the treatment of chronic skin ulcers or wounds is surprising.
- the topical doses effective in the treatment of skin wounds may be lower than those used orally and thereby indicate a direct effect on the wound. Indeed, to produce similar systemic concentrations to those observed after oral administration would be difficult by giving the drug topically, since the oral doses are very high.
- the active compound can be formulated in any suitable manner together with a conventional diluent or carrier.
- the active compound is preferably administered by the topical route using a gel, cream, foam, ointment, powder or liquid spray or solution.
- Other types of application may include impregnated bandages or other dressings or impregnated films.
- a particularly suitable composition is a cream containing, say, 5% by weight pentoxifylline.
- the dose of the active agent will depend on the nature and degree of the complaint, the age and condition of the patient and other factors known to those skilled in the art.
- a typical daily dosage is 0.01 to 5000 mg.
- the daily dose can be lower than has previously been used for pentoxifylline (Trental) given orally, e.g. below 1200 mg per day, preferably below 800, 400, 200 or 100 mg, administered as one, two or three topical applications each day.
- the active compound may be pentoxifylline itself or a salt form, prodrug or metabolite thereof. Such compounds and their activity will be known to or can be readily determined by, one of ordinary skill in the art.
- the pentoxifylline is intended for topical adminstration to a patient suffering an ulcer or wound and who is being treated with an anticoagulant, for example, warfarin, or an inhibitor of platelet aggregation, for example, aspirin.
- the topical pentoxifylline is also beneficial for treating patients suffering an ulcer or wound, and who are receiving antihypertensive therapy; being treated with theophylline or aminophylline; who have risk factors complicated by haemorrhage, for example recent surgery, peptic ulcer, cerebral and/or retinal bleeding; or who exhibit intolerance to oral pentoxifylline or other methylxantinones, such as caffeine or theobromine.
- the following Methods are given as examples to illustrate how the beneficial actions of topical pentoxifylline in wound healing are demonstrated.
- pentoxifylline when given topically are demonstrated in a study similar to that described above (Dale et al, supra), except that the drug is administered at 12 hourly intervals directly on to the skin wound, e.g. as 5% pentoxifylline in a suitable vehicle, which could be for example a cream, ointment or gel.
- the daily dose administered topically is less than 1200 mg (the dose used in the oral study).
- the beneficial effects of topically applied pentoxifylline, for example 5% in a suitable vehicle applied daily, are also or alternatively demonstrated in an animal model of wound healing as for example described by Xia et al (1999) J. Pathol 188(4), 431-438.
- the following Example illustrates a composition suitable for use in the invention.
- Example Pentoxifylline at 5% (50mg/ml) is prepared by adding to a cream consisting of purifed water with glycerol stearate 3.8%, cetyl alcohol 2.9%, PEG- 100 stearate 2.9%, white soft paraffin 9.3%, isopropyl myristate 5.6%, sorbitol 4.7% and benzyl alcohol 1 %.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne l'utilisation de la pentoxifylline pour la prévention ou le traitement des ulcères et des lésions chroniques ou aiguës impliquant la peau.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0401398.3 | 2004-01-22 | ||
| GBGB0401398.3A GB0401398D0 (en) | 2004-01-22 | 2004-01-22 | New theraputic use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005070433A1 true WO2005070433A1 (fr) | 2005-08-04 |
Family
ID=31971283
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2005/000217 WO2005070433A1 (fr) | 2004-01-22 | 2005-01-21 | Utilisation de la pentoxifylline pour la prevention ou le traitement des ulceres |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB0401398D0 (fr) |
| WO (1) | WO2005070433A1 (fr) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090163504A1 (en) * | 2006-10-27 | 2009-06-25 | Kopacki Matthew H | Method for healing a wound using a phosphodiesterase type five inhibitor |
| US20090163509A1 (en) * | 2006-10-27 | 2009-06-25 | Kopacki Matthew H | Method for healing a wound using an alpha-adrenergic antagonist |
| US20090170857A1 (en) * | 2006-10-27 | 2009-07-02 | Kopacki Matthew H | Method for healing a wound using a direct vasodilator |
| US10143694B2 (en) | 2006-10-27 | 2018-12-04 | Matthew H. Kopacki | Advanced formulations and therapies for treating hard-to-heal wounds |
| US10772813B2 (en) * | 2016-06-03 | 2020-09-15 | Colradel, LLC | Compositions and methods of administering a colchicine based topical composition for the prevention of radiation fibrosis |
| US20210393639A1 (en) * | 2019-03-08 | 2021-12-23 | South Dakota Board Of Regents | Vasoactive topical compound to affect tissue blood flow, reduce tissue necrosis and promote healing |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0544391A1 (fr) * | 1991-09-02 | 1993-06-02 | Teva Pharmaceutical Industries, Ltd. | Compositions pour le traitement local du psoriasis et du dermatite atopique |
| WO1997035618A1 (fr) * | 1996-03-22 | 1997-10-02 | Kao Corporation | Preparation dermatologique |
| WO1997035557A1 (fr) * | 1996-03-22 | 1997-10-02 | Kao Corporation | Composition topique pour soigner la peau |
| EP0930069A2 (fr) * | 1998-01-13 | 1999-07-21 | Johnson & Johnson Medical Ltd. | Compositions destinees a diminuer la formation de cicatrices |
| US6204270B1 (en) * | 1999-11-12 | 2001-03-20 | Eyal S. Ron | Ophthalmic and mucosal preparations |
| US6294350B1 (en) * | 1997-06-05 | 2001-09-25 | Dalhousie University | Methods for treating fibroproliferative diseases |
| US20020111292A1 (en) * | 1998-07-10 | 2002-08-15 | Mundy Gregory R. | Inhibitors of proteasomal activity for stimulating bone and hair growth |
| US20020122800A1 (en) * | 2000-12-05 | 2002-09-05 | Sonis Stephen T. | Treatment of inflammatory oral diseases with a combination of inhibitors of TNF-alpha and immunosuppressive agents |
| US20030148955A1 (en) * | 1999-04-19 | 2003-08-07 | Pluenneke John D. | Soluble tumor necrosis factor receptor treatment of medical disorders |
| US20040147534A1 (en) * | 2003-01-23 | 2004-07-29 | Foote Mary Ann | Topical composition and method for treating occlusive wounds |
-
2004
- 2004-01-22 GB GBGB0401398.3A patent/GB0401398D0/en not_active Ceased
-
2005
- 2005-01-21 WO PCT/GB2005/000217 patent/WO2005070433A1/fr active Application Filing
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0544391A1 (fr) * | 1991-09-02 | 1993-06-02 | Teva Pharmaceutical Industries, Ltd. | Compositions pour le traitement local du psoriasis et du dermatite atopique |
| WO1997035618A1 (fr) * | 1996-03-22 | 1997-10-02 | Kao Corporation | Preparation dermatologique |
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| US20090163504A1 (en) * | 2006-10-27 | 2009-06-25 | Kopacki Matthew H | Method for healing a wound using a phosphodiesterase type five inhibitor |
| US20090163509A1 (en) * | 2006-10-27 | 2009-06-25 | Kopacki Matthew H | Method for healing a wound using an alpha-adrenergic antagonist |
| US20090170857A1 (en) * | 2006-10-27 | 2009-07-02 | Kopacki Matthew H | Method for healing a wound using a direct vasodilator |
| US10143694B2 (en) | 2006-10-27 | 2018-12-04 | Matthew H. Kopacki | Advanced formulations and therapies for treating hard-to-heal wounds |
| US10864214B2 (en) | 2006-10-27 | 2020-12-15 | Medergo Associates, Llc | Advanced formulations and therapies for treating hard-to-heal wounds |
| US10772813B2 (en) * | 2016-06-03 | 2020-09-15 | Colradel, LLC | Compositions and methods of administering a colchicine based topical composition for the prevention of radiation fibrosis |
| US20210393639A1 (en) * | 2019-03-08 | 2021-12-23 | South Dakota Board Of Regents | Vasoactive topical compound to affect tissue blood flow, reduce tissue necrosis and promote healing |
| US12280057B2 (en) * | 2019-03-08 | 2025-04-22 | South Dakota Board Of Regents | Vasoactive topical compound to affect tissue blood flow, reduce tissue necrosis and promote healing |
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|---|---|
| GB0401398D0 (en) | 2004-02-25 |
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